Bifunctional azine conjugates as selective degradation agents of SMARCA2 and therapeutic uses thereof

Abstract

The present disclosure provides bifunctional compounds of formula (IA) through the ubiquitin proteasome pathway as selective SMARCA2 degradation agents, and therapeutic uses thereof for the treatment of cancer.

Description

Cross-references to related applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 507,074, filed June 8, 2023, which is incorporated herein by reference in its entirety. Technical Field

[0002] This invention provides novel bifunctional compounds for the protein hydrolysis and degradation of SMARCA2, and their therapeutic use in treating SMARCA2-mediated diseases, including cancer. Background Technology

[0003] The mammalian SWI / SNF chromatin remodeling complex contains one of two mutually exclusive and highly homologous catalytic ATPase subunits, SMARCA2 or SMARCA4. Subunit mutations within this complex are prevalent in cancers, and SMARCA4-mutant cancers exhibit acute sensitivity to SMARCA2 depletion, making SMARCA2 an attractive oncology target.

[0004] Several groups have developed small-molecule inhibitors of SMARCA2, but progress has been hampered by the requirement for selectivity relative to SMARCA4. See, for example, Wanior, M. et al. J. Med. Chem. 63:14680(2020). Kofink, C. et al. Nature Commun. 13:5969 (2022). Two regions in the SMARCA2 protein with well-defined binding pockets associated with the discovery of small molecule inhibitors are the catalytic ATPase domain and the conserved bromine domain that interacts with acetylated chromatin. The high sequence homology between the ATPase domains of these proteins makes the development of sufficiently selective inhibitors challenging. Known ATPase domain ligands are dual inhibitors of SMARCA2 / 4 and exhibit dose-limiting tolerance issues. Alternatively, while the bromine domain shows greater selective potential, its function is dispensable, and current ligands are ineffective in inhibiting cell proliferation.

[0005] While selectively targeting SMARCA2 instead of SMARCA4 using inhibitors has proven challenging to date, repurposing non-inhibitory bromodomain binders as targeted protein degraders shows promise. However, current degraders exhibit poorer selectivity for targeting SMARCA2 compared to SMARCA4. See, for example, WO 2021 / 083949, WO 2020 / 251971, and WO 2019 / 195201. Summary of the Invention

[0006] This article presents bifunctional compounds that exhibit effective inhibition and selectivity of SMARCA2 while retaining SMARCA4.

[0007] This article provides bifunctional compounds represented by formula (I):

[0008] Formula (I) Or its pharmaceutically acceptable salt, wherein: R 1 Hydrogen or optionally via 1 to 3 R a Replacement C 1-6 alkyl; R 2 Hydrogen, halogenated group, hydroxyl group, -OR c Optional location via 1 to 3 R a Replacement C 1-6 alkyl; R 3 For hydrogen, -CN, C 1-6 Alkyl, C 6-12 Aryl, C 3-12 Cycloalkyl or 5-12-membered heteroaryl groups, each optionally denoted by 1 to 3 R groups. d replace; L comprises up to 8 joint sections represented by -L1-L2-L3-L4-L5-L6-L7-L8-, where each L1, L2, L3, L4, L5, L6, L7, or L8 is independently: i) Choose any location within 1-3 R's b Replacement C 3-12 cycloalkyl; ii) Choose any location with a distance of 1-3 R. b Replacement C 6-12 Aryl; iii) Choose any location via 1-3 R's. b Substituted 4-12 membered heterocyclic groups; iv) Choose any location via 1-3 R... b Substituted 5-12 heteroaryl groups; v) Direct key; vi) Choose any location with a radius of 1-3 R. b Replacement C 1-12 alkylene chains; or vii) -(CH2) m -C(O)-, -(CH2) m -C(O)O-, -(CH2) m -O-、-(CH2) m -N(R c )-、-(CH2) m-S-、-(CH2) m -C(S)-、-(CH2) m -C(S)-O-, -(CH2) m -S(O)2-、-(CH2) m -S(O)=N-、-(CH2) m -S(O)2NH-、-(CH2) m -C(O)-N(R c )-、-C(O)-N(R c )-(CH2) m -、-CH2) m -OC(O)-N(R c )-、-(CH2) m -OC(O)-O- or -NH-(CH2) m -C(O)-, where m is 0, 1, 2, 3, 4, 5 or 6; Each R a Independent of halogenated group or -OR c ; Each R b Independently, it can be an oxo group, imino group, sulfoxide imino group, halogen group, nitro group, -CN, or C. 1-6 Alkyl, C 2-6 alkenyl, C 3-15 cycloalkyl, C 1-8 Haloalkyl, C 6-12 aryl, 5-12 heteroaryl, 4-12 heterocyclic, -OR c -C(O)-R c -C(O)OR c -C(O)-N(R) c (R) c ), -N(R c (R) c ), -N(R c )C(O)-R c -N(R) c )C(O)OR c -N(R) c )C(O)N(R c (R) c ), -N(R c )S(O)2(R c -NR c S(O)2N(R c (R) c ), -N(R c )S(O)2O(R c -OC(O)R c-OC(O)-N(R) c (R) c ), -Si(R c )3、-SR c -S(O)R c -S(O)(NH)R c -S(O)2R c or -S(O)2N(R) c (R) c ), where C 1-6 Alkyl, C 2-6 alkenyl, C 3-15 cycloalkyl, C 1-8 Haloalkyl, C 6-12 Each of the aryl, 5-12-membered heteroaryl, and 4-12-membered heterocyclic groups may be optionally etched via 1 to 3 R groups. d replace; Each R c Independently hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Each R d Independent of halogenated group, -CN, -OR c C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; W is -C(R) g - or -N-; Y represents a direct bond, C represents a direct bond. 1-4 Alkylene chains, -C(O)-, -C(O)O-, -O-, -N(R) g )-, -S- -C(S)-, -C(S)-O-, -OC(O)O-, -C(O)-N(R g )-or-OC(O)-N(R g )-; Ring B is C 6-12 aryl, 5-12-membered heteroaryl, or 4-12-membered heterocyclic, each optionally denoted by 1 to 3 R... j replace; R g It is hydrogen or C 1-6 Alkyl; and Each R j Independent of halogenated group, -CN, -OR c C 1-6 Alkyl, C 6-12 Aryl or C 1-6 Halogenated alkyl groups.

[0009] In several specific embodiments, Y is a direct bond, and the bifunctional compound of formula (I) is represented by formula (II):

[0010] Equation (II) in, R 1 R 2 R 3 L and W are as defined above; X is CH or N; p is 0, 1, or 2; and R j Halogenated group or C 1-3 alkyl.

[0011] In several specific embodiments, the bifunctional compound of formula (II) is represented by formula (IIa), (IIb), (IIc) or (IId):

[0012] Formula (IIa)

[0013] Equation (IIb)

[0014] Formula (IIc)

[0015] Formula (IId).

[0016] In a more specific implementation, R 1 and R 2 Each is hydrogen, Y is a direct bond, L1 is -C(O)-, L' is -L2-L3-L4-L5-L6-L7-L8-, and the bifunctional compound is represented by the structure of formula (III) and substructures (IIIa), (IIIb), (IIIc) and (IIId):

[0017] Equation (III)

[0018] Formula (IIIa),

[0019] Formula (IIIb)

[0020] Formula (IIIc),

[0021] Formula (IIId).

[0022] In even more specific implementations, R 1 and R 2 Each is hydrogen, Y is a direct bond, L1 is -C(O)-, and L8 is... (V is CH or N) and L” is -L2-L3-L4-L5-L6-L7- and the bifunctional compound is represented by the structure of formula (IV), (IVa), (IVb) and its individual substructures:

[0023] Formula (IV)

[0024] Formula (IVa)

[0025] Formula (IVa1)

[0026] Formula (IVa2)

[0027] Formula (IVa3)

[0028] Formula (IVa4)

[0029] Formula (IVb)

[0030] Formula (IVb1)

[0031] Formula (IVb2)

[0032] Formula (IVb3)

[0033] Formula (IVb4) In several implementations, each of the joint sections (i.e., L1, L2, L3, L4, L5, L6, L7, or L8) is independently: i) Select the bivalent ring portion of the group consisting of the following groups: , , , , , , , , , , , ; , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and ; v) Direct key; vi) C 1-6 alkylene chains; or vii) -C(O)-、-O-、-C(O)-N(R c )-、-(CH2) m -C(O)- or -NH-(CH2) m -C(O)-, where m is 0, 1, 2 or 3; in, m can be 0, 1, 2, or 3; n is 0, 1, or 2; R b Halogenated group, -CN, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups; and R c It is hydrogen or C 1-3 alkyl.

[0034] This document also provides a pharmaceutical composition comprising compounds of formulas (I), (II), (III), and (IV), (IA), or any of the substructures or specific compounds of Examples 1-196, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients or carriers. Detailed Implementation

[0035] Specific degradation of SMARCA2 can be achieved by using heterobifunctional small molecules to recruit SMARCA2 to ubiquitin ligases with higher selectivity than SMARCA4, thereby promoting the ubiquitination and proteasome degradation of SMARCA2. Therefore, this document provides bifunctional compounds, each comprising a selective SMARCA2 binder, a covalent linker moiety (L), and a ligase utilization moiety (LHM) for targeting ubiquitin ligases. Preferably, the LHM targets the cereblon (CRBN) protein, which is a substrate recognition subunit of the two universally expressed and biologically important Cullin RING E3 ubiquitin ligase complexes. See, for example, WO 2019 / 099926, WO 2020 / 023851, and U.S. Publication No. 2019 / 0192668.

[0036] In addition to the compounds of formulas (I)-(IV) and their substructures described herein, several embodiments further provide compounds having structures represented by formula (IA):

[0037] Formula (IA) Or its stereoisomers, pharmaceutically acceptable salts, wherein: R 1 Hydrogen or optionally via 1 to 3 R a Replacement C 1-6 alkyl; R 2 Hydrogen, halogenated group, hydroxyl group, -OR c Optional location via 1 to 3 R a Replacement C 1-6 alkyl; R 3 For hydrogen, -CN, C 1-6 Alkyl, C 6-12 Aryl, C 3-12 Cycloalkyl groups, 5-12-membered heteroaryl groups, each optionally denoted by 1 to 3 R groups d Replace, or -OR e ; L comprises up to 8 joint sections represented by -L1-L2-L3-L4-L5-L6-L7-L8-, where each L1, L2, L3, L4, L5, L6, L7, or L8 is independently: i) Choose any location within 1-3 R's b Replacement C 3-12 cycloalkyl; ii) Choose any location with a distance of 1-3 R. b Replacement C 6-12 Aryl; iii) Choose any location via 1-3 R's. b Substituted 4-12 membered heterocyclic groups; iv) Choose any location via 1-3 R... b Substituted 5-12 heteroaryl groups; v) Direct key; vi) Choose any location with a radius of 1-3 R. b Replacement C 1-12 alkylene chains; or vii) -(CH2) m -C(O)-, -(CH2) m -C(O)O-, -(CH2) m -O-、-(CH2) m -N(R c )-、-(CH2) m -S-、-(CH2) m -C(S)-、-(CH2) m -C(S)-O-, -(CH2) m -S(O)2-、-(CH2) m -S(O)=N-、-(CH2) m -S(O)2NH-、-(CH2) m -C(O)-N(R c )-、-C(O)-N(R c )-(CH2) m -、-(CH2) m -OC(O)-N(R c )-、-(CH2) m -OC(O)-O- or -NH-(CH2) m -C(O)-, where m is 0, 1, 2, 3, 4, 5 or 6; Each R a Independent of halogenated group or -OR c ; Each R b Independently, it can be an oxo group, imino group, sulfoxide imino group, halogen group, nitro group, -CN, or C. 1-6 Alkyl, C 2-6 alkenyl, C 3-15 cycloalkyl, C 1-8 Haloalkyl, C 6-12aryl, 5-12 heteroaryl, 4-12 heterocyclic, -OR c -C(O)-R c -C(O)OR c -C(O)-N(R) c (R) c ), -N(R c (R) c ), -N(R c )C(O)-R c -N(R) c )C(O)OR c -N(R) c )C(O)N(R c (R) c ), -N(R c )S(O)2(R c -NR c S(O)2N(R c (R) c ), -N(R c )S(O)2O(R c -OC(O)R c -OC(O)-N(R) c (R) c ), -Si(R c )3、-SR c -S(O)R c -S(O)(NH)R c -S(O)2R c or -S(O)2N(R) c (R) c ), where C 1-6 Alkyl, C 2-6 alkenyl, C 3-15 cycloalkyl, C 1-8 Haloalkyl, C 6-12 Each of the aryl, 5-12-membered heteroaryl, and 4-12-membered heterocyclic groups may be optionally etched via 1 to 3 R groups. d replace; Each R c Independently hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 6-12 Aryl or C 1-6 Haloalkyl, wherein C 1-6 Alkyl groups optionally via C 1-3 Alkyl substitution; Each R d Independent of halogenated group, -CN, -OR c C 1-6 Alkyl, C6-12 Aryl or C 1-6 Halogenated alkyl groups; R e C 1-6 Alkyl, C 3-12 cycloalkyl, C 6-12 Aryl and 5-12 heteroaryl groups, each selectively hydroxylated by C 1-6 Alkyl or halogroup substitution; W is -C(R) g - or -N-; Y represents a direct bond, C represents a direct bond. 1-4 Alkylene chains, -C(O)-, -C(O)O-, -O-, -N(R) g )-, -S- -C(S)-, -C(S)-O-, -OC(O)O-, -C(O)-N(R g )-or-OC(O)-N(R g )-; Ring B is C 6-12 aryl, 5-12-membered heteroaryl, or 4-12-membered heterocyclic, each optionally denoted by 1 to 3 R... j replace; R g It is hydrogen or C 1-6 Alkyl; and Each R j Independently halogenated, oxo-substituted, -CN, -OR c C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0038] In a more specific implementation, each L1, L2, L3, L4, L5, L6, L7, or L8 is independently: i) Select the bivalent ring portion of the group consisting of the following groups: , , , , , , , , , , , ; , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ; , , , , , , , , , , , , ; ii) Direct key; iii) C 1-6 alkylene chains; or iv) -C(O)-, -O-, -(CH2) m -C(O)-N(R c )-、-(CH2) m -N(R c )-、-C(O)-N(R c )-(CH2) m -or -NH-(CH2) m -C(O)-, -(CH2) m -S(O)2NH-, where m is 0, 1, 2 or 3; in, n is 0, 1, or 2; R b Halogenated group, -OR c -CN,C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; and R c For hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, phenyl or C1-6 Haloalkyl, wherein C 1-6 Alkyl groups optionally via C 1-3 Alkyl-substituted.

[0039] In other, more specific embodiments, Y is a direct bond, -NHC(O)-, or -NH-; and Ring B is: , , , , , , , or Where n is 0, 1, or 2, R j Halogenated group, -CN, -OR c C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0040] In several implementation schemes, R 3 For optional passage via one or more C 1-6 Alkyl, C 1-6 Benzene substituted with alkoxy or halogroup; optionally via one or more C 1-6 Benzyl groups substituted with alkyl or halogroups; optionally via one or more C16 groups. 1-6 Alkyl-substituted pyridyl; CN; C 3-6 Cyclopropyl; optionally via one or more C 1-6 Alkyl-substituted pyrazolyl; tetrahydropyranyl; optionally via one or more C 1-6 Alkyl-substituted 1,2-oxazolyl; pyrazolo[1,5-a]pyridyl; or -OR e , where R e For optional location C 1-6 alkyl or halogenated phenyl, C 3-6 cycloalkyl, C 1-6 Alkyl or optionally C 1-6 Alkyl-substituted pyrazolyl group.

[0041] In even more specific implementations, R 3It is phenyl, benzyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, CN, cyclopropyl, 1-methyl-1H-pyrazole-3-yl, 3-methylphenyl, 2-methylphenyl, 3-chlorophenyl, 3,4-dichlorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-fluorophenyl, 4-fluorophenyl, tetrahydropyran-4-yl, 3-methyl-1H-pyrazole-1-yl, 4-methyl-1H-pyrazole-1-yl, 5-methyl-1H-pyrazole-1-yl, 1-methyl-1H-pyrazole-3-yl, 1-methyl-1H-pyrazole-4-yl, 1-methyl-1H-pyrazole-5-yl, pyrazolo[1,5-a]pyridin-2-yl, 5-methyl-1,2-oxazol-3-yl, 5-isopropyl-1,2-oxazol-3-yl, 3-methyl-1,2-oxazol-5-yl, or -OR e , where R e It can be phenyl, 2-chlorophenyl, 2-methylphenyl, cyclopropyl, cyclohexyl, methyl, or 1-methyl-1H-pyrazole-3-yl.

[0042] In some implementations, R 1 For hydrogen, R 2 It is hydrogen, Y is a direct bond, R 3 For -OR e W is CH, and the compound has a structure represented by formula (IA1):

[0043] Formula (IA1) in, Ring B is or ; n is 0, 1, or 2; R j Halogenated group, -CN, -OR c C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R e C 1-6 Alkyl, C 3-12 cycloalkyl, C 6-12 Aryl and 5-12 heteroaryl groups, each selectively hydroxylated by C 1-6 Alkyl or halogroup substitution; R c It is hydrogen or C 1-3 alkyl; L1 is -C(O)- or -C(O)N(R) c )-;and L a for , , , , , , , , , , , , , or .

[0044] In a more specific embodiment of formula (IA1), B is ; n is 0 or 1; R j It is fluorine or chlorine; R e C 1-6 Alkyl, C 3-12 cycloalkyl, C 6-12 Aryl and 5-12 heteroaryl groups, each selectively hydroxylated by C 1-6 Alkyl or halogroup substitution; L 1 -C(O)N(R) c )-, where R c It is methyl or ethyl; and L a for .

[0045] In several implementation schemes, R e C 1-3 alkyl.

[0046] In a more specific implementation, R e It can be methyl, phenyl, cyclopropyl, cyclohexyl, 1-methyl-1H-pyrazole-3-yl or phenyl substituted with chlorine or methyl.

[0047] In other, more specific embodiments of formula (IA1), ring B is ; n is 0, 1, or 2; R j It is fluorine or chlorine; R e It is methyl, ethyl, or propyl; R c It is hydrogen, methyl, or ethyl; L1 is -C(O)- or -C(O)N(R) c )-;and L a for , , or .

[0048] In some implementations, R 1 and R 2 Where is hydrogen, W is CH, and the compound has a structure represented by formula (IA2):

[0049] Formula (IA2) in, n is 0, 1, or 2; Y is a direct bond, -NHC(O)- or -NH-; X is either N or CH; Rj is C 1-3 Alkyl or halogroup; R 3 C 6-12 Aryl, C 3-12 Cycloalkyl groups, 5-12-membered heteroaryl groups, each optionally denoted by 1 to 3 R groups d Replace, or -OR e ; R c It is hydrogen or C 1-6 methyl; Each R d Independent of halogenated group, -CN, -OR c C 1-6 Alkyl, C 6-12 Aryl or C 1-6 Halogenated alkyl groups; and R e C 1-6 Alkyl, C 3-12 cycloalkyl, C 6-12 Aryl and 5-12 heteroaryl groups, each selectively hydroxylated by C 1-6 Alkyl or halogroup substitution; and L b for , , , , , , , , , , , , , , , , , , , , , , , , or .

[0050] In a more specific implementation of formula (IA2), R 3 It is phenyl, 2-fluorophenyl, 5-methyl-1,2-oxazol-5-yl, 5-isopropyl-1,2-oxazol-5-yl, pyrazolo[1,5-a]pyridyl, -OR e , where R e It can be phenyl, 2-chlorophenyl, 2-methylphenyl, 1-methyl-1H-pyrazole-3-yl, cyclohexyl or methyl.

[0051] In some implementations, R 1 and R 2 Where is hydrogen, W is CH, and the compound has a structure represented by formula (IA3):

[0052] Formula (IA3) in, n is 0, 1, or 2; Y is a direct bond, -NHC(O)- or -NH-; X is either N or CH; R 3 C 6-12 Aryl, C 3-12 Cycloalkyl groups, 5-12-membered heteroaryl groups, each optionally denoted by 1 to 3 R groups d Replace, or -OR e ; R c For hydrogen, C 1-3 Alkyl or C 3-6 cycloalkyl; Each R d Independent of halogenated group, -CN, -OR c C 1-6 Alkyl, C 6-12 Aryl or C 1-6 Halogenated alkyl groups; R e C 1-6 Alkyl, C 3-12 cycloalkyl, C 6-12 Aryl and 5-12 heteroaryl groups, each selectively hydroxylated by C 1-6 Alkyl or halogroup substitution; R j C 1-3 Alkyl or halogroup; and L c for , , , , , , , , , , , , , , , , , , or .

[0053] In some implementations, R 1 and R 2 For hydrogen, W is CH, Y is a direct bond, and R is... 3 It is phenyl, and the compound has a structure represented by formula (IA4):

[0054] Equation (IA4) in, n is 0, 1, or 2; X is either N or CH; R c Hydrogen or optionally C 1-3 alkoxy-substituted C 1-3 alkyl; R j C 1-3 Alkyl or halogroup; and L d for , , , , , , , , or .

[0055] In some implementations, R 1 and R 2 For hydrogen, W is CH, Y is a direct bond, and R is... 3 It is phenyl, and the compound has a structure represented by formula (IA5).

[0056] Formula (IA5) in, n is 0, 1, or 2; X is either N or CH; Q is a direct bond, -N(R) c - or -NHS(O)2-, Rc It is hydrogen or C 1-3 alkyl; R j C 1-3 Alkyl or halogroup; and L e for , , or ,or .

[0057] In some implementations, R 1 and R 2 Where is hydrogen, W is CH, Y is a direct bond, and the compound has a structure represented by formula (IA6): , Equation (IA6) in, B is , , or ; R 3 C 6-12 Aryl, C 3-12 Cycloalkyl groups, 5-12-membered heteroaryl groups, each optionally denoted by 1 to 3 R groups d Replace, or -OR e ; R c It is hydrogen or C 1-6 alkyl; Each R d Independent of halogenated group, -CN, -OR c C 1-6 Alkyl, C 6-12 Aryl or C 1-6 Halogenated alkyl groups; R e C 1-6 Alkyl, C 3-12 cycloalkyl, C 6-12 Aryl and 5-12 heteroaryl groups, each selectively hydroxylated by C 1-6 Alkyl or halogroup substitution; L1 is -C(O)-, -C(O)-N(R) c -(CH2)- or -C(O)-N(R) c )-;and L f for , , , , , or .

[0058] SMARCA2 binder Each of the bifunctional compounds of formulas (I) and (IA) comprises a selective SMARCA1 binding moiety, which is illustrated as formula (A):

[0059] Formula (A) in, In a more specific implementation, R 1 and R 2 Each is hydrogen.

[0060] In other more specific implementations, R 1 C is optionally substituted with 1 to 3 halogenated or hydroxyl groups. 1-3 Alkyl. In a more specific embodiment, R 1 It is -CF2H or -C(CH3)2OH, and R 2 It is hydrogen.

[0061] In several implementation schemes, R 3 It is phenyl, pyridyl, pyrazolyl, cyclopropyl or C 1-3 Alkyl groups, each optionally alkylated by 1 to 3 R groups d Replace, where R d C 1-3 Alkyl, halogroup or phenyl.

[0062] In a more specific implementation, R 3 It can be phenyl, benzyl, 2-pyridyl, 3-pyridyl, -CN, 1-methyl-1H-pyrazole-3-yl, 3-methylphenyl, 2-methylphenyl, 3-chlorophenyl or 3,4-dichlorophenyl.

[0063] In several implementation schemes, R 3 For optional passage via one or more C 1-6 Alkyl, C 1-6 Benzene substituted with alkoxy or halogroup; optionally via one or more C 1-6 Benzyl groups substituted with alkyl or halogroups; optionally via one or more C16 groups. 1-6 Alkyl-substituted pyridyl; CN; C 3-6 Cyclopropyl; optionally via one or more C 1-6 Alkyl-substituted pyrazolyl; tetrahydropyranyl; optionally via one or more C 1-6 Alkyl-substituted 1,2-oxazolyl; pyrazolo[1,5-a]pyridyl; or -OR e , where R e For optional location C 1-6 alkyl or halogenated phenyl, C3-6 cycloalkyl, C 1-6 Alkyl or optionally C 1-6 Alkyl-substituted pyrazolyl group.

[0064] In even more specific implementations, R 3 It is phenyl, benzyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, CN, cyclopropyl, 1-methyl-1H-pyrazole-3-yl, 3-methylphenyl, 2-methylphenyl, 3-chlorophenyl, 3,4-dichlorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-fluorophenyl, 4-fluorophenyl, tetrahydropyran-4-yl, 3-methyl-1H-pyrazole-1-yl, 4-methyl-1H-pyrazole-1-yl, 5-methyl-1H-pyrazole-1-yl, 1-methyl-1H-pyrazole-3-yl, 1-methyl-1H-pyrazole-4-yl, 1-methyl-1H-pyrazole-5-yl, pyrazolo[1,5-a]pyridin-2-yl, 5-methyl-1,2-oxazol-3-yl, 5-isopropyl-1,2-oxazol-3-yl, 3-methyl-1,2-oxazol-5-yl, or -OR e , where R e It can be phenyl, 2-chlorophenyl, 2-methylphenyl, cyclopropyl, cyclohexyl, methyl, or 1-methyl-1H-pyrazole-3-yl.

[0065] In one particular implementation, R 1 and R 2 Each is hydrogen, R 3 It is phenyl, and the SMARCA2 binder portion has the structure of formula (A1):

[0066] In another specific implementation, R 1 and R 2 Each is hydrogen, R 3 For -OR e As defined in this article.

[0067] Ligase utilization portion (LHM) The LHM portion of the bifunctional compound of formula (I) targets the CRBN of the E3 ligase. Once utilized by the bifunctional compound, the E3 ligase is able to induce ubiquitination of SMARCA2 and subsequent proteasome degradation.

[0068] The LHM portion of formula (I) typically contains a glutarimide or dihydrouracil moiety coupled to the ring structure, as represented by formula (B):

[0069] Formula (B) in, W is -C(R) g- or -N-; Y represents a direct bond, C represents a direct bond. 1-4 Alkylene chains, -C(O)-, -C(O)O-, -O-, -N(R) g )-, -S- -C(S)-, -C(S)-O-, -OC(O)O-, -C(O)-N(R g )-or-OC(O)-N(R g )-; Ring B is C 6-12 aryl, 5-12-membered heteroaryl, or 4-12-membered heterocyclic, each optionally denoted by 1 to 3 R... j replace; Each R j Independently, it can be a halogenated group, -CN, oxo group, or -OR. c C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; and R g It is hydrogen or C 1-6 alkyl.

[0070] In a more specific implementation, W is -CH-, Y is a direct bond; and the B ring is , , , , , where R j H, halogenated or C 1-3 alkyl.

[0071] In other embodiments, W is -CH-, Y is -NHC(O)- or -NH-, and ring B is , , , or , where R j H, halogenated or C 1-3 alkyl.

[0072] In other implementations, W is -N-, Y is a direct bond; and the B ring is , , , , , where R j For H or C 1-3 alkyl.

[0073] In a more specific implementation, the LHM portion is: , or .

[0074] In other, more specific implementations, the LHM portion is: or .

[0075] In other, more specific implementations, the LHM portion is: , , or , connector Each bifunctional compound of formula (I) includes a linker (L), which is a divalent portion that couples the SMARCA2 binding agent portion to the LHM. The structure of the linker portion (e.g., length or rigidity) can affect the efficiency or selectivity of the degradation process. The linker comprises a continuous sequence of covalent bonds between the individual connection points of the SMARCA2 binding agent portion and the LHM, including bonds indicated by the wavy lines of formulas (A) and (B) and their individual substructures.

[0076] Typically, the joint portion comprises multiple bivalent segments (i.e., -L1-L2-L3-L4-L5-L6-L7-L8-), which, in addition to providing individual connection points with the SMARCA2 binder portion and the LHM, collectively contribute to the joint's length and rigidity. In several embodiments, the joint segments L1, L2, L3, L4, L5, L6, L7, and L8 are each independently: i) Choose any location within 1-3 R's b Replacement C 3-12 cycloalkyl; ii) Choose any location with a distance of 1-3 R. b Replacement C 6-12 Aryl; iii) Choose any location via 1-3 R's. b Substituted 4-12 membered heterocyclic groups; iv) Choose any location via 1-3 R... b Substituted 5-12 heteroaryl groups; v) Direct key; vi) Choose any location with a radius of 1-3 R. d Replacement C 1-12 alkylene chains; or vii) -(CH2) m -C(O)-, -(CH2) m -C(O)O-, -(CH2) m -O-、-(CH2) m -N(R c )-、-(CH2) m -S-、-(CH2) m-C(S)-、-(CH2) m -C(S)-O-, -(CH2) m -S(O)2-、-(CH2) m -S(O)=N-、-(CH2) m -S(O)2NH-、-(CH2) m -C(O)-N(R c )-、-C(O)-N(R c )-(CH2) m -、-CH2) m -OC(O)-N(R c )-、-(CH2) m -OC(O)-O- or -NH-(CH2) m -C(O)-, where m is 0, 1, 2, 3, 4, 5 or 6; Where R d R c and R d As defined in this article.

[0077] It should be understood that, unless otherwise specified and limited by the requirement of valence, the divalent junction section (e.g., L) described herein is not considered a valid junction. 1 or L 2 This is not limited to the direction of the stated segment. For example, for a given linker segment, such as -C(O)-NH-, it can be connected to the rest of the molecule in either direction: i.e., -C(O)-NH- or -NH-C(O)-, provided that the connection does not violate the valence rule.

[0078] Unless otherwise specified, it should be further understood that the first joint section L 1 Directly coupled to the SMARCA2 binder portion, while the last joint segment L 8 Directly coupled to LHM.

[0079] One or more joint segments may be direct keys. For illustration, in the sequence of joint segments represented by -L2-L3-L4--, when L3 is a direct key, it does not actually exist, because L2 and L4 are directly coupled to each other.

[0080] In another embodiment, the joint has one or more rings that tend to increase joint stiffness. The combination of chains and rings can be used to adjust the relative orientation of the bifunctional groups or the distance between them.

[0081] In several specific embodiments, the linkers (L) of compounds of formulas (I), (II), (IIa), (IIb), (IIc), and (IId) are presented as -L1-L2-L3-L4-L5-L6-L7-L8-, where each L1, L2, L3, L4, L5, L6, L7, or L8 is independently:

[0082]

[0083] v) Direct key; vi) C 1-6 alkylene chains; or vii) -C(O)-、-O-、-C(O)-N(R c )-、-(CH2) m -C(O)- or -NH-(CH2) m -C(O)-, where m is 0, 1, 2 or 3; in, n is 0, 1, or 2; R b Halogenated group, -CN, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups; and R c It is hydrogen or C 1-3 alkyl.

[0084] In a more specific embodiment, one or more connector segments form a diamine connector portion having one of the following structures:

[0085] In other specific embodiments, the linker (L') of compounds of formula (III) and its sub-formulas (IIIa), (IIIb), (IIIc) and (IIId) may have one of the following structures:

[0086]

[0087] In other specific embodiments, the linker (L'') of compounds of formulas (IV), (IVa), and (IVb) and their respective substructures may have one of the following structures:

[0088] definition The following description illustrates exemplary methods, parameters, etc. However, it should be understood that such description is not intended to limit the scope of this disclosure, but is provided as a description of exemplary embodiments.

[0089] A dash ("-") not between two letters or symbols is used to indicate the connection point of substituents. For example, -C(O)NH2 is connected by carbon atoms. For convenience, a dash is added before or at the end of a chemical group; a chemical group may or may not be depicted using one or more dashes without losing its ordinary meaning. A wavy line drawn through a line in the structure indicates the connection point of groups. Unless chemically or structurally required, the order in which chemical groups are written or named does not indicate or imply directionality.

[0090] prefix "C" u-v "Indicates that the following groups have u to v carbon atoms. For example, "C 1-6 "alkyl" indicates that an alkyl group has 1 to 6 carbon atoms.

[0091] The use of "about" in this article to refer to a certain value or parameter includes (and describes) the meaning of that value or parameter. itself The implementation schemes are described below. In some implementations, the term "about" includes an indicated amount ± 10%. In other implementations, the term "about" includes an indicated amount ± 5%. In some other implementations, the term "about" includes an indicated amount ± 1%. Furthermore, the term "about X" includes a description of "X". Additionally, unless expressly stated otherwise herein, the singular forms "a" and "the" include multiple references. Thus, by way of example, reference to "the compound" includes multiple such compounds and reference to "the assay" includes reference to one or more assays known to those skilled in the art and their equivalents.

[0092] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain that does not contain unsaturation. As used herein, alkyl groups have 1 to 20 carbon atoms (i.e., C64-C ... 1-20 Alkyl groups, 1 to 12 carbon atoms (i.e., C464) 1-12 Alkyl groups, 1 to 8 carbon atoms (i.e., C464) 1-8 Alkyl groups, 1 to 6 carbon atoms (i.e., C646) 1-6 Alkyl groups or 1 to 4 carbon atoms (i.e., C46) 1-4Alkyl groups. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by its chemical name or identified by its molecular formula, it can encompass all positional isomers having that number of carbons; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3); and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0093] "alkylene" or "alkylene chain" refers to an unbranched or branched divalent hydrocarbon chain that connects the remainder of the molecule to a group, is unsaturated, and has 1 to 20 carbon atoms, or more typically 1 to 12 carbon atoms (C2). 1-12 Alkylene or 1 to 8 carbon atoms (C 1-8 Alkylene or 1 to 3 carbon atoms (C 1-3 Alkylenes, such as methylene, ethylene, propylene, n-butylene, etc. An alkylene chain can be connected to the rest of the molecule and groups via one or any two carbons within the chain.

[0094] "Alkenyl" refers to a group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C2O4 ... 2-20 Alkenyl) or more typically 2 to 12 carbon atoms (i.e., C12) 2-12 alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 Alkenyl) or 2 to 4 carbon atoms (i.e., C) 2-4 Alkyl groups (alkenyl). Examples of alkenyl groups include vinyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0095] "Alkenyl" and "alkenyl chain" refer to unbranched or branched divalent hydrocarbon chains that connect the rest of the molecule to a group, contain at least one double bond, and have 2 to 20 carbon atoms, or more typically 2 to 12 or 2 to 8 carbon atoms, such as vinylene, propenene, n-butenene, etc. Alkenyl chains are connected to the rest of the molecule by single bonds and to groups by double or single bonds. The connection point between the alkenyl chain and the rest of the molecule and the group can be one carbon or any two carbons within the chain.

[0096] "Alkyne" refers to a group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C360, C460, C560, C6 ... 2-20(alkynyl group) or more typically 2 to 12 carbon atoms (i.e., C12-C ... 2-12 (alkynyl group) or more typically 2 to 8 carbon atoms (i.e., C10, C20, C30, C40, C50, C60, C70, C80, C9 ... 2-8 acetylsyl), 2 to 6 carbon atoms (i.e., C10, C20, C30, C40, C50, C60, C7 ... 2-6 (alkynyl group) or 2 to 4 carbon atoms (i.e., C46) 2-4 Alkyl groups (alkynyl). The term "alkynyl" also includes those groups having one triple bond and one double bond.

[0097] "Alynyl" and "alynyl chain" refer to an unbranched or branched divalent hydrocarbon chain that connects the rest of the molecule to a group, contains at least one triple bond, and has 2 to 20 carbon atoms, or more typically 2 to 12 carbon atoms or 2 to 8 carbon atoms. The alynyl chain is connected to the rest of the molecule by a single bond and to the group by a double or single bond. The connection point between the alynyl chain and the rest of the molecule and the group can be one carbon atom or any two carbon atoms within the chain.

[0098] "Alkoxy" refers to the "alkyl-O-" group. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexyloxy, and 1,2-dimethylbutoxy.

[0099] "Haloalkoxy" refers to an alkoxy group as defined above, in which one or more hydrogen atoms are replaced by halogens.

[0100] "Alkylthio" refers to the "alkyl-S-" group.

[0101] "Amino" refers to the -NR group. y R y , where each R y Independently selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclic, cycloalkyl or heteroaryl, each of which may optionally be substituted as defined herein.

[0102] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, aryl groups have 6 to 20 ring carbon atoms (i.e., C64 carbon atoms). 6-20 aryl), 6 to 15 carbon ring atoms (i.e., C 6-15 aryl group) or 6 to 10 carbon ring atoms (i.e., C46, ​​C56, C6 ... 6-10 Aryl groups. Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthracene. However, aryl groups do not encompass or overlap in any way with heteroaryl groups as defined below. If one or more aryl groups are fused with a heteroaryl group, the resulting ring system is a heteroaryl group. If one or more aryl groups are fused with a heterocyclic group, the resulting ring system is a heterocyclic group.

[0103] "Cyano" refers to the group -CN.

[0104] "Keto" or "oxo" refers to the group =O.

[0105] "Carbamoyl" refers to "O-carbamoyl", which is the group -OC(O)NR. y R z ; and "N-carbamoyl", which refers to the group -NR y C(O)OR z , where R y and R z The elements are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl or heteroaryl; each of which may optionally be substituted.

[0106] "Carboxyl group" or "carboxylic acid" refers to -C(O)OH.

[0107] "Ester" refers to both -OC(O)R and -C(O)OR, where R is a substituent; each of them may be optionally substituted, as defined herein.

[0108] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having a monocyclic or multiple rings (including fused, bridged, and spirocyclic systems). The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond). As used herein, cycloalkyl groups have 3 to 15 cyclic carbon atoms (i.e., C64, C16, C26, C64 ... 3-20 cycloalkyl groups), 3 to 12 cyclic carbon atoms (i.e., C12+ ... 3-12 cycloalkyl groups), 3 to 10 cyclic carbon atoms (i.e., C14 and C24). 3-10 cycloalkyl groups), 3 to 8 cyclic carbon atoms (i.e., C1646-C ... 3-8 cycloalkyl groups or 3 to 6 cyclic carbon atoms (i.e., C16, C26, C36, C46, ​​C56, C6 ... 3-6 Cycloalkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[2.2.2]octyl-1-yl. Cycloalkyl groups can be attached to the rest of the molecule by a single ring atom (e.g., as a substituent) or by two ring atoms (e.g., as a linker).

[0109] "Ethylene glycol unit" refers to a divalent monomer having a -CH2CH2O- structure, which can be repeating and extend into longer chains. The linker segment can have up to 12 ethylene glycol units, or more typically up to 6 ethylene glycol units.

[0110] A "propylene glycol unit" refers to a divalent monomer having a -CH(CH3)-CH2O- structure, which can be repeating and extend into longer chains. The linker segment can have up to 12 propylene glycol units, or more typically up to 6 propylene glycol units.

[0111] "Halogen" or "halogenated group" includes fluorine, chlorine, bromine and iodine.

[0112] "Haloalkyl" refers to an unbranched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. For example, when a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl groups substituted with two ("di") or three ("tri") halogen groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0113] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are independently substituted with the same or different heteroatoms (such as N, O, S, etc.). The term "heteroalkyl" includes unbranched or branched saturated chains having carbon atoms and heteroatoms. For example, one, two, or three carbon atoms may be independently substituted with the same or different heteroatoms. Heteroatomic groups include, but are not limited to, -N(R)-, -O-, -S-, -S(O)-, -S(O)2-, etc., where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, or heterocyclic, each of which may be optionally substituted. Examples of heteroalkyl groups include -OCH3, -CH2OCH3, -SCH3, -CH2SCH3, -NRCH3, and -CH2NRCH3, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted. As used herein, heteroalkyl groups include 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0114] "Heteroaryl" refers to a 5-15 membered or more typically 5-12 membered aromatic group having a monocyclic, polycyclic, or polycyclic aromatic ring and 1-3 independent cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl groups include 3 to 12 cyclic carbon atoms (i.e., C46, ​​C56, C6 ... 3-12 (heteroaryl) or 3 to 8 carbon ring atoms (i.e., C 3-8A heteroaryl group; and 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 1 to 4 heteroatoms, 1 to 3 cyclic heteroatoms, 1 to 2 cyclic heteroatoms, or 1 cyclic heteroatom. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridinyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophene, indazole, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, wherein the heteroaryl group can be linked by either ring of the fused system. Any aromatic ring having one or more fused rings and containing at least one heteroatom is considered a heteroaryl group, regardless of its connection to the rest of the molecule (i.e., through either fused ring). A heteroaryl group does not encompass aryl groups (which do not have heteroatoms) or heterocyclic groups (which have at least one non-aromatic ring) or overlaps thereof. Heteroaryl groups can be attached to the rest of the molecule via a single ring atom (e.g., as a substituent) or via two ring atoms (e.g., as a linker).

[0115] "Heterocyclic group" refers to a 3-15 membered or more typically 5-12 membered saturated or unsaturated cyclic alkyl group having 1-3 independently selected cyclic heteroatoms chosen from nitrogen, oxygen, and sulfur. The term "heterocyclic group" includes heterocyclic alkenyl groups (i.e., heterocyclic groups having at least one double bond), bicyclic heterocyclic groups, bridged heterocyclic groups, fused heterocyclic groups, and spirocyclic groups. Heterocyclic groups can be monocyclic or multiple rings, wherein the multiple rings can be fused, bridged, or spirocyclic. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclic group, regardless of its connection (i.e., whether it can be bonded by carbon atoms or heteroatoms). Furthermore, the term heterocyclic group is intended to cover any non-aromatic ring containing at least one heteroatom that can be fused to an aryl or heteroaryl ring, regardless of its connection to the rest of the molecule. As used herein, heterocyclic groups have 3 to 15 ring atoms (e.g., 3-15 membered heterocyclic groups, 3-12 membered heterocyclic groups, 4-10 membered heterocyclic groups, 4-8 membered heterocyclic groups, or 4-6 membered heterocyclic groups; having 1 to 5 ring heteroatoms independently selected from nitrogen, sulfur, or oxygen, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatomation). Heterocyclic groups may contain one or more oxo groups and / or thionyl groups. Examples of heterocyclic groups include pyrrolidinyl, piperidinyl, piperazine, oxetyl, dioxetyl, and nitrogen-containing heterocyclic groups. Butyl, azaheterocyclic butyl, morpholino, thiomorpholino, 4-7 sulfonamides, 4-7 cyclic carbamates, 4-7 cyclic carbonates, 4-7 cyclic sulfides, and morpholino. As used herein, heterocyclic groups may include bridging structures (i.e., “bridged heterocyclic groups”), wherein a quaternary to 10-membered ring portion is connected at two non-adjacent atoms of the heterocyclic group to one or more (e.g., 1 or 2) quaternary to 10-membered ring portions having at least one heteroatom (wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur). As used herein, bridging... Heterocyclic groups include bicyclic and tricyclic systems. The term “spiroheterocyclic group” as used herein also refers to a cyclic system in which a ternary to ten-membered heterocyclic group has one or more additional rings, wherein the one or more additional rings are ternary to ten-membered cycloalkyl groups or ternary to ten-membered heterocyclic groups, and wherein a single atom of the one or more additional rings is also an atom of the ternary to ten-membered heterocyclic group. Examples of spiroheterocyclic rings include bicyclic and tricyclic systems such as 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.4]octyl, and 6-oxa-1-azaspiro[3.5]octyl. Heterospiro[3.3]heptyl. Examples of fused heterocyclic rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 1-oxo-1,2,3,4-tetrahydroisoquinolinyl, 1-oxo-1,2-dihydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridyl, indololinyl, and isoindololinyl, wherein the heterocyclic group can be linked by any ring of the fused system. As used herein, a bicyclic heterocyclic group is a heterocyclic group attached to another cyclic group at two points, wherein the other cyclic group itself may be a heterocyclic group or a carbocyclic group.Heteroaryl groups can be attached to the rest of the molecule via a single ring atom (e.g., as a substituent) or via two ring atoms (e.g., as a linker).

[0116] "Fused" refers to a ring joining an adjacent ring and sharing two adjacent ring atoms, which form covalent bonds.

[0117] "Bridging" refers to ring fusion, in which non-adjacent atoms on the ring are joined by divalent substituents (such as alkylene groups, alkylene groups containing one or two heteroatoms, or alkylene groups with a single heteroatom). Quinine cycloyl and adamantyl groups are examples of bridging ring systems.

[0118] "Spiro" refers to a cyclic substituent that is bonded by two bonds at the same carbon atom. Examples of spiro groups include 1,1-diethylcyclopentane, dimethyl-dioxacyclopentane, and 4-benzyl-4-methylpiperidine, where cyclopentane and piperidine are spiro substituents, respectively.

[0119] "Hydroxy" refers to the -OH group. "Hydroxyalkyl" refers to an unbranched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by hydroxyl groups.

[0120] "Nitro" refers to the group -NO2.

[0121] "Imine" refers to a group containing a C=N double bond, such as C=NR. y Or =NC(O)R y , where R y The group consisting of hydrogen, alkyl, aryl, cyano, haloalkyl, or heteroaryl groups may be optionally substituted. The imino group may become a linker segment by attaching to the remaining molecule at carbon and nitrogen, respectively.

[0122] "Sulfonyl" refers to the group -S(O)2R, where R is a substituent or a defined group.

[0123] "alkylsulfonyl" refers to the group -S(O)2R, where R is a substituent or a defined group.

[0124] "alkylsulfinyl" refers to the group -S(O)R, where R is a substituent or a defined group.

[0125] "Thiocyanate base" - SCN.

[0126] "Thiol" refers to the group -SR, where R is a substituent or a defined group.

[0127] "Thionyl" or "thion" refers to the group (=S) or (S).

[0128] Certain commonly used alternative chemical names may be used. For example, divalent groups such as "alkyl" and "aryl" may also be referred to as "alkylene" and "arylene," respectively. Furthermore, unless otherwise explicitly indicated, when a combination of groups is referred to herein as a moiety (e.g., arylalkyl), the last group mentioned contains the atoms that link said moiety to the remainder of the molecule.

[0129] The terms "optional" or "optionally" mean that the event or situation described below may or may not occur, and the description includes both scenarios where the event or situation occurs and scenarios where it does not occur. Furthermore, the term "optionally substituted" means that any one or more hydrogen atoms on a specified atom or group may or may not be substituted with any of the components other than hydrogen. "Optionally substituted" can be zero to a maximum number of possible substitutions, and each occurrence is independent. When the term "substituted" is used, the substitution must occur at the substituted hydrogen atom of the indicated substituent. Optional substitutions may be the same as or different from the (desired) substitution.

[0130] When a part is "optionally substituted" and refers to a general term such as any "alkyl", "alkenyl", "alkynyl", "haloalkyl", "cycloalkyl", "aryl", or "heteroaryl", then the general term may refer to any previously explicitly stated term, such as (C 1-3 Alkyl), (C 4-6 alkyl), -O(C) 1-4 Alkyl), (C 3-10 cycloalkyl), O-(C 3-10 Cycloalkyl), etc. For example, "any aryl" includes "aryl" and "-O (aryl)," as well as examples of aryl such as phenyl or naphthyl, etc. Furthermore, the term "any heterocyclic" includes both the term "heterocyclic" and "O- (heterocyclic)," as well as examples of heterocyclic groups such as oxobutyryl, tetrahydropyranyl, morpholinyl, piperidinyl, etc. Similarly, the term "any heteroaryl" includes both the term "heteroaryl" and "O- (heteroaryl)," as well as specific heteroaryl groups such as pyridine, etc.

[0131] Some compounds of formula (I) may exist as "stereoisomers" or mixtures of stereoisomers. A stereoisomer is a compound consisting of identical atoms bonded by identical bonds, but with different three-dimensional structures that are not interchangeable. The compounds of this disclosure or their pharmaceutically acceptable salts may contain one or more asymmetric centers, and thus may produce enantiomers (two stereoisomers whose molecules are non-overlapping mirror images of each other), diastereomers, and other stereoisomeric forms, which can be defined according to the absolute stereochemical definition (…). R )-or( S This disclosure is intended to include all such possible isomers, as well as their racemic mixtures (i.e., equal amounts of...). R )and( S (Enantiomers) and optically pure forms. Optically active (+) and (-), ( R )-and( S -Isomers can be prepared using chiral synthons or chiral reagents, or separated using conventional techniques such as HPLC or SFC using chiral columns.

[0132] "&1" means that a compound containing "&1" at a specific chemical element or atom (e.g., carbon) is prepared as a mixture of two stereoisomers at the indicated chemical element or atom (e.g., a mixture of diastereomers having de or de% as described above). "&2", if present, indicates a second group of isomers.

[0133] This disclosure also includes “deuterated analogues” of compounds of formula (I), wherein one to n hydrogen atoms bonded to a carbon atom are replaced with deuterium, where n is the number of hydrogen atoms in the molecule. Such compounds exhibit increased metabolic resistance and are therefore used to increase the half-life of any compound of formula (I) when administered to mammals, particularly humans. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by using starting materials in which one or more hydrogen atoms have been replaced with deuterium.

[0134] The therapeutic compounds of this disclosure, deuterated or substituted, may possess improved drug metabolism and pharmacokinetic (DMPK) properties related to distribution, metabolism, and excretion (ADME). Substitution with a heavier isotope (such as deuterium) can provide certain therapeutic advantages due to higher metabolic stability, such as increased in vivo half-life, reduced dose requirement, and / or improved therapeutic index. 18F-labeled compounds can be used in PET or SPECT studies. Isotopically labeled compounds of this disclosure can generally be prepared by replacing unlabeled reagents with readily available isotopically labeled reagents through the procedures or examples and preparations disclosed below. It should be understood that deuterium in this context is considered a substituent in compounds of formula (I).

[0135] The concentration of such heavier isotopes (specifically, deuterium) can be defined by isotopic enrichment coefficients. In the compounds of this disclosure, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen," that position should be understood as having a naturally occurring isotopic composition of hydrogen. Therefore, in the compounds of this disclosure, any atom specifically designated as deuterium (D) is intended to represent deuterium.

[0136] In many cases, the compounds of this disclosure are capable of forming acidic and / or basic salts due to the presence of amino and / or carboxyl groups or similar groups.

[0137] Pharmaceutically acceptable salts, hydrates, or solvates of the compounds described herein are also provided. “Pharmaceutically acceptable” or “physiologically acceptable” means compounds, salts, compositions, dosage forms, and other materials that can be used to prepare pharmaceutical compositions suitable for veterinary or human use.

[0138] The term "pharmaceutically acceptable salt" for a given compound refers to a salt that retains the biological efficacy and properties of the given compound and is biologically or otherwise desirable. "Pharmaceutically acceptable salt" or "physiologically acceptable salt" includes, for example, salts formed from inorganic acids and salts formed from organic acids. Furthermore, if the compound described herein is obtained as an acid addition salt, the free base can be obtained by alkalizing a solution of the acidic salt. Conversely, if the product is a free base, the addition salt, especially a pharmaceutically acceptable addition salt, can be produced according to conventional procedures for preparing acid addition salts from base compounds by dissolving the free base in a suitable organic solvent and treating the solution with acid. Those skilled in the art will recognize the various synthetic methods that can be used to prepare non-toxic, pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be obtained from inorganic acids and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and so on. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include (by example only) sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary, secondary, and tertiary amines, such as alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dienylamines (i.e., HN(alkenyl)2), trienylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), di(substituted)... Suitable amines include (for example only) alkenylamines (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl)amines (i.e., N(substituted alkenyl)3), mono-cycloalkylamines, di-cycloalkylamines, or tri-cycloalkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-arylamines, di-arylamines, or tri-arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines. Specific examples of suitable amines include (by way of example only) isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, etc.

[0139] The term "substituted" means that any one or more hydrogen atoms on a specified atom or group are replaced by one or more substituents other than hydrogen, provided that the substitution does not exceed the normal valence of the specified atom. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amide, amidyl, aryl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, guanidinyl, haloyl, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclic, hydroxyl, hydrazyl, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thion, or combinations thereof. Polymers or similar indeterminate structures obtained by defining substituents with an unlimited number of other substituents (e.g., substituted aryl with a substituted alkyl group, which itself is substituted aryl, which is further substituted heteroalkyl, etc.) are not intended to be included herein. Unless otherwise stated, the maximum number of successive substitutions in the compounds described herein is three. For example, a successive substitution of a substituted aryl group by two other substituted aryl groups is limited to ((substituted aryl) substituted aryl) substituted aryl. Similarly, the above definition is not intended to include disallowed substitution patterns (e.g., a methyl group substituted with five fluorine atoms or a heteroaryl group having two adjacent oxygen ring atoms). Such disallowed substitution patterns are well known to those skilled in the art. When used to modify chemical groups, the term “substituted” may describe other chemical groups as defined herein. Unless otherwise specified, when a group is described as optionally substituted, any substituents of that group are themselves unsubstituted. For example, in some embodiments, the term “substituted alkyl” refers to an alkyl group having one or more substituents, including hydroxyl, haloyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl. In other embodiments, the one or more substituents may be further substituted with a haloyl, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein each is substituted. In other embodiments, the substituents may be further substituted with a halogroup, alkyl group, haloalkyl group, alkoxy group, hydroxy group, cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group, wherein each of these is unsubstituted. Those skilled in the art will recognize that the substituents and other portions of compounds of the general formula herein should be selected to provide compounds that are sufficiently stable to provide pharmaceutically usable compounds that can be formulated into acceptable stable pharmaceutical compositions. Compounds having such stability are considered to fall within the scope of this invention. Those skilled in the art will understand that any combination of the foregoing definitions and substituents should not produce inoperable substances or compounds.

[0140] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutical acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption-delaying agents, etc. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, its use in a therapeutic composition should be considered. Supplemental active ingredients may also be incorporated into the composition.

[0141] A solvate is formed through the interaction of a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0142] Targeted SMARCA2 degradation The compounds disclosed herein have been shown to selectively degrade SMARCA2 while retaining SMARCA4 through cell-based profiling.

[0143] The additional biological activities (including selectivity data) of compounds of formula (I) are summarized in Table 1 of this paper.

[0144] Pharmaceutical compositions and uses of bifunctional compounds of formula (I) The bifunctional compound of formula (I) has been shown to selectively degrade SMARCA2 and is therefore particularly useful for the treatment of SMARCA4-deficient cancers.

[0145] Multiple embodiments provide pharmaceutical compositions of formula (I) compounds or substructures of Examples 1-58 or specific compounds and pharmaceutically acceptable carriers.

[0146] Other embodiments provide methods for treating SMARCA2-mediated diseases or conditions (including for increasing T cell activation, for treating cancer, for inhibiting the growth or proliferation of cancer cells), said methods comprising administering to an individual in need a therapeutically effective amount of a compound of formula (I), a substructure of Examples 1-58, or any of the compounds.

[0147] SMARCA2-mediated diseases can include cancers selected from the following groups: acoustic neuroma, acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, and chronic myeloid (granulocytic) leukemia. Blood disorders, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, proliferative abnormalities (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocytosis, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer. Leiomyosarcoma, leukemia, liposarcoma, liver cancer, lung cancer, lymphangiosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's; Burkitt's), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC) Non-small cell lung cancer, oligodendroglioma, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pineal tumor, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, malignant rhabdomyosarcoma (MRT), rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovial tumor, sweat gland carcinoma, thyroid cancer, Waldenström macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor.

[0148] In some embodiments, the compound of formula (I) or any of the substructures or compounds of Examples 1-58 may be co-administered with a therapeutically effective amount of one or more additional therapeutic agents or pharmaceutically acceptable salts thereof. The additional therapeutic agents include, for example, chemotherapeutic agents disclosed in WO WO2021083949.

[0149] Construction of compound (I) The synthesis or construction of compounds of formula (I) can be carried out in multiple steps, typically involving the separate preparation of the SMARCA2 binder and the LHM moiety as building blocks, followed by the covalent bonding of the individual building blocks. Generally, one or both building blocks can be prepared using one or more linker precursors. The linker precursor comprises one or more linker segments (L... s It also has terminal reactive groups for further coupling. The two building blocks can eventually couple (by forming another linker segment) to give the compound of formula (I).

[0150] The following procedure illustrates a general method for preparing constructive components. Specific examples (Examples 1-58) were synthesized according to the general procedure described herein and characterized by their respective physicochemical properties.

[0151] intermediate Intermediate 1 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-(5-methyl-isoxazol-3-yl)piperidine-4-carboxylic acid

[0152] Step 1: Synthesis of 4-(5-methylisoxazol-3-yl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl) ester 4-methyl ester

[0153] NaH (18.0 g, 451 mmol, 60% purity, 2.50 eq) was added to a solution of methyl 2-(5-methylisoxazol-3-yl)acetate (28.0 g, 180 mmol, 1.00 eq) in DMF (280 mL) at 0–5 °C under N2, and the mixture was stirred at 0–5 °C for 1 h. Next, tert-butyl bis(2-chloroethyl)carbamate (48.0 g, 198 mmol, 1.10 eq) was added at 0–5 °C, and the mixture was heated to 60 °C and stirred at 60 °C for 15 h. The mixture was cooled to 25 °C and then poured into a saturated aqueous solution of NH4Cl (500 mL), followed by extraction with EtOAc (250 mL * 2). The combined organic layers were washed with brine (250 mL * 2), dried over Na₂SO₄, filtered, and concentrated to produce a dark brown liquid product (57.8 g, crude product). The crude product was used directly in the next step. LCMS: C 16 H 24 Theoretical value of N₂O₅: 324.4; Experimental value: m / z = 325.2 [M+H] + .

[0154] Step 2: Synthesis of methyl 4-(5-methylisoxazol-3-yl)piperidine-4-carboxylate

[0155] A solution of 4-(5-methylisoxazol-3-yl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl) methyl ester (57.8 g, 178 mmol, 1.00 eq) in HCl / EtOAc (2 M, 578 mL, 6.49 eq) was stirred at 20–25 °C for 2 h. The reaction mixture was filtered and the filter cake was dried under vacuum. The crude product was used directly in the next step. A dark brown liquid of 4-(5-methylisoxazol-3-yl)piperidine-4-carboxylic acid methyl ester (49.7 g, crude product, HCl) was obtained. LCMS: C 11 H 16 Theoretical value for N₂O₃: 224.1; Experimental value: m / z = 225.1 [M+H] + .

[0156] Step 3: Synthesis of methyl 1-(6-chloropyridazine-4-yl)-4-(5-methylisoxazol-3-yl)piperidine-4-carboxylate

[0157] DIEA (94.6 g, 732 mmol, 127 mL, 4.00 eq) was added to a solution of methyl 4-(5-methylisoxazol-3-yl)piperidine-4-carboxylate hydrochloride (47.7 g, 183 mmol, 1.00 eq, HCl) in IPA (480 mL) at 20 °C, followed by the addition of 3,5-dichloropyridazine (30.0 g, 201 mmol, 1.10 eq) at 20 °C. The reaction mixture was stirred at 70 °C for 12 h. The reaction mixture was quenched with H₂O (1.00 L) and then extracted with DCM (500 mL * 3). The organic layer was washed with brine (500 mL * 2), dried over Na₂SO₄, filtered, and concentrated to give the product. The residue was purified by column chromatography (SiO₂) using a gradient of 30–100% ethyl acetate / petroleum ether. Methyl 1-(6-chloropyridazin-4-yl)-4-(5-methylisoxazol-3-yl)piperidine-4-carboxylate was obtained as a brown solid (5.10 g, 7.92 mmol, 4.16% yield, 52.3% purity). LCMS: C 15 H 17 Theoretical value for ClN4O3: 336.1; Experimental value: m / z = 337.1 [M+H] + .

[0158] Step 4: Synthesis of methyl 1-(6-(2-methoxyphenyl)pyridazin-4-yl)-4-(5-methylisoxazol-3-yl)piperidine-4-carboxylate

[0159] A mixture of methyl 1-(6-chloropyridazin-4-yl)-4-(5-methylisoxazol-3-yl)piperidin-4-carboxylate (2.54 g, 7.54 mmol, 1.00 eq), (2-methoxyphenyl)boronic acid (2.29 g, 15.0 mmol, 2.00 eq), K₂CO₃ (3.13 g, 22.6 mmol, 3.00 eq), and RuPhos Pd G₃ (630 mg, 754 μmol, 0.10 eq) in dioxane (127 mL) and H₂O (12.7 mL) was degassed and purged three times with N₂ at 25 °C. The mixture was then stirred at 90 °C under an N₂ atmosphere for 12 h. The mixture was then poured into H₂O (150 mL) and extracted with ethyl acetate (150 mL * 3). The combined organic phases were washed with brine (150 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by RP-FC using a 25–55% MeCN / H₂O gradient. The eluent was concentrated under vacuum. The aqueous phase was lyophilized to yield the product. Methyl 1-(6-(2-methoxyphenyl)pyridazin-4-yl)-4-(5-methylisoxazol-3-yl)piperidine-4-carboxylate (1.90 g, 4.50 mmol, 35.9% yield, 96.6% purity) was given as a pale yellow solid. LCMS: C 22 H 24 Theoretical value for N4O4: 408.2; Experimental value: m / z = 409.1 [M+H] + .

[0160] Step 5: Synthesize the title compound BBr3 (2 M, 3.79 mL, 2.00 eq) was added to a solution of methyl 1-(6-(2-methoxyphenyl)pyridazin-4-yl)-4-(5-methylisoxazol-3-yl)piperidine-4-carboxylate (1.60 g, 3.79 mmol, 1.00 eq) in DCM (50.0 mL) at 0 °C. The reaction mixture was stirred at 15 °C for 3 h. The resulting mixture was quenched by adding HCl solution (1 N, 5.00 mL). The mixture was extracted with EtOAc (10.0 mL * 3), dried over Na2SO4, and concentrated under reduced pressure to yield methyl 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(5-methylisoxazol-3-yl)piperidine-4-carboxylate (3.80 g, crude product) as a pale yellow solid. Next, LiOH·H2O (977 mg, 23.3 mmol, 10.0 eq) was added to a solution of methyl 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(5-methylisoxazol-3-yl)piperidine-4-carboxylate (3.10 g, 2.33 mmol, 1.00 eq) in THF (30.0 mL) and H2O (30.0 mL), and the mixture was stirred at 15 °C for 4 h. The resulting mixture was quenched by adding HCl solution (1 N, 30.0 mL) and then concentrated under vacuum. The mixture was purified by RP-FC using a 1-31% MeCN / H2O gradient. The residue was dissolved in CAN (5.00 mL) and H2O (5.00 mL), concentrated under vacuum to remove CAN, and then concentrated by lyophilization. 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(5-methylisoxazol-3-yl)piperidine-4-carboxylic acid (444 mg, 1.13 mmol, 30.5% yield, 96.5% purity) was obtained as a white solid. LCMS: C 20 H 20 Theoretical value for N4O4: 380.1; Experimental value: m / z = 381.1 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6) δ 9.01 - 8.95 (m,1H), 7.98 - 7.81 (m, 1H), 7.56 (d, J = 2.8 Hz, 1H), 7.42 - 7.33 (m, 1H), 7.02 -6.94 (m, 2H), 6.45 (s, 1H), 3.79 - 3.67 (m, 4H), 2.39 - 2.31 (m, 2H), 2.24 -2.15 (m, 5H).

[0161] Intermediate 2 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(2-methoxyphenyl)piperidine-4-carboxylic acid

[0162] Step 1: Synthesis of 4-(2-methoxyphenyl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl) ester 4-methyl ester

[0163] Following step 1 of intermediate 1, this intermediate was synthesized using methyl 2-(2-methoxyphenyl)acetate. 4-(2-methoxyphenyl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl) ester 4-methyl ester (2.90 g, 5.69 mmol, 4.60% yield, 68.6% purity) was a yellow solid. LCMS: C 19 H 27 Theoretical value for NO5: 349.2; Experimental value: m / z = 250.1 [M-100+H] + .

[0164] Step 2: Synthesis of methyl 4-(2-methoxyphenyl)piperidine-4-carboxylate

[0165] The intermediate was synthesized according to step 2 of intermediate 1. Methyl 4-(2-methoxyphenyl)piperidine-4-carboxylate (2.52 g, crude product, HCl) was obtained as a brown oil. LCMS: C 14 H 19 Theoretical value for NO3: 249.1; Experimental value: m / z = 250.1 [M+H] + .

[0166] Step 3: Synthesis of methyl 1-(6-chloropyridazine-4-yl)-4-(2-methoxyphenyl)piperidine-4-carboxylate

[0167] Following step 3 of intermediate 1, methyl 4-(2-methoxyphenyl)piperidine-4-carboxylate was used to synthesize the intermediate. Methyl 1-(6-chloropyridazin-4-yl)-4-(2-methoxyphenyl)piperidine-4-carboxylate was obtained as a yellow oil (2.05 g, 5.51 mmol, 84.5% yield, 97.3% purity). LCMS: C 18 H 20 Theoretical value of ClN3O3: 361.1; Experimental value: m / z = 362.2 [M+H] + .

[0168] Step 4: Synthesis of methyl 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(2-methoxyphenyl)piperidine-4-carboxylate

[0169] Following step 4 of intermediate 1, this intermediate (2.5 g, crude product) was synthesized using methyl 1-(6-chloropyridazine-4-yl)-4-(2-methoxyphenyl)piperidine-4-carboxylate and (2-hydroxyphenyl)boronic acid. LCMS: C 24 H 25 Theoretical value for N3O4: 419.2; Experimental value: m / z = 420.2 [M+H] + .

[0170] After alkaline hydrolysis, the title compound was obtained as a grayish-white solid (1.44 g, 3.52 mmol, 73.9% yield, 99.2% purity). 1 H NMR: (400 MHz, DMSO- d 6) δ 8.94 (d, J = 2.8 Hz, 1H), 8.10 (dd, J =1.6, 8.4 Hz, 1H), 7.54 (d, J = 2.8 Hz, 1H), 7.36 - 7.30 (m, 2H), 7.29 - 7.23(m, 1H), 7.01 (d, J = 7.6 Hz, 1H), 6.97 - 6.89 (m, 3H), 3.99 - 3.91 (m, 2H), 3.74 (s, 3H), 3.61 - 3.51 (m, 2H), 2.38 (br d, J = 14.0 Hz, 2H), 2.10 - 2.00(m, 2H).

[0171] Intermediate 4 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(tetrahydro-2H-pyran-4-yl)piperidin-4-carboxylic acid

[0172] Step 1: Synthesis of ethyl 4-(tetrahydro-2H-pyran-4-yl)piperidine-4-carboxylate

[0173] At -10°C, DIPA (4.71 g, 46.6 mmol, 6.58 mL, 1.20 mL) was added. eq Add n-BuLi (2.50 M, 18.7 mL, 1.20 mL) to a solution of THF (50.0 mL). eq The mixture was stirred at -10°C for 0.5 h. Then, ethyl piperidine-4-carboxylate (10.0 g, 38.9 mmol, 1.00 mmol) was added at -10°C. eq 10.0 mL of THF was added dropwise to the reaction mixture, and the mixture was stirred at -10 °C for 2 h. 4-Iodotetrahydro-2H-pyran (9.06 g, 42.8 mmol, 1.10 mL) was added dropwise to the reaction mixture at -10 °C. eq A solution of 4-(tetrahydro-2H-pyran-4-yl)piperidine-4-carboxylate in 10.0 mL was added to the mixture and stirred at -10 °C for 1 h. The mixture was heated to 25 °C and stirred at 25 °C for 12 h. The reaction mixture was poured into a saturated ice-cold NH4Cl solution (500 mL) at 0 °C, and the aqueous phase was extracted with ethyl acetate (500 mL * 2). The combined organic phases were washed with H2O (500 mL) and brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give a crude product. The residue was purified by column chromatography (SiO2) using a 1-20% ethyl acetate / petroleum ether gradient. Ethyl 4-(tetrahydro-2H-pyran-4-yl)piperidine-4-carboxylate (8.90 g, crude product) was obtained as a yellow oil. 1 H NMR: (400 MHz, MeOD) δ 4.21 (q, J = 7.2 Hz, 2H), 4.06 - 3.88 (m,4H), 3.41 - 3.32 (m, 2H), 2.74 (br s, 2H), 2.14 (br d, J = 12.4 Hz, 2H), 1.70 -1.62 (m, 1H), 1.61 - 1.55 (m, 2H), 1.46 - 1.44 (m, 9H), 1.43 - 1.32 (m, 4H), 1.29 (t, J = 7.2 Hz, 3H) Step 2: Synthesis of ethyl 4-(tetrahydro-2H-pyran-4-yl)piperidine-4-carboxylate

[0174] The intermediate was synthesized according to step 2 of intermediate 1. Ethyl 4-(tetrahydro-2H-pyran-4-yl)piperidine-4-carboxylate was obtained as a pale yellow solid (6.00 g, 21.6 mmol, 82.9% yield, 100% purity, HCl). LCMS: C 13 H23 Theoretical value of NO3: 241.2, experimental value: m / z = 242.2 [M+H] + .

[0175] Step 3: Synthesis of ethyl 1-(6-chloropyridazine-4-yl)-4-(tetrahydro-2H-pyran-4-yl)piperidine-4-carboxylate

[0176] Following step 3 of intermediate 1, this intermediate was synthesized using ethyl 4-(tetrahydro-2H-pyran-4-yl)piperidine-4-carboxylate (5.40 g, 15.0 mmol, 69.4% yield, 98.2% purity). LCMS: C 17 H 24 Theoretical value of ClN3O3: 353.2, experimental value: m / z = 354.1 [M+H] + .

[0177] Step 4: Synthesis of methyl 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(2-methoxyphenyl)piperidine-4-carboxylate

[0178] Following step 4 of intermediate 1, this intermediate was synthesized using ethyl 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(tetrahydro-2H-pyran-4-yl)piperidin-4-carboxylate and (2-hydroxyphenyl)boronic acid (4.50 g, 10.6 mmol, 78.1% yield, 97.1% purity). LCMS: C 23 H 29 Theoretical value of N3O4: 411.2; Experimental value: m / z = 412.2 [M+H] + .

[0179] Following alkaline hydrolysis, the title compound was obtained as a beige solid (2.43 g, 6.28 mmol, 88.7% yield, 99.1% purity). LCMS: C 21 H 25 Theoretical value for N3O4: 383.2; Experimental value: m / z = 384.1 [M+H] + . 1 H NMR: (400MHz, DMSO- d 6) δ 13.96 - 13.48 (m, 1H), 8.93 (d, J = 2.8 Hz, 1H), 8.10 (d, J = 8.0Hz, 1H), 7.53 (d, J= 2.8 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 6.96 - 6.87 (m, 2H), 4.22 (br d, J = 13.6 Hz, 2H), 3.87 (br dd, J = 3.2, 10.8 Hz, 2H), 3.22 (br t, J =11.2 Hz, 2H), 2.96 (br t, J = 12.4 Hz, 2H), 2.10 (br d, J = 13.2 Hz, 2H), 1.68 -1.59 (m, 1H), 1.55 - 1.42 (m, 4H), 1.36 - 1.22 (m, 2H) Intermediate 5 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(3-methyl-1H-pyrazol-1-yl)piperidine-4-carboxylic acid

[0180] Step 1: Synthesis of di-tert-butyl 1-(1-benzyl-4-(ethoxycarbonyl)piperidin-4-yl)hydrazine-1,2-dicarboxylate

[0181] At -65°C under N2, DIPA (15.5 g, 153 mmol, 21.6 mL, 1.40 μL) was added. eq Add n-BuLi (2.5 M, 60.9 mL, 1.39 g) to a solution in THF (270 mL). eq The reaction mixture was stirred at -65°C for 1 h. Then, ethyl 1-benzylpiperidine-4-carboxylate (27.0 g, 109 mmol, 1.00 g) was added at -65°C. eq The mixture was added dropwise to the reaction mixture and stirred at -65°C for 1 h. The mixture containing (1...) was then stirred at -65°C... E 1,2-Diazaenedicarboxylic acid 1,2-bis(1,1-dimethylethyl) ester (27.5 g, 120 mmol, 1.10 g) eq50.0 mL of THF was added to the mixture. The reaction mixture was heated to 25 °C and stirred at 25 °C under N2 for 12 h. The reaction mixture was poured into a saturated NH4Cl solution (1.50 L) and extracted with ethyl acetate (600 mL * 3). The combined organic phases were washed with brine (1.50 L), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by RP-FC and purified using a 25-46% MeCN / H2O gradient. The eluent was concentrated under vacuum to remove acetonitrile and adjusted to pH = 7 with saturated NaHCO3 solution. The aqueous phase was extracted with ethyl acetate (1.00 L * 3), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give di-tert-butyl 1-(1-benzyl-4-(ethoxycarbonyl)piperidin-4-yl)hydrazide-1,2-dicarboxylic acid (48.8 g, 97.1 mmol, 88.9% yield) as a yellow solid. LCMS: C 25 H 39 Theoretical value for N3O6: 477.3; Experimental value: m / z = 478.1 [M+H] + .

[0182] Step 2: Synthesis of ethyl 1-benzyl-4-hydrazinopiperidine-4-carboxylate

[0183] At 25°C, 1-(1-benzyl-4-(ethoxycarbonyl)piperidin-4-yl)hydrazide-1,2-dicarboxylic acid di-tert-butyl ester (48.8 g, 102 mmol, 1.00 mmol) was subjected to oxidation. eq Add HCl / EtOAc (2 M, 500 mL, 9.79 g / mL) to the EtOAc (50.0 mL) solution. eq The mixture was heated to 40°C and stirred at 40°C for 12 h. The reaction mixture was concentrated under vacuum to yield ethyl 1-benzyl-4-hydrazinopyridine-4-carboxylate (36.0 g, crude product, HCl) as a white solid. LCMS: C 15 H 23 Theoretical value of N3O2: 277.2, experimental value: m / z = 278.1 [M+H] + .

[0184] Step 3: Synthesis of ethyl 1-benzyl-4-(3-methyl-1H-pyrazole-1-yl)piperidine-4-carboxylate

[0185] Ethyl 1-benzyl-4-hydrazinopyridine-4-carboxylate (39.0 g, 141 mmol, 1.00 g) eq) and 4,4-dimethoxybut-2-one (18.6 g, 141 mmol, 18.7 mL, 1.00 eq The mixture in EtOH (195 mL) and AcOH (19.5 mL) was degassed and purged three times with N2, and then stirred at 50 °C under N2 for 2 h. The reaction mixture was concentrated under vacuum. The residue was purified by RP-FC using a 10–40% MeCN / H2O gradient. The eluent was concentrated under vacuum to remove acetonitrile and H2O, and the residual aqueous solution was lyophilized to give ethyl 1-benzyl-4-(3-methyl-1H-pyrazol-1-yl)piperidine-4-carboxylate (22.0 g, 64.4 mmol, 45.8% yield) as a yellow solid. LCMS: C 19 H 25 Theoretical value of N3O2: 327.2, experimental value: m / z = 328.1 [M+H] + .

[0186] Step 4: Synthesis of ethyl 4-(3-methyl-1H-pyrazol-1-yl)piperidine-4-carboxylate

[0187] Ethyl 1-benzyl-4-(3-methyl-1H-pyrazol-1-yl)piperidin-4-carboxylate (22.0 g, 67.2 mmol, 1.00 mmol) under N2 eq Add Pd / C (2.22 g, 2.08 mmol, 10% purity, 0.031 mg) to a solution of MeOH (110 mL). eq The suspension was degassed under vacuum and purged three times with H2. The mixture was stirred at 25°C for 12 h with H2 (50 psi). The reaction mixture was filtered and the filtrate was concentrated to give ethyl 4-(3-methyl-1H-pyrazol-1-yl)piperidine-4-carboxylate (15.6 g, 64.8 mmol, 96.5% yield) as a yellow solid. 1 H NMR: (400 MHz, DMSO- d 6) δ 8.69 (s, 1H), 7.90 (d, J = 2.4 Hz, 1H), 6.18 (d, J = 2.4 Hz, 1H), 4.08 (q, J = 7.2 Hz, 2H), 3.24 (d, J = 13.2 Hz, 2H), 2.87 (s, 2H), 2.68 (d, J= 15.2 Hz, 2H), 2.49 - 2.40(m, 2H), 2.17 (s, 3H), 1.10 (t, J = 7.2 Hz, 3H).

[0188] Step 5: Synthesis of ethyl 1-(6-chloropyridazin-4-yl)-4-(3-methyl-1H-pyrazol-1-yl)piperidine-4-carboxylate

[0189] Following step 3 of intermediate 1, this intermediate was synthesized using ethyl 4-(3-methyl-1H-pyrazol-1-yl)piperidine-4-carboxylate (12.5 g, 35.5 mmol, 53.9% yield). LCMS: C 16 H 20 Theoretical value of ClN5O2: 349.1; Experimental value: m / z = 350.0 [M+H] + .

[0190] Step 6: Synthesis of ethyl 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(3-methyl-1H-pyrazol-1-yl)piperidine-4-carboxylate

[0191] Following step 4 of intermediate 1, this intermediate was synthesized using ethyl 1-(6-chloropyridazin-4-yl)-4-(3-methyl-1H-pyrazol-1-yl)piperidine-4-carboxylate and (2-hydroxyphenyl)boronic acid (8.50 g, 16.7 mmol, 83.4% yield). LCMS: C 22 H 25 Theoretical value for N5O3: 407.2; Experimental value: m / z = 408.2 [M+H] + .

[0192] Following alkaline hydrolysis, the title compound was obtained as a light brown solid (1.07 g, 2.75 mmol, 37.3% yield, 97.4% purity). LCMS: C 20 H 21 Theoretical value for N5O3: 379.4; Experimental value: m / z = 380.1 [M+H] + . 1 H NMR: (400MHz, MeOD) δ 8.84 (d, J = 2.8 Hz, 1H), 7.81 - 7.70 (m, 2H), 7.50 (d, J= 3.2 Hz,1H), 7.43 - 7.35 (m, 1H), 7.07 - 6.94 (m, 2H), 6.13 (d, J = 2.2 Hz, 1H), 3.98 -3.85 (m, 2H), 3.77 - 3.62 (m, 2H), 2.66 - 2.55 (m, 4H), 2.25 (s, 3H) Intermediate 6 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(pyridin-4-yl)piperidin-4-carboxylic acid

[0193] Step 1: Synthesis of 4-(pyridin-4-yl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl) ester 4-methyl ester

[0194] Following step 1 of intermediate 1, this intermediate was synthesized using methyl 2-(4-fluorophenyl)acetate (9.20 g, 25.4 mmol, 9.84% yield, 88.4% purity). LCMS: C 17 H 24 Theoretical value of N₂O₄: 320.2, experimental value: m / z = 321.3 [M+H] + .

[0195] Step 2: Synthesis of methyl 4-(pyridin-4-yl)piperidine-4-carboxylate

[0196] The intermediate (9.20 g, crude product, HCl) was synthesized according to step 2 of intermediate 1. LCMS: C 12 H 16 Theoretical value of N2O2: 220.1, experimental value: m / z = 221.1 [M+H] + .

[0197] Step 3: Synthesis of methyl 1-(6-chloropyridazin-4-yl)-4-(pyridin-4-yl)piperidine-4-carboxylate

[0198] Following step 3 of intermediate 1, this intermediate was synthesized using methyl 4-(pyridin-4-yl)piperidin-4-carboxylate (6.67 g, 19.8 mmol, 62.0% yield, 98.8% purity). LCMS: C 16 H 17 Theoretical value of ClN4O2: 332.1, experimental value: m / z = 333.2 [M+H]+ .

[0199] Step 4: Synthesis of methyl 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(pyridin-4-yl)piperidine-4-carboxylate

[0200] Following step 4 of intermediate 1, this intermediate was synthesized using methyl 1-(6-chloropyridazin-4-yl)-4-(pyridin-4-yl)piperidin-4-carboxylate and (2-hydroxyphenyl)boronic acid (4.20 g, 10.6 mmol, 63.9% yield, 98.2% purity). LCMS: C 22 H 22 Theoretical value for N4O3: 390.2; Experimental value: m / z = 391.2 [M+H] + .

[0201] Following alkaline hydrolysis, the title compound was obtained as a brown solid (1.88 g, 4.58 mmol, 96.6% yield, 96.2% purity, Li salt). LCMS: C 21 H 20 The theoretical value of N4O3 is 376.2, and the experimental value is m / z = 377.2. 1 H NMR: (400 MHz, D2O) δ 8.56 (d, J = 3.2 Hz, 1H), 8.32 (d, J = 6.4 Hz, 2H), 7.31 - 7.25 (m, 4H), 7.19 - 7.10 (m, 1H), 6.68 (d, J = 8.0 Hz, 1H), 6.57 (t, J = 7.2 Hz, 1H), 3.68 -3.59 (m, 2H), 3.25 - 3.14 (m, 2H), 2.32 (d, J = 13.6 Hz, 2H), 1.68 - 1.78 (m, 2H).

[0202] Intermediate 7 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(3-methoxyphenyl)piperidine-4-carboxylic acid

[0203] Step 1: Synthesis of 4-(3-methoxyphenyl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl) ester 4-methyl ester

[0204] Following step 1 of intermediate 1, this intermediate was synthesized using methyl 2-(3-methoxyphenyl)acetate (7.70 g, 11.0 mmol, 6.62% yield, 50.0% purity). LCMS: C 19 H 27 Theoretical value for NO5: 349.2; Experimental value: m / z = 250.1 [M-100+H] + .

[0205] Step 2: Synthesis of methyl 4-(3-methoxyphenyl)piperidine-4-carboxylate

[0206] The intermediate (7.40 g, crude product, HCl) was synthesized according to step 2 of intermediate 1. LCMS: C 14 H 19 Theoretical value for NO3: 249.1; Experimental value: m / z = 250.1 [M+H] + .

[0207] Step 3: Synthesis of methyl 1-(6-chloropyridazine-4-yl)-4-(3-methoxyphenyl)piperidine-4-carboxylate

[0208] Following step 3 of intermediate 1, this intermediate was synthesized using methyl 4-(3-methoxyphenyl)piperidine-4-carboxylate (5.90 g, 16.0 mmol, 57.3% yield, 98.3% purity). LCMS: C 18 H 20 Theoretical value of ClN3O3: 361.1; Experimental value: m / z = 362.2 [M+H] + .

[0209] Step 4: Synthesis of methyl 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(3-methoxyphenyl)piperidine-4-carboxylate

[0210] Following step 4 of intermediate 8, this intermediate was synthesized using methyl 1-(6-chloropyridazine-4-yl)-4-(3-methoxyphenyl)piperidine-4-carboxylate and (2-hydroxyphenyl)boronic acid (3.20 g, 7.40 mmol, 59.5% yield, 97% purity). LCMS: C 24 H 25 Theoretical value for N3O4: 419.2; Experimental value: m / z = 420.1 [M+H] + .

[0211] Following alkaline hydrolysis, the title compound was obtained as a grayish-white solid (1.04 g, 2.56 mmol, 39.8% yield, 99.9% purity). LCMS: C 23 H 23 Theoretical value of N3O4: 405.2, experimental value: m / z = 406.2 [M+H] + . 1 H NMR: (400MHz, DMSO- d 6) δ 8.86 (d, J = 3.20 Hz, 1 H), 7.58 (m, 1 H), 7.43 - 7.51 (m, 2 H), 7.30 (t, J = 8.00 Hz, 1 H), 6.98 - 7.10 (m, 4 H), 6.87 (dd, J = 8.40, 2.40 Hz, 1H), 4.19 - 4.43 (m, 2 H), 3.80 (s, 3 H), 3.60 (s, 2 H), 2.73 (d, J=13.2 Hz, 2H), 2.06 - 2.20 (m, 2 H).

[0212] Intermediate 8 4-(4-fluorophenyl)-1-(6-(2-hydroxyphenyl)pyridazin-4-yl)piperidine-4-carboxylic acid

[0213] Step 1: Synthesis of 4-(4-fluorophenyl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl) ester 4-methyl ester

[0214] Following step 1 of intermediate 1, this intermediate (8.36 g, crude product) was synthesized using methyl 2-(4-fluorophenyl)acetate. LCMS: C 18 H 24 Theoretical value of FNO4: 337.2, experimental value: m / z = 282.2 [M-56+H] + .

[0215] Step 2: Synthesis of methyl 4-(4-fluorophenyl)piperidine-4-carboxylate

[0216] The intermediate (7.64 g, crude product, HCl) was synthesized according to step 2 of intermediate 1. LCMS: C 13 H 16Theoretical value for FNO2: 237.1; Experimental value: m / z = 238.2 [M+H] + .

[0217] Step 3: Synthesis of methyl 1-(6-chloropyridazine-4-yl)-4-(4-fluorophenyl)piperidine-4-carboxylate

[0218] Following step 3 of intermediate 1, this intermediate was synthesized using methyl 4-(4-fluorophenyl)piperidine-4-carboxylate (2.61 g, 7.31 mmol, 41.0% yield, 98.0% purity). LCMS: C 17 H 17 Theoretical value of ClFN3O2: 349.1; Experimental value: m / z = 350.2 [M+H] + .

[0219] Step 4: Synthesis of methyl 4-(4-fluorophenyl)-1-(6-(2-hydroxyphenyl)pyridazin-4-yl)piperidine-4-carboxylate

[0220] Pd(dppf)Cl2 (494 mg, 675 μmol, 0.10 eq) was added to a solution of methyl 1-(6-chloropyridazin-4-yl)-4-(4-fluorophenyl)piperidin-4-carboxylate (2.41 g, 6.75 mmol, 1.00 eq), (2-hydroxyphenyl)boronic acid (1.86 g, 13.5 mmol, 2.00 eq), and K2CO3 (2.80 g, 20.3 mmol, 3.00 eq) in dioxane (24.1 mL) and H2O (4.82 mL) under a nitrogen atmosphere. The mixture was stirred at 110 °C for 12 h. The mixture was poured into H2O (100 mL) and extracted with ethyl acetate (100 mL * 3). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by MPLC (SiO2) using a 10–50% petroleum ether / ethyl acetate gradient (751 mg, 1.80 mmol, 26.6% yield, 97.6% purity). LCMS: C 23 H 22 Theoretical value of FN3O3: 407.2; Experimental value: m / z = 408.2 [M+H] + .

[0221] Following alkaline hydrolysis, the title compound was given as a white solid (1.14 g, 2.62 mmol, 79.2% yield, 98.8% purity, HCl). LCMS: C 22 H20 Theoretical value for FN3O3: 393.1; Experimental value: m / z = 394.2 [M+H] + . 1 H NMR: (400 MHz, DMSO-d6) δ 13.43 - 12.64 (m, 1H), 9.01 (d, J = 3.2 Hz, 1H), 7.57 -7.52 (m, 2H), 7.49 - 7.43 (m, 3H), 7.24 - 7.19 (m, 2H), 7.13 (d, J = 8.0 Hz,1H), 7.05 - 6.99 (m, 1H), 4.45 - 4.21 (m, 2H), 4.04 - 4.00 (m, 1H), 3.51 -3.43 (m, 2H), 2.57 (br d, J = 13.6 Hz, 2H), 2.05 - 1.96 (m, 2H). 19 F NMR: (400MHz, DMSO-d6) δ -115.561.

[0222] Intermediate 9 4-(2-Fluorophenyl)-1-(6-(2-hydroxyphenyl)pyridazin-4-yl)piperidine-4-carboxylic acid

[0223] Step 1: Synthesis of 4-(2-fluorophenyl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl) ester 4-methyl ester

[0224] NaH (16.4 g, 411 mmol, 60.0% in mineral oil) was added to a solution of methyl 2-(2-fluorophenyl)acetate (28.0 g, 164 mmol) in DMF (560 mL) under N2 at 0–5 °C, and the mixture was stirred at 0–5 °C for 1 h. Next, tert-butyl bis(2-chloroethyl)carbamate (51.8 g, 214 mmol) was added, and the mixture was heated to 60 °C and stirred until completion was determined by LCMS. Once complete, the reaction mixture was quenched at 0 °C with saturated NH4Cl solution (300 mL). The mixture was poured into H2O (500 mL) and extracted with EtOAc (500 mL x 3). The combined organic phases were washed with H₂O (500 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to give a crude, yellow, oily product (54.0 g), which was then advanced without any further purification. The theoretical LCMS value for C₁₈H₈FO₂ was 337.2, and the experimental value was 282.2 [M⁻⁶⁺H]. + .

[0225] Step 2: Synthesis of methyl 4-(2-fluorophenyl)piperidine-4-carboxylate

[0226] A 1:1 mixture of concentrated HCl in EtOAc (300 mL) was added to a solution of 4-(2-fluorophenyl)piperidin-1,4-dicarboxylic acid 1-(tert-butyl) 4-methyl ester (54.0 g, 160 mmol) in EtOAc (200 mL). The mixture was stirred at 25 °C until completion was determined by LCMS. Once complete, the reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was adjusted to pH 8 with saturated sodium bicarbonate solution and extracted with DCM (100 mL). The aqueous phase was adjusted to pH 10 with saturated sodium carbonate solution and extracted with DCM (200 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product (16.0 g, HCl salt) as a yellow oil, which was proceeded without any further purification. LCMS C 17 H 17 The theoretical value for ClFN3O2 is 237.1, and the experimental value is m / z = 238.2 [M+H]. + .

[0227] Step 3: Synthesis of methyl 1-(6-chloropyridazine-4-yl)-4-(2-fluorophenyl)piperidine-4-carboxylate

[0228] DIPEA (46.9 mL, 269 mmol) and 3,5-dichloropyridazine (12.0 g, 80.9 mmol) were added to a solution of methyl 4-(2-fluorophenyl)piperidin-4-carboxylate (16.0 g, 67.4 mmol) in IPA (160 mL). The mixture was stirred at 25 °C until complete as determined by LCMS. Once complete, the reaction mixture was filtered and concentrated under reduced pressure to give a crude residue. The residue was dissolved in a small amount of DCM, poured into H2O (200 mL), and then extracted with DCM (200 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give a crude product. The crude residue was purified by rapid column chromatography (petroleum ether / ethyl acetate: 15% to 50%) to give the desired product (9.45 g, 39% yield) as a yellow solid. LCMS C 17 H 17 The theoretical value for ClFN3O2 is 349.1, and the experimental value is m / z = 350.2 [M+H]. + .

[0229] Step 4: Synthesis of methyl 4-(2-fluorophenyl)-1-(6-(2-hydroxyphenyl)pyridazin-4-yl)piperidine-4-carboxylate

[0230] Under a nitrogen atmosphere at 25 °C, K₂CO₃ (8.43 g, 60.9 mmol), Pd(dppf)Cl₂ (2.23 g, 3.05 mmol), and (2-hydroxyphenyl)boronic acid (5.61 g, 40.6 mmol) were added to a solution of methyl 1-(6-chloropyridazine-4-yl)-4-(2-fluorophenyl)piperidine-4-carboxylate (7.40 g, 20.3 mmol) in 1,4-dioxane (75 mL) and H₂O (15 mL). The mixture was then heated to 90 °C and stirred until completion was determined by LCMS. Once complete, the reaction mixture was filtered through diatomaceous earth (washed with EtOAc) and concentrated to a minimum solvent under reduced pressure. The residue was poured into H₂O (200 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated to obtain a crude residue. The crude product was purified by rapid column chromatography to obtain the desired product (2.75 g, 30.6% yield) as a yellow solid. LCMS C 23 H 22 The theoretical value of FN3O3 m / z is 407.2, and the experimental value is 408.3 [M+H]. + .

[0231] Following alkaline hydrolysis, the title compound (1.97 g, 71% yield) was obtained as a pale yellow solid. LC-MSC 22 H 20 The theoretical value for FN3O3 is 393.2, and the experimental value is m / z = 394.2 [M+H]. + .

[0232] Intermediate 10 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(5-isopropylisoxazol-3-yl)piperidine-4-carboxylic acid

[0233] Step 1: Synthesis of (5-isopropylisoxazol-3-yl)methanol

[0234] LAH (2.5 M in THF, 118 mL) was added to a solution of methyl 5-isopropylisoxazole-3-carboxylate (25.0 g, 148 mmol) in THF (125 mL) at 0 °C under N2. The mixture was then heated and stirred at 25 °C under N2 until completion was determined by LCMS. Once complete, the mixture was cooled to 0 °C, and then 1 M HCl (800 mL) was slowly added dropwise under N2 with stirring for 30 min. The mixture was then extracted with MTBE (200 mL x 3), washed with a saturated aqueous solution of NaHCO3 (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give a crude product as a yellow oil, which was advanced without any further purification (13.0 g). LCMS C7H 11 Theoretical NO2 value: 141.1, experimental value: 142.6 [M+H] + .

[0235] Step 2: Synthesis of methyl methanesulfonate (5-isopropylisoxazol-3-yl)

[0236] MsCl (16.6 mL, 215 mmol) was added dropwise to a solution of (5-isopropylisoxazol-3-yl)methanol (20.1 g, 142 mmol) and TEA (39.6 mL, 285 mmol) in DCM (201 mL) at 0 °C. The mixture was heated and stirred at 25 °C until completion was determined by LCMS. Once complete, the mixture was poured into ice-cold water (500 mL) and extracted with DCM (250 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give a crude product as a yellow oil, which was advanced without any further purification (28.1 g). LCMS C8H 13 The theoretical value of NO4S is 219.1, and the experimental value is m / z = 220.4 [M+H]. + .

[0237] Step 3: Synthesis of 2-(5-isopropylisoxazol-3-yl)acetonitrile

[0238] To a solution of methyl methanesulfonic acid (5-isopropylisoxazol-3-yl) (29.6 g, 135 mmol) in DMF (150 mL), NaCN (10.2 g, 208 mmol) was added. The mixture was then heated to 60 °C and stirred until completion was determined by LCMS. Once complete, the reaction mixture was diluted with a saturated aqueous solution of Na₂CO₃ (750 mL) and extracted with MTBE (250 mL x 3). The organic layer was washed with brine (100 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to yield a crude residue. The crude residue was purified by rapid column chromatography (petroleum ether / ethyl acetate - 5% to 20%) to give the desired product (13.9 g, 69% yield) as a yellow oil. LCMS C8H 10 Theoretical N₂O value: 150.1, experimental value: 151.2 [M+H] + .

[0239] Step 4: 4-Cyano-4-(5-isopropylisoxazol-3-yl)piperidine-1-carboxylic acid tert-butyl ester

[0240] As described in step 1 for intermediate 9, 2-(5-isopropylisoxazol-3-yl)acetonitrile was used instead of methyl 2-(2-fluorophenyl)acetate to synthesize the intermediate. LCMS C 17 H 25The theoretical value for N3O3 is 319.2, and the experimental value is m / z = 220.1 [M-Boc+H]. + .

[0241] Step 5: Synthesis of 4-(5-isopropylisoxazol-3-yl)piperidine-4-carboxynitrile

[0242] As described in step 2 of intermediate 9, this intermediate (9.65 g) was prepared using tert-butyl 4-cyano-4-(5-isopropylisoxazol-3-yl)piperidin-1-carboxylate (step 7) instead of 4-(2-fluorophenyl)piperidin-1,4-dicarboxylate 1-(tert-butyl) ester 4-methyl. LCMS C 12 H 17 Theoretical value of N3O: 219.1, experimental value: m / z = 220.1 [M+H] + .

[0243] Step 6: Synthesis of 1-(6-chloropyridazin-4-yl)-4-(5-isopropylisoxazol-3-yl)piperidine-4-carboxynitrile

[0244] As described in step 3 of intermediate 9, this intermediate (14.5 g) was prepared using 4-(5-isopropylisoxazol-3-yl)piperidine-4-carboxynitrile instead of 4-(2-fluorophenyl)piperidine-4-carboxylate. LCMS C 16 H 18 The theoretical value for ClN5O is 331.1, and the experimental value is m / z = 332.1 [M+H]. + .

[0245] Step 7: Synthesis of 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(5-isopropylisoxazol-3-yl)piperidine-4-carboxynitrile

[0246] At 25 °C, K₂CO₃ (5.00 g, 36.2 mmol) and RuPhos Pd G₃ (504 mg, 603 µmol) were added to a solution of 1-(6-chloropyridazin-4-yl)-4-(5-isopropylisoxazol-3-yl)piperidin-4-carboxynitrile (4.00 g, 12.1 mmol), (2-hydroxyphenyl)boronic acid (3.33 g, 24.1 mmol), in 1,4-dioxane (40 mL) and H₂O (4 mL). The mixture was degassed and purged three times with N₂. The mixture was then heated to 90 °C and stirred until completion was determined by LCMS. Once complete, the residue was diluted with H₂O (50.0 mL) and extracted with EtOAc (50.0 mL x 3). The combined organic layers were washed with brine (50.0 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to produce a crude residue. The residue was purified by rapid column chromatography (petroleum ether / ethyl acetate - 5 to 100%) to give the desired product as a brown solid (2.00 g, 42% yield). LCMS C 22 H 23 The theoretical value for N5O2 is 389.2, and the experimental value is m / z = 390.3 [M+H]. + .

[0247] Step 8: Synthesize the title compound NaOH (2.05 g, 51.4 mmol) was added to a solution of 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(5-isopropylisoxazol-3-yl)piperidin-4-carboxynitrile (2.00 g, 5.14 mmol) in THF (6 mL), MeOH (6 mL), and H2O (6 mL) at 25 °C. The mixture was heated to 80 °C and stirred until completion was determined by LCMS. Once complete, the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude residue. The crude residue (26.0%–46.0%) was purified by RP-FC. The desired eluent was concentrated to half its volume under reduced pressure, frozen at -78°C, and lyophilized to dryness to give the desired compound as a yellow solid (1.14 g, 58% yield). LCMS C 22 H 24 The theoretical value for N4O4 is 408.2, and the experimental value is m / z = 409.1 [M+H]. + .

[0248] Intermediate 11 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(pyrazolo[1,5-) a pyridin-2-yl)piperidine-4-carboxylic acid

[0249] Step 1: Synthesis of 2-(pyrazolo[1,5- a ethyl pyridin-2-yl)

[0250] At 25°C, 2-(pyrazolo[1,5- a 23.0 g (130 mmol) of pyridin-2-yl)acetic acid was dissolved in EtOH (115 mL) and H₂SO₄ (6.40 g, 65.2 mmol, 3.48 mL) was added. The reaction mixture was then heated to 80 °C and stirred until completion was determined by LC-MSC. Once complete, the reaction mixture was concentrated under vacuum to produce a crude residue. The residue was quenched with ice water (175 mL) and then extracted with DCM (175 mL x 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to give the title compound (25.4 g) as a dark brown liquid. LC-MSC 11 H 12 The theoretical value of N2O2 is 204.1, and the experimental value is m / z = 205.1 [M+H]. + .

[0251] Step 2: Synthesis of 4-(pyrazolo[1,5- a 4-ethyl 1-(tert-butyl)pyridin-2-yl)piperidine-1,4-dicarboxylic acid ester

[0252] As described in step 1 of intermediate 9, 2-(pyrazolo[1,5- a The intermediate (34.5 g) was synthesized by substituting ethyl pyridin-2-yl)acetate for methyl 2-(2-fluorophenyl)acetate. LCMS C 20 H 27 The theoretical value of N3O4 is 373.2, and the experimental value is m / z = 318.2 [M-56+H]. + .

[0253] Step 3: 4-(pyrazolo[1,5- a Ethyl pyridin-2-yl)piperidine-4-carboxylate

[0254] As described in step 2 of intermediate 9, 4-(pyrazolo[1,5-a The intermediate (42.9 g) was synthesized by replacing 4-(2-fluorophenyl)piperidin-1,4-dicarboxylic acid 1-(tert-butyl) ester 4-ethyl ester (step 13) with 4-(2-fluorophenyl)piperidin-1,4-dicarboxylic acid 1-(tert-butyl) ester 4-methyl ester. LCMS C 19 H 20 The theoretical value for ClN5O2 is 273.2, and the experimental value is m / z = 274.2 [M+H]. + .

[0255] Step 4: Synthesis of 1-(6-chloropyridazin-4-yl)-4-(pyrazolo[1,5-) a Ethyl pyridin-2-yl)piperidine-4-carboxylate

[0256] As described in step 3 for intermediate 9, 4-(pyrazolo[1,5- a The intermediate (11.0 g) was synthesized by substituting ethyl pyridin-2-yl)piperidin-4-carboxylate for 4-(2-fluorophenyl)piperidin-4-carboxylate. LCMS C 19 H 20 The theoretical value for ClN5O2 is 385.1, and the experimental value is m / z = 386.2 [M+H]. + .

[0257] Step 5: Synthesis of 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(pyrazolo[1,5- a Ethyl pyridin-2-yl)piperidine-4-carboxylate

[0258] As described in step 4 of intermediate 9, 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(pyrazolo[1,5-) a The intermediate was prepared by substituting ethyl pyridin-2-yl)piperidin-4-carboxylate for methyl 1-(6-chloropyridazin-4-yl)-4-(2-fluorophenyl)piperidin-4-carboxylate (42% yield, via four steps). LCMS C 25 H 25 The theoretical value for N5O3 is 443.2, and the experimental value is m / z = 444.2 [M+H]. + .

[0259] Following alkaline hydrolysis, the title compound (2.50 g) was obtained. LCMS C 23 H 21 The theoretical value for N5O3 is 415.2, and the experimental value is 416.2 [M+H]. + .

[0260] Intermediate 12 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(1-methyl-1 H -pyrazol-4-yl)piperidine-4-carboxylic acid

[0261] Step 1: Synthesis of 4-(1-methyl- ... H 4-methyl pyrazol-4-yl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl) ester

[0262] As described in step 1 of intermediate 9, 2-(1-methyl- ... H The intermediate (80.8 g) was synthesized by replacing methyl 2-(2-fluorophenyl)acetate with methyl pyrazol-4-yl)acetate. LCMS C 16 H 25 The theoretical value of N3O4 is 323.2, and the experimental value is m / z = 268.2 [M-56+H]. + .

[0263] Step 2: Synthesis of 4-(1-methyl- ... H Methyl pyrazol-4-yl)piperidine-4-carboxylate

[0264] As described in step 2 of intermediate 9, 4-(1-methyl- ... H The intermediate (82.5 g) was synthesized by substituting 4-(2-fluorophenyl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl) ester 4-methyl ester for pyrazol-4-yl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl) ester 4-methyl ester. LCMS C 11 H 17 The theoretical value of N3O2 is 223.1, and the experimental value is m / z = 224.3 [M+H]. + .

[0265] Step 3: Synthesis of 1-(6-chloropyridazine-4-yl)-4-(1-methyl-1-yl) H Methyl pyrazol-4-yl)piperidine-4-carboxylate

[0266] As in step 3 of intermediate 9, 4-(1-methyl- ... H The intermediate (7.8 g) was synthesized by replacing methyl pyrazol-4-yl)piperidine-4-carboxylate with 4-(2-fluorophenyl)piperidine-4-carboxylate. LCMS C 15 H 18The theoretical value for ClN5O2 is 335.1, and the experimental value is m / z = 336.2 [M+H]. + .

[0267] Step 4: Synthesis of 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(1-methyl-1 H Methyl pyrazol-4-yl)piperidine-4-carboxylate

[0268] As described in step 4 of intermediate 9, 1-(6-chloropyridazine-4-yl)-4-(1-methyl-1-yl) H The intermediate (4.1 g, 44% yield, via four steps) was synthesized by replacing methyl 1-(6-chloropyridazin-4-yl)-4-(2-fluorophenyl)piperidine-4-carboxylate with methyl pyrazol-4-yl)piperidine-4-carboxylate. LCMS C 21 H 23 The theoretical value for N5O3 is 393.2, and the experimental value is m / z = 394.2 [M+H]. + .

[0269] Following alkaline hydrolysis, the title compound was given (2.2 g, 79% yield). LCMS C 20 H 21 The theoretical value for N5O3 is 379.2, and the experimental value is 380.2 [M+H]. + .

[0270] Intermediate 13 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(3-methylisoxazol-5-yl)piperidine-4-carboxylic acid

[0271] Step 1: Synthesis of 4-(3-methylisoxazol-5-yl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl) ester 4-methyl ester

[0272] As described in step 1 of intermediate 9, this intermediate (57.8 g) was prepared using methyl 2-(3-methylisoxazol-5-yl)acetate instead of methyl 2-(2-fluorophenyl)acetate. LCMS C 16 H 24 The theoretical value of N₂O₅ is 324.2, and the experimental value is m / z = 325.2 [M+H]. + .

[0273] Step 2: Synthesis of methyl 4-(3-methylisoxazol-5-yl)piperidine-4-carboxylate

[0274] As described in step 2 of intermediate 9, this intermediate (49.7 g) was synthesized using 4-(3-methylisoxazol-5-yl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl) ester 4-methyl ester instead of 4-(2-fluorophenyl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl) ester 4-methyl ester. LCMS C 11 H 16 The theoretical value for N₂O₃ is 224.1, and the experimental value is m / z = 225.1 [M+H]. + .

[0275] Step 3: Synthesis of methyl 1-(6-chloropyridazine-4-yl)-4-(3-methylisoxazol-5-yl)piperidine-4-carboxylate

[0276] As described in step 3 of intermediate 9, methyl 4-(3-methylisoxazol-5-yl)piperidine-4-carboxylate was used instead of methyl 4-(2-fluorophenyl)piperidine-4-carboxylate to synthesize this intermediate (5.1 g). LCMS C 15 H 17 The theoretical value for ClN4O3 is 336.1, and the experimental value is m / z = 337.1 [M+H]. + .

[0277] Step 4: Synthesis of methyl 1-(6-(2-methoxyphenyl)pyridazin-4-yl)-4-(3-methylisoxazol-5-yl)piperidine-4-carboxylate

[0278] As described in step 7 of intermediate 10, this intermediate (1.90 g, 36% yield, via four steps) was synthesized using methyl 1-(6-chloropyridazin-4-yl)-4-(3-methylisoxazol-5-yl)piperidin-4-carboxylate instead of methyl 1-(6-chloropyridazin-4-yl)-4-(5-isopropylisoxazol-3-yl)piperidin-4-carboxynitrile and (2-methoxyphenyl)boronic acid instead of (2-hydroxyphenyl)boronic acid. LCMS C 22 H 24 The theoretical value for N4O4 is 408.2, and the experimental value is m / z = 409.1 [M+H]. + .

[0279] Step 5: Synthesis of methyl 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(3-methylisoxazol-5-yl)piperidine-4-carboxylate

[0280] BBr3 (2 M, 3.79 mL) was added to a solution of methyl 1-(6-(2-methoxyphenyl)pyridazin-4-yl)-4-(3-methylisoxazol-5-yl)piperidine-4-carboxylate (1.60 g, 3.79 mmol) in DCM (50 mL) at 0 °C. The reaction mixture was then heated to 25 °C and stirred until completion was determined by LCMS. Once complete, the reaction mixture was quenched by adding HCl solution (1 N, 5.0 mL). The resulting mixture was extracted with EtOAc (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude pale yellow solid (3.80 g) that was advanced without any further purification. LCMS C 21 H 22 The theoretical value for N4O4 is 394.2, and the experimental value is m / z = 395.2 [M+H]. + .

[0281] Following alkaline hydrolysis, the title compound was obtained (444 mg, 31% yield). LCMS C 20 H 20 The theoretical value for N4O4 is 380.2, and the experimental value is m / z = 381.1 [M+H]. + .

[0282] Intermediate 14 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(5-methyl-1 H -pyrazol-1-yl)piperidine-4-carboxylic acid

[0283] Step 1: Synthesis of di-tert-butyl 1-(1-benzyl-4-(ethoxycarbonyl)piperidin-4-yl)hydrazine-1,2-dicarboxylate

[0284] 1-Benzylpiperidin-4-carboxylic acid ethyl ester (20.0 g, 80.8 mmol) was added dropwise to a solution of LDA (2 M in THF, 44.4 mL) in THF (120 mL) at -70 °C, and the mixture was stirred at -70 °C for 0.5 h. Then, (…) EA solution of di-tert-butyl 1,2-dicarboxylate (19.5 g, 84.9 mmol) in THF (40.0 mL) was prepared. The mixture was heated to 25 °C and stirred until completion was determined by LCMS. Once complete, the reaction mixture was poured into a saturated NH4Cl solution (200 mL) and extracted with MTBE (100 mL x 3). The organic layer was washed with brine (50.0 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give a crude residue. The crude product was purified by rapid column chromatography (petroleum ether / EtOAc - 10% to 50%) to give the title compound (15.0 g, 39% yield) as a yellow solid. LCMS C 15 H 21 Theoretical value for NO2: 477.3; experimental value: m / z = 478.4 [M+H] + .

[0285] Step 2: Synthesis of ethyl 1-benzyl-4-hydrazinopiperidine-4-carboxylate

[0286] As described in step 2 of intermediate 9, this intermediate (12.0 g, bisHCl salt) was synthesized using di-tert-butyl 1-(1-benzyl-4-(ethoxycarbonyl)piperidin-4-yl)hydrazine-1,2-dicarboxylate instead of 4-(2-fluorophenyl)piperidin-1,4-dicarboxylate-1-(tert-butyl) 4-methyl ester. LCMS C 15 H 23 The theoretical value of N3O2 is 277.2, and the experimental value is m / z = 278.5 [M+H]. + .

[0287] Step 3: Synthesis of 1-benzyl-4-(5-methyl-1-yl) H ethyl pyrazol-1-yl)piperidine-4-carboxylate

[0288] A solution of 4,4-dimethoxybut-2-one (1.60 mL, 12.0 mmol) in AcOH (75.0 mL) was stirred at 120 °C for 1 h. The mixture was cooled to 60 °C and ethyl 1-benzyl-4-hydrazidopiperidine-4-carboxylate (4.66 g, 12.04 mmol) was added to the mixture at 60 °C. The mixture was then heated and stirred at 120 °C until completion was determined by LCMS. Once complete, the reaction mixture was adjusted to pH 10 with Na₂CO₃ solution, followed by extraction with EtOAc (60.0 mL x 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to give a crude product as a black / brown oil, which was advanced without any further purification (4.0 g). LCMS C 19 H 25 The theoretical value of N3O2 is 327.2, and the experimental value is m / z = 328.4 [M=H] + .

[0289] Step 4: Synthesis of 4-(5-ethyl-1-ethyl) H ethyl pyrazol-1-yl)piperidine-4-carboxylate

[0290] In a N2 atmosphere, 1-benzyl-4-(5-methyl-1 H Ethyl pyrazol-1-yl)piperidine-4-carboxylate (5.13 g, 15.6 mmol) was added to a solution of EtOH (40.0 mL) with Pd / C (516 mg, 485 μmol, 10% purity). The suspension was degassed and charged with H2 three times. H2 (50 psi) was added to the mixture and stirred at 25 °C until completion was determined by LCMS. Once complete, the reaction mixture was filtered through diatomaceous earth (washed with EtOH), and the resulting filtrate was concentrated under vacuum to give a colorless oily substance (3.4 g) that proceeded with any further purification. LCMS C 12 H 19 Theoretical value of N3O2: 237.2, experimental value: 238.5 [M+H] + .

[0291] Step 5: Synthesis of 1-(6-chloropyridazine-4-yl)-4-(5-methyl-1-yl) H ethyl pyrazol-1-yl)piperidine-4-carboxylate

[0292] As in step 3 of intermediate 9, 4-(5-methyl-1-yl) HThe intermediate (2.9 g) was synthesized by replacing ethyl pyrazol-1-yl)piperidine-4-carboxylate with methyl 4-(2-fluorophenyl)piperidine-4-carboxylate. LCMS C 16 H 20 The theoretical value for ClN5O2 is 349.1, and the experimental value is m / z = 350.3 [M+H]. + .

[0293] Step 6: Synthesis of 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(5-methyl-1 H ethyl pyrazol-1-yl)piperidine-4-carboxylate

[0294] As described in step 7 of intermediate 10, 1-(6-chloropyridazine-4-yl)-4-(5-methyl-1-yl) H Ethyl pyrazol-1-yl)piperidine-4-carboxylate was used in place of 1-(6-chloropyridazin-4-yl)-4-(5-isopropylisoxazol-3-yl)piperidine-4-carboxynitrile to synthesize the intermediate (3.0 g). LCMS C 22 H 25 The theoretical value for N5O3 is 407.2, and the experimental value is m / z = 408.3 [M+H]. + .

[0295] Following step 8 of intermediate 10, the title compound was obtained (1.14 g, 10% yield, after six steps). LCMS C 20 H 21 The theoretical value for N5O3 is 379.2, and the experimental value is 380.3 [M+H]. + .

[0296] Intermediate 15 Synthesis of 2-(5-(4-(aminomethyl)-4-phenylpiperidin-1-yl)pyridazin-3-yl)phenol

[0297] Step 1: Synthesis of tert-butyl ((1-(6-chloropyridazin-4-yl)-4-phenylpiperidin-4-yl)methyl)carbamate

[0298] As described in step 3 of intermediate 9, tert-butyl ((4-phenylpiperidin-4-yl)methyl)carbamate was used instead of methyl 4-(2-fluorophenyl)piperidin-4-carbamate to synthesize this intermediate. LCMS C 21 H 27 The theoretical value for ClN4O2 is 402.2, and the experimental value is 403.2 [M+H]. + .

[0299] Step 2: Synthesis of tert-butyl ((1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-phenylpiperidin-4-yl)methyl)carbamate

[0300] As described in step 4 of intermediate 9, this intermediate was synthesized using methyl 1-(6-chloropyridazin-4-yl)-4-phenylpiperidin-4-yl)methyl)carbamate instead of methyl 1-(6-chloropyridazin-4-yl)-4-(2-fluorophenyl)piperidin-4-carboxylate to give the title compound as a yellow solid (1.13 g, 49% yield, after two steps). LCMS C 27 H 32 The theoretical value for N4O3 is 460.3, and the experimental value is 461.3 [M+H]. + .

[0301] Following alkaline hydrolysis, the title compound was obtained. LCMS C 22 H 24 The theoretical value for N4O is 360.2, and the experimental value is m / z = 361.2 [M+H]. + .

[0302] Intermediate 16 methyl 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-(2-methylphenoxy)piperidine-4-carboxylate

[0303] Step 1: Synthesis of 1-[(tert-butoxy)carbonyl]-4-(2-methylphenoxy)piperidine-4-carboxylic acid

[0304] o-Cresol (2.500 g, 23.11 mmol, 1.0 Equiv.) was dissolved in anhydrous THF (116 ml, 0.2 M). Powdered NaOH (4.624 g, 115.591 mmol, 5.0 eq) and 1-Boc-piperidin-4-one (13.819 g, 69.355 mmol, 3.0 Equiv.) were added to the solution at 0 °C. Chloroform (9.26 ml, 115.591 mmol, 5.0 Equiv.) was added dropwise, and the reaction mixture was stirred at 0 °C for 1 h, followed by stirring overnight at RT. The reaction mixture was diluted with water and ethyl acetate. The layers were separated, and the aqueous layer was extracted twice with ethyl acetate. The aqueous layer was acidified to pH 2 (using 1 M HCl) and extracted three times with ethyl acetate. The organic phase extracted from the acidic aqueous phase was dried with MgSO4, filtered, and the solvent was evaporated to produce 1-[(tert-butoxy)carbonyl]-4-(2-methylphenoxy)piperidine-4-carboxylic acid (0.612 g, 1.825 mmol, 8%), which was a yellow solid. 1 H NMR (DMSO- d 6): 12.86 (s, 1H), 7.18 (dd, J = 7.6, 1.8 Hz, 1H), 7.08 (td,J = 7.9, 1.8 Hz, 1H), 6.85 (td, J = 7.4, 1.0 Hz, 1H), 6.59 (d, J = 8.2 Hz,1H), 3.77 (d, J = 13.3 Hz, 2H), 3.15 - 2.86 (m, 2H), 2.23 (s, 3H), 2.11 (d, J= 13.5 Hz, 2H), 2.01 - 1.74 (m, 2H), 1.42 (d, J = 10.3 Hz, 9H).

[0305] Step 2: Synthesis of methyl 4-(2-methylphenoxy)piperidine-4-carboxylate hydrochloride

[0306] Thionyl chloride (0.293 mL, 4.014 mmol, 2.2 eq) was carefully added to a stirred solution of 1-[(tert-butoxy)carbonyl]-4-(2-methylphenoxy)piperidine-4-carboxylic acid (0.612 g, 1,825 mmol, 1 eq) in anhydrous methanol (6.08 mL, 0.3 M). The resulting solution was stirred under reflux overnight. It was then cooled to RT and the volatiles were evaporated to dryness. The residue was wet-milled with diethyl ether, filtered, washed with diethyl ether, collected, and dried under reduced pressure to give methyl 4-(2-methylphenoxy)piperidine-4-carboxylic acid hydrochloride (0.494 g, 1.711 mmol, 94%) as a brown solid. 1 H NMR (DMSO- d 6):9.01 (s, 2H), 7.23 (dd, J = 7.6, 1.8 Hz, 1H), 7.11 (td, J = 7.8, 1.8 Hz, 1H), 6.91 (td, J = 7.4, 1.0 Hz, 1H), 6.48 (dd, J = 8.2, 1.0 Hz, 1H), 3.75 (s, 3H), 3.23 (d, J = 13.0 Hz, 2H), 2.95 (s, 2H), 2.30 (t, J = 4.7 Hz, 4H), 2.27 (s, 3H).

[0307] Step 3: Synthesis of methyl 1-(6-chloropyridazine-4-yl)-4-(2-methylphenoxy)piperidine-4-carboxylate

[0308] A mixture of 3,5-dichloropyridazine (0.255 g, 1.711 mmol, 1.0 eq), methyl 4-(2-methylphenoxy)piperidine-4-carboxylate hydrochloride (0.494 g, 1.711 mmol, 1.0 eq), and anhydrous NMP (3.42 ml, 0.5 M) and N,N-diisopropylethylamine (0.894 ml, 5.134 mmol, 3.0 eq) was stirred at 100 °C for 1 h under argon atmosphere in a sealed vial. The reaction mixture was poured into cold water with vigorous stirring, the precipitate was filtered, washed with water, collected, and dried under reduced pressure to yield a grayish-white solid, methyl 1-(6-chloropyridazine-4-yl)-4-(2-methylphenoxy)piperidine-4-carboxylate (0.47 g, 1.234 mmol, 72%). 1 H NMR (DMSO- d6): 8.99 (d, J = 2.7 Hz, 1H), 7.21 (d, J = 7.3Hz, 1H), 7.16 - 7.05 (m, 2H), 6.89 (t, J = 7.4 Hz, 1H), 6.50 (d, J = 8.1 Hz,1H), 3.93 (d, J = 13.6 Hz, 2H), 3.74 (s, 3H), 3.22 (td, J = 13.4, 12.2, 3.4Hz, 2H), 2.24 (s, 3H), 2.21 - 2.05 (m, 4H).

[0309] Step 4: Synthesis of methyl 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-(2-methylphenoxy)piperidine-4-carboxylate

[0310] Methyl 1-(6-chloropyridazin-4-yl)-4-(2-methylphenoxy)piperidine-4-carboxylate (0.47 g, 1.234 mmol, 1.0 eq) was placed in a pressure vessel with K₂CO₃ (0.512 g, 3.70 mmol, 3.0 eq), 2-hydroxyphenylboronic acid (0.255 g, 1.851 mmol, 1.5 eq), and Pd(PPh₃)₄ (0.143 g, 0.1234 mmol, 0.1 eq), followed by the addition of dioxane (6.17 ml, 0.2 M) and water (1.23 ml, 1.0 M). Argon gas was bubbled through the mixture for 15 min. The reaction mixture was then stirred at 100 °C overnight. After cooling to RT, diatomaceous earth was added and the mixture was evaporated under reduced pressure to produce a dry loading for FC purification on silica gel (DCM - AcOEt 100:0 to 30:70) to produce methyl 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-(2-methylphenoxy)piperidine-4-carboxylate (0.292 g, 0.696 mmol, 56%) as a grayish-white solid. 1 H NMR (DMSO- d6): 14.54 (s, 1H), 8.98 (d, J = 2.9 Hz, 1H), 8.10 (dd, J = 8.4, 1.6 Hz, 1H), 7.59 (d, J = 2.9 Hz, 1H), 7.34 (td, J = 7.6,1.5 Hz, 1H), 7.24 - 7.18 (m, 1H), 7.13 (t, J = 7.7 Hz, 1H), 6.98 - 6.85 (m,3H), 6.53 (d, J = 8.2 Hz, 1H), 4.07 (t, J = 15.0 Hz, 2H), 3.75 (s, 3H), 3.26(s, 2H), 2.26(s, 3H), 2.16 (dd, J = 14.4, 4.2 Hz, 4H).

[0311] After alkaline hydrolysis, the title compound (0.185 g, 0.443 mmol, 62%) was obtained as a white solid. 1 HNMR (DMSO- d 6): 14.00 (s, 2H), 8.98 (d, J = 2.8 Hz, 1H), 8.11 (dd, J = 8.4,1.7 Hz, 1H), 7.59 (d, J = 2.9 Hz, 1H), 7.34 (td, J = 7.5, 1.6 Hz, 1H), 7.21(d, 1H), 7.14 (td, J = 7.8, 1.7 Hz, 1H), 6.93 - 6.83 (m, 3H), 6.66 (d, J =8.1 Hz, 1H), 4.10 (d, J = 13.6 Hz, 2H), 3.33 (s, 2H), 2.20 - 2.08 (m, 7H).

[0312] Intermediate 17 1-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-4-phenylpiperidine-4-carboxylic acid

[0313] Step 1: Synthesis of methyl 4-phenylpiperidine-4-carboxylate hydrochloride

[0314] Thionyl chloride (5.402 mL, 74.466 mmol, 1.8 eq) was carefully added to a stirred solution of 4-phenylpiperidine-4-carboxylate (10.0 g, 41.37 mmol, 1.0 eq) in anhydrous methanol (51.71 mL, 0.8 M) at 0 °C. The resulting solution was stirred under reflux overnight. It was then cooled to RT and the volatiles were evaporated. The obtained solid was wet-milled with MTBE and filtered. The solid was collected and dried under reduced pressure to give methyl 4-phenylpiperidine-4-carboxylate hydrochloride (10.5 g, 39.004 mmol, 94%) as a brown solid. LCMS (m / z): C 13 H 19 NO2 + [M+H] + Calculated value: 220.13, experimental value: 220.65. 1 H NMR (300 MHz, DMSO- d 6) δ 9.22 (d, J = 27.4 Hz, 2H), 7.46 - 7.28 (m, 5H), 3.64 (s, 3H), 3.23 (d, J = 13.0 Hz, 2H), 2.92 (q, J = 11.2 Hz, 2H), 2.55 (d, J = 13.8 Hz, 2H), 2.19 (ddd, J = 14.8, 11.5, 3.9 Hz, 2H).

[0315] Step 2: Synthesis of methyl 1-(6-chloropyridazine-4-yl)-4-phenylpiperidine-4-carboxylate

[0316] To a 500 mL pressure vial equipped with a magnetic stirrer, charge 3,5-dichloropyridazine (4.648 g, 31.203 mmol, 1.2 eq) and methyl 4-phenylpiperidin-4-carboxylate hydrochloride (7.0 g, 26.003 mmol, 1.0 eq). Add dimethyl sulfoxide (52.01 mL, 0.5 M) and... N , N -Diisopropylethylamine (DIPEA) (27.176 ml, 156.018 mmol, 6.0 eq). The reaction mixture was stirred overnight at 100 °C. DIPEA was evaporated and the compound was precipitated in water, followed by sonication, filtration, and drying to give methyl 1-(6-chloropyridazin-4-yl)-4-phenylpiperidin-4-carboxylate (8.5 g, 23.056 mmol, 89%) as a brown solid. LCMS (m / z): C17 H 19 ClN3O2 + [M+H] + Calculated value: 332.12, Experimental value: 333.40. 1 H NMR (300 MHz, DMSO- d 6) δ 8.99 (d, J = 2.7 Hz, 1H), 7.44 - 7.28(m, 5H), 7.12 (d, J = 2.7 Hz, 1H), 4.00 (dt, J = 14.1, 4.0 Hz, 2H), 3.65 (s, 3H), 3.23 - 3.07 (m, 4H), 1.94 (ddd, J = 13.6, 11.4, 4.0 Hz, 2H).

[0317] Step 3: Synthesis of methyl 1-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-4-phenylpiperidine-4-carboxylate

[0318] A 500 mL pressure flask equipped with a magnetic stirrer and an argon balloon was filled with 2-(methoxymethoxy)phenylboronic acid (1.54 g, 8.463 mmol, 1.2 eq) and methyl 1-(6-chloropyridazin-4-yl)-4-phenylpiperidin-4-carboxylate (2.6 g, 7.052 mmol, 1.0 eq). A solution of dioxane (70.52 mL, 0.1 M) and potassium carbonate (2.924 g, 21.157 mmol, 3.0 eq) in water (14.1 mL, 0.5 M) was added. Argon gas was bubbled through the mixture for 20 min, followed by the addition of tetra(triphenylphosphine)palladium (0.815 g, 0.705 mmol, 0.1 eq). The flask was purged with argon gas, then capped, and the reaction mixture was stirred at 100 °C for 7 h. The compound was purified by FC using MTBE / DCM (0 to 70%) to give methyl 1-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-4-phenylpiperidin-4-carboxylate (2.56 g, 5.787 mmol, 82%) as a yellow solid. LCMS (m / z): C 25 H 28 ClN3O4 + [M+H] + Calculated value: 434.21, Experimental value: 434.90. 1H NMR (300 MHz, DMSO- d 6) δ 8.98 (d, J = 3.1 Hz, 1H), 7.61 (dd, J =7.6, 1.8 Hz, 1H), 7.48 - 7.33 (m, 5H), 7.33 - 7.18 (m, 3H), 7.12 (td, J =7.4, 1.1 Hz, 1H), 5.20 (s, 2H), 3.96 (d, J = 13.7 Hz, 2H), 3.64 (s, 3H), 3.22- 3.03 (m, 2H), 2.55 (s, 2H), 2.05 - 1.86 (m, 2H).

[0319] After alkaline hydrolysis, the title compound (2.3 g, 5.318 mmol, 92%) was obtained as a grayish-white solid. LCMS (m / z): C 24 H 26 N3O4 + [M+H] + Calculated value: 420.19, Experimental value: 420.22. 1 H NMR (300 MHz, DMSO- d 6) δ 12.80 (s, 1H), 8.98 (d, J = 3.1 Hz, 1H), 7.61 (dd, J = 7.6, 1.8 Hz,1H), 7.45 - 7.32 (m, 5H), 7.31 - 7.21 (m, 3H), 7.12 (td, J = 7.4, 1.1 Hz, 1H), 5.20 (s, 2H), 3.97 (d, J = 13.6 Hz, 2H), 3.57 (s, 5H), 3.15 (t, J = 12.1Hz, 2H), 1.97 - 1.82 (m, 2H).

[0320] Intermediate 20 1-[6-(2-hydroxyphenyl)pyridazine-4-yl]-4-phenoxypiperidine-4-carboxylic acid

[0321] Step 1: Synthesis of 1-[(tert-butoxy)carbonyl]-4-phenoxypiperidine-4-carboxylic acid

[0322] Phenol (1.50 g, 15.938 mmol) was dissolved in anhydrous tetrahydrofuran (31.88 ml, 0.5 M) and cooled to 0 °C. Powdered NaOH (3.19 g, 79.69 mmol) and 1-Boc-piperidin-4-one (9.53 g, 47.82 mmol) were added, followed by dropwise addition of chloroform (6.38 ml, 79.69 mmol), and the resulting mixture was stirred at 0 °C for 1 h, then stirred overnight at room temperature. Once complete, the reaction mixture was diluted with water and extracted twice with ethyl acetate. The aqueous layer was acidified to pH = 2 (using 0.5 M HCl) and extracted with ethyl acetate (x2). The combined organic extracts from the acid washes were dried over magnesium sulfate, filtered, and evaporated. A crude product (2.11 g, 37%) as a yellow oil was obtained. LCMS: C 17 H 23 Theoretical value for NO5: 321.3; Experimental value: m / z = 322.1 [M+H] + .

[0323] 1 H NMR (300 MHz, DMSO-d6) δ 12.99 (s, 1H), 7.32 - 7.25 (m, 2H), 7.02 -6.94 (m, 1H), 6.90 - 6.84 (m, 2H), 3.75 - 3.65 (m, 2H), 3.14 - 2.99 (m, 2H), 2.04 (d, J = 13.9 Hz, 2H), 1.93 - 1.86 (m, 2H), 1.39 (s, 9H).

[0324] Step 2: Synthesis of 4-phenoxypiperidine-4-carboxylate

[0325] 1-[(tert-butoxy)carbonyl]-4-phenoxypiperidine-4-carboxylic acid (2.10 g, 5.89 mmol) was dissolved in anhydrous dichloromethane (58.95 mL, 0.1 M), and 4 M HCl was added to a solution in dioxane (73.69 mL, 294.7 mmol). The resulting solution was stirred at room temperature for 72 h. Once complete, the solvent was removed under reduced pressure to give 1.59 g, 92%, a brown solid of 4-phenoxypiperidine-4-carboxylic acid salt. LCMS: C 12 H 15 Theoretical value of NO3: 221.7, experimental value: m / z = 222.1 [M+H]+.

[0326] NMR (300 MHz, DMSO-d6) δ 13.65 (s, 1H), 9.13 (d, J = 21.6 Hz, 2H), 7.36 - 7.27 (m, 2H), 7.05 - 6.98 (m, 1H), 6.93 - 6.86 (m, 2H), 3.19 (d, J =12.4 Hz, 2H), 3.06 - 2.93 (m, 2H), 2.27 - 2.18 (m, 4H).

[0327] Step 3: Synthesis of 1-(6-chloropyridazine-4-yl)-4-phenoxypiperidine-4-carboxylic acid

[0328] To a solution of 3,5-dichloropyridazine (1.72 g, 11.59 mmol) in anhydrous dimethylformamide (23.19 ml, 0.2 M), 4-phenoxypiperidine-4-carboxylic acid salt (1.44 g, 4.638 mmol) and DIPEA (4.85 ml, 23.83 mmol) were added. The resulting mixture was stirred at 100 °C for 3 h. Once complete, the reaction mixture was quenched with citric acid to pH 5 and extracted three times with dichloromethane. The organic phase was dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by rapid chromatography (DCM / MeOH, 100:0 to 90:10) to give 1-(6-chloropyridazine-4-yl)-4-phenoxypiperidine-4-carboxylic acid (824 mg, 48%) as a brown powder. LCMS: C 16 H 16 The theoretical value of ClN3O3 is 333.7, and the experimental value is: m / z = 333.8 [M+H]+.

[0329] 1H NMR (300 MHz, DMSO-d6) δ 13.43 (s, 1H), 8.97 (d, J = 2.7 Hz, 1H), 7.30 (tt, J = 7.4, 2.4 Hz, 2H), 7.11 (d, J = 2.7 Hz, 1H), 7.04 - 6.97 (m,1H), 6.93 - 6.86 (m, 2H), 3.86 (d, J = 13.9 Hz, 2H), 3.32 - 3.24 (m, 2H), 2.16 - 2.04 (m, 4H).

[0330] Step 4: Synthesis of 1-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-4-phenoxypiperidine-4-carboxylic acid

[0331] 2-(methoxymethoxy)phenylboronic acid (0.565 g, 3.11 mmol), 1-(6-chloropyridazin-4-yl)-4-phenoxypiperidine-4-carboxylic acid (0.768 g, 2.07 mmol), anhydrous K₂CO₃ (0.859 g, 6.21 mmol), and tetrakis(triphenylphosphine)palladium (0.239 g, 0.207 mmol) were added to a sealed container under an argon atmosphere. Dioxane (20.71 mL) and H₂O (4.14 mL) were added sequentially, and the resulting solution was degassed using an argon balloon for 5 minutes. The mixture was stirred overnight at 100 °C. Once complete, the solvent was removed under reduced pressure, and the residue was purified by rapid chromatography (DCM / MeOH, 98:02 to 85:15) to give 1-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-4-phenoxypiperidine-4-carboxylic acid (503 mg, 54%). LCMS: C 24 H 25 The theoretical value of N3O5 is 435.4, and the experimental value is: m / z = 436.5 [M+H]+.

[0332] 1 H NMR (300 MHz, DMSO-d6) δ 13.68 (s, 1H), 8.97 (d, J = 3.0 Hz, 1H), 7.62 (dd, J = 7.6, 1.8 Hz, 1H), 7.41 (ddd, J = 9.0, 7.3, 1.8 Hz, 1H), 7.33 -7.21 (m, 4H), 7.12 (td, J = 7.4, 1.1 Hz, 1H), 6.98 (t, J = 7.4 Hz, 1H), 6.91(d, J = 7.9 Hz, 2H), 5.20 (s, 2H), 3.84 (d, J = 13.4 Hz, 2H), 3.31 (s, 5H), 2.16 - 2.02 (m, 4H).

[0333] Step 5: Synthesize the title compound 1-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-4-phenoxypiperidine-4-carboxylic acid (0.346 g, 0.763 mmol) was dissolved in anhydrous dichloromethane (7.63 mL, 0.1 M), and trifluoroacetic acid (2.92 mL, 38.14 mmol) was added dropwise. The resulting solution was stirred overnight at room temperature. Once complete, the solvent was removed under reduced pressure, and the residue was purified by RP-FC to give the title compound (120 mg, 29%) in the form of a trifluoroacetate salt.

[0334] 1 H NMR (300 MHz, DMSO-d6) δ 13.63 (s, 2H), 8.98 (d, J = 2.9 Hz, 1H), 7.86 (d, J = 7.9 Hz, 1H), 7.56 (d, J = 3.0 Hz, 1H), 7.42 - 7.29 (m, 3H), 7.05- 6.90 (m, 5H), 4.11 (d, J = 13.6 Hz, 2H), 3.52 - 3.41 (m, 2H), 2.23 - 2.12 (m, 4H).

[0335] Intermediate 21 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-[(1-methyl-1H-pyrazol-3-yl)oxy]piperidine-4-carboxylic acid

[0336] Step 1: Synthesis of 1-[(tert-butoxy)carbonyl]-4-[(1-methyl-1H-pyrazol-3-yl)oxy]piperidine-4-carboxylic acid

[0337] A solution of 2-methyl-1H-pyrazole-5-one (3.0 g, 30.58 mmol) in anhydrous tetrahydrofuran (152.9 ml, 0.2 M) was cooled to 0 °C and powdered NaOH (6.116 g, 152.89 mmol) and 1-Boc-piperidin-4-one (18.279 g, 91.738 mmol, 3.0 eq) were added sequentially. Anhydrous chloroform (12.249 ml, 152.897 mmol, 5.0 eq) was added dropwise to the solution and the resulting mixture was stirred overnight at room temperature. Once complete, the reaction mixture was diluted with water and extracted twice with ethyl acetate. The aqueous layer was acidified to pH = 2 (using 0.5 M HCl) and extracted with ethyl acetate (x2). The combined organic extracts from the acid washes were dried over magnesium sulfate, filtered, and evaporated. A crude product (3.60 g, 36%) as a yellow oil was obtained. LCMS: C 15 H 23 The theoretical value of N3O5 is 325.1, and the experimental value is: m / z = 326.4 [M+H]+.

[0338] 1H NMR (300 MHz, DMSO-d6) δ 12.83 (s, 1H), 7.45 (d, J = 2.3 Hz, 1H), 5.62 (d, J = 2.3 Hz, 1H), 3.73 (dt, J = 13.6, 3.7 Hz, 2H), 3.63 (s, 3H), 3.05(s, 2H), 2.13 (d, J = 13.9 Hz, 2H), 1.83 (ddd, J = 14.0, 11.6, 4.7 Hz, 2H), 1.41 (s, 9H).

[0339] Step 2: Synthesis of methyl 4-[(1-methyl-1H-pyrazol-3-yl)oxy]piperidine-4-carboxylate hydrochloride

[0340] A solution of 1-[(tert-butoxy)carbonyl]-4-[(1-methyl-1H-pyrazol-3-yl)oxy]piperidine-4-carboxylic acid (3.6 g, 11.06 mmol) in MeOH (110.64 mL, 0.1 M) was cooled to 0 °C and SOCl2 (2.40 mL, 33.19 mmol) was added dropwise. The resulting solution was stirred under reflux overnight. Once complete, the reaction mixture was cooled to room temperature and the volatiles were evaporated. The solid obtained was wet-milled with MTBE and filtered. The solid was collected and dried under reduced pressure to give methyl 4-[(1-methyl-1H-pyrazol-3-yl)oxy]piperidine-4-carboxylic acid hydrochloride (2.88 g, 94%). LCMS: C 11 H 17 Theoretical value of N3O3: 239.1, experimental value: m / z = 240.2 [M+H]+.

[0341] 1H NMR (300 MHz, DMSO-d6) δ 9.53 (s, 2H), 7.49 (d, J = 2.3 Hz, 1H), 5.65 (d, J = 2.3 Hz, 1H), 3.66 (s, 3H), 3.62 (s, 3H), 3.23 - 3.14 (m, 2H), 3.08 - 2.89 (m, 2H), 2.35 - 2.15 (m, 4H).

[0342] Step 3: Synthesis of methyl 1-(6-chloropyridazin-4-yl)-4-[(1-methyl-1H-pyrazol-3-yl)oxy]piperidine-4-carboxylate

[0343] N,N-diisopropylethylamine (10.9 ml, 62.67 mmol) was added to a stirred solution of 4-[(1-methyl-1H-pyrazol-3-yl)oxy]piperidine-4-carboxylate hydrochloride (2.88 g, 10.44 mmol) in DMSO (52.23 ml, 0.2 M), followed by the addition of 3,5-dichloropyridazine (1.71 g, 11.49 mmol). The reaction mixture was stirred overnight at 100 °C. Once complete, excess DIPEA was removed under reduced pressure. Cold water was added to the solution and the mixture was sonicated for 15 min. The resulting solid was filtered to give methyl 1-(6-chloropyridazine-4-yl)-4-[(1-methyl-1H-pyrazol-3-yl)oxy]piperidine-4-carboxylate (3.63 g, 10.319 mmol). LCMS: C 15 H 18 The theoretical value of ClN5O3 is 351.1, and the experimental value is: m / z = 352.3 [M+H]+.

[0344] 1H NMR (300 MHz, DMSO-d6) δ 8.98 (d, J = 2.7 Hz, 1H), 7.48 (d, J =2.3 Hz, 1H), 7.12 (d, J = 2.7 Hz, 1H), 5.64 (d, J = 2.3 Hz, 1H), 3.91 (d, J =13.5 Hz, 2H), 3.65 (s, 3H), 3.64 (s, 3H), 3.26 (d, J = 11.1 Hz, 2H), 2.22 (d,J = 14.1 Hz, 2H), 2.10 - 1.94 (m, 2H).

[0345] Step 4: Synthesis of methyl 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-[(1-methyl-1H-pyrazol-1-yl)oxy]piperidine-4-carboxylate

[0346] Methyl 1-(6-chloropyridazin-4-yl)-4-[(1-methyl-1H-pyrazol-3-yl)oxy]piperidine-4-carboxylate (2.0 g, 5.685 mmol, 1.0 eq), K₂CO₃ (2.357 g, 17.056 mmol, 3.0 eq), and 2-hydroxyphenylboronic acid (0.863 g, 6.254 mmol, 1.1 eq) were added to a sealed container under an argon atmosphere. Dioxane (28.43 ml, 0.2 M) and water (5.69 ml, 1.0 M) were added sequentially, and the resulting solution was degassed using an argon balloon for 15 min. Tetra(triphenylphosphine)palladium (0.657 g, 0.569 mmol, 0.1 eq) was then added to the mixture, and the resulting solution was stirred at 100 °C for 16 h. Once complete, the solvent was evaporated and the crude mixture was purified by rapid chromatography (DCM / MeOH, 98:02 to 85:15) to give methyl 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-[(1-methyl-1H-pyrazol-1-yl)oxy]piperidine-4-carboxylate (1.1 g, 42%) as a yellow solid. LCMS: C 21 H 23 The theoretical value of N5O4 is 409.4, and the experimental value is: m / z = 410.4 [M+H]+.

[0347] 1H NMR (300 MHz, DMSO-d6) 1H NMR δ 14.57 (s, 1H), 8.98 (d, J = 2.8Hz, 1H), 8.12 (dd, J = 8.4, 1.7 Hz, 1H), 7.70 - 7.53 (m, 4H), 7.50 (d, J =2.3 Hz, 1H), 7.34 (ddd, J = 8.4, 7.3, 1.6 Hz, 1H), 6.98 - 6.87 (m, 2H), 5.67(d, J = 2.3 Hz, 1H), 4.16 - 3.97 (m, 2H), 3.67 (s, 3H), 3.45 - 3.29 (m, 3H),2.28 (d, J = 14.0 Hz, 2H), 2.08 (ddd, J = 14.4, 11.2, 4.3 Hz, 2H).

[0348] After alkaline hydrolysis, the title compound (0.116 g, 12%) was obtained as a grayish-white solid. LCMS: C 20 H 21 The theoretical value of N5O4 is 395.4, and the experimental value is: m / z = 396.2 [M+H]+.

[0349] 1H NMR (300 MHz, DMSO-d6) δ 13.76 (s, 1H), 8.98 (d, J = 2.8 Hz, 1H), 8.12 (dd, J = 8.4, 1.7 Hz, 1H), 7.59 (d, J = 2.9 Hz, 1H), 7.49 (d, J = 2.3Hz, 1H), 7.34 (td, J = 7.6, 1.6 Hz, 1H), 6.99 - 6.87 (m, 2H), 5.67 (d, J =2.3 Hz, 1H), 4.14 - 4.03 (m, 2H), 3.66 (s, 3H), 3.43 - 3.34 (m, 2H), 2.34 -2.23 (m, 2H), 2.07 (ddd, J = 15.1, 11.4, 4.3 Hz, 2H).

[0350] Intermediate 22 4-Cyclopropoxy-1-[6-(2-hydroxyphenyl)pyridazin-4-yl]piperidine-4-carboxylic acid

[0351] Step 1: Synthesis of benzyl 4-cyclopropoxy-4-(hydroxymethyl)piperidine-1-carboxylate

[0352] Benzyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (5.41 g, 21.86 mmol) and cyclopropanol (28.14 g, 484 mmol) were packed into a flask under an argon atmosphere. The mixture was cooled to 15°C using an ice-water bath. Boron trifluoride diethyl ether (6.887 g, 48.53 mmol) was then added dropwise while maintaining the bath temperature at 15°C. After the addition was complete, the cooling bath was removed and stirring was continued for 1 h. DCM was added, followed by slow addition of water. The contents were transferred to a separatory funnel and the layers were separated. The aqueous layer was washed three times with DCM and the combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by RP-FC column chromatography to give benzyl 4-cyclopropoxy-4-(hydroxymethyl)piperidine-1-carboxylate (3.07, 46%) as a colorless oil. LCMS: C 17 H 23 Theoretical value of NO4: 305.3, experimental value: m / z = 306.6 [M+H]+.

[0353] 1 H NMR (300 MHz, DMSO- d 6) 7.42 - 7.29 (m, 5H), 5.07 (s, 2H), 4.63 (t,J = 5.5 Hz, 1H), 3.71 (dt, J = 13.2, 4.2 Hz, 2H), 3.48 (d, J = 5.5 Hz, 2H), 3.27 (tt, J = 6.2, 3.1 Hz, 1H), 3.09 (s, 2H), 1.75 - 1.63 (m, 2H), 1.47 (ddd,J = 13.8, 11.4, 4.6 Hz, 2H), 0.52 - 0.36 (m, 4H).

[0354] Step 2: Synthesis of 4-cyclopropoxy-4-formylpiperidine-1-carboxylic acid benzyl ester

[0355] 95% Dys-Martin periodane (5.543 g, 13.069 mmol) was added to a stirred solution of 4-cyclopropoxy-4-(hydroxymethyl)piperidine-1-carboxylate (3.07 g, 10.05 mmol) in dichloromethane (50.27 ml, 0.2 M), and the resulting mixture was stirred at room temperature for 2 h. Once complete, DCM (50 mL) and water (50 M) were added, followed by a saturated aqueous solution of Na₂S₂O₃ (50 mL), and the mixture was stirred for 15 min. The contents were transferred to a separatory funnel and the layers were separated. The aqueous layer was washed twice with DCM, and the combined organic layer was washed with brine. The organic layer was collected, dried over Na₂SO₄, filtered, and concentrated under vacuum to give a colorless oily 4-cyclopropoxy-4-formylpiperidine-1-carboxylate (2.73 g, 81%). LCMS: C 17 H 21 Theoretical value of NO4: 303.3, experimental value: m / z = 304.2 [M+H]+.

[0356] 1H NMR (300 MHz, DMSO-d6) 9.58 (s, 1H), 7.42 - 7.32 (m, 5H), 5.08 (s,2H), 3.69 (dt, J = 13.5, 4.6 Hz, 2H), 3.32 - 3.14 (m, 3H), 1.87 - 1.76 (m,2H), 1.67 (ddd, J = 14.3, 10.4, 4.5 Hz, 2H), 0.58 - 0.44 (m, 4H).

[0357] Step 3: Synthesis of 1-[(benzyloxy)carbonyl]-4-cyclopropoxypiperidine-4-carboxylic acid

[0358] 4-Cyclopropoxy-4-formylpiperidine-1-carboxylate (2.73 g, 8.09 mmol) and potassium dihydrogen phosphate (3.30 g, 24.29 mmol) were packed into a flask. Then, tert-butanol (80.99 ml), water (20.25 ml), and 2-methyl-2-butene (10.297 ml, 97.19 mmol) were added sequentially. Sodium chlorite (2.75 g, 24.29 mmol) was added, and the reaction mixture was stirred at room temperature for 2 h. Once complete as determined by LCMS, the reaction mixture was diluted with DCM and the pH was adjusted to approximately 12 using 1 M NaOH. The contents were transferred to a separatory funnel, and the layers were separated. The aqueous layer was then acidified to approximately pH 2 with 1 M HCl and extracted three times with EtOAc. The combined organic layers were dried over Na₂SO₄, filtered, and evaporated to give 1-[(benzyloxy)carbonyl]-4-cyclopropoxypiperidine-4-carboxylic acid (1.76 g, 65% yield) as a colorless oil. LCMS: C 17 H 21 Theoretical value of NO5: 318.3, experimental value: m / z = 319.3 [M+H]+.

[0359] 1 H NMR (300 MHz, DMSO- d 6) 12.80 (s, 1H), 7.41 - 7.29 (m, 5H), 5.08 (s,2H), 3.60 (dt, J = 13.4, 4.6 Hz, 2H), 3.30 - 3.16 (m, 3H), 1.91 - 1.79 (m,4H), 0.59 - 0.37 (m, 4H).

[0360] Step 4: 4-Cyclopropoxypiperidine-1,4-dicarboxylic acid 1-benzyl ester 4-methyl ester

[0361] Trimethylsilyl)diazomethane (2 M in hexane) (17.02 ml, 34.03 mmol) was added dropwise to a cooled (10°C) solution of 1-[(benzyloxy)carbonyl]-4-cyclopropoxypiperidine-4-carboxylic acid (1.76 g, 5.24 mmol) in methanol (20.94 ml, 0.25 M). Addition continued until a pale yellow color remained in the solution. The cooling bath was then removed and the reaction mixture was stirred at room temperature for 1 h. Once complete, acetic acid was added dropwise until the yellow color disappeared and the solution became colorless. The residual solvent was evaporated and the residue was purified by chromatography (hexane / MTBE, 100:0 to 75:25) to give a colorless oily 4-cyclopropoxypiperidine-1,4-dicarboxylic acid 1-benzyl ester 4-methyl ester (1.39 g, 79%). LCMS: C 18 H 23 Theoretical value of NO5: 333.3, experimental value: m / z = 334.2 [M+H]+.

[0362] 1 H NMR (300 MHz, DMSO- d 6) 7.42 - 7.29 (m, 5H), 5.08 (s, 2H), 3.70 (s,3H), 3.64 - 3.53 (m, 2H), 3.30 - 3.19 (m, 3H), 1.96 - 1.79 (m, 4H), 0.52 -0.38 (m, 4H).

[0363] Step 5: Synthesis of methyl 4-cyclopropoxypiperidine-4-carboxylate

[0364] 1.29 g (3.90 mmol) of 1-benzyl 4-methyl 4-cyclopropoxypiperidine-1,4-dicarboxylic acid was dissolved in 37 ml (0.02 M) of THF in a 250 ml three-necked RBF equipped with argon and hydrogen balloons. The reaction mixture was degassed with argon and Pd / C (10 wt%; 0.62 g, 5.8 mmol) was added, followed by further degassed with argon and filling with hydrogen. The reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered through a diatomaceous earth mat and evaporated to dryness to provide methyl 4-cyclopropoxypiperidine-4-carboxylic acid (0.78 g, 96%) as a gray solid.

[0365] 1 H NMR (300 MHz, DMSO- d6) δ 3.68 (s, 3H), 3.22 - 3.17 (m, 1H), 2.81 -2.68 (m, 2H), 2.63 - 2.53 (m, 2H), 1.92 - 1.81 (m, 2H), 1.76 - 1.62 (m, 2H), 0.51 - 0.33 (m, 4H).

[0366] Step 6: Synthesis of methyl 1-(6-chloropyridazine-4-yl)-4-cyclopropoxypiperidine-4-carboxylate

[0367] A mixture of 3,5-dichloropyridazine (0.55 g, 3.72 mmol), methyl 4-cyclopropoxypiperidine-4-carboxylate (0.78 g, 3.72 mmol), N-methyl-2-pyrrolidone (7.44 ml, 0.5 M), and N,N-diisopropylethylamine (1.9 ml, 11.16 mmol) was stirred for 1 h at 100 °C in a sealed vial under argon atmosphere. Once complete, the reaction mixture was quenched with cold water and extracted three times with ethyl acetate. The combined organic extracts, dried over Na₂SO₄, were filtered and concentrated under vacuum to give methyl 1-(6-chloropyridazine-4-yl)-4-cyclopropoxypiperidine-4-carboxylate (1.4 g, 87%) as a viscous brown solid, which was used in the next step without further purification. LCMS: C 14 H 18 The theoretical value of ClN3O3 is 311.7, and the experimental value is: m / z = 313.0 [M+H]+.

[0368] 1 H NMR (300 MHz, DMSO- d 6) δ 8.97 (d, J = 2.7 Hz, 1H), 7.11 (d, J = 2.7Hz, 1H), 3.71 (s, 3H), 3.45 - 3.36 (m, 1H), 2.22 - 2.14 (m, 2H), 1.99 - 1.86(m, 6H), 0.53 - 0.38 (m, 4H).

[0369] Step 7: Synthesis of methyl 4-cyclopropoxy-1-[6-(2-hydroxyphenyl)pyridazin-4-yl]piperidine-4-carboxylate

[0370] Methyl 1-(6-chloropyridazine-4-yl)-4-cyclopropoxypiperidine-4-carboxylate (1.4 g, 3.59 mmol) was added to a pressure vessel containing K₂CO₃ (1.49 g, 10.78 mmol) and 2-hydroxyphenylboronic acid (0.74 g, 5.39 mmol). Dioxane (18.0 ml, 0.2 M) and H₂O (3.6 ml, 1.0 M) were added, and the resulting mixture was degassed with an argon balloon for 15 min. Tetra(triphenylphosphine)palladium (0.415 g, 0.359 mmol, 0.1 eq) was added to the reaction mixture, and the solution was stirred at 100 °C for 18 h. Once complete, the reactants were concentrated under vacuum and the residue was purified by chromatography (hexane / EtOAc, 0-100%) to provide methyl 4-cyclopropoxy-1-[6-(2-hydroxyphenyl)pyridazin-4-yl]piperidine-4-carboxylate as a yellow solid (0.58 g, 44% yield). LCMS: C 20 H 23 The theoretical value of N3O4 is 369.4, and the experimental value is: m / z = 370.7 [M+H]+.

[0371] 1 H NMR (300 MHz, DMSO-d6) δ 14.58 (s, 1H), 8.97 (d, J = 2.8 Hz, 1H), 8.11 (dd, J = 8.4, 1.7 Hz, 1H), 7.58 (d, J = 2.9 Hz, 1H), 7.43 - 7.18 (m,1H), 7.01 - 6.84 (m, 2H), 3.91 - 3.78 (m, 2H), 3.72 (s, 3H), 3.56 - 3.43 (m,2H), 3.31 - 3.26 (m, 1H), 2.02 (t, J = 5.6 Hz, 4H), 0.57 - 0.41 (m, 4H).

[0372] After alkaline hydrolysis, the title compound (468.4 mg, 82%) was obtained as a grayish-white solid. LCMS: C 19 H 21 The theoretical value of N3O4 is 355.3, and the experimental value is: m / z = 356.3 [M+H]+.

[0373] 1H NMR (300 MHz, DMSO-d6) δ 13.57 (s, 2H), 8.96 (d, J = 2.8 Hz, 1H), 8.11 (dd, J = 8.4, 1.7 Hz, 1H), 7.57 (d, J = 2.9 Hz, 1H), 7.34 (ddd, J = 8.5,7.2, 1.6 Hz, 1H), 6.99 - 6.84 (m, 2H), 3.90 - 3.77 (m, 2H), 3.54 - 3.43 (m,2H), 2.00 (t, J = 5.6 Hz, 4H), 0.61 - 0.40 (m, 4H).

[0374] Intermediate 23 4-(cyclohexyloxy)-1-[6-(2-hydroxyphenyl)pyridazin-4-yl]piperidine-4-carboxylic acid

[0375] Step 1: Synthesis of benzyl 4-(cyclohexyloxy)-4-(hydroxymethyl)piperidine-1-carboxylate

[0376] A solution of 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (6.0 g, 24.26 mmol) in cyclohexanol (50.523 ml, 485.252 mmol, 20.0 eq) was cooled to +15 °C, followed by dropwise addition of boron trifluoride diethyl ether (6.88 g, 48.525 mmol, 2.0 eq). After the addition was complete, the cooling bath was removed and stirring was continued for 1 h. DCM was added, followed by water slowly. The contents were transferred to a separatory funnel and the layers were separated. The aqueous layer was washed three times with DCM. The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by RP-FC column (330 g column, 80 mL flow rate, water / MeCN + 0.1% FA, gradient 95:5 to 35:65) to give benzyl 4-(cyclohexyloxy)-4-(hydroxymethyl)piperidine-1-carboxylate (3.68 g, 44%) as a colorless oil. LCMS: C 20 H 29 Theoretical value of NO4: 347.2, experimental value: m / z = 349.0 [M+H]+.

[0377] 1H NMR (300 MHz, DMSO-d6) δ 7.44 - 7.26 (m, 6H), 5.07 (s, 2H), 4.62(t, J = 5.2 Hz, 1H), 3.77 - 3.67 (m, 2H), 3.55 (br s, 1H), 3.15 (br s, J =19.2 Hz, 2H), 1.75 - 1.61 (m, 4H), 1.61 - 1.38 (m, 6H), 1.28 - 1.17 (m, 4H).

[0378] Step 2: Synthesis of 4-(cyclohexyloxy)-4-formylpiperidine-1-carboxylic acid benzyl ester

[0379] 95% Dys-Martin periodane (5.84 g, 13.76 mmol) was added to a stirred solution of 4-(cyclohexyloxy)-4-(hydroxymethyl)piperidine-1-carboxylate (3.68 g, 10.59 mmol) in dichloromethane (106 ml, 0.1 M), and the resulting mixture was stirred at room temperature for 2 h. Once complete, DCM (50 mL) and water (50 M) were added, followed by a saturated aqueous solution of Na₂S₂O₃ (50 mL), and the mixture was stirred for 15 min. The contents were transferred to a separatory funnel and the layers were separated. The aqueous layer was washed twice with DCM, and the combined organic layer was washed with brine. The organic layer was collected, dried over Na₂SO₄, filtered, and concentrated under vacuum to give a colorless oily 4-(cyclohexyloxy)-4-carboxylate (3.65 g, 100%). LCMS: C 20 H 27 Theoretical value of NO4: 345.1, experimental value: m / z = 346.2 [M+H]+.

[0380] 1 H NMR (300 MHz, DMSO-d6) δ 9.57 (s, 1H), 7.42 - 7.27 (m, 5H), 5.08(s, 2H), 3.71 (dt, J = 13.5, 4.5 Hz, 2H), 3.20 (d, J = 11.3 Hz, 2H), 1.81 -1.54 (m, 8H), 1.52 - 1.42 (m, 1H), 1.36 - 1.09 (m, 5H).

[0381] Step 3: Synthesis of 1-[(benzyloxy)carbonyl]-4-(cyclohexyloxy)piperidine-4-carboxylic acid

[0382] Benzyl 4-(cyclohexyloxy)-4-formylpiperidin-1-carboxylate (3.65 g, 10.56 mmol) and potassium dihydrogen phosphate (4.31 g, 31.69 mmol) were packed into a flask. Then, tert-butanol (106 ml), water (26 ml), and 2-methyl-2-butene (13.43 ml, 126.8 mmol) were added sequentially. Sodium chlorite (3.58 g, 31.69 mmol) was added, and the reaction mixture was stirred at room temperature for 2 h. Once complete as determined by LCMS, the reaction mixture was diluted with DCM and the pH was adjusted to approximately 12 using 1 M NaOH. The contents were transferred to a separatory funnel, and the layers were separated. The aqueous layer was then acidified to approximately pH 2 with 1 M HCl and extracted three times with EtOAc. The combined organic layers were dried over Na₂SO₄, filtered, and evaporated to obtain 1-[(benzyloxy)carbonyl]-4-(cyclohexyloxy)piperidine-4-carboxylic acid (0.77 g, 17%) containing 14 wt% tert-butanol. LCMS: C 20 H 27 Theoretical value of NO5: 361.0, experimental value: m / z = 362.2 [M+H]+.

[0383] 1H NMR (300 MHz, DMSO-d6) δ 12.81 (s, 1H), 7.44 - 7.24 (m, 5H), 5.07(s, 2H), 3.67 - 3.56 (m, 2H), 1.77 (t, J = 5.8 Hz, 6H), 1.65 (d, J = 5.2 Hz, 2H), 1.50 - 1.38 (m, 1H), 1.35 - 1.14 (m, 6H), 1.12 (s, 9H).

[0384] Step 4: Synthesis of 4-(cyclohexyloxy)piperidine-1,4-dicarboxylic acid 1-benzyl ester 4-methyl ester

[0385] Trimethylsilyl)diazomethane (2 M in hexane) (5.95 ml, 11.91 mmol) was added dropwise to a cooled (10 °C) solution of 1-[(benzyloxy)carbonyl]-4-(cyclohexyloxy)piperidine-4-carboxylic acid (0.77 g, 1.83 mmol) in methanol (7.33 ml, 0.25 M). Addition continued until a pale yellow color remained in the solution. The cooling bath was then removed and the reaction mixture was stirred at room temperature for 1 h. Once complete, acetic acid was added dropwise until the yellow color disappeared and the solution became colorless. The residual solvent was evaporated and the residue was purified by chromatography (hexane / MTBE, 100:0 to 75:25) to give a colorless oily 4-(cyclohexyloxy)piperidine-1,4-dicarboxylic acid 1-benzyl ester 4-methyl ester (0.64 g, 93%).

[0386] 1 H NMR (300 MHz, DMSO-d6) δ 7.41 - 7.27 (m, 5H), 5.07 (s, 2H), 3.67(s, 3H), 3.66 - 3.56 (m, 2H), 3.38 (m, 1H), 3.25 (br, 2H), 1.80 (t, J = 4.5Hz, 4H), 1.76 - 1.59 (m, 4H), 1.45 (d, J = 10.7 Hz, 1H), 1.31 - 1.10 (m, 5H).

[0387] Step 5: Synthesis of methyl 4-(cyclohexyloxy)piperidine-4-carboxylate

[0388] 4-(cyclohexyloxy)piperidine-1,4-dicarboxylic acid 1-benzyl ester 4-methyl ester (0.64 g, 1.70 mmol) was dissolved in THF (17 ml) in a 100 ml three-necked RBF equipped with argon and hydrogen balloons. The reaction mixture was degassed with argon and Pd / C (10 wt%; 0.18 g, 0.17 mmol) was added, followed by degassed again with argon and filled with hydrogen. The reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered through a diatomaceous earth mat and evaporated to dryness to provide 4-(cyclohexyloxy)piperidine-4-carboxylic acid methyl ester (0.4 g, 92%) as a black solid.

[0389] 1¹H NMR (300 MHz, chloroform-d) δ 4.04 - 3.89 (m, 1H), 3.75 (s, 3H), 3.38 - 3.16 (m, 4H), 2.26 - 2.17 (m, 2H), 2.01 - 1.92 (m, 2H), 1.73 (d, J = 11.9 Hz, 5H), 1.27 (dd, J = 24.7, 13.7 Hz, 6H).

[0390] Step 6: Synthesis of methyl 1-(6-chloropyridazine-4-yl)-4-(cyclohexyloxy)piperidine-4-carboxylate

[0391] A mixture of 3,5-dichloropyridazine (0.25 g, 1.73 mmol), methyl 4-(cyclohexyloxy)piperidine-4-carboxylate (0.40 g, 1.56 mmol), and N,N-diisopropylethylamine (1.65 ml, 9.45 mmol) in DMSO was stirred at 100 °C for 1 h in a sealed vial under argon atmosphere. Once complete, the reaction mixture was quenched with cold water and extracted three times with ethyl acetate. The combined organic extracts, dried over Na₂SO₄, were filtered and concentrated under vacuum to give methyl 1-(6-chloropyridazine-4-yl)-4-(cyclohexyloxy)piperidine-4-carboxylate (0.50 g, 89%) as a viscous brown solid, which was used in the next step without further purification. LCMS: C 17 H 24 The theoretical value of ClN3O3 is 353.1, and the experimental value is: m / z = 354.2 [M+H]+.

[0392] 1 H NMR (300 MHz, DMSO-d6) δ 8.96 (d, J = 2.7 Hz, 1H), 7.10 (d, J =2.7 Hz, 1H), 3.72 (d, J = 4.7 Hz, 1H), 3.68 (s, 4H), 3.39 (td, J = 8.8, 4.2Hz, 3H), 1.90 (q, J = 4.5 Hz, 4H), 1.75 - 1.59 (m, 4H), 1.23 (q, J = 11.5,10.8 Hz, 6H).

[0393] Step 7: Synthesis of methyl 4-(cyclohexyloxy)-1-{6-[2-(methoxymethoxy)phenyl]pyridazine-4-yl}piperidine-4-carboxylate

[0394] Under an argon atmosphere, a sealed vial was filled with tetrakis(triphenylphosphine)palladium (0.162 g, 0.14 mmol), 2-(methoxymethoxy)phenylboronic acid (0.31 g, 1.67 mmol), and methyl 1-(6-chloropyridazin-4-yl)-4-(cyclohexyloxy)piperidine-4-carboxylate (0.5 g, 1.39 mmol). 1,4-Dioxane (13.99 ml, 0.1 M) was added, followed by K₂CO₃ (0.112 g, 0.814 mmol) dissolved in H₂O (2.8 ml, 0.5 M). Argon gas was bubbled through the mixture for 20 min, the vial was sealed, and the mixture was stirred at 100 °C for 16 h. Once complete, the solvent was evaporated, and the residue was purified by chromatography (EtOAc / hexane, 0 to 100%) to give methyl 4-(cyclohexyloxy)-1-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}piperidine-4-carboxylate (0.52 g, 79%) as a pale yellow solid. LCMS: C 25 H 33 Theoretical value of N3O5: 455.2, experimental value: m / z = 456.9 [M+H]+.

[0395] 1 H NMR (300 MHz, DMSO-d6) δ 8.96 (d, J = 3.1 Hz, 1H), 7.62 (dd, J = 7.6,1.8 Hz, 1H), 7.42 (ddd, J = 9.0, 7.4, 1.8 Hz, 1H), 7.27 - 7.19 (m, 2H), 7.12(td, J = 7.5, 1.1 Hz, 1H), 5.20 (s, 2H), 3.67 (s, 5H), 3.40 (d, J = 9.5 Hz,3H), 1.99 - 1.81 (m, 4H), 1.68 (d, J = 11.5 Hz, 4H), 1.45 (d, J = 11.2 Hz,1H), 1.21 (d, J = 20.7 Hz, 6H).

[0396] Step 8: Synthesis of 4-(cyclohexyloxy)-1-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}piperidine-4-carboxylic acid

[0397] Methyl 4-(cyclohexyloxy)-1-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}piperidine-4-carboxylic acid (0.52 g, 1.10 mmol) was dissolved in dioxane (11.07 mL) and H₂O (4.43 mL), and lithium hydroxide monohydrate (0.232 g, 5.536 mmol, 5.0 eq) was added in a single addition. The reaction mixture was stirred at room temperature for 16 h. Once complete, the mixture was neutralized with 4 M HCl and evaporated under vacuum. The residue was purified using RP-FC (ACN / water) to give 4-(cyclohexyloxy)-1-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}piperidine-4-carboxylic acid (0.45 g, 87%) as a yellow solid.

[0398] LCMS: C 24 H 31 The theoretical value of N3O5 is 441.2, and the experimental value is: m / z = 442.1 [M+H]+.

[0399] 1 H NMR (300 MHz, DMSO-d6) δ 12.95 (br, 1H), 8.99 (d, J = 3.1 Hz, 1H), 7.60 (dd, J = 7.6, 1.7 Hz, 1H), 7.53 (t, J = 7.9 Hz, 1H), 7.40 (s, 1H), 7.30(d, J = 8.4 Hz, 1H), 7.19 (t, J = 7.5 Hz, 1H), 5.23 (s, 2H), 3.88 (s, 2H), 3.33 (s, 3H), 1.95 (d, J = 13.3 Hz, 4H), 1.77 (s, 2H), 1.67 (s, 2H), 1.46 (s, 2H), 1.35 - 1.14 (m, 6H).

[0400] Synthetic title compound 4-(cyclohexyloxy)-1-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}piperidine-4-carboxylic acid (0.45 g, 0.968 mmol) was dissolved in dioxane (9.68 ml, 0.1 M) and hydrogen chloride (4.0 M in dioxane) (7.26 ml, 29.05 mmol) was added in a single addition. The reaction mixture was stirred at room temperature for 16 h. Once complete, the volatiles were evaporated and the residue was purified by RP-FC (ACN / water in 0.1% formic acid, 5% / 95% to 75% / 25%) to give 4-(cyclohexyloxy)-1-[6-(2-hydroxyphenyl)pyridazin-4-yl]piperidine-4-carboxylic acid (0.25 g, 66%) as a yellow solid. LCMS: C 22 H 27 The theoretical value of N3O4 is 397.2, and the experimental value is: m / z = 398.2 [M+H]+.

[0401] 1 H NMR (300 MHz, DMSO-d6) δ 13.71 (s, 1H), 8.95 (d, J = 2.8 Hz, 1H), 8.18 - 8.04 (m, 1H), 7.57 (d, J = 2.9 Hz, 1H), 7.33 (ddd, J = 8.5, 7.2, 1.6Hz, 1H), 7.01 - 6.84 (m, 2H), 3.95 - 3.76 (m, 2H), 3.48 (ddt, J = 13.6, 8.6,4.1 Hz, 3H), 2.02 - 1.61 (m, 8H), 1.26 (dt, J = 21.9, 10.6 Hz, 6H).

[0402] Intermediate 24 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxypiperidine-4-carboxylic acid

[0403] Step 1: Synthesis of methyl 1-(6-chloropyridazine-4-yl)-4-methoxypiperidine-4-carboxylate

[0404] A mixture of 3,5-dichloropyridazine (0.71 g, 4.76 mmol), methyl 4-methoxypiperidine-4-carboxylate hydrochloride (1.00 g, 4.769 mmol), and N-methyl-2-pyrrolidone (9.54 ml, 0.5 M) and N,N-diisopropylethylamine (2.49 ml, 14.31 mmol) was stirred at 100 °C for 1 h in a sealed vial under argon atmosphere. Once complete, the reaction mixture was quenched with cold water and then extracted three times with EtOAc. The combined organic extracts, dried over Na₂SO₄, were filtered and concentrated under vacuum to give methyl 1-(6-chloropyridazine-4-yl)-4-methoxypiperidine-4-carboxylate (1.09 g, 63%) as a viscous brown solid, which was used in the next step without further purification. LCMS: C 12 H 16 The theoretical value of ClN3O3 is 285.0, and the experimental value is: m / z = 287.1 [M+H]+.

[0405] 1 H NMR (300 MHz, DMSO-d6) δ 8.98 (d, J = 2.8 Hz, 1H), 7.11 (d, J =2.7 Hz, 1H), 3.80 (dt, J = 13.6, 4.2 Hz, 2H), 3.70 (s, 3H), 3.26 (m, 2H), 3.18 (s, 3H), 2.05 - 1.81 (m, 4H).

[0406] Step 2: Synthesis of methyl 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxypiperidine-4-carboxylate

[0407] Methyl 1-(6-chloropyridazin-4-yl)-4-methoxypiperidine-4-carboxylate (1.09 g, 3.02 mmol), K₂CO₃ (1.25 g, 9.06 mmol), and 2-hydroxyphenylboronic acid (0.625 g, 4.53 mmol) were dissolved in 1,4-dioxane (15.1 ml) and H₂O (3.02 ml) in a pressure vessel. The prepared solution was degassed with argon for 5 min, and tetrakis(triphenylphosphine)palladium (0.349 g, 0.302 mmol) was added in a single batch. The reaction mixture was stirred at 100 °C for 18 h. Once complete, the solvent was evaporated, and the residue was purified by rapid chromatography (hexane: EtOAc; 0–100%) to provide methyl 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxypiperidine-4-carboxylate (0.64 g, 54%) as a pale yellow solid. LCMS: C18 H 21 The theoretical value of N3O4 is 343.1, and the experimental value is: m / z = 344.6 [M+H]+.

[0408] 1 H NMR (300 MHz, DMSO- d 6) δ 14.57 (s, 1H), 8.97 (d, J = 2.9 Hz, 1H), 8.12 (dd, J = 8.3, 1.6 Hz, 1H), 7.73 - 7.50 (m, 1H), 7.44 - 7.28 (m, 1H), 6.99 - 6.87 (m, 2H), 3.98 (dt, J = 13.6, 4.2 Hz, 2H), 3.71 (s, 3H), 3.43 -3.28 (m, 2H), 3.23 (s, 3H), 1.97 (p, J = 4.2 Hz, 4H).

[0409] Following alkaline hydrolysis, the title compound (0.30 g, 55% yield) was obtained as a pale yellow solid. LCMS: C 17 H 19 The theoretical value of N3O4 is 329.1, and the experimental value is: m / z = 330.1 [M+H]+.

[0410] 1 H NMR (300 MHz, DMSO-d6) δ 13.67 (s, 2H), 8.97 (d, J = 2.9 Hz, 1H), 8.17 - 8.07 (m, 1H), 7.58 (d, J = 3.0 Hz, 1H), 7.34 (ddd, J = 8.5, 7.2, 1.6Hz, 1H), 6.99 - 6.87 (m, 2H), 3.97 (d, J = 13.5 Hz, 2H), 3.32 (s, 2H), 3.25(s, 3H), 1.99 - 1.89 (m, 4H).

[0411] Intermediate 25 4-(2-Chlorophenoxy)-1-[6-(2-hydroxyphenyl)pyridazin-4-yl]piperidine-4-carboxylic acid

[0412] Step 1: 1-[(tert-butoxy)carbonyl]-4-(2-chlorophenoxy)piperidine-4-carboxylic acid

[0413] o-Chlorophenol (2 g, 15.556 mmol, 1.0 equiv.) was dissolved in anhydrous tetrahydrofuran (27 mL, 0.5 M) and cooled to 0 °C. Powdered NaOH (3.11 g, 77.784 mmol, 5.0 eq) and tert-butyl 3-oxazolidinyl butane-1-carboxylate (9.299 g, 46.670 mmol, 3.0 equiv.) were added to the solution at 0 °C. Chloroform (6.23 mL, 77.78 mmol, 5.0 equiv.) was then added dropwise over 15 min intervals, and the reaction mixture was stirred at 0 °C for 1 h, followed by stirring overnight at room temperature. RM was diluted with water and extracted with diethyl ether (30 mL x 3). The aqueous layer was acidified to pH = 2 (using 2 M HCl), resulting in a yellow precipitate. The yellow precipitate was dissolved in EtOAc, and the aqueous layer was extracted three times with EtOAc. The organic phase was dried over MgSO4, filtered, and evaporated on a rotary evaporator to obtain 5.1 g (83%) of 1-[(tert-butoxy)carbonyl]-4-(2-chlorophenoxy)piperidine-4-carboxylic acid as a yellow solid. LCMS (m / z): C 17 H 21 ClNO5 [MH] Calculated value: 354.11, Experimental value: 354.95. 1 H NMR (300 MHz, DMSO-d6) δ 13.49 (s, 1H), 7.47 (dd, J =7.9, 1.6 Hz, 1H), 7.26 (ddd, J = 8.2, 7.4, 1.7 Hz, 1H), 7.00 (td, J = 7.7,1.3 Hz, 1H), 6.80 (dd, J = 8.3, 1.4 Hz, 1H), 3.77 (d, J = 13.3 Hz, 2H), 3.02(s, 2H), 2.09 (d, J = 14.0 Hz, 2H), 1.91 (ddd, J = 14.0, 11.7, 4.6 Hz, 2H),1.39 (s, 9H).

[0414] Step 2: Methyl 4-(2-chlorophenoxy)piperidine-4-carboxylate hydrochloride

[0415] Thionyl chloride (1.684 ml, 23.22 mmol, 1.8 eq) was carefully added to a stirred solution of 232800123-VVI01-024 (5.1 g, 12.9 mmol, 1.0 eq) in anhydrous methanol (16.12 ml, 0.8 M) at 0 °C. The resulting solution was stirred under reflux overnight. It was then cooled to RT and the volatiles were evaporated. The obtained solid was wet-milled with MTBE and filtered. The solid was collected and dried under reduced pressure to give methyl 4-(2-chlorophenoxy)piperidine-4-carboxylate hydrochloride (4.0 g, 11.105 mmol, 86%) as a grayish-white solid. LCMS (m / z): C 13 H 17 ClNO3 + [M+H] + Calculated value: 270.09, Experimental value: 270.50. 1 H NMR (300 MHz, DMSO-d6) δ 9.18 (d, J = 33.6 Hz, 2H), 7.53 (dd, J = 8.0, 1.7 Hz, 1H), 7.29 (td, J = 7.9, 1.7 Hz, 1H), 7.07 (td, J =7.7, 1.3 Hz, 1H), 6.75 (dd, J = 8.3, 1.3 Hz, 1H), 3.79 (s, 3H), 3.25 (d, J =13.3 Hz, 2H), 2.96 (d, J = 11.3 Hz, 2H), 2.31 (dq, J = 10.7, 6.8, 5.4 Hz,4H).

[0416] Step 3: Methyl 4-(2-chlorophenoxy)-1-(6-chloropyridazine-4-yl)piperidine-4-carboxylate

[0417] To a 150 mL pressure vial equipped with a magnetic stirrer, charge 3,5-dichloropyridazine (0.993 g, 6.663 mmol, 1.2 eq) and methyl 4-(2-chlorophenoxy)piperidine-4-carboxylate hydrochloride (2.0 g, 5.552 mmol, 1.0 eq). Add dimethyl sulfoxide (11.1 mL, 0.5 M) and... N , N-Diisopropylethylamine (DIPEA) (5.803 ml, 33.314 mmol, 6.0 eq). The reaction mixture was stirred overnight at 100 °C. UPLC indicated complete conversion. DIPEA was evaporated on a rotary evaporator, water was added and a precipitate was obtained, which was sonicated and then filtered to obtain a brown solid, which was methyl DP 4-(2-chlorophenoxy)-1-(6-chloropyridazin-4-yl)piperidine-4-carboxylate (1.8 g, 3.814 mmol, 69%). LCMS (m / z): C 17 H 18 Cl2N3O3 + [M+H] + Calculated value: 382.07, Experimental value: 383.40. 1 H NMR (300 MHz, DMSO-d6) δ8.98 (d, J = 2.7 Hz, 1H), 7.50 (dd, J = 7.9, 1.7 Hz, 1H), 7.28 (ddd, J = 8.3,7.4, 1.7 Hz, 1H), 7.18 - 6.98 (m, 2H), 6.77 (dd, J = 8.3, 1.4 Hz, 1H), 3.93 (d, J = 13.7 Hz, 2H), 3.77 (s, 3H), 3.27 - 3.11 (m, 2H), 2.25 - 2.03 (m, 4H).

[0418] Step 4: Methyl 4-(2-chlorophenoxy)-1-[6-(2-hydroxyphenyl)pyridazin-4-yl]piperidine-4-carboxylate

[0419] In a pressure vial, methyl 4-(2-chlorophenoxy)-1-(6-chloropyridazin-4-yl)piperidin-4-carboxylate (1.7 g, 3.602 mmol, 1.0 eq), 2-hydroxyphenylboronic acid (0.547 g, 3.963 mmol, 1.1 eq), anhydrous potassium carbonate (1.494 g, 10.807 mmol, 3.0 eq), dioxane (36.02 ml, 0.1 M), and water (7.2 ml, 0.5 M) were added. The resulting reaction mixture was degassed with Ar for 30 min, followed by the addition of tetrakis(triphenylphosphine)palladium (0.416 g, 0.36 mmol, 0.1 eq), and the reaction mixture was stirred at 100 °C for 10 h. UPLC showed complete conversion. The crude mixture was purified by FC using EtOAc / Cyc (0-60%) eluent, and methyl 4-(2-chlorophenoxy)-1-[6-(2-hydroxyphenyl)pyridazin-4-yl]piperidine-4-carboxylate (0.985 g, 2.15 mmol, 60%) was isolated as a yellow solid. LCMS (m / z): C 23 H 23 ClN3O4 + [M+H] + Calculated value: 440.14, Experimental value: 440.95. ¹H NMR (300 MHz, DMSO-d⁶) δ 14.50 (s, 1H), 8.98 (d, J = 2.8 Hz, 1H), 8.09 (dd, J = 8.5, 1.7 Hz, 1H), 7.59 (d, J = 2.9 Hz, 1H), 7.51 (dd, J = 8.0, 1.7 Hz, 1H), 7.37 - 7.25 (m, 2H), 7.06 (td, J = 7.7, 1.3 Hz, 1H), 6.96 - 6.88 (m, 2H), 6.80 (dd, J = 8.3, 1.4 Hz, 1H), 4.10 (d, J = ... 13.6 Hz, 2H), 3.78 (s, 3H), 3.38 (d, J = 4.5 Hz, 2H), 2.29 - 2.12 (m, 4H).

[0420] Following alkaline hydrolysis, the title compound (0.425 g, 0.979 mmol, 46%) was obtained. LCMS (m / z): C 22 H 21 ClN3O4 + [M+H] + Calculated value: 426.12, Experimental value: 426.19. 1H NMR (300 MHz, DMSO-d6) δ14.02 (s, 2H), 8.98 (d, J = 2.8 Hz, 1H), 8.11 - 8.02 (m, 1H), 7.59 (d, J =2.9 Hz, 1H), 7.50 (dd, J = 7.9, 1.7 Hz, 1H), 7.32 (qd, J = 7.6, 1.6 Hz, 2H), 7.03 (td, J = 7.7, 1.3 Hz, 1H), 6.98 - 6.82 (m, 3H), 4.12 (d, J = 13.4 Hz,2H), 3.28 (d, J = 4.2 Hz, 2H), 2.30 - 2.12 (m, 4H).

[0421] Intermediate 26 Synthesis of 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenyl-N-(piperidin-4-yl)-N-propylpiperidin-4-carboxamide

[0422] Step 1: 4-(N-propyl-1-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-4-phenylpiperidin-4-amido)piperidin-1-carboxylic acid tert-butyl ester

[0423] To a solution of 1-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-4-phenylpiperidin-4-carboxylic acid (intermediate 11) (0.6 g, 1.044 mmol, 1.0 eq) in dimethylacetamide (3.93 mL, 0.266 M), N,N-diisopropylethylamine (DIPEA) (0.909 mL, 5.221 mmol, 5.0 eq), HATU (1.191 g, 3.132 mmol, 3.0 eq), and 1-Boc-4-propylaminopiperidine (1.518 g, 6.265 mmol, 6.0 eq) were added. The mixture was stirred at 50 °C for 3 days. The reaction mixture was then diluted with DCM (50 mL) and extracted with NaHCO3 (50 mL). The basic phase was then extracted again with DCM (50 mL). The combined organic layers were extracted with water (50 mL). The organic layer was dried over MgSO4 and the solvent was evaporated. The crude product was purified by rapid chromatography by elution with hexane:EtOAc (0-70%) followed by washing with EtOAc:MeOH (9:1). The accepted impurities were purified by RP-FC, yielding 0.36 g (0.531 mmol, 51% yield) of the title compound. LCMS (m / z): C 37 H 49 [M+H] of N5O5 + Calculated value: 643.83, Experimental value: 644.84. 1 H NMR (300 MHz, DMSO- d 6) δ 8.92(d, J = 3.0 Hz, 1H), 7.61 (dd, J = 7.6, 1.8 Hz, 1H), 7.46 - 7.36 (m, 3H), 7.33 (d, J = 7.5 Hz, 2H), 7.28 - 7.20 (m, 2H), 7.17 (d, J = 3.0 Hz, 1H), 7.12 (td, J = 7.4, 1.1 Hz, 1H), 5.20 (s, 2H), 3.89 (d, J = 13.1 Hz, 2H), 3.75 (d,J = 12.4 Hz, 2H), 3.46 (s, 1H), 3.30 (s, 3H), 2.96 (d, J = 8.3 Hz, 2H), 2.35(d, J = 13.6 Hz, 2H), 2.18 (t, J = 12.5 Hz, 2H), 2.02 (s, 2H), 1.49 - 1.35(m, 4H), 1.33 (s, 9H), 0.91 - 0.74 (m, 4H).

[0424] TFA (1.42 ml, 18.592 mmol, 35.0 eq) was added to a solution of 4-(N-propyl-1-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-4-phenylpiperidin-4-amido)piperidin-1-carboxylic acid tert-butyl ester (0.36 g, 0.531 mmol, 1.0 eq) in anhydrous DCM (2.12 ml, 0.25 M). The reaction mixture was stirred at room temperature for 2 h. UPLC showed complete conversion of the starting material to the desired product. The solvent was evaporated and the received crude extract was wet-milled twice with diethyl ether. After drying, 0.391 g of the title compound (0.484 mmol, 91% yield) was given. LCMS (m / z): C 30 H 37 [M+H] of N5O2 + Calculated value: 499.66, experimental value: 500.71. 1 H NMR (300 MHz, DMSO- d 6) δ 8.95 (d, J = 3.0 Hz, 1H), 8.66 (s, 1H), 8.31 (s, 1H), 7.59 (dd, J = 7.9, 1.6 Hz, 1H), 7.46 (td, J =8.0, 7.5, 1.8 Hz, 3H), 7.41 (d, J = 3.5 Hz, 2H), 7.33 (q, J = 8.9, 6.9 Hz,2H), 7.09 (d, J = 8.2 Hz, 1H), 7.06 - 6.98 (m, 1H), 4.14 (s, 3H), 3.68 - 3.56(m, 4H), 3.19 - 3.08 (m, 2H), 2.99 (t, J = 7.9 Hz, 2H), 2.44 (s, 3H), 2.21(s, 2H), 1.87 - 1.61 (m, 2H), 1.57 - 1.39 (m, 2H), 0.97 - 0.89 (m, 2H), 0.84(t, J = 7.3 Hz, 2H).

[0425] Intermediate 27 Synthesis of N-cyclopropyl-1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenyl-N-(piperidin-4-yl)piperidin-4-carboxamide

[0426] The title compound was prepared by replacing 1-Boc-4-propylaminopiperidine with 1-Boc-4-cyclopropylaminopiperidine in a manner similar to that used in the synthesis of 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenyl-N-(piperidin-4-yl)-N-propylpiperidine-4-carboxamide (intermediate 26). The title compound was obtained (0.118 g, 94% yield). LCMS (m / z): C 30 H 35 Calculated [M+H]+ for N5O2: 497.64, experimental value: 498.65. ¹H NMR (300 MHz, DMSO-d6) δ 8.70 (d, J = 3.1 Hz, 1H), 7.55 (ddd, J = 7.8, 5.4, 1.7 Hz, 2H), 7.51 - 7.45 (m, 2H), 7.45 - 7.36 (m, 3H), 7.34 (d, J = 3.2 Hz, 1H), 7.18 - 7.08 (m, 2H), 4.10 (d, J = 69.1 Hz, 2H), 3.89 - 3.48 (m, 3H), 3.33 (d, J = 27.4 Hz, 2H), 2.75 - 2.50 (m,2H), 2.36 (s, 5H), 2.12 (s, 2H), 1.56 - 1.24 (m, 2H), 0.91 (s, 2H), 0.64 (s,2H).

[0427] Intermediate 28 synthesis racemic -2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)acetaldehyde

[0428] Step 1: Synthesis of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine

[0429] At 20 °C, K₂CO₃ (43.0 g, 311 mmol) and Pd(dppf)Cl₂ (11.4 g, 15.5 mmol) were added to a solution of 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine (65.0 g, 155 mmol), 1-bromo-4-iodobenzene (52.8 g, 186 mmol), in 1,4-dioxane (650 mL) and H₂O (165 mL), and the mixture was purged three times with N₂. The mixture was heated and stirred at 80 °C until completion was determined by LCMS. Once complete, the reaction mixture was cooled to room temperature and filtered through diatomaceous earth, washed with EtOAc. The collected filtrate was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain a crude residue. The crude residue was purified by rapid column chromatography (petroleum ether / ethyl acetate = 0 to 100%) to obtain the desired product, which was then wet-milled at 25 °C with petroleum ether / ethyl acetate (50:1, 500 mL) for 15 min to obtain the desired compound as a white solid (163 g, 80% yield). LCMS C 25 H 20 The theoretical value for BrNO2 is 447.1, and the experimental value is m / z = 448.2 [M+H]. + .

[0430] Step 2: Synthesis of ethyl 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-yl)acetate

[0431] DavePhos (11.5 g, 29.3 mmol), Cs₂CO₃ (143 g, 439 mmol), and Pd₂(dba)₃ (13.4 g, 14.6 mmol) were added to a solution of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (67.0 g, 146 mmol), 2-(piperidin-4-yl)ethyl acetate (37.6 g, 219 mmol), in 2-MeTHF (670 mL) and H₂O (67 mL), and the mixture was purged with N₂ (3x). The mixture was stirred at 100 °C until completion was determined by LCMS. Once complete, the mixture was poured into H₂O (1000 mL) and extracted with 2-MeTHF (800 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to give a crude residue. The residue was purified by rapid column chromatography (petroleum ether / ethyl acetate = 0 to 100%), and the purified material was wet-milled with MTBE (200 mL) at 20 °C for 30 min to obtain the desired product as a pale yellow solid (76.3 g, 45% yield). LCMS C 34 H 36 The theoretical value of N₂O₄ is 536.3, and the experimental value is m / z = 537.4 [M+H]. + .

[0432] Step 3: Synthesis of 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-yl)ethanol-1-ol

[0433] Flow program: Solution 1: ethyl 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-yl)acetate (1.00 eq, 76.0 g in THF, 760 mL). Solution 2: LiAlH4 (2.00 eq, 0.707 g, 114 mL, 2.50 M). The entire flow reaction was carried out under an inert N2 atmosphere. The volume of the 1 / 8” PFA coil in flow reactor 1 was 60 mL. The residence time in flow reactor 1 was 2 min. For flow reactor 1, the bath was set at 20 °C. For solution 1, the flow rate of pump 1 was adjusted to 26.1 mL / min. For solution 2, the flow rate of pump 2 was adjusted to 3.9 mL / min. The mixture was collected in a bottle quenched with Na₂SO₄-10H₂O. Pumps 1 and 2 were started, and the reaction mixture was collected after 5 min of running. Once the reaction was determined to be complete by LCMS, the reaction mixture was filtered through diatomaceous earth to remove Na₂SO₄, and washed with THF (500 mL) and DCM (500 mL). The crude filtrate was concentrated under vacuum to give the desired product as a gray solid, which was advanced without any further purification (67.7 g). LCMS C 32 H 34 The theoretical value of N₂O₃ is 494.3, and the experimental value is m / z = 495.3 [M+H]. + .

[0434] Step 4: Synthesis racemic -3-(4-(4-(2-hydroxyethyl)piperidin-1-yl)phenyl)piperidin-2,6-dione

[0435] The oven-dried flask was purged under vacuum and backfilled with N2 (3X). Pd / C (14.2 g, 66.7 mmol, 50% purity), Pd(OH)2 (14.2 g, 50.5 mmol, 50% purity), 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-yl)ethanol-1-ol (74.0 g, 149 mmol) and THF (740 mL) were added to the flask. The suspension was purged with N2 and H2 (3X) was added. The reaction mixture was stirred at 25°C with H2 (50 psi) until completion was determined by LCMS. Once complete, the mixture was filtered and washed with THF (2.00 L). The collected filtrate was refluxed at 80°C for 15 minutes and then filtered while hot to obtain the filtrate. The collected filtrate was concentrated to produce a crude residue, which was then wet-milled with MTBE (60 mL) to obtain the desired compound as a white solid, which was advanced (40.0 g) without any further purification. LCMSC18 H 24 The theoretical value for N₂O₃ is 316.2, and the experimental value is m / z = 317.2 [M+H]. + .

[0436] Step 5: Synthesize the title compound The small vials were purged and dried in the oven and then backfilled with N2 (3x), followed by addition at 25°C. racemic -( R 3-(4-(4-(2-hydroxyethyl)piperidin-1-yl)phenyl)piperidin-2,6-dione (30.0 g, 94.8 mmol) was added to a solution of DMSO (300 mL). Then, IBX (39.0 g, 139 mmol, 1.47 mmol) was added sequentially. eq The mixture was stirred at 25°C until completion was determined by LCMS. Once complete, the mixture was cooled to 15°C and 2-MeTHF (300 mL) was added to prevent product precipitation during reaction quenching. H₂O (500 mL) was added to quench the reaction, and the reaction mixture was then extracted with 2-MeTHF (300 mL x 3) and DCM (800 mL x 10). The combined organic layers were washed with brine (500 mL) and saturated NaHCO₃ solution (500 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to give a crude residue. The residue was purified by rapid column chromatography (petroleum ether / ethyl acetate (w / 10% DCM) = 0-33%) to give the desired product (26.0 g, 84% yield) as a green solid. LCMS C 18 H 22 The theoretical value for N₂O₃ is 314.2, and the experimental value is m / z = 315.3 [M+H]. + .

[0437] Intermediate 29 ( S )-2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)acetaldehyde

[0438] Separation was performed using an SFC (column: DAICEL CHIRALPAK AS (250 mm * 30 mm, 10 μm); mobile phase: [CO2-i-PrOH / ACN]; B%: 70%, isocratic elution mode). racemic-2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)acetaldehyde (24.9 g, 79.4 mmol). The title compound (first eluting isomer) was given as a yellow solid (7.00 g, 44.6% yield). LCMS C 18 H 22 The theoretical value for N₂O₃ is 314.2, and the experimental value is m / z = 315.3 [M+H]. + .

[0439] Intermediate 30 racemic -3-((4-(piperidin-4-yl)phenyl)amino)piperidin-2,6-dione

[0440] Step 1: Synthesis racemic -( R 4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-carboxylic acid tert-butyl ester

[0441] Add tert-butyl 4-(4-aminophenyl)piperidin-1-carboxylate (23.5 g, 85.0 mmol, 1.0 eq) and NaHCO3 (21.4 g, 255.0 mmol, 3.0 eq) to a solution of 4-(4-aminophenyl)piperidin-1-carboxylate (23.5 g, 85.0 mmol, 1.0 eq) in DMF (250 mL) at room temperature. racemic 3-Bromopiperidin-2,6-dione (24.5 g, 127.5 mmol, 1.5 eq) was added, and the reaction mixture was stirred at 65 °C until completion was determined by LCMS. Once complete, the mixture was quenched with ice water (500 mL) and stirred at room temperature for 15 min. The reaction mixture was filtered and concentrated to obtain a crude product. The crude product was wet-milled with MTBE (150 mL) to obtain the desired product as a gray solid, which was then advanced (26 g) without any further purification. LCMS C 21 H 29 Theoretical value for N3O4: 387.2, experimental value: 386.1 [MH] - .

[0442] Step 2: Synthesize the title compound At 0℃ racemic 4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-carboxylic acid tert-butyl ester (22.5 g, 58.1 mmol) was added to a solution containing 4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-carboxylic acid tert-butyl ester in DCM (66 mL). NDioxane in HCl (43.6 mL, 174.3 mmol) was added, and the reaction mixture was stirred at room temperature until completion was determined by LCMS. Once complete, the mixture was concentrated to yield a crude product. The crude product was wet-milled with MTBE (100 mL) to yield the desired product as a gray solid, which was advanced without any further purification (16.0 g, HCl salt). LCMS C 16 H 21 Theoretical value of N3O2: 287.2, experimental value: 288.2 [M+H] + .

[0443] Intermediate 31 (1 r 4 r )-4-(4-(( RS 2,6-Dioxopiperidin-3-yl)phenoxy)cyclohexane-1-carboxaldehyde

[0444] Step 1: Synthesis (1) r 4 r methyl 4-(4-bromophenoxy)cyclohexane-1-carboxylate

[0445] To (1) r 4 r Methyl 4-hydroxycyclohexane-1-carboxylate (20.0 g, 126 mmol) was added to a solution of toluene (400 mL) along with PPh3 (36.4 g, 139 mmol) and 4-bromophenol (24.0 g, 139 mmol). The mixture was then cooled to 0 °C and DEAD (27.5 mL, 151 mmol) was added. The reaction mixture was then heated to 25 °C and the reaction proceeded until completion was determined by LCMS. Once complete, the reaction mixture was poured into petroleum ether (1000 mL), where a precipitate formed. The mixture was filtered, and the filter cake was washed with petroleum ether (200 mL x 2). The combined filtrates were washed with brine (500 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give a crude residue. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 0 to 100%) to give the desired compound as a white solid (23.0 g, 58% yield, in two steps). LCMS C 14 H 17 The theoretical value of BrO3 is 312.1, and the experimental value is m / z = 313.2 [M+H]. + .

[0446] Step 2: Synthesis (1) r 4 r 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenoxy)cyclohexane-1-carboxylic acid methyl ester

[0447] As described in step 1 for intermediate 28, using (1 r 4 r The intermediate was prepared by replacing methyl 4-(4-bromophenoxy)cyclohexane-1-carboxylate with 1-bromo-4-iodobenzene (12.0 g, 72% yield). LCMS C 33 H 33 Theoretical value of NO5: 523.2, experimental value: m / z = 524.2 [M+H] + .

[0448] Step 3: Synthesis ((1) r, 4 r )-4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenoxy)cyclohexyl)methanol

[0449] At 0℃ under N2, towards (1 r 4 r LiBH4 (2.00 M in THF, 236 mL) was added to a solution of 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenoxy)cyclohexane-1-carboxylate (6.00 g, 11.4 mmol) in THF (60 mL). The mixture was heated to 25 °C and allowed to react until complete as determined by LCMS. Once complete, the reaction mixture was cooled to 0 °C and a 5% NaHCO3 solution (100 mL) was slowly added to the mixture at 0 °C. The mixture was extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine (150 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated to give the desired compound as a pale yellow solid, which was advanced without any further purification (5.0 g, 87% yield). LCMS C 32 H 33 The theoretical value of NO4 is 495.2, and the experimental value is m / z = 496.3 [M+H]. + .

[0450] Step 4: Synthesis ( RS )-3-(4-(((1 r 4 r )-4-(hydroxymethyl)cyclohexyl)oxy)phenyl)piperidine-2,6-dione

[0451] In an N2 atmosphere, towards ((1) r, 4 r Pd / C (600 mg, 10% purity) and Pd(OH)₂ (600 mg, 20% purity) were added to a solution of 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenoxy)cyclohexyl)methanol (3.00 g, 5.95 mmol) in THF (30 mL). The suspension was degassed and purged three times with H₂. The mixture was stirred at 25 °C under H₂ (15 Psi) until completion was determined by LCMS. Once complete, the reaction mixture was filtered through a diatomaceous earth layer and washed with THF. The collected filtrate was concentrated under vacuum to yield the desired product as a yellow solid, which was advanced (2.50 g) without any further purification. LCMS C 18 H 23 Theoretical value of NO4: 317.2, experimental value: m / z = 318.3 [M+H] + .

[0452] Step 5: Synthesize the title compound At 25℃ ( RS )-3-(4-(((1 r 4 R DMP (2.58 g, 6.09 mmol) was slowly added to a solution of 1.0 g (1.0 g, 3.04 mmol) in DMSO (10.0 mL). The reaction mixture was stirred at 25 °C until completion was determined by LCMS. Once complete, the mixture was adjusted to pH 10 with a saturated aqueous solution of Na₂CO₃ and the aqueous layer was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with a semi-saturated solution of Na₂S₂O₃ (50 mL) and brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to give a crude residue. The crude product was wet-milled at 25 °C with petroleum ether / ethyl acetate (3:1, 5 mL) for 15 min to give the desired product as a white solid, which was advanced without any further purification (0.66 g). LCMS C 18 H 21 The theoretical value of NO4 is 315.2, and the experimental value is m / z = 316.2 [M+H]. + .

[0453] Intermediate 32 racemic -( R)-2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-yl)acetic acid

[0454] Step 1: Synthesis of tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate

[0455] Cesium carbonate (7.30 g, 22.40 mmol) was added to a stirred solution of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (5 g, 11.20 mmol) and 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylic acid tert-butyl ester (2.87 g, 11.20 mmol) in 1,4-dioxane (50 mL). The resulting mixture was purged with N2 for 10 min. Pd2(dba)3 (0.513 g, 0.560 mmol) and RuPhos (0.523 g, 1.120 mmol) were then added. The resulting mixture was purged with N2 for 5 min and heated to 100 °C for 16 h. After the reaction was complete, the reaction mixture was cooled to RT and filtered through diatomaceous earth, washed with ethyl acetate (300 mL). The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a crude compound as a brown liquid. The crude compound was purified by rapid column chromatography using ethyl acetate / petroleum ether (0-30%) as eluent to give the desired compound as a pale yellow solid (5.6 g, 77% yield). LCMS C 38 H 43 The theoretical value of N3O5 is 621.3, and the experimental value is m / z = 622.2 [M+H]. + .

[0456] Step 2: Synthesis of 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-1-oxa-4,9-diazaspiro[5.5]undecane

[0457] As described in the synthesis of intermediate 30, step 2, tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate was used instead. racemic -( RThe intermediate (4.5 g, HCl salt) was prepared by tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-carboxylate. LCMSC 33 H 35 Theoretical value of N3O3: 521.3, experimental value: 522.4 [M+H] + .

[0458] Step 3: Synthesis of tert-butyl 2-(4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-yl)acetate

[0459] TEA (5.11 mL, 36.7 mmol) and tert-butyl 2-chloroacetate (3.15 mL, 22.00 mmol) were added to a solution of (4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-1-oxa-4,9-diazaspiro[5.5]undecane (4.5 g, 7.33 mmol) in MeCN (50 mL) under RT. The reaction mixture was stirred at 60 °C until complete as determined by LCMS. After the reaction was complete, the reaction mixture was cooled to room temperature. Once cooled, water (100 mL) was added and the mixture was extracted with EtOAc (2 x 250 mL). The extract was further separated with water (200 mL), brine (100 mL) and saturated salt (100 mL). The combined organic layers were washed with (mL) water, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to yield a crude product. The crude product was purified by FCC using 30% ethyl acetate / petroleum ether as eluent (isocratic elution) to give the desired product (3.0 g, 61% yield) as a grayish-white solid. LC-MSC 39 H 45 The theoretical value of N3O5 is 636.3, and the experimental value is m / z = 637.4 [M+H]. + .

[0460] Step 4: Synthesis racemic -( R 2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-yl)tert-butyl acetate

[0461] Pd(OAc)₂ (0.4 g, 1.782 mmol) and 10% Pd / C (0.5 g, 4.70 mmol) were added to a stirred solution of 2-(4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-yl)acetate (3 g, 4.72 mmol) in 1,4-dioxane (30 mL) under a nitrogen atmosphere and at RT. The mixture was stirred at RT under a hydrogen pressure (1 atm) until completion was determined by LCMS. Once complete, the reaction mixture was filtered through diatomaceous earth and washed with ethyl acetate (100 mL). The eluent was concentrated under reduced pressure to give a crude compound, which was washed with toluene (2 x 50 mL) and MTBE (2 x 30 mL) and concentrated under reduced pressure to give the desired compound as a grayish-white solid, which was advanced without any further purification (1.8 g). LCMS C 25 H 35 The theoretical value of N3O5 is 457.3, and the experimental value is 458.6 [M+H]. + .

[0462] Step 5: Synthesize the title compound As described in step 2 of the synthesis of intermediate 30, using racemic -( R The intermediate (0.91 g, HCl salt) was prepared by substituting racemic (R)-4-(4-((2,6-dioxopiperidin-3-yl)phenyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-yl)acetic acid tert-butyl ester for racemic (R)-4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-carboxylic acid tert-butyl ester. LCMS C21H27N3O5 theoretical value 401.2, experimental value 402.2 [M+H]+.

[0463] Intermediate 33 2-((3aR,6aR)-5-(4-(2,6-dioxopiperidin-3-yl)phenyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)acetic acid

[0464] Step 1: Synthesis of tert-butyl (3aS,6aS)-5-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

[0465] Cesium carbonate (7.30 g, 22.40 mmol) was added to a stirred solution of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (5 g, 11.20 mmol) and (3aS,6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (2.378 g, 11.20 mmol) in dioxane (60 mL). The resulting mixture was purged with N2 for 10 min. Pd2(dba)3 (0.513 g, 0.560 mmol) and RuPhos (0.523 g, 1.120 mmol) were then added. The resulting mixture was purged with N2 for 5 min and heated to 100 °C for 16 h. After the reaction was complete, as confirmed by LCMS, the reaction mixture was cooled to RT, filtered through a diatomaceous earth mat, and washed with ethyl acetate (300 mL). The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a crude product as a brown liquid. The product was purified by rapid chromatography using a 0-30% ethyl acetate / petroleum ether gradient to give tert-butyl (3aS,6aS)-5-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid as a pale yellow solid (4.5 g, 66% yield). LCMS: C 36 H 39 Theoretical value for N3O4: 577.3; Experimental value: m / z = 578.2 [M+H] + .

[0466] Step 2: Synthesis of (3aR,6aR)-2-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)octahydropyrrolo[3,4-c]pyrrole

[0467] Dioxane (9.74 ml, 38.9 mmol) containing 4 M HCl was added to a stirred solution of (3aS,6aS)-5-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (4.5 g, 7.79 mmol) in DCM (20 mL). The resulting reaction mixture was stirred at RT for 2 h. After the reaction was complete, as confirmed by LCMS, the reaction mixture was concentrated under reduced pressure and washed with n-hexane (3 x 100 mL) and dried to give (3aR,6aR)-2-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)octahydropyrrolo[3,4-c]pyrrole (3.5 g, 70% yield) as a grayish-white solid. LCMS: C 31H 31 Theoretical value of N3O2: 477.2; Experimental value: m / z = 478.2 [M+H] + .

[0468] Step 3: Synthesis of tert-butyl 2-((3aR,6aR)-5-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)acetate

[0469] Triethylamine (1.557 g, 15.39 mmol) and tert-butyl 2-chloroacetate (2.201 ml, 15.39 mmol) were added to a solution of (3aR,6aR)-2-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)octahydropyrrolo[3,4-c]pyrrole (3.5 g, 5.13 mmol) in MeCN (20 ml) at RT. The reaction mixture was stirred at 60 °C for 2 h. After the reaction was complete as confirmed by LCMS, the reaction mixture was cooled to room temperature. Water (100 mL) was then added and the mixture was extracted with EtOAc (2 x 250 mL). The combined organic layers were washed with water (200 mL) and brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by rapid chromatography using 30% ethyl acetate / petroleum ether as eluent to give tert-butyl 2-((3aR,6aR)-5-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)acetate (3.5 g, 70% yield) as a grayish-white solid. LCMS: C 37 H 41 Theoretical value for N3O4: 591.3; Experimental value: m / z = 592.2 [M+H] + .

[0470] Step 4: Synthesis of tert-butyl 2-((3aR,6aR)-5-(4-(2,6-dioxopiperidin-3-yl)phenyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)acetate

[0471] Pd(OAc)₂ (0.200 g, 0.891 mmol) and 10% Pd / C (0.300 g, 2.82 mmol) were added to a stirred solution of 2-((3aR,6aR)-5-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)acetate (1.3 g, 2.197 mmol) in 1,4-dioxane (30 mL) under a nitrogen atmosphere and at RT. The resulting mixture was stirred at RT for 16 h under H₂ (1 atm pressure). After the reaction was complete, as confirmed by LCMS, the reaction mixture was filtered through a diatomaceous earth bed, washed with ethyl acetate (100 mL), and concentrated under reduced pressure. The crude product was washed with toluene (2 x 50 mL) and MTBE (2 x 30 mL) and concentrated under reduced pressure to give tert-butyl 2-((3aR,6aR)-5-(4-(2,6-dioxopiridin-3-yl)phenyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)acetate (0.7 g, 73% yield) as a grayish-white solid. LCMS: C 23 H 31 Theoretical value for N3O4: 413.2; Experimental value: m / z = 414.1 [M+H] + .

[0472] Step 5: Synthesize the title compound A stirred solution of 2-((3aR,6aR)-5-(4-(2,6-dioxopiridine-3-yl)phenyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)tert-butyl acetate (650 mg, 1.572 mmol) in DCM (6.5 mL) was cooled to 0 °C and TFA (1.203 mL, 15.72 mmol) was added. The reaction mixture was stirred at RT for 6 h. After the reaction was complete, as confirmed by LCMS, n-hexane (50 mL) was added and the mixture was stirred for 10 min. The clear solvent layer was decanted and repeated twice. The resulting residue was concentrated and dried under reduced pressure to give the crude product. The crude product was purified by RP-FC with MeCN / H2O and the collected fraction was lyophilized to give the title compound (0.37 g, 64% yield, TFA salt) as a grayish-white solid. LCMS: C 19 H 23 Theoretical value for N3O4: 357.2; Experimental value: m / z = 358.2 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ (ppm): 10.77 -10.69 (m, 1H), 7.01 (d,J = 8.5 Hz, 2H), 6.46 (d, J = 8.8 Hz, 2H), 4.32 (s, 2H), 3.72-3.68 (m, 1H), 3.56-3.50 (m, 3H), 3.42 (br d, J = 7.4 Hz, 3H), 3.10 (t, J =9.4 Hz, 2H), 2.68-2.58 (m, 2H), 2.50 - 2.48 (m, 2H), 2.18-2.08 (m, 1H), 2.03-1.94 (m, 1H).

[0473] Intermediate 34 7-(4-(2,6-dioxopiperidin-3-yl)phenyl)-7-azaspiro[3.5]nonane-2-carboxaldehyde

[0474] Step 1: Synthesis of 2-methyl 7-(tert-butyl)-7-azaspiro[3.5]nonane-2,7-dicarboxylic acid ester

[0475] Cesium carbonate (8.17 g, 25.06 mmol) was added to a stirred solution of 7-(tert-butoxycarbonyl)-7-azaspiro[3.5]nonane-2-carboxylic acid (4.5 g, 16.71 mmol) in DMF (40 mL), followed by iodomethane (2.85 g, 20.05 mmol). The mixture was stirred at RT for 16 h. After the reaction was complete, as confirmed by LCMS, the reaction mixture was poured into ice-cold water (100 mL) and extracted with ethyl acetate (2 x 200 mL). The organic layer was washed with a saline solution (20 mL), dried over sodium sulfate, and concentrated under reduced pressure to give 2-methyl 7-(tert-butyl) 7-azaspiro[3.5]nonane-2,7-dicarboxylic acid (4 g, 80% yield) as a yellow oil. LCMS: C 15 H 25 Theoretical value for NO4: 283.2, experimental value: m / z = 184.2 [M-Boc] + .

[0476] Step 2: Synthesis of methyl 7-azaspiro[3.5]nonane-2-carboxylate

[0477] Dioxane (35.3 mL, 141 mmol) containing 4 M HCl was added to a stirred solution of 2-methyl 7-azaspiro[3.5]nonane-2,7-dicarboxylate 7-(tert-butyl) ester (4 g, 14.12 mmol) in DCM (20 mL). The resulting mixture was stirred at RT for 5 h. After the reaction was complete, as confirmed by LCMS, the reaction mixture was concentrated under reduced pressure, washed with n-hexane (3 x 100 mL), and dried to give methyl 7-azaspiro[3.5]nonane-2-carboxylate·HCl (3 g, 95%) as a yellow solid. LCMS: C 10 H 17 Theoretical value for NO2: 183.2; Experimental value: m / z = 184.2 [M+H] + .

[0478] Step 3: Synthesis of methyl 7-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-7-azaspiro[3.5]nonane-2-carboxylate

[0479] Cesium carbonate (22.99 g, 70.6 mmol) was added to a stirred solution of methyl 7-azaspiro[3.5]nonane-2-carboxylate in HCl (3.10 g, 14.11 mmol) and 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (6.3 g, 14.11 mmol) in dioxane (100 mL). The resulting mixture was purged with N2 for 10 min. Pd2(dba)3 (0.646 g, 0.706 mmol) and RuPhos (0.659 g, 1.411 mmol) were then added. The resulting reaction mixture was purged with N2 for 5 min and heated to 100 °C for 16 h. After the reaction was complete, as confirmed by LCMS, the reaction mixture was cooled to RT, filtered through a diatomaceous earth mat, and washed with ethyl acetate (300 mL). The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to give a crude product as a brown liquid. The crude product was purified by rapid chromatography using a 0-25% ethyl acetate / petroleum ether gradient to give methyl 7-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)spiro[3,5]nonane-2-carboxylate (5.3 g, 52% yield) as a pale yellow solid. LCMS: C 35 H 36 Theoretical value for N₂O₄: 548.3; Experimental value: m / z = 549.2 [M+H] + .

[0480] Step 4: Synthesis of (7-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-7-azaspiro[3.5]non-2-yl)methanol

[0481] Methyl 7-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)spiro[3.5]nonane-2-carboxylate (5.3 g, 9.68 mmol) was added dropwise to a stirred solution of 7-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)spiro[3.5]nonane-2-carboxylate (5.3 g, 9.68 mmol) in THF (50 mL) at 0 °C. The reaction mixture was stirred at RT for 2 h. After the reaction was complete, as confirmed by LCMS, the mixture was quenched with ethyl acetate (25 mL) followed by quenching with saturated sodium sulfate solution (20 mL). The reaction mixture was filtered through a diatomaceous earth mat, the filtrate was diluted with ethyl acetate (200 mL) and washed with water (2 x 100 mL) and brine (50 mL), the organic layer was dried over sodium sulfate and concentrated under reduced pressure to give crude product (5 g). The product was crudely prepared by wet milling a mixture of DCM (50 mL) and hexane (40 mL) to give 4.3 g (80% yield) of green, gelatinous (7-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)spiro[3.5]non-2-yl)methanol. LCMS: C 34 H 36 Theoretical value of N₂O₃: 520.3; Experimental value: m / z = 521.3 [M+H] + .

[0482] Step 5: Synthesis of 3-(4-(2-(hydroxymethyl)-7-azaspiro[3.5]non-7-yl)phenyl)piperidin-2,6-dione

[0483] Pd(OAc)₂ (0.4 g, 1.782 mmol) and 10% Pd / C (0.8 g, 7.52 mmol) were added to a stirred solution of (7-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)spiro[3.5]non-2-yl)methanol (4.3 g, 8.27 mmol) in 1,4-dioxane (40 mL) under a nitrogen atmosphere and at RT. The resulting reaction mixture was stirred at RT for 16 h under H₂ pressure (1 atm). After the reaction was complete, as confirmed by LCMS, the reaction mixture was filtered through a diatomaceous earth bed, washed with ethyl acetate (100 mL), and concentrated under reduced pressure. The crude extract was washed with toluene (2 x 50 mL) and MTBE (2 x 30 mL) and concentrated under reduced pressure to give 2.5 g (83% yield) of 3-(4-(2-(hydroxymethyl)-7-azaspiro[3.5]non-7-yl)phenyl)piperidin-2,6-dione as a grayish-white solid. LCMS: C 20 H 26 Theoretical value of N₂O₃: 342.2; Experimental value: m / z = 343.2 [M+H] + .

[0484] Step 6: Synthesize the title compound Des Martin periodane (4.64 g, 10.95 mmol) was added to a stirred solution of 3-(4-(2-(hydroxymethyl)-7-azaspiro[3.5]non-7-yl)phenyl)piperidin-2,6-dione (2.5 g, 7.30 mmol) in DMSO (5 mL) under a nitrogen atmosphere at 0 °C. The resulting reaction mixture was stirred at RT for 2 h. After the reaction was complete, as confirmed by LCMS, the reaction mixture was quenched with sodium thiosulfate solution (20 mL) and extracted with ethyl acetate (2 x 50 mL). The organic layer was washed with sodium bicarbonate (20 mL) and brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was purified by RP-FC with MeCN / H2O. The collected fraction was lyophilized to give the title compound (0.903 g, 25% yield, as TFA salt) as a grayish-white solid. LCMS: C 20 H 24 Theoretical value for N₂O₃: 340.2; Experimental value: m / z = 341.3 [M+H] + . 1 HNMR (400 MHz, DMSO- d 6) δ (ppm): 10.82 (s, 1H), 9.75-9.66 (m, 1H), 7.33-7.04(m, 4H), 3.81 (dd, J= 4.0, 10.5 Hz, 1H), 3.30-3.22 (m, 3H), 3.19 (d, J = 7.8 Hz,2H), 2.71-2.62 (m, 1H), 2.46 (t, J = 4.2 Hz, 1H), 2.28-2.07 (m, 2H), 2.02 (d, J =7.5 Hz, 4H), 1.83 (br s, 2H), 1.65 (br s, 2H).

[0485] Intermediate 35 Synthesis of 2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)-4-methylpiperidin-4-yl)acetaldehyde

[0486] Step 1: Synthesis of 2-(4-methylpiperidin-4-yl)ethanol-1-ol

[0487] Dioxane (0.027 mL, 4.11 mmol) containing 4 M HCl was added to a stirred solution of tert-butyl 4-(2-hydroxyethyl)-4-methylpiperidin-1-carboxylate (1 g, 4.11 mmol) in DCM (10 mL) at 0 °C. The resulting mixture was stirred at RT for 5 h. After the reaction was complete, as confirmed by LCMS, the reaction mixture was concentrated under reduced pressure, washed with n-hexane (3 x 100 mL), and dried to give a colorless, gel-like 2-(4-methylpiperidin-4-yl)ethanol-1-ol (HCl salt). LCMS: C8H 17 Theoretical value of NO: 143.1, experimental value: m / z = 144.2 [M+H] + .

[0488] Step 2: Synthesis of 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-4-methylpiperidin-4-yl)ethanol-1-ol

[0489] Cesium carbonate (5.47 g, 16.80 mmol) was added to a stirred solution of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (1.5 g, 3.36 mmol) and 2-(4-methylpiperidin-4-yl)ethanol-1-ol HCl (0.604 g, 3.36 mmol) in 1,4-dioxane (50 mL) at room temperature. The resulting mixture was purged with N2 for 10 min. Pd2(dba)3 (0.154 g, 0.168 mmol) and RuPhos (0.157 g, 0.336 mmol) were then added. The resulting mixture was purged with N2 for 5 min, and the reaction mixture was heated to 100 °C for 16 h. After the reaction was complete, as confirmed by LCMS, the reaction mixture was cooled to RT, filtered through a diatomaceous earth mat, and washed with ethyl acetate (300 mL). The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to give a crude compound as a brown liquid. Similarly, a 1.5 g batch yielded 0.5 g of crude product. The crude products from the two batches were mixed and purified by rapid chromatography using a 0-30% ethyl acetate / petroleum ether gradient to give 1 g (30%) of 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-4-methylpiperidin-4-yl)ethanol-1-ol as a pale yellow solid. LCMS: C 33 H 36 Theoretical value for N₂O₃: 508.3; Experimental value: m / z = 509.4 [M+H] + .

[0490] Step 3: Synthesis of 3-(4-(4-(2-hydroxyethyl)-4-methylpiperidin-1-yl)phenyl)piperidin-2,6-dione

[0491] Pd(OAc)₂ (0.1 g, 0.445 mmol) and 10% Pd / C (0.2 g, 1.879 mmol) were added to a stirred solution of 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-4-methylpiperidin-4-yl)ethanol-1-ol (1 g, 1.966 mmol) in 1,4-dioxane (10 mL) under a nitrogen atmosphere and at RT. The resulting mixture was stirred at RT for 16 h under H₂ pressure. After the reaction was complete, as confirmed by LCMS, the reaction mixture was filtered through a diatomaceous earth bed, washed with ethyl acetate (100 mL), and concentrated under reduced pressure. The crude extract was washed with toluene (2 x 50 mL) and MTBE (2 x 30 mL) and concentrated under reduced pressure to give 0.5 g (74%) of 3-(4-(4-(2-hydroxyethyl)-4-methylpiperidin-1-yl)phenyl)piperidin-2,6-dione as a grayish-white solid. LCMS: C 19 H 26 Theoretical value for N₂O₃: 330.2; Experimental value: m / z = 331.2 [M+H] + .

[0492] Step 4: Synthesize the title compound Under a nitrogen atmosphere at 0 °C, 0.45 g (1.362 mmol) of 3-(4-(4-(2-hydroxyethyl)-4-methylpiperidin-1-yl)phenyl)piperidin-2,6-dione in DMSO (5 mL) was added to a stirred solution with a stirring atmosphere. The resulting reaction mixture was stirred at RT for 2 h. After the reaction was complete, as confirmed by LCMS, the reaction mixture was quenched with sodium thiosulfate solution (20 mL) and extracted with ethyl acetate (2 x 50 mL). The organic layer was washed with sodium bicarbonate (20 mL) and brine solution (20 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by RP-FC using MeCN / H2O. The collected fraction was freeze-dried to obtain 2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)-4-methylpiperidin-4-yl)acetaldehyde (0.11 g, 20% yield, TFA salt), a grayish-white solid. LCMS: C 19 H 24 Theoretical value for N₂O₃: 328.2; Experimental value: m / z = 329.2 [M+H] + . 1 H NMR (400 MHz, DMSO- d6) δ(ppm): 10.89-10.79 (m, 1H), 9.86-9.73 (m, 1H), 7.38-6.81 (m, 4H), 3.73-3.62(m, 1H), 3.41-3.31 (m, 2H), 3.28-3.17 (m, 2H), 2.70-2.63 (m, 1H), 2.50-2.45(m, 3H), 2.25-1.99 (m, 2H), 1.82-1.69 (m, 2H), 1.67-1.56 (m, 2H), 1.14 (s,3H) Intermediate 36 3-(4-(2-oxo-6-azaspiro[3.4]oct-6-yl)phenyl)piperidin-2,6-dione

[0493] Step 1: Synthesis of 6-azaspiro[3.4]oct-2-one

[0494] Dioxane (27.7 mL, 111 mmol) containing 4 M HCl was added to a stirred solution of 2-oxo-6-azaspiro[3.4]octane-6-carboxylic acid tert-butyl ester (2.5 g, 11.10 mmol) in DCM (50 mL) at 0 °C. The resulting reaction mixture was stirred at RT for 2 h. After the reaction was complete, as confirmed by LCMS, the reaction mixture was concentrated under reduced pressure and washed with n-hexane (3 x 100 mL) and dried to give a brown gel-like 6-azaspiro[3.4]octane-2-one (2.89 g, 94% yield, HCl salt). LCMS: C7H 11 Theoretical value of NO: 125.1, experimental value: m / z = 126.2 [M+H] + .

[0495] Step 2: Synthesis of 6-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-6-azaspiro[3.4]oct-2-one

[0496] Cesium carbonate (14.02 g, 43.0 mmol) was added to a stirred solution of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (4.3 g, 9.641 mmol) and 6-azaspiro[3.4]oct-2-one HCl (1.55 g, 9.641 mmol) in 1,4-dioxane (50 mL). The resulting mixture was purged with N2 for 10 min. Then, Pd2(dba)3 (0.492 g, 0.538 mmol) and RuPhos (0.502 g, 1.075 mmol) were added. The resulting mixture was purged with N2 for 5 min and heated to 100 °C for 16 h. After the reaction was complete, as confirmed by LCMS, the reaction mixture was cooled to RT, filtered through a diatomaceous earth mat, and washed with ethyl acetate (300 mL). The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to give a crude compound as a brown liquid. The crude compound was purified by rapid chromatography using a 0-30% ethyl acetate / petroleum ether gradient to give a pale yellow solid, 6-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-6-azaspiro[3.4]oct-2-one (1 g, 75% purity). LCMS: C 32 H 30 Theoretical value for N₂O₃: 490.2; Experimental value: m / z = 491.1 [M+H] + .

[0497] Step 3: Synthesize the title compound Pd(OAc)₂ (0.1 g, 0.445 mmol) and 10% Pd / C (0.2 g, 1.879 mmol) were added to a stirred solution of 6-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-6-azaspiro[3.4]oct-2-one (1 g, 2.038 mmol) in 1,4-dioxane (10 mL) under a nitrogen atmosphere and at RT. The resulting reaction mixture was stirred at RT for 16 h under H₂ pressure (1 atm). After the reaction was complete, as confirmed by LCMS, the reaction mixture was filtered through a diatomaceous earth bed, washed with ethyl acetate (100 mL), and concentrated under reduced pressure. The crude product was washed with toluene (2 x 50 mL) and MTBE (2 x 30 mL) and concentrated under reduced pressure. The crude product was purified by RP-FC with MeCN / H₂O. The collected fraction was freeze-dried to obtain a grayish-white solid, 3-(4-(2-oxo-6-azaspiro[3.4]oct-6-yl)phenyl)piperidine-2,6-dione (0.104 g, 11.4% yield, TFA salt). LCMS: C 18 H20 Theoretical value for N₂O₃: 312.1 m / z; Experimental value: m / z = 313.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 10.79-10.71 (m, 1H), 7.01 (d, J = 8.6 Hz, 2H), 6.49 (d, J = 8.8Hz, 2H), 3.69 (d, J = 5.8 Hz, 1H), 3.33 (t, J = 6.8 Hz, 2H), 3.18-3.01 (m, 4H), 2.69-2.54 (m, 2H), 2.49-2.31 (m, 2H), 2.17 (t, J = 6.7 Hz, 2H), 2.10-1.94 (m,2H).

[0498] Intermediate 37 8-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2-oxa-8-azaspiro[4.5]decane-3-carboxaldehyde

[0499] Step 1: Synthesis of tert-butyl 4-allyl-4-formylpiperidine-1-carboxylate

[0500] At -25°C, tert-butyl 4-formylpiperidin-1-carboxylate (5 g, 23.44 mmol) was added partically to a stirred solution of 4-formylpiperidin-1-carboxylate (50 ml) in THF, followed by 3-bromoprop-1-ene (2.431 ml, 28.1 mmol) and... t -BuOK (3.16 g, 28.1 mmol). The reaction mixture was stirred between -25 °C and -15 °C for 1 h. After the reaction was complete, as confirmed by LCMS, the reaction mixture was cooled to RT. The reaction mixture was quenched with saturated ammonium chloride solution (200 mL) and extracted with ethyl acetate (2 x 200 mL). The organic layer was washed with brine (50 mL), dried over sodium sulfate, and concentrated to give the crude product. The crude compound was purified by rapid chromatography using a 0-25% ethyl acetate / petroleum ether gradient to give tert-butyl 4-allyl-4-carboxylidene-1-carboxylate (3 g, 50% yield) as a colorless oil. LCMS: C 14 H 23 Theoretical value for NO3: 253.2; Experimental value: m / z = 153.1 [M-Boc]- .

[0501] Step 2: Synthesis of tert-butyl 4-allyl-4-(hydroxymethyl)piperidine-1-carboxylate

[0502] NaBH4 (0.896 g, 23.68 mmol) was added fractionally to a stirred solution of 4-allyl-4-carboxylidene-1-carboxylate (3 g, 11.84 mmol) in THF (30 mL) at 0 °C. The reaction mixture was stirred at RT for 2 h. After the reaction was complete as confirmed by TLC, the reaction mixture was cooled to room temperature. Water (100 mL) was then added and the mixture was extracted with EtOAc (2 x 250 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure to give 4-allyl-4-(hydroxymethyl)piperidine-1-carboxylate (3 g, 90% yield) as a colorless oil. LCMS: C 14 H 25 Theoretical value of NO3: 255.2, experimental value: m / z = 156.2 [M-Boc] - .

[0503] Step 3: Synthesis of tert-butyl 3-(hydroxymethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxylate

[0504] Add tert-butyl 4-allyl-4-(hydroxymethyl)piperidine-1-carboxylate (3 g, 11.75 mmol) to a stirred solution of DCM (30 mL) at 0 °C. m -CPBA (8.11 g, 47.0 mmol), the reaction mixture was stirred at RT for 16 h. After the reaction was complete, as confirmed by TLC, the reaction mixture was cooled to room temperature. The reaction mixture was then quenched with sodium sulfite (100 mL), extracted with EtOAc (2 x 250 mL), and the combined organic layers were washed with sodium bicarbonate (100 mL) and brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by rapid chromatography with 20% ethyl acetate / petroleum ether to give tert-butyl 3-(hydroxymethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (2 g, 62% yield) as a colorless oil. LCMS: C 14 H 25 Theoretical value for NO4: 271.2; Experimental value: m / z = 172.1 [M-Boc] - .

[0505] Step 4: Synthesis of (2-oxa-8-azaspiro[4.5]dec-3-yl)methanol

[0506] Dioxane (18.43 mL, 73.7 mmol) containing 4 M HCl was added to a stirred solution of tert-butyl 3-(hydroxymethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (2 g, 7.37 mmol) in DCM (20 mL) at 0 °C. The resulting mixture was stirred at RT for 2 h. After the reaction was complete, as confirmed by LCMS, the reaction mixture was concentrated under reduced pressure and washed with n-hexane (3 x 100 mL), dried and lyophilized to give (2-oxa-8-azaspiro[4.5]dec-3-yl)methanol (1.7 g, 97% yield, HCl salt) as a grayish-white gelatinous solid. LCMS: C9H 17 Theoretical value for NO2: 171.1; Experimental value: m / z = 172.2 [M+H] + .

[0507] Step 5: Synthesis of (8-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-2-oxa-8-azaspiro[4.5]dec-3-yl)methanol

[0508] Cesium carbonate (7.30 g, 22.40 mmol) was added to a stirred solution of (2-oxa-8-azaspiro[4.5]dec-3-yl)methanol-HCl (0.931 g, 4.48 mmol) and 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (2 g, 4.48 mmol) in dioxane (30 mL). The resulting mixture was purged with N2 for 10 min. Pd2(dba)3 (0.041 g, 0.045 mmol) and RuPhos (0.042 g, 0.090 mmol) were then added. The resulting reaction mixture was purged with N2 for 5 min and heated to 100 °C for 16 h. After the reaction was complete, as confirmed by LCMS, the reaction mixture was cooled to RT, filtered through a diatomaceous earth mat, and washed with ethyl acetate (300 mL). The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to give a crude compound as a brown liquid. The crude compound was purified by rapid chromatography using a 0-30% ethyl acetate / petroleum ether gradient to give a pale yellow solid (8-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-2-oxa-8-azaspiro[4.5]dec-3-yl)methanol (0.6 g, 50% yield). LCMS: C34 H 36 Theoretical value for N₂O₄: 536.3 m / z; Experimental value: m / z = 537.3 [M+H] + .

[0509] Step 6: Synthesis of 3-(4-(3-(hydroxymethyl)-2-oxa-8-azaspiro[4.5]dec-8-yl)phenyl)piperidin-2,6-dione

[0510] Pd(OAc)₂ (0.05 g, 0.223 mmol) and 10% Pd / C (0.1 g, 0.940 mmol) were added to a stirred solution of (8-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-2-oxa-8-azaspiro[4.5]dec-3-yl)methanol (0.6 g, 1.118 mmol) in 1,4-dioxane (10 mL) under a nitrogen atmosphere and at RT. The resulting mixture was stirred at RT for 16 h under H₂ pressure (1 atm). After the reaction was complete, as confirmed by LCMS, the reaction mixture was filtered through a diatomaceous earth bed, washed with ethyl acetate (100 mL), and concentrated under reduced pressure. The crude extract was washed with toluene (2 x 50 mL) and MTBE (2 x 30 mL) and concentrated under reduced pressure to give 0.4 g (90% yield) of 3-(4-(3-(hydroxymethyl)-2-oxa-8-azaspiro[4.5]dec-8-yl)phenyl)piperidin-2,6-dione as a grayish-white solid. LCMS: C 20 H 26 Theoretical value for N₂O₄: 358.2; Experimental value: m / z = 359.1 [M+H] + .

[0511] Step 7: Synthesize the title compound Under a nitrogen atmosphere at 0 °C, 0.4 g (1.116 mmol) of 3-(4-(3-(hydroxymethyl)-2-oxa-8-azaspiro[4.5]dec-8-yl)phenyl)piperidin-2,6-dione in DMSO (5 mL) was added to a stirred solution. The resulting mixture was stirred at RT for 4 h. After the reaction was complete, as confirmed by LCMS, the reaction mixture was quenched with sodium thiosulfate solution (20 mL) and extracted with ethyl acetate (2 x 50 mL). The organic layer was washed with sodium bicarbonate (20 mL) and brine solution (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by RP-FC with MeCN / H2O. The collected fraction was freeze-dried to obtain 0.124 g of 8-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2-oxa-8-azaspiro[4.5]decane-3-carboxaldehyde (TFA salt), a grayish-white solid. LCMS: C 20 H 24 Theoretical value for N₂O₄: 356.2; Experimental value: m / z = 357.2 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ (ppm):10.88-10.80 (m, 1H), 9.64 (d, J = 1.5 Hz, 1H), 7.24-6.98 (m, 4H), 4.43 (dd, J =1.4, 7.2 Hz, 1H), 3.84 - 3.69 (m, 2H), 3.30 (br d, J = 6.3 Hz, 2H), 2.73-2.52(m, 4H), 2.46 (br t, J = 3.8 Hz, 2H), 2.37-1.94 (m, 4H), 1.92-1.77 (m, 2H), 1.75-1.57 (m, 4H).

[0512] Intermediate 38 Racemic-(4-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperazin-1-yl)acetic acid

[0513] Step 1: Synthesis of 2-[4-(4-bromophenyl)piperazin-1-yl]tert-butyl acetate

[0514] Dibromobenzene (588 mg, 2.496 mmol, 1 equiv), Pd2(dba)3 (228 mg, 0.250 mmol, 0.1 equiv), BINAP (310 mg, 0.499 mmol, 0.2 equiv), and Cs2CO3 (2440 mg, 7.488 mmol, 3 equiv) were added to a mixture of 2-(piperazin-1-yl)-tert-butyl acetate (500 mg, 2.496 mmol, 1 equiv) and toluene (5 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1 / 1) to give 2-[4-(4-bromophenyl)piperazin-1-yl]-tert-butyl acetate (300 mg, 33.82%) as a yellow oil. LCMS: (C 16 H 23 Required mass of BrN2O2 = 355.1; Observational mass = 355.1 [M+H] + .

[0515] Step 2: Synthesis of 2-(4-{4-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}piperazin-1-yl)tert-butyl acetate

[0516] Add 10 mL of H₂O containing 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine (1.76 g, 4.223 mmol, 1.5 equiv), XPhos Pd G₂ (0.44 g, 0.563 mmol, 0.2 equiv), and K₃PO₄ (1.79 g, 8.445 mmol, 3 equiv) to a mixture of 2-[4-(4-bromophenyl)piperazin-1-yl]tert-butyl acetate (1 g, 2.815 mmol, 1 equiv), xylosporin-1-yl)pyridine (1.76 g, 4.223 mmol, 1.5 equiv), xylosporin-1-yl)pyridine (0.44 g, 0.563 mmol, 0.2 equiv), and kJ of K₃PO₄ (1.79 g, 8.445 mmol, 3 equiv). Stir the resulting mixture at 60 °C under a nitrogen atmosphere for 2 h. Concentrate the mixture under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1 / 2) to give 2-(4-{4-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}piperazin-1-yl)tert-butyl acetate (650 mg, 36.74%) as a yellow solid. LCMS: (C 35 H 39 Required mass of N3O4 = 566.3; Observed mass = 566.3 [M+H] + .

[0517] Step 3: Synthesis of 2-{4-[4-(2,6-dioxopiperidin-3-yl)phenyl]piperazin-1-yl}tert-butyl acetate

[0518] Pd / C (650 mg) was added to a mixture of 2-(4-{4-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}piperazin-1-yl)tert-butyl acetate (650 mg, 1.149 mmol, 1 equiv) in THF (25 mL) at room temperature. The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. The mixture was filtered. The filtrate was concentrated under reduced pressure. This yielded 2-{4-[4-(2,6-dioxopiperazin-3-yl)phenyl]piperazin-1-yl}tert-butyl acetate (400 mg, crude product) as a pale yellow solid. LCMS: (C 21 H 29 Required mass of N3O4 = 388.2; Observational mass = 388.2 [M+H] + .

[0519] Step 4: Synthesis of racemic-(4-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperazin-1-yl)acetic acid A mixture of 2-{4-[4-(2,6-dioxadiazin-3-yl)phenyl]piperazin-1-yl}acetate tert-butyl ester (2 g, 5.162 mmol, 1 equiv) in HCl (gas) / 1,4-dioxane (20 mL, 4 M) was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum and further lyophilized. The crude product was purified by wet milling with n-hexane. This yielded racemic 4-{4-[(3R)-2,6-dioxadiazin-3-yl]phenyl}piperazin-1-yl)acetic acid (1.5316 g, 81.58%) as a grayish-white solid. LCMS: (C 17 H 21 Required mass of N3O4 = 332.2; Observational mass = 332.2 [M+H] + .

[0520] 1 H NMR (400 MHz, DMSO- d 6) δ 10.79 (s, 1H), 7.12 (d, J = 8.0 Hz, 2H), 6.97 (d, J= 8.4 Hz, 2H), 4.22 (s, 2H), 4.07 - 2.88 (m, 9H), 2.72 - 2.59 (m,1H), 2.48 - 2.40 (m, 1H), 2.22 - 2.06 (m, 1H), 2.06 - 1.94 (m, 1H).

[0521] Intermediate 39 3-(4-(3-oxo-1-oxa-8-azaspiro[4.5]dec-8-yl)phenyl)piperidin-2,6-dione

[0522] Step 1: Synthesis of 8-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-1-oxa-8-azaspiro[4.5]dec-3-one

[0523] Cesium carbonate (18.2 g, 56 mmol) was added to a stirred solution of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine 1 (5 g, 11.2 mmol), 1-oxa-8-azaspiro[4.5]dec-3-one·HCl 2 (2.141 g, 11.2 mmol) in dioxane (60 mL). The resulting mixture was purged with N2 for 10 min. Pd2(dba)3 (0.513 g, 0.560 mmol) and RuPhos (0.523 g, 1.120 mmol) were then added. The resulting mixture was purged with N2 for 5 min and the reaction mixture was heated to 100 °C for 16 h. After the reaction was complete, as confirmed by LCMS, the reaction mixture was cooled to RT, filtered through a diatomaceous earth pad, and washed with ethyl acetate (300 mL). The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to give a crude compound as a brown liquid. The crude compound was purified by Biotage-Isolera (silica gel: 230-400 mesh) using ethyl acetate / petroleum ether (0-30%) as eluent to give a crude product (2 g) as a yellow solid. The crude product was purified by preparative HPLC using an Xselect C18 250 mm column, method: water / MeCN containing 0.1% TFA, flow rate: 12 mL / min. The collected fraction was lyophilized to give a pale yellow solid, 8-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-1-oxa-8-azaspiro[4.5]dec-3-one (1.1 g, 13% yield): LCMS: m / z = 522.1 [M+H] + .

[0524] 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.75 - 7.69 (m, 1H), 7.51-7.30 (m,12H), 7.14-7.03 (m, 2H), 6.54-6.47 (m, 1H), 5.41 (s, 2H), 5.37 (s, 2H), 4.03 (s, 2H), 3.43-3.27 (m, 4H), 2.51 (s, 2H), 1.86 (d, J = 4.5 Hz, 4H).

[0525] Step 2: Synthesize the title compound Pd(OAc)₂ (0.150 g, 0.668 mmol) and 10% Pd / C (0.200 g, 1.879 mmol) were added to a stirred solution of 8-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-1-oxa-8-azaspiro[4.5]dec-3-one 3 (1.1 g, 2.113 mmol) in 1,4-dioxane (30 mL) under a nitrogen atmosphere and at RT. The resulting mixture was stirred at RT for 16 h under H₂ pressure (1 atm). After the reaction was complete, as confirmed by LCMS, the reaction mixture was filtered through a diatomaceous earth bed, washed with ethyl acetate (100 mL), and concentrated under reduced pressure. The crude compound was washed with toluene (2 x 50 mL) and MTBE (2 x 30 mL), the residue was concentrated under reduced pressure, and lyophilized to give the title compound (0.504 g) as a grayish-white solid. g, 52% yield (TFA salt). LCMS: m / z = 343.2 [M+H] + .

[0526] 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 10.85-10.79 (m, 1H), 7.10 (br s,2H), 7.03-7.01 (m, 2H), 4.07-4.06 (m, 2H), 3.76 (br s, 1H), 3.28 (br s, 4H), 2.64 (d, J = 5.5 Hz, 2H), 2.11-2.04 (m, 4H), 2.51 (s, 2H), 1.85-1.84 (m, 4H).

[0527] Intermediate 40 Racemic-(R)-1-(4-(2,6-dioxopiperidin-3-yl)-2,3-difluorophenyl)piperidin-4-carboxaldehyde

[0528] Step 1: Synthesis of 1-(4-bromo-2,3-difluorophenyl)-4-(dimethoxymethyl)piperidine

[0529] At 20°C, 1-bromo-2,3-difluoro-4-iodobenzene (20.0 g, 62.7 mmol, 1.00 μL) was subjected to oxidation. eq ), 4-(dimethoxymethyl)piperidine (10.9 g, 68.9 mmol, 1.10 g) eq ), BINAP (1.56 g, 2.51 mmol, 0.04 eq ), t-BuONa (12.0 g, 125 mmol, 2.00 eq ) and Pd2(dba)3 (1.15 g, 1.25 mmol, 0.02 eq Toluene (200 mL) was added to the solution of [the compound], and the mixture was purged three times with N2. The mixture was stirred at 100 °C for 16 h. LC-MS showed 28.9% detection of the desired MS. The mixture was concentrated directly under vacuum. The residue was purified by column chromatography (SiO2, ethyl acetate / petroleum ether = 0 / 1 to 1 / 20, ethyl acetate / petroleum ether = 1 / 10, Rf = 0.30). The fraction was then concentrated under vacuum to give the title compound (14.0 g, 31.5 mmol, 50.3% yield, 79.0% purity) as a yellow solid. δ 7.21 - 7.12 (m, 1H), 6.67 -6.55 (m, 1H), 4.10 (d, J = 7.1 Hz, 1H), 3.46 (br d, J = 12.0 Hz, 2H), 3.38 (s,6H), 2.73 - 2.60 (td, 2H), 1.85 (br d, J = 13.9 Hz, 2H), 1.56 - 1.43 (m, 2H), 1.26 (t, 1H) Step 2: Synthesis of 2,6-bis(benzyloxy)-3-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2,3-difluorophenyl)pyridine

[0530] At 20°C, 1-(4-bromo-2,3-difluorophenyl)-4-(dimethoxymethyl)piperidine (13.0 g, 29.7 mmol, 1.00 mmol) was subjected to oxidation. eq ), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine (16.1 g, 38.6 mmol, 1.30 eq ), Cs2CO3 (24.1 g, 74.2 mmol, 2.50 eq ) and Pd(dppf)Cl2.CH2Cl2 (1.21 g, 1.48 mmol, 0.05 eqDioxane (260 mL) and H2O (52.0 mL) were added to the solution and the mixture was purged three times with N2. The mixture was stirred at 100 °C under N2 atmosphere for 16 h. The residue was added to water (200 mL) and extracted with ethyl acetate (60.0 mL x 3). The combined organic layers were washed with brine (100 mL x 1), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, ethyl acetate / petroleum ether = 0 / 1 to 1 / 20, ethyl acetate / petroleum ether = 1 / 10, Rf = 0.25). The fraction was then concentrated under vacuum. The desired product, 2,6-bis(benzyloxy)-3-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2,3-difluorophenyl)pyridine (8.80 g, 13.8 mmol, 46.5% yield, 88.0% purity), was obtained as a yellow solid. NMR: (400 MHz, CDCl3) δ 7.56 - 7.29 (m, 11H), 7.10 - 6.95 (m, 1H), 6.46 (d, J = 8.1 Hz, 1H), 5.46 - 5.23 (m, 4H), 4.12 (d, J = 7.2 Hz, 1H), 3.54 (brd, J = 11.9 Hz, 2H), 3.40 (s, 6H), 2.71 (t, J = 11.4 Hz, 2H), 1.87 (br d, J = 12.8Hz, 2H), 1.81 - 1.71 (m, 1H), 1.64 - 1.48 (m, 3H) Step 3: Synthesis of racemic-(R)-3-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2,3-difluorophenyl)piperidin-2,6-dione

[0531] Racemic reaction of -(R)-3-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2,3-difluorophenyl)piperidin-2,6-dione (43.0 g, 76.7 mmol, 1.00 μL) under N2 atmosphere. eqPd / C (12.9 g, 12.1 mmol, 10% purity) and Pd(OH)₂ (12.9 g, 27.5 mmol, 30% purity) were added to a solution of THF (430 mL). The suspension was degassed and purged three times with H₂. The mixture was stirred at 25 °C for 6 h with H₂ (50 psi), then filtered and concentrated. The crude product was wet-milled at 25 °C for 30 min using MTBE (20.0 mL), filtered, and the filter cake was dried under reduced pressure to yield racemic-(R)-3-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2,3-difluorophenyl)piperidin-2,6-dione (8.00 g, 20.9 mmol, 88.8% yield) as a white solid. 1 H NMR: (400 MHz, DMSO- d 6) δ 10.92 (s, 1H), 7.18 -6.69 (m, 2H), 4.16 (d, J = 6.5 Hz, 1H), 4.11 - 4.00 (m, 1H), 3.47 - 3.38 (m,3H), 3.32 (s, 6H), 2.85 - 2.64 (m, 3H), 2.30 - 2.13 (m, 1H), 2.10 - 1.95 (m,1H), 1.84 - 1.68 (m, 3H), 1.52 - 1.35 (m, 2H) Step 4: Synthesize the title compound Racemic-(R)-3-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2,3-difluorophenyl)piperidin-2,6-dione (4.00 g, 10.4 mmol, 1.00 mmol) eq Slowly add HCl (2.00M, 93.1 mL, 17.8 mL) dropwise to a solution of THF (93.0 mL). eq After addition, the reaction solution was stirred at 70 °C for 1 h. Then, a saturated NaHCO3 solution was added to the reaction mixture until pH = 7, followed by extraction with EtOAc (30.0 mL x 3), drying over Na2SO4, filtration, and concentration to obtain the crude product. The crude product was wet-milled with EtOAc (10.0 mL) at 25 °C for 30 min to yield the title compound as a white solid (2.00 g, 5.86 mmol, 56.0% yield, 98.4% purity). LCMS: m / z = 337.2 (M+H) + 1 H NMR: (400 MHz, DMSO- d6) δ 10.88 (s, 1H), 9.64 (s, 1H), 6.99 (br t, J = 7.5 Hz, 1H), 6.82 (br t, J = 7.9 Hz, 1H), 4.12 - 3.94 (m, 1H), 3.35 - 3.26 (m, 2H), 2.88 -2.67 (m, 3H), 2.55 (br d, J = 3.1 Hz, 1H), 2.49 - 2.43 (m, 1H), 2.26 - 2.09 (m,1H), 2.05 - 1.88 (m, 3H), 1.73 - 1.56 (m, 2H) Intermediate 41 Synthesis of racemic-(R)-2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)-4-fluoropiperidin-4-yl)acetaldehyde

[0532] Step 1: Synthesis of tert-butyl 4-fluoro-4-(2-hydroxyethyl)piperidine-1-carboxylate

[0533] A mixture of tert-butyl 4-(2-ethoxy-2-oxoethyl)-4-fluoropiperidine-1-carboxylate (10.5 g, 36.3 mmol, 1.00 eq) in THF (105 mL) was degassed under vacuum and purged several times with N2. The mixture was cooled to -20 to 0 °C, and then LiAlH4 (2.50 M, 29.0 mL, 2.00 eq) was added dropwise to the mixture under N2 at -20 to 0 °C. The resulting mixture was stirred under N2 at -20 to 0 °C for 2 h. H2O (5.00 mL) was added dropwise to the reaction mixture at -20 to 0 °C to quench the reaction under N2 flow, followed by drying the mixture with Na2SO4, filtering, and concentrating under vacuum. The crude product, tert-butyl 4-fluoro-4-(2-hydroxyethyl)piperidine-1-carboxylate (9.00 g, crude product), which was a colorless oil, was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 4.00 - 3.79 (m, 4H), 3.08 (br t, J = 12.0 Hz,2H), 1.95 - 1.83 (m, 5H), 1.70 - 1.50 (m, 2H), 1.45 (s, 9H) Step 2: Synthesis of 2-(4-Fluoroperidin-4-yl)ethyl-1-ol hydrochloride

[0534] HCl / dioxane (2.00 M, 53.2 mL, 2.47 eq) was added to a mixture of tert-butyl 4-fluoro-4-(2-hydroxyethyl)piperidin-1-carboxylate (10.6 g, 43.1 mmol, 1.00 eq) and dioxane (11.0 mL) at 10–20 °C. The resulting mixture was stirred at 10–20 °C for 12 h. The mixture was concentrated under vacuum. The crude 2-(4-fluoropiperidin-4-yl)ethanol-1-ol hydrochloride (7.92 g, 43.1 mmol, 100% yield, HCl), as a white solid, was used in the next step without further purification. 1 H NMR (400 MHz, DMSO) δ 9.20 (br s, 2H), 4.74 - 4.01 (m, 1H), 3.61- 3.49 (m, 2H), 3.16 (br d, J = 12.4 Hz, 2H), 3.02 - 2.85 (m, 2H), 2.10 - 1.87(m, 4H), 1.86 - 1.71 (m, 2H) Step 3: Synthesis of 2-(1-(4-bromophenyl)-4-fluoropiperidin-4-yl)ethanol-1-ol

[0535] K₂CO₃ (15.6 g, 113 mmol, 1.10 eq), CuI (1.44 g, 7.54 mmol, 0.20 eq), and L-proline (1.74 g, 15.0 mmol, 0.40 eq) were added to a mixture of 1-bromo-4-iodobenzene (11.7 g, 41.4 mmol, 1.10 eq), 2-(4-fluoropiperidin-4-yl)ethanol-1-ol hydrochloride (6.92 g, 37.7 mmol, 1.00 eq, HCl) in DMSO (82.0 mL) at 15–25 °C under N₂. The resulting mixture was stirred at 75–80 °C under N₂ for 16 h. The mixture was poured into H2O (200 mL), extracted with ethyl acetate (80.0 mL * 3), and the combined organic layers were washed with 3.00% NH3·H2O solution (50.0 mL) and brine (50.0 mL). The mixture was dried over Na2SO4, filtered, and concentrated under vacuum. The solution was then analyzed by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1, petroleum ether / ethyl acetate = 2 / 1, R...). f = 0.21) The residue was purified and concentrated under vacuum. Crude 2-(1-(4-bromophenyl)-4-fluoropiperidin-4-yl)ethanol-1-ol was obtained as a yellow solid (5.70 g, 18.2 mmol, 48.4% yield, 96.7% purity). LCMS: C 13 H 17 The theoretical value of BrFNO is 301.0, and the experimental value is: m / z = 304.1 (M+H). + .

[0536] Step 4: Synthesis of 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-4-fluoropiperidin-4-yl)ethanol-1-ol

[0537] A mixture of 2-(1-(4-bromophenyl)-4-fluoropiperidin-4-yl)ethanol-1-ol (5.70 g, 18.8 mmol, 1.00 eq) in dioxane (114 mL) and H₂O (22.8 mL) was supplemented with 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyridine (10.2 g, 24.5 mmol, 1.30 eq) and Cs₂CO₃ (15.4 g, 47.2 mmol, 2.50 eq), and the suspension was degassed under vacuum and purged several times with N₂. Then, Pd(dppf)Cl₂.CH₂Cl₂ (1.54 g, 1.89 mmol, 0.10 eq) was added to the mixture under N₂. The resulting mixture was stirred at 100 °C for 16 h. The reaction mixture was poured into water (400 mL) and extracted with ethyl acetate (200 mL * 3). The organic phase was washed with brine (200 mL), dried over Na₂SO₄, and concentrated under vacuum. The solution was then analyzed by column chromatography (SiO₂, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1, petroleum ether / ethyl acetate = 2 / 1, R...). f = 0.21) The purified residue was concentrated under vacuum. 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-4-fluoropiperidin-4-yl)ethanol-1-ol (7.10 g, 13.7 mmol, 72.8% yield, 99.1% purity) was given as a yellow solid. LCMS: C 32 H 33 Theoretical value of FN2O3: 512.2, experimental value: m / z = 513.3 (M+H) + 1 H NMR (400MHz, CDCl3) δ 7.60 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.8 Hz, 2H), 7.48 - 7.28 (m,10H), 6.99 (br d, J = 8.4 Hz, 2H), 6.47 (d, J = 8.2 Hz, 1H), 5.52 - 5.31 (m, 4H), 3.98 - 3.83 (m, 2H), 3.55 (br d, J = 12.4 Hz, 2H), 3.15 (dt, J = 2.0, 12.2 Hz,2H), 2.09 - 1.78 (m, 6H), 1.65 (br d, J = 4.4 Hz, 1H) Step 5: Synthesis of racemic-(R)-3-(4-(4-fluoro-4-(2-hydroxyethyl)piperidin-1-yl)phenyl)piperidin-2,6-dione

[0538] Pd / C (1.98 g, 1.86 mmol, 10% purity, 0.145 eq) was added to a solution of 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-4-fluoropiperidin-4-yl)ethanol-1-ol (6.60 g, 12.9 mmol, 1.00 eq) in THF (200 mL) under N2 conditions, followed by the addition of Pd(OH)2 (1.98 g, 2.82 mmol, 20% purity, 0.219 eq). The suspension was degassed and purged three times with H2. The mixture was stirred at 25 °C for 14 h under H2 (50 Psi). The mixture was filtered through a diatomaceous earth mat to obtain a filtrate. The filter cake was washed with THF (200 mL * 3), and the combined filtrates were concentrated under vacuum. The residue was wet-milled with MTBE (30.0 mL) at 20–25 °C for 30 min, filtered, and the filter cake was washed with MTBE (8.00 mL * 3) and dried under vacuum. Racemic (R)-3-(4-(4-fluoro-4-(2-hydroxyethyl)piperidin-1-yl)phenyl)piperidin-2,6-dione (3.93 g, 11.0 mmol, 85.6% yield, 93.8% purity) was obtained as a white solid. LCMS: C 18 H 23 Theoretical value of FN2O3: 334.2, experimental value: m / z = 335.2 (M+H) + 1 H NMR (400 MHz, DMSO) δ 10.77 (s, 1H), 7.04 (br d, J =8.4 Hz, 2H), 6.92 (br d, J = 8.4 Hz, 2H), 4.48 (br t, J = 5.2 Hz, 1H), 3.72 (brdd, J = 4.8, 10.8 Hz, 1H), 3.63 - 3.52 (m, 2H), 3.46 (br d, J = 12.0 Hz, 2H), 2.92 (br t, J= 12.0 Hz, 2H), 2.71 - 2.56 (m, 1H), 2.48 - 2.34 (m, 1H), 2.22 -1.94 (m, 2H), 1.92 - 1.65 (m, 6H) Step 6: Synthesize the title compound

[0539] IBX (4.27 g, 15.2 mmol, 1.50 eq) was added to a mixture of racemic (R)-3-(4-(4-fluoro-4-(2-hydroxyethyl)piperidin-1-yl)phenyl)piperidin-2,6-dione (3.40 g, 10.17 mmol, 1.00 eq) in DMSO (34.0 mL) at 20–25 °C, and the mixture was stirred at 20–25 °C for 4 h. The mixture was poured into H₂O (150 mL), extracted with ethyl acetate (100 mL * 4), and the combined organic layers were washed with saturated NaHCO₃ (50.0 mL) and brine (150 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude product was wet-milled with ethyl acetate (50.0 mL) at 25 °C for 30 min, filtered, the filter cake was washed with ethyl acetate (5.00 mL * 3), and dried under vacuum. Racemic (R)-2-(1-(4-(2,6-dioxopiridin-3-yl)phenyl)-4-fluoropiperidin-4-yl)acetaldehyde was obtained as a yellow solid (2.65 g, 7.75 mmol, 76.2% yield, 97.2% purity). LCMS: C 18 H 21 Theoretical value of FN2O3: 332.2; Experimental value: m / z = 333.2(M+H) + .

[0540] 1 H NMR (400 MHz, DMSO) δ 10.77 (s, 1H), 9.79 (br d, J = 1.2 Hz, 1H), 7.06(d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 3.73 (dd, J= 4.8, 11.0 Hz, 1H),3.58 - 3.45 (m, 2H), 3.08 - 2.91 (m, 2H), 2.87 - 2.75 (m, 2H), 2.69 - 2.57(m, 1H), 2.49 - 2.41 (m, 1H), 2.20 - 2.06 (m, 1H), 2.05 - 1.80 (m, 5H) Intermediate 42 rel -( R )-1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-carboxylic acid

[0541] Step 1: Synthesis of tert-butyl 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidine-4-carboxylate

[0542] A mixture of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (170 g, 380 mmol), tert-butyl piperidine-4-carboxylate (84.6 g, 457 mmol), K3PO4 (242 g, 1.14 mol), and XPhos Pd G3 (32.2 g, 38.0 mmol) in DMF (1000 mL) was stirred at 100 °C until completion was determined by LC-MSC. Once complete, H2O (2.00 L) was added to the mixture and extracted with ethyl acetate (700 mL x 2). The organic layer was washed with brine (700 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude residue. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 100:1 to 20:1) to give the desired compound as a yellow solid (160 g, mmol, 71% yield). LC-MSC 35 H 38 The theoretical value of N₂O₄ is 550.3, and the experimental value is m / z = 551.3 [M+H]. + .

[0543] Step 2: Synthesis racemic -( R 1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-carboxylic acid tert-butyl ester

[0544] Air was purged from a mixture of tert-butyl 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-carboxylate (75.0 g, 136.1 mmol) and Pd / C (15.0 g, 14.1 mmol, 10% purity) and Pd(OH)₂ (15.0 g, 21.3 mmol, 20% purity) in THF (750 mL) and backfilled with N₂ (3x). Next, N₂ was purged from the container and backfilled with H₂ (3x), followed by stirring at 50 °C until completion was determined by LCMS. Once complete, the mixture was filtered through diatomaceous earth and the filtrate was concentrated under vacuum to give the desired compound, which was then advanced (96 g) without any further purification. LCMS C 21 H 28 The theoretical value for N₂O₄ is 372.2, and the experimental value is m / z = 373.3 [M+H]. + .

[0545] Step 3: Synthesis racemic -( R )-1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-carboxylic acid

[0546] At 0℃ racemic -( R 45.0 g (120 mmol) of tert-butyl piperidine-4-carboxylate (45.0 g, 120 mmol) was slowly added to a solution in DCM (500 mL) with TFA (179 mL, 2.42 mol), and the mixture was stirred at 30 °C until completion was determined by LCMS. Once complete, the mixture was concentrated to produce a crude residue. The residue was purified by RP-FC (5-95%) to give the desired compound (40.3 g, 75% yield, in two steps) as a grayish-white solid. LCMS C 17 H 20 The theoretical value for N₂O₄ is 316.2, and the experimental value is m / z = 317.1 [M+H]. + .

[0547] Step 4: Synthesis rel -( R 1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-carboxylic acid tert-butyl ester

[0548] Purification was performed using SFC (DAICEL CHIRALPAK AS (250 mm * 30 mm, 10 μm); mobile phase: [CO2-i-PrOH / ACN]; B%: 35%, isocratic elution mode). racemic -( R 1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-carboxylic acid tert-butyl ester. The desired compound was obtained as a white solid (first eluting isomer, 20.0 g, 40% yield). LC-MSC 21 H 28 The theoretical value for N₂O₄ is 372.2, and the experimental value is 373.4 [M+H]. + .

[0549] Step 5: Synthesis rel -( R 1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-carboxylic acid tert-butyl ester

[0550] Purification was performed using SFC (DAICEL CHIRALPAK AS (250 mm * 30 mm, 10 μm); mobile phase: [CO2-i-PrOH / ACN]; B%: 35%, isocratic elution mode). racemic -( R 1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-carboxylic acid tert-butyl ester. The desired compound was obtained as a white solid (second eluting isomer, 19.0 g, 37% yield). LC-MSC 21 H 28 The theoretical value for N₂O₄ is 372.2, and the experimental value is 373.4 [M+H]. + .

[0551] Step 6: Synthesis rel -( R )-1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-carboxylic acid

[0552] As described in step 3 of intermediate 41, using rel -( R )-1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-carboxylic acid tert-butyl ester is substituted racemic -( R The compound was prepared by tert-butyl 1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-carboxylate (22 g, 93% yield). LCMS C 17 H20 The theoretical value for N₂O₄ is 316.1, and the experimental value is m / z = 317.2 [M+H]. + .

[0553] Synthetic title compound As described in step 3 of intermediate 41, using rec -( R )-1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-carboxylic acid tert-butyl ester is substituted racemic -( R The compound was prepared by tert-butyl 1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-carboxylate (14.2 g, 94% yield). LCMS C 17 H 20 The theoretical value for N₂O₄ is 316.1, and the experimental value is m / z = 317.2 [M+H]. + .

[0554] Example Purification procedure Preparative-scale HPLC was performed using columns such as SunFire Prep C18 OBD, XBridge Prep OBD C18, and Xbridge Shield RP18 OBD, with solvent systems such as (water-0.1% formic acid) / acetonitrile, (water-10 mmol / L NH4HCO3) / acetonitrile, or (water-10 mmol / L NH4HCO3) / acetonitrile. Chromatography A refers to silica gel purification, typically eluted in a pre-packed cartridge with a mixture of EtOAc in hexane or petroleum ether; Chromatography B refers to elution with a mixture of MeOH in DCM; and Chromatography C refers to elution using C18 reversed-phase silica gel with a mixture of acetonitrile in water. In biological examples, compounds without stereochemical plots were tested as mixtures of racemic or diastereomers.

[0555] abbreviation The abbreviations used in the examples include the following: BOP (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium; BINAP (2,2-bis(diphenylphosphino)-1,1-naphthyl); Bn (benzyl); Boc (tert-butoxycarbonyl); CBz (benzyloxycarbonyl); HATU (hexafluorophosphate) N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethylammonium N-oxide); DMSO (dimethyl sulfoxide); THF (tetrahydrofuran); EtOAc (ethyl acetate); ACN (acetonitrile); Et2O (diethyl ether); DCM (dichloromethane); MeOH (methanol); EtOH (ethanol); DCE (1,2-dichloroethane); TEA (trimethylamine); TFA (trifluoroacetic acid); DIEA (N,N-diisopropylethylamine); DIPEA ( N , N -Diisopropylethylamine); DMF ( N , N -dimethylformamide); NMP ( N 1-Methyl-2-pyrrolidone); N,N-dimethylacetamide (DMA); EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide); HFIP (hexafluoroisopropanol); HOBT (hydroxybenzotriazole); STAB (sodium triacetoxyborohydride); Pd2(dba)3 (tris(dibenzylacetone)dipalladium); Pd(dppf)Cl2 ([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)); PE (petroleum ether); RuPhos (third-generation palladium ring: methanesulfonate (2-dicyclohexylphosphino-2',6'-bis(dimethylamino)-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)); SFC (supercritical fluid chromatography); T3P (propanephosphonic anhydride); XantPhos (9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthan); TFA (trifluoroacetic acid); rt or RT (room temperature); anh (anhydrous); eq. or equiv. (equivalent); FC (rapid chromatography).

[0556] Example 1 Racemic-N-[(3R)-2,6-dioxopiperidin-3-yl]-4-(4-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carbonyl}piperazin-1-yl)pyridine-2-carboxamide

[0557] Step 1: Synthesis of methyl 1-(6-chloropyridazine-4-yl)-4-phenylpiperidine-4-carboxylate

[0558] A vial was filled with DMSO containing 5-bromo-3-chloropyridazine (0.50 g, 2.5849 mmol), methyl 4-phenylpiperidin-4-carboxylate (0.57 g, 2.5849 mmol), and N,N-diisopropylethylamine (1.81 mL, 1.34 g, 10.3397 mmol). The solution was heated to 120°C overnight and then purified directly by RP-FC to yield the title compound (750 mg, 86%). LCMS: C 17 H 18 Theoretical value of ClN3O2: 331.2, experimental value: 332.4 [M+H] + .

[0559] Step 2: Synthesis of methyl 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-phenylpiperidine-4-carboxylate

[0560] Methyl 1-(6-chloropyridazine-4-yl)-4-phenylpiperidin-4-carboxylate (500.00 mg, 1.5069 mmol), tetrakis(triphenylphosphine)palladium(0) (0.17 g, 0.1507 mmol), potassium carbonate (0.83 g, 6.0277 mmol), and 2-hydroxyphenylboronic acid (207.85 mg, 1.5069 mmol) were added to a flask equipped with a stir bar. 12 mL of anhydrous and pre-purged 1,4-dioxane was added to these dried powders. The vial was sealed and heated to 95°C overnight. Once complete, the crude mixture was filtered through diatomaceous earth and purified by RP-FC to provide the title compound (70 mg, 12%). LCMS: C 23 H 23 Theoretical value of N3O3: 389.5, experimental value: m / z = 390.5 [M+H] + .

[0561] Step 3: Synthesis of 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-phenylpiperidin-4-carboxylic acid

[0562] Methyl 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-phenylpiperidin-4-carboxylate (200 mg, 0.5135 mmol) was dissolved in 2 mL of 1:1 dioxane:1M NaOH. The mixture was stirred until complete, approximately 3 hours, then filtered and purified directly by RP-FC to provide the title compound in quantitative yield. LCMS: C 22 H 21 Theoretical value of N3O3: 375.4, experimental value: m / z = 376.4 [M+H]+ .

[0563] Step 4: Synthesis of 4-fluoropyridinecarboxylic acid

[0564] NaOH (3.87 g, 96.7 mmol, 1.50 eq) was added to a solution of methyl 4-fluoropyridinecarboxylate (10.0 g, 64.4 mmol, 1.00 eq) in THF (100 mL) and H₂O (50.0 mL) at 25 °C. The mixture was then stirred at 25 °C for 2 h. The pH of the mixture was adjusted to 2–3 with 1 N HCl and then lyophilized without purification. 4-Fluoropyridinecarboxylic acid (18.0 g, 122 mmol, 94.8% yield, 95.8% purity) was obtained as a white solid. LCMS C₆H₄FNO₂ theoretical value: 141.0, experimental value: m / z = 141.1 [M+H] + .

[0565] 1 H NMR: (400 MHz, DMSO) δ 8.70 (dd, J = 8.4, 5.6 Hz, 1H), 7.83 (dd, J = 9.6, 2.4 Hz, 1H), 7.54 (ddd, J = 8.8, 5.6, 2.4 Hz, 1H).

[0566] Step 5: Synthesis of racemic-(R)-N-(2,6-dioxopiperidin-3-yl)-4-fluoropyridinecarboxamide

[0567] A solution of 4-fluoropyridinecarboxylic acid (9.00 g, 61.1 mmol, 95.8% purity, 1.00 eq) in SOCl2 (147 g, 1.24 mol, 90.0 mL, 20.3 eq) was stirred at 90 °C for 1 h. The mixture was concentrated to remove SOCl2. The residue was dissolved in DCM (200 mL). The mixture was added dropwise at 0 °C to a solution of 3-aminopiperidine-2,6-dione (10.1 g, 61.1 mmol, 1.00 eq, HCl) and NET3 (30.9 g, 305 mmol, 42.5 mL, 5.00 eq) in DCM (200 mL). The mixture was then stirred at 25 °C for 12 h. The mixture was concentrated under vacuum to obtain the unpurified crude product. Racemic (R)-N-(2,6-dioxopiperidin-3-yl)-4-fluoropyridine carboxamide (19.0 g, 58.1 mmol, 95.1% yield, 76.8% purity) was obtained as a blue solid. LCMS C 11 H 10 Theoretical value of FN3O3: 251.1, experimental value: m / z = 252.0 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.89 (br s, 1H), 9.16 (d, J = 8.5 Hz, 1H), 8.67 - 8.82 (m, 1H), 7.81 - 7.91 (m, 1H) 7.60 (ddd, J = 8.8, 5.6, 2.8 Hz,1H), 4.69 - 4.89 (m, 1H), 3.38 (br d, J = 7.2 Hz, 1H), 2.74 - 2.87 (m, 1H),2.53 - 2.59 (m, 1H), 2.23 (qd, J = 13.2, 4.4 Hz, 1H), 2.00 (dtd, J = 12.8,5.2, 5.2, 2.4 Hz, 1H).

[0568] Step 6: Synthesis of racemic (R)-4-(2-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

[0569] Racemic (R)-N-(2,6-dioxopiperidin-3-yl)-4-fluoropyridinecarboxamide (17.0 g, 51.9 mmol, 76.8% purity, 1.00 eq) and tert-butyl piperazine-1-carboxylate (9.68 g, 51.9 mmol, 1.00 eq) in DMF (170 mL) was mixed with DIEA (26.8 g, 207 mmol, 36.2 mL, 4.00 eq). The mixture was then stirred at 100 °C for 12 h. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (3 x 250 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 1 / 1). Racemic (R)-4-(2-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-4-yl)piperazine-1-carboxylic acid tert-butyl ester was obtained as a yellow solid (1.86 g, 3.98 mmol, 7.66% yield, 89.3% purity). LCMS C 20 H 27 Theoretical value of N5O5: 417.2, experimental value: m / z = 418.3 [M+H] + .

[0570] 1 H NMR (400 MHz, DMSO) δ 10.85 (s, 1H), 8.96 (d, J = 8.4 Hz, 1H), 8.24 (d, J = 6.0 Hz, 1H), 7.46 (d, J = 2.8 Hz, 1H), 7.00 (dd, J = 6.0, 2.8Hz, 1H), 4.69 - 4.80 (m, 1H), 3.44 (br dd, J = 14.8, 5.6 Hz, 8H), 2.74 - 2.85(m, 1H), 2.13 - 2.24 (m, 1H), 1.96 - 2.04 (m, 1H), 1.42 (s, 9H) Step 7: Synthesis of racemic-(R)-N-(2,6-dioxopiperidin-3-yl)-4-(piperazin-1-yl)pyridinecarboxamide

[0571] 1.86 g (3.98 mmol, 89.3% purity, 1.00 eq) of racemic-(R)-4-(2,6-dioxadiazin-3-yl)carbamoyl)pyridin-4-yl)piperazin-1-carboxylic acid tert-butyl ester (1.86 g, 3.98 mmol, 89.3% purity, 1.00 eq) in DCM (18.0 mL) was added to a solution of the mixture at 25 °C. The mixture was then stirred at 25 °C for 12 h. The mixture was filtered and the filter cake was concentrated to give an unpurified crude product. Racemic-(R)-N-(2,6-dioxadiazin-3-yl)-4-(piperazin-1-yl)pyridinecarboxamide (1.50 g, 3.83 mmol, 96.3% yield, 90.4% purity, HCl salt) was given as a grayish-white solid. LCMS C 15 H 19 Theoretical value of N5O3: 317.1, experimental value: m / z = 318.1 [M+H] + .

[0572] 1 H NMR (400 MHz, D2O) δ 8.25 (d, J = 7.2 Hz, 1H), 7.73 (d, J = 2.8 Hz, 1H), 7.25 (dd, J = 7.2, 2.8 Hz, 1H), 4.89 - 5.00 (m, 1H), 3.93 - 4.13 (m,4H), 3.72 (s, 1H), 3.40 - 3.51 (m, 4H), 2.72 - 2.93 (m, 2H), 2.17 - 2.37 (m,2H).

[0573] Step 8: Synthesize the title compound Stir a mixture of DMF containing 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carboxylic acid (10.00 mg, 0.0266 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylene]dimethylammonium; hexafluoro-λ5-phosphate (phosphanuide) (20.26 mg, 0.0533 mmol), and N,N-diisopropylethylamine (13.77 mg, 0.1065 mmol). Add racemic-(R)-N-(2,6-dioxopiperidin-3-yl)-4-(piperazin-1-yl)pyridinecarboxamide (8.45 mg, 0.0266 mmol) and stir at rt until complete as determined by LCMS. The solution was injected onto an RP-FC and purified using a 0–70% MeCN / H2O gradient to provide the title compound (2.7 mg, 15%). LCMS: C 37 H 38 Theoretical value of N8O5: 674.3, experimental value: m / z = 675.3 [M+H] + .

[0574] Example 2 (3RS)-3-{4-[(1S)-1-(1-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carbonyl}piperidin-4-yl)ethoxy]phenyl}piperidin-2,6-dione

[0575] Step 1: Synthesis of (S)-4-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenoxy)ethyl)piperidine-1-carboxylic acid tert-butyl ester

[0576] Add 4-[2,6-bis(benzyloxy)pyridin-3-yl]phenol (500.00 mg, 1.3040 mmol), 4-[(1R)-1-hydroxyethyl]piperidin-1-carboxylic acid tert-butyl ester (897.07 mg, 3.9119 mmol), triphenylphosphine (1.03 g, 3.9119 mmol), and THF (10.00 mL) as described in PCT publication WO2023 / 018238 for compound 3 to a 20 mL vial. Cool the reaction mixture to 0 °C, then add diisopropyl azodicarbonate (0.77 mL, 0.79 g, 3.9119 mmol) dropwise. Stir the reaction mixture, heat to RT for 16 h, and then concentrate. The residue was purified by FC (80 g silica, 0-25% EtOAc / hex) to yield the title compound (415 mg, 54%) as a colorless oil. LCMS: C 37 H 42 Theoretical value of N2O5: 594.7, experimental value: m / z = 595.7 [M+H] + .

[0577] Step 2: Synthesis of (3RS)-3-{4-[(1S)-1-(piperidin-4-yl)ethoxy]phenyl}piperidin-2,6-dione

[0578] Add tert-butyl 4-[(1S)-1-{4-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxy}ethyl]piperidine-1-carboxylate (415.00 mg, 0.6978 mmol), Pd / C (400.00 mg, mmol), EtOH (5.00 mL), and THF (5.00 mL) to a 20 mL vial. Purge the reaction mixture with H2 for 10 min, then stir for 16 h under an H2 atmosphere (balloon). Filter the reaction mixture through a diatomaceous earth pad and concentrate. Dissolve the crude material in TFA / DCM 1:1 and stir for 30 min, then concentrate and lyophilize to obtain the title compound (247 mg, 85%) as a white solid. LCMS: C 18 H 24 Theoretical value of N₂O₃: 316.2, experimental value: m / z = 317.5 [M+H] + .

[0579] Step 3: Synthesize the title compound Stir a solution of DMF containing 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carboxylic acid (10.00 mg, 0.0266 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylene]dimethylammonium; hexafluoro-λ5-phosphate (20.26 mg, 0.0533 mmol) and N,N-diisopropylethylamine (13.77 mg, 0.1065 mmol). Add racemic-N-[(3R)-2,6-dioxopiperidin-3-yl]-4-(piperazin-1-yl)pyridin-2-carboxamide (8.45 mg, 0.0266 mmol) and stir at rt until complete as determined by LCMS. The solution was injected onto an RP-FC and purified using a 0–70% MeCN / H2O gradient to provide the title compound (6.5 mg, 33%). LCMS: C 40 H 43 Theoretical value of N5O5: 673.3, experimental value: m / z = 674.3 [M+H] + .

[0580] Example 3 (3RS)-3-{4-[(1R)-1-(1-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carbonyl}piperidin-4-yl)ethoxy]phenyl}piperidin-2,6-dione

[0581] Stir a mixture containing 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carboxylic acid (11.00 mg, 0.0293 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylene]dimethylammonium; hexafluoro-λ5-phosphate (22.28 mg, 0.0586 mmol) and N,N-diisopropylethylamine (20.47 μL, 15.15 mg, 0.1172 mmol). Add (3RS)-3-{4-[(1R)-1-(piperidin-4-yl)ethoxy]phenyl}piperidin-2,6-dione (9.27 mg, 0.0293 mmol) prepared according to step 2 of Example 2, and stir at rt until complete as determined by LCMS. The solution was injected onto an RP-FC and purified using a 0–70% MeCN / H2O gradient to provide the title compound (4.6 mg, 23%). LCMS: C 40 H 43 Theoretical value of N5O5: 673.3, experimental value: m / z = 674.3 [M+H]+ .

[0582] Example 4 Racemic-(3R)-3-{4-[(1-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carbonyl}piperidin-4-yl)oxy]phenyl}piperidin-2,6-dione

[0583] Step 1: Synthesis of 4-(2,6-bis(benzyloxy)pyridin-3-yl)phenol

[0584] 2,6-bis(benzyloxy)-3-bromopyridine (290 g, 783 mmol, 1.00 eq) and (4-hydroxyphenyl)boronic acid (118 g, 861 mmol, 1.10 eq) were dissolved in dioxane (2.90 L). K₂CO₃ (216 g, 1.57 mol, 2.00 eq) and H₂O (580 mL) were added to the reactor under N₂. The suspension was degassed under vacuum and purged several times with N₂. Pd(dppf)Cl₂ (28.6 g, 39.1 mmol, 0.05 eq) was added to the reactor under N₂. The suspension was degassed under vacuum and purged several times with N₂. The mixture was stirred at 110 °C for 12 h. The reaction solution was concentrated under reduced pressure, then diluted with water (500 mL) and extracted with ethyl acetate (3 x 500 mL). The organic layer was washed twice with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, N-heptane / ethyl acetate = 100 / 1 to 10 / 1). 4-(2,6-bis(benzyloxy)pyridin-3-yl)phenol (240 g, 597 mmol, 76.3% yield, 95.5% purity) was obtained as a grayish-white solid.

[0585] 1 H NMR (400 MHz, DMSO) δ ppm 9.45 (s, 1H) 7.65 (d, J = 8.07 Hz, 1H)7.20 - 7.46 (m, 12H) 6.77 (d, J = 8.56 Hz, 2H) 6.51 (d, J = 8.07 Hz, 1H) 5.37 (d, J = 13.0 Hz, 4H).

[0586] Step 2: Synthesis of benzyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenoxy)piperidine-1-carboxylate

[0587] 4-(2,6-bis(benzyloxy)pyridin-3-yl)phenol (120 g, 313 mmol, 1.00 eq) was loaded into THF (840 mL) in reactor R-1 (2.00 L flask, in parallel) equipped with a stirrer. Benzyl 4-hydroxypiperidin-1-carboxylate (77.3 g, 328 mmol, 1.05 eq) was loaded into R-1. PPh3 (86.1 g, 328 mmol, 1.05 eq) was loaded into R-1. DEAD (57.2 g, 328 mmol, 59.7 mL, 1.05 eq) was added at 0 °C under a nitrogen atmosphere. The mixture was stirred at 25 °C under N2 for 12 h. The reaction solution was concentrated under reduced pressure. The crude product was wet-milled at 20 °C with MTBE (500 mL) for 1 h. The filtrate was concentrated under vacuum at 40–45 °C. The crude product was then purified by preparative HPLC (column: Phenomenex luna C18 (250 × 70 mm, 10 μm); mobile phase: [water (HCl)-ACN]; B%: 100–100% 40 min). A yellow oily product of benzyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenoxy)piperidine-1-carboxylate (260 g, 427 mmol, crude product) was obtained. LCMS: C 38 H 36 Theoretical value of N₂O₅: 600.3, experimental value: m / z = 601.4 [M+H] + .

[0588] 1 H NMR: (400 MHz, DMSO) δ ppm 7.69 (d, J = 8.07 Hz, 1H) 7.24 - 7.50(m, 17H) 6.99 (d, J = 8.68 Hz, 2H) 6.52 (d, J = 8.07 Hz, 1H) 5.38 (d, J =15.1 Hz, 4H) 5.09 (s, 2H) 4.60 (dt, J = 7.55, 3.99 Hz, 1H) 3.69 - 3.79 (m,2H) 3.30 (br d, J = 5.99 Hz, 2H) 1.88 - 1.97 (m, 2H) 1.56 (ddt, J = 12.6, 8.44, 4.29, 4.29 Hz, 2H).

[0589] Step 3: Synthesis of 5-(4-(piperidin-4-yloxy)phenyl)pyridine-2,6(1H,3H)-dione

[0590] Benzyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenoxy)piperidine-1-carboxylate (100 g, 166 mmol, 1.00 eq) was charged into a 500 mL DCM in a reactor R-1 (2.00 L flask, in parallel) equipped with a stirrer. HBr (521 g, 2.13 mol, 350 mL, 33% purity, 12.7 eq) was charged into R-1 at 20 °C. The mixture was stirred at 50 °C under N2 for 12 h. The reaction solution was concentrated under reduced pressure. A yellow oily 5-(4-(piperidine-4-yloxy)phenyl)pyridin-2,6(1H,3H)-dione (40.0 g, 139 mmol, 83.9% yield, 95.2% purity) was obtained. LCMS: C 16 H 18 Theoretical value of N2O3: 286.1, experimental value: m / z = 286.9 [M+H] + .

[0591] Step 4: Synthesis of racemic-(R)-3-(4-(piperidin-4-yloxy)phenyl)piperidin-2,6-dione

[0592] Set up reactor R-1 (2.00 L flask) with a stirrer. Purge the flask with argon for 2 min. Add Pd(OH)₂ (20.0 g, 14.2 mmol, 10% purity, 0.12 eq) and Pd / C (20.0 g, 18.7 mmol, 10% purity, 0.13 eq) soaked in MeOH (100 mL) to R-1. Add 5-(4-(piperidin-4-yloxy)phenyl)pyridine-2,6(1H,3H)-dione (40.0 g, 139 mmol, 1.00 eq) along with MeOH (700 mL) to R-1. Replace the gas with hydrogen three times and stir at 50 °C for 12 h. Filter the reaction mixture and wash with MeOH (2.00 L). Add HCl / EA (120 mL) dropwise. Racemic (R)-3-(4-(piperidin-4-yloxy)phenyl)piperidin-2,6-dione (30.0 g, 90.3 mmol, 64.6% yield, 97.8% purity, HCl salt) was obtained as a white solid. LCMS: C 16 H 20 Theoretical value of N₂O₃: 288.1, experimental value: m / z = 288.9 [M+H] + . 1H NMR: (400 MHz, DMSO) δ ppm 10.7 (s, 1H) 9.18 - 9.39 (m, 2H) 7.14 (d,J = 8.58 Hz, 2H) 6.95 (d, J = 8.70 Hz, 2H) 4.63 (dt, J = 7.12, 3.77 Hz, 1H)3.79 (dd, J = 11.5, 4.83 Hz, 1H) 3.12 - 3.28 (m, 2H) 2.98 - 3.11 (m, 2H) 2.60- 2.72 (m, 1H) 2.45 (br t, J = 3.99 Hz, 1H) 2.06 - 2.22 (m, 3H) 1.95 - 2.04(m, 1H) 1.80 - 1.90 (m, 2H) Step 5: Synthesize the title compound Stir a solution of DMF containing 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carboxylic acid (5.00 mg, 0.0133 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylene]dimethylammonium; hexafluoro-λ5-phosphate (10.13 mg, 0.0266 mmol), and N,N-diisopropylethylamine (9.30 μL, 6.89 mg, 0.0533 mmol). Add racemic-(3R)-3-[4-(piperidin-4-yloxy)phenyl]piperidin-2,6-dione (3.84 mg, 0.0133 mmol) and stir at rt until complete as determined by LCMS. The solution was injected onto an RP-FC and purified using a 0–70% MeCN / H2O gradient to provide the title compound (2.0 mg, 14%). LCMS: C 38 H 39 Theoretical value of N5O5: 645.3, experimental value: m / z = 646.3 [M+H] + .

[0593] Example 5 Racemic-(3R)-3-{4-[(1-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carbonyl}piperidin-4-yl)methoxy]phenyl}piperidin-2,6-dione

[0594] Step 1: Synthesis of tert-butyl 4-((4-(2,6-bis(benzyloxy)pyridin-3-yl)phenoxy)methyl)piperidine-1-carboxylate

[0595] Add 4-[2,6-bis(benzyloxy)pyridin-3-yl]phenol (200.00 mg, 0.5216 mmol), tert-butyl 4-(hydroxymethyl)piperidin-1-carboxylate (336.88 mg, 1.5648 mmol), triphenylphosphine (0.41 g, 1.5648 mmol), and THF (4.00 mL) to a 20 mL vial. Cool the reaction mixture to 0 °C, then add diisopropyl azodicarbonate (0.31 mL, 0.32 g, 1.5648 mmol) dropwise. Stir the reaction mixture and heat to RT for 16 h, then concentrate. Purify the residue by FC (40 g silica, 0-25% EtOAc / hex) to provide the title compound (277 mg, 92%) as a colorless oil: C 36 H 40 Theoretical value of N₂O₅: 580.6, experimental value: m / z = 581.5 [M+H] + .

[0596] Step 2: Synthesis of racemic-(R)-3-(4-(piperidin-4-ylmethoxy)phenyl)piperidin-2,6-dione

[0597] Add tert-butyl 4-{4-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxymethyl}piperidine-1-carboxylate (277.00 mg, 0.4770 mmol), Pd / C (100.00 mg, mmol), EtOH (2.00 mL), and THF (2.00 mL) to a 20 mL vial. Purge the reaction mixture with H2 for 10 min, then stir for 16 h under an H2 atmosphere (balloon). Filter the reaction mixture through a diatomaceous earth mat and concentrate. Add dioxane containing 4N hydrogen chloride (1.00 mL, 0.15 g, 4.0000 mmol) to the crude product. Stir the reaction mixture for 1 h and then concentrate. LCMS: C 17 H 22 Theoretical value of N2O3: 302.2, experimental value: m / z = 303.3 [M+H] + .

[0598] Step 3: Synthesize the title compound Stir a solution of DMF containing 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carboxylic acid (5.00 mg, 0.0133 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylene]dimethylammonium; hexafluoro-λ5-phosphate (10.13 mg, 0.0266 mmol), and N,N-diisopropylethylamine (9.30 μL, 6.89 mg, 0.0533 mmol). Add racemic-(3R)-3-[4-(piperidin-4-ylmethoxy)phenyl]piperidin-2,6-dione (4.03 mg, 0.0133 mmol) and stir at rt until complete as determined by LCMS. The solution was injected onto an RP-FC and purified using a 0–70% MeCN / H2O gradient to provide the title compound (1.2 mg, 14%). LCMS: C 39 H 41 Theoretical value of N5O5: 659.3, experimental value: m / z = 660.3 [M+H] + .

[0599] Example 6 Racemic-(3R)-3-(4-{4-[(4-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carbonyl}piperazin-1-yl)methyl]piperidin-1-yl}phenyl)piperidin-2,6-dione

[0600] Stir a solution of DMF containing 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carboxylic acid (5.00 mg, 0.0133 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylene]dimethylammonium; hexafluoro-λ5-phosphate (10.13 mg, 0.0266 mmol) and N,N-diisopropylethylamine (9.30 μL, 6.89 mg, 0.0533 mmol). Add racemic-(3R)-3-{4-[4-(piperazin-1-ylmethyl)piperidin-1-yl]phenyl}piperidin-2,6-dione (5.43 mg, 0.0146 mmol) synthesized as described in Example 40 of PCT Publication WO2022 / 235715 for compound HCB36, and stir at rt until complete as determined by LCMS. Inject the solution into an RP-FC and purify using a 0-70% MeCN / H2O gradient to provide the title compound (1.0 mg, 9%). LCMS: C 43 H 49Theoretical value of N7O4: 727.3, experimental value: m / z = 728.4 [M+H] + .

[0601] Example 7 Racemic-(3R)-3-[4-(4-{[(1-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carbonyl}piperidin-4-yl)amino]methyl}piperidin-1-yl)phenyl]piperidin-2,6-dione

[0602] Step 1: Synthesis of racemic-(R)-3-(4-(4-((piperidin-4-ylamino)methyl)piperidin-1-yl)phenyl)piperidin-2,6-dione

[0603] Racemic-1-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-carboxaldehyde (100.00 mg, 0.3329 mmol) and tert-butyl 4-aminopiperidin-1-carboxylate (66.68 mg, 0.3329 mmol), synthesized as described in Example 59 of PCT Publication WO2022 / 235715 for compound HCB62, were dissolved in DCE and N,N-diisopropylethylamine (297.61 μL, 226.18 mg, 1.7500 mmol) was added and the reaction mixture was stirred for 30 min. Sodium triacetoxyborohydride (211.69 mg, 0.9988 mmol) was added and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated and purified by RP-FC to produce tert-butyl Racemic-(R)-3-(4-(4-((piperidin-4-ylamino)methyl)piperidin-1-yl)phenyl)piperidin-2,6-dione (146 mg, 83%). The material was dissolved in a 1:1 TFA:DCM solution and stirred for 1 h, followed by concentration and purification by RP-FC to provide the title compound, which was used as a crude product without further purification. LCMS: C 27 H 40 Theoretical value of N4O4: 384.5, experimental value: m / z = 385.6 [M+H] + .

[0604] Step 2: Synthesize the title compound Stir a mixture of DMF containing 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carboxylic acid (5.00 mg, 0.0133 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylene]dimethylammonium; hexafluoro-λ5-phosphate (10.13 mg, 0.0266 mmol), and N,N-diisopropylethylamine (9.30 μL, 6.89 mg, 0.0533 mmol). Add racemic-(3R)-3-(4-{4-[(piperidin-4-ylamino)methyl]piperidin-1-yl}phenyl)piperidin-2,6-dione (5.63 mg, 0.0146 mmol) and stir at rt until complete as determined by LCMS. The solution was injected onto an RP-FC and purified using a 0–70% MeCN / H2O gradient to provide the title compound (0.8 mg, 8%). LCMS: C 44 H 51 Theoretical value of N7O4: 741.4, experimental value: m / z = 742.4 [M+H] + .

[0605] Example 8 (3S)-3-(4-{4-[(6-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carbonyl}-2,6-diazaspiro[3.3]hept-2-yl)methyl]piperidin-1-yl}phenyl)piperidin-2,6-dione

[0606] Step 1: Synthesis of (S)-3-(4-(4-((2,6-diazaspiro[3.3]hept-2-yl)methyl)piperidin-1-yl)phenyl)piperidin-2,6-dione

[0607] The intermediate was synthesized using tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate according to step 1 of Example 7. LCMS: C 22 H 30 Theoretical value of N4O2: 382.5, experimental value: m / z = 383.4 [M+H] + .

[0608] Step 2: Synthesize the title compound Stir a mixture of DMF containing 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carboxylic acid (30.00 mg, 0.0799 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylene]dimethylammonium; hexafluoro-λ5-phosphate (60.77 mg, 0.1598 mmol) and N,N-diisopropylethylamine (0.06 mL, 41.31 mg, 0.3196 mmol). Add (3S)-3-[4-(4-{2,6-diazaspiro[3.3]hept-2-ylmethyl}piperidin-1-yl)phenyl]piperidin-2,6-dione (33.62 mg, 0.0879 mmol) and stir at rt until complete as determined by LCMS. The solution was injected onto an RP-FC and purified using a 0–70% MeCN / H2O gradient to provide the title compound (10.1 mg, 16%). LCMS: C 44 H 49 Theoretical value of N7O4: 739.4, experimental value: m / z = 740.4 [M+H] + .

[0609] Example 9 (3S)-3-(4-{4-[(2-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carbonyl}-2,6-diazaspiro[3.4]oct-6-yl)methyl]piperidin-1-yl}phenyl)piperidin-2,6-dione

[0610] Step 1: (S)-3-(4-(4-((2,6-diazaspiro[3.4]oct-6-yl)methyl)piperidin-1-yl)phenyl)piperidin-2,6-dione

[0611] The intermediate was synthesized using tert-butyl 2,6-diazaspiro[3,4]octane-2-carboxylate according to step 1 of Example 7. LCMS: C 23 H 32 Theoretical value of N4O2: 396.5, experimental value: m / z = 397.5 [M+H] + .

[0612] Step 2: Synthesize the title compound Stir a mixture of DMF containing 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carboxylic acid (8.00 mg, 0.0213 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylene]dimethylammonium; hexafluoro-λ5-phosphate (16.20 mg, 0.0426 mmol) and N,N-diisopropylethylamine (14.89 μL, 11.02 mg, 0.0852 mmol). Add (3S)-3-[4-(4-{2,6-diazaspiro[3,4]oct-6-ylmethyl}piperidin-1-yl)phenyl]piperidin-2,6-dione (9.29 mg, 0.0234 mmol) and stir at rt until complete as determined by LCMS. The solution was injected onto an RP-FC and purified using a 0–70% MeCN / H2O gradient to provide the title compound (3.4 mg, 21%). LCMS: C 45 H 51 Theoretical value of N7O4: 753.4, experimental value: m / z = 754.4 [M+H] + .

[0613] Example 10 N-({1-[(1-{4-[(3S)-2,6-dioxopiridine-3-yl]phenyl}piperidin-4-yl)methyl]piperidin-3-yl}methyl)-1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carboxamide

[0614] Step 1: (3S)-3-(4-(4-((3-(aminomethyl)piperidin-1-yl)methyl)piperidin-1-yl)phenyl)piperidin-2,6-dione

[0615] The intermediate was synthesized using tert-butyl (piperidin-3-ylmethyl)carbamate according to step 1 of Example 7. LCMS: C 23 H 34 Theoretical value of N4O2: 398.5, experimental value: m / z = 399.5 [M+H] + .

[0616] Step 2: Synthesize the title compound Stir a mixture of DMF containing 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carboxylic acid (8.00 mg, 0.0213 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylene]dimethylammonium; hexafluoro-λ5-phosphate (16.20 mg, 0.0426 mmol) and N,N-diisopropylethylamine (14.89 μL, 11.02 mg, 0.0852 mmol). Add (3S)-3-[4-(4-{[3-(aminomethyl)piperidin-1-yl]methyl}piperidin-1-yl)phenyl]piperidin-2,6-dione (9.34 mg, 0.0234 mmol) and stir at rt until complete as determined by LCMS. The solution was injected onto an RP-FC and purified using a 0–70% MeCN / H2O gradient to provide the title compound (0.8 mg, 5%). LCMS: C 45 H 51 Theoretical value of N7O4: 755.4, experimental value: m / z = 756.4 [M+H] + .

[0617] Example 11 Racemic-(3R)-3-[4-({1-[(1-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carbonyl}piperidin-4-yl)methyl]piperidin-4-yl}methoxy)phenyl]piperidin-2,6-dione

[0618] Step 1: Synthesis of racemic-(R)-3-(4-(piperidin-4-ylmethoxy)phenyl)piperidin-2,6-dione

[0619] To a 20 mL vial, tert-butyl 4-{4-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxymethyl}piperidine-1-carboxylate (277.00 mg, 0.4770 mmol), Pd / C (100.00 mg, mmol), EtOH (2.00 mL), and THF (2.00 mL) were added. The reaction mixture was purged with H2 for 10 min, followed by stirring under an H2 atmosphere (balloon) for 16 h. The reaction mixture was then filtered through a diatomaceous earth mat, concentrated, and a Boc intermediate (162 mg, 84%) was provided. This intermediate was dissolved in a 1:1 TFA:DCM solution for 1 h, concentrated, and lyophilized to yield the title compound. LCMS: C 17 H 22Theoretical value of N₂O₃: 302.4, experimental value: m / z = 303.3 [M+H] + .

[0620] Step 2: Synthesis of racemic-(R)-3-(4-((1-(piperidin-4-ylmethyl)piperidin-4-yl)methoxy)phenyl)piperidin-2,6-dione

[0621] Racemic (R)-3-(4-(piperidin-4-ylmethoxy)phenyl)piperidin-2,6-dione and tert-butyl 4-formylpiperidin-1-carboxylate were dissolved in anhydrous DCE. N,N-diisopropylethylamine (72.20 μL, 53.43 mg, 0.4134 mmol) was added and the reaction mixture was stirred for 30 min. Sodium triacetoxyborohydride (52.57 mg, 0.2480 mmol) was added. The mixture was then stirred overnight at rt and purified by RP-FC to provide a Boc-protected intermediate (30 mg, 66%). This material was dissolved in 1:1 TFA:DCM, stirred at room temperature for 1 h, then concentrated and used in the next step without further purification. LCMS:C 23 H 33 Theoretical value of N3O3: 399.3, experimental value: m / z = 400.4 [M+H] + .

[0622] Step 3: Synthesize the title compound Stir a mixture of DMF containing 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carboxylic acid (15.00 mg, 0.0400 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylene]dimethylammonium; hexafluoro-λ5-phosphate (30.38 mg, 0.0799 mmol) and N,N-diisopropylethylamine (27.91 μL, 20.66 mg, 0.1598 mmol). Add racemic-(3R)-3-(4-{[1-(piperidin-4-ylmethyl)piperidin-4-yl]methoxy}phenyl)piperidin-2,6-dione (17.56 mg, 0.0439 mmol) and stir at rt until complete as determined by LCMS. The solution was injected onto an RP-FC and purified using a 0–70% MeCN / H2O gradient to provide the title compound (1.2 mg, 4%). LCMS: C 45 H 52 Theoretical value of N6O5: 756.4, experimental value: m / z = 757.4 [M+H] + .

[0623] Example 12 Racemic-(3R)-3-[4-({1-[(1-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carbonyl}piperidin-4-yl)methyl]piperidin-4-yl}oxy)phenyl]piperidin-2,6-dione

[0624] Step 1: Synthesis of racemic-(R)-3-(4-((1-(piperidin-4-ylmethyl)piperidin-4-yl)oxy)phenyl)piperidin-2,6-dione

[0625] Racemic (3R)-3-[4-(piperidin-4-yloxy)phenyl]piperidin-2,6-dione (25.00 mg, 0.0827 mmol) and tert-butyl 4-formylpiperidin-1-carboxylate (17.63 mg, 0.0827 mmol) were dissolved in anhydrous DCE. N,N-diisopropylethylamine (72.20 μL, 53.43 mg, 0.4134 mmol) was added and the reaction mixture was stirred for 30 min. Sodium triacetoxyborohydride (52.57 mg, 0.2480 mmol) was added. The mixture was stirred overnight at rt, then concentrated and purified by RP-FC to give a Boc intermediate (30 mg, 69%), which was then dissolved in 1:1 TFA:DCM and stirred for 1 h, followed by concentration and lyophilization. LCMS: C 27 H 39 Theoretical value of N3O5: 485.6, experimental value: m / z = 486.6 [M+H] + .

[0626] Step 2: Synthesize the title compound Stir a solution of DMF containing 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carboxylic acid (30.00 mg, 0.0799 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylene]dimethylammonium; hexafluoro-λ5-phosphate (60.77 mg, 0.1598 mmol) and N,N-diisopropylethylamine (55.83 μL, 41.31 mg, 0.3196 mmol). Add racemic-(3R)-3-(4-{[1-(piperidin-4-ylmethyl)piperidin-4-yl]oxy}phenyl)piperidin-2,6-dione (33.89 mg, 0.0879 mmol) and stir at rt until complete as determined by LCMS. The solution was injected onto an RP-FC and purified using a 0–70% MeCN / H2O gradient to provide the title compound (3.4 mg, 6%). LCMS: C 44 H 50 Theoretical value of N6O5: 742.4, experimental value: m / z = 743.4 [M+H] + .

[0627] Example 13 Racemic-(3R)-3-(4-{[1-(1-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carbonyl}piperidin-4-carbonyl)piperidin-4-yl]oxy}phenyl)piperidin-2,6-dione

[0628] Step 1: Synthesis of racemic-(R)-3-(4-((1-(piperidin-4-carbonyl)piperidin-4-yl)oxy)phenyl)piperidin-2,6-dione

[0629] A mixture of DMF containing racemic-(3R)-3-[4-(piperidin-4-yloxy)phenyl]piperidin-2,6-dione (45.00 mg, 0.1561 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylene]dimethylammonium; hexafluoro-λ5-phosphate (118.68 mg, 0.3121 mmol) and N,N-diisopropylethylamine (80.68 mg, 0.6242 mmol) was stirred. 1-(tert-butoxycarbonyl)piperidin-4-carboxylic acid (35.78 mg, 0.1561 mmol) was added and stirred at rt until complete as determined by LCMS. The mixture was directly injected and purified using RP FC to yield a Boc-protected intermediate (28 mg, 36%). The material was then dissolved in a 1:1 TFA:DCM mixture and stirred at rt for 1 h, followed by concentration and use in the next step. LCMS:C 22 H 29 Theoretical value of N3O4: 399.5, experimental value: m / z = 400.5 [M+H] + .

[0630] Step 2: Synthesize the title compound Stir a mixture of DMF containing 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carboxylic acid (22.00 mg, 0.0586 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylene]dimethylammonium; hexafluoro-λ5-phosphate (44.56 mg, 0.1172 mmol), and N,N-diisopropylethylamine (40.94 μL, 30.30 mg, 0.2344 mmol). Add racemic-(3R)-3-(4-{[1-(piperidin-4-carbonyl)piperidin-4-yl]oxy}phenyl)piperidin-2,6-dione (25.75 mg, 0.0645 mmol) and stir at rt until complete as determined by LCMS. The solution was injected onto an RP-FC and purified using a 0–70% MeCN / H2O gradient to provide the title compound (7.2 mg, 15%). LCMS: C 44 H 48 Theoretical value of N6O5: 756.4, experimental value: m / z = 757.2 [M+H] + .

[0631] Example 14 Racemic-(3R)-3-(4-{[1-(1-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carbonyl}piperidin-4-carbonyl)piperidin-4-yl]methoxy}phenyl)piperidin-2,6-dione

[0632] Step 1: Synthesis of racemic-(R)-3-(4-((1-(piperidin-4-carbonyl)piperidin-4-yl)methoxy)phenyl)piperidin-2,6-dione

[0633] A mixture of racemic (3R)-3-[4-(piperidin-4-ylmethoxy)phenyl]piperidin-2,6-dione (45.00 mg, 0.1488 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylene]dimethylammonium; hexafluoro-λ5-phosphate (113.17 mg, 0.2976 mmol) and N,N-diisopropylethylamine (103.97 μL, 76.94 mg, 0.5953 mmol) was stirred. 1-(tert-butoxycarbonyl)piperidin-4-carboxylic acid (34.12 mg, 0.1488 mmol) was added and stirred at rt until complete as determined by LCMS. The mixture was directly injected into RP-FC, and the Boc-protected intermediate (45 mg, 58%) was separated. Concentrate and dissolve in a 1:1 TFA:DCM mixture and stir for 1 h, then concentrate and freeze-dry for use in the next step. LCMS:C 23 H 31 Theoretical value of N3O4: 413.6, experimental value: m / z = 414.6 [M+H] + .

[0634] Step 2: Synthesize the title compound Stir a mixture of DMF containing 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carboxylic acid (22.00 mg, 0.0586 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylene]dimethylammonium; hexafluoro-λ5-phosphate (44.56 mg, 0.1172 mmol), and N,N-diisopropylethylamine (40.94 μL, 30.30 mg, 0.2344 mmol). Add racemic-(3R)-3-(4-{[1-(piperidin-4-carbonyl)piperidin-4-yl]methoxy}phenyl)piperidin-2,6-dione (26.66 mg, 0.0645 mmol) and stir at rt until complete as determined by LCMS. The solution was injected onto an RP-FC and purified using a 0–70% MeCN / H2O gradient to provide the title compound (2.4 mg, 5%). LCMS: C 45 H 50 Theoretical value of N6O4: 770.4, experimental value: m / z = 771.4 [M+H] + .

[0635] Example 15 (3R)-3-(4-{4-[(6-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carbonyl}-2,6-diazaspiro[3.3]hept-2-yl)methyl]piperidin-1-yl}phenyl)piperidin-2,6-dione

[0636] Step 1: Synthesis of (1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-phenylpiperidin-4-yl)(2,6-diazaspiro[3.3]hept-2-yl) methyl ketone

[0637] A solution of DMF containing 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carboxylic acid (10.00 mg, 0.0266 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylene]dimethylammonium; hexafluoro-λ5-phosphate (20.26 mg, 0.0533 mmol) and N,N-diisopropylethylamine (18.61 μL, 13.77 mg, 0.1065 mmol) was added. Tert-butyl 2,6-diazaspiro[3,3]heptane-2-carboxylate (5.81 mg, 0.0293 mmol) was added and stirred at rt until completion was determined by LCMS. The solution was directly injected and purified by RP-FC to yield the Boc intermediate (6.2 mg, 37%). The material was dissolved in a 1:1 TFA:DCM solution and stirred at rt for 1 h, then concentrated, lyophilized, and used without further purification. LCMS:C 27 H 29 Theoretical value of N5O2: 455.3, experimental value: m / z = 456.5 [M+H] + .

[0638] Step 2: Synthesize the title compound Add 2-[5-(4-{2,6-diazaspiro[3.3]heptane-2-carbonyl}-4-phenylpiperidin-1-yl)pyridazin-3-yl]phenol (42.00 mg, 0.0922 mmol), triethylamine (63.04 μL, 46.65 mg, 0.4610 mmol), 1-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-carboxaldehyde (33.23 mg, 0.1106 mmol), and DCE (3.00 mL) to a scintillation vial. Stir at rt and add sodium triacetoxyborohydride (68.39 mg, 0.3227 mmol). Stir until the starting material is completely consumed as determined by MS. The reaction was complete and clean after 90 minutes. Quench the reaction with bicarbonate solution and extract with EtOAc. Dry the organic layer with brine followed by Na2SO4. The solution was concentrated and injected onto an RP-FC plate and purified using a 0–70% MeCN / H2O gradient to provide the title compound (27.4 mg, 40%). LCMS: C 44 H 49 Theoretical value of N7O4: 739.4, experimental value: m / z = 740.4 [M+H] + .

[0639] 1H NMR (500 MHz, DMSO) δ 10.69 (d, J = 2.5 Hz, 1H), 9.57 (d, J = 0.9Hz, 1H), 7.35 (t, J = 7.2 Hz, 1H), 7.30 - 7.23 (m, 1H), 7.00 - 6.88 (m, 5H),6.90 - 6.75 (m, 5H), 5.83 (d, J = 7.6 Hz, 1H), 4.11 (dd, J = 7.5, 5.9 Hz,1H), 3.68 - 3.54 (m, 3H), 3.60 (s, 3H), 3.57 - 3.49 (m, 1H), 3.49 (t, J = 4.1Hz, 1H), 3.10 (d, J = 4.8 Hz, 1H), 2.92 (d, J = 13.3 Hz, 1H), 2.74 (ddd, J =12.4, 10.9, 2.9 Hz, 2H), 2.61 - 2.45 (m, 5H), 2.43 - 2.37 (m, 2H), 2.37 (tt,J = 4.7, 2.3 Hz, 1H), 2.13 - 1.99 (m, 2H), 1.98 - 1.89 (m, 3H), 1.89 - 1.81(m, 2H), 1.72 - 1.65 (m, 2H), 1.59 - 1.38 (m, 2H), 1.26 (dtdd, J = 16.3,12.6, 7.9, 3.6 Hz, 2H).

[0640] Example 16 (3R)-3-(4-{4-[(6-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carbonyl}-2,6-diazaspiro[3.4]oct-2-yl)methyl]piperidin-1-yl}phenyl)piperidin-2,6-dione

[0641] Step 1: Synthesis of (1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-phenylpiperidin-4-yl)(2,6-diazaspiro[3.4]oct-6-yl) methyl ketone

[0642] A solution of DMF containing 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carboxylic acid (99.00 mg, 0.2637 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylene]dimethylammonium; hexafluoro-λ5-phosphate (250.67 mg, 0.6592 mmol) and N,N-diisopropylethylamine (230.29 μL, 170.41 mg, 1.3185 mmol) was added. Tert-butyl 2,6-diazaspiro[3,4]octane-2-carboxylate (75.57 mg, 0.3560 mmol) was added and stirred at rt until complete as determined by LCMS. The solution was injected and purified directly by RP-FC to provide the Boc intermediate (170 mg, 99%). The material was dissolved in a 1:1 TFA:DCM solution and stirred at rt for 1 h, then concentrated and lyophilized for use in the next step. LCMS:C 28 H 31 Theoretical value of N5O2: 469.3, experimental value: m / z = 470.5 [M+H] + .

[0643] Step 2: Synthesize the title compound Add 2-[5-(4-{2,6-diazaspiro[3,4]octane-6-carbonyl}-4-phenylpiperidin-1-yl)pyridazin-3-yl]phenol (42.00 mg, 0.0922 mmol), triethylamine (63.04 μL, 46.65 mg, 0.4610 mmol), 1-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-carboxaldehyde (33.23 mg, 0.1106 mmol), and DCE (3.00 mL) to a scintillation vial. Stir at rt and add sodium triacetoxyborohydride (68.39 mg, 0.3227 mmol). Stir until the starting material is completely consumed as determined by MS. The reaction was complete and clean after 90 minutes. Quench the reaction with bicarbonate solution and extract with EtOAc. Dry the organic layer with brine followed by Na2SO4. The solution was concentrated and injected onto an RP-FC plate and purified using a 0–70% MeCN / H2O gradient to provide the title compound (19.8 mg, 29%). LCMS: C 45 H 51 Theoretical value of N7O4: 753.4, experimental value: m / z = 754.4 [M+H] + .

[0644] 1H NMR (500 MHz, DMSO) δ 10.70 (s, 1H), 8.86 (d, J = 2.8 Hz, 1H), 8.04 (dd, J = 8.5, 1.7 Hz, 1H), 7.46 (d, J = 3.2 Hz, 1H), 7.32 (d, J = 7.5Hz, 2H), 7.29 - 7.19 (m, 4H), 6.96 (d, J = 8.2 Hz, 2H), 6.88 - 6.78 (m, 4H), 5.69 (s, 1H), 4.05 (d, J = 14.5 Hz, 2H), 3.64 (dd, J = 11.0, 4.9 Hz, 1H),3.54 (d, J = 12.0 Hz, 2H), 3.43 (s, 1H), 3.30 (q, J = 9.0 Hz, 3H), 3.02 (s,1H), 2.95 (s, 1H), 2.79 (s, 1H), 2.68 - 2.64 (m, 1H), 2.61 - 2.51 (m, 1H),2.49 (s, 2H), 2.47 (d, J = 2.2 Hz, 2H), 2.39 (dt, J = 17.2, 4.6 Hz, 5H), 2.20(s, 1H), 2.08 - 1.99 (m, 2H), 1.97 - 1.89 (m, 3H), 1.69 (t, J = 7.3 Hz, 1H),1.62 (s, 1H), 1.50 (d, J = 12.3 Hz, 1H), 1.10 (s, 2H), 1.00 (dd, J = 15.5,5.1 Hz, 2H); LCMS: C 45 H 51 Theoretical value of N7O4: 753.4, experimental value: m / z = 754.8 [M+H] + .

[0645] Example 17 (3R)-3-(4-{4-[(2-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carbonyl}-2,6-diazaspiro[3.4]oct-6-yl)methyl]piperidin-1-yl}phenyl)piperidin-2,6-dione

[0646] Step 1: Synthesis of (1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-phenylpiperidin-4-yl)(2,6-diazaspiro[3.4]oct-2-yl) methyl ketone

[0647] A solution of DMF containing 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carboxylic acid (99.00 mg, 0.2637 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylene]dimethylammonium; hexafluoro-λ5-phosphate (250.67 mg, 0.6592 mmol) and N,N-diisopropylethylamine (230.29 μL, 170.41 mg, 1.3185 mmol) was added. Tert-butyl 2,6-diazaspiro[3,4]octane-6-carboxylate (75.57 mg, 0.3560 mmol) was added and stirred at rt until complete as determined by LCMS. The solution was injected and purified directly by RP-FC to provide the Boc intermediate (170 mg, 99%). The material was dissolved in a 1:1 TFA:DCM solution and stirred at rt for 1 h, then concentrated and lyophilized for use in the next step. LCMS:C 28 H 31 Theoretical value of N5O2: 469.3, experimental value: m / z = 470.5 [M+H] + .

[0648] Step 2: Synthesize the title compound Add 2-[5-(4-{2,6-diazaspiro[3,4]octane-2-carbonyl}-4-phenylpiperidin-1-yl)pyridazin-3-yl]phenol (42.00 mg, 0.0922 mmol), triethylamine (63.04 μL, 46.65 mg, 0.4610 mmol), 1-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-carboxaldehyde (33.23 mg, 0.1106 mmol), and DCE (3.00 mL) to a scintillation vial. Stir at rt and add sodium triacetoxyborohydride (68.39 mg, 0.3227 mmol). Stir until the starting material is completely consumed as determined by MS. The reaction was complete and clean after 90 minutes. Quench the reaction with bicarbonate solution and extract with EtOAc. Dry the organic layer with brine followed by Na2SO4. The solution was concentrated and injected onto an RP-FC and purified using a 0–70% MeCN / H2O gradient to provide the title compound (24.0 mg, 31%). LCMS: C 45 H 51Theoretical value of N7O4: 753.4, experimental value: m / z = 754.4 [M+H] + .

[0649] 1 H NMR (500 MHz, DMSO) δ 10.70 (d, J = 3.6 Hz, 1H), 9.57 (s, 1H), 8.89 (d, J = 2.9 Hz, 1H), 8.02 (dd, J = 8.4, 1.7 Hz, 1H), 7.48 (d, J = 3.0Hz, 1H), 7.35 (dd, J = 8.4, 7.0 Hz, 1H), 7.30 - 7.22 (m, 3H), 7.00 - 6.93 (m,3H), 6.93 - 6.81 (m, 3H), 6.84 - 6.77 (m, 2H), 4.16 - 3.99 (m, 3H), 3.87 (s,1H), 3.78 (s, 1H), 3.63 (ddd, J = 16.4, 11.5, 4.7 Hz, 3H), 3.59 (d, J = 4.8Hz, 1H), 3.50 (dt, J = 12.6, 4.1 Hz, 1H), 3.31 (t, J = 11.7 Hz, 1H), 3.17 (s,1H), 3.10 (d, J = 4.7 Hz, 2H), 2.73 (ddd, J = 12.3, 10.9, 2.9 Hz, 1H), 2.61 -2.45 (m, 4H), 2.43 - 2.34 (m, 3H), 2.29 (d, J = 15.9 Hz, 2H), 2.05 (tdd, J =13.7, 8.2, 3.2 Hz, 2H), 1.98 - 1.81 (m, 2H), 1.68 (dd, J = 8.6, 3.8 Hz, 1H), 1.66 (s, 2H), 1.57 - 1.38 (m, 1H), 1.33 - 1.18 (m, 1H), 1.17 (s, 2H), 1.15 (d, J = 11.2 Hz, 2H).

[0650] Example 18 Racemic-(3R)-3-(4-{4-[2-(1-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carbonyl}piperidin-4-yl)acetyl]piperazin-1-yl}phenyl)piperidin-2,6-dione

[0651] Step 1: Synthesis of (1-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carbonyl}piperidin-4-yl)acetic acid

[0652] A mixture of DMF containing 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carboxylic acid (70.00 mg, 0.1865 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylene]dimethylammonium; hexafluoro-λ5-phosphate (177.24 mg, 0.4661 mmol) and N,N-diisopropylethylamine (162.83 μL, 120.49 mg, 0.9323 mmol) was added. 2-(piperidin-4-yl)tert-butyl acetate (49.09 μL, 46.63 mg, 0.2517 mmol) was added and stirred at rt until complete as determined by LCMS. The mixture was directly injected into an RP-FC and purified to separate the t-Bu protected intermediate (80 mg, 69%). The material was dissolved in a 1:1 TFA:DCM solution and stirred at rt for 1 h. LCMS:C 29 H 32 Theoretical value of N4O4: 500.6, experimental value: m / z = 501.4 [M+H] + .

[0653] Step 2: Synthesize the title compound Stir a solution of DMF containing (1-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carbonyl}piperidin-4-yl)acetic acid (10.00 mg, 0.0200 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylene]dimethylammonium; hexafluoro-λ5-phosphate (18.99 mg, 0.0499 mmol) and N,N-diisopropylethylamine (17.44 μL, 12.91 mg, 0.0999 mmol). Add racemic-(3R)-3-[4-(piperazin-1-yl)phenyl]piperidine-2,6-dione (6.55 mg, 0.0240 mmol) synthesized as described in PCT publication WO2023 / 018238 for compound 5, and stir at rt until complete as determined by LCMS. Inject the solution onto an RP-FC and purify using a 0–70% MeCN / H2O gradient to provide the title compound (4.3 mg, 29%). LCMS: C 44 H 49Theoretical value of N7O5: 755.4, experimental value: m / z = 756.7 [M+H] + .

[0654] Example 19 Racemic-(3R)-3-(6-{4-fluoro-4-[(6-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carbonyl}-2,6-diazaspiro[3.3]hept-2-yl)methyl]piperidin-1-yl}pyridin-3-yl)piperidin-2,6-dione

[0655] Step 1: Synthesis of (4-fluoro-1-(5-iodopyridin-2-yl)piperidin-4-yl)methanol

[0656] (4-Fluoroperidin-4-yl)methanol (4.50 g, 26.5 mmol, 1.00 eq, HCl) and K₂CO₃ (12.8 g, 92.9 mmol, 3.50 eq) were added to a solution of 2-bromo-5-iodopyridine (5.92 g, 26.5 mmol, 1.00 eq) in DMF (45.0 mL) at 20 °C. The mixture was heated to 90 °C and stirred at 90 °C for 16 h. The reaction mixture was poured into water (225 mL), stirred at 20 °C for 5 min, filtered, and the filter cake was concentrated under vacuum. The crude product was wet-milled at 25 °C with petroleum ether:ethyl acetate = 3:1 (25.0 mL), filtered, and the filter cake was concentrated under vacuum. The filtrate was concentrated under vacuum and then purified by silica gel chromatography (SiO₂, petroleum ether:ethyl acetate = 12:1 to 5:1). (4-fluoro-1-(5-iodopyridin-2-yl)piperidin-4-yl)methanol (4.04 g, crude product) was obtained as a white solid. LCMS: C 11 H 14 Theoretical value of FIN2O: 336.0, experimental value: m / z = 337.0 [M+H] + . 1 H NMR (400 MHz, MeOD) δ 8.22 (d, J = 2.0 Hz, 1H), 7.73 (dd, J = 2.4, 9.2 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 4.10 - 4.06 (m, 2H), 3.56 (d, J = 19.6 Hz, 2H), 3.25 - 3.18 (m, 2H), 1.89 - 1.84 (m, 2H), 1.77 -1.64 (m, 2H).

[0657] Step 2: Synthesis of (1-(2',6'-bis(benzyloxy)-[3,3'-bipyridine]-6-yl)-4-fluoropiperidin-4-yl)methanol

[0658] XPhos Pd G3 (824 mg, 974 µmol, 0.10 eq) was added to a solution of (4-fluoro-1-(5-iodopyridin-2-yl)piperidin-4-yl)methanol (3.60 g, 10.7 mmol, 1.10 eq) and 2,6-bis(benzyloxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine (4.06 g, 9.74 mmol, 1.00 eq) in dioxane (32.4 mL) and H2O (3.60 mL). K3PO4 (5.17 g, 24.3 mmol, 2.50 eq) was added to the mixture at 20 °C under N2 atmosphere, followed by degassing and purging the mixture three times with N2. The mixture was then stirred at 90 °C under N2 atmosphere for 12 h. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 3:1 to 1:1). A white solid (1-(2',6'-bis(benzyloxy)-[3,3'-bipyridinyl]-6-yl)-4-fluoropiperidin-4-yl)methanol (3.64 g, 7.25 mmol, 74.5% yield, 99.6% purity) was obtained. LCMS: C 30 H 30 Theoretical value of FN3O3: 499.2, experimental value: m / z = 500.2 [M+H] + . 1 H NMR: (400 MHz, MeOD) δ 8.27 (d, J = 2.4 Hz, 1H), 7.77 (dd, J= 12, 11.2 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.40 - 7.38 (m, 2H), 7.35 -7.23 (m, 8H), 6.85 (d, J = 8.8 Hz, 1H), 6.47 (d, J = 8 Hz, 1H), 5.37 (s, 2H), 5.34 (s, 2H), 4.09 - 4.06 (m, 2H), 3.56 (d, J = 20 Hz, 2H), 3.27 - 3.20 (m,2H), 1.91 - 1.85 (m, 2H),. 1.80 - 1.63 (m, 2H).

[0659] Step 3: Synthesis of racemic-(R)-3-(6-(4-fluoro-4-(hydroxymethyl)piperidin-1-yl)pyridin-3-yl)piperidin-2,6-dione

[0660] AcOH (313 mg, 5.20 mmol, 298 μL, 1.00 eq) and Pd / C (1.30 g, 10.0% purity) were added to a solution of (1-(2',6'-bis(benzyloxy)-[3,3'-bipyridinyl]-6-yl)-4-fluoropiperidin-4-yl)methanol (2.60 g, 5.20 mmol, 1.00 eq) in THF (13.0 mL) and EtOH (13.0 mL) at 20 °C under a nitrogen atmosphere. The suspension was degassed and purged three times with H2, and then the mixture was stirred at 50 °C for 2 h under H2 (50.0 Psi). The reaction mixture was filtered and the filtrate was concentrated under vacuum. The crude product was purified by silica gel chromatography (SiO2, dichloromethane:methanol = 15:1 to 10:1). Racemic (R)-3-(6-(4-fluoro-4-(hydroxymethyl)piperidin-1-yl)pyridin-3-yl)piperidin-2,6-dione (1.17 g, 3.64 mmol, 70.0% yield) was obtained as a grayish-white solid. 1 H NMR: (400 MHz, MeOD) δ 7.97 (d, J = 2.0 Hz, 1H), 7.46 (dd, J = 2.4, 8.8 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 4.09 (d, J = 12.8 Hz, 2H), 3.79 (dd, J = 11.6, 11.6 Hz,, 1H), 3.56 (d, J = 20 Hz,2H), 3.27 - 3.21 (m, 2H), 2.77 - 2.63 (m, 2H), 2.27 - 2.10 (m, 2H), 1.91 -1.85 (m, 2H), 1.805 - 1.63 (m, 2H).

[0661] Step 4: Synthesis of racemic-(R)-1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)-4-fluoropiperidine-4-carboxaldehyde

[0662] Racemic-(R)-3-(6-(4-fluoro-4-(hydroxymethyl)piperidin-1-yl)pyridin-3-yl)piperidin-2,6-dione Add Desmond-Martin periodane (3.16 g, 7.45 mmol, 2.31 mL, 2.00 eq) to a solution of racemic (R)-3-(6-(4-fluoro-4-(hydroxymethyl)piperidin-1-yl)pyridin-3-yl)piperidin-2,6-dione (1.20 g, 3.72 mmol, 1.00 eq) in DCM (24.0 mL) cooled to 0 °C, and stir the mixture at 20 °C for 12 h. Quench the mixture with saturated Na₂SO₃ solution (50.0 mL), extract with DCM:EtOH = 10:1 (4 x 50.0 mL), dry the organic layer with Na₂SO₄, filter, and concentrate under vacuum. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (FA)-ACN]; B%: 4%-34%, 10 min). The product was then concentrated under vacuum to remove ACN and further concentrated by lyophilization to yield a white solid product: racemic-(R)-1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)-4-fluoropiperidine-4-carboxaldehyde (265 mg, 822 μmol, 26.2% yield, 99.0% purity). LCMS: C 16 H 18 Theoretical value of FN3O3: 319.1, experimental value: m / z = 338.1 [M+H2O+H]+. 1H NMR: (400 MHz, CDCl3) δ 9.77 (d, J = 4.8 Hz, 1H), 8.08 (d, J = 2.4 Hz, 1H), 8.03 (s, 1H), 7.38 (dd, J = 2.4, 8.8 Hz, 1H), 6.74 (d, J = 8.8 Hz, 1H), 4.25 - 4.21 (m,2H), 3.70 (dd, J = 5.6, 10.8 Hz, 1H) 3.38 - 3.32 (m, 2H), 2.79 - 2.73 (m, 2H), 2.27 - 2.23 (m, 2H), 1.95 - 1.88 (m, 4H).

[0663] Step 5: Synthesize the title compound Add 2-[5-(4-{2,6-diazaspiro[3,4]octane-2-carbonyl}-4-phenylpiperidin-1-yl)pyridazin-3-yl]phenol (15.00 mg, 0.0381 mmol), triethylamine (26.06 μL, 0.1906 mmol), 1-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-carboxaldehyde (13.74 mg, 0.0457 mmol), and DCE (3.00 mL) to a scintillation vial. Stir at rt and add sodium triacetoxyborohydride (28.28 mg, 0.1334 mmol). Stir until the starting material is completely consumed as determined by MS. The reaction was complete and clean after 90 minutes. Quench the reaction with bicarbonate solution and extract with EtOAc. Dry the organic layer with brine followed by Na2SO4. The solution was concentrated and injected onto an RP-FC plate and purified using a 0–70% MeCN / H2O gradient to provide the title compound (7.7 mg, 44%). LCMS: C 43 H 47 Theoretical value of N8O4F: 758.4, experimental value: m / z = 759.4 [M+H] + .

[0664] Example 20 Racemic-(3R)-3-{4-[4-(6-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carbonyl}-2,6-diazaspiro[3.3]heptane-2-carbonyl)piperidin-1-yl]phenyl}piperidin-2,6-dione

[0665] Step 1: Synthesis of tert-butyl 1-(4-bromophenyl)piperidine-4-carboxylate

[0666] L-hydroxyproline (9.27 g, 70.7 mmol, 0.400 eq), K₂CO₃ (48.8 g, 353 mmol, 2.00 eq), and CuI (6.73 g, 35.3 mmol, 0.200 eq) were added to a solution of 1-bromo-4-iodobenzene (50.0 g, 176 mmol, 1.00 eq) and piperidine-4-carboxylic acid tert-butyl ester (36.0 g, 194 mmol, 1.10 eq) in DMSO (500 mL) under N₂. The reaction mixture was stirred at 90 °C for 12 h. The reaction mixture was poured into H₂O (500 mL) and then extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with brine (2 x 500 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 - 50 / 1 - 40 / 1). Tert-butyl 1-(4-bromophenyl)piperidine-4-carboxylate was given as a white solid (43.0 g, 107 mmol, 50.6% yield, 84.9% purity). LCMS: C 16 H 22 Theoretical value of BrNO2: 339.1, experimental value: m / z = 340.1 [M+H] + . 1 H NMR: (400 MHz, DMSO) δ7.47 - 7.29 (m, 2H), 6.89 - 6.75 (m, 2H), 3.62 - 3.57 (m, 2H), 2.78 - 2.72(m, 2H), 2.38 - 2.36 (m, 1H), 1.86 - 1.82 (m, 2H), 1.60 - 1.56 (m, 2H), 1.40 (s, 9H).

[0667] Step 2: Synthesis of tert-butyl 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidine-4-carboxylate

[0668] At 20 °C, tert-butyl 1-(4-bromophenyl)piperidin-4-carboxylate (38.0 g, 94.8 mmol, 84.9% purity, 1.00 eq), K₂CO₃ (39.3 g, 284 mmol, 3.00 eq), and Pd(dppf)Cl₂ (3.47 g, 4.74 mmol, 0.05 eq) were added to a solution of (2,6-bis(benzyloxy)pyridin-3-yl)boronic acid (47.5 g, 114 mmol, 1.20 eq) in dioxane (400 mL) and H₂O (80 mL). The reaction mixture was stirred at 90 °C for 12 h. The reaction mixture was poured into H₂O (500 mL) and then extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with brine (2 x 500 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 - 50 / 1 - 40 / 1). Tert-butyl 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidine-4-carboxylate was given as a white solid (46.0 g, 81.2 mmol, 75.8% yield, 97.2% purity). LCMS: C 35 H 38 Theoretical value of N₂O₄: 550.3, experimental value: m / z = 551.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.60 (d, J = 8.0 Hz, 2H), 7.50 (d,J = 8.4 Hz, 1H), 7.43 - 7.35 (m, 10H), 6.97 (d, J = 8.4 Hz, 2H), 6.47 (d, J =8.4 Hz, 1H), 5.45 (s, 2H), 5.37 (s, 2H), 3.71 - 3.66 (m, 2H), 2.86 - 2.79 (m,2H), 2.40 - 2.35 (m, 1H), 2.03 - 1.99 (m, 2H), 1.90 - 1.85 (m, 2H), 1.48 (s, 9H).

[0669] Step 3: Synthesis of racemic (R)-1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-carboxylic acid tert-butyl ester x

[0670] Pd / C (10.0 g, 72.4 mmol, 97.2% purity, 1.00 eq) was added to a solution of tert-butyl 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-carboxylate (41.0 g, 72.4 mmol, 97.2% purity, 1.00 eq) in THF (410 mL) under N2. The suspension was degassed under vacuum and purged three times with H2. The reaction mixture was stirred at 25 °C for 12 h under H2 (50 psi). The suspension was filtered through a diatomaceous earth pad and the pad was washed with THF (4 x 500 mL). The solution was concentrated under reduced pressure using a rotary evaporator. Racemic (R)-1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-carboxylic acid tert-butyl ester was obtained as a white solid (30.0 g, 77.6 mmol, 95.7% yield, 96.3% purity). LCMS: C 21 H 28 Theoretical value of N₂O₄: 372.2, experimental value: m / z = 373.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.77(s, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 3.73 - 3.69 (m,1H), 3.58 (d, J = 12.4 Hz, 2H), 2.75 - 2.70 (m, 2H), 2.68 - 2.62 (m, 1H), 2.43 - 3.36 (m, 2H), 2.20 - 2.00 (m, 2H), 1.86 - 1.83 (m, 2H), 1.61 - 1.59(m, 2H), 1.40 (s, 9H).

[0671] Step 4: Synthesis of racemic-(R)-1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-carboxylic acid

[0672] TFA (29.5 g, 258 mmol, 19.1 mL, 10.0 eq) was added to a solution of racemic (R)-1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-carboxylic acid tert-butyl ester (10.0 g, 25.8 mmol, 96.3% purity, 1.00 eq) in DCM (270 mL) at 25 °C. The reaction mixture was then stirred at 25 °C for 12 h. The reaction mixture was concentrated under vacuum. The residue was treated with petroleum ether / ethyl acetate = 1 / 1 (40.0 mL) at 25 °C for 10 min, followed by filtration, and the filter cake was concentrated under vacuum. Racemic (R)-1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-carboxylic acid was obtained as a white solid (9.00 g, 20.3 mmol, 60.5% yield, 97.3% purity, TFA salt). LCMS: C 17 H 20 Theoretical value of N₂O₄: 316.1, experimental value: m / z = 317.2 [M+H] + . 1 H NMR (400 MHz, D2O) δ 7.61 (d, J = 8.8Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 4.08 - 4.03 (m, 1H), 3.78 - 3.74 (m, 2H), 3.71 - 3.67 (m, 2H), 2.85 - 2.80 (m, 1H), 2.77 - 2.75 (m, 2H), 2.37 - 2.15 (m, 6H).

[0673] Step 5: Synthesize the title compound Stir a solution of DMF containing 2-[5-(4-{2,6-diazaspiro[3.3]heptane-2-carbonyl}-4-phenylpiperidin-1-yl)pyridin-3-yl]phenol (10.00 mg, 0.0220 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylene]dimethylammonium; hexafluoro-λ5-phosphate (20.87 mg, 0.0549 mmol) and N,N-diisopropylethylamine (19.17 μL, 14.19 mg, 0.1098 mmol). Add racemic-1-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-carboxylic acid and stir at rt until complete as determined by LCMS. The solution was injected onto an RP-FC and purified using a 0–70% MeCN / H2O gradient to provide the title compound (4.6 mg, 28%). LCMS: C 44 H47 Theoretical value of N7O4: 753.4, experimental value: m / z = 754.4 [M+H] + .

[0674] Example 21 Racemic-(3R)-3-{4-[4-(1-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carbonyl}-4-methylpiperidin-4-carbonyl)piperazin-1-yl]phenyl}piperidin-2,6-dione

[0675] Step 1: Synthesis of methyl 1-(1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-phenylpiperidine-4-carbonyl)-4-methylpiperidine-4-carboxylate

[0676] A solution of DMF containing 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carboxylic acid (71.00 mg, 0.1891 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylene]dimethylammonium; hexafluoro-λ5-phosphate (179.77 mg, 0.4728 mmol) and N,N-diisopropylethylamine (165.15 μL, 122.21 mg, 0.9456 mmol) was stirred. Methyl 4-methylpiperidin-4-carboxylate (27.87 μL, 40.14 mg, 0.2553 mmol) was added and stirred at rt until complete as determined by LCMS. The solution was directly injected into an RP-FC and purified to provide the title compound (80 mg, 73%). LCMS: C 30 H 34 Theoretical value of N4O4: 514.6, experimental value: m / z = 515.5 [M+H] + .

[0677] Step 2: Synthesis of 1-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carbonyl}-4-methylpiperidin-4-carboxylic acid

[0678] A mixture of methyl 1-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carbonyl}-4-methylpiperidin-4-carboxylate (29.00 mg, 0.0564 mmol) and lithium hydroxide monohydrate (8.51 mg, 0.2029 mmol) in MeOH and H₂O was stirred at rt for 2 h. The mixture was then acidified to pH = 5 with HCl and extracted with EtoAC x 3. The combined organic matter was washed with brine, dried over Na₂SO₄, and concentrated. The crude product was used in the next step without further purification.

[0679] Step 3: Synthesize the title compound Stir a mixture of DMF containing 1-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carbonyl}-4-methylpiperidin-4-carboxylic acid (10.10 mg, 0.0202 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylene]dimethylammonium; hexafluoro-λ5-phosphate (19.18 mg, 0.0504 mmol) and N,N-diisopropylethylamine (17.62 μL, 13.04 mg, 0.1009 mmol). Add racemic-(3R)-3-[4-(piperazin-1-yl)phenyl]piperidin-2,6-dione (6.62 mg, 0.0242 mmol) and stir at rt until complete as determined by LCMS. The solution was injected onto an RP-FC and purified using a 0–70% MeCN / H2O gradient to provide the title compound (5.9 mg, 35%). LCMS: C 44 H 49 Theoretical value of N7O4: 755.4, experimental value: m / z = 756.4 [M+H] + .

[0680] Example 22 Racemic-(3R)-3-(4-{4-[4-(4-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carbonyl}piperazin-1-yl)butyryl]piperazin-1-yl}phenyl)piperidin-2,6-dione

[0681] Step 1: Synthesis of 4-(4-(1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-phenylpiperidin-4-carbonyl)piperazin-1-yl)butyric acid

[0682] A solution of DMF containing 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carboxylic acid (17.00 mg, 0.0453 mmol), [chloro(dimethylamino)methylene]dimethylammonium, hexafluoro-λ5-phosphate (25.41 mg, 0.0906 mmol), and 1-methylimidazole (14.87 mg, 0.1811 mmol) was stirred. Ethyl 4-(piperazin-1-yl)butyrate (9.98 mg, 0.0498 mmol) was added and stirred at rt until complete as determined by LCMS. The product was directly injected into an RP-FC to purify and separate the ester-protected product. The product was then dissolved in THF with 1.2 equivalents of LiOH monohydrate and concentrated to yield the final product. (25 mg, 90%) LCMS: C 30 H 35 Theoretical value of N5O4: 529.6, experimental value: m / z = 530.5 [M+H] + .

[0683] Step 2: Synthesize the title compound A mixture of DMF containing racemic (3R)-3-[4-(piperazin-1-yl)phenyl]piperidin-2,6-dione (3.10 mg, 0.0113 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylene]dimethylammonium; hexafluoro-λ5-phosphate (8.97 mg, 0.0236 mmol) and N,N-diisopropylethylamine (8.24 μL, 6.10 mg, 0.0472 mmol) was added. 4-(4-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidin-4-carbonyl}piperazin-1-yl)butyric acid (5.00 mg, 0.0094 mmol) was added and stirred at rt until complete as determined by LCMS. The solution was injected onto an RP-FC and purified using a 0-70% MeCN / H2O gradient to provide the title compound (1.2 mg, 15%). LCMS: C 45 H 52 Theoretical value of N8O5: 784.4, experimental value: m / z = 785.4 [M+H] + .

[0684] Example 23 (3R)-3-(4-{4-[(6-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methylpiperidin-4-carbonyl}-2,6-diazaspiro[3.3]hept-2-yl)methyl]piperidin-1-yl}phenyl)piperidin-2,6-dione

[0685] Step 1: Synthesis of (1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methylpiperidin-4-yl)(2,6-diazaspiro[3.3]hept-2-yl) methyl ketone

[0686] Stir a solution of DMF containing 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methylpiperidin-4-carboxylic acid (10.00 mg, 0.0319 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylene]dimethylammonium; hexafluoro-λ5-phosphate (24.27 mg, 0.0638 mmol) and N,N-diisopropylethylamine (22.30 μL, 16.50 mg, 0.1276 mmol). Add tert-butyl 2,6-diazaspiro[3,3]heptane-2-carboxylate (6.33 mg, 0.0319 mmol) and stir at rt until complete as determined by LCMS. The Boc-protected intermediate (6.1 mg, 38%) was directly purified by RP-FC, then dissolved in a 1:1 TFA:DCM mixture and stirred at rt for 30 mL. The solution was concentrated to yield the product, which was then proceeded to the next step. LCMS: C 22 H 27 Theoretical value of N5O2: 393.3, experimental value: m / z = 394.3 [M+H] + .

[0687] Step 2: Synthesize the title compound Add 2-[5-(4-{2,6-diazaspiro[3,4]octane-2-carbonyl}-4-phenylpiperidin-1-yl)pyridazin-3-yl]phenol (15.00 mg, 0.0381 mmol), triethylamine (26.06 μL, 0.1906 mmol), 1-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-carboxaldehyde (13.74 mg, 0.0457 mmol), and DCE (3.00 mL) to a scintillation vial. Stir at rt and add sodium triacetoxyborohydride (28.28 mg, 0.1334 mmol). Stir until the starting material is completely consumed as determined by MS. The reaction was complete and clean after 90 minutes. Quench the reaction with bicarbonate solution and extract with EtOAc. Dry the organic layer with brine followed by Na2SO4. The solution was concentrated and injected onto an RP-FC plate and purified using a 0–70% MeCN / H2O gradient to provide the title compound (7.4 mg, 29%). LCMS: C 43 H 47Theoretical value of N8O4F: 677.4, experimental value: m / z = 678.4 [M+H] + .

[0688] Example 24 (3R)-3-(4-{4-[(6-{4-cyclopropyl-1-[6-(2-hydroxyphenyl)pyridazin-4-yl]piperidin-4-carbonyl}-2,6-diazaspiro[3.3]hept-2-yl)methyl]piperidin-1-yl}phenyl)piperidin-2,6-dione

[0689] Step 1: Synthesis of (4-cyclopropyl-1-(6-(2-hydroxyphenyl)pyridazin-4-yl)piperidin-4-yl)(2,6-diazaspiro[3.3]hept-2-yl)methyl ketone

[0690] Stir a solution of DMF containing 4-cyclopropyl-1-[6-(2-hydroxyphenyl)pyridazin-4-yl]piperidin-4-carboxylic acid (10.00 mg, 0.0295 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylene]dimethylammonium; hexafluoro-λ5-phosphate (22.41 mg, 0.0589 mmol), and N,N-diisopropylethylamine (20.58 μL, 15.23 mg, 0.1179 mmol). Add tert-butyl 2,6-diazaspiro[3,3]heptane-2-carboxylate (5.84 mg, 0.0295 mmol) and stir at rt until complete as determined by LCMS. The Boc intermediate (4.9 mg, 31%) was directly injected and purified by RP-FC, then dissolved in 1:1 TFA:DCM and stirred at rt ...

Claims

1. A compound having a structure represented by formula (IA): Formula (IA) Or its stereoisomers, pharmaceutically acceptable salts, wherein: R 1 Hydrogen or optionally via 1 to 3 R a Replacement C 1-6 alkyl; R 2 Hydrogen, halogenated group, hydroxyl group, -OR c Optional location via 1 to 3 R a Replacement C 1-6 alkyl; R 3 For hydrogen, -CN, C 1-6 Alkyl, C 6-12 Aryl, C 3-12 Cycloalkyl groups, 5-12-membered heteroaryl groups, each optionally denoted by 1 to 3 R groups d Replace, or -OR e ; L comprises up to 8 joint sections represented by -L1-L2-L3-L4-L5-L6-L7-L8-, where each L1, L2, L3, L4, L5, L6, L7, or L8 is independently: i) Choose any location within 1-3 R's b Replacement C 3-12 cycloalkyl; ii) Choose any location within 1-3 R's. b Replacement C 6-12 Aryl; iii) Choose any location within 1-3 R's. b Substituted 4-12 membered heterocyclic groups; iv) Choose any location via 1-3 R... b Substituted 5-12 heteroaryl groups; v) Direct key; vi) Choose any location with a radius of 1-3 R. b Replacement C 1-12 alkylene chains; or vii) -(CH2) m -C(O)-, -(CH2) m -C(O)O-, -(CH2) m -O-、-(CH2) m -N(R c )-、-(CH2) m -S-、-(CH2) m -C(S)-、-(CH2) m -C(S)-O-, -(CH2) m -S(O)2-、-(CH2) m -S(O)=N-、-(CH2) m -S(O)2NH-、-(CH2) m -C(O)-N(R c )-、-C(O)-N(R c )-(CH2) m -、-(CH2) m -OC(O)-N(R c )-、-(CH2) m -OC(O)-O- or -NH-(CH2) m -C(O)-, where m is 0, 1, 2, 3, 4, 5 or 6; Each R a Independent of halogenated group or -OR c ; Each R b Independently, it can be an oxo group, imino group, sulfoxide imino group, halogen group, nitro group, -CN, or C. 1-6 Alkyl, C 2-6 alkenyl, C 3-15 cycloalkyl, C 1-8 Haloalkyl, C 6-12 aryl, 5-12 heteroaryl, 4-12 heterocyclic, -OR c -C(O)-R c -C(O)OR c -C(O)-N(R) c (R) c ), -N(R c (R) c ), -N(R c )C(O)-R c -N(R) c )C(O)OR c -N(R) c )C(O)N(R c (R) c ), -N(R c )S(O)2(R c -NR c S(O)2N(R c (R) c ), -N(R c )S(O)2O(R c -OC(O)R c -OC(O)-N(R) c (R) c ), -Si(R c )3、-SR c -S(O)R c -S(O)(NH)R c -S(O)2R c or -S(O)2N(R) c (R) c ), where C 1-6 Alkyl, C 2-6 alkenyl, C 3-15 cycloalkyl, C 1-8 Haloalkyl, C 6-12 Each of the aryl, 5-12-membered heteroaryl, and 4-12-membered heterocyclic groups may be optionally etched via 1 to 3 R groups. d replace; Each R c Independently hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 6-12 Aryl or C 1-6 Haloalkyl, wherein C 1-6 Alkyl groups optionally via C 1-3 Alkyl substitution; Each R d Independent of halogenated group, -CN, -OR c C 1-6 Alkyl, C 6-12 Aryl or C 1-6 Halogenated alkyl groups; R e C 1-6 Alkyl, C 3-12 cycloalkyl, C 6-12 Aryl and 5-12 heteroaryl groups, each selectively hydroxylated by C 1-6 Alkyl or halogroup substitution; W is -C(R) g - or -N-; Y represents a direct bond, C represents a direct bond. 1-4 Alkylene chains, -C(O)-, -C(O)O-, -O-, -N(R) g )-, -S- -C(S)-, -C(S)-O-, -OC(O)O-, -C(O)-N(R g )-or-OC(O)-N(R g )-; Ring B is C 6-12 aryl, 5-12-membered heteroaryl, or 4-12-membered heterocyclic, each optionally denoted by 1 to 3 R... j replace; R g It is hydrogen or C 1-6 Alkyl; and Each R j Independently halogenated, oxo-substituted, -CN, -OR c C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

2. The compound of claim 1, wherein each L1, L2, L3, L4, L5, L6, L7 or L8 is independently: i) Select the bivalent ring portion of the group consisting of the following groups: 、 、 、 、 、 、 、 、 、 、 、 ； 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； 、 、 、 、 、 、 、 、 、 、 、 、 ； ii) Direct key; iii) C 1-6 alkylene chains; or iv) -C(O)-, -O-, -(CH2) m -C(O)-N(R c )-、-(CH2) m -N(R c )-、-C(O)-N(R c )-(CH2) m -or -NH-(CH2) m -C(O)-, -(CH2) m -S(O)2NH-, where m is 0, 1, 2 or 3; in, n is 0, 1, or 2; R b Halogenated group, -OR c -CN,C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; and R c For hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, phenyl or C 1-6 Haloalkyl, wherein C 1-6 Alkyl groups optionally via C 1-3 Alkyl-substituted.

3. The compound according to claim 1 or claim 2, wherein, Y is a direct bond, -NHC(O)-, or -NH-; and Ring B is: , , , , , , , or Where n is 0, 1, or 2, R j Halogenated group, -CN, -OR c C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

4. The compound according to any one of claims 1 to 3, wherein R 3 for: Optionally via one or more C 1-6 Alkyl, C 1-6 Benzene substituted with alkoxy or halogroup; Optionally via one or more C 1-6 Benzyl groups substituted with alkyl or halogroups; Optionally via one or more C 1-6 Alkyl-substituted pyridinyl group; CN; C 3-6 Cyclopropyl; Optionally via one or more C 1-6 Alkyl-substituted pyrazolyl group; Tetrahydropyranyl, Optionally via one or more C 1-6 Alkyl-substituted 1,2-oxazolyl; Pyrazolo[1,5-a]pyridyl; or -OR e , where R e For optional location C 1-6 alkyl or halogenated phenyl, C 3-6 cycloalkyl, C 1-6 Alkyl or optionally C 1-6 Alkyl-substituted pyrazolyl group.

5. The compound of claim 4, wherein R 3 It is phenyl, benzyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, CN, cyclopropyl, 1-methyl-1H-pyrazole-3-yl, 3-methylphenyl, 2-methylphenyl, 3-chlorophenyl, 3,4-dichlorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-fluorophenyl, 4-fluorophenyl, tetrahydropyran-4-yl, 3-methyl-1H-pyrazole-1-yl, 4-methyl-1H-pyrazole-1-yl, 5-methyl-1H-pyrazole-1-yl, 1-methyl-1H-pyrazole-3-yl, 1-methyl-1H-pyrazole-4-yl, 1-methyl-1H-pyrazole-5-yl, pyrazolo[1,5-a]pyridin-2-yl, 5-methyl-1,2-oxazol-3-yl, 5-isopropyl-1,2-oxazol-3-yl, 3-methyl-1,2-oxazol-5-yl, or -OR e , where R e It can be phenyl, 2-chlorophenyl, 2-methylphenyl, cyclopropyl, cyclohexyl, methyl, or 1-methyl-1H-pyrazole-3-yl.

6. The compound according to any one of claims 1 to 5, wherein R 1 It is hydrogen and R 2 It is hydrogen.

7. The compound according to any one of claims 1 to 5, wherein R 1 For hydrogen, R 2 It is hydrogen, Y is a direct bond, R 3 For -OR e W is CH, and the compound has a structure represented by formula (IA1): Formula (IA1) in, Ring B is or ; n is 0, 1, or 2; R j Halogenated group, -CN, -OR c C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R e C 1-6 Alkyl, C 3-12 cycloalkyl, C 6-12 Aryl and 5-12 heteroaryl groups, each selectively hydroxylated by C 1-6 Alkyl or halogroup substitution; R c It is hydrogen or C 1-3 alkyl; L1 is -C(O)- or -C(O)N(R) c )-;and L a for , , , , , , , , , , , , , or .

8. The compound of claim 7, wherein B is ; n is 0 or 1; R j It is either fluorine or chlorine; R e C 1-6 Alkyl, C 3-12 cycloalkyl, C 6-12 Aryl and 5-12 heteroaryl groups, each selectively hydroxylated by C 1-6 Alkyl or halogroup substitution; L 1 -C(O)N(R) c )-, where R c It is methyl or ethyl; and L a for .

9. The compound of claim 7 or claim 8, wherein R e C 1-3 alkyl.

10. The compound according to any one of claims 7 to 9, wherein R e It can be methyl, phenyl, cyclopropyl, cyclohexyl, 1-methyl-1H-pyrazole-3-yl or phenyl substituted with chlorine or methyl.

11. The compound of claim 7, wherein ring B is ; n is 0, 1, or 2; R j It is either fluorine or chlorine; R e It can be methyl, ethyl, or propyl; R c It can be hydrogen, methyl, or ethyl; L1 is -C(O)- or -C(O)N(R) c )-;and L a for , , or .

12. The compound according to any one of claims 1 to 5, wherein R 1 and R 2 Where is hydrogen, W is CH, and the compound has a structure represented by formula (IA2): Formula (IA2) in, n is 0, 1, or 2; Y is a direct bond, -NHC(O)- or -NH-; X is either N or CH; Rj is C 1-3 Alkyl or halogroup; R 3 C 6-12 Aryl, C 3-12 Cycloalkyl groups, 5-12-membered heteroaryl groups, each optionally denoted by 1 to 3 R groups d Replace, or -OR e ; R c It is hydrogen or C 1-6 methyl; Each R d Independent of halogenated group, -CN, -OR c C 1-6 Alkyl, C 6-12 Aryl or C 1-6 Halogenated alkyl groups; and R e C 1-6 Alkyl, C 3-12 cycloalkyl, C 6-12 Aryl and 5-12 heteroaryl groups, each selectively hydroxylated by C 1-6 Alkyl or halogroup substitution; and L b for , , , , , , , , , , , , , , , , , , , , , , , , or .

13. The compound of claim 12, wherein R 3 It is phenyl, 2-fluorophenyl, 5-methyl-1,2-oxazol-5-yl, 5-isopropyl-1,2-oxazol-5-yl, pyrazolo[1,5-a]pyridyl, -OR e , where R e It can be phenyl, 2-chlorophenyl, 2-methylphenyl, 1-methyl-1H-pyrazole-3-yl, cyclohexyl or methyl.

14. The compound according to any one of claims 1 to 5, wherein R 1 and R 2 Where is hydrogen, W is CH, and the compound has a structure represented by formula (IA3): Formula (IA3) in, n is 0, 1, or 2; Y is a direct bond, -NHC(O)- or -NH-; X is either N or CH; R 3 C 6-12 Aryl, C 3-12 Cycloalkyl groups, 5-12-membered heteroaryl groups, each optionally denoted by 1 to 3 R groups d Replace, or -OR e ; R c For hydrogen, C 1-3 Alkyl or C 3-6 cycloalkyl; Each R d Independent of halogenated group, -CN, -OR c C 1-6 Alkyl, C 6-12 Aryl or C 1-6 Halogenated alkyl groups; R e C 1-6 Alkyl, C 3-12 cycloalkyl, C 6-12 Aryl and 5-12 heteroaryl groups, each selectively hydroxylated by C 1-6 Alkyl or halogroup substitution; R j C 1-3 Alkyl or halogroup; and L c for , , , , , , , , , , , , , , , , , , or .

15. The compound of claim 14, wherein R 3 The following are possible meanings: phenyl, 2-pyridyl, 4-pyridyl, 2-fluorophenyl, 4-fluorophenyl, 3-methyl-1H-pyrazole-1-yl, 4-methyl-1H-pyrazole-1-yl, 5-methyl-1H-pyrazole-1-yl, 1-methyl-1H-pyrazole-4-yl, 1-methyl-1H-pyrazole-5-yl, tetrahydropyran-4-yl, 3-methyl-1,2-oxazol-5-yl, 5-isopropyl-1,2-oxazol-3-yl, pyrazolo[1,5-a]pyridyl, -OR e , where R e It can be phenyl, 2-chlorophenyl, 2-methylphenyl, 1-methyl-1H-pyrazole-3-yl, cyclopropyl, cyclohexyl or methyl.

16. The compound according to any one of claims 1 to 5, wherein R 1 and R 2 For hydrogen, W is CH, Y is a direct bond, and R is... 3 It is phenyl, and the compound has a structure represented by formula (IA4): Equation (IA4) in, n is 0, 1, or 2; X is either N or CH; R c Hydrogen or optionally C 1-3 alkoxy-substituted C 1-3 alkyl; R j C 1-3 Alkyl or halogroup; and L d for , , , , , , , , or .

17. The compound according to any one of claims 1 to 5, wherein R 1 and R 2 For hydrogen, W is CH, Y is a direct bond, and R is... 3 It is phenyl, and the compound has a structure represented by formula (IA5): Formula (IA5) in, n is 0, 1, or 2; X is either N or CH; Q is a direct bond, -N(R) c - or -NHS(O)2-, R c It is hydrogen or C 1-3 alkyl; R j C 1-3 Alkyl or halogroup; and L e for , , or or .

18. The compound according to any one of claims 1 to 5, wherein R 1 and R 2 Where is hydrogen, W is CH, Y is a direct bond, and the compound has a structure represented by formula (IA6): ， Equation (IA6) in, B is , , or ; R 3 C 6-12 Aryl, C 3-12 Cycloalkyl groups, 5-12-membered heteroaryl groups, each optionally denoted by 1 to 3 R groups d Replace, or -OR e ; R c It is hydrogen or C 1-6 alkyl; Each R d Independent of halogenated group, -CN, -OR c C 1-6 Alkyl, C 6-12 Aryl or C 1-6 Halogenated alkyl groups; R e C 1-6 Alkyl, C 3-12 cycloalkyl, C 6-12 Aryl and 5-12 heteroaryl groups, each selectively hydroxylated by C 1-6 Alkyl or halogroup substitution; L1 is -C(O)-, -C(O)-N(R) c -(CH2)- or -C(O)-N(R) c )-;and L f for , , , , , or .

19. The compound of claim 18, wherein R 3 It is phenyl, 1-methyl-1H-pyrazole-5-yl, 5-methyl-1H-pyrazole-1-yl or -OR e , where R e It is 1-methyl-1H-pyrazole-3-yl or methyl.

20. A compound having a structure represented by formula (I): Formula (I) Or its stereoisomers, pharmaceutically acceptable salts, wherein: R 1 Hydrogen or optionally via 1 to 3 R a Replacement C 1-6 alkyl; R 2 Hydrogen, halogenated group, hydroxyl group, -OR c Optional location via 1 to 3 R a Replacement C 1-6 alkyl; R 3 For hydrogen, -CN, C 1-6 Alkyl, C 6-12 Aryl, C 3-12 Cycloalkyl or 5-12-membered heteroaryl groups, each optionally denoted by 1 to 3 R groups. d replace; L comprises up to 8 joint sections represented by -L1-L2-L3-L4-L5-L6-L7-L8-, where each L1, L2, L3, L4, L5, L6, L7, or L8 is independently: i) Choose any location within 1-3 R's b Replacement C 3-12 cycloalkyl; ii) Choose any location within 1-3 R's. b Replacement C 6-12 Aryl; iii) Choose any location within 1-3 R's. b Substituted 4-12 membered heterocyclic groups; iv) Choose any location via 1-3 R... b Substituted 5-12 heteroaryl groups; v) Direct key; vi) Choose any location with a radius of 1-3 R. b Replacement C 1-12 alkylene chains; or vii) -(CH2) m -C(O)-, -(CH2) m -C(O)O-, -(CH2) m -O-、-(CH2) m -N(R c )-、-(CH2) m -S-、-(CH2) m -C(S)-、-(CH2) m -C(S)-O-, -(CH2) m -S(O)2-、-(CH2) m -S(O)=N-、-(CH2) m -S(O)2NH-、-(CH2) m -C(O)-N(R c )-、-C(O)-N(R c )-(CH2) m -、-CH2) m -OC(O)-N(R c )-、-(CH2) m -OC(O)-O- or -NH-(CH2) m -C(O)-, where m is 0, 1, 2, 3, 4, 5 or 6; Each R a Independent of halogenated group or -OR c ; Each R b Independently, it can be an oxo group, imino group, sulfoxide imino group, halogen group, nitro group, -CN, or C. 1-6 Alkyl, C 2-6 alkenyl, C 3-15 cycloalkyl, C 1-8 Haloalkyl, C 6-12 aryl, 5-12 heteroaryl, 4-12 heterocyclic, -OR c -C(O)-R c -C(O)OR c -C(O)-N(R) c (R) c ), -N(R c (R) c ), -N(R c )C(O)-R c -N(R) c )C(O)OR c -N(R) c )C(O)N(R c (R) c ), -N(R c )S(O)2(R c -NR c S(O)2N(R c (R) c ), -N(R c )S(O)2O(R c -OC(O)R c -OC(O)-N(R) c (R) c ), -Si(R c )3、-SR c -S(O)R c -S(O)(NH)R c -S(O)2R c or -S(O)2N(R) c (R) c ), where C 1-6 Alkyl, C 2-6 alkenyl, C 3-15 cycloalkyl, C 1-8 Haloalkyl, C 6-12 Each of the aryl, 5-12-membered heteroaryl, and 4-12-membered heterocyclic groups may be optionally etched via 1 to 3 R groups. d replace; Each R c Independently hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Each R d Independent of halogenated group, -CN, -OR c C 1-6 Alkyl, C 6-12 Aryl or C 1-6 Halogenated alkyl groups; W is -C(R) g - or -N-; Y represents a direct bond, C represents a direct bond. 1-4 Alkylene chains, -C(O)-, -C(O)O-, -O-, -N(R) g )-, -S- -C(S)-, -C(S)-O-, -OC(O)O-, -C(O)-N(R g )-or-OC(O)-N(R g )-; Ring B is C 6-12 aryl, 5-12-membered heteroaryl, or 4-12-membered heterocyclic, each optionally denoted by 1 to 3 R... j replace; R g It is hydrogen or C 1-6 Alkyl; and Each R j Independent of halogenated group, -CN, -OR c C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

21. The compound of claim 20, wherein, Y is a direct bond or -NHC(O)-; and Ring B is: , , , , Where n is 0, 1, or 2, R j Halogenated group, -CN, -OR c C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

22. The compound of claim 21, having a structure represented by formula (II): Equation (II) in, W can be CN or N; X is CH or N; p is 0, 1, or 2; and R j Halogenated group or C 1-3 alkyl.

23. The compound of claim 22, having a structure represented by formula (IIa), (IIb), (IIc) or (IId): Formula (IIa), Formula (IIb) Formula (IIc) or Formula (IId).

24. The compound according to any one of claims 20 to 23, wherein each L1, L2, L3, L4, L5, L6, L7 or L8 is independently: i) Select the bivalent ring portion of the group consisting of the following groups: , , , , , , , , , , , ; , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and ; ii) Direct key; iii) C 1-6 alkylene chains; or iv) -C(O)-, -O-, -C(O)-N(R) c )-、-(CH2) m -C(O)- or -NH-(CH2) m -C(O)-, where m is 0, 1, 2 or 3; in, n is 0, 1, or 2; R b Halogenated group, -CN, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups; and R c It is hydrogen or C 1-3 alkyl.

25. The compound according to any one of claims 20 to 24, wherein R 1 It is hydrogen or C substituted with 1 to 3 fluorine or hydroxyl groups. 1-6 alkyl.

26. The compound according to any one of claims 20 to 25, wherein R 3 It can be phenyl, benzyl, 2-pyridyl, 3-pyridyl, CN, cyclopropyl, 1-methyl-1H-pyrazole-3-yl, 3-methylphenyl, 2-methylphenyl, 3-chlorophenyl or 3,4-dichlorophenyl.

27. The compound according to any one of claims 20 to 26, wherein R 1 It is hydrogen and R 2 It is hydrogen.

28. The compound of claim 27, having the structure represented by formula (III), Equation (III) in W is either N or CH; X is either N or CH; L' is -L2-L3-L4-L5-L6-L7-L8-; and R 3 CN, cyclopropyl, C 1-3 Alkyl groups, optionally with one or two halogenated groups or C 1-3 Alkyl-substituted phenyl or optionally C 1-3 Alkyl-substituted pyrazolyl group.

29. The compound of claim 28, having a structure represented by formula (IIIa), (IIIb), (IIIc) or (IIId): Formula (IIIa), Formula (IIIb) Formula (IIIc) or Formula (IIId), in, L' is 。 30. The compound of claim 27, having a structure represented by formula (IV): Formula (IV) in W is either N or CH; X is either N or CH; V is either N or CH; L'' is -L2-L3-L4-L5-L6-L7-; and R 3 CN, cyclopropyl, C 1-3 Alkyl groups, optionally with one or two halogenated groups or C 1-3 Alkyl-substituted phenyl or optionally C 1-3 Alkyl-substituted pyrazolyl group.

31. The compound of claim 30, having a structure represented by any one of the formulas (IVa1), (IVa2), (IVa3), (IVa4), (IVb1), (IVb2), (IVb3), and (IVb4): Formula (IVa1) Formula (IVa2) Formula (IVa3) Formula (IVa4) Formula (IVb1) Formula (IVb2) Formula (IVb3) Formula (IVb4) in, L'' is 。 32. The compound of claim 1, wherein the compound is selected from the group consisting of the compounds of Examples 1-196.

33. A pharmaceutical composition comprising a compound as described in any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier.

34. The pharmaceutical composition of claim 33, wherein the pharmaceutical composition further comprises one or more additional therapeutic agents or pharmaceutically acceptable salts thereof.

35. The compound of any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 33 or claim 34, used in a therapeutic manner.

36. The compound of any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 33 or claim 34, for the treatment of SMARCA2-mediated diseases.

37. The compound or pharmaceutical composition of claim 36, wherein the SMARCA2-mediated disease is a cancer selected from the group consisting of: acoustic neuroma, acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchial carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia. Leukemia, Chronic myeloid leukemia (granulocytic leukemia), Chronic myeloid leukemia, Colon cancer, Colorectal cancer, Craniopharyngioma, Cystic adenocarcinoma, Diffuse large B-cell lymphoma, Proliferative dysplasia (dysplasia and metaplasia), Embryonic carcinoma, Endometrial cancer, Endothelial sarcoma, Ependymoma, Epithelial carcinoma, Erythroleukemia, Esophageal cancer, Estrogen receptor-positive breast cancer, Essential thrombocytosis, Ewing's tumor, Fibrosarcoma, Follicular lymphoma, Germ cell testicular cancer, Glioma, Glioblastoma, Gliosarcoma, Heavy chain disease, Hemangioblastoma, Liver cancer, Liver Cellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, liver cancer, lung cancer, lymphangiosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's; Burkitt's), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline Cancer (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pineal tumor, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, malignant rhabdomyosarcoma (MRT), rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovial tumor, sweat gland carcinoma, thyroid cancer, Waldenström macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor.

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