Bifunctional azine conjugates as selective degrading agents for SMARCA2 and their therapeutic applications

Abstract

This disclosure provides a bifunctional compound of formula (IA) as a selective SMARCA2 degrading agent via the ubiquitin-proteosome pathway, and its therapeutic applications for treating cancer. Also provided herein are pharmaceutical compositions comprising the compounds of formulas (I), (II), (III), and (IV), (IA), or any one of the substructures or specific compounds from Examples 1 to 196, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients or carriers. TIFF2026519821000676.tif48165

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 63 / 507,074, filed on 8 June 2023, which is incorporated herein by reference in its entirety. [Background technology]

[0002] The present invention provides novel bifunctional compounds for proteolytically degrading SMARCA2, and therapeutic applications thereof for treating SMARCA2-mediated diseases, including cancer.

[0003] Description of related technology fields The mammalian switch / sucrose non-fermentable (mSWI / SNF) chromatin remodeling complex contains one of two mutually exclusive and highly homologous catalytic ATPase subunits, SMARCA2 or SMARCA4. Subunit mutations within the complex are frequently observed in cancer, and SMARCA4-mutated cancers exhibit acute sensitivity to SMARCA2 depletion, making SMARCA2 an attractive oncological target. Several groups have developed small molecule inhibitors of SMARCA2, but progress in these molecules has been hampered by the need for greater selectivity than that for SMARCA4. See, for example, Wanior, M. et al J. Med. Chem. 63:14680 (2020) and Kofink, C. et al Nature Commun. 13:5969 (2022). Two regions of the SMARCA2 protein with clearly defined binding pockets relevant to the discovery of small molecule inhibitors are the catalytic ATPase domain and the conserved bromodomain, which can interact with acetylated chromatin. The high sequence homology between the ATPase domains of these proteins makes it difficult to develop inhibitors with sufficient selectivity. Known ATPase domain ligands are dual inhibitors of SMARCA2 / 4 and exhibit dose-limiting tolerability issues. Alternatively, the bromodomain shows the potential for greater selectivity, but its function is unnecessary, and current ligands are not effective in inhibiting cell proliferation. Selective targeting of SMARCA2 over SMARCA4 has so far proven difficult with the use of inhibitors, but reusing non-inhibitory bromodomain conjugates as targeted proteolytic agents is promising. However, current proteolytic agents have shown lower selectivity when targeting SMARCA2 than SMARCA4. See, for example, WO2021 / 083949, WO2020 / 251971, and WO2019 / 195201. [Prior art documents] [Patent Documents]

[0004] [Patent Document 1] International Publication No. 2021 / 083949 [Patent Document 2] International Publication No. 2020 / 251971 [Patent Document 3] International Publication No. 2019 / 195201 [Non-patent literature]

[0005]

Non-Patent Document 1

Non-Patent Document 2

Summary of the Invention

[0006] Provided herein is a bifunctional compound that exhibits both potent inhibition and selectivity for SMARCA2 while sparing SMARCA4.

[0007] Provided herein is a compound of formula (I):

Chemical formula

[0008] In various specific embodiments, Y is a direct bond, and the bifunctional compound of formula (I) is of formula (II):

Chemical formula

[0009] In various specific embodiments, the bifunctional compound of formula (II) is of formula (IIa), (IIb), (IIc), or (IId):

Chemical formula

[0010] In a more specific embodiment, R 1 and R 2 Each of these 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 given by formula (III), as well as substructures (IIIa), (IIIb), (IIIc), and (IIId): [ka] It is represented by the following structure:

[0011] In a more specific embodiment, R 1 and R 2 However, each is hydrogen, Y is a direct bond, L1 is -C(O)-, and L8 is [ka] (where V is CH or N), L'' is -L2-L3-L4-L5-L6-L7-, and the bifunctional compound has the structure of formula (IV), (IVa), (IVb), and their respective substructures: [ka] [ka] It is represented as follows.

[0012] In various embodiments, each of the linker segments, i.e., L1, L2, L3, L4, L5, L6, L7, or L8, operates independently. i) [ka] A divalent ring portion selected from the group consisting of, v) direct binding; vi)C 1-6 Alkylene chain, 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), m is 0, 1, 2, or 3, n is 0, 1, or 2, R b However, Hello, -CN, C 1-3 Alkyl, or C 1-3 It is a haloalkyl, R c However, hydrogen or C 1-3 It is alkyl.

[0013] Also provided herein are pharmaceutical compositions comprising a compound of formula (I), (II), (III), and (IV), (IA), or any one of the substructures or specific compounds from Examples 1 to 196, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. [Modes for carrying out the invention]

[0014] 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 ubiquitination and proteasomal degradation of SMARCA2. Therefore, provided herein are bifunctional compounds comprising a selective SMARCA2 conjugate for targeting ubiquitin ligases, a covalent linker moiety (L), and a ligase harness moiety (LHM), respectively. Preferably, the LHM targets cereblon (CRBN) protein, a substrate-recognizing subunit of two ubiquitous and biologically important kaline ring E3 ubiquitin ligase complexes. See, for example, WO2019 / 099926, WO2020 / 023851, and U.S. Publication No. 2019 / 0192668.

[0015] In addition to the compounds of formulas (I) to (IV) and their substructures described herein, various embodiments include formula (IA): [ka] A compound having a structure represented by the formula, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the formula is R 1 However, 1 to 3 R a Hydrogen or C which can be optionally substituted. 1-6 It is alkyl, R 2 However, 1 to 3 R a Hydrogen, halo, hydroxyl, -OR can be arbitrarily substituted. c , C 1-6 It is alkyl, R 3 However, hydrogen, -CN, C 1-6 Alkyl, C 6-12 Ariel, C 3-12 Cycloalkyl, 5-12 member heteroaryl, each containing 1-3 R d , or -OR e It is arbitrarily replaced with, L contains up to 8 linker segments represented as -L1-L2-L3-L4-L5-L6-L7-L8-, and each L1, L2, L3, L4, L5, L6, L7, or L8 is independent of the others. i) 1 to 3 R b C is arbitrarily replaced by 3-12 Cycloalkyl, ii) 1 to 3 R b C is arbitrarily replaced by 6-12 Ariel, iii) 1 to 3 R b A 4-12 member heterocycline that can be arbitrarily substituted, iv) 1 to 3 R b A 5-12 member heteroaryl that can be arbitrarily substituted, v) direct binding; vi) 1 to 3 R b C is arbitrarily replaced by 1-12 Alkylene chain, 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 However, independently, halo, or -OR c And, Each R b However, independently, oxo, imino, sulfoxyimino, halo, nitro, -CN, C 1-6 Alkyl, C 2-6 Alkenil, C 3-15 Cycloalkyl, C 1-8 Haloalkyl, C 6-12 Aryl, 5-12 member heteroaryl, 4-12 member heterocyclyl, -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 ) and C 1-6 Alkyl, C 2-6 Alkenil, C 3-15 Cycloalkyl, C 1-8 Haloalkyl, C 6-12 Each of the aryl, 5-12 member heteroaryl, and 4-12 member heterocyclyl has 1-3 R d It can be arbitrarily replaced with Each R c However, independently, hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-12 Aryl, or C 1-6 It is a haloalkyl, C 1-6 Alkyl is C 1-3 Optionally substituted with alkoxy, Each R d However, independently, Haro, -CN, -OR c , C 1-6 Alkyl, C 6-12 Aryl, or C 1-6 It is a haloalkyl, R e However, C 1-6 Alkyl, C 3-12 Cycloalkyl, C 6-12 Aryls are 5-12 member heteroaryls, and each is C 1-6 Optionally substituted with alkyl or halo, W is -C(R g )- or -N-, Y is directly bonded, C 1-4 Alkylene chain, -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 )- and, Ring B, C 6-12 They are aryl, 5-12 membered heteroaryl, or 4-12 membered heterocyclyl, each containing 1-3 R j It is arbitrarily replaced with, R g However, hydrogen or C 1-6 It is alkyl, Each R j However, independently, Halo, Oxo, -CN, -OR c , C 1-6 Alkyl, or C 1-6 Further, we provide haloalkyl compounds, their stereoisomers, and pharmaceutically acceptable salts.

[0016] In a more specific embodiment, each L1, L2, L3, L4, L5, L6, L7, or L8 operates independently. i) [ka] [ka] A divalent ring portion selected from the group consisting of, ii) direct binding; iii) C 1-6 Alkylene chain, 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), n is 0, 1, or 2, R b But, hello, -OR c ,-CN,C 1-6 Alkyl, or C 1-6 It is a haloalkyl, R c However, hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, or C 1-6 It is a haloalkyl, C 1-6 Alkyl is C 1-3 It can be arbitrarily substituted with alkoxy.

[0017] In other, more specific embodiments, Y is a direct bond, -NHC(O)-, or -NH- Ring B, [ka] And in the formula, n is 0, 1, or 2, and R j However, Haro, -CN, -OR c , C 1-6 Alkyl, or C 1-6 It is a haloalkyl group.

[0018] In various embodiments, R 3 However, one or more C 1-6 Alkyl, C 1-6 Phenyl atoms optionally substituted with alkoxy or halo atoms, and one or more carbon atoms. 1-6 benzyl optionally substituted with alkyl or halo, one or more carbon atoms. 1-6 Pyridinyl, CN, C compounds optionally substituted with alkyl groups. 3-6 Cyclopropyl, one or more C 1-6 Pyrazolyls, tetrahydropyranyls, and one or more C atoms optionally substituted with alkyl groups. 1-6 1,2-oxazolyl, pyrazolo[1,5-a]pyridinyl, or -OR, optionally substituted with alkyl groups. e (R e However, C 1-6Phenyl, C, optionally substituted with alkyl or halo 3-6 Cycloalkyl, C 1-6 Alkyl, or C 1-6 It is a pyrazolyl compound that can be optionally substituted with an alkyl group.

[0019] In a more specific embodiment, R 3 Phenyl, benzyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 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]pyridine-2-yl, 5-methyl-1,2-oxazole-3-yl, 5-isopropyl-1,2-oxazole-3-yl, 3-methyl-1,2-oxazole-5-yl, or -OR e And R e However, these are phenyl, 2-chlorophenyl, 2-methylphenyl, cyclopropyl, cyclohexyl, methyl, or 1-methyl-1H-pyrazole-3yl.

[0020] In a particular embodiment, R 1 However, it is hydrogen, R 2 However, it is hydrogen, Y is a direct bond, and R 3 However, -OR e And W is CH, and the compound is given by formula (IA1): [ka] It has a structure represented by the formula, in which, Ring B, [ka] And, n is 0, 1, or 2, R j However, Haro, -CN, -OR c , C 1-6 Alkyl, or C 1-6 It is a haloalkyl, R e However, C 1-6 Alkyl, C 3-12 Cycloalkyl, C 6-12 Aryls are 5-12 member heteroaryls, and each is C 1-6 Optionally substituted with alkyl or halo, R c However, hydrogen or C 1-3 It is alkyl, L1 is -C(O)- or -C(O)N(R c )- and, L a but, [ka] That is the case.

[0021] In a more specific embodiment of equation (IA1), B is [ka] And, n is 0 or 1, R j However, it is fluoro or chloro, and R e However, C 1-6 Alkyl, C 3-12 Cycloalkyl, C 6-12 Aryls are 5-12 member heteroaryls, and each is C 1-6 Optionally substituted with alkyl or halo, L 1 However, -C(O)N(R c )- and R c However, it is methyl or ethyl, L a but, [ka] That is the case.

[0022] In various embodiments, R e However, C 1-3 It is alkyl.

[0023] In a more specific embodiment, R e However, it is methyl, phenyl, cyclopropyl, cyclohexyl, 1-methyl-1H-pyrazole-3yl, or phenyl substituted with chloro or methyl.

[0024] In other, more specific embodiments of formula (IA1), ring B is, [ka] And, n is 0, 1, or 2, and R j However, it is fluoro or chloro, and R e However, it is methyl, ethyl, or propyl, and R c L1 is hydrogen, methyl, or ethyl, and L1 is -C(O)- or -C(O)N(R) c )- and, L a but, [ka] That is the case.

[0025] In a particular embodiment, R 1 and R 2 However, W is hydrogen, W is CH, and the compound is given by formula (IA2): [ka] It has a structure represented by the formula, in which, n is 0, 1, or 2, Y is a direct bond, -NHC(O)-, or -NH-. X is N or CH, Rj is C 1-3 Alkyl or halo, R 3 However, C 6-12 Ariel, C 3-12Cycloalkyl, 5-12 member heteroaryl, each containing 1-3 R d , or -OR e It is arbitrarily replaced with, R c However, hydrogen or C 1-6 It is methyl, Each R d However, independently, Haro, -CN, -OR c , C 1-6 Alkyl, C 6-12 Aryl, or C 1-6 It is a haloalkyl, R e However, C 1-6 Alkyl, C 3-12 Cycloalkyl, C 6-12 Aryls are 5-12 member heteroaryls, and each is C 1-6 Optionally substituted with alkyl or halo, L b but, [ka] [ka] That is the case.

[0026] In a more specific embodiment of equation (IA2), R 3 However, phenyl, 2-fluorophenyl, 5-methyl-1,2-oxazol-5-yl, 5-isopropyl-1,2-oxazol-5-yl, pyrazolo[1,5-a]pyridinyl, -OR e And R e However, these are phenyl, 2-chlorophenyl, 2-methylphenyl, 1-methyl-1H-pyrazole-3-yl, cyclohexyl, or methyl.

[0027] In a particular embodiment, R 1 and R 2 However, W is hydrogen, W is CH, and the compound is of formula (IA3): [ka] It has a structure represented by the formula, in which, n is 0, 1, or 2, Y is a direct bond, -NHC(O)-, or -NH-. X is N or CH, R 3 However, C 6-12 Ariel, C 3-12 Cycloalkyl, 5-12 member heteroaryl, each containing 1-3 R d , or -OR e It is arbitrarily replaced with, R c However, hydrogen, C 1-3 Alkyl, or C 3-6 It is a cycloalkyl, Each R d However, independently, Haro, -CN, -OR c , C 1-6 Alkyl, C 6-12 Aryl, or C 1-6 It is a haloalkyl, R e However, C 1-6 Alkyl, C 3-12 Cycloalkyl, C 6-12 Aryls are 5-12 member heteroaryls, and each is C 1-6 Optionally substituted with alkyl or halo, R j However, C 1-3 Alkyl or halo, L c but, [ka] That is the case.

[0028] In a particular embodiment, R 1 and R 2 However, it is hydrogen, W is CH, Y is a direct bond, and R 3 However, it is phenyl, and the compound is of formula (IA4): [ka] It has a structure represented by the formula, in which, n is 0, 1, or 2, X is N or CH, R c However, hydrogen or C 1-3 C arbitrarily substituted with alkoxy 1-3 It is alkyl, R j However, C 1-3 Alkyl or halo, L d but, [ka] That is the case.

[0029] In a particular embodiment, R 1 and R 2 However, it is hydrogen, W is CH, Y is a direct bond, and R 3 However, it is phenyl, and the compound is of formula (IA5) [ka] It has a structure represented by the formula, in which, n is 0, 1, or 2, X is N or CH, Q is a direct bond, -N(R c )-, or -NHS(O)2-, R c However, hydrogen or C 1-3 It is alkyl, R j However, C 1-3 Alkyl or halo, L e but, [ka] That is the case.

[0030] In a particular embodiment, R 1 and R 2 is hydrogen, W is CH, Y is a direct bond, and the compound is given by formula (IA6): [ka] It has a structure represented by the formula, in which, B, [ka] And, R 3 However, C 6-12 Ariel, C 3-12 Cycloalkyl, 5-12 member heteroaryl, each containing 1-3 R d , or -OR e It is arbitrarily replaced with, R c However, hydrogen or C 1-6 It is alkyl, Each R d However, independently, Haro, -CN, -OR c , C 1-6 Alkyl, C 6-12 Aryl, or C 1-6 It is a haloalkyl, R e However, C 1-6 Alkyl, C 3-12 Cycloalkyl, C 6-12 Aryls are 5-12 member heteroaryls, and each is C 1-6 Optionally substituted with alkyl or halo, L1 is -C(O)-, -C(O)-N(R c )-(CH2)-, or -C(O)-N(R c )- and, L f but, [ka] That is the case.

[0031] SMARCA2 binder The difunctional compounds of formulas (I) and (IA) are, respectively, formula (A): [ka] It comprises a selective SMARCA1 binding moiety, represented as, In a more specific embodiment, R 1 and R 2However, each of them is hydrogen.

[0032] In other, more specific embodiments, R 1 However, C is optionally substituted with 1 to 3 halos or hydroxyls. 1-3 It is alkyl. In a more specific embodiment, R 1 However, it is -CF2H or -C(CH3)2OH, and R 2 But it's hydrogen.

[0033] In various embodiments, R 3 However, phenyl, pyridinyl, pyrazolyl, cyclopropyl, or C 1-3 It is an alkyl group, and each has 1 to 3 R atoms. d It is arbitrarily replaced with R d However, C 1-3 It is alkyl, halo, or phenyl.

[0034] In a more specific embodiment, R 3 These are phenyl, benzyl, 2-pyridinyl, 3-pyridinyl, -CN, 1-methyl-1H-pyrazole-3yl, 3-methylphenyl, 2-methylphenyl, 3-chlorophenyl, or 3,4-dichlorophenyl.

[0035] In various embodiments, R 3 However, one or more C 1-6 Alkyl, C 1-6 Phenyl atoms optionally substituted with alkoxy or halo atoms, and one or more carbon atoms. 1-6 benzyl optionally substituted with alkyl or halo, one or more carbon atoms. 1-6 Pyridinyl, CN, C compounds optionally substituted with alkyl groups. 3-6 Cyclopropyl, one or more C 1-6 Pyrazolyls, tetrahydropyranyls, and one or more C atoms optionally substituted with alkyl groups. 1-6 1,2-oxazolyl, pyrazolo[1,5-a]pyridinyl, or -OR, optionally substituted with alkyl groups. e (R e However, C 1-6 Phenyl, C, optionally substituted with alkyl or halo 3-6Cycloalkyl, C 1-6 Alkyl, or C 1-6 It is a pyrazolyl compound that can be optionally substituted with an alkyl group.

[0036] In a more specific embodiment, R 3 Phenyl, benzyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 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]pyridine-2-yl, 5-methyl-1,2-oxazole-3-yl, 5-isopropyl-1,2-oxazole-3-yl, 3-methyl-1,2-oxazole-5-yl, or -OR e And R e However, these are phenyl, 2-chlorophenyl, 2-methylphenyl, cyclopropyl, cyclohexyl, methyl, or 1-methyl-1H-pyrazole-3yl.

[0037] In a particular embodiment, R 1 and R 2 However, each is hydrogen, and R 3 However, it is phenyl, and the SMARCA2 binding site is, formula (A1): [ka] It has the structure of [the object].

[0038] In another specific embodiment, as defined herein, R 1 and R 2 However, each is hydrogen, and R 3 However, -OR e That is the case.

[0039] Ligauze harness portion (LHM) The LHM moiety of the bifunctional compound of formula (I) targets the CRBN of the E3 ligase. When utilized by the bifunctional compound, the E3 ligase can induce ubiquitination and subsequent proteasomal degradation of SMARCA2.

[0040] The LHM portion of equation (I) is typically represented by equation (B): [ka] As shown in the formula, it includes a glutarimide or dihydrouracil moiety that binds to a ring structure, W is -C(R g )- or -N-, Y is directly bonded, C 1-4 Alkylene chain, -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 )- and, Ring B, C 6-12 They are aryl, 5-12 membered heteroaryl, or 4-12 membered heterocyclyl, each containing 1-3 R j It is arbitrarily replaced with, Each R j However, independently, Haro, -CN, Oxo, -OR c , C 1-6 Alkyl, or C 1-6 It is a haloalkyl, R g However, hydrogen or C 1-6 It is alkyl.

[0041] In a more specific embodiment, W is -CH, Y is a direct bond, and the B ring is [ka] And R j However, H, halo, or C 1-3 It is alkyl.

[0042] In yet another embodiment, W is -CH-, Y is -NHC(O)- or -NH-, and the B ring is [ka] And R j However, H, halo, or C 1-3 It is alkyl.

[0043] In other embodiments, W is -N-, Y is a direct bond, and the B ring is [ka] And R j However, H or C 1-3 It is alkyl.

[0044] In a more specific embodiment, the LHM portion is [ka] That is the case.

[0045] In other, more specific embodiments, the LHM portion is [ka] That is the case.

[0046] In other, more specific embodiments, the LHM portion is [ka] That is the case.

[0047] Linker Each bifunctional compound of formula (I) includes a linker (L), which is a divalent moiety that binds the SMARCA2 binding moiety to LHM. The structure of the linker moiety (e.g., length or stiffness) may affect the efficiency or selectivity of the decomposition process. The linker includes a continuous sequence of covalent bonds between the SMARCA2 binding moiety and each binding site with LHM, including the bonds shown by the wavy lines in formulas (A) and (B) and their respective substructures.

[0048] Typically, the linker portion includes multiple divalent segments (i.e., -L1-L2-L3-L4-L5-L6-L7-L8-) that, in addition to providing the respective bonding points with the SMARCA2 binder portion and LHM, collectively contribute to the overall length and stiffness of the linker. In various embodiments, linker segments L1, L2, L3, L4, L5, L6, L7, and L8 each independently contribute to the overall length and stiffness of the linker. i) 1 to 3 R b C is arbitrarily replaced by 3-12 Cycloalkyl, ii) 1 to 3 R b C is arbitrarily replaced by 6-12 Ariel, iii) 1 to 3 R b A 4-12 member heterocycline that can be arbitrarily substituted, iv) 1 to 3 R b A 5-12 member heteroaryl that can be arbitrarily substituted, v) direct binding; vi) 1 to 3 R d C is arbitrarily replaced by 1-12 Alkylene chain, 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), R d , R c and R d However, as defined herein.

[0049] Unless otherwise specified and provided that the valence is satisfied, the divalent linker segments described herein (e.g., L 1 or L 2 It should be understood that these are not limited to the direction in which they are expressed. For example, for a given linker segment, e.g., -C(O)-NH-, the way in which it is connected to the rest of the molecule may be in either the -C(O)-NH- or -NH-C(O)- direction, provided that the connection does not violate the valence rules.

[0050] Unless otherwise specified, the first linker segment L 1 However, while it directly binds to the SMARCA2 binder portion, the last linker segment L 8 However, please further understand that it directly binds with LHM.

[0051] One or more linker segments can be directly coupled. For example, in a sequence of linker segments represented as -L2-L3-L4--, if L3 is directly coupled, it does not actually exist because L2 and L4 are directly coupled to each other.

[0052] In another embodiment, the linker has one or more rings, which tend to increase the rigidity of the linker. The combination of chain bonds and rings(s) can be used to adjust the relative orientation of the difunctional groups or the distance between them.

[0053] In various specific embodiments, the linker (L) of the compounds of formulas (I), (II), (IIa), (IIb), (IIc), and (IId) is represented as -L1-L2-L3-L4-L5-L6-L7-L8-, where each L1, L2, L3, L4, L5, L6, L7, or L8 is independently [ka] v) direct binding; vi)C 1-6 Alkylene chain, 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), n is 0, 1, or 2, R b However, Hello, -CN, C 1-3 Alkyl, or C 1-3 It is a haloalkyl, R c However, hydrogen or C 1-3 It is alkyl.

[0054] In a more specific embodiment, one or more linker segments form a diamine linker portion having one of the following structures: [ka]

[0055] In other specific embodiments, the linker (L') of the compound of formula (III), and its substructure formulas (IIIa), (IIIb), (IIIc), and (IIId) are as follows: [ka] [ka] [ka] It may have one of the following.

[0056] In yet another specific embodiment, the linker (L'') of the compounds of formulas (IV), (IVa), and (IVb), and their respective substructures, are as follows: [ka] [ka] It may have one of the following.

[0057] definition The following description illustrates exemplary methods, parameters, etc. However, it should be recognized that such description is not intended to limit the scope of this disclosure, but rather is provided as a description of exemplary embodiments.

[0058] A dash ("-") without a space between two letters or symbols is used to indicate the bonding point of a substituent. For example, -C(O)NH2 is bonded through a carbon atom. Dashes at the beginning or end of a chemical group are for convenience only, and the chemical group can be depicted with or without one or more dashes without losing its usual meaning. A wavy line drawn through a line in the structure indicates the bonding point of a group. Unless chemically or structurally required, the order in which chemical groups are described or named does not indicate or imply direction.

[0059] Prefix “C” u-v " indicates that the following group has u to v carbon atoms. For example, "C 1-6 The term "alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0060] In this specification, references to values ​​or parameters “about” include (and are described) embodiments directed to the value or parameter itself. In certain embodiments, the term “about” includes the indicated amount ± 10%. In other embodiments, the term “about” includes the indicated amount ± 5%. In certain other embodiments, the term “about” includes the indicated amount ± 1%. Also, the term “about X” includes a description of “X.” Furthermore, the singular forms “a” and “the” include plural references unless the context explicitly indicates otherwise. Thus, for example, a reference to “compound” includes multiple such compounds, and a reference to “assay” includes a reference to one or more assays and their equivalents known to those skilled in the art.

[0061] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain that does not contain unsaturated carbon atoms. As used herein, alkyl refers to a chain with 1 to 20 carbon atoms (i.e., C 1-20 Alkyl), 1 to 12 carbon atoms (i.e., C 1-12 Alkyl), 1 to 8 carbon atoms (i.e., C 1-8 Alkyl), 1 to 6 carbon atoms (i.e., C 1-6 Alkyl) or 1 to 4 carbon atoms (i.e., C 1-4 Alkyl compounds 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 carbon atoms is named by its chemical name or identified by its molecular formula, all positional isomers having that number of carbon atoms may be included. 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).

[0062] An alkylene or alkylene chain is a molecule in which the rest of the molecule is linked to a radical group, is unsaturated, and contains 1 to 20 carbon atoms, or more typically 1 to 12 carbon atoms (C). 1-12 Alkylene, or 1 to 8 carbon atoms (C) 1-8 Alkylene, or 1-3 carbon atoms (C 1-3 Alkylenes refer to unbranched or branched divalent hydrocarbon chains, such as methylene, ethylene, propylene, and n-butylene. Alkylene chains can bond to the rest of the molecule and radical groups via one carbon in the chain or via any two carbons in the chain.

[0063] "Alkenyl" contains at least one carbon-carbon double bond and 2 to 20 carbon atoms (i.e., C 2-20 Alkenyls), or more typically 2 to 12 carbon atoms (i.e., C 2-12 Alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 Alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 Alkenyls), or 2-4 carbon atoms (i.e., C 2-4 This refers to an alkyl group having an alkenyl group. Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0064] "Alkenylene" and "alkenylene chain" refer to unbranched or branched divalent hydrocarbon chains that link the rest of a molecule to a radical group, contain at least one double bond, and have 2 to 20 carbon atoms, or more typically 2 to 12 carbon atoms, or 2 to 8 carbon atoms, such as etenylene, propenylene, n-butenylene, etc. Alkenylene chains are bonded to the rest of the molecule via single bonds and to the radical group via double or single bonds. The bonding points between the rest of the molecule and the radical group of an alkenylene chain can be via one carbon or any two carbons in the chain.

[0065] "Alkynnyl" contains at least one carbon-carbon triple bond and 2 to 20 carbon atoms (i.e., C 2-20 Alkynnyl) or more typically 2 to 12 carbon atoms (i.e., C 2-12 Alkynnyl) or more typically 2 to 8 carbon atoms (i.e., C 2-8 Alkynyl), 2-6 carbon atoms (i.e., C 2-6 Alkynyl) or 2-4 carbon atoms (i.e., C 2-4 This refers to alkyl groups that have an alkynyl bond. The term "alkynyl" also includes those groups that have one triple bond and one double bond.

[0066] "Alkynylene" and "alkynylene chain" refer to an unbranched or branched divalent hydrocarbon chain having 2 to 20 carbon atoms, or more typically 2 to 12 carbon atoms, or 2 to 8 carbon atoms, with the rest of the molecule linked to a radical group and containing at least one triple bond. Alkynylene chains are bonded to the rest of the molecule via single bonds and to the radical group via double or single bonds. The bonding points between the rest of the molecule and the radical group of an alkynylene chain can be via one carbon or any two carbons in the chain.

[0067] "Alkoxy" refers to the group "alkyl-O-". Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0068] A "haloalkoxy" refers to an alkoxy group as defined above, in which one or more hydrogen atoms are replaced by halogens.

[0069] "Alkylthio" refers to the group "alkyl-S-".

[0070] "Amino" is the base -NR y R y This refers to each R yThese are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, or heteroaryl, each of which is optionally substituted and as defined herein.

[0071] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) including a condensed system. As used herein, aryl refers to a ring carbon atom (i.e., C) with 6 to 20 carbon atoms. 6-20 aryl), 6 to 15 carbocyclic atoms (i.e., C 6-15 aryl), or 6 to 10 carbon ring atoms (i.e., C 6-10 It has an aryl group. Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. However, aryl does not in any way encompass or overlap with heteroaryls as defined below. When one or more aryl groups are fused with a heteroaryl, the resulting ring system is a heteroaryl. When one or more aryl groups are fused with a heterocyclyl, the resulting ring system is a heterocyclyl.

[0072] "Cyano" refers to the group -CN.

[0073] "Keto" or "oxo" refers to the base = oxygen.

[0074] "Carbamoyl" is -OC(O)NR y R z The "O-carbamoyl" group and -NR refer to the group. y C(O)OR z The term "N-carbamoyl" refers to both the group and the R group. y and R z These are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl, each of which can be optionally substituted.

[0075] "Carboxyl" or "carboxylic acid" refers to -C(O)OH.

[0076] "Ester" refers to both -OC(O)R and -C(O)OR, where R is a substituent, each of which may be optionally substituted as defined herein.

[0077] "Cycloalkyl" refers to saturated or partially unsaturated cyclic alkyl groups having one or more rings, including fused ring systems, crosslinked ring systems, and spiro ring systems. The term "cycloalkyl" includes a cycloalkenyl group (i.e., a ring group having at least one double bond). As used herein, cycloalkyl refers to a ring group having 3 to 15 carbon atoms (i.e., C 3-20 Cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 Cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 Cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 Cycloalkyl, or a ring of 3-6 carbon atoms (i.e., C 3-6 It has a cycloalkyl group. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[2.2.2]octan-1-yl. The cycloalkyl group may be bonded 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).

[0078] An "ethylene glycol unit" refers to a divalent monomer having the structure -CH2CH2O-, which can be repeated and extended into longer chains. A linker segment may have up to 12 ethylene glycol units, or more typically up to 6.

[0079] A "propylene glycol unit" refers to a divalent monomer having the structure -CH(CH3)-CH2O-, which can be repeated and extended into longer chains. A linker segment may have up to 12 propylene glycol units, or more typically up to 6.

[0080] "Halogen" or "halo" includes fluoro, chloro, bromo, and iodine.

[0081] "Haloalkyl" refers to an unbranched or branched alkyl group as defined above, in which one or more hydrogen atoms are replaced by halogens. For example, if 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 it binds to. Dihaloalkyl and trihaloalkyl refer to alkyl groups substituted with two ("di") or three ("tri") halo groups, which may, but may not, be the same halogen. Examples of haloalkyls include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0082] A "heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced by the same or different heteroatoms, such as N, O, and S. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon and heteroatoms. For example, one, two, or three carbon atoms may be independently replaced by the same or different heteroatoms. Examples of heteroatom groups include, but are not limited to, -N(R)-, -O-, -S-, -S(O)-, and -S(O)2-, where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, or heterocyclyl, 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, a heteroalkyl group comprises 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.

[0083] "Heteroaryl" independently refers to a 5- to 15-membered, or more typically 5- to 12-membered aromatic group having a single ring, multiple rings, or multiple fused rings having 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl refers to a ring carbon atom (i.e., C) with 3 to 12 ring carbon atoms. 3-12 Heteroaryls), or 3 to 8 carbon ring atoms (i.e., C 3-8 A heteroaryl group comprises a heteroaryl group and, independently, 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, prinyl, pyridyl, pyridadinyl, benzothiazolyl, and pyrazolyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, and heteroaryls can be bonded via any of the rings in the fused system. Any aromatic ring having one or more fused rings containing at least one heteroatom is considered a heteroaryl regardless of its bond to the rest of the molecule (i.e., via any one of the fused rings). A heteroaryl does not contain or overlap with an aryl (which has no heteroatom) or a heterocyclyl (which has at least one non-aromatic ring). A heteroaryl can be bonded to the rest of the molecule by a single ring atom (e.g., as a substituent) or two ring atoms (e.g., as a linker).

[0084] A "heterocyclyl" independently refers to a 3- to 15-membered, more typically 5- to 12-membered saturated or unsaturated cyclic alkyl group having 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. The term "heterocyclyl" includes heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond), bicyclic heterocyclyl groups, bridging heterocyclyl groups, condensed heterocyclyl groups, and spiroheterocyclyl groups. A heterocyclyl can be a single ring or multiple rings, and the multiple rings can be condensed, bridging, or spiro. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the bonding (i.e., it can be bonded via carbon atoms or heteroatoms). Furthermore, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which may be condensed into an aryl or heteroaryl ring, regardless of the bonding with the rest of the molecule. As used herein, a heterocyclyl has 3 to 15 ring atoms (e.g., a 3 to 15-membered heterocyclyl, a 3 to 12-membered heterocyclyl, a 4 to 10-membered heterocyclyl, a 4 to 8-membered heterocyclyl, or a 4 to 6-membered heterocyclyl) and independently has 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom selected from nitrogen, sulfur, or oxygen. A heterocyclyl may contain one or more oxo groups and / or thioxo groups. Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanil, azetidinyl, Examples include azetidinyl, morpholinyl, thiomorpholinyl, 4- to 7-membered sultams, 4- to 7-membered cyclic carbamates, 4- to 7-membered cyclic carbonates, 4- to 7-membered cyclic sulfides, and morpholinyl. As used herein, heterocyclyls may include a cross-linked structure (i.e., a "cross-linked heterocyclyl") in which a 4- to 10-membered cyclic moiety is bonded at two non-adjacent atoms of the heterocyclyl to one or more (e.g., one or two) 4- to 10-membered cyclic moieties having at least one heteroatom, each heteroatom independently selected from nitrogen, oxygen, and sulfur. As used herein, cross-linked heterocyclyls include bicyclic and tricyclic systems.Furthermore, as used herein, the term “spiro-heterocyclyl” refers to a ring system in which a 3- to 10-membered heterocyclyl has one or more additional rings, one or more of which are 3- to 10-membered cycloalkyl or 3- to 10-membered heterocyclyl atoms, and one or more of which are single atoms of a 3- to 10-membered heterocyclyl atom. Examples of spiro-heterocyclyl rings include bicyclic and tricyclic ring systems such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of condensed heterocyclyl 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]pyridinyl, indolinyl, and isoindolinyl; heterocyclyls can be bonded via any of the rings in the condensation system. As used herein, a bicyclic heterocyclyl group is a heterocyclyl group bonded to another cyclic group at two points, the other cyclic group may be a heterocyclic group or a carbocyclic group itself. Heteroaryls can be bonded 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).

[0085] "Condensation" refers to a ring that bonds with an adjacent ring, sharing two adjacent ring atoms that form a covalent bond.

[0086] "Bridgering" refers to a ring fusion in which non-adjacent atoms on a ring are linked by divalent substituents such as an alkylenyl group, an alkylenyl group containing one or two heteroatoms, or a single heteroatom. Quinuclidinyl and admantanyl are examples of bridged ring systems.

[0087] "Spiro" refers to a ring substituent linked by two bonds between the same carbon atoms. Examples of spiro groups include 1,1-diethylcyclopentane, dimethyl-dioxolane, and 4-benzyl-4-methylpiperidine, with cyclopentane and piperidine being spiro substituents.

[0088] "Hydroxy" or "hydroxyl" refers to an -OH group. "Hydroxyalkyl" refers to an unbranched or branched alkyl group as defined above, in which one or more hydrogen atoms are replaced by hydroxyl groups.

[0089] "Nitro" refers to the group -NO2.

[0090] "Imino" refers to a C=N double bond, for example, C=NR y , or =NC(O)R y This refers to a group containing R y The imino is selected from the group consisting of hydrogen, alkyl, aryl, cyano, haloalkyl, or heteroaryl, each of which can be optionally substituted. The imino can be a linker segment by bonding with the remainder at carbon and nitrogen, respectively.

[0091] "Sulfonyl" refers to the group -S(O)2R, where R is a substituent or a defined group.

[0092] "Alkylsulfonyl" refers to the group -S(O)2R, where R is a substituent or a defined group.

[0093] "Alkylsulfinyl" refers to the group -S(O)R, where R is a substituent or a defined group.

[0094] "Thiocyanate" - SCN.

[0095] "Thiol" refers to the group -SR, where R is a substituent or a defined group.

[0096] "Thioxo" or "thion" refers to a group (=S) or (S).

[0097] Certain alternative chemical names that are commonly used may be used. For example, divalent groups such as divalent "alkyl" groups and divalent "aryl" groups may also be referred to as "alkylene" or "alkylenyl" groups, "arylene" or "aryrenyl" groups, respectively. Also, unless otherwise explicitly indicated, in this specification, when a combination of groups is referred to as one part, for example, an arylalkyl, the last group mentioned contains the atom to which that part is bonded to the rest of the molecule.

[0098] The terms “arbitrary” or “optionally” mean that the event or situation described thereafter may or may not occur, and that the description includes both cases in which such event or situation occurs and cases in which it does not. The term “optionally substituted” means that any one or more hydrogen atoms on a given atom or group may or may not be substituted by a non-hydrogen part. “Optionally substituted” ranges from zero to the maximum number of possible substitutions, with each occurrence being independent. Where the term “substitution” is used, the substitution must occur on a substituted hydrogen atom of the given substituent. An optional substitution may be the same as or different from a (mandatory) substitution.

[0099] If a part is "arbitrarily substituted" and refers to any common term such as "alkyl," "alkenyl," "alkynyl," "haloalkyl," "cycloalkyl," "aryl," or "heteroaryl," then the common term is (C 1-3 (Alkyl), (C 4-6 Alkyl), -O(C 1-4 (Alkyl), (C 3-10 Cycloalkyl), O-(C 3-10It can refer to any preceding specific term such as cycloalkyl. For example, "any aryl" includes both "aryl" and "-O(aryl)," as well as examples of aryls such as phenyl or naphthyl. Similarly, the term "any heterocyclyl" includes both the terms "heterocyclyl" and "O-(heterocyclyl)," as well as examples of heterocyclyls such as oxetanyl, tetrahydropyranil, morpholino, and piperidinyl. Likewise, the term "any heteroaryl" includes the terms "heteroaryl" and "O-(heteraryl)," as well as specific heteroaryls such as pyridine.

[0100] Some compounds of formula (I) may exist as “stereoisomers” or mixtures of stereoisomers. Stereoiomers refer to compounds that are composed of the same atoms bonded together by the same bonds but have different, incompatible three-dimensional structures. The compounds of this disclosure, or their pharmaceutically acceptable salts, may contain one or more chiral centers and thus give rise to enantiomers (two stereoisomers that are mirror images of each other and cannot be superimposed), diastereomers, and other stereoisomer forms that can be defined as (R)- or (S)- in terms of absolute stereochemistry. 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 may be prepared using chiral synthons or chiral reagents, or decomposed using conventional techniques such as HPLC or SFC with a chiral column.

[0101] "&1" indicates that a compound containing the "&1" notation for a specific chemical element or atom (e.g., carbon) in the compound was prepared as a mixture of two stereoisomers at the chemical element or atom of interest (e.g., a diastereomer mixture having de or de% as described above). "&2" indicates a second set of isomers, if present.

[0102] This disclosure also includes “deuterated analogues” of compounds of formula (I) in which 1 to n hydrogens bonded to a carbon atom are replaced by deuterium, where n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are therefore useful for increasing 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 hydrogens are replaced by deuterium.

[0103] The deuterium-labeled or substituted therapeutic compounds of this disclosure may have improved DMPK (drug metabolism and pharmacokinetic) properties with respect to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium may provide specific therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life, reduced dose requirements, and / or improved therapeutic index. 18 1F-labeled compounds may be useful in PET or SPECT studies. The isotope-labeled compounds of this disclosure can generally be prepared by substituting readily available isotope-labeling reagents for non-isotope-labeling reagents and performing the procedures disclosed in the schemes or examples and preparations described below. In this context, deuterium is understood to be a substituent in the compound of formula (I).

[0104] The concentrations of such heavier isotopes, particularly deuterium, can be defined by the isotopic enrichment factor. In the compounds of this disclosure, any atom not specifically designated as a particular isotope represents any stable isotope of that atom. Unless otherwise specified, where a position is specifically designated as "H" or "hydrogen," that position is understood to have hydrogen in its naturally occurring isotopic composition. Thus, in the compounds of this disclosure, any atom specifically designated as deuterium (D) represents deuterium.

[0105] In many cases, the compounds of this disclosure can form acids and / or base salts due to the presence of an amino group and / or a carboxyl group or similar groups.

[0106] 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 useful for preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0107] The term "pharmaceutically acceptable salt" of a particular compound refers to a salt that retains the biological efficacy and properties of a given compound and is not biologically or otherwise undesirable. Examples of "pharmaceutically acceptable" or "physiologically acceptable" salts include salts with inorganic acids and salts with organic acids. Furthermore, if the compounds described herein are obtained as acid addition salts, the free base can be obtained by making a solution of its salt basic. Conversely, if the product is a free base, the addition salt, in particular a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, following conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will know of the various synthesis methods available for preparing non-toxic, pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Examples of salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of 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, and salicylic acid. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Examples of salts derived from inorganic bases include sodium, potassium, lithium, ammonium, calcium, and magnesium salts.Examples of salts derived from organic bases include salts of 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)), dialkenylamines (i.e., HN(alkenyl)2), trialkenylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), di(substituted alkyl)amines (i.e., HN( Examples of suitable amines include, but are not limited to, substituted alkenyl(2), tri(substituted alkenyl)amines (i.e., N(substituted alkenyl)3), mono, di, or tricycloalkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono, di, or triarylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines. Specific examples of suitable amines, though not limited to these, include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, and N-ethylpiperidine.

[0108] The term "substitution" means that any one or more hydrogen atoms on a given atom or group are replaced by one or more substituents other than hydrogen, provided that the valence does not exceed the normal valence of the given atom. Examples of substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amide, amidino, aryl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thion, or combinations thereof. Polymers or similar amorphous structures obtained by defining substituents and adding substituents indefinitely (e.g., a substituted aryl having a substituted alkyl group is itself substituted with a substituted aryl group and further substituted with a substituted heteroalkyl group) are not intended to be included herein. Unless otherwise specified, the maximum number of consecutive substitutions in the compounds described herein is three. For example, the sequential substitution of a substituted aryl group with two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definitions are not intended to include unacceptable substitution patterns (e.g., a methyl group substituted with five fluorine atoms or a heteroaryl group having two adjacent oxygen ring atoms). Such unacceptable substitution patterns are well known to those skilled in the art. When used to modify a chemical group, the term “substituted” may refer to other chemical groups as defined herein. Unless otherwise specified, where it is stated that a group is optionally substituted, the substituents of the group may themselves be unsubstituted. For example, in some embodiments, the term “substituted alkyl” refers to alkyl groups having one or more substituents, including hydroxyl, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, one or more substituents are each substituted and may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl.In other embodiments, each substituent may be unsubstituted and further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and those skilled in the art will recognize that substituents and other parts of the compounds of the general formula herein should be selected in order to provide compounds that are stable enough to provide pharmaceutically useful compounds that can be formulated into acceptablely stable pharmaceutical compositions. Compounds having such stability are considered to be within the scope of the present invention. Those skilled in the art should understand that the above definitions and any combination of substituents should not result in unmanipulable species or compounds.

[0109] As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes, optionally and in whole, solvents, dispersions, coatings, antimicrobial and antifungal agents, isotonic agents and absorption retarders, etc. The use of such media and agents with pharmaceutically active substances is well known to those skilled in the art. Any conventional media or agent is intended for use in therapeutic compositions, provided it is not incompatible with the active ingredient. Auxiliary active ingredients may also be incorporated into the composition.

[0110] A "solvate" is formed by 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.

[0111] Targeted SMARCA2 degradation The compounds of this disclosure are demonstrated by cell-based profiling to selectively degrade SMARCA2 while suppressing SMARCA4.

[0112] Additional biological activity data, including selectivity data for the compound of formula (I), is summarized in Table 1 of this specification.

[0113] Pharmaceutical compositions and uses of the difunctional compound of formula (I) The bifunctional compound of formula (I) has been demonstrated to selectively degrade SMARCA2 and is therefore particularly useful in the treatment of SMARCA4-deficient cancers.

[0114] Various embodiments provide pharmaceutical compositions of a compound of formula (I), or any one of the substructures or specific compounds from Examples 1 to 58, and a pharmaceutically acceptable carrier.

[0115] Further embodiments provide methods for treating SMARCA2-mediated diseases or disorders, comprising increasing T cell activation, treating cancer, or inhibiting the growth or proliferation of cancer cells, wherein the method comprises administering a therapeutically effective amount of any one of the compounds of formula (I), the substructures of Examples 1 to 58, or the compounds to a subject requiring such treatment.

[0116] SMARCA2-mediated diseases include 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, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic lung cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, and cystadenocarcinoma. Lymphoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasia and metaplasia), embryonic carcinoma, endometrial cancer, endosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, liver cancer, lung cancer, intralymphatic sarcoma, li Mangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin, and uterus, T-cell or B-cell derived lymphoid malignancies, 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, It may be a cancer selected from the group consisting of ovarian cancer, pancreatic cancer, papillary carcinoma, papillary carcinoma, pineal gland tumor, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, malignant rhabdoid tumor (MRT), rhabdomyosarcoma, sarcoma, sebaceous carcinoma, seminomas, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synoviomas, sweat gland carcinoma, thyroid cancer, Waldenström macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor.

[0117] In some embodiments, the compound of formula (I), or any one of the substructures or compounds of Examples 1 to 58, may be co-administered in a therapeutically effective amount of one or more additional therapeutic agents or pharmaceutically acceptable salts thereof. Examples of additional therapeutic agents include the chemotherapeutic agents disclosed in WO2021 / 083949.

[0118] Construction of the compound of formula (I) The synthesis or construction of compounds of formula (I) can typically be carried out in multiple steps, involving the separate preparation of the SMARCA2 binder and the components of the LHM moiety, followed by the bonding of these components via covalent bond formation. Generally speaking, either or both components can be prepared together with one or more linker precursors. The linker precursors include one or more linker segments (L s ) contains and has terminal reactive groups for further coupling. The two components are ultimately coupled (through the formation of a further linker segment) to obtain the compound of formula (I).

[0119] The following scheme illustrates a general approach to adjusting the components. Specific examples (Examples 1-58) were synthesized and characterized by their respective physiological and chemical properties according to the general scheme described herein.

[0120] intermediate Intermediate 1 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-(5-methyl-isoxazole-3-yl)piperidine-4-carboxylic acid [ka] Step 1: Synthesis of 1-(tert-butyl)4-methyl-4-(5-methylisoxazole-3-yl)piperidine-1,4-dicarboxylate [ka] To a solution of methyl 2-(5-methylisoxazole-3-yl)acetate (28.0 g, 180 mmol, 1.00 equivalent) in DMF (280 mL), NaH (18.0 g, 451 mmol, 60% purity, 2.50 equivalents) was added under N2 at 0-5°C, and the mixture was stirred at 0-5°C for 1 hour. Then, tert-butylbis(2-chloroethyl)carbamate (48.0 g, 198 mmol, 1.10 equivalents) was added at 0-5°C, and the mixture was heated to 60°C and stirred at 60°C for 15 hours. The mixture was cooled to 25°C, then poured into a saturated NH4Cl (500 mL) aqueous solution, and then extracted with ELISA (250 mL x 2). The combined organic layers were washed with brine (250 mL x 2), dried over Na2SO4, filtered, and concentrated to obtain the product as a dark brown liquid (57.8 g, crude). The crude product was used directly in the next step. LC-MS:C 16 H 24 N2O5 requirement value: 324.4, measured value: m / z = 325.2 [M + H] + .

[0121] Step 2: Synthesis of methyl 4-(5-methylisoxazole-3-yl)piperidine-4-carboxylate [ka] A solution of 1-(tert-butyl)4-methyl-4-(5-methylisoxazole-3-yl)piperidine-1,4-dicarboxylate (57.8 g, 178 mmol, 1.00 equivalent) in HCl / siRNA (2 M, 578 mL, 6.49 equivalents) was stirred at 20-25°C for 2 hours. The reaction mixture was filtered, and the filter cake was dried under vacuum. The crude product was used directly in the next step. Methyl 4-(5-methylisoxazole-3-yl)piperidine-4-carboxylate (49.7 g, crude, HCl) was obtained as a dark brown liquid. LCMS:C 11 H 16 N2O3 requirement value: 224.1, measured value: m / z = 225.1 [M+H] + .

[0122] Step 3: Synthesis of methyl 1-(6-chloropyridazine-4-yl)-4-(5-methylisoxazole-3-yl)piperidine-4-carboxylate [ka] To a solution of methyl 4-(5-methylisoxazole-3-yl)piperidine-4-carboxylate hydrochloride (47.7 g, 183 mmol, 1.00 equivalent, HCl) in IPA (480 mL), DIEA (94.6 g, 732 mmol, 127 mL, 4.00 equivalent) was added at 20°C, followed by the addition of 3,5-dichloropyridazine (30.0 g, 201 mmol, 1.10 equivalent) at 20°C. The reaction mixture was stirred at 70°C for 12 hours. The reaction mixture was quenched with H2O (1.00 L) and then extracted with DCM (500 mL x 3). The organic layer was washed with brine (500 mL x 2), dried over Na2SO4, filtered, and concentrated to obtain the product. The residue was purified by column chromatography (SiO2) using a gradient of 30-100% ethyl acetate in petroleum ether. Methyl 1-(6-chloropyridazin-4-yl)-4-(5-methylisoxazole-3-yl)piperidine-4-carboxylate (5.10 g, 7.92 mmol, 4.16% yield, 52.3% purity) was obtained as a brown solid. LCMS:C 15 H 17 ClN4O3 required value: 336.1, measured value: m / z = 337.1 [M+H] + .

[0123] Step 4: Synthesis of methyl 1-(6-(2-methoxyphenyl)37-iridazine-4-yl)-4-(5-methylisoxazole-3-yl)piperidine-4-carboxylate [ka] A mixture of methyl 1-(6-chloropyridazin-4-yl)-4-(5-methylisoxazole-3-yl)piperidine-4-carboxylate (2.54 g, 7.54 mmol, 1.00 equivalent), (2-methoxyphenyl)boronic acid (2.29 g, 15.0 mmol, 2.00 equivalent), K2CO3 (3.13 g, 22.6 mmol, 3.00 equivalent), and RuPhos Pd G3 (630 mg, 754 μmol, 0.10 equivalent) in dioxane (127 mL) and H2O (12.7 mL) was degassed at 25°C, purged three times with N2, and then stirred at 90°C for 12 hours under an N2 atmosphere. The mixture was then poured into H2O (150 mL) and extracted with ethyl acetate (150 mL x 3). The mixed organic phase was washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by RP-FC using a gradient of 25–55% MeCN in H2O. The eluate was concentrated under vacuum. The aqueous phase was freeze-dried to obtain the product. Methyl 1-(6-(2-methoxyphenyl)pyridazin-4-yl)-4-(5-methylisoxazole-3-yl)piperidine-4-carboxylate (1.90 g, 4.50 mmol, 35.9% yield, 96.6% purity) was obtained as a pale yellow solid. LCMS:C 22 H 24 N4O4 requirement value: 408.2, measured value: m / z = 409.1 [M+H] + .

[0124] Step 5: Synthesis of the title compound To a solution of methyl 1-(6-(2-methoxyphenyl)pyridazin-4-yl)-4-(5-methylisoxazole-3-yl)piperidine-4-carboxylate (1.60 g, 3.79 mmol, 1.00 equivalent) in DCM (50.0 mL), BBr3 (2 M, 3.79 mL, 2.00 equivalent) was added at 0°C. The reaction mixture was stirred at 15°C for 3 hours. The resulting mixture was quenched by adding HCl solution (1 N, 5.00 mL). The resulting mixture was extracted with ELISA (10.0 mL x 3), dried over Na2SO4, and concentrated under reduced pressure to obtain methyl 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(5-methylisoxazole-3-yl)piperidine-4-carboxylate (3.80 g, crude) as a pale yellow solid. Next, to a solution of methyl 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(5-methylisoxazole-3-yl)piperidine-4-carboxylate (3.10 g, 2.33 mmol, 1.00 equivalent) in THF (30.0 mL) and H2O (30.0 mL), LiOH·H2O (977 mg, 23.3 mmol, 10.0 equivalent) was added, and the mixture was stirred at 15°C for 4 hours. The resulting mixture was quenched by adding HCl solution (1N, 30.0 mL), and then concentrated under vacuum. This was purified by RP-FC using a gradient of 1-31% MeCN in H2O. The residue was dissolved in CAN (5.00 mL) and H2O (5.00 mL), concentrated under vacuum to remove CAN, and then concentrated under lyophilization. 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(5-methylisoxazole-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 N4O4 requirement value: 380.1, measured value: m / z = 381.1 [M+H] + . 1H NMR:(400 MHz, DMSO-d6) 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).

[0125] Intermediate 2 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(2-methoxyphenyl)piperidine-4-carboxylic acid [ka] Step 1: Synthesis of 1-(tert-butyl)4-methyl4-(2-methoxyphenyl)piperidine-1,4-dicarboxylate [ka] This intermediate was synthesized using methyl 2-(2-methoxyphenyl) acetate according to step 1 of intermediate 1. 1-(tert-butyl)4-methyl 4-(2-methoxyphenyl)piperidine-1,4-dicarboxylate (2.90 g, 5.69 mmol, 4.60% yield, 68.6% purity) was a yellow solid. LCMS:C 19 H 27 NO5 required value: 349.2, measured value: m / z = 250.1 [M - 100 + H] + .

[0126] Step 2: Synthesis of methyl 4-(2-methoxyphenyl)piperidine-4-carboxylate [ka] This intermediate was synthesized according to step 2 of intermediate 1. Methyl 4-(2-methoxyphenyl)piperidine-4-carboxylate (2.52 g, crude, HCl) was obtained as a brown oil. LCMS:C 14 H19 NO3 required value: 249.1, measured value: m / z = 250.1 [M+H] + .

[0127] Step 3: Synthesis of methyl 1-(6-chloropyridazine-4-yl)-4-(2-methoxyphenyl)piperidine-4-carboxylate [ka] This intermediate was synthesized using methyl 4-(2-methoxyphenyl)piperidine-4-carboxylate according to step 3 of intermediate 1. Methyl 1-(6-chloropyridazin-4-yl)-4-(2-methoxyphenyl)piperidine-4-carboxylate (2.05 g, 5.51 mmol, 84.5% yield, 97.3% purity) was obtained as a yellow oil. LCMS:C 18 H 20 ClN3O3 required value: 361.1, measured value: m / z = 362.2 [M+H] + .

[0128] Step 4: Synthesis of methyl 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(2-methoxyphenyl)piperidine-4-carboxylate [ka] This intermediate was synthesized using 1-(6-chloropyridazine-4-yl)-4-(2-methoxyphenyl)piperidine-4-carboxylate and (2-hydroxyphenyl)boronic acid according to step 4 of intermediate 1. LCMS:C 24 H 25 N3O4 requirement value: 419.2, measured value: m / z = 420.2 [M+H] + .

[0129] After basic hydrolysis, the title compound was obtained as an off-white solid (1.44 g, 3.52 mmol, 73.9% yield, 99.2% purity). 1H NMR:(400 MHz, DMSO-d6) 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).

[0130] Intermediate 4 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(tetrahydro-2H-pyran-4-yl)piperidine-4-carboxylic acid [ka] Step 1: Synthesis of ethyl 4-(tetrahydro-2H-pyran-4-yl)piperidine-4-carboxylate [ka] To a solution of DIPA (4.71 g, 46.6 mmol, 6.58 mL, 1.20 equivalents) in THF (50.0 mL), n-BuLi (2.50 M, 18.7 mL, 1.20 equivalents) was added at -10°C, and the mixture was stirred at -10°C for 0.5 hours. Next, ethylpiperidine-4-carboxylate (10.0 g, 38.9 mmol, 1.00 equivalent) in THF (10.0 mL) was added dropwise to the reaction mixture at -10°C, and the mixture was stirred at -10°C for 2 hours. A solution of 4-iodotetrahydro-2H-pyran (9.06 g, 42.8 mmol, 1.10 equivalents) in THF (10.0 mL) was added to the mixture at -10°C, and the mixture was stirred at -10°C for 1 hour. The mixture was warmed to 25°C and stirred at 25°C for 12 hours. The reaction mixture was poured into a saturated ice NH4Cl solution (500 mL) at 0°C, and the aqueous phase was extracted with ethyl acetate (500 mL x 2). The mixed organic phase was washed with H2O (500 mL) and brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the crude product. The residue was purified by column chromatography (SiO2) using a gradient of 1-20% ethyl acetate in petroleum ether. Ethyl 4-(tetrahydro-2H-pyran-4-yl)piperidine-4-carboxylate (8.90 g, crude) 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)

[0131] Step 2: Synthesis of ethyl 4-(tetrahydro-2H-pyran-4-yl)piperidine-4-carboxylate [ka] This intermediate was synthesized according to step 2 of intermediate 1. Ethyl 4-(tetrahydro-2H-pyran-4-yl)piperidine-4-carboxylate (6.00 g, 21.6 mmol, 82.9% yield, 100% purity, HCl) was obtained as a pale yellow solid. LCMS:C 13 H 23 NO3 required value 241.2, measured value: m / z = 242.2 [M+H] + .

[0132] Step 3: Synthesis of ethyl 1-(6-chloropyridazine-4-yl)-4-(tetrahydro-2H-pyran-4-yl)piperidine-4-carboxylate [ka] This intermediate was synthesized using ethyl 4-(tetrahydro-2H-pyran-4-yl)piperidine-4-carboxylate according to step 3 of intermediate 1 (5.40 g, 15.0 mmol, 69.4% yield, 98.2% purity). LCMS:C 17 H 24 ClN3O3 requirement value: 353.2, measured value: m / z = 354.1 [M+H] + .

[0133] Step 4: Synthesis of methyl 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(2-methoxyphenyl)piperidine-4-carboxylate [ka] This intermediate was synthesized according to step 4 of intermediate 1 using ethyl 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(tetrahydro-2H-pyran-4-yl)piperidine-4-carboxylate and (2-hydroxyphenyl)boronic acid (4.50 g, 10.6 mmol, 78.1% yield, 97.1% purity). LCMS:C 23 H 29 N3O4 requirement value: 411.2, measured value: m / z = 412.2 [M+H] + .

[0134] After basic hydrolysis, the title compound was obtained as a beige solid (2.43 g, 6.28 mmol, 88.7% yield, 99.1% purity). LC-MS:C 21 H 25 N3O4 requirement value: 383.2, measured value: m / z = 384.1 [M+H] + . 1 H NMR:(400 MHz, DMSO-d6) δ 13.96 -13.48 (m, 1H), 8.93 (d, J = 2.8 Hz, 1H), 8.10 (d, J = 8.0 Hz, 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)

[0135] Intermediate 5 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(3-methyl-1H-pyrazole-1-yl)piperidine-4-carboxylic acid [ka] Step 1: Synthesis of di-tert-butyl 1-(1-benzyl-4-(ethoxycarbonyl)piperidine-4-yl)hydrazine-1,2-dicarboxylate [ka] To a solution of DIPA (15.5 g, 153 mmol, 21.6 mL, 1.40 equivalents) in THF (270 mL), n-BuLi (2.5 M, 60.9 mL, 1.39 equivalents) was added at -65°C under a N2 atmosphere. The reaction mixture was stirred at -65°C for 1 hour. Then, ethyl 1-benzylpiperidine-4-carboxylate (27.0 g, 109 mmol, 1.00 equivalent) was added dropwise to the reaction mixture at -65°C, and the mixture was stirred at -65°C for 1 hour. 1,2-bis(1,1-dimethylethyl)-(1E)-1,2-diazendicarboxylate (27.5 g, 120 mmol, 1.10 equivalents) in THF (50.0 mL) was added to the mixture at -65°C. The reaction mixture was warmed to 25°C and stirred at 25°C for 12 hours under a N2 atmosphere. The reaction mixture was poured into saturated NH4Cl solution (1.50 L) and extracted with ethyl acetate (600 mL x 3). The combined organic phase was washed with brine (1.50 L), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by RP-FC and then purified using a gradient of 25-46% MeCN in H2O. The eluate 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 x 3), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain di-tert-butyl 1-(1-benzyl-4-(ethoxycarbonyl)piperidine-4-yl)hydrazine-1,2-dicarboxylate (48.8 g, 97.1 mmol, 88.9% yield) as a yellow solid. LCMS:C 25 H 39 N3O6 requirement value: 477.3, measured value: m / z = 478.1 [M+H] + .

[0136] Step 2: Synthesis of ethyl 1-benzyl-4-hydrazinylpiperidine-4-carboxylate [ka] To a solution of di-tert-butyl 1-(1-benzyl-4-(ethoxycarbonyl)piperidine-4-yl)hydrazine-1,2-dicarboxylate (48.8 g, 102 mmol, 1.00 equivalent) in siRNA (50.0 mL), HCl / siRNA (2 M, 500 mL, 9.79 equivalents) was added at 25°C. The mixture was heated to 40°C and stirred at 40°C for 12 hours. The reaction mixture was concentrated under vacuum to obtain ethyl 1-benzyl-4-hydrazinylpiperidine-4-carboxylate (36.0 g, crude, HCl) as a white solid. LCMS:C 15 H 23 N3O2 requirement value: 277.2, measured value: m / z = 278.1 [M+H] + .

[0137] Step 3: Synthesis of ethyl 1-benzyl-4-(3-methyl-1H-pyrazole-1-yl)piperidine-4-carboxylate [ka] A mixture of ethyl 1-benzyl-4-hydrazinylpiperidine-4-carboxylate (39.0 g, 141 mmol, 1.00 equivalent) and 4,4-dimethoxybutan-2-one (18.6 g, 141 mmol, 18.7 mL, 1.00 equivalent) in EtOH (195 mL) and AcOH (19.5 mL) was degassed, purged three times with N2, and then stirred under N2 at 50°C for 2 hours. The reaction mixture was concentrated under vacuum. The residue was purified by RP-FC using a gradient of 10-40% MeCN in H2O. The eluate was concentrated under vacuum to remove acetonitrile and H2O, and the aqueous residue was freeze-dried to obtain ethyl 1-benzyl-4-(3-methyl-1H-pyrazole-1-yl)piperidine-4-carboxylate (22.0 g, 64.4 mmol, 45.8% yield) as a yellow solid. LCMS:C 19 H 25 N3O2 requirement value: 327.2, measured value: m / z = 328.1 [M+H] + .

[0138] Step 4: Synthesis of ethyl 4-(3-methyl-1H-pyrazole-1-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-benzyl-4-(3-methyl-1H-pyrazole-1-yl)piperidine-4-carboxylate (22.0 g, 67.2 mmol, 1.00 equivalent) in MeOH (110 mL), Pd / C (2.22 g, 2.08 mmol, 10% purity, 0.031 equivalent) was added under N2. The suspension was degassed under vacuum and purged three times with H2. The mixture was stirred under H2 (50 psi) at 25°C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain ethyl 4-(3-methyl-1H-pyrazole-1-yl)piperidine-4-carboxylate (15.6 g, 64.8 mmol, 96.5% yield) as a yellow solid. 1 H NMR:(400 MHz, DMSO-d6) 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).

[0139] Step 5: Synthesis of ethyl 1-(6-chloropyridazine-4-yl)-4-(3-methyl-1H-pyrazole-1-yl)piperidine-4-carboxylate [ka] This intermediate was synthesized using ethyl 4-(3-methyl-1H-pyrazole-1-yl)piperidine-4-carboxylate according to step 3 of intermediate 1 (12.5 g, 35.5 mmol, 53.9% yield). LCMS:C 16 H 20 ClN5O2 requirement value: 349.1, measured value: m / z = 350.0 [M+H]+ .

[0140] Step 6: Synthesis of ethyl 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(3-methyl-1H-pyrazole-1-yl)piperidine-4-carboxylate [ka] This intermediate was synthesized according to step 4 of intermediate 1 using ethyl 1-(6-chloropyridazin-4-yl)-4-(3-methyl-1H-pyrazole-1-yl)piperidine-4-carboxylate and (2-hydroxyphenyl)boronic acid (8.50 g, 16.7 mmol, 83.4% yield). LCMS:C 22 H 25 N5O3 requirement value: 407.2, measured value: m / z = 408.2 [M + H] + .

[0141] After basic hydrolysis, the title compound was obtained as a pale brown solid (1.07 g, 2.75 mmol, 37.3% yield, 97.4% purity). LC-MS:C 20 H 21 N5O3 requirement value: 379.4, measured value: m / z = 380.1 [M+H] + . 1 H NMR:(400 MHz, 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)

[0142] Intermediate 6 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(pyridine-4-yl)piperidine-4-carboxylic acid [ka] Step 1: Synthesis of 1-(tert-butyl)4-methyl4-(pyridine-4-yl)piperidine-1,4-dicarboxylate [ka] This intermediate was synthesized using methyl 2-(4-fluorophenyl) acetate according to step 1 of intermediate 1 (9.20 g, 25.4 mmol, 9.84% yield, 88.4% purity). LCMS:C 17 H 24 N2O4 requirement value: 320.2, measured value: m / z = 321.3 [M+H] + .

[0143] Step 2: Synthesis of methyl 4-(pyridine-4-yl)piperidine-4-carboxylate [ka] This intermediate was synthesized according to step 2 of intermediate 1 (9.20 g, crude, HCl). LCMS:C 12 H 16 N2O2 requirement value: 220.1, measured value: m / z = 221.1 [M+H] + .

[0144] Step 3: Synthesis of methyl 1-(6-chloropyridazine-4-yl)-4-(pyridine-4-yl)piperidine-4-carboxylate [ka] This intermediate was synthesized using methyl 4-(pyridine-4-yl)piperidine-4-carboxylate according to step 3 of intermediate 1 (6.67 g, 19.8 mmol, 62.0% yield, 98.8% purity). LCMS:C 16 H 17 ClN4O2 required value: 332.1, measured value: m / z = 333.2 [M + H] + .

[0145] Step 4: Synthesis of methyl 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(pyridine-4-yl)piperidine-4-carboxylate [ka] This intermediate was synthesized using methyl 1-(6-chloropyridazin-4-yl)-4-(pyridine-4-yl)piperidine-4-carboxylate and (2-hydroxyphenyl)boronic acid according to step 4 of intermediate 1 (4.20 g, 10.6 mmol, 63.9% yield, 98.2% purity). LCMS:C 22 H 22 N4O3 requirement value: 390.2, measured value: m / z = 391.2 [M+H] + .

[0146] After basic hydrolysis, the title compound (1.88 g, 4.58 mmol, 96.6% yield, 96.2% purity, Li salt) was obtained as a brown solid. LC-MS:C 21 H 20 N4O3 requirement value: 376.2, measured value: 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).

[0147] Intermediate 7 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(3-methoxyphenyl)piperidine-4-carboxylic acid [ka] Step 1: Synthesis of 1-(tert-butyl)4-methyl4-(3-methoxyphenyl)piperidine-1,4-dicarboxylate [ka] This intermediate was synthesized using methyl 2-(3-methoxyphenyl) acetate according to step 1 of intermediate 1 (7.70 g, 11.0 mmol, 6.62% yield, 50.0% purity). LCMS:C 19 H 27 NO5 required value: 349.2, measured value: m / z = 250.1 [M - 100 + H] + .

[0148] Step 2: Synthesis of methyl 4-(3-methoxyphenyl)piperidine-4-carboxylate [ka] This intermediate was synthesized according to step 2 of intermediate 1 (7.40 g, crude, HCl). LCMS:C 14 H 19 NO3 required value: 249.1, measured value: m / z = 250.1 [M+H] + .

[0149] Step 3: Synthesis of methyl 1-(6-chloropyridazine-4-yl)-4-(3-methoxyphenyl)piperidine-4-carboxylate [ka] This intermediate was synthesized using methyl 4-(3-methoxyphenyl)piperidine-4-carboxylate according to step 3 of intermediate 1 (5.90 g, 16.0 mmol, 57.3% yield, 98.3% purity). LCMS:C 18 H 20 ClN3O3 required value: 361.1, measured value: m / z = 362.2 [M+H] + .

[0150] Step 4: Synthesis of methyl 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(3-methoxyphenyl)piperidine-4-carboxylate [ka] This intermediate was synthesized according to step 4 of intermediate 8 using methyl 1-(6-chloropyridazin-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 N3O4 requirement value: 419.2, measured value: m / z = 420.1 [M+H] + .

[0151] After basic hydrolysis, the title compound (1.04 g, 2.56 mmol, 39.8% yield, 99.9% purity) was obtained as an off-white solid. LC-MS:C 23 H 23 N3O4 requirement value: 405.2, measured value: m / z = 406.2 [M+H] + . 1 H NMR:(400 MHz, DMSO-d6) 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, 1 H), 4.19 -4.43 (m, 2 H), 3.80 (s, 3 H), 3.60 (s, 2 H), 2.73 (d, J=13.2 Hz, 2 H), 2.06 -2.20 (m, 2 H).

[0152] Intermediate 8 4-(4-fluorophenyl)-1-(6-(2-hydroxyphenyl)pyridazin-4-yl)piperidine-4-carboxylic acid [ka] Step 1: Synthesis of 1-(tert-butyl)4-methyl4-(4-fluorophenyl)piperidine-1,4-dicarboxylate [ka] This intermediate was synthesized using methyl 2-(4-fluorophenyl) acetate according to step 1 of intermediate 1 (8.36 g, crude). LCMS:C 18 H 24 FNO4 required value: 337.2, measured value: m / z = 282.2 [M-56+H] + .

[0153] Step 2: Synthesis of methyl 4-(4-fluorophenyl)piperidine-4-carboxylate [ka] This intermediate was synthesized according to step 2 of intermediate 1 (7.64 g, crude, HCl). LCMS:C 13 H 16 FNO2 required value: 237.1, measured value: m / z = 238.2 [M+H] + .

[0154] Step 3: Synthesis of methyl 1-(6-chloropyridazine-4-yl)-4-(4-fluorophenyl)piperidine-4-carboxylate [ka] This intermediate was synthesized using methyl 4-(4-fluorophenyl)piperidine-4-carboxylate according to step 3 of intermediate 1 (2.61 g, 7.31 mmol, 41.0% yield, 98.0% purity). LCMS:C 17 H 17 ClFN3O2 required value: 349.1, measured value: m / z = 350.2 [M+H] + .

[0155] Step 4: Synthesis of methyl 4-(4-fluorophenyl)-1-(6-(2-hydroxyphenyl)pyridazin-4-yl)piperidine-4-carboxylate [ka] To a solution of methyl 1-(6-chloropyridazin-4-yl)-4-(4-fluorophenyl)piperidine-4-carboxylate (2.41 g, 6.75 mmol, 1.00 equivalent), (2-hydroxyphenyl)boronic acid (1.86 g, 13.5 mmol, 2.00 equivalent), and K2CO3 (2.80 g, 20.3 mmol, 3.00 equivalent) in dioxane (24.1 mL) and H2O (4.82 mL), Pd(dppf)Cl2 (494 mg, 675 μmol, 0.10 equivalent) was added under an N2 atmosphere. The mixture was stirred at 110°C for 12 hours. The mixture was poured into H2O (100 mL) and extracted with ethyl acetate (100 mL x 3). The mixed organic phase was 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 FN3O3 required value: 407.2, measured value: m / z = 408.2 [M+H] + .

[0156] After basic hydrolysis, the title compound (1.14 g, 2.62 mmol, 79.2% yield, 98.8% purity, HCl) was obtained as a white solid. LC-MS:C 22 H 20 FN3O3 required value: 393.1, measured value: m / z = 394.2 [M+H] + . 1H 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:(400 MHz, DMSO-d6) δ -115.561.

[0157] Intermediate 9 4-(2-fluorophenyl)-1-(6-(2-hydroxyphenyl)pyridazin-4-yl)piperidine-4-carboxylic acid [ka] Step 1: Synthesis of 1-(tert-butyl)4-methyl4-(2-fluorophenyl)piperidine-1,4-dicarboxylate [ka] To a solution of methyl 2-(2-fluorophenyl)acetate (28.0 g, 164 mmol) in DMF (560 mL), NaH (16.4 g, 411 mmol, 60.0% in mineral oil) was added under N2 at 0-5°C, and the mixture was stirred at 0-5°C for 1 hour. Then, tert-butylbis(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 LC-MS. 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 ELISA (500 mL x 3). The combined organic phase was washed with H2O (500 mL x 3), dried on anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the crude product (54.0 g) as a yellow oil, which was then further purified. LCMS C9H9FO2 requirement 337.2, measured value 282.2 [M-56+H] + .

[0158] Step 2: Synthesis of methyl 4-(2-fluorophenyl)piperidine-4-carboxylate [ka] A solution of 1-(tert-butyl)4-methyl4-(2-fluorophenyl)piperidine-1,4-dicarboxylate (54.0 g, 160 mmol) in siRNA (200 mL) was added to a 1:1 mixture of concentrated HCl in siRNA (300 mL). The mixture was stirred at 25°C until complete analysis was determined by LC-MS. Once complete, the reaction mixture was filtered and concentrated under reduced pressure to obtain the 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 phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product (16.0 g, HCl salt) as a yellow oil, which was then proceeded to without any further purification. LC-MS C 17 H 17 ClFN3O2 required value 237.1, measured value m / z = 238.2 [M+H] + .

[0159] Step 3: Synthesis of methyl 1-(6-chloropyridazine-4-yl)-4-(2-fluorophenyl)piperidine-4-carboxylate [ka] To a solution of methyl 4-(2-fluorophenyl)piperidine-4-carboxylate (16.0 g, 67.4 mmol) in IPA (160 mL), DIPEA (46.9 mL, 269 mmol) and 3,5-dichloropyridazine (12.0 g, 80.9 mmol) were added. The mixture was stirred at 25°C until complete analysis was determined by LC-MS. Once complete, the reaction mixture was filtered and concentrated under reduced pressure to obtain the crude residue. The residue was dissolved in a minimal amount of DCM, poured into H2O (200 mL), and then extracted with DCM (200 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude residue was purified by flash column chromatography (petroleum ether in ethyl acetate: 15%~50%) to obtain the desired product as a yellow solid (9.45 g, 39% yield). LC-MS C 17 H 17 ClFN3O2 requirement value 349.1, measured value m / z = 350.2 [M+H] + .

[0160] Step 4: Synthesis of methyl 4-(2-fluorophenyl)-1-(6-(2-hydroxyphenyl)pyridazin-4-yl)piperidine-4-carboxylate [ka] To a solution of methyl 1-(6-chloropyridazin-4-yl)-4-(2-fluorophenyl)piperidine-4-carboxylate (7.40 g, 20.3 mmol) in 1,4-dioxane (75 mL) and H2O (15 mL), 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 at 25°C under an N2 atmosphere. The mixture was then heated to 90°C and stirred until complete was determined by LC-MS. Once complete, the reaction mixture was filtered through Celite (washed with siRNA) and concentrated under reduced pressure to the minimum amount of solvent. The residue was poured into H2O (200 mL) and extracted with siRNA (300 mL x 3). The combined organic layer was dried over Na2SO4, filtered, and concentrated to obtain the crude residue. The crude product was purified by flash column chromatography to obtain the desired product as a yellow solid (2.75 g, 30.6% yield). LCMS C 23 H 22 FN3O3 required value m / z = 407.2, measured value 408.3 [M+H] + .

[0161] After basic hydrolysis, the title compound was obtained as a pale yellow solid (1.97 g, 71% yield). LC-MS C 22 H 20 FN3O3 required value 393.2, measured value m / z = 394.2 [M+H] + .

[0162] Intermediate 10 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(5-isopropylisoxazole-3-yl)piperidine-4-carboxylic acid [ka] Step 1: Synthesis of (5-isopropylisoxazole-3-yl)methanol [ka] To a solution of methyl 5-isopropyl isoxazole-3-carboxylate (25.0 g, 148 mmol) in THF (125 mL), LAH (2.5 M in THF, 118 mL) was added under N2 at 0°C. The mixture was then warmed and stirred under N2 at 25°C until completion was determined by LC-MS. Once complete, the mixture was cooled to 0°C, and then 1 M HCl (800 mL) was slowly added dropwise under N2 while stirring for 30 minutes. The mixture was then extracted with MTBE (200 mL x 3), washed with saturated NaHCO3 aqueous solution (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the crude product as a yellow oil, which was proceeded to without any further purification (13.0 g). LC-MS C7H 11 NO2 requirement value 141.1, measured value 142.6 [M+H] + .

[0163] Step 2: Synthesis of (5-isopropylisoxazole-3-yl)methylmethanesulfonate [ka] To a solution of (5-isopropylisoxazole-3-yl)methanol (20.1 g, 142 mmol) and TEA (39.6 mL, 285 mmol) in DCM (201 mL), MsCl (16.6 mL, 215 mmol) was added dropwise at 0 °C. The mixture was then warmed and stirred at 25 °C until completion was determined by LC-MS. Once complete, the mixture was poured into ice-cold water (500 mL) and extracted with DCM (250 mL x 3). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the crude product as a yellow oil, which was then carried out without any further purification (28.1 g). LC-MS C8H 13 NO4S required value 219.1, measured value m / z = 220.4 [M+H] + .

[0164] Step 3: Synthesis of 2-(5-isopropylisoxazole-3-yl)acetonitrile [ka] To a solution of (5-isopropylisoxazole-3-yl)methylmethanesulfonate (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 complete was determined by LC-MS. Once complete, the reaction mixture was diluted with saturated Na2CO3 aqueous solution (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 obtain the crude residue. The crude residue was purified by flash column chromatography (petroleum ether in ethyl acetate - 5%~20%) to obtain the desired product as a yellow oil (13.9 g, 69% yield). LC-MS C8H 10 N2O requirement value 150.1, measured value 151.2 [M+H] + .

[0165] Step 4: tert-butyl 4-cyano-4-(5-isopropylisoxazole-3-yl)piperidine-1-carboxylate [ka] This intermediate was synthesized using 2-(5-isopropylisoxazole-3-yl)acetonitrile instead of methyl 2-(2-fluorophenyl)acetate, as described in step 1 of intermediate 9. LCMS C 17 H 25 N3O3 requirement value 319.2, measured value m / z = 220.1 [M - Boc + H] + .

[0166] Step 5: Synthesis of 4-(5-isopropylisoxazole-3-yl)piperidine-4-carbonitrile [ka] This intermediate was prepared as described in step 2 of intermediate 9, using tert-butyl 4-cyano-4-(5-isopropylisoxazole-3-yl)piperidine-1-carboxylate (step 7) instead of 1-(tert-butyl)4-methyl 4-(2-fluorophenyl)piperidine-1,4-dicarboxylate (9.65 g). LCMS C 12 H 17 N3O requirement value 219.1, measured value m / z = 220.1 [M+H] + .

[0167] Step 6: Synthesis of 1-(6-chloropyridazine-4-yl)-4-(5-isopropylisoxazole-3-yl)piperidine-4-carbonitrile [ka] This intermediate was prepared as described in step 3 of intermediate 9, using 4-(5-isopropylisoxazole-3-yl)piperidine-4-carbonitride instead of 4-(2-fluorophenyl)piperidine-4-carboxylate (14.5 g). LCMS C 16 H 18 ClN5O required value 331.1, measured value m / z = 332.1 [M+H] + .

[0168] Step 7: Synthesis of 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(5-isopropylisoxazole-3-yl)piperidine-4-carbonitrile [ka] To a solution of 1-(6-chloropyridazin-4-yl)-4-(5-isopropylisoxazole-3-yl)piperidine-4-carbonitrile (4.00 g, 12.1 mmol) and (2-hydroxyphenyl)boronic acid (3.33 g, 24.1 mmol) in 1,4-dioxane (40 mL), K2CO3 (5.00 g, 36.2 mmol) and RuPhos Pd G3 (504 mg, 603 μmol) were added at 25°C. 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  (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 obtain the crude residue. The residue was purified by flash column chromatography (petroleum ether in ethyl acetate - 5-100%) to obtain the desired product as a brown solid (2.00 g, 42% yield). LCMS C 22 H 23 N5O2 requirement value 389.2, measured value m / z = 390.3 [M+H] + .

[0169] Step 8: Synthesis of the title compound To a solution of 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(5-isopropylisoxazole-3-yl)piperidine-4-carbonitrile (2.00 g, 5.14 mmol) in THF (6 mL), MeOH (6 mL), and H2O (6 mL), NaOH (2.05 g, 51.4 mmol) was added at 25°C, and the mixture was heated to 80°C and stirred until complete by LC-MS. Once complete, the reaction mixture was diluted with H2O (20 mL) and extracted with siRNA (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 the crude residue. The crude residue was purified by RP-FC (26.0%~46.0%). The desired eluate was concentrated under reduced pressure to half its volume, frozen at -78°C, and lyophilized to obtain the desired compound as a yellow solid (1.14 g, 58% yield). LCMS C 22 H24 N4O4 requirement value 408.2, measured value m / z = 409.1 [M+H] + .

[0170] Intermediate 11 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(pyrazolo[1,5-A]pyridin-2-yl)piperidine-4-carboxylic acid [ka] Step 1: Synthesis of ethyl 2-(pyrazolo[1,5-a]pyridine-2-yl)acetate [ka] To a solution of 2-(pyrazolo[1,5-a]pyridine-2-yl)acetic acid (23.0 g, 130 mmol) in EtOH (115 mL), H2SO4 (6.40 g, 65.2 mmol, 3.48 mL) was added at 25°C. The reaction mixture was then heated to 80°C and stirred until completion was determined by LC-MS. Once complete, the reaction mixture was concentrated under vacuum to obtain the crude residue. The residue was quenched with ice water (175 mL) and subsequently extracted with DCM (175 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the title compound as a dark brown liquid (25.4 g). LC-MS C 11 H 12 N2O2 requirement value 204.1, measured value m / z = 205.1 [M+H] + .

[0171] Step 2: Synthesis of 1-(tert-butyl)4-ethyl-4-(pyrazolo[1,5-a]pyridine-2-yl)piperidine-1,4-dicarboxylate [ka] This intermediate was synthesized as described in step 1 of intermediate 9, using ethyl 2-(pyrazolo[1,5-a]pyridine-2-yl)acetate instead of methyl 2-(2-fluorophenyl)acetate (34.5 g). LCMS C 20 H27 N3O4 requirement value 373.2, measured value m / z = 318.2 [M-56+H] + .

[0172] Step 3: Ethyl 4-(pyrazolo[1,5-a]pyridine-2-yl)piperidine-4-carboxylate [ka] This intermediate was synthesized as described in step 2 of intermediate 9, using 1-(tert-butyl)4-ethyl-4-(pyrazolo[1,5-a]pyridine-2-yl)piperidine-1,4-dicarboxylate (step 13) instead of 1-(tert-butyl)4-methyl-4-(2-fluorophenyl)piperidine-1,4-dicarboxylate (42.9 g). LCMS C 19 H 20 ClN5O2 required value 273.2, measured value m / z = 274.2 [M+H] + .

[0173] Step 4: Synthesis of ethyl 1-(6-chloropyridazine-4-yl)-4-(pyrazolo[1,5-a]pyridine-2-yl)piperidine-4-carboxylate [ka] This intermediate was synthesized as described in step 3 of intermediate 9, using ethyl 4-(pyrazolo[1,5-a]pyridine-2-yl)piperidine-4-carboxylate instead of 4-(2-fluorophenyl)piperidine-4-carboxylate (11.0 g). LCMS C 19 H 20 ClN5O2 required value 385.1, measured value m / z = 386.2 [M+H] + .

[0174] Step 5: Synthesis of ethyl 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(pyrazolo[1,5-a]pyridine-2-yl)piperidine-4-carboxylate [ka] This intermediate was prepared as described in step 4 of intermediate 9, using ethyl 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(pyrazolo[1,5-a]pyridin-2-yl)piperidine-4-carboxylate instead of methyl 1-(6-chloropyridazin-4-yl)-4-(2-fluorophenyl)piperidine-4-carboxylate (42% yield over 4 steps). LCMS C 25 H 25 N5O3 requirement value 443.2, measured value m / z = 444.2 [M+H] + .

[0175] After basic hydrolysis, the title compound (2.50 g) was obtained. LC-MS C 23 H 21 N5O3 requirement value 415.2, measured value 416.2 [M+H] + .

[0176] Intermediate 12 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(1-methyl-1H-pyrazole-4-yl)piperidine-4-carboxylic acid [ka] Step 1: Synthesis of 1-(tert-butyl)4-methyl-4-(1-methyl-1H-pyrazole-4-yl)piperidine-1,4-dicarboxylate [ka] This intermediate was synthesized using methyl 2-(1-methyl-1H-pyrazole-4-yl)acetate instead of methyl 2-(2-fluorophenyl)acetate, as described in step 1 of intermediate 9 (80.8 g). LCMS C 16 H 25 N3O4 requirement value 323.2, measured value m / z = 268.2 [M-56+H] + .

[0177] Step 2: Synthesis of methyl 4-(1-methyl-1H-pyrazole-4-yl)piperidine-4-carboxylate [ka] This intermediate was synthesized as described in step 2 of intermediate 9 (82.5 g), using 1-(tert-butyl)4-methyl-4-(1-methyl-1H-pyrazole-4-yl)piperidine-1,4-dicarboxylate instead of 1-(tert-butyl)4-methyl-4-(2-fluorophenyl)piperidine-1,4-dicarboxylate. LCMS C 11 H 17 N3O2 requirement value 223.1, measured value m / z = 224.3 [M+H] + .

[0178] Step 3: Synthesis of methyl 1-(6-chloropyridazine-4-yl)-4-(1-methyl-1H-pyrazole-4-yl)piperidine-4-carboxylate [ka] This intermediate was synthesized as in step 3 of intermediate 9 (7.8g) LCMS C, using methyl 4-(1-methyl-1H-pyrazole-4-yl)piperidine-4-carboxylate instead of 4-(2-fluorophenyl)piperidine-4-carboxylate. 15 H 18 ClN5O2 required value 335.1, measured value m / z = 336.2 [M+H] + .

[0179] Step 4: Synthesis of methyl 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(1-methyl-1H-pyrazole-4-yl)piperidine-4-carboxylate [ka] This intermediate was synthesized as described in step 4 of intermediate 9, using methyl 1-(6-chloropyridazin-4-yl)-4-(1-methyl-1H-pyrazole-4-yl)piperidine-4-carboxylate instead of methyl 1-(6-chloropyridazin-4-yl)-4-(2-fluorophenyl)piperidine-4-carboxylate (41 g over 4 steps, 44% yield). LCMS C 21 H 23 N5O3 requirement value 393.2, measured value m / z = 394.2 [M+H] + .

[0180] After basic hydrolysis, the title compound was obtained (2.2 g, 79% yield). LCMS C 20 H 21 N5O3 requirement value 379.2, measured value 380.2 [M+H] + .

[0181] Intermediate 13 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(3-methylisoxazole-5-yl)piperidine-4-carboxylic acid [ka] Step 1: Synthesis of 1-(tert-butyl)4-methyl-4-(3-methylisoxazole-5-yl)piperidine-1,4-dicarboxylate [ka] This intermediate was prepared as described in step 1 of intermediate 9, using methyl 2-(3-methylisoxazole-5-yl)acetate instead of methyl 2-(2-fluorophenyl)acetate (57.8 g). LCMS C 16 H 24 N2O5 requirement value 324.2, measured value m / z = 325.2 [M+H] + .

[0182] Step 2: Synthesis of methyl 4-(3-methylisoxazole-5-yl)piperidine-4-carboxylate [ka] This intermediate was synthesized as described in step 2 of intermediate 9 (49.7 g), using 1-(tert-butyl)4-methyl-4-(3-methylisoxazole-5-yl)piperidine-1,4-dicarboxylate instead of 1-(tert-butyl)4-methyl-4-(2-fluorophenyl)piperidine-1,4-dicarboxylate. LCMS C 11 H 16 N2O3 requirement value 224.1, measured value m / z = 225.1 [M+H] + .

[0183] Step 3: Synthesis of methyl 1-(6-chloropyridazine-4-yl)-4-(3-methylisoxazole-5-yl)piperidine-4-carboxylate [ka] This intermediate was synthesized as described in step 3 of intermediate 9 (5.1 g), using methyl 4-(3-methylisoxazol-5-yl)piperidine-4-carboxylate instead of methyl 4-(2-fluorophenyl)piperidine-4-carboxylate. LCMS C 15 H 17 ClN4O3 required value 336.1, measured value m / z = 337.1 [M+H] + .

[0184] Step 4: Synthesis of methyl 1-(6-(2-methoxyphenyl)pyridazin-4-yl)-4-(3-methylisoxazole-5-yl)piperidine-4-carboxylate [ka] This intermediate was synthesized as described in step 7 of intermediate 10, using methyl 1-(6-chloropyridazin-4-yl)-4-(3-methylisoxazole-5-yl)piperidine-4-carboxylate instead of 1-(6-chloropyridazin-4-yl)-4-(5-isopropylisoxazole-3-yl)piperidine-4-carbonate and (2-hydroxyphenyl)boronic acid instead of (2-methoxyphenyl)boronic acid (1.90 g over 4 steps, 36% yield). LCMS C 22 H 24 N4O4 requirement value 408.2, measured value m / z = 409.1 [M+H] + .

[0185] Step 5: Synthesis of methyl 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(3-methylisoxazole-5-yl)piperidine-4-carboxylate [ka] To a solution of methyl 1-(6-(2-methoxyphenyl)pyridazin-4-yl)-4-(3-methylisoxazole-5-yl)piperidine-4-carboxylate (1.60 g, 3.79 mmol) in DCM (50 mL), BBr3 (2 M, 3.79 mL) was added at 0°C. The reaction mixture was then heated to 25°C and stirred until completion was determined by LC-MS. Once complete, the reaction mixture was quenched by adding HCl solution (1 N, 5.0 mL). The resulting mixture was extracted with siRNA (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude pale yellow solid, which was then carried forward without any further purification (3.80 g). LC-MS C 21 H 22 N4O4 requirement value 394.2, measured value m / z = 395.2 [M+H] + .

[0186] After basic hydrolysis, the title compound was obtained (444 mg, 31% yield). LCMS C 20 H 20N4O4 requirement value 380.2, measured value m / z = 381.1 [M+H] + .

[0187] Intermediate 14 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(5-methyl-1H-pyrazole-1-yl)piperidine-4-carboxylic acid [ka] Step 1: Synthesis of di-tert-butyl 1-(1-benzyl-4-(ethoxycarbonyl)piperidine-4-yl)hydrazine-1,2-dicarboxylate [ka] To a solution of LDA (2M in THF, 44.4 mL) in THF (120 mL), ethyl 1-benzylpiperidine-4-carboxylate (20.0 g, 80.8 mmol) was added dropwise at -70°C, and the mixture was stirred at -70°C for 0.5 hours. Next, a solution of di-tert-butyl(E)-diazene-1,2-dicarboxylate (19.5 g, 84.9 mmol) in THF (40.0 mL) was added to the mixture at -70°C. The mixture was warmed to 25°C and stirred until complete was determined by LC-MS. 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 obtain the crude residue. The crude product was purified by flash column chromatography (petroleum ether in ¼ - 10% to 50%) to obtain the title compound as a yellow solid (15.0 g, 39% yield). LCMS C 15 H 21 NO2 requirement value 477.3, measured value m / z = 478.4 [M+H] + .

[0188] Step 2: Synthesis of ethyl 1-benzyl-4-hydrazinylpiperidine-4-carboxylate [ka] This intermediate was synthesized as described in step 2 of intermediate 9, using di-tert-butyl 1-(1-benzyl-4-(ethoxycarbonyl)piperidine-4-yl)hydrazine-1,2-dicarboxylate instead of 1-(tert-butyl)4-methyl4-(2-fluorophenyl)piperidine-1,4-dicarboxylate (12.0 g, bis-HCl salt). LCMS C 15 H 23 N3O2 requirement value 277.2, measured value m / z = 278.5 [M+H] + .

[0189] Step 3: Synthesis of ethyl 1-benzyl-4-(5-methyl-1H-pyrazole-1-yl)piperidine-4-carboxylate [ka] A solution of 4,4-dimethoxybutan-2-one (1.60 mL, 12.0 mmol) in AcOH (75.0 mL) was stirred at 120°C for 1 hour. The mixture was cooled to 60°C, and ethyl 1-benzyl-4-hydrazinepiperidine-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 completeness was determined by LC-MS. Once complete, the reaction mixture was adjusted to pH 10 with Na2CO3 solution and then extracted with siRNA (60.0 mL × 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the crude product as a black / brown oil, which was proceeded to without any further purification (4.0 g). LC-MS C 19 H 25 N3O2 requirement value 327.2, measured value m / z = 328.4 [M=H] + .

[0190] Step 4: Synthesis of ethyl 4-(5-methyl-1H-pyrazole-1-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-benzyl-4-(5-methyl-1H-pyrazole-1-yl)piperidine-4-carboxylate (5.13 g, 15.6 mmol) in EtOH (40.0 mL), Pd / C (516 mg, 485 μmol, 10% purity) was added under an N2 atmosphere. The suspension was degassed and packed three times with H2. The mixture was packed with H2 (50 psi) and stirred at 25°C until completion was determined by LC-MS. Once complete, the reaction mixture was filtered through Celite, washed with EtOH, and the resulting filtrate was concentrated under vacuum to obtain a colorless oil, which was then proceeded to with any further purification (3.4 g). LC-MS C 12 H 19 N3O2 requirement value 237.2, measured value 238.5 [M+H] + .

[0191] Step 5: Synthesis of ethyl 1-(6-chloropyridazine-4-yl)-4-(5-methyl-1H-pyrazole-1-yl)piperidine-4-carboxylate [ka] This intermediate was synthesized as in step 3 of intermediate 9 (2.9 g), using ethyl 4-(5-methyl-1H-pyrazole-1-yl)piperidine-4-carboxylate instead of methyl 4-(2-fluorophenyl)piperidine-4-carboxylate. LCMS C 16 H 20 ClN5O2 required value 349.1, measured value m / z = 350.3 [M+H] + .

[0192] Step 6: Synthesis of ethyl 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(5-methyl-1H-pyrazole-1-yl)piperidine-4-carboxylate [ka] This intermediate was synthesized as described in step 7 of intermediate 10 (3.0 g), using ethyl 1-(6-chloropyridazin-4-yl)-4-(5-methyl-1H-pyrazole-1-yl)piperidine-4-carboxylate instead of 1-(6-chloropyridazin-4-yl)-4-(5-isopropylisoxazole-3-yl)piperidine-4-carbonitrate. LCMS C 22 H 25 N5O3 requirement value 407.2, measured value m / z = 408.3 [M+H] + .

[0193] Following step 8 of intermediate 10, the title compound was obtained (1.14 g over 6 steps, 10% yield). LCMS C 20 H 21 N5O3 requirement value 379.2, measured value 380.3 [M+H] + .

[0194] Intermediate 15 Synthesis of 2-(5-(4-(aminomethyl)-4-phenylpiperidine-1-yl)pyridazine-3-yl)phenol [ka] Step 1: Synthesis of tert-butyl((1-(6-chloropyridazine-4-yl)-4-phenylpiperidine-4-yl)methyl)carbamate [ka] This intermediate was synthesized as described in step 3 of intermediate 9, using tert-butyl((4-phenylpiperidine-4-yl)methyl)carbamate instead of methyl 4-(2-fluorophenyl)piperidine-4-carboxylate. LCMS C 21 H 27 ClN4O2 requirement value 402.2, measured value 403.2 [M+H] + .

[0195] Step 2: Synthesis of tert-butyl((1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-phenylpiperidine-4-yl)methyl)carbamate [ka] This intermediate was synthesized as described in step 4 of intermediate 9, using tert-butyl((1-(6-chloropyridazin-4-yl)-4-phenylpiperidine-4-yl)methyl)carbamate instead of methyl 1-(6-chloropyridazin-4-yl)-4-(2-fluorophenyl)piperidine-4-carboxylate, to obtain the title compound as a yellow solid (1.13 g over two steps, 49% yield). LCMS C 27 H 32 N4O3 requirement value 460.3, measured value 461.3 [M+H] + .

[0196] The title compound was obtained after basic hydrolysis. LCMS C 22 H 24 N4O requirement value 360.2, measured value m / z = 361.2 [M+H] + .

[0197] Intermediate 16 Methyl 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-(2-methylphenoxy)piperidine-4-carboxylate [ka] Step 1: Synthesis of 1-[(tert-butoxy)carbonyl]-4-(2-methylphenoxy)piperidine-4-carboxylic acid [ka] o-cresol (2.500 g, 23.11 mmol, 1.0 equivalent) was dissolved in anhydrous THF (116 ml, 0.2 M). Powdered NaOH (4.624 g, 115.591 mmol, 5.0 equivalents) and 1-Boc-piperidine-4-one (13.819 g, 69.35 mmol, 3.0 equivalents) were added to the solution at 0°C. Chloroform (9.26 ml, 115.591 mmol, 5.0 equivalents) was added dropwise, and the reaction mixture was stirred at 0°C for 1 hour, followed by 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 over MgSO4, filtered, and the solvent was evaporated to obtain 1-[(tert-butoxy)carbonyl]-4-(2-methylphenoxy)piperidine-4-carboxylic acid (0.612 g, 1.825 mmol, 8%) as a yellow solid. 1 H NMR (DMSO-d6):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).

[0198] Step 2: Synthesis of methyl 4-(2-methylphenoxy)piperidine-4-carboxylate hydrochloride [ka] Thionyl chloride (0.293 ml, 4.014 mmol, 2.2 equivalents) 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 equivalent) in anhydrous methanol (6.08 ml, 0.3 M). The resulting solution was stirred overnight under reflux. It was then cooled to RT and dried to evaporate volatile substances. The residue was ground with diethyl ether, filtered, washed with diethyl ether, recovered, and dried under reduced pressure to obtain methyl 4-(2-methylphenoxy)piperidine-4-carboxylate hydrochloride (0.494 g, 1.711 mmol, 94%) as a brown solid. 1 H NMR (DMSO-d6):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).

[0199] Step 3: Synthesis of methyl 1-(6-chloropyridazine-4-yl)-4-(2-methylphenoxy)piperidine-4-carboxylate [ka] A mixture of 3,5-dichloropyridazine (0.255 g, 1.711 mmol, 1.0 equivalent), methyl 4-(2-methylphenoxy)piperidine-4-carboxylate hydrochloride (0.494 g, 1.711 mmol, 1.0 equivalent), and N,N-diisopropylethylamine (0.894 ml, 5.134 mmol, 3.0 equivalent) in anhydrous NMP (3.42 ml, 0.5 M) was stirred at 100°C for 1 hour under an argon atmosphere in a sealed vial. The reaction mixture was poured into cold water with vigorous stirring, the formed precipitate was filtered, washed with water, collected, and dried under reduced pressure to obtain methyl 1-(6-chloropyridazin-4-yl)-4-(2-methylphenoxy)piperidine-4-carboxylate (0.47 g, 1.234 mmol, 72%) as an off-white solid. 1 H NMR (DMSO-d6):8.99 (d, J = 2.7 Hz, 1H), 7.21 (d, J = 7.3 Hz, 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, 3.4 Hz, 2H), 2.24 (s, 3H), 2.21 -2.05 (m, 4H).

[0200] Step 4: Synthesis of methyl 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-(2-methylphenoxy)piperidine-4-carboxylate [ka] Methyl 1-(6-chloropyridazin-4-yl)-4-(2-methylphenoxy)piperidine-4-carboxylate (0.47 g, 1.234 mmol, 1.0 equivalent) was placed in a pressure vessel containing K2CO3 (0.512 g, 3.70 mmol, 3.0 equivalents), 2-hydroxyphenylboronic acid (0.255 g, 1.851 mmol, 1.5 equivalents), and Pd(PPh3)4 (0.143 g, 0.1234 mmol, 0.1 equivalent), followed by the addition of dioxane (6.17 ml, 0.2 ml) and water (1.23 ml, 1.0 M). The mixture was bubbling with argon for 15 minutes. The reaction mixture was then stirred overnight at 100°C. After cooling to RT, Celite was added, and the mixture was evaporated under reduced pressure to provide a drying load for FC purification on silica gel (DCM-AcOEt 100:0~30:70), yielding methyl 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-(2-methylphenoxy)piperidine-4-carboxylate (0.292 g, 0.696 mmol, 56%) as an off-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).

[0201] After basic hydrolysis, the title compound was obtained as a white solid (0.185 g, 0.443 mmol, 62%). 1H NMR (DMSO-d6):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).

[0202] Intermediate 17 1-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-4-phenylpiperidine-4-carboxylic acid [ka] Step 1: Synthesis of methyl 4-phenylpiperidine-4-carboxylate hydrochloride [ka] Thionyl chloride (5.402 ml, 74.466 mmol, 1.8 equivalents) was carefully added at 0°C to a stirred solution of 4-phenylpiperidine-4-carboxylic acid hydrochloride (10.0 g, 41.37 mmol, 1.0 equivalent) in anhydrous methanol (51.71 ml, 0.8 M). The resulting solution was stirred overnight under reflux. It was then cooled to RT to evaporate volatile substances. The resulting solid was ground with MTBE and filtered. The solid was recovered and dried under reduced pressure to obtain 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 for + : 220.13, Measured value: 220.65. 1H NMR (300 MHz, DMSO-d6) 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).

[0203] Step 2: Synthesis of methyl 1-(6-chloropyridazine-4-yl)-4-phenylpiperidine-4-carboxylate [ka] A 500 mL pressure vial equipped with a magnetic stirrer was filled with 3,5-dichloropyridazine (4.648 g, 31.203 mmol, 1.2 equivalents) and methyl 4-phenylpiperidine-4-carboxylate hydrochloride (7.0 g, 26.003 mmol, 1.0 equivalent). Dimethyl sulfoxide (52.01 ml, 0.5 M) and N,N-diisopropylethylamine (DIPEA) (27.176 ml, 156.018 mmol, 6.0 equivalents) were added. The reaction mixture was stirred overnight at 100°C. DIPEA was evaporated, the compound precipitated in water, followed by sonication, filtration, and drying to obtain methyl 1-(6-chloropyridazine-4-yl)-4-phenylpiperidine-4-carboxylate (8.5 g, 23.056 mmol, 89%) as a brown solid. LCMS(m / z):C 17 H 19 ClN3O2 + [M+H] calculated for + :332.12, measured value:333.40. 1H NMR (300 MHz, DMSO-d6) 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).

[0204] Step 3: Synthesis of methyl 1-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-4-phenylpiperidine-4-carboxylate [ka] A flame-dried 500 mL pressure vial equipped with a magnetic stirrer and an argon balloon was filled with 2-(methoxymethoxy)phenylboronic acid (1.54 g, 8.463 mmol, 1.2 equivalents) and methyl 1-(6-chloropyridazin-4-yl)-4-phenylpiperidine-4-carboxylate (2.6 g, 7.052 mmol, 1.0 equivalent). Dioxane (70.52 ml, 0.1 M) and a solution of potassium carbonate (2.924 g, 21.157 mmol, 3.0 equivalents) in water (14.1 ml, 0.5 M) were added. The mixture was bubbling with argon for 20 minutes, and then tetrakis(triphenylphosphine)palladium (0.815 g, 0.705 mmol, 0.1 equivalent) was added. After purging the reaction vial with argon, the cap was closed and the reaction mixture was stirred at 100°C for 7 hours. The compound was purified by FC using MTBE / DCM (0-70%) to obtain methyl 1-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-4-phenylpiperidine-4-carboxylate (2.56 g, 5.787 mmol, 82%) as a yellow solid. LCMS (m / z):C 25 H 28 ClN3O4 + [M+H] calculated for + : 434.21, measured value: 434.90. 1H NMR (300 MHz, DMSO-d6) 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).

[0205] After basic hydrolysis, the title compound was obtained as an off-white solid (2.3 g, 5.318 mmol, 92%). LC-MS (m / z):C 24 H 26 N3O4 + [M+H] calculated for + : 420.19, measured value: 420.22. 1 H NMR (300 MHz, DMSO-d6) 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 = 12.1 Hz, 2H), 1.97 -1.82 (m, 2H).

[0206] Intermediate 20 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenoxypiperidine-4-carboxylic acid [ka] Step 1: Synthesis of 1-[(tert-butoxy)carbonyl]-4-phenoxypiperidine-4-carboxylic acid [ka] 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-piperidine-4-one (9.53 g, 47.82 mmol) were added, followed by dropwise addition of chloroform (6.38 ml, 79.69 mmol). The resulting mixture was stirred at 0°C for 1 hour, followed by stirring at room temperature overnight. Upon completion, 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 extract from the acidic washes was dried over magnesium sulfate, filtered, and evaporated. The crude product was obtained as yellow oil (2.11 g, 37%). LCMS:C 17 H 23 NO5 required value: 321.3, measured value: m / z = 322.1 [M+H] + .

[0207] 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).

[0208] Step 2: Synthesis of 4-phenoxypiperidine-4-carboxylic acid hydrochloride [ka] 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 a solution of 4 M HCl in dioxane (73.69 mL, 294.7 mmol) was added. The resulting solution was stirred at room temperature for 72 hours. After completion, the solvent was removed under reduced pressure to obtain 4-phenoxypiperidine-4-carboxylic acid hydrochloride (1.59 g, 92%) as a yellowish-brown solid. LCMS:C 12 H 15 NO3 required value 221.7, measured value: m / z = 222.1 [M + H] + .

[0209] 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).

[0210] Step 3: Synthesis of 1-(6-chloropyridazine-4-yl)-4-phenoxypiperidine-4-carboxylic acid [ka] 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 hydrochloride (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 hours. After completion, the reaction was quenched with citric acid to pH=approximately 5 and extracted three times with dichloromethane. The organic phase was dried on magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (DCM / MeOH, 100:0~90:10) to obtain 1-(6-chloropyridazine-4-yl)-4-phenoxypiperidine-4-carboxylic acid (824 mg, 48%) as a yellowish-brown powder. LCMS:C 16 H 16 ClN3O3 required value 333.7, measured value: m / z = 333.8[M+H]+.

[0211] 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).

[0212] Step 4: Synthesis of 1-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-4-phenoxypiperidine-4-carboxylic acid [ka] 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 over time, and the resulting solution was degassed with 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 resulting residue was purified by flash chromatography (DCM / MeOH, 98:02~85:15) to obtain 1-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-4phenoxypiperidine-4-carboxylic acid (503 mg, 54%). LCMS:C 24 H 25 N3O5 requirement value: 435.4, measured value: m / z = 436.5 [M + H] + .

[0213] 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).

[0214] Step 5: Synthesis of 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. After completion, the solvent was removed under reduced pressure, and the residue was purified via RP-FC to obtain the title compound (120 mg, 29%) as trifluoroacetate.

[0215] 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).

[0216] Intermediate 21 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-[(1-methyl-1H-pyrazole-3-yl)oxy]piperidine-4-carboxylic acid [ka] Step 1: Synthesis of 1-[(tert-butoxy)carbonyl]-4-[(1-methyl-1H-pyrazole-3-yl)oxy]piperidine-4-carboxylic acid [ka] 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-piperidine-4-one (18.279 g, 91.738 mmol, 3.0 equivalents) were added over time. Anhydrous chloroform (12.249 ml, 152.897 mmol, 5.0 equivalents) 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 extract from the acidic washes was dried over magnesium sulfate, filtered, and evaporated. The crude product was obtained as a yellow oil (3.60 g, 36%). LCMS:C 15 H 23 N3O5 requirement value: 325.1, measured value: m / z = 326.4 [M + H] + .

[0217] 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).

[0218] Step 2: Synthesis of methyl 4-[(1-methyl-1H-pyrazole-3-yl)oxy]piperidine-4-carboxylate hydrochloride [ka] A solution of 1-[(tert-butoxy)carbonyl]-4-[(1-methyl-1H-pyrazole-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 overnight under reflux. After completion, the reaction mixture was cooled to room temperature, and volatile substances were evaporated. The resulting solid was ground with MTBE and filtered. The solid was collected and dried under reduced pressure to obtain methyl 4-[(1-methyl-1H-pyrazole-3-yl)oxy]piperidine-4-carboxylate hydrochloride (2.88 g, 94%). LCMS:C 11 H 17 N3O3 requirement value 239.1, measured value: m / z = 240.2 [M + H] +.

[0219] 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).

[0220] Step 3: Synthesis of methyl 1-(6-chloropyridazine-4-yl)-4-[(1-methyl-1H-pyrazole-3-yl)oxy]piperidine-4-carboxylate [ka] To a stirred solution of methyl 4-[(1-methyl-1H-pyrazole-3-yl)oxy]piperidine-4-carboxylate hydrochloride (2.88 g, 10.44 mmol) in DMSO (52.23 ml, 0.2 M), N,N-diisopropylethylamine (10.9 ml, 62.67 mmol) was added, followed by 3,5-dichloropyridazine (1.71 g, 11.49 mmol). The reaction mixture was stirred overnight at 100°C. After completion, excess DIPEA was removed under reduced pressure. Cold water was added to the solution, and the mixture was sonicated for 15 minutes. The resulting solid was filtered to obtain methyl 1-(6-chloropyridazine-4-yl)-4-[(1-methyl-1H-pyrazole-3-yl)oxy]piperidine-4-carboxylate (3.63 g, 10.319 mmol). LCMS:C 15 H 18 ClN5O3 required value 351.1, measured value: m / z = 352.3 [M + H] +.

[0221] 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).

[0222] Step 4: Synthesis of methyl 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-[(1-methyl-1H-pyrazole-3-yl)oxy]piperidine-4-carboxylate [ka] Methyl 1-(6-chloropyridazine-4-yl)-4-[(1-methyl-1H-pyrazole-3-yl)oxy]piperidine-4-carboxylate (2.0 g, 5.685 mmol, 1.0 equivalent), K2CO3 (2.357 g, 17.056 mmol, 3.0 equivalents), and 2-hydroxyphenylboronic acid (0.863 g, 6.254 mmol, 1.1 equivalents) 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 over time, and the resulting solution was degassed with an argon balloon for 15 minutes. Then, tetrakis(triphenylphosphine)palladium (0.657 g, 0.569 mmol, 0.1 equivalents) was added to the mixture, and the resulting solution was stirred at 100°C for 16 hours. Upon completion, the solvent was evaporated, and the crude mixture was purified by flash chromatography (DCM / MeOH, 98:02~85:15) to obtain methyl 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-[(1-methyl-1H-pyrazole-3-yl)oxy]piperidine-4-carboxylate (1.1 g, 42%) as a yellow solid. LCMS:C 21 H 23 N5O4 requirement value: 409.4, measured value: m / z = 410.4 [M + H] + .

[0223] 1H NMR (300 MHz, DMSO-d6) 1H NMR δ 14.57 (s, 1H), 8.98 (d, J = 2.8 Hz, 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).

[0224] After basic hydrolysis, the title compound was obtained as an off-white solid (0.116 g, 12%). LC-MS:C 20 H 21 N5O4 requirement value 395.4, measured value: m / z = 396.2 [M + H] + .

[0225] 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 = 2.3 Hz, 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).

[0226] Intermediate 22 4-Cyclopropoxy-1-[6-(2-hydroxyphenyl)pyridazin-4-yl]piperidine-4-carboxylic acid [ka] Step 1: Synthesis of benzyl 4-cyclopropoxy-4-(hydroxymethyl)piperidine-1-carboxylate [ka] A flask was packed with benzyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (5.41 g, 21.86 mmol) and cyclopropanol (28.14 g, 484 mmol) under an argon atmosphere. The mixture was cooled to 15°C using an ice bath. Then, while maintaining the bath temperature at 15°C, trifluoride diethyl ether (6.887 g, 48.53 mmol) was added dropwise. After the addition was complete, the flask was removed from the cooling bath and stirred for 1 hour. DCM was added, followed by slow addition of water. The contents were transferred to a separation 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 resulting residue was purified via an RP-FC column to obtain benzyl 4-cyclopropoxy-4-(hydroxymethyl)piperidine-1-carboxylate (3.07%, 46%) as a colorless oil. LCMS:C 17 H 23 NO4 required value 305.3, measured value: m / z = 306.6 [M + H] +.

[0227] 1 H NMR (300 MHz, DMSO-d6) 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).

[0228] Step 2: Synthesis of benzyl 4-cyclopropoxy-4-formylpiperidine-1-carboxylate [ka] Dess-Martin periodinane, 95% (5.543 g, 13.069 mmol) was added to a stirred solution of benzyl 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 hours. After completion, DCM (50 mL) and water (50 M) were added, followed by saturated aqueous solution Na2S2O3 (50 ml), and the mixture was stirred for 15 minutes. The contents were transferred to a separation funnel, and the layers were separated. The aqueous layer was washed twice with DCM, the combined organic layers were washed with brine, collected, dried over Na2SO4, filtered, and concentrated under vacuum to obtain benzyl 4-cyclopropoxy-4-formylpiperidine-1-carboxylate (2.73 g, 81%) as a colorless oil. LCMS:C 17 H 21 NO4 required value 303.3, measured value: m / z = 304.2 [M + H] +.

[0229] 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).

[0230] Step 3: Synthesis of 1-[(benzyloxy)carbonyl]-4-cyclopropoxypiperidine-4-carboxylic acid [ka] A flask was packed with benzyl 4-cyclopropoxy-4-formylpiperidine-1-carboxylate (2.73 g, 8.09 mmol) and monobasic potassium phosphate (3.30 g, 24.29 mmol). Then, T-butanol (80.99 mL), water (20.25 mL), and 2-methyl-2-butene (10.297 mL, 97.19 mmol) were added over time. Sodium chlorite (2.75 g, 24.29 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After completion by LC-MS, 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 separation funnel, and the layers were separated. The aqueous layer was then acidified to approximately 2 pH with 1 M HCl and extracted three times with ELISA. The combined organic layers were dried over Na2SO4, filtered, and evaporated to obtain 1-[(benzyloxy)carbonyl]-4-cyclopropoxypiperidine-4-carboxylic acid (1.76 g, 65% yield) as a colorless oil. LCMS:C 17 H 21 NO5 required value 318.3, measured value: m / z = 319.3 [M + H] + .

[0231] 1 H NMR (300 MHz, DMSO-d6) 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).

[0232] Step 4: 1-Benzyl 4-methyl-4-cyclopropoxypiperidine-1,4-dicarboxylate [ka] (Trimethylsilyl)diazomethane (2M in hexane) (17.02 ml, 34.03 mmol) was added dropwise to a chilled (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 was continued until a pale yellow color remained in the solution. The mixture was then removed from the cooling bath and the reaction was stirred at room temperature for 1 hour. Upon completion, 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, 100:0~75:25) to obtain 1-benzyl 4-methyl-4-cyclopropoxypiperidine-1,4-dicarboxylate (1.39 g, 79%) as a colorless oil. LCMS:C 18 H 23 NO5 required value 333.3, measured value: m / z = 334.2 [M + H] + .

[0233] 1 H NMR (300 MHz, DMSO-d6) 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).

[0234] Step 5: Synthesis of methyl 4-cyclopropoxypiperidine-4-carboxylate [ka] 1-Benzyl-4-methyl-4-cyclopropoxypiperidine-1,4-dicarboxylate (1.29 g, 3.90 mmol) was dissolved in THF (37 ml, 0.02 M) in a 250 ml three-necked RBF equipped with argon and hydrogen balloons. The reaction mixture was degassed with argon, Pd / C (10 wt%, 0.62 g, 5.8 mmol) was added again, followed by degassing with argon and filling with hydrogen. The reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered through a Celite pad and evaporated to dry, yielding methyl 4-cyclopropoxypiperidine-4-carboxylate (0.78 g, 96%) as a gray solid.

[0235] 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).

[0236] Step 6: Synthesis of methyl 1-(6-chloropyridazine-4-yl)-4-cyclopropoxypiperidine-4-carboxylate [ka] A mixture of 3,5-dichloropyridazine (0.55 g, 3.72 mmol), methyl 4-cyclopropoxypiperidine-4-carboxylate (0.78 g, 3.72 mmol), and N,N-diisopropylethylamine (1.9 ml, 11.16 mmol) in N-methyl-2-pyrrolidone (7.44 ml, 0.5 M) was stirred in a sealed vial under an argon atmosphere at 100°C for 1 hour. Upon completion, the reaction was quenched with cold water and extracted three times with ethyl acetate. The combined organic extract was dried over Na2SO4, filtered, and concentrated under vacuum to obtain 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 ClN3O3 required value 311.7, measured value: m / z = 313.0 [M + H] +.

[0237] 1 H NMR (300 MHz, DMSO-d6) δ 8.97 (d, J = 2.7 Hz, 1H), 7.11 (d, J = 2.7 Hz, 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).

[0238] Step 7: Synthesis of methyl 4-cyclopropoxy-1-[6-(2-hydroxyphenyl)pyridazin-4-yl]piperidine-4-carboxylate [ka] Methyl-1-(6-chloropyridazin-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 minutes. Tetrakis(triphenylphosphine)palladium (0.415 g, 0.359 mmol, 0.1 equivalent) was added to the reaction mixture, and the solution was stirred at 100°C for 18 hours. Upon completion, the reaction mixture was concentrated under vacuum, and the resulting residue was purified by chromatography (hexane / siRNA, 0-100%) to obtain methyl 4-cyclopropoxy-1-[6-(2-hydroxyphenyl)pyridazin-4-yl]piperidine-4-carboxylate (0.58 g, 44% yield) as a yellow solid. LCMS:C 20 H 23 N3O4 requirement value: 369.4, measured value: m / z = 370.7 [M+H]+.

[0239] 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).

[0240] After basic hydrolysis, the title compound was obtained as an off-white solid (468.4 mg, 82%). LC-MS:C 19 H 21 N3O4 requirement value 355.3, measured value: m / z = 356.3 [M + H] + .

[0241] 1 H 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).

[0242] Intermediate 23 4-(cyclohexyloxy)-1-[6-(2-hydroxyphenyl)pyridazin-4-yl]piperidine-4-carboxylic acid [ka] Step 1: Synthesis of benzyl 4-(cyclohexyloxy)-4-(hydroxymethyl)piperidine-1-carboxylate [ka] A solution of benzyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (6.0 g, 24.26 mmol) in cyclohexanol (50.523 ml, 485.25 mmol, 20.0 equivalents) was cooled to +15°C, and then boron trifluoride diethyl etherate (6.88 g, 48.525 mmol, 2.0 equivalents) was added dropwise. After the addition was complete, the solution was removed from the cooling bath and stirred for 1 hour. DCM was added, followed by slow addition of water. The contents were transferred to a separation 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 obtained residue was purified using an RP-FC column (330g column, 80mL flow rate, water / MeCN + 0.1% FA, gradient 95:5~35:65) to obtain benzyl 4-(cyclohexyloxy)-4-(hydroxymethyl)piperidine-1-carboxylate (3.68g, 44%) as a colorless oil. LCMS:C 20 H 29 NO4 required value 347.2, measured value: m / z = 349.0 [M+H]+.

[0243] 1 H 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).

[0244] Step 2: Synthesis of benzyl 4-(cyclohexyloxy)-4-formylpiperidine-1-carboxylate [ka] Dess-Martin periodinane, 95% (5.84 g, 13.76 mmol) was added to a stirred solution of benzyl 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 hours. After completion, DCM (50 mL) and water (50 M) were added, followed by saturated aqueous solution Na2S2O3 (50 ml), and the mixture was stirred for 15 minutes. The contents were transferred to a separation funnel, and the layers were separated. The aqueous layer was washed twice with DCM, the combined organic layers were washed with brine, collected, dried over Na2SO4, filtered, and concentrated under vacuum to obtain benzyl 4-(cyclohexyloxy)-4-formylpiperidine-1-carboxylate (3.65 g, 100%) as a colorless oil. LCMS:C 20 H 27 NO4 required value 345.1, measured value: m / z = 346.2 [M + H] + .

[0245] 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).

[0246] Step 3: Synthesis of 1-[(benzyloxy)carbonyl]-4-(cyclohexyloxy)piperidine-4-carboxylic acid [ka] A flask was packed with benzyl 4-(cyclohexyloxy)-4-formylpiperidine-1-carboxylate (3.65 g, 10.56 mmol) and monobasic potassium phosphate (4.31 g, 31.69 mmol). Then, T-butanol (106 mL), water (26 mL), and 2-methyl-2-butene (13.43 mL, 126.8 mmol) were added over time. Sodium chlorite (3.58 g, 31.69 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After completion by LC-MS, 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 separation funnel, and the layers were separated. The aqueous layer was then acidified to approximately 2 pH with 1 M HCl and extracted three times with ELISA. 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% t-butanol. LCMS:C 20 H 27 NO5 required value 361.0, measured value: m / z = 362.2 [M + H] + .

[0247] 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).

[0248] Step 4: Synthesis of 1-benzyl 4-methyl 4-(cyclohexyloxy)piperidine-1,4-dicarboxylate [ka] (Trimethylsilyl)diazomethane (2M in hexane) (5.95 ml, 11.91 mmol) was added dropwise to a chilled (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). The addition was continued until a pale yellow color remained in the solution. The mixture was then removed from the cooling bath and the reaction was stirred at room temperature for 1 hour. 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, 100:0~75:25) to obtain 1-benzyl 4-methyl 4-(cyclohexyloxy)piperidine-1,4-dicarboxylate (0.64 g, 93%) as a colorless oil.

[0249] 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 = 4.5 Hz, 4H), 1.76 -1.59 (m, 4H), 1.45 (d, J = 10.7 Hz, 1H), 1.31 -1.10 (m, 5H).

[0250] Step 5: Synthesis of methyl 4-(cyclohexyloxy)piperidine-4-carboxylate [ka] 1-Benzyl 4-methyl 4-(cyclohexyloxy)piperidine-1,4-dicarboxylate (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, Pd / C (10 wt%, 0.18 g, 0.17 mmol) was added again, followed by degassing with argon and filling with hydrogen. The reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered through a Celite pad, evaporated and dried to obtain methyl 4-(cyclohexyloxy)piperidine-4-carboxylate (0.4 g, 92%) as a black solid.

[0251] 1 H 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).

[0252] Step 6: Synthesis of methyl 1-(6-chloropyridazine-4-yl)-4-(cyclohexyloxy)piperidine-4-carboxylate [ka] 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 (5.25 ml, 0.3 M) was stirred in a sealed vial under an argon atmosphere at 100°C for 1 hour. After completion, the reaction was quenched with cold water and extracted three times with ethyl acetate. The combined organic extract was dried over Na2SO4, filtered, and concentrated under vacuum to obtain 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 ClN3O3 requirement value 353.1, measured value: m / z = 354.2 [M + H] +.

[0253] 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, 4.2 Hz, 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).

[0254] Step 7: Synthesis of methyl 4-(cyclohexyloxy)-1-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}piperidine-4-carboxylate [ka] A sealed vial was filled under an argon atmosphere 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). The mixture was bubbling with argon for 20 minutes, the vial was sealed, and the mixture was stirred at 100°C for 16 hours. Upon completion, the solvent was evaporated, and the residue was purified by chromatography (siRNA / hexane, 0-100%) to obtain 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 N3O5 requirement value: 455.2, measured value: m / z = 456.9 [M + H] +.

[0255] 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).

[0256] Step 8: Synthesis of 4-(cyclohexyloxy)-1-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}piperidine-4-carboxylic acid [ka] Methyl 4-(cyclohexyloxy)-1-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}piperidine-4-carboxylate (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 equivalents) was added all at once. The reaction mixture was stirred at room temperature for 16 hours. After completion, the mixture was neutralized with 4 M HCl and evaporated under vacuum. The residue was purified using RP-FC (ACN / water) to obtain 4-(cyclohexyloxy)-1-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}piperidine-4-carboxylic acid (0.45 g, 87%) as a yellow solid.

[0257] LCMS:C 24 H 31 N3O5 requirement value: 441.2, measured value: m / z = 442.1 [M + H] + .

[0258] 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).

[0259] Title Compound Synthesis 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 all at once. The reaction mixture was stirred at room temperature for 16 hours. After completion, volatile substances were evaporated, and the residue was purified by RP-FC (ACN / water in 0.1% formic acid, 5% / 95%~75% / 25%) to obtain 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 N3O4 requirement value 397.2, measured value: m / z = 398.2[M+H]+.

[0260] 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, 1.6 Hz, 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).

[0261] Intermediate 24 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxypiperidine-4-carboxylic acid [ka] Step 1: Synthesis of methyl 1-(6-chloropyridazine-4-yl)-4-methoxypiperidine-4-carboxylate [ka] 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,N-diisopropylethylamine (2.49 ml, 14.31 mmol) in N-methyl-2-pyrrolidone (9.54 ml, 0.5 M) was stirred in a sealed vial under an argon atmosphere at 100°C for 1 hour. Upon completion, the reaction was quenched with cold water and then extracted three times with siRNA. The combined organic extract was dried over Na2SO4, filtered, and concentrated under vacuum to obtain 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 ClN3O3 required value 285.0, measured value: m / z = 287.1 [M + H] +.

[0262] 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).

[0263] Step 2: Synthesis of methyl 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxypiperidine-4-carboxylate [ka] 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 minutes, and tetrakis(triphenylphosphine)palladium (0.349 g, 0.302 mmol) was added all at once. The reaction mixture was stirred at 100°C for 18 hours. Upon completion, the solvent was evaporated, and the residue was purified by flash chromatography (hexane: siRNA, 0-100%) to obtain methyl 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxypiperidine-4-carboxylate (0.64 g, 54%) as a pale yellow solid. LCMS:C 18 H 21 N3O4 requirement value 343.1, measured value: m / z = 344.6 [M + H] + .

[0264] 1 H NMR (300 MHz, DMSO-d6) 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).

[0265] After basic hydrolysis, the title compound was obtained as a pale yellow solid (0.30 g, 55% yield). LC-MS:C 17 H 19 N3O4 requirement value 329.1, measured value: m / z = 330.1 [M + H] + .

[0266] 1H 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, 1.6 Hz, 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).

[0267] Intermediate 25 4-(2-chlorophenoxy)-1-[6-(2-hydroxyphenyl)pyridazin-4-yl]piperidine-4-carboxylic acid [ka] Step 1: 1-[(tert-butoxy)carbonyl]-4-(2-chlorophenoxy)piperidine-4-carboxylic acid [ka] o-chlorophenol (2 g, 15.556 mmol, 1.0 equivalent) 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 equivalents) and t-butyl 3-oxoazetidine-1-carboxylate (9.299 g, 46.670 mmol, 3.0 equivalents) were added to the solution at 0°C. Then, chloroform (6.23 mL, 77.78 mmol, 5.0 equivalents) was added dropwise over 15 minutes, and the reaction mixture was stirred at 0°C for 1 hour, 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) to obtain a yellow precipitate. The yellow precipitate was dissolved in toluene, and the aqueous layer was extracted three times with toluene. The organic phase was dried over MgSO4, filtered, and evaporated on a rotary evaporator to obtain 1-[(tert-butoxy)carbonyl]-4-(2-chlorophenoxy)piperidine-4-carboxylic acid as a yellow solid (5.1 g, 83%). LCMS(m / z):C 17 H 21 ClNO5 - [MH] calculated for - :354.11, measured 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). Step 2: Methyl 4-(2-chlorophenoxy)piperidine-4-carboxylate hydrochloride [ka]

[0268] Thionyl chloride (1.684 ml, 23.22 mmol, 1.8 equivalents) was carefully added to a stirred solution of 232800123-VVI01-024 (5.1 g, 12.9 mmol, 1.0 equivalent) in anhydrous methanol (16.12 ml, 0.8 M) at 0°C. The resulting solution was stirred overnight under reflux. It was then cooled to RT to evaporate the volatile substances. The resulting solid was ground with MTBE and filtered. The solid was recovered and dried under reduced pressure to obtain methyl 4-(2-chlorophenoxy)piperidine-4-carboxylate hydrochloride (4.0 g, 11.105 mmol, 86%) as an off-white solid. LCMS(m / z):C 13 H 17 ClNO3 + [M+H] calculated for + : 270.09, measured 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, 5.4Hz, 4H).

[0269] Step 3: Methyl 4-(2-chlorophenoxy)-1-(6-chloropyridazine-4-yl)piperidine-4-carboxylate [ka] A 150 mL pressure vial equipped with a magnetic stirrer was filled with 3,5-dichloropyridazine (0.993 g, 6.663 mmol, 1.2 equivalents) and methyl 4-(2-chlorophenoxy)piperidine-4-carboxylate hydrochloride (2.0 g, 5.552 mmol, 1.0 equivalent). Dimethyl sulfoxide (11.1 ml, 0.5 M) and N,N-diisopropylethylamine (DIPEA) (5.803 ml, 33.314 mmol, 6.0 equivalents) were added. The reaction mixture was stirred overnight at 100°C. UPLC showed complete conversion. DIPEA was evaporated on a rotary evaporator, water was added to obtain a precipitate, which was sonicated, and then the brown solid, which was DP-methyl 4-(2-chlorophenoxy)-1-(6-chloropyridazin-4-yl)piperidine-4-carboxylate (1.8 g, 3.814 mmol, 69%), was filtered. LCMS(m / z):C 17 H 18 Cl2N3O3 + [M+H] calculated for + :382.07, measured value:383.40. 1 H NMR (300 MHz, DMSO-d6) δ 8.98 (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).

[0270] Step 4: Methyl 4-(2-chlorophenoxy)-1-[6-(2-hydroxyphenyl)pyridazine-4-yl]piperidine-4-carboxylate [ka] In a pressurized vial, methyl 4-(2-chlorophenoxy)-1-(6-chloropyridazin-4-yl)piperidine-4-carboxylate (1.7 g, 3.602 mmol, 1.0 equivalent), 2-hydroxyphenylboronic acid (0.547 g, 3.963 mmol, 1.1 equivalent), anhydrous potassium carbonate (1.494 g, 10.807 mmol, 3.0 equivalent), 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 minutes, then tetrakis(triphenylphosphine)palladium (0.416 g, 0.36 mmol, 0.1 equivalent) was added, and the reaction mixture was stirred at 100°C for 10 hours. UPLC showed complete conversion. The crude mixture was purified by FC using eluate siRNA / Cyc (0-60%) to isolate methyl 4-(2-chlorophenoxy)-1-[6-(2-hydroxyphenyl)pyridazin-4-yl]piperidine-4-carboxylate (0.985 g, 2.15 mmol, 60%) as a yellow solid. LCMS (m / z):C 23 H 23 ClN3O4 + [M+H] calculated for + : 440.14, measured 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).

[0271] After basic hydrolysis, the title compound was obtained (0.425 g, 0.979 mmol, 46%). LC-MS (m / z):C 22H 21 ClN3O4 + [M+H] calculated for + : 426.12, measured value: 426.19. 1 H NMR (300 MHz, DMSO-d6) δ 14.02 (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).

[0272] Intermediate 26 Synthesis of 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenyl-N-(piperidine-4-yl)-N-propylpiperidine-4-carboxamide [ka] Step 1: tert-butyl 4-(N-propyl 1-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-4-phenylpiperidine-4-amide)piperidine-1-carboxylate [ka] A solution of 1-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-4-phenylpiperidine-4-carboxylic acid (Intermediate 11) (0.6 g, 1.044 mmol, 1.0 eq) in dimethylacetamide (3.93 mL, 0.266 M) was treated with 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). 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 flash chromatography eluting with hexanes:EtOAc (0 - 70%) then washing through with EtOAc:MeOH (9:1). The impure product obtained was purified by RP-FC to give 0.36 g (0.531 mmol, 51% yield) of the title compound. LCMS (m / z): C 37 H 49 Calculated [M+H] for + N5O5: 643.83, found: 644.84. 1H NMR (300 MHz, DMSO-d6) 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).

[0273] To a solution of tert-butyl 4-(N-propyl 1-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-4-phenylpiperidine-4-amide)piperidine-1-carboxylate (0.36 g, 0.531 mmol, 1.0 equivalent) in anhydrous DCM (2.12 ml, 0.25 M), TFA (1.42 ml, 18.592 mmol, 35.0 equivalents) was added. The reaction mixture was stirred at room temperature for 2 hours. UPLC showed complete conversion of the starting material to the desired product. The solvent was evaporated, and the resulting crude product was pulverized twice with diethyl ether. After drying, 0.391 g of the title compound was obtained (0.484 mmol, 91% yield). LCMS (m / z):C 30 H 37 [M+H] calculated for N5O2 + : 499.66, measured value: 500.71. 1H NMR (300 MHz, DMSO-d6) 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).

[0274] Intermediate 27 Synthesis of N-cyclopropyl-1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenyl-N-(piperidine-4-yl)piperidine-4-carboxamide [ka] The title compound was prepared in the same manner as the synthesis of 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenyl-N-(piperidine-4-yl)-N-propylpiperidine-4-carboxamide (intermediate 26) by substituting 1-Boc-4-propylaminopiperidine with 1-Boc-4-cyclopropylaminopiperidine. The title compound was obtained in 0.118 g (94% yield). LCMS(m / z):C 30 H 35The calculated [M+H]+ for N5O2 was 497.64, while the measured value was 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).

[0275] Intermediate 28 Synthesis of RAC-2-(1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-yl)acetaldehyde [ka] Step 1: Synthesis of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine [ka] 2,6-Bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (65.0 g, 155 mmol) and 1-bromo-4-iodobenzene (52.8 g, 186 mmol) in 1,4-dioxane (650 mL) and H2O (165 mL) were added to K2CO3 (43.0 g, 311 mmol) and Pd(dppf)Cl2 (11.4 g, 15.5 mmol) at 20 °C and purged three times with N2. The mixture was heated and stirred at 80 °C until judged complete by LCMS. When complete, the reaction mixture was cooled to room temperature, filtered through celite, and rinsed with EtOAc. The collected filtrate was extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, concentrated to give a crude residue. The crude residue was purified by flash column chromatography (petroleum ether in ethyl acetate = 0 - 100%) to give the desired product, which was then triturated at 25 °C for 15 minutes with petroleum ether in ethyl acetate (50:1, 500 mL) to give the desired compound as a white solid. (163 g, 80% yield). LCMS C 25 H 20 BrNO2 Calcd 447.1, Found m / z = 448.2 [M+H] + .

[0276] Step 2: Synthesis of ethyl 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-yl)acetate [Chemical formula] To a solution of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (67.0 g, 146 mmol) and ethyl 2-(piperidine-4-yl)acetate (37.6 g, 219 mmol) in 2-MeTHF (670 mL) and H2O (67 mL), DavePhos (11.5 g, 29.3 mmol), Cs2CO3 (143 g, 439 mmol), and Pd2(dba)3 (13.4 g, 14.6 mmol) were added and the mixture was purged with N2 (3x). The mixture was stirred at 100°C until complete 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, concentrated, and the crude residue was obtained. The residue was purified by flash column chromatography (petroleum ether in ethyl acetate = 0-100%) to obtain the purified product, which was then ground in MTBE (200 mL) at 20°C for 30 minutes to obtain the desired product as a pale yellow solid (76.3 g, 45% yield). LCMS C 34 H 36 N2O4 requirement value 536.3, measured value m / z = 537.4 [M+H] + .

[0277] Step 3: Synthesis of 2-(1-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)piperidine-4-yl)ethane-1-ol [ka] Flow procedure: Solution 1: Ethyl 2-(1-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)piperidine-4-yl) acetate (1.00 equivalent, 76.0 g in THF, 760 mL). Solution 2: LiAlH4 (2.00 equivalent, 0.707 g, 114 mL, 2.50 M). The entire flow reaction process was carried out under an inert atmosphere of N2. The volume of the 1 / 8” PFA coil in fluid reactor 1 was 60 mL. The residence time in fluid reactor 1 was 2 minutes. The bath in fluid reactor 1 was set to 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 run for 5 minutes before the reaction mixture was collected. Once the reaction was determined to be complete by LCMS, the reaction mixture was filtered through Celite and rinsed with THF (500 mL) and DCM (500 mL) to remove Na2SO4. The crude filtrate was concentrated under vacuum to obtain the desired product as a gray solid, which was then proceeded to without any further purification (67.7 g). LCMS C 32 H 34 N2O3 requirement value 494.3, measured value m / z = 495.3 [M+H] + .

[0278] Step 4: Synthesis of rac-3-(4-(4-(2-hydroxyethyl)piperidine-1-yl)phenyl)piperidine-2,6-dione [ka] A flask dried in an oven was purged under vacuum and packed with N2 (3X). Subsequently, Pd / C (14.2g, 66.7 mmol, 50% purity), Pd(OH)2 (14.2g, 50.5 mmol, 50% purity), and 2-(1-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)piperidine-4-yl)ethane-1-ol (74.0g, 149 mmol) were added, and THF (740 mL) was added to the bottle. The suspension was purged with N2 and packed with H2 (3×). The reaction mixture was stirred at 25°C under H2 (50 psi) until it was determined to be complete by LC-MS. Once complete, the mixture was filtered with THF rinse (2.00 L). The recovered filtrate was refluxed at 80°C for 15 minutes, and then filtered while still hot to obtain the filtrate. The recovered filtrate was concentrated to obtain a crude residue, which was then ground with MTBE (60 mL) to obtain the desired compound as a white solid. This was then proceeded to without any further purification (40.0 g). LCMS C 18 H 24 N2O3 requirement value 316.2, measured value m / z = 317.2 [M+H] + .

[0279] Step 5: Synthesis of the title compound The oven-dried vials were purged and then refilled with N2 (3x), followed by the addition of a solution of rac-(R)-3-(4-(4-(2-hydroxyethyl)piperidine-1-yl)phenyl)piperidine-2,6-dione (30.0 g, 94.8 mmol) in DMSO (300 mL) at 25°C. IBX (39.0 g, 139 mmol, 1.47 equivalents) was then added gradually, and the mixture was stirred at 25°C until completion was determined by LC-MS. Once complete, the mixture was cooled to 15°C, and 2-MeTHF (300 mL) was added to prevent precipitation of the product 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 obtain the crude residue. The residue was purified by flash column chromatography (petroleum ether / ethyl acetate (w / 10% DCM) = 0-33%) to obtain the desired product as a green solid (26.0 g, 84% yield). LCMS C 18 H 22 N2O3 requirement value 314.2, measured value m / z = 315.3 [M+H] + .

[0280] Intermediate 29 (S)-2-(1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-yl)acetaldehyde [ka] rac-2-(1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-yl)acetaldehyde (24.9 g, 79.4 mmol) was separated by SFC (column: DAIEL CHIRALPAK AS (250 mm*30 mm, 10 μm); mobile phase: [CO2-i-PrOH / ACN]; B%: 70%, fixed composition elution mode). The title compound (first eluted isomer) was obtained as a yellow solid (7.00 g, 44.6% yield). LCMS C 18 H 22N2O3 requirement value 314.2, measured value m / z = 315.3 [M+H] + .

[0281] Intermediate 30 RAC-3-((4-(piperidine-4-yl)phenyl)amino)piperidine-2,6-dione [ka] Step 1: Synthesis of rac-tert-butyl(R)-4-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperidine-1-carboxylate [ka] To a solution of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (23.5 g, 85.0 mmol, 1.0 equivalent) and NaHCO3 (21.4 g, 255.0 mmol, 3.0 equivalents) in DMF (250 mL), rac-3-bromopiperidine-2,6-dione (24.5 g, 127.5 mmol, 1.5 equivalents) was added at room temperature, and the reaction mixture was stirred at 65°C until the reaction was deemed complete by LC-MS. Once complete, the mixture was quenched with ice water (500 mL) and stirred at room temperature for 15 minutes. The reaction mixture was filtered and concentrated to obtain the crude product. The crude product was pulverized with MTBE (150 mL) to obtain the desired product as a gray solid, which was then proceeded to without any further purification (26 g). LC-MS C 21 H 29 N3O4 requirement value 387.2, measured value 386.1 [MH] - .

[0282] Step 2: Synthesis of the title compound To a solution of rac-tert-butyl-4-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperidine-1-carboxylate (22.5 g, 58.1 mmol) in DCM (66 mL), 4N HCl in dioxane (43.6 mL, 174.3 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature until complete by LC-MS. Once complete, the mixture was concentrated to obtain the crude product. The crude product was pulverized with MTBE (100 mL) to obtain the desired product as a gray solid, which was then proceeded to without any further purification (16.0 g, HCl salt). LC-MS C 16 H 21 N3O2 requirement value 287.2, measured value 288.2 [M+H] + .

[0283] Intermediate 31 (1R,4R)-4-(4-((RS)-2,6-dioxopiperidine-3-yl)phenoxy)cyclohexane-1-carbaldehyde [ka] Step 1: Synthesis of methyl(1r,4r)-4-(4-bromophenoxy)cyclohexane-1-carboxylate [ka] To a solution of methyl(1r,4r)-4-hydroxycyclohexane-1-carboxylate (20.0 g, 126 mmol) in toluene (400 mL), PPh3 (36.4 g, 139 mmol) and 4-bromophenol (24.0 g, 139 mmol) were added. The mixture was then cooled to 0°C, and DEAD (27.5 mL, 151 mmol) was added to the mixture. The reaction mixture was then heated to 25°C and allowed to react until completion was determined by LC-MS. Once complete, the reaction mixture was poured into petroleum ether (1000 mL) to form a precipitate. The mixture was filtered, and the filter cake was washed with petroleum ether (200 mL x 2). The combined filtrate was washed with brine (500 mL x 3), dried on anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the crude residue. The residue was purified by column chromatography (petroleum ether in ethyl acetate = 0-100%) to obtain the desired compound as a white solid (23.0 g, 58% yield over two steps). LCMS C 14 H 17 BrO3 requirement value 312.1, measured value m / z = 313.2 [M+H] + .

[0284] Step 2: Synthesis of methyl(1r,4r)-4-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenoxy)cyclohexane-1-carboxylate [ka] This intermediate was prepared using methyl(1r,4r)-4-(4-bromophenoxy)cyclohexane-1-carboxylate instead of 1-bromo-4-iodobenzene, as described in step 1 of intermediate 28 (12.0 g, 72% yield). LCMS C 33 H 33 NO5 required value 523.2, measured value m / z = 524.2 [M+H] + .

[0285] Step 3: Synthesis of ((1r,4r)-4-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenoxy)cyclohexyl)methanol [ka] To a solution of (1r,4r)-4-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenoxy)cyclohexane-1-carboxylate (6.00 g, 11.4 mmol) in THF (60 mL), LiBH4 (2.00 M in THF, 236 mL) was added under N2 at 0°C. The mixture was warmed to 25°C and reacted until complete was determined by LC-MS. Once complete, the reaction mixture was cooled to 0°C, and a 5% solution of NaHCO3 (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 layer was washed with brine (150 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the desired compound as a pale yellow solid, which was then proceeded to without any further purification (5.0 g, 87% yield). LC-MS C 32 H 33 NO4 required value 495.2, measured value m / z = 496.3 [M+H] + .

[0286] Step 4: Synthesis of (RS)-3-(4-(((1r,4R)-4-(hydroxymethyl)cyclohexyl)oxy)phenyl)piperidine-2,6-dione [ka] To a solution of ((1r,4r)-4-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenoxy)cyclohexyl)methanol (3.00 g, 5.95 mmol) in THF (30 mL), Pd / C (600 mg, 10% purity) and Pd(OH)2 (600 mg, 20% purity) were added under an N2 atmosphere. The suspension was degassed and purged three times with H2. The mixture was stirred under H2 (15 Psi) at 25°C until completeness was determined by LC-MS. Once complete, the reaction mixture was filtered through a layer of Celite and washed with THF. The recovered filtrate was concentrated under vacuum to obtain the desired product as a yellow solid, which was then proceeded to without any further purification (2.50 g). LC-MS C 18 H 23NO4 required value 317.2, measured value m / z = 318.3 [M+H] + .

[0287] Step 5: Synthesis of the title compound To a solution of (RS)-3-(4-(((1r,4R)-4-(hydroxymethyl)cyclohexyl)oxy)phenyl)piperidine-2,6-dione (1.0 g, 3.04 mmol) in DMSO (10.0 mL), DMP (2.58 g, 6.09 mmol) was slowly added at 25°C. The reaction was stirred at 25°C until completion was determined by LC-MS. Once complete, the mixture was adjusted to pH=10 with saturated aqueous Na2CO3, and the aqueous layer was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with semi-saturated Na2S2O3 solution (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the crude residue. The crude product was pulverized in petroleum ether / ethyl acetate (3:1, 5 mL) at 25°C for 15 minutes to obtain the desired product as a white solid, which was then carried out without any further purification (0.66 g). LCMS C 18 H 21 NO4 required value 315.2, measured value m / z = 316.2 [M+H] + .

[0288] Intermediate 32 RAC-(R)-2-(4-(4-(2,6-dioxopiperidine-3-yl)phenyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-yl)acetic acid [ka] Step 1: Synthesis of tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate [ka] To a stirred solution of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (5 g, 11.20 mmol) and tert-butyl1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (2.87 g, 11.20 mmol) in 1,4-dioxane (50 mL), cesium carbonate (7.30 g, 22.40 mmol) was added at room temperature. The resulting mixture was purged with N2 for 10 minutes. Then, Pd2(dba)3 (0.513 g, 0.560 mmol) and RuPhos (0.523 g, 1.120 mmol) were added. The resulting mixture was purged with N2 for 5 minutes and heated to 100°C for 16 hours. After the reaction was complete, the reaction mixture was cooled to RT, filtered through Celite, and rinsed with ethyl acetate (300 mL). The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (2 × 200 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the crude compound as a brown liquid. The crude compound was purified by flash column chromatography using ethyl acetate / petroleum ether (0-30%) as the eluent to obtain the desired compound as a pale yellow solid (5.6 g, 77% yield). LCMS C 38 H 43 N3O5 requirement value 621.3, measured value m / z = 622.2 [M+H] + .

[0289] Step 2: Synthesis of 4-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)-1-oxa-4,9-diazaspiro[5.5]undecane [ka] This intermediate was prepared as described in the synthesis of intermediate 30 step 2, using tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate instead of rac-tert-butyl(R)-4-(4-((2,6-dioxopiperidine-3-yl)amino)phenyl)piperidine-1-carboxylate (4.5 g, HCl salt). LCMS C 33 H35 N3O3 requirement value 521.3, measured value 522.4 [M+H] + .

[0290] Step 3: Synthesis of tert-butyl 2-(4-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-yl) acetate [ka] To a solution of (4-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)-1-oxa-4,9-diazaspiro[5.5]undecane (4.5 g, 7.33 mmol) in MeCN (50 mL), TEA (5.11 mL, 36.7 mmol) and tert-butyl 2-chloroacetate (3.15 mL, 22.00 mmol) were added by RT. The reaction mixture was stirred at 60°C until completion was determined by LC-MS. Once the reaction was complete, the reaction mixture was removed. The mixture was cooled to room temperature. After cooling, water (100 mL) was added, and the mixture was extracted with Depositphotos (2 × 250 mL). The combined organic layer was washed with water (200 mL) and brine (100 mL), dried on anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by FCC using 30% ethyl acetate / petroleum ether (fixed composition elution) as the eluent to obtain the desired product as an off-white solid (3.0 g, 61% yield). LCMS C 39 H 45 N3O5 requirement value 636.3, measured value m / z = 637.4 [M+H] + .

[0291] Step 4: Synthesis of rac-tert-butyl(R)-2-(4-(4-(2,6-dioxopiperidine-3-yl)phenyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-yl) acetate [ka] To a stirred solution of tert-butyl 2-(4-(4-(2,6-bis(benzyloxy)pyridine-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), Pd(OAc)2 (0.4 g, 1.782 mmol) and 10% Pd / C (0.5 g, 4.70 mmol) were added at RT under an N2 atmosphere. The resulting mixture was stirred at RT under an H2 pressure (1 atm) until completion was determined by LC-MS. Once complete, the reaction mixture was filtered through Celite and washed with ethyl acetate (100 mL). The eluate was concentrated under reduced pressure to obtain the crude compound, which was washed with toluene (2 x 50 mL) and MTBE (2 x 30 mL). The mixture was concentrated under reduced pressure to obtain the desired compound as an off-white solid, which was then removed without any further purification (1.8 g). LCMS C 25 H 35 N3O5 requirement value 457.3, measured value 458.6 [M+H] + .

[0292] Step 5: Synthesis of the title compound This intermediate was prepared as described in the synthesis of intermediate 30 step 2, using rac-tert-butyl(R)-2-(4-(4-(2,6-dioxopiperidine-3-yl)amino)phenyl)piperidine-1-carboxylate (0.91 g, HCl salt) instead of rac-tert-butyl(R)-2-(4-(4-(2,6-dioxopiperidine-3-yl)phenyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-yl)acetate. LCMS C21H27N3O5 requirement 401.2, measured value 402.2[M+H]+.

[0293] Intermediate 33 2-((3AR,6AR)-5-(4-(2,6-dioxopiperidine-3-yl)phenyl)hexahydropyrrolo[3,4-C]pyrrole-2(1H)-yl)acetic acid [ka] Step 1: Synthesis of tert-butyl(3aS,6aS)-5-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate [ka] To a stirred solution of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (5 g, 11.20 mmol) and tert-butyl(3aS,6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (2.378 g, 11.20 mmol) in dioxane (60 mL), cesium carbonate (7.30 g, 22.40 mmol) was added at room temperature. The resulting mixture was purged with N2 for 10 minutes. Then, Pd2(dba)3 (0.513 g, 0.560 mmol) and RuPhos (0.523 g, 1.120 mmol) were added. The resulting mixture was purged with N2 for 5 minutes and heated to 100°C for 16 hours. After confirming the completion of the reaction by LC-MS, the reaction mixture was cooled to RT, filtered through a Celite pad, and washed with ethyl acetate (300 mL). The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (2 × 200 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product as a brown liquid. This was purified by flash chromatography using a 0-30% ethyl acetate / petroleum ether gradient to obtain tert-butyl(3aS,6aS)-5-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (4.5 g, 66% yield) as a pale yellow solid. LC-MS:C 36 H 39 N3O4 requirement value: 577.3, measured value: m / z = 578.2 [M+H] + .

[0294] Step 2: Synthesis of (3aR,6aR)-2-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)octahydropyrrolo[3,4-c]pyrrole [ka] To a stirred solution of tert-butyl(3aS,6aS)-5-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (4.5 g, 7.79 mmol) in DCM (20 mL), 4 M HCl (9.74 ml, 38.9 mmol) in dioxane was added at 0°C. The resulting reaction mixture was stirred at RT for 2 hours. After confirming the completion of the reaction by LC-MS, the reaction mixture was concentrated under reduced pressure, washed with n-hexane (3 × 100 mL), and dried to obtain (3aR,6aR)-2-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)octahydropyrrolo[3,4-c]pyrrole (3.5 g, 70% yield) as an off-white solid. LC-MS:C 31 H 31 N3O2 requirement value: 477.2, measured value: m / z = 478.2 [M + H] + .

[0295] Step 3: Synthesis of tert-butyl 2-((3aR,6aR)-5-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl) acetate [ka] To a solution of (3aR,6aR)-2-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)octahydropyrrolo[3,4-c]pyrrole (3.5 g, 5.13 mmol) in MeCN (20 ml), triethylamine (1.557 g, 15.39 mmol) and tert-butyl 2-chloroacetate (2.201 ml, 15.39 mmol) were added by RT. The reaction mixture was stirred at 60°C for 2 hours. After confirming the completion of the reaction by LC-MS, the reaction mixture was cooled to room temperature. Then, water (100 mL) was added, and the mixture was extracted with ethyl acetate (2 × 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 obtain the crude product. The crude product was purified by flash chromatography using 30% ethyl acetate / petroleum ether as the eluent to obtain tert-butyl 2-((3aR,6aR)-5-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl) acetate (3.5 g, 70% yield) as an off-white solid. LCMS:C 37 H 41 N3O4 requirement value: 591.3, measured value: m / z = 592.2 [M+H] + .

[0296] Step 4: Synthesis of tert-butyl 2-((3aR,6aR)-5-(4-(2,6-dioxopiperidine-3-yl)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl) acetate [ka] A stirred solution of tert-butyl 2-((3aR,6aR)-5-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)acetate (1.3 g, 2.197 mmol) in 1,4-dioxane (30 mL) was added with Pd(OAc)2 (0.200 g, 0.891 mmol) and 10% Pd / C (0.300 g, 2.82 mmol) at RT under N2 atmosphere. The resulting mixture was stirred at RT for 16 h under H2 (1 atm pressure). After confirming the completion of the reaction by LCMS, the reaction mixture was filtered through a celite bed, washed with ethyl acetate (100 mL), and concentrated under reduced pressure. The crude product was washed with toluene (2x50 mL), MTBE (2x30 mL), and concentrated under reduced pressure to give tert-butyl 2-((3aR,6aR)-5-(4-(2,6-dioxopiperidin-3-yl)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)acetate (0.7 g, 73% yield) as an off-white solid. LCMS:C 23 H 31 N3O4 Calcd 413.2, Found: m / z = 414.1 [M+H] + .

[0297] Step 5: Synthesis of the title compound A stirred solution of tert-butyl 2-((3aR,6aR)-5-(4-(2,6-dioxopiperidin-3-yl)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)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 confirming the completion of the reaction by LCMS, n-hexane (50 mL) was added and 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 a crude product. The crude product was purified by RP-FC using MeCN in H2O and the collected fractions were lyophilized to give the title compound (0.37 g, 64% yield, TFA salt) as an off-white solid. LCMS:C 19 H 23N3O4 requirement value: 357.2, measured value: m / z = 358.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) 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).

[0298] Intermediate 34 7-(4-(2,6-dioxopiperidine-3-yl)phenyl)-7-azaspiro[3.5]nonane-2-carbaldehyde [ka] Step 1: Synthesis of 7-(tert-butyl)2-methyl7-azaspiro[3.5]nonane-2,7-dicarboxylate [ka] 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), cesium carbonate (8.17 g, 25.06 mmol) was added, followed by methyl iodide (2.85 g, 20.05 mmol). The mixture was stirred at RT for 16 hours. After confirming completion of the reaction by LC-MS, the reaction mixture was poured into ice-cold water (100 mL) and extracted with ethyl acetate (2 × 200 mL). The organic layer was washed with brine solution (20 mL), dried over sodium sulfate, and concentrated under reduced pressure to obtain 7-(tert-butyl)2-methyl7-azaspiro[3.5]nonane-2,7-dicarboxylate (4 g, 80% yield) as a yellow oil. LC-MS:C 15 H 25NO4 requirement value: 283.2, measured value: m / z = 184.2 [M-Boc] + .

[0299] Step 2: Synthesis of methyl 7-azaspiro[3.5]nonane-2-carboxylate [ka] To a stirred solution of 7-(tert-butyl)2-methyl7-azaspiro[3.5]nonane-2,7-dicarboxylate (4 g, 14.12 mmol) in DCM (20 mL), 4 M HCl in dioxane (35.3 mL, 141 mmol) was added at 0°C. The resulting mixture was stirred at RT for 5 hours. After confirming the completion of the reaction by LC-MS, the reaction mixture was concentrated under reduced pressure, washed with n-hexane (3 × 100 mL), and dried to obtain methyl7-azaspiro[3.5]nonane-2-carboxylate.HCl (3 g, 95%) as a yellow solid. LC-MS:C 10 H 17 NO2 requirement value: 183.2, measured value: m / z = 184.2 [M+H] + .

[0300] Step 3: Synthesis of methyl 7-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)-7-azaspiro[3.5]nonane-2-carboxylate [ka] To a stirred solution of methyl 7-azaspiro[3,5]nonane-2-carboxylate.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), cesium carbonate (22.99 g, 70.6 mmol) was added at room temperature. The resulting mixture was purged with N2 for 10 minutes. Then, Pd2(dba)3 (0.646 g, 0.706 mmol) and RuPhos (0.659 g, 1.411 mmol) were added. The resulting reaction mixture was purged with N2 for 5 minutes and heated to 100 °C for 16 hours. After confirming completion of the reaction by LC-MS, the reaction mixture was cooled to RT, filtered through a Celite pad, and washed with ethyl acetate (300 mL). The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (2 × 200 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to obtain the crude product as a brown liquid. The crude product was purified by flash chromatography using a 0–25% ethyl acetate / petroleum ether gradient to obtain methyl 7-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)spiro[3.5]nonane-2-carboxylate (5.3 g, 52% yield) as a pale yellow solid. LCMS:C 35 H 36 N2O4 requirement value: 548.3, measured value: m / z = 549.2 [M + H] + .

[0301] Step 4: Synthesis of (7-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)-7-azaspiro[3.5]nonan-2-yl)methanol [ka] To a stirred solution of methyl 7-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)spiro[3.5]nonane-2-carboxylate (5.3 g, 9.68 mmol) in THF (50 mL), LiAlH4 (1 M solution in THF, 9.68 mL, 19.35 mmol) was added dropwise at 0°C. The reaction mixture was stirred at RT for 2 hours. After confirming completion of the reaction by LC-MS, the mixture was quenched with ethyl acetate (25 mL), followed by a saturated solution of sodium sulfate (20 mL). The reaction mixture was filtered through a Celite pad, the filtrate was diluted with ethyl acetate (200 mL), washed with water (2 × 100 mL) and brine (50 mL), the organic layer was dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude product (5 g). The crude product was pulverized with a mixture of DCM (50 mL) and hexane (40 mL) to obtain (7-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)spiro[3.5]nonan-2-yl)methanol (4.3 g, 80% yield) as a green gum. LCMS:C 34 H 36 N2O3 requirement value: 520.3, measured value: m / z = 521.3 [M+H] + .

[0302] Step 5: Synthesis of 3-(4-(2-(hydroxymethyl)-7-azaspiro[3.5]nonan-7-yl)phenyl)piperidine-2,6-dione [ka] To a stirred solution of (7-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)spiro[3.5]nonan-2-yl)methanol (4.3 g, 8.27 mmol) in 1,4-dioxane (40 mL), Pd(OAc)2 (0.4 g, 1.782 mmol) and 10% Pd / C (0.8 g, 7.52 mmol) were added at RT under an N2 atmosphere. The resulting reaction mixture was stirred at RT under H2 pressure (1 atm) for 16 hours. After confirming the completion of the reaction by LC-MS, the reaction mixture was filtered through a Celite 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 obtain 3-(4-(2-(hydroxymethyl)-7-azaspiro[3.5]nonan-7-yl)phenyl)piperidine-2,6-dione (2.5 g, 83% yield) as an off-white solid. LCMS:C 20 H 26 N2O3 requirement value: 342.2, measured value: m / z = 343.2 [M + H] + .

[0303] Step 6: Synthesis of the Title Compound To a stirred solution of 3-(4-(2-(hydroxymethyl)-7-azaspiro[3.5]nonane-7-yl)phenyl)piperidine-2,6-dione (2.5 g, 7.30 mmol) in DMSO (5 mL), Des-Martin periodinane (4.64 g, 10.95 mmol) was added at 0°C under an N2 atmosphere. The resulting reaction mixture was stirred in RT for 2 hours. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched with sodium thiosulfate solution (20 mL) and extracted with ethyl acetate (2 × 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 obtain the crude product. The crude product was purified by RP-FC using MeCN in H2O. The recovered fraction was lyophilized to obtain the title compound (0.903 g, 25% yield, as TFA, salt) as an off-white solid. LCMS:C 20 H 24 N2O3 requirement value: 340.2, measured value: m / z = 341.3 [M+H] +. 1 H NMR (400 MHz, DMSO-d6) 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).

[0304] Intermediate 35 Synthesis of 2-(1-(4-(2,6-dioxopiperidine-3-yl)phenyl)-4-methylpiperidine-4-yl)acetaldehyde [ka] Step 1: Synthesis of 2-(4-methylpiperidine-4-yl)ethane-1-ol [ka] To a stirred solution of tert-butyl 4-(2-hydroxyethyl)-4-methylpiperidine-1-carboxylate (1 g, 4.11 mmol) in DCM (10 mL), 4 M HCl in dioxane (0.027 mL, 4.11 mmol) was added at 0°C. The resulting mixture was stirred at RT for 5 hours. After confirming the completion of the reaction by LC-MS, the reaction mixture was concentrated under reduced pressure, washed with n-hexane (3 × 100 mL), and dried to obtain 2-(4-methylpiperidine-4-yl)ethane-1-ol (HCl salt) as a colorless gum. LC-MS: C8H 17 NO requirement value: 143.1, measured value: m / z = 144.2 [M+H] + .

[0305] Step 2: Synthesis of 2-(1-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)-4-methylpiperidine-4-yl)ethane-1-ol [ka] To a stirred solution of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (1.5 g, 3.36 mmol) and 2-(4-methylpiperidine-4-yl)ethane-1-ol HCl (0.604 g, 3.36 mmol) in 1,4-dioxane (50 mL), cesium carbonate (5.47 g, 16.80 mmol) was added at room temperature. The resulting mixture was purged with N2 for 10 minutes. Then, Pd2(dba)3 (0.154 g, 0.168 mmol) and RuPhos (0.157 g, 0.336 mmol) were added. The resulting mixture was purged with N2 for 5 minutes, and the reaction mixture was heated to 100 °C for 16 hours. After confirming completion of the reaction by LC-MS, the reaction mixture was cooled to RT, filtered through a Celite pad, and washed with ethyl acetate (300 mL). The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (2 × 200 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to obtain the crude compound as a brown liquid. Similarly, an additional 1.5 g batch was prepared to obtain 0.5 g of the crude product. The crude products from both batches were mixed and purified by flash chromatography using a 0–30% ethyl acetate / petroleum ether gradient to obtain 2-(1-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)-4-methylpiperidine-4-yl)ethane-1-ol (1 g, 30%) as a pale yellow solid. LCMS:C 33 H 36 N2O3 requirement value: 508.3, measured value: m / z = 509.4 [M+H] + .

[0306] Step 3: Synthesis of 3-(4-(4-(2-hydroxyethyl)-4-methylpiperidine-1-yl)phenyl)piperidine-2,6-dione [ka] To a stirred solution of 2-(1-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)-4-methylpiperidine-4-yl)ethane-1-ol (1 g, 1.966 mmol) in 1,4-dioxane (10 mL), Pd(OAc)2 (0.1 g, 0.445 mmol) and 10% Pd / C (0.2 g, 1.879 mmol) were added at RT under an N2 atmosphere. The resulting mixture was stirred at RT under H2 bladder pressure for 16 hours. After confirming the completion of the reaction by LC-MS, the reaction mixture was filtered through a Celite 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 obtain 3-(4-(4-(2-hydroxyethyl)-4-methylpiperidine-1-yl)phenyl)piperidine-2,6-dione (0.5 g, 74%) as an off-white solid. LCMS:C 19 H 26 N2O3 requirement value: 330.2, measured value: m / z = 331.2 [M + H] + .

[0307] Step 4: Synthesis of the title compound To a stirred solution of 3-(4-(4-(2-hydroxyethyl)-4-methylpiperidine-1-yl)phenyl)piperidine-2,6-dione (0.45 g, 1.362 mmol) in DMSO (5 mL), Dess-Martin periodinane (0.866 g, 2.043 mmol) was added at 0°C under a N2 atmosphere. The resulting reaction mixture was stirred in RT for 2 hours. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched with sodium thiosulfate solution (20 mL) and extracted with ethyl acetate (2 × 50 mL). The organic layer was washed with sodium bicarbonate (20 mL) and brine solution (20 mL), dried on sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by RP-FC using MeCN in H2O. The recovered fraction was freeze-dried to obtain 2-(1-(4-(2,6-dioxopiperidine-3-yl)phenyl)-4-methylpiperidine-4-yl)acetaldehyde (0.11 g, 20% yield, TFA salt) as an off-white solid. LCMS:C 19 H24 N2O3 requirement value: 328.2, measured 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)

[0308] Intermediate 36 3-(4-(2-oxo-6-azapiro[3,4]octan-6-yl)phenyl)piperidine-2,6-dione [ka] Step 1: Synthesis of 6-Azaspiro[3.4]Octane-2-On [ka] To a stirred solution of tert-butyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate (2.5 g, 11.10 mmol) in DCM (50 mL), 4 M HCl (27.7 mL, 111 mmol) in dioxane was added at 0°C. The resulting reaction mixture was stirred at RT for 2 hours. After confirming the completion of the reaction by LC-MS, the reaction mixture was concentrated under reduced pressure, washed with n-hexane (3 × 100 mL), and dried to obtain 6-azaspiro[3.4]octane-2-one (2.89 g, 94% yield, HCl salt) as a brown gum. LC-MS: C7H 11 NO requirement value 125.1, measured value: m / z = 126.2 [M+H] + .

[0309] Step 2: Synthesis of 6-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)-6-azaspiro[3,4]octan-2one [ka] To a stirred solution of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (4.3 g, 9.641 mmol) and 6-azaspiro[3.4]octan-2-one HCl (1.55 g, 9.641 mmol) in 1,4-dioxane (50 mL), cesium carbonate (14.02 g, 43.0 mmol) was added at room temperature. The resulting mixture was purged with N2 for 10 minutes. 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 minutes and heated to 100°C for 16 hours. After confirming completion of the reaction by LC-MS, the reaction mixture was cooled to RT, filtered through a Celite pad, and washed with ethyl acetate (300 mL). The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (2 × 200 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to obtain the crude compound as a brown liquid. The crude compound was purified by flash chromatography using a 0-30% ethyl acetate / petroleum ether gradient to obtain 6-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)-6-azaspiro[3,4]octan-2-one (1 g, 75% purity) as a pale yellow solid. LCMS:C 32 H 30 N2O3 requirement value: 490.2, measured value: m / z = 491.1 [M+H] + .

[0310] Step 3: Synthesis of the title compound To a stirred solution of 6-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)-6-azaspiro[3.4]octan-2-one (1 g, 2.038 mmol) in 1,4-dioxane (10 mL), Pd(OAc)2 (0.1 g, 0.445 mmol) and 10% Pd / C (0.2 g, 1.879 mmol)) were added at RT under an N2 atmosphere. The resulting reaction mixture was stirred at RT under H2 pressure (1 atm) for 16 hours. After confirming the completion of the reaction by LC-MS, the reaction mixture was filtered through a Celite 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), concentrated under reduced pressure, and purified by RP-FC using MeCN in H2O. The recovered fraction was freeze-dried to obtain 3-(4-(2-oxo-6-azaspiro[3,4]octan-6-yl)phenyl)piperidine-2,6-dione (0.104 g, 11.4% yield, TFA salt) as an off-white solid. LCMS:C 18 H 20 N2O3 requirement value: 312.1, measured 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 = 8.8 Hz, 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).

[0311] Intermediate 37 8-(4-(2,6-dioxopiperidine-3-yl)phenyl)-2-oxa-8-azaspiro[4,5]decane-3-carbaldehyde [ka] Step 1: Synthesis of tert-butyl 4-allyl-4-formylpiperidine-1-carboxylate [ka] To a stirred solution of tert-butyl 4-formylpiperidine-1-carboxylate (5 g, 23.44 mmol) in THF (50 ml), 3-bromopropa-1-ene (2.431 ml, 28.1 mmol) and t-BuOK (3.16 g, 28.1 mmol) were gradually added at -25°C. The reaction mixture was stirred at -25°C to -15°C for 1 hour. After confirming the completion of the reaction by LC-MS, 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 × 200 mL). The organic layer was washed with brine (50 mL), dried over sodium sulfate, and concentrated to obtain the crude product. The crude compound was purified by flash chromatography using a 0-25% ethyl acetate / petroleum ether gradient to obtain tert-butyl 4-allyl-4-formylpiperidine-1-carboxylate (3 g, 50% yield) as a colorless oil. LCMS:C 14 H 23 NO3 required value 253.2, measured value: m / z = 153.1 [M-Boc] - .

[0312] Step 2: Synthesis of tert-butyl 4-allyl-4-(hydroxymethyl)piperidine-1-carboxylate [ka] To a stirred solution of tert-butyl 4-allyl-4-formylpiperidine-1-carboxylate (3 g, 11.84 mmol) in THF (30 mL), NaBH4 (0.896 g, 23.68 mmol) was gradually added at 0°C. The reaction mixture was stirred at RT for 2 hours. After confirming the completion of the reaction by TLC, the reaction mixture was cooled to room temperature. Water (100 mL) was then added, and the mixture was extracted with ELISA (2 × 250 mL). The combined organic layer was washed with brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure to obtain tert-butyl 4-allyl-4-(hydroxymethyl)piperidine-1-carboxylate (3 g, 90% yield) as a colorless oil. LCMS:C 14 H 25 NO3 required value 255.2, measured value: m / z = 156.2 [M-Boc] - .

[0313] Step 3: Synthesis of tert-butyl 3-(hydroxymethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxylate [ka] To a stirred solution of tert-butyl 4-allyl-4-(hydroxymethyl)piperidine-1-carboxylate (3 g, 11.75 mmol) in DCM (30 mL), m-CPBA (8.11 g, 47.0 mmol) was added at 0°C, and the reaction mixture was stirred at RT for 16 hours. After confirming the completion of the reaction by TLC, the reaction mixture was cooled to room temperature. The reaction mixture was then quenched with sodium sulfite (100 mL), extracted with ethyl acetate (2 × 250 mL), and the combined organic layer was washed with sodium bicarbonate (100 mL) and brine (100 mL). The mixture was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash chromatography using 20% ​​ethyl acetate in petroleum ether to obtain 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 25NO4 required value: 271.2, measured value: m / z = 172.1 [M-Boc] - .

[0314] Step 4: Synthesis of (2-oxa-8-azaspiro[4,5]decane-3-yl)methanol [ka] 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), 4 M HCl in dioxane (18.43 mL, 73.7 mmol) was added at 0°C. The resulting mixture was stirred at RT for 2 hours. After confirming the completion of the reaction by LC-MS, the reaction mixture was concentrated under reduced pressure, washed with n-hexane (3 × 100 mL), dried, and lyophilized to obtain (2-oxa-8-azaspiro[4.5]decane-3-yl)methanol (1.7 g, 97% yield, HCl salt) as an off-white, gum-like solid. LC-MS: C9H 17 NO2 requirement value: 171.1, measured value: m / z = 172.2 [M+H] + .

[0315] Step 5: Synthesis of (8-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)-2-oxa-8-azaspiro[4.5]decane-3-yl)methanol [ka] To a stirred solution of (2-oxa-8-azaspiro[4,5]decane-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), cesium carbonate (7.30 g, 22.40 mmol) was added at room temperature. The resulting mixture was purged with N2 for 10 minutes. Then, Pd2(dba)3 (0.041 g, 0.045 mmol) and RuPhos (0.042 g, 0.090 mmol) were added. The resulting reaction mixture was purged with N2 for 5 minutes and heated to 100 °C for 16 hours. After confirming completion of the reaction by LC-MS, the reaction mixture was cooled to RT, filtered through a Celite pad, and washed with ethyl acetate (300 mL). The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (2 × 200 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to obtain the crude compound as a brown liquid. The crude compound was purified by flash chromatography using a 0-30% ethyl acetate / petroleum ether gradient to obtain (8-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)-2-oxa-8-azaspiro[4.5]decane-3-yl)methanol (0.6 g, 50% yield) as a pale yellow solid. LCMS:C 34 H 36 N2O4 requirement value: 536.3, measured value: m / z = 537.3 [M + H] + .

[0316] Step 6: Synthesis of 3-(4-(3-(hydroxymethyl)-2-oxa-8-azapiro[4.5]decane-8-yl)phenyl)piperidine-2,6-dione [ka] To a stirred solution of (8-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)-2-oxa-8-azaspiro[4.5]decane-3-yl)methanol (0.6 g, 1.118 mmol) in 1,4-dioxane (10 mL), Pd(OAc)2 (0.05 g, 0.223 mmol) and 10% Pd / C (0.1 g, 0.940 mmol) were added at RT under an N2 atmosphere. The resulting mixture was stirred at RT under H2 pressure (1 atm) for 16 hours. After confirming the completion of the reaction by LC-MS, the reaction mixture was filtered through a Celite 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 obtain 3-(4-(3-(hydroxymethyl)-2-oxa-8-azaspiro[4.5]decane-8-yl)phenyl)piperidine-2,6-dione (0.4 g, 90% yield) as an off-white solid. LCMS:C 20 H 26 N2O4 requirement value: 358.2, measured value: m / z = 359.1 [M + H] + .

[0317] Step 7: Synthesis of the Title Compound To a stirred solution of 3-(4-(3-(hydroxymethyl)-2-oxa-8-azaspiro[4.5]decane-8-yl)phenyl)piperidine-2,6-dione (0.4 g, 1.116 mmol) in DMSO (5 mL), Des-Martin periodinane (0.710 g, 1.674 mmol) was added at 0°C under a N2 atmosphere. The resulting mixture was stirred at RT for 4 hours. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched with sodium thiosulfate solution (20 mL) and extracted with ethyl acetate (2 × 50 mL). The organic layer was washed with sodium bicarbonate (20 mL) and brine solution (20 mL), dried on sodium sulfate, and concentrated under reduced pressure. The crude product was purified by RP-FC using MeCN in H2O. The recovered fraction was freeze-dried to obtain 8-(4-(2,6-dioxopiperidine-3-yl)phenyl)-2-oxa-8-azaspiro[4.5]decane-3-carbaldehyde (0.124 g, TFA salt) as an off-white solid. LCMS:C20 H 24 N2O4 requirement value: 356.2, measured value: m / z = 357.2 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) 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).

[0318] Intermediate 38 RAC-(4-{4-[(3R)-2,6-dioxopiperidine-3-yl]phenyl}piperazine-1-yl)acetic acid [ka] Step 1: Synthesis of tert-butyl 2-[4-(4-bromophenyl)piperazin-1-yl]acetate [ka] To a mixture of tert-butyl 2-(piperazin-1-yl) acetate (500 mg, 2.496 mmol, 1 equivalent) in toluene (5 mL), dibromobenzene (588 mg, 2.496 mmol, 1 equivalent), Pd2(dba)3 (228 mg, 0.250 mmol, 0.1 equivalent), BINAP (310 mg, 0.499 mmol, 0.2 equivalents), and Cs2CO3 (2440 mg, 7.488 mmol, 3 equivalents) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100°C for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA(1 / 1) to obtain tert-butyl 2-[4-(4-bromophenyl)piperazin-1-yl]acetate (300 mg, 33.82%) as a yellow oil. LCMS:(C 16 H 23 (BrN2O2) Desired mass = 355.1; Observed mass = 355.1 [M + H] + .

[0319] Step 2: Synthesis of tert-butyl 2-(4-{4-[2,6-bis(benzyloxy)pyridine-3-yl]phenyl}piperazine-1-yl) acetate [ka] To a mixture of tert-butyl 2-[4-(4-bromophenyl)piperazin-1-yl]acetate (1 g, 2.815 mmol, 1 equivalent) in dioxane (50 mL), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.76 g, 4.223 mmol, 1.5 equivalents), XPhos Pd G2 (0.44 g, 0.563 mmol, 0.2 equivalents), and K3PO4 (1.79 g, 8.445 mmol, 3 equivalents) in H2O (10 mL) were added. The resulting mixture was stirred at 60°C for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA(1 / 2) to obtain tert-butyl 2-(4-{4-[2,6-bis(benzyloxy)pyridine-3-yl]phenyl}piperazin-1-yl) acetate (650 mg, 36.74%) as a yellow solid. LCMS:(C 35 H 39 N3O4) Desired mass = 566.3; Observed mass = 566.3 [M + H] + .

[0320] Step 3: Synthesis of tert-butyl 2-{4-[4-(2,6-dioxopiperidine-3-yl)phenyl]piperazine-1-yl}acetate [ka] A mixture of tert-butyl 2-(4-{4-[2,6-bis(benzyloxy)pyridine-3-yl]phenyl}piperazin-1-yl) acetate (650 mg, 1.149 mmol, 1 equivalent) in THF (25 mL) was mixed with Pd / C (650 mg) at room temperature. The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. This yielded tert-butyl 2-{4-[4-(2,6-dioxopiperidine-3-yl)phenyl]piperazin-1-yl} acetate (400 mg, crude) as a pale yellow solid. LCMS:(C) 21 H 29 N3O4) Desired mass = 388.2; Observed mass = 388.2[M+H]+ .

[0321] Step 4: Synthesis of rac-(4-{4-[(3R)-2,6-dioxopiperidine-3-yl]phenyl}piperazin-1-yl)acetic acid A mixture of tert-butyl 2-{4-[4-(2,6-dioxopiperidine-3-yl)phenyl]piperazin-1-yl}acetate (2 g, 5.162 mmol, 1 equivalent) in HCl(gas) / 1,4-dioxane (20 mL, 4 M) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum and then freeze-dried. The crude product was purified by grinding with n-hexane. This yielded rac-(4-{4-[(3R)-2,6-dioxopiperidine-3-yl]phenyl}piperazin-1-yl)acetic acid (1.5316 g, 81.58%) as an off-white solid. LCMS:(C 17 H 21 N3O4) Desired mass = 332.2; Observed mass = 332.2[M+H] + .

[0322] 1 H NMR (400 MHz, DMSO-d6) 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).

[0323] Intermediate 39 3-(4-(3-oxo-1-oxa-8-azaspiro[4,5]decane-8-yl)phenyl)piperidine-2,6-dione [ka] Step 1: Synthesis of 8-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)-1-oxa-8-azaspiro[4.5]decan-3one [ka] To a stirred solution of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine 1 (5 g, 11.2 mmol) and 1-oxa-8-azaspiro[4.5]decane-3-one.HCl 2 (2.141 g, 11.2 mmol) in dioxane (60 mL), cesium carbonate (18.2 g, 56 mmol) was added at room temperature. The resulting mixture was purged with N2 for 10 minutes. Then, Pd2(dba)3 (0.513 g, 0.560 mmol) and RuPhos (0.523 g, 1.120 mmol) were added. The resulting mixture was purged with N2 for 5 minutes, and the reaction mixture was heated to 100 °C for 16 hours. After confirming completion of the reaction by LC-MS, the reaction mixture was cooled to RT, filtered through a Celite pad, and washed with ethyl acetate (300 mL). The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (2 × 200 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to obtain the crude compound as a brown liquid. The crude compound was purified using ethyl acetate / petroleum ether (0-30%) as the eluate via Biotage-Isolera (silica gel: 230-400 mesh) to obtain the crude product (2 g) as a yellow solid. The crude product was purified by preparative HPLC using a column: Xselect C18 250 mm, method: 0.1% TFA in water / MeCN, flow rate: 12 mL / min. The recovered fraction was lyophilized to obtain 8-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)-1-oxa-8-azaspiro[4.5]decane-3-one (1.1 g, 13% yield) as a pale yellow solid: LCMS: m / z = 522.1 [M + H] + .

[0324] 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).

[0325] Step 2: Synthesis of the title compound To a stirred solution of 8-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)-1-oxa-8-azaspiro[4.5]decane-3-one 3 (1.1 g, 2.113 mmol) in 1,4-dioxane (30 mL), Pd(OAc)2 (0.150 g, 0.668 mmol) and 10% Pd / C (0.200 g, 1.879 mmol) were added by RT under an N2 atmosphere. The resulting mixture was then heated under H2 pressure (1 atm) RT. The mixture was stirred for 16 hours. After confirming the completion of the reaction by LC-MS, the reaction mixture was filtered through a Celite bed, washed with ethyl acetate (100 mL), and concentrated under reduced pressure. The crude compound was washed with toluene (2 × 50 mL) and MTBE (2 × 30 mL), the resulting residue was concentrated under reduced pressure, and lyophilized to obtain the title compound (0.504 g, 52% yield, TFA salt) as an off-white solid. LC-MS: m / z = 343.2 [M + H] + .

[0326] 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).

[0327] Intermediate 40 RAC-(R)-1-(4-(2,6-dioxopiperidine-3-yl)-2,3-difluorophenyl)piperidine-4-carbaldehyde [ka] Step 1: Synthesis of 1-(4-bromo-2,3-difluorophenyl)-4-(dimethoxymethyl)piperidine [ka] To a solution of 1-bromo-2,3-difluoro-4-iodobenzene (20.0 g, 62.7 mmol, 1.00 equivalent), 4-(dimethoxymethyl)piperidine (10.9 g, 68.9 mmol, 1.10 equivalent), BINAP (1.56 g, 2.51 mmol, 0.04 equivalent), t-BuONa (12.0 g, 125 mmol, 2.00 equivalent), and Pd2(dba)3 (1.15 g, 1.25 mmol, 0.02 equivalent), 200 mL of toluene was added at 20°C, and the mixture was purged three times with N2. The mixture was stirred at 100°C for 16 hours. LC-MS showed that 28.9% of the desired MS was detected. 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 obtain 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)

[0328] Step 2: Synthesis of 2,6-bis(benzyloxy)-3-(4-(4-(dimethoxymethyl)piperidine-1-yl)-2,3-difluorophenyl)pyridine [ka] To a solution of 1-(4-bromo-2,3-difluorophenyl)-4-(dimethoxymethyl)piperidine (13.0 g, 29.7 mmol, 1.00 equivalent), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (16.1 g, 38.6 mmol, 1.30 equivalent), Cs2CO3 (24.1 g, 74.2 mmol, 2.50 equivalent), and Pd(dppf)Cl2.CH2Cl2 (1.21 g, 1.48 mmol, 0.05 equivalent), dioxane (260 mL) and H2O (52.0 mL) were added at 20°C, and the mixture was purged three times with N2. The mixture was stirred at 100°C for 16 hours under an N2 atmosphere. The residue was added to water (200 mL) and extracted with ethyl acetate (60.0 mL x 3). The combined organic layer was 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)piperidine-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 (br d, J = 11.9 Hz, 2H), 3.40 (s, 6H), 2.71 (t, J = 11.4 Hz, 2H), 1.87 (br d, J = 12.8 Hz, 2H), 1.81 -1.71 (m, 1H), 1.64 -1.48 (m, 3H)

[0329] Step 3: Synthesis of rac-(R)-3-(4-(4-(dimethoxymethyl)piperidine-1-yl)-2,3-difluorophenyl)piperidine-2,6-dione [ka] To a solution of rac-(R)-3-(4-(4-(dimethoxymethyl)piperidine-1-yl)-2,3-difluorophenyl)piperidine-2,6-dione (43.0 g, 76.7 mmol, 1.00 equivalent) in THF (430 mL), Pd / C (12.9 g, 12.1 mmol, 10% purity) and Pd(OH)2 (12.9 g, 27.5 mmol, 30% purity) were added under an N2 atmosphere. The suspension was degassed and purged three times with H2. The mixture was stirred at 25°C for 6 hours under H2 (50 psi), then filtered and concentrated. The crude product was ground with MTBE (20.0 mL) at 25°C for 30 minutes, filtered, and the cake was dried under reduced pressure to obtain rac-(R)-3-(4-(4-(dimethoxymethyl)piperidine-1-yl)-2,3-difluorophenyl)piperidine-2,6-dione (8.00 g, 20.9 mmol, 88.8% yield) as a white solid. 1 H NMR:(400 MHz, DMSO-d6) 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)

[0330] Step 4: Synthesis of the title compound To a solution of rac-(R)-3-(4-(4-(dimethoxymethyl)piperidine-1-yl)-2,3-difluorophenyl)piperidine-2,6-dione (4.00 g, 10.4 mmol, 1.00 equivalent) in THF (93.0 mL), HCl (2.00 M, 93.1 mL, 17.8 equivalents) was slowly added dropwise. After the addition, the reaction solution was stirred at 70°C for 1 hour. Next, saturated NaHCO3 solution was added to the reaction mixture to a pH of 7, and then extracted with siRNA (30.0 mL × 3). The mixture was dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was ground with siRNA (10.0 mL) at 25°C for 30 minutes to obtain the title compound (2.00 g, 5.86 mmol, 56.0% yield, 98.4% purity) as a white solid. 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)

[0331] Intermediate 41 Synthesis of RAC-(R)-2-(1-(4-(2,6-dioxopiperidine-3-yl)phenyl)-4-fluoropiperidine-4-yl)acetaldehyde [ka] Step 1: Synthesis of tert-butyl 4-fluoro-4-(2-hydroxyethyl)piperidine-1-carboxylate [ka] A mixture of tert-butyl 4-(2-ethoxy-2-oxoethyl)-4-fluoropiperidine-1-carboxylate (10.5 g, 36.3 mmol, 1.00 equivalent) 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 equivalent) was added dropwise to the mixture with N2 at -20 to 0°C. The resulting mixture was stirred with N2 at -20 to 0°C for 2 hours. H2O (5.00 mL) was added dropwise to the reaction mixture at -20 to 0°C, the reaction was quenched under a stream of N2, and then the mixture was dried over Na2SO4, filtered, and concentrated under vacuum. The crude product, tert-butyl 4-fluoro-4-(2-hydroxyethyl)piperidine-1-carboxylate (9.00 g, crude), was used as a colorless oil 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)

[0332] Step 2: Synthesis of 2-(4-fluoropiperidine-4-yl)ethane-1-ol hydrochloride [ka] To a mixture of tert-butyl 4-fluoro-4-(2-hydroxyethyl)piperidine-1-carboxylate (10.6 g, 43.1 mmol, 1.00 equivalent) in dioxane (11.0 mL), HCl / dioxane (2.00 M, 53.2 mL, 2.47 equivalents) was added at 10-20°C. The resulting mixture was stirred at 10-20°C for 12 hours. The mixture was concentrated under vacuum. Crude 2-(4-fluoropiperidine-4-yl)ethane-1-ol hydrochloride (7.92 g, 43.1 mmol, 100% yield, HCl) was used as a white solid in the next step without further purification. 1H 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)

[0333] Step 3: Synthesis of 2-(1-(4-bromophenyl)-4-fluoropiperidine-4-yl)ethane-1-ol [ka] To a mixture of 1-bromo-4-iodobenzene (11.7 g, 41.4 mmol, 1.10 equivalents) and 2-(4-fluoropiperidine-4-yl)ethane-1-ol hydrochloride (6.92 g, 37.7 mmol, 1.00 equivalent, HCl) in DMSO (82.0 mL), K2CO3 (15.6 g, 113 mmol, 3.00 equivalents), CuI (1.44 g, 7.54 mmol, 0.20 equivalents), and L-PROLINE (1.74 g, 15.0 mmol, 0.40 equivalents) were added at 15-25°C under N2 conditions. The resulting mixture was stirred under N2 conditions at 75-80°C for 16 hours. The mixture was poured into H2O (200 mL), extracted with ethyl acetate (80.0 mL x 3), and the combined organic layer was washed with 3.00% NH3.H2O solution (50.0 mL) and brine (50.0 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was analyzed by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1, petroleum ether / ethyl acetate = 2 / 1, R f The compound was purified using LCMS (0.21) and concentrated under vacuum. The crude compound 2-(1-(4-bromophenyl)-4-fluoropiperidine-4-yl)ethane-1-ol (5.70 g, 18.2 mmol, 48.4% yield, 96.7% purity) was obtained as a yellow solid. LCMS:C 13 H 17 BrFNO requested value: 301.0, measured value: m / z = 304.1 (M+H) + .

[0334] Step 4: Synthesis of 2-(1-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)-4-fluoropiperidine-4-yl)ethane-1-ol [ka] To a mixture of dioxane (114 mL) and 2-(1-(4-bromophenyl)-4-fluoropiperidine-4-yl)ethane-1-ol (5.70 g, 18.8 mmol, 1.00 equivalent) in H2O (22.8 mL), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (10.2 g, 24.5 mmol, 1.30 equivalent) and Cs2CO3 (15.4 g, 47.2 mmol, 2.50 equivalent) were added. 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 equivalent) was added to the mixture under N2. The resulting mixture was stirred at 100°C for 16 hours. The reaction mixture was poured into water (400 mL), extracted with ethyl acetate (200 mL x 3), washed with brine (200 mL), dried over Na2SO4, and concentrated under vacuum. The residue was analyzed by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1, petroleum ether / ethyl acetate = 2 / 1, R f The solution was purified using LCMS (=0.21) and concentrated under vacuum. 2-(1-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)-4-fluoropiperidine-4-yl)ethane-1-ol (7.10 g, 13.7 mmol, 72.8% yield, 99.1% purity) was obtained as a yellow solid. LCMS:C 32 H 33 FN2O3 required value: 512.2, measured value: m / z = 513.3 (M+H) + 1H NMR (400 MHz, 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)

[0335] Step 5: Synthesis of rac-(R)-3-(4-(4-fluoro-4-(2-hydroxyethyl)piperidine-1-yl)phenyl)piperidine-2,6-dione [ka] To a mixture of 2-(1-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)-4-fluoropiperidine-4-yl)ethane-1-ol (6.60 g, 12.9 mmol, 1.00 equivalent) in THF (200 mL), Pd / C (1.98 g, 1.86 mmol, 10% purity, 0.145 equivalent), followed by Pd(OH)2 (1.98 g, 2.82 mmol, 20% purity, 0.219 equivalent) was added under N2. The suspension was degassed and purged three times with H2. The mixture was stirred under H2 (50 Psi) at 25°C for 14 hours. The mixture was filtered through a Celite pad to obtain the filtrate. The filter cake was washed with THF (200 mL x 3), and the combined filtrate was concentrated under vacuum. The residue was ground with MTBE (30.0 mL) at 20-25°C for 30 minutes, filtered, and the filtered cake was washed with MTBE (8.00 mL x 3) and dried in vacuum. rac-(R)-3-(4-(4-fluoro-4-(2-hydroxyethyl)piperidine-1-yl)phenyl)piperidine-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 23FN2O3 required value: 334.2, measured 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 (br dd, 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)

[0336] Step 6: Synthesis of the Title Compound [ka] To a mixture of rac-(R)-3-(4-(4-fluoro-4-(2-hydroxyethyl)piperidine-1-yl)phenyl)piperidine-2,6-dione (3.40 g, 10.17 mmol, 1.00 equivalent) in DMSO (34.0 mL), IBX (4.27 g, 15.2 mmol, 1.50 equivalent) was added at 20-25°C, and the resulting mixture was stirred at 20-25°C for 4 hours. The mixture was poured into H2O (150 mL), extracted with ethyl acetate (100 mL x 4), washed with saturated NaHCO3 (50.0 mL) and brine (150 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was ground with ethyl acetate (50.0 mL) for 30 minutes at 25°C, filtered, and the filtered cake was washed with ethyl acetate (5.00 mL x 3) and dried under vacuum. rac-(R)-2-(1-(4-(2,6-dioxopiperidine-3-yl)phenyl)-4-fluoropiperidine-4-yl)acetaldehyde (2.65 g, 7.75 mmol, 76.2% yield, 97.2% purity) was obtained as a yellow solid. LC-MS:C 18 H 21FN2O3 required value: 332.2, measured value: m / z = 333.2 (M + H) + .

[0337] 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)

[0338] Intermediate 42 REL-(R)-1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-carboxylic acid [ka] Step 1: Synthesis of tert-butyl 1-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)piperidine-4-carboxylate [ka] A mixture of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (170 g, 380 mmol), tert-butylpiperidine-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 complete analysis was determined by LC-MS. Once complete, H2O (2.00 L) was added to the mixture, and it was 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 the crude residue. The residue was purified by column chromatography (petroleum ether in ethyl acetate = 100:1~20:1) to obtain the desired compound as a yellow solid (160 g, mmol, 71% yield). LC-MS C 35 H 38 N2O4 requirement value 550.3, measured value m / z = 551.3 [M+H] + .

[0339] Step 2: Synthesis of rac-tert-butyl(R)-1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-carboxylate [ka] A mixture of tert-butyl 1-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)piperidine-4-carboxylate (75.0 g, 136.1 mmol), 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) was purged with air and packed with N2 (3x). The container was purged with N2, packed with H2 (3x), and then stirred at 50°C until completion was determined by LCMS. Once complete, the mixture was filtered through Celite, and the filtrate was concentrated under vacuum to obtain the desired compound, which was then proceeded to without any further purification (96 g). LCMS C 21 H 28 N2O4 requirement value 372.2, measured value m / z = 373.3 [M+H]+ .

[0340] Step 3: Synthesis of rac-(R)-1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-carboxylic acid [ka] To a solution of rac-tert-butyl(R)-1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-carboxylate (45.0 g, 120 mmol) in DCM (500 mL), TFA (179 mL, 2.42 mol) was slowly added at 0°C, and the mixture was stirred at 30°C until completion was determined by LC-MS. Once complete, the mixture was concentrated to obtain the crude residue. The residue was purified by RP-FC (5-95%) to obtain the desired compound as an off-white solid (40.3 g, 75% yield over two steps). LC-MS C 17 H 20 N2O4 requirement value 316.2, measured value m / z = 317.1 [M+H] + .

[0341] Step 4: Synthesis of rel-tert-butyl(R)-1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-carboxylate [ka] rac-tert-butyl(R)-1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-carboxylate was purified by SFC (DAICEL CHIRALPAK AS (250 mm*30 mm, 10 μm); mobile phase: [CO2-i-PrOH / ACN]; B%: 35%, fixed composition elution mode). The desired compound was obtained as a white solid (first eluted isomer, 20.0 g, 40% yield). LCMS C 21 H 28 N2O4 requirement value 372.2, measured value 373.4 [M+H] + .

[0342] Step 5: Synthesis of rel-tert-butyl(R)-1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-carboxylate [ka] rac-tert-butyl(R)-1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-carboxylate was purified by SFC (DAICEL CHIRALPAK AS (250 mm*30 mm, 10 μm); mobile phase: [CO2-i-PrOH / ACN]; B%: 35%, fixed composition elution mode). The desired compound was obtained as a white solid (second eluted isomer, 19.0 g, 37% yield). LCMS C 21 H 28 N2O4 requirement value 372.2, measured value 373.4 [M+H] + .

[0343] Step 6: Synthesis of rel-(R)-1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-carboxylic acid [ka] This compound was prepared as described in step 3 of intermediate 41, using rel-tert-butyl(R)-1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-carboxylate instead of rac-tert-butyl(R)-1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-carboxylate (22 g, 93% yield). LCMS C 17 H 20 N2O4 requirement value 316.1, measured value m / z = 317.2 [M+H] + .

[0344] Title Compound Synthesis This compound was prepared as described in step 3 of intermediate 41, using rec-tert-butyl(R)-1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-carboxylate instead of rac-tert-butyl(R)-1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-carboxylate (14.2 g, 94% yield). LCMS C 17 H 20 N2O4 requirement value 316.1, measured value m / z = 317.2 [M+H] + . [Examples]

[0345] 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 typically refers to purification on silica gel in pre-packaged cartridges, eluting with a mixture of toluene in hexane or petroleum ether; Chromatography B refers to elution with a mixture of meH in DCM; and Chromatography C refers to the use of C18 reversed-phase silica gel, eluting with a mixture of acetonitrile in water. Compounds drawn without stereochemistry were tested as racemic or diasteromer mixtures in the biological examples.

[0346] Abbreviation The abbreviations used in the examples include: BOP (benzotriazole-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; BINAP (2,2-bis(diphenylphosphin)-1,1-binaphthyl); Bn (benzyl), Boc (tert-butoxycarbonyl); CBz (benzyloxycarbonyl), HATU (N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridine-1-ylmethylene]-N-methylmethanaminonium hexafluorophosphate N-oxy D); DMSO (dimethyl sulfoxide); THF (tetrahydrofuran); Â (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-methyl-2-pyrrolide) N,N-dimethylacetamide (DMA); EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide); HFIP (hexafluoroisopropanol); HOBT (hydroxybenzotriazole); STAB (sodium triacetoxyburohydride); Pd2(dba)3 (tris(dibenzylideneacetone)dipalladium); Pd(dppf)Cl2 ([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)); PE (petroleum ether); RuPhos (paradacycle 3rd generation Substitute: Methanesulfonato(2-dicyclohexylphosphino-2',6'-bis(dimethylamino)-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)); SFC (supercritical fluid chromatography); T3P (propanephosphonic acid cyclic anhydride); XantPhos(9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene); TFA (trifluoroacetic acid); rt or RT (room temperature); anh (anhydride); eq. or equiv. (equivalent), FC (flash chromatography).

[0347] Example 1 RAC-N-[(3R)-2,6-dioxopiperidine-3-yl]-4-(4-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carbonyl}piperazine-1-yl)pyridine-2-carboxamide [ka] Step 1: Synthesis of methyl 1-(6-chloropyridazine-4-yl)-4-phenylpiperidine-4-carboxylate [ka] A vial was filled with 5-bromo-3-chloropyridazine (0.50 g, 2.5849 mmol), methyl 4-phenylpiperidine-4-carboxylate (0.57 g, 2.5849 mmol), and N,N-diisopropylethylamine (1.81 mL, 1.34 g, 10.3397 mmol) in DMSO. This solution was heated overnight to 120°C and then directly purified via RP-FC to obtain the title compound (750 mg, 86%). LCMS:C 17 H 18 ClN3O2 required value: 331.2, measured value: m / z = 332.4 [M+H] + .

[0348] Step 2: Synthesis of methyl 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-phenylpiperidine-4-carboxylate [ka] In a flask equipped with a stirring bar, methyl 1-(6-chloropyridazin-4-yl)-4-phenylpiperidine-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 these dried powders, 12 mL of dried and pre-spared 1,4-dioxane was added. The vial was sealed and heated overnight to 95°C. Upon completion, the crude mixture was filtered through Celite and purified by RP-FC to obtain the title compound (70 mg, 12%). LCMS:C 23 H 23 N3O3 requirement value: 389.5, measured value: m / z = 390.5 [M+H] + .

[0349] Step 3: Synthesis of 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-phenylpiperidine-4-carboxylic acid [ka] Methyl 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-phenylpiperidine-4-carboxylate (200 mg, 0.5135 mmol) was dissolved in 2 mL of 1:1 dioxane:1 M NaOH. The mixture was stirred for approximately 3 hours until complete, then filtered and purified directly via RP-FC to obtain the title compound in quantitative yield. LCMS:C 22 H 21 N3O3 requirement value: 375.4, measured value: m / z = 376.4 [M+H] + .

[0350] Step 4: Synthesis of 4-fluoropicolinic acid [ka] A solution of methyl 4-fluoropicolinate (10.0 g, 64.4 mmol, 1.00 equivalent) in THF (100 mL) and H2O (50.0 mL) was mixed with NaOH (3.87 g, 96.7 mmol, 1.50 equivalent) at 25°C. The mixture was then stirred at 25°C for 2 hours. The mixture was adjusted to pH 2-3 with 1N HCl and lyophilized without purification. 4-fluoropicolinic acid (18.0 g, 122 mmol, 94.8% yield, 95.8% purity) was obtained as a white solid. LCMS C6H4FNO2 demand: 141.0, measured value: m / z = 141.1 [M+H] + .

[0351] 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).

[0352] Step 5: Synthesis of rac-(R)-N-(2,6-dioxopiperidine-3-yl)-4-fluoropicolinamide [ka] A solution of 4-fluoropicolinic acid (9.00 g, 61.1 mmol, 95.8% purity, 1.00 equivalent) in SOCl2 (147 g, 1.24 mol, 90.0 mL, 20.3 equivalents) was stirred at 90°C for 1 hour. The mixture was concentrated and the SOCl2 was removed. 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 equivalent, HCl) and NEt3 (30.9 g, 305 mmol, 42.5 mL, 5.00 equivalent) in DCM (200 mL). The mixture was then stirred at 25°C for 12 hours. The mixture was concentrated under vacuum to obtain the crude product without purification. rac-(R)-N-(2,6-dioxopiperidine-3-yl)-4-fluoropicolinamide (19.0 g, 58.1 mmol, 95.1% yield, 76.8% purity) was obtained as a blue solid. LCMS C 11H 10 FN3O3 required value: 251.1, measured 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).

[0353] Step 6: Synthesis of rac-tert-butyl(R)-4-(2-((2,6-dioxopiperidine-3-yl)carbamoyl)pyridine-4-yl)piperazine-1-carboxylate [ka] To a solution of rac-(R)-N-(2,6-dioxopiperidine-3-yl)-4-fluoropicolinamide (17.0 g, 51.9 mmol, 76.8% purity, 1.00 equivalent) and tert-butylpiperazine-1-carboxylate (9.68 g, 51.9 mmol, 1.00 equivalent) in DMF (170 mL), DIEA (26.8 g, 207 mmol, 36.2 mL, 4.00 equivalent) was added. The mixture was then stirred at 100 °C for 12 hours. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (3 × 250 mL). The combined organic layer was washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1~1 / 1) to obtain rac-tert-butyl(R)-4-(2-((2,6-dioxopiperidine-3-yl)carbamoyl)pyridine-4-yl)piperazine-1-carboxylate (1.86 g, 3.98 mmol, 7.66% yield, 89.3% purity) as a yellow solid. LCMS C 20 H 27 N5O5 requirement value: 417.2, measured value: m / z = 418.3 [M+H] + .

[0354] 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, 2.8 Hz, 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)

[0355] Step 7: Synthesis of rac-(R)-N-(2,6-dioxopiperidine-3-yl)-4-(piperazine-1-yl)picolinamide [ka] To a solution of rac-tert-butyl(R)-4-(2-((2,6-dioxopiperidine-3-yl)carbamoyl)pyridine-4-yl)piperazine-1-carboxylate (1.86 g, 3.98 mmol, 89.3% purity, 1.00 equivalent) in DCM (18.0 mL), HCl / dioxane (4.00 M, 19.6 mL, 19.7 equivalents) was added at 25°C. The mixture was then stirred at 25°C for 12 hours. The mixture was filtered, and the cake was concentrated to obtain the crude product without purification. rac-(R)-N-(2,6-dioxopiperidine-3-yl)-4-(piperazine-1-yl)picolinamide (1.50 g, 3.83 mmol, 96.3% yield, 90.4% purity, HCl salt) was obtained as an off-white solid. LCMS C 15 H 19 N5O3 requirement value: 317.1, measured value: m / z = 318.1 [M + H] + .

[0356] 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).

[0357] Step 8: Synthesis of the title compound 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carboxylic acid (10.00 mg, 0.0266 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridine-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda 5-phosphanoid (20.26 mg, 0.0533 mmol), and N,N-diisopropylethylamine (13.77 mg, 0.1065 mmol) were stirred in DMF. rac-(R)-N-(2,6-dioxopiperidine-3-yl)-4-(piperazine-1-yl)picolinamide (8.45 mg, 0.0266 mmol) was added, and the mixture was stirred at rt until LC-MS analysis was complete. The solution was injected into an RP-FC and purified under a gradient of 0-70% MeCN in H2O to obtain the title compound (2.7 mg, 15%). LC-MS:C 37 H 38 N8O5 required value: 674.3, measured value: m / z = 675.3 [M+H] + .

[0358] Example 2 (3RS)-3-{4-[(1S)-1-(1-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carbonyl}piperidine-4-yl)ethoxy]phenyl}piperidine-2,6-dione [ka] Step 1: Synthesis of tert-butyl(S)-4-(1-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenoxy)ethyl)piperidine-1-carboxylate [ka] In a 20 mL vial, 4-[2,6-bis(benzyloxy)pyridine-3-yl]phenol (500.00 mg, 1.3040 mmol), synthesized as described in compound 3 of PCT publication WO2023 / 018238, tert-butyl 4-[(1R)-1-hydroxyethyl]piperidine-1-carboxylate (897.07 mg, 3.9119 mmol), triphenylphosphine (1.03 g, 3.9119 mmol), and THF (10.00 mL) were added. The reaction mixture was cooled to 0°C, and then diisopropyl azodicarboxylate (0.77 mL, 0.79 g, 3.9119 mmol) was added dropwise. The reaction mixture was stirred for 16 hours while warming to RT, and then concentrated. The obtained residue was purified by FC (80g silica, 0-25% RINKAN / hex) to obtain the title compound as a colorless oil (415mg, 54%). LCMS:C 37 H 42 N2O5 requirement value: 594.7, measured value: m / z = 595.7 [M + H] + .

[0359] Step 2: Synthesis of (3RS)-3-{4-[(1S)-1-(piperidine-4-yl)ethoxy]phenyl}piperidine-2,6-dione [ka] In a 20 mL vial, tert-butyl 4-[(1S)-1-{4-[2,6-bis(benzyloxy)pyridine-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) were added. The reaction mixture was spurged with H2 for 10 minutes, then stirred under an H2 atmosphere (balloon) for 16 hours. The reaction mixture was then filtered through a Celite pad and concentrated. The crude substance was dissolved in TFA / DCM 1:1, stirred for 30 minutes, concentrated, and lyophilized to obtain the title compound as a white solid (247 mg, 85%). LCMS:C 18 H 24N2O3 requirement value: 316.2, measured value: m / z = 317.5 [M + H] + .

[0360] Step 3: Synthesis of the title compound 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carboxylic acid (10.00 mg, 0.0266 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridine-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda 5-phosphanoid (20.26 mg, 0.0533 mmol), and N,N-diisopropylethylamine (13.77 mg, 0.1065 mmol) were stirred in DMF. rac-N-[(3R)-2,6-dioxopiperidine-3-yl]-4-(piperazine-1-yl)pyridine-2-carboxamide (8.45 mg, 0.0266 mmol) was added, and the mixture was stirred at rt until LC-MS analysis was complete. The solution was injected into an RP-FC and purified under a gradient of 0-70% MeCN in H2O to obtain the title compound (6.5 mg, 33%). LC-MS:C 40 H 43 N5O5 requirement value: 673.3, measured value: m / z = 674.3 [M + H] + .

[0361] Experimental Example 3 (3RS)-3-{4-[(1R)-1-(1-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carbonyl}piperidine-4-yl)ethoxy]phenyl}piperidine-2,6-dione [ka] 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carboxylic acid (11.00 mg, 0.0293 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridine-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda 5-phosphanoid (22.28 mg, 0.0586 mmol), and N,N-diisopropylethylamine (20.47 μL, 15.15 mg, 0.1172 mmol) were stirred in DMF. Step 2: (3RS)-3-{4-[(1R)-1-(piperidine-4-yl)ethoxy]phenyl}piperidine-2,6-dione (9.27 mg, 0.0293 mmol) prepared according to the reverse methyl diastereomer of Example 2 was added and stirred at rt until LC-MS was completed. The solution was injected into an RP-FC and purified under a gradient of 0-70% MeCN in H2O to obtain the title compound (4.6 mg, 23%). LC-MS:C 40 H 43 N5O5 requirement value: 673.3, measured value: m / z = 674.3 [M + H] + .

[0362] Example 4 RAC-(3R)-3-{4-[(1-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carbonyl}piperidine-4-yl)oxy]phenyl}piperidine-2,6-dione [ka] Step 1: Synthesis of 4-(2,6-bis(benzyloxy)pyridine-3-yl)phenol [ka] 2,6-Bis(benzyloxy)-3-bromopyridine (290 g, 783 mmol, 1.00 equivalent) and (4-hydroxyphenyl)boronic acid (118 g, 861 mmol, 1.10 equivalent) were dissolved in dioxane (2.90 L). K2CO3 (216 g, 1.57 mol, 2.00 equivalent) and H2O (580 mL) were packed into the reactor under N2 conditions. The suspension was degassed under vacuum and purged several times with N2. Pd(dppf)Cl2 (28.6 g, 39.1 mmol, 0.05 equivalent) was packed into the reactor under N2 conditions. The suspension was degassed under vacuum and purged several times with N2. The mixture was stirred at 110°C for 12 hours. The reaction solution was concentrated under reduced pressure, then diluted with water (500 mL), and extracted with ethyl acetate (3 × 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)pyridine-3-yl)phenol (240 g, 597 mmol, 76.3% yield, 95.5% purity) was obtained as an off-white solid.

[0363] 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).

[0364] Step 2: Synthesis of benzyl 4-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenoxy)piperidine-1-carboxylate [ka] 4-(2,6-bis(benzyloxy)pyridine-3-yl)phenol (120 g, 313 mmol, 1.00 equivalent) was packed into THF (840 mL) in reactor R-1 (2.00 L bottle, parallel) equipped with a stirrer. Benzyl 4-hydroxypiperidine-1-carboxylate (77.3 g, 328 mmol, 1.05 equivalent) was packed into R-1. PPh3 (86.1 g, 328 mmol, 1.05 equivalent) was packed into R-1. Under a nitrogen atmosphere, DEAD (57.2 g, 328 mmol, 59.7 mL, 1.05 equivalent) was added at 0°C. The mixture was stirred under N2 at 25°C for 12 hours. The reaction solution was concentrated under reduced pressure. The crude product was ground in MTBE (500 mL) at 20°C for 1 hour. The filtrate was concentrated at 40-45°C under vacuum. The crude product was then purified by preparative HPLC (column: Phenomenex luna C18 (250×70mm, 10um); mobile phase: [water(HCl)-ACN]; B%: 100-100% 40 min). Benzyl 4-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenoxy)piperidine-1-carboxylate (260g, 427 mmol, crude) was obtained as a yellow oil. LCMS:C 38 H 36 N2O5 requirement value: 600.3, measured value: m / z = 601.4 [M+H] + .

[0365] 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).

[0366] Step 3: Synthesis of 5-(4-(piperidine-4-yloxy)phenyl)pyridine-2,6(1H,3H)-dione [ka] Benzyl 4-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenoxy)piperidine-1-carboxylate (100 g, 166 mmol, 1.00 equivalent) was packed into a DCM (500 mL) in reactor R-1 (2.00 L bottle, parallel) equipped with a stirrer. HBr (521 g, 2.13 mol, 350 mL, 33% purity, 12.7 equivalents) was packed into R-1 at 20°C. The mixture was stirred under N2 at 50°C for 12 hours. The reaction solution was concentrated under reduced pressure. 5-(4-(piperidine-4-yloxy)phenyl)pyridine-2,6(1H,3H)-dione (40.0 g, 139 mmol, 83.9% yield, 95.2% purity) was obtained as a yellow oil. LCMS:C 16 H 18 N2O3 requirement value: 286.1, measured value: m / z = 286.9 [M + H] + .

[0367] Step 4: Synthesis of rac-(R)-3-(4-(piperidine-4-yloxy)phenyl)piperidine-2,6-dione [ka] Reactor R-1 (2.00L bottle) equipped with a stirrer was set up. Argon was blown into the bottle for 2 minutes. Pd(OH)2 (20.0g, 14.2 mmol, 10% purity, 0.12 equivalents) and Pd / C (20.0g, 18.7 mmol, 10% purity, 0.13 equivalents) immersed in MeOH (100mL) were added to R-1. 5-(4-(piperidine-4-yloxy)phenyl)pyridine-2,6(1H,3H)-dione (40.0g, 139 mmol, 1.00 equivalent) was packed into R-1 together with MeOH (700mL). Hydrogen was replaced three times and the mixture was stirred at 50°C for 12 hours. The reaction product was filtered and washed with MeOH (2.00L). HCl / EA (120mL) was added dropwise. rac-(R)-3-(4-(piperidine-4-yloxy)phenyl)piperidine-2,6-dione (30.0 g, 90.3 mmol, 64.6% yield, 97.8% purity, HCl salt) was obtained as a white solid. LC-MS:C 16 H 20 N2O3 requirement value: 288.1, measured value: m / z = 288.9 [M + H] + . 1 H 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)

[0368] Step 5: Synthesis of the title compound 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carboxylic acid (5.00 mg, 0.0133 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridine-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda 5-phosphanoid (10.13 mg, 0.0266 mmol), and N,N-diisopropylethylamine (9.30 μL, 6.89 mg, 0.0533 mmol) were stirred in DMF. rac-(3R)-3-[4-(piperidine-4-yloxy)phenyl]piperidine-2,6-dione (3.84 mg, 0.0133 mmol) was added, and the mixture was stirred at rt until LC-MS analysis was complete. The solution was injected into an RP-FC and purified under a gradient of 0-70% MeCN in H2O to obtain the title compound (2.0 mg, 14%). LC-MS:C 38 H 39 N5O5 requirement value: 645.3, measured value: m / z = 646.3 [M+H] + .

[0369] Example 5 RAC-(3R)-3-{4-[(1-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carbonyl}piperidine-4-yl)methoxy]phenyl}piperidine-2,6-dione [ka] Step 1: Synthesis of tert-butyl 4-((4-(2,6-bis(benzyloxy)pyridine-3-yl)phenoxy)methyl)piperidine-1-carboxylate [ka] In a 20 mL vial, 4-[2,6-bis(benzyloxy)pyridine-3-yl]phenol (200.00 mg, 0.5216 mmol), tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (336.88 mg, 1.5648 mmol), triphenylphosphine (0.41 g, 1.5648 mmol), and THF (4.00 mL) were added. The reaction mixture was cooled to 0°C, and then diisopropyl azodicarboxylate (0.31 mL, 0.32 g, 1.5648 mmol) was added dropwise. The reaction mixture was stirred for 16 hours while being heated to RT, and then concentrated. The resulting residue was purified with FC (40 g silica, 0-25% siRNA / hex) to obtain the title compound as a colorless oil (277 mg, 92%). 36 H 40 N2O5 requirement value: 580.6, measured value: m / z = 581.5 [M + H] + .

[0370] Step 2: Synthesis of rac-(R)-3-(4-(piperidine-4-ylmethoxy)phenyl)piperidine-2,6-dione [ka] In a 20 mL vial, tert-butyl 4-{4-[2,6-bis(benzyloxy)pyridine-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 spurged with H2 for 10 minutes, then stirred under an H2 atmosphere (balloon) for 16 hours. The reaction mixture was then filtered through a Celite pad and concentrated. 4N hydrogen chloride in dioxane (1.00 mL, 0.15 g, 4.0000 mmol) was added to the crude product. The reaction mixture was stirred for 1 hour and then concentrated. LCMS:C 17 H 22 N2O3 requirement value: 302.2, measured value: m / z = 303.3 [M+H] + .

[0371] Step 3: Synthesis of the title compound 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carboxylic acid (5.00 mg, 0.0133 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridine-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda 5-phosphanoid (10.13 mg, 0.0266 mmol), and N,N-diisopropylethylamine (9.30 μL, 6.89 mg, 0.0533 mmol) were stirred in DMF. rac-(3R)-3-[4-(piperidine-4-ylmethoxy)phenyl]piperidine-2,6-dione (4.03 mg, 0.0133 mmol) was added, and the mixture was stirred at rt until LC-MS analysis was complete. The solution was injected into an RP-FC and purified under a gradient of 0-70% MeCN in H2O to obtain the title compound (1.2 mg, 14%). LC-MS:C 39 H 41 N5O5 requirement value: 659.3, measured value: m / z = 660.3 [M+H] + .

[0372] Example 6 RAC-(3R)-3-(4-{4-[(4-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carbonyl}piperazine-1-yl)methyl]piperidine-1-yl}phenyl)piperidine-2,6-dione [ka] 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carboxylic acid (5.00 mg, 0.0133 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridine-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda-5-phosphanoid (10.13 mg, 0.0266 mmol), and N,N-diisopropylethylamine (9.30 μL, 6.89 mg, 0.0533 mmol) were stirred in DMF. rac-(3R)-3-{4-[4-(piperazin-1-ylmethyl)piperidine-1-yl]phenyl}piperidine-2,6-dione (5.43 mg, 0.0146 mmol), synthesized as described for compound HCB36 in Example 40 of PCT Publication WO2022 / 235715, was added and stirred at rt until LC-MS was completed. The solution was injected into an RP-FC and purified under a gradient of 0-70% MeCN in H2O to obtain the title compound (1.0 mg, 9%). LC-MS:C 43 H 49 N7O4 required value: 727.3, measured value: m / z = 728.4 [M+H] + .

[0373] Example 7 RAC-(3R)-3-[4-(4-{[(1-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carbonyl}piperidine-4-yl)amino]methyl}piperidine-1-yl)phenyl]piperidine-2,6-dione [ka] Step 1: Synthesis of rac-(R)-3-(4-(4-((piperidine-4-ylamino)methyl)piperidine-1-yl)phenyl)piperidine-2,6-dione [ka] rac-1-{4-[(3R)-2,6-dioxopiperidine-3-yl]phenyl}piperidine-4-carbaldehyde (100.00 mg, 0.3329 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (66.68 mg, 0.3329 mmol), synthesized as described for compound HCB62 in Example 59 of PCT Publication WO2022 / 235715, 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 minutes. Sodium triacetoxyborohydride (211.69 mg, 0.9988 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction product was concentrated and crudely purified via RP-FC to obtain tert-butylrac-(R)-3-(4-(4-((piperidine-4-ylamino)methyl)piperidine-1-yl)phenyl)piperidine-2,6-dione (146 mg, 83%). The substance was dissolved in 1:1 TFA:DCM, stirred for 1 hour, then concentrated and purified via RP-FC to obtain the title compound, which was used as the crude product without further purification. LCMS:C 27 H 40 N4O4 required value: 384.5, measured value: m / z = 385.6 [M+H] + .

[0374] Step 2: Synthesis of the title compound 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carboxylic acid (5.00 mg, 0.0133 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridine-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda 5-phosphanoid (10.13 mg, 0.0266 mmol), and N,N-diisopropylethylamine (9.30 μL, 6.89 mg, 0.0533 mmol) were stirred in DMF. rac-(3R)-3-(4-{4-[(piperidine-4-ylamino)methyl]piperidine-1-yl}phenyl)piperidine-2,6-dione (5.63 mg, 0.0146 mmol) was added, and the mixture was stirred at rt until LCMS analysis was complete. The solution was injected into an RP-FC and purified under a gradient of 0-70% MeCN in H2O to obtain the title compound (0.8 mg, 8%). LC-MS:C 44 H 51 N7O4 required value: 741.4, measured value: m / z = 742.4 [M+H] + .

[0375] Example 8 (3S)-3-(4-{4-[(6-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carbonyl}-2,6-diazaspiro[3.3]heptan-2-yl)methyl]piperidine-1-yl}phenyl)piperidine-2,6-dione [ka] Step 1: Synthesis of (S)-3-(4-(4-((2,6-diazaspiro[3,3]heptan-2-yl)methyl)piperidine-1-yl)phenyl)piperidine-2,6-dione [ka] This 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 30N4O2 requirement value: 382.5, measured value: m / z = 383.4 [M + H] + .

[0376] Step 2: Synthesis of the title compound 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carboxylic acid (30.00 mg, 0.0799 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridine-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda 5-phosphanoid (60.77 mg, 0.1598 mmol), and N,N-diisopropylethylamine (0.06 mL, 41.31 mg, 0.3196 mmol) were stirred in DMF. (3S)-3-[4-(4-{2,6-diazaspiro[3,3]heptan-2-ylmethyl}piperidine-1-yl)phenyl]piperidine-2,6-dione (33.62 mg, 0.0879 mmol) was added and stirred at rt until LC-MS was completed. The solution was injected into an RP-FC and purified under a gradient of 0-70% MeCN in H2O to obtain the title compound (10.1 mg, 16%). LC-MS:C 44 H 49 N7O4 required value: 739.4, measured value: m / z = 740.4 [M+H] + .

[0377] Example 9 (3S)-3-(4-{4-[(2-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carbonyl}-2,6-diazaspiro[3.4]octan-6-yl)methyl]piperidine-1-yl}phenyl)piperidine-2,6-dione [ka] Step 1: (S)-3-(4-(4-((2,6-diazaspiro[3,4]octan-6-yl)methyl)piperidine-1-yl)phenyl)piperidine-2,6-dione [ka] This 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 N4O2 requirement value: 396.5, measured value: m / z = 397.5 [M + H] + .

[0378] Step 2: Synthesis of the title compound 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carboxylic acid (8.00 mg, 0.0213 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridine-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda 5-phosphanoid (16.20 mg, 0.0426 mmol), and N,N-diisopropylethylamine (14.89 μL, 11.02 mg, 0.0852 mmol) were stirred in DMF. (3S)-3-[4-(4-{2,6-diazaspiro[3,4]octan-6-ylmethyl}piperidine-1-yl)phenyl]piperidine-2,6-dione (9.29 mg, 0.0234 mmol) was added and stirred at rt until LC-MS was completed. The solution was injected into an RP-FC and purified under a gradient of 0-70% MeCN in H2O to obtain the title compound (3.4 mg, 21%). LC-MS:C 45 H 51 N7O4 required value: 753.4, measured value: m / z = 754.4 [M+H] + .

[0379] Example 10 N-({1-[(1-{4-[(3S)-2,6-dioxopiperidine-3-yl]phenyl}piperidine-4-yl)methyl]piperidine-3-yl}methyl)-1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carboxamide [ka] Step 1: (3S)-3-(4-(4-((3-(aminomethyl)piperidine-1-yl)methyl)piperidine-1-yl)phenyl)piperidine-2,6-dione [ka] This intermediate was synthesized using tert-butyl(piperidine-3-ylmethyl)carbamate according to step 1 of Example 7. LCMS:C 23 H 34 N4O2 requirement value: 398.5, measured value: m / z = 399.5 [M + H] + .

[0380] Step 2: Synthesis of the title compound 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carboxylic acid (8.00 mg, 0.0213 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridine-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda 5-phosphanoid (16.20 mg, 0.0426 mmol), and N,N-diisopropylethylamine (14.89 μL, 11.02 mg, 0.0852 mmol) were stirred in DMF. (3S)-3-[4-(4-{[3-(aminomethyl)piperidine-1-yl]methyl}piperidine-1-yl)phenyl]piperidine-2,6-dione (9.34 mg, 0.0234 mmol) was added, and the mixture was stirred at rt until LCMS analysis was complete. The solution was injected into an RP-FC and purified under a gradient of 0-70% MeCN in H2O to obtain the title compound (0.8 mg, 5%). LC-MS:C 45 H 51 N7O4 required value: 755.4, measured value: m / z = 756.4 [M+H] + .

[0381] Example 11 RAC-(3R)-3-[4-({1-[(1-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carbonyl}piperidine-4-yl)methyl]piperidine-4-yl}methoxy)phenyl]piperidine-2,6-dione [ka] Step 1: Synthesis of rac-(R)-3-(4-(piperidine-4-ylmethoxy)phenyl)piperidine-2,6-dione [ka] In a 20 mL vial, tert-butyl 4-{4-[2,6-bis(benzyloxy)pyridine-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 spurged with H2 for 10 minutes, then stirred under an H2 atmosphere (balloon) for 16 hours. The reaction mixture was then filtered through a Celite pad and concentrated to obtain a Boc intermediate (162 mg, 84%), which was dissolved in 1:1 TFA:DCM for 1 hour, concentrated, and lyophilized to obtain the title compound. LCMS:C 17 H 22 N2O3 requirement value: 302.4, measured value: m / z = 303.3 [M+H] + .

[0382] Step 2: Synthesis of rac-(R)-3-(4-((1-(piperidine-4-ylmethyl)piperidine-4-yl)methoxy)phenyl)piperidine-2,6-dione [ka] rac-(R)-3-(4-(piperidine-4-ylmethoxy)phenyl)piperidine-2,6-dione and tert-butyl4-formylpiperidine-1-carboxylate were dissolved in dry DCE. N,N-diisopropylethylamine (72.20 μL, 53.43 mg, 0.4134 mmol) was added, and the reaction mixture was stirred for 30 minutes. Sodium triacetoxyborohydride (52.57 mg, 0.2480 mmol) was added. The mixture was then stirred overnight in rt and purified via RP-FC to obtain a Boc-protected intermediate (30 mg, 66%). This substance was dissolved in 1:1 TFA:DCM, stirred at room temperature for 1 hour, then concentrated, and used in the next step without further purification. LCMS:C 23 H 33 N3O3 requirement value: 399.3, measured value: m / z = 400.4 [M+H] + .

[0383] Step 3: Synthesis of the title compound 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carboxylic acid (15.00 mg, 0.0400 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridine-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda 5-phosphanoid (30.38 mg, 0.0799 mmol), and N,N-diisopropylethylamine (27.91 μL, 20.66 mg, 0.1598 mmol) were stirred in DMF. rac-(3R)-3-(4-{[1-(piperidine-4-ylmethyl)piperidine-4-yl]methoxy}phenyl)piperidine-2,6-dione (17.56 mg, 0.0439 mmol) was added, and the mixture was stirred at rt until LCMS analysis was complete. The solution was injected into an RP-FC and purified under a gradient of 0-70% MeCN in H2O to obtain the title compound (1.2 mg, 4%). LC-MS:C 45 H 52 N6O5 required value: 756.4, measured value: m / z = 757.4 [M+H] + .

[0384] Example 12 RAC-(3R)-3-[4-({1-[(1-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carbonyl}piperidine-4-yl)methyl]piperidine-4-yl}oxy)phenyl]piperidine-2,6-dione [ka] Step 1: Synthesis of rac-(R)-3-(4-((1-(piperidine-4-ylmethyl)piperidine-4-yl)oxy)phenyl)piperidine-2,6-dione [ka] rac-(3R)-3-[4-(piperidine-4-yloxy)phenyl]piperidine-2,6-dione (25.00 mg, 0.0827 mmol) and tert-butyl 4-formylpiperidine-1-carboxylate (17.63 mg, 0.0827 mmol) were dissolved in dry DCE. N,N-diisopropylethylamine (72.20 μL, 53.43 mg, 0.4134 mmol) was added, and the reaction mixture was stirred for 30 minutes. Sodium triacetoxyborohydride (52.57 mg, 0.2480 mmol) was added. The mixture was stirred overnight in rt, then concentrated, and purified via RP-FC to obtain the Boc intermediate (30 mg, 69%), which was then dissolved in 1:1 TFA:DCM, stirred for 1 hour, then concentrated, and lyophilized. LCMS:C 27 H 39 N3O5 requirement value: 485.6, measured value: m / z = 486.6 [M + H] + .

[0385] Step 2: Synthesis of the title compound 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carboxylic acid (30.00 mg, 0.0799 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridine-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda 5-phosphanoid (60.77 mg, 0.1598 mmol), and N,N-diisopropylethylamine (55.83 μL, 41.31 mg, 0.3196 mmol) were stirred in DMF. rac-(3R)-3-(4-{[1-(piperidine-4-ylmethyl)piperidine-4-yl]oxy}phenyl)piperidine-2,6-dione (33.89 mg, 0.0879 mmol) was added, and the mixture was stirred at rt until LC-MS analysis was complete. The solution was injected into an RP-FC and purified under a gradient of 0-70% MeCN in H2O to obtain the title compound (3.4 mg, 6%). LC-MS:C 44 H 50 N6O5 required value: 742.4, measured value: m / z = 743.4 [M+H] + .

[0386] Example 13 RAC-(3R)-3-(4-{[1-(1-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carbonyl}piperidine-4-carbonyl)piperidine-4-yl]oxy}phenyl)piperidine-2,6-dione [ka] Step 1: Synthesis of rac-(R)-3-(4-((1-(piperidine-4-carbonyl)piperidine-4-yl)oxy)phenyl)piperidine-2,6-dione [ka] rac-(3R)-3-[4-(piperidine-4-yloxy)phenyl]piperidine-2,6-dione (45.00 mg, 0.1561 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridine-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda 5-phosphanui (118.68 mg, 0.3121 mmol), and N,N-diisopropylethylamine (80.68 mg, 0.6242 mmol) were stirred in DMF. 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (35.78 mg, 0.1561 mmol) was added, and the mixture was stirred at rt until LC-MS was completed. Direct injection was performed, and the mixture was purified using RP FC to obtain the Boc-protected intermediate (28 mg, 36%). Next, this substance was dissolved in 1:1 TFA:DCM, stirred at rt for 1 hour, then concentrated, and used in the next step: LCMS:C 22 H 29 N3O4 requirement value: 399.5, measured value: m / z = 400.5 [M+H] + .

[0387] Step 2: Synthesis of the title compound 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carboxylic acid (22.00 mg, 0.0586 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridine-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda 5-phosphanoid (44.56 mg, 0.1172 mmol), and N,N-diisopropylethylamine (40.94 μL, 30.30 mg, 0.2344 mmol) were stirred in DMF. rac-(3R)-3-(4-{[1-(piperidine-4-carbonyl)piperidine-4-yl]oxy}phenyl)piperidine-2,6-dione (25.75 mg, 0.0645 mmol) was added, and the mixture was stirred at rt until LCMS analysis was complete. The solution was injected into an RP-FC and purified under a gradient of 0-70% MeCN in H2O to obtain the title compound (7.2 mg, 15%). LC-MS:C 44 H 48N6O5 required value: 756.4, measured value: m / z = 757.2 [M+H] + .

[0388] Example 14 RAC-(3R)-3-(4-{[1-(1-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carbonyl}piperidine-4-carbonyl)piperidine-4-yl]methoxy}phenyl)piperidine-2,6-dione [ka] Step 1: Synthesis of rac-(R)-3-(4-((1-(piperidine-4-carbonyl)piperidine-4-yl)methoxy)phenyl)piperidine-2,6-dione [ka] rac-(3R)-3-[4-(piperidine-4-ylmethoxy)phenyl]piperidine-2,6-dione (45.00 mg, 0.1488 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridine-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda 5-phosphanoid (113.17 mg, 0.2976 mmol), and N,N-diisopropylethylamine (103.97 μL, 76.94 mg, 0.5953 mmol) were stirred in DMF. 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (34.12 mg, 0.1488 mmol) was added and stirred at rt until LC-MS was completed. Direct injection into RP-FC was performed to isolate the Boc-protected intermediate (45 mg, 58%). Concentrate, dissolve in 1:1 TFA:DCM, stir for 1 hour, then concentrate, freeze-dry, and use in the next step. LCMS:C 23 H 31 N3O4 requirement value: 413.6, measured value: m / z = 414.6 [M + H] + .

[0389] Step 2: Synthesis of the title compound 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carboxylic acid (22.00 mg, 0.0586 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridine-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda 5-phosphanoid (44.56 mg, 0.1172 mmol), and N,N-diisopropylethylamine (40.94 μL, 30.30 mg, 0.2344 mmol) were stirred in DMF. rac-(3R)-3-(4-{[1-(piperidine-4-carbonyl)piperidine-4-yl]methoxy}phenyl)piperidine-2,6-dione (26.66 mg, 0.0645 mmol) was added, and the mixture was stirred at rt until LCMS analysis was complete. The solution was injected into an RP-FC and purified under a gradient of 0-70% MeCN in H2O to obtain the title compound (2.4 mg, 5%). LC-MS:C 45 H 50 N6O4 required value: 770.4, measured value: m / z = 771.4 [M+H] + .

[0390] Example 15 (3R)-3-(4-{4-[(6-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carbonyl}-2,6-diazaspiro[3.3]heptan-2-yl)methyl]piperidine-1-yl}phenyl)piperidine-2,6-dione [ka] Step 1: Synthesis of (1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-phenylpiperidine-4-yl)(2,6-diazaspiro[3,3]heptan-2-yl)methanone [ka] 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carboxylic acid (10.00 mg, 0.0266 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridine-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda 5-phosphanoid (20.26 mg, 0.0533 mmol), and N,N-diisopropylethylamine (18.61 μL, 13.77 mg, 0.1065 mmol) were stirred in DMF. tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (5.81 mg, 0.0293 mmol) was added, and the mixture was stirred at rt until LC-MS was completed. The mixture was injected directly and purified via RP-FC to obtain the Boc intermediate (6.2 mg, 37%). This substance was dissolved in 1:1 TFA:DCM, stirred at rt for 1 hour, then concentrated, freeze-dried, and used without further purification. LCMS:C 27 H 29 N5O2 requirement value: 455.3, measured value: m / z = 456.5 [M + H] + .

[0391] Step 2: Synthesis of the title compound In a scintillation vial, 2-[5-(4-{2,6-diazaspiro[3,3]heptan-2-carbonyl}-4-phenylpiperidine-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-dioxopiperidine-3-yl]phenyl}piperidine-4-carbaldehyde (33.23 mg, 0.1106 mmol), and DCE (3.00 mL) were added and stirred at rt. Sodium triacetoxyborohydride (68.39 mg, 0.3227 mmol) was added. The mixture was stirred until the starting materials were completely consumed by MS. The reaction was completed after 90 minutes and the mixture was purified. The reaction was quenched by adding bicarbonate and extracted with RINKAN. The organic layer was dried over brine and then Na2SO4. The solution was concentrated and injected into an RP-FC, and purified under a gradient of 0–70% MeCN in H2O to obtain the title compound (27.4 mg, 40%). LCMS:C 44 H 49 N7O4 required value: 739.4, measured value: m / z = 740.4 [M+H] + .

[0392] 1H NMR (500 MHz, DMSO) δ 10.69 (d, J = 2.5 Hz, 1H), 9.57 (d, J = 0.9 Hz, 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 = 4.1 Hz, 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).

[0393] Example 16 (3R)-3-(4-{4-[(6-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carbonyl}-2,6-diazaspiro[3.4]octan-2-yl)methyl]piperidine-1-yl}phenyl)piperidine-2,6-dione [ka] Step 1: Synthesis of (1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-phenylpiperidine-4-yl)(2,6-diazaspiro[3,4]octan-6-yl)methanone [ka] 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carboxylic acid (99.00 mg, 0.2637 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridine-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda 5-phosphanoid (250.67 mg, 0.6592 mmol), and N,N-diisopropylethylamine (230.29 μL, 170.41 mg, 1.3185 mmol) were stirred in DMF. tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (75.57 mg, 0.3560 mmol) was added, and the mixture was stirred at rt until LCMS analysis was complete. The mixture was injected and purified directly via RP-FC to obtain a Boc intermediate (170 mg, 99%). This substance was dissolved in 1:1 TFA:DCM, stirred at rt for 1 hour, then concentrated and lyophilized for use in the next step: LCMS:C 28 H 31 N5O2 requirement value: 469.3, measured value: m / z = 470.5 [M + H] + .

[0394] Step 2: Synthesis of the title compound In a scintillation vial, 2-[5-(4-{2,6-diazaspiro[3,4]octane-6-carbonyl}-4-phenylpiperidine-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-dioxopiperidine-3-yl]phenyl}piperidine-4-carbaldehyde (33.23 mg, 0.1106 mmol), and DCE (3.00 mL) were added and stirred at rt. Sodium triacetoxyborohydride (68.39 mg, 0.3227 mmol) was added. The mixture was stirred until the starting materials were completely consumed by MS. The reaction was completed after 90 minutes and the mixture was purified. The reaction was quenched by adding bicarbonate and extracted with RINKAN. The organic layer was dried over brine and then Na2SO4. The solution was concentrated and injected into an RP-FC, and purified under a gradient of 0–70% MeCN in H2O to obtain the title compound (19.8 mg, 29%). LCMS:C 45 H 51 N7O4 required value: 753.4, measured value: m / z = 754.4 [M+H] + .

[0395] 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 = 7.5 Hz, 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 N7O4 required value: 753.4, measured value: m / z = 754.8 [M+H] + .

[0396] Example 17 (3R)-3-(4-{4-[(2-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carbonyl}-2,6-diazaspiro[3.4]octan-6-yl)methyl]piperidine-1-yl}phenyl)piperidine-2,6-dione [ka] Step 1: Synthesis of (1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-phenylpiperidine-4-yl)(2,6-diazaspiro[3,4]octan-2-yl)methanone [ka] 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carboxylic acid (99.00 mg, 0.2637 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridine-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda 5-phosphanoid (250.67 mg, 0.6592 mmol), and N,N-diisopropylethylamine (230.29 μL, 170.41 mg, 1.3185 mmol) were stirred in DMF. tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate (75.57 mg, 0.3560 mmol) was added, and the mixture was stirred at rt until LCMS analysis was complete. The mixture was injected and purified directly via RP-FC to obtain a Boc intermediate (170 mg, 99%). This substance was dissolved in 1:1 TFA:DCM, stirred at rt for 1 hour, then concentrated and lyophilized for use in the next step: LCMS:C 28 H 31 N5O2 requirement value: 469.3, measured value: m / z = 470.5 [M + H] + .

[0397] Step 2: Synthesis of the title compound In a scintillation vial, 2-[5-(4-{2,6-diazaspiro[3,4]octan-2-carbonyl}-4-phenylpiperidine-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-dioxopiperidine-3-yl]phenyl}piperidine-4-carbaldehyde (33.23 mg, 0.1106 mmol), and DCE (3.00 mL) were added and stirred at rt. Sodium triacetoxyborohydride (68.39 mg, 0.3227 mmol) was then added. The mixture was stirred until the starting materials were completely consumed by MS. The reaction was completed after 90 minutes and the mixture was purified. The reaction was quenched by adding bicarbonate and extracted with RINKAN. The organic layer was dried over brine and then Na2SO4. The solution was concentrated and injected into an RP-FC, and purified under a gradient of 0–70% MeCN in H2O to obtain the title compound (24.0 mg, 31%). LCMS:C 45 H 51 N7O4 required value: 753.4, measured value: m / z = 754.4 [M+H] + .

[0398] 1H 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 = 3.0 Hz, 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 = 4.8 Hz, 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).

[0399] Example 18 RAC-(3R)-3-(4-{4-[2-(1-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carbonyl}piperidine-4-yl)acetyl]piperazine-1-yl}phenyl)piperidine-2,6-dione [ka] Step 1: Synthesis of (1-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carbonyl}piperidine-4-yl)acetic acid [ka] 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carboxylic acid (70.00 mg, 0.1865 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridine-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda 5-phosphanoid (177.24 mg, 0.4661 mmol), and N,N-diisopropylethylamine (162.83 μL, 120.49 mg, 0.9323 mmol) were stirred in DMF. tert-butyl 2-(piperidine-4-yl) acetate (49.09 μL, 46.63 mg, 0.2517 mmol) was added, and the mixture was stirred at rt until LC-MS analysis was complete. The mixture is directly injected into an RP-FC and purified to isolate the t-Bu protecting intermediate (80 mg, 69%). This substance is dissolved in a 1:1 TFA:DCM solution and stirred at rt for 1 hour. LCMS:C 29 H 32 N4O4 requirement value: 500.6, measured value: m / z = 501.4 [M+H] + .

[0400] Step 2: Synthesis of the title compound (1-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carbonyl}piperidine-4-yl)acetic acid (10.00 mg, 0.0200 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridine-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda 5-phosphanoid (18.99 mg, 0.0499 mmol), and N,N-diisopropylethylamine (17.44 μL, 12.91 mg, 0.0999 mmol) were stirred in DMF. rac-(3R)-3-[4-(piperazin-1-yl)phenyl]piperidine-2,6-dione (6.55 mg, 0.0240 mmol), synthesized as described in compound 5 of PCT publication WO2023 / 018238, was added and stirred at rt until LC-MS was completed. The solution was injected into an RP-FC and purified under a gradient of 0-70% MeCN in H2O to obtain the title compound (4.3 mg, 29%). LC-MS:C 44 H 49 N7O5 required value: 755.4, measured value: m / z = 756.7 [M+H] + .

[0401] Example 19 RAC-(3R)-3-(6-{4-fluoro-4-[(6-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carbonyl}-2,6-diazaspiro[3,3]heptan-2-yl)methyl]piperidine-1-yl}pyridine-3-yl)piperidine-2,6-dione [ka] Step 1: Synthesis of (4-fluoro-1-(5-iodopyridine-2-yl)piperidine-4-yl)methanol [ka] To a solution of 2-bromo-5-iodopyridine (5.92 g, 26.5 mmol, 1.00 equivalent) in DMF (45.0 mL), (4-fluoropiperidine-4-yl)methanol (4.50 g, 26.5 mmol, 1.00 equivalent, HCl) and K2CO3 (12.8 g, 92.9 mmol, 3.50 equivalent) were added at 20°C. The mixture was heated to 90°C and stirred at 90°C for 16 hours. The reaction mixture was poured into water (225 mL), stirred at 20°C for 5 minutes, filtered, and the filtered cake was concentrated under vacuum. The crude product was ground in petroleum ether:ethyl acetate = 3:1 (25.0 mL) at 25°C for 2 hours, filtered, and the filtered cake was concentrated under vacuum. The filtrate was concentrated under vacuum and then purified by silica gel chromatography (SiO2, petroleum ether:ethyl acetate = 12:1~5:1). (4-Fluoro-1-(5-iodopyridine-2-yl)piperidine-4-yl)methanol (4.04 g, crude) was obtained as a white solid. LCMS:C 11 H 14 FIN2O required value: 336.0, measured 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).

[0402] Step 2: Synthesis of (1-(2',6'-bis(benzyloxy)-[3,3'-bipyridine]-6-yl)-4-fluoropiperidine-4-yl)methanol [ka] To a solution of (4-fluoro-1-(5-iodopyridine-2-yl)piperidine-4-yl)methanol (3.60 g, 10.7 mmol, 1.10 equivalents) and 2,6-bis(benzyloxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4.06 g, 9.74 mmol, 1.00 equivalent) in dioxane (32.4 mL) and H2O (3.60 mL), XPhos Pd G3 (824 mg, 974 μmol, 0.10 equivalents) was added. K3PO4 (5.17 g, 24.3 mmol, 2.50 equivalents) was added to the mixture at 20°C under N2 conditions, the mixture was degassed, purged three times with N2, and stirred at 90°C for 12 hours under an N2 atmosphere. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 3:1 to 1:1). (1-(2',6'-bis(benzyloxy)-[3,3'-bipyridine]-6-yl)-4-fluoropiperidine-4-yl)methanol (3.64 g, 7.25 mmol, 74.5% yield, 99.6% purity) was obtained as a white solid. LCMS:C 30 H 30 FN3O3 required value: 499.2, measured 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).

[0403] Step 3: Synthesis of rac-(R)-3-(6-(4-fluoro-4-(hydroxymethyl)piperidine-1-yl)pyridine-3-yl)piperidine-2,6-dione [ka] To a solution of (1-(2',6'-bis(benzyloxy)-[3,3'-bipyridine]-6-yl)-4-fluoropiperidine-4-yl)methanol (2.60 g, 5.20 mmol, 1.00 equivalent) in THF (13.0 mL) and EtOH (13.0 mL), AcOH (313 mg, 5.20 mmol, 298 μL, 1.00 equivalent) and Pd / C (1.30 g, 10.0% purity) were added at 20°C under an N2 atmosphere. The suspension was degassed, purged three times with H2, and the mixture was stirred at 50°C for 2 hours 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 = 15:1~10:1). rac-(R)-3-(6-(4-fluoro-4-(hydroxymethyl)piperidine-1-yl)pyridine-3-yl)piperidine-2,6-dione (1.17 g, 3.64 mmol, 70.0% yield) was obtained as an off-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).

[0404] Step 4: Synthesis of rac-(R)-1-(5-(2,6-dioxopiperidine-3-yl)pyridine-2-yl)-4-fluoropiperidine-4-carbaldehyde [ka] rac-(R)-3-(6-(4-fluoro-4-(hydroxymethyl)piperidine-1-yl)pyridine-3-yl)piperidine-2,6-dione To a solution of rac-(R)-3-(6-(4-fluoro-4-(hydroxymethyl)piperidine-1-yl)pyridine-3-yl)piperidine-2,6-dione (1.20 g, 3.72 mmol, 1.00 equivalent) in 24.0 mL of DCM cooled to 0°C, des-martin periodinane (3.16 g, 7.45 mmol, 2.31 mL, 2.00 equivalent) was added, and the mixture was stirred at 20°C for 12 hours. The mixture was quenched with saturated Na2SO3 solution (50.0 mL), extracted with DCM:EtOH = 10:1 (4 x 50.0 mL), and the organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; B%: 4%~34%, 10 min), then concentrated under vacuum to remove ACN, and concentrated by lyophilization to obtain the product rac-(R)-1-(5-(2,6-dioxopiperidine-3-yl)pyridine-2-yl)-4-fluoropiperidine-4-carbaldehyde (265 mg, 822 umol, 26.2% yield, 99.0% purity) as a white solid. LCMS:C 16 H 18 FN3O3 required value: 319.1, measured 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).

[0405] Step 5: Synthesis of the title compound In a scintillation vial, 2-[5-(4-{2,6-diazaspiro[3,4]octan-2-carbonyl}-4-phenylpiperidine-1-yl)pyridazin-3-yl]phenol (15.00 mg, 0.0381 mmol), triethylamine (26.06 μL, 0.1906 mmol), 1-{4-[(3R)-2,6-dioxopiperidine-3-yl]phenyl}piperidine-4-carbaldehyde (13.74 mg, 0.0457 mmol), and DCE (3.00 mL) were added and stirred at rt. Sodium triacetoxyborohydride (28.28 mg, 0.1334 mmol) was added. The mixture was stirred until the starting materials were completely consumed by MS. The reaction was completed after 90 minutes and the solution was purified. The reaction was quenched by adding bicarbonate and extracted with siRNA. The organic layer was brined and then dried over Na2SO4. The solution was concentrated and injected into an RP-FC, and purified under a gradient of 0–70% MeCN in H2O to obtain the title compound (7.7 mg, 44%). LC-MS:C 43 H 47 N8O4F required value: 758.4, measured value: m / z = 759.4 [M+H] + .

[0406] Example 20 RAC-(3R)-3-{4-[4-(6-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carbonyl}-2,6-diazaspiro[3,3]heptan-2-carbonyl)piperidine-1-yl]phenyl}piperidine-2,6-dione [ka] Step 1: Synthesis of tert-butyl 1-(4-bromophenyl)piperidine-4-carboxylate [ka] To a solution of 1-bromo-4-iodobenzene (50.0 g, 176 mmol, 1.00 equivalent) and tert-butylpiperidine-4-carboxylate (36.0 g, 194 mmol, 1.10 equivalents) in DMSO (500 mL), L-hydroxyproline (9.27 g, 70.7 mmol, 0.400 equivalents), K2CO3 (48.8 g, 353 mmol, 2.00 equivalents), and CuI (6.73 g, 35.3 mmol, 0.200 equivalents) were added under N2. The reaction mixture was stirred at 90°C for 12 hours. The reaction mixture was poured into H2O (500 mL) and then extracted with ethyl acetate (3 × 500 mL). The combined organic layer was washed with brine (2 × 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 (43.0 g, 107 mmol, 50.6% yield, 84.9% purity) was obtained as a white solid. LCMS:C 16 H 22 BrNO2 required value: 339.1, measured value: m / z = 340.1 [M+H] + . 1 H NMR:(400 MHz, DMSO) δ 7.47 -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).

[0407] Step 2: Synthesis of tert-butyl 1-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)piperidine-4-carboxylate [ka] To a solution of (2,6-bis(benzyloxy)pyridine-3-yl)boronic acid (47.5 g, 114 mmol, 1.20 equivalents) in dioxane (400 mL) and H2O (80 mL), tert-butyl 1-(4-bromophenyl)piperidine-4-carboxylate (38.0 g, 94.8 mmol, 84.9% purity, 1.00 equivalent), K2CO3 (39.3 g, 284 mmol, 3.00 equivalent), and Pd(dppf)Cl2 (3.47 g, 4.74 mmol, 0.05 equivalent) were added at 20°C. The reaction mixture was stirred at 90°C for 12 hours. The reaction mixture was poured into H2O (500 mL) and then extracted with ethyl acetate (3 × 500 mL). The combined organic layers were washed with brine (2 × 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)pyridine-3-yl)phenyl)piperidine-4-carboxylate (46.0 g, 81.2 mmol, 75.8% yield, 97.2% purity) was obtained as a white solid. LCMS:C 35 H 38 N2O4 requirement value: 550.3, measured 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).

[0408] Step 3: Synthesis of rac-tert-butyl(R)-1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-carboxylate [ka] To a solution of tert-butyl 1-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)piperidine-4-carboxylate (41.0 g, 72.4 mmol, 97.2% purity, 1.00 equivalent) in THF (410 mL), Pd / C (10.0 g, 72.4 mmol, 10.0% purity, 1.00 equivalent) was added under N2. The suspension was degassed under vacuum and purged three times with H2. The reaction mixture was stirred at 25°C for 12 hours under H2 (50 psi). The suspension was filtered through a Celite pad, and the pad was washed with THF (4 × 500 mL). The solution was concentrated under reduced pressure using a rotary evaporator. rac-tert-butyl(R)-1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-carboxylate (30.0 g, 77.6 mmol, 95.7% yield, 96.3% purity) was obtained as a white solid. LCMS:C 21 H 28 N2O4 requirement value: 372.2, measured 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).

[0409] Step 4: Synthesis of rac-(R)-1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-carboxylic acid [ka] To a solution of rac-tert-butyl(R)-1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-carboxylate (10.0 g, 25.8 mmol, 96.3% purity, 1.00 equivalent) in DCM (270 mL), TFA (29.5 g, 258 mmol, 19.1 mL, 10.0 equivalent) was added at 25°C. The reaction mixture was then stirred at 25°C for 12 hours. 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 minutes, then filtered, and the filtered cake was concentrated under vacuum. rac-(R)-1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-carboxylic acid (9.00 g, 20.3 mmol, 60.5% yield, 97.3% purity, TFA salt) was obtained as a white solid. LCMS:C 17 H 20 N2O4 requirement value: 316.1, measured value: m / z = 317.2 [M + H] + . 1 H NMR (400 MHz, D2O) δ 7.61 (d, J = 8.8 Hz, 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).

[0410] Step 5: Synthesis of the title compound 2-[5-(4-{2,6-diazaspiro[3,3]heptan-2-carbonyl}-4-phenylpiperidine-1-yl)pyridazin-3-yl]phenol (10.00 mg, 0.0220 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridine-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda 5-phosphanoid (20.87 mg, 0.0549 mmol), and N,N-diisopropylethylamine (19.17 μL, 14.19 mg, 0.1098 mmol) were stirred in DMF. rac-1-{4-[(3R)-2,6-dioxopiperidine-3-yl]phenyl}piperidine-4-carboxylic acid was added and the mixture was stirred at rt until LC-MS analysis was complete. The solution was injected into an RP-FC and purified under a gradient of 0-70% MeCN in H2O to obtain the title compound (4.6 mg, 28%). LC-MS:C 44 H 47 N7O4 required value: 753.4, measured value: m / z = 754.4 [M+H] + .

[0411] Example 21 RAC-(3R)-3-{4-[4-(1-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carbonyl}-4-methylpiperidine-4-carbonyl)piperazine-1-yl]phenyl}piperidine-2,6-dione [ka] Step 1: Synthesis of methyl 1-(1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-phenylpiperidine-4-carbonyl)-4-methylpiperidine-4-carboxylate [ka] 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carboxylic acid (71.00 mg, 0.1891 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridine-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda 5-phosphanoid (179.77 mg, 0.4728 mmol), and N,N-diisopropylethylamine (165.15 μL, 122.21 mg, 0.9456 mmol) were stirred in DMF. Methyl 4-methylpiperidine-4-carboxylate (27.87 μL, 40.14 mg, 0.2553 mmol) was added, and the mixture was stirred at rt until LC-MS analysis was complete. The mixture was directly injected into an RP-FC and purified to obtain the title compound (80 mg, 73%). LC-MS:C 30 H 34 N4O4 required value: 514.6 Measured value: m / z = 515.5 [M+H] + .

[0412] Step 2: Synthesis of 1-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carbonyl}-4-methylpiperidine-4-carboxylic acid [ka] A mixture of methyl 1-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carbonyl}-4-methylpiperidine-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 hours. 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.

[0413] Step 3: Synthesis of the title compound 1-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carbonyl}-4-methylpiperidine-4-carboxylic acid (10.10 mg, 0.0202 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridine-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda 5-phosphanoid (19.18 mg, 0.0504 mmol), and N,N-diisopropylethylamine (17.62 μL, 13.04 mg, 0.1009 mmol) were stirred in DMF. rac-(3R)-3-[4-(piperazin-1-yl)phenyl]piperidine-2,6-dione (6.62 mg, 0.0242 mmol) was added, and the mixture was stirred at rt until LCMS analysis was complete. The solution was injected into an RP-FC and purified under a gradient of 0-70% MeCN in H2O to obtain the title compound (5.9 mg, 35%). LC-MS:C 44 H 49 N7O4 required value: 755.4, measured value: m / z = 756.4 [M+H] + .

[0414] Example 22 RAC-(3R)-3-(4-{4-[4-(4-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carbonyl}piperazine-1-yl)butanoyl]piperazine-1-yl}phenyl)piperidine-2,6-dione [ka] Step 1: Synthesis of 4-(4-(1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-phenylpiperidine-4-carbonyl)piperazin-1-yl)butanoic acid [ka] 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carboxylic acid (17.00 mg, 0.0453 mmol), [chloro(dimethylamino)methylidene]dimethylazanium; hexafluoro-lambda 5-phosphanui (25.41 mg, 0.0906 mmol), and 1-methylimidazole (14.87 mg, 0.1811 mmol) were stirred in DMF. Ethyl 4-(piperazin-1-yl) (9.98 mg, 0.0498 mmol)butanoate was added and the mixture was stirred at rt until LC-MS analysis was complete. The mixture was injected directly into an RP-FC, purified, and the ester-protected product was isolated. This product was then dissolved in 1.2 equivalents of LiOH monohydrate in THF and concentrated to obtain the final product (25 mg, 90%). LC-MS:C 30 H 35 N5O4 requirement value: 529.6, measured value: m / z = 530.5 [M+H] + .

[0415] Step 2: Synthesis of the title compound rac-(3R)-3-[4-(piperazin-1-yl)phenyl]piperidine-2,6-dione (3.10 mg, 0.0113 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridine-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda 5-phosphanoid (8.97 mg, 0.0236 mmol), and N,N-diisopropylethylamine (8.24 μL, 6.10 mg, 0.0472 mmol) were stirred in DMF. 4-(4-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carbonyl}piperazin-1-yl)butanoic acid (5.00 mg, 0.0094 mmol) was added, and the mixture was stirred at rt until LCMS analysis was complete. The solution was injected into an RP-FC and purified under a gradient of 0-70% MeCN in H2O to obtain the title compound (1.2 mg, 15%). LC-MS:C 45 H 52 N8O5 required value: 784.4, measured value: m / z = 785.4 [M+H] + .

[0416] Example 23 (3R)-3-(4-{4-[(6-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methylpiperidine-4-carbonyl}-2,6-diazaspiro[3.3]heptan-2-yl)methyl]piperidine-1-yl}phenyl)piperidine-2,6-dione [ka] Step 1: Synthesis of (1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methylpiperidine-4-yl)(2,6-diazaspiro[3,3]heptan-2-yl)methanone [ka] 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methylpiperidine-4-carboxylic acid (10.00 mg, 0.0319 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridine-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda 5-phosphanoid (24.27 mg, 0.0638 mmol), and N,N-diisopropylethylamine (22.30 μL, 16.50 mg, 0.1276 mmol) were stirred in DMF. tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (6.33 mg, 0.0319 mmol) was added, and the mixture was stirred at rt until LCMS analysis was complete. The Boc-protected intermediate (6.1 mg, 38%) was directly purified by RP-FC, then dissolved in 1:1 TFA:DCM and stirred at rt for 30 minutes. The mixture was concentrated to obtain the product, and the process proceeded to the next step: LCMS:C 22 H 27 N5O2 requirement value: 393.3, measured value: m / z = 394.3 [M + H] + .

[0417] Step 2: Synthesis of the title compound In a scintillation vial, 2-[5-(4-{2,6-diazaspiro[3,4]octan-2-carbonyl}-4-phenylpiperidine-1-yl)pyridazin-3-yl]phenol (15.00 mg, 0.0381 mmol), triethylamine (26.06 μL, 0.1906 mmol), 1-{4-[(3R)-2,6-dioxopiperidine-3-yl]phenyl}piperidine-4-carbaldehyde (13.74 mg, 0.0457 mmol), and DCE (3.00 mL) were added and stirred at rt. Sodium triacetoxyborohydride (28.28 mg, 0.1334 mmol) was added. The mixture was stirred until the starting materials were completely consumed by MS. The reaction was completed after 90 minutes and the solution was purified. The reaction was quenched by adding bicarbonate and extracted with siRNA. The organic layer was brined and then dried over Na2SO4. The solution was concentrated and injected into an RP-FC, and purified under a gradient of 0–70% MeCN in H2O to obtain the title compound (7.4 mg, 29%). LC-MS:C 43 H 47 N8O4F required value: 677.4, measured value: m / z = 678.4 [M+H] + .

[0418] Example 24 (3R)-3-(4-{4-[(6-{4-cyclopropyl-1-[6-(2-hydroxyphenyl)pyridazin-4-yl]piperidine-4-carbonyl}-2,6-diazaspiro[3.3]heptan-2-yl)methyl]piperidine-1-yl}phenyl)piperidine-2,6-dione [ka] Step 1: Synthesis of (4-cyclopropyl-1-(6-(2-hydroxyphenyl)pyridazin-4-yl)piperidine-4-yl)(2,6-diazaspiro[3,3]heptan-2-yl)methanone [ka] 4-Cyclopropyl-1-[6-(2-hydroxyphenyl)pyridazin-4-yl]piperidine-4-carboxylic acid (10.00 mg, 0.0295 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridine-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda 5-phosphanoid (22.41 mg, 0.0589 mmol), and N,N-diisopropylethylamine (20.58 μL, 15.23 mg, 0.1179 mmol) were stirred in DMF. tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (5.84 mg, 0.0295 mmol) was added, and the mixture was stirred at rt until LCMS analysis was complete. The Boc intermediate was directly injected and purified via RP-FC (4.9 mg, 31%), then dissolved in 1:1 TFA:DCM, stirred at rt for 1 hour, then concentrated, lyophilized, and used for the next step: LCMS:C 24 H 29 N5O2 requirement value: 419.2, measured value: m / z = 420.3 [M + H] + .

[0419] Step 2: Synthesis of the title compound In a scintillation vial, 2-[5-(4-{2,6-diazaspiro[3,4]octan-2-carbonyl}-4-phenylpiperidine-1-yl)pyridazin-3-yl]phenol (15.00 mg, 0.0358 mmol), triethylamine (24.5 μL, 0.1788 mmol), 1-{4-[(3R)-2,6-dioxopiperidine-3-yl]phenyl}piperidine-4-carbaldehyde (13.0 mg, 0.0429 mmol), and DCE (3.00 mL) were added and stirred at rt. Sodium triacetoxyborohydride (26.5 mg, 0.1251 mmol) was then added. The mixture was stirred until the starting materials were completely consumed by MS. The reaction was completed after 90 minutes and the mixture was purified. The reaction was quenched by adding bicarbonate and extracted with siRNA. The organic layer was brined and then dried over Na2SO4. The solution was concentrated and injected into an RP-FC, and purified under a gradient of 0–70% MeCN in H2O to obtain the title compound (8.0 mg, 31%). LC-MS:C 43 H 47 N8O4F required value: 704.4, measured value: m / z = 705.4 [M+H] + .

[0420] Example 25 (3R)-3-(4-{4-[(8-fluoro-2-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carbonyl}-2,6-diazaspiro[3.4]octan-6-yl)methyl]piperidine-1-yl}phenyl)piperidine-2,6-dione [ka] Step 1: Synthesis of (8-fluoro-2,6-diazaspiro[3,4]octan-2-yl)(1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-phenylpiperidine-4-yl)methanone [ka] 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carboxylic acid (40.00 mg, 0.1065 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridine-3-yloxy})methylidene]dimethylazanium; h...

Claims

1. Formula (IA): 【Chemical 631】 A compound having a structure represented by the formula, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the formula is R １ However, 1 to 3 R ａ Hydrogen or C which can be optionally substituted. １－６ It is alkyl, R ２ However, 1 to 3 R ａ Hydrogen, halo, hydroxyl, -O-R are arbitrarily substituted. ｃ , C １－６ It is alkyl, R ３ is hydrogen, -CN, C １－６ alkyl, C ６－１２ aryl, C ３－１２ cycloalkyl, 5- to 12-membered heteroaryl, each of which is optionally substituted with 1 to 3 R ｄ , or -O-R ｅ and is optionally substituted, L is -L １ -L ２ -L ３ -L ４ -L ５ -L ６ -L ７ -L ８ It includes up to 8 linker segments represented by -, each L １ , L ２ , L ３ , L ４ , L ５ , L ６ , L ７ , or L ８ However, they became independent, i) 1 to 3 R ｂ C is arbitrarily replaced by ３－１２ Cycloalkyl, ii) 1 to 3 R ｂ C is arbitrarily replaced by ６－１２ Ariel, iii) 1 to 3 R ｂ A 4-12 member heterocycline that is arbitrarily substituted, iv) 1 to 3 R ｂ A 5-12 member heteroaryl that can be arbitrarily substituted, v) direct binding; vi) 1 to 3 R ｂ C is arbitrarily replaced by １－１２ Alkylene chain, or vii) - (CH ２ ) ｍ -C(O)-,-(CH ２ ) ｍ -C(O)O-, -(CH ２ ) ｍ -O-, -(CH ２ ) ｍ -N(R) ｃ )-,-(CH ２ ) ｍ -S-, -(CH ２ ) ｍ -C(S)-,-(CH ２ ) ｍ -C(S)-O-, -(CH ２ ) ｍ -S(O) ２ -, - (CH ２ ) ｍ -S(O)=N-, -(CH ２ ) ｍ -S(O) ２ NH-,-(CH ２ ) ｍ -C(O)-N(R ｃ )-, -C(O)-N(R ｃ )-(CH ２ ) ｍ -, - (CH ２ ) ｍ -O-C(O)-N(R ｃ )-,-(CH ２ ) ｍ -O-C(O)-O-, or -NH-(CH ２ ) ｍ -C(O)- (where m is 0, 1, 2, 3, 4, 5, or 6), Each R ａ However, independently, halo, or -OR ｃ And, Each R ｂ is independently oxo, imino, sulfoximino, halo, nitro, -CN, C １－６ alkyl, C ２－６ alkenyl, C ３－１５ cycloalkyl, C １－８ haloalkyl, C ６－１２ aryl, 5- to 12-membered heteroaryl, 4- to 12-membered heterocyclyl, -O-R ｃ , -C(O)-R ｃ , -C(O)O-R 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)O-R ｃ , -N(R ｃ )(C(O)N(R ｃ )(R ｃ , -N(R ｃ )(S(O) ２ (R ｃ ), -NR ｃ (S(O) ２ (N(R ｃ (R ｃ ), -N(R ｃ (S(O) ２ (O(R ｃ ), -OC(O)R ｃ , -OC(O)-N(R ｃ (R ｃ ), -Si(R ｃ ), ３ , -S-R ｃ , -S(O)R ｃ , -S(O)(NH)R ｃ , -S(O) ２ (R ｃ ), or -S(O) ２ (N(R ｃ (R ｃ ), and 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 member heteroaryl, and 4-12 member heterocyclyl has 1-3 R ｄ It can be arbitrarily replaced with, Each R ｃ However, independently, hydrogen, C １－６ Alkyl, C ３－６ Cycloalkyl, C ６－１２ Aryl, or C １－６ It is a haloalkyl, C １－６ Alkyl is C １－３ Optionally substituted with alkoxy, Each R ｄ However, independently, Halo, -CN, -OR ｃ , C １－６ Alkyl, C ６－１２ Aryl, or C １－６ It is a haloalkyl, R ｅ However, C １－６ Alkyl, C ３－１２ Cycloalkyl, C ６－１２ Aryls are 5- to 12-membered heteroaryls, each being C １－６ Optionally substituted with alkyl or halo, W is -C(R ｇ ) - or -N-, Y is directly bonded, C １－４ Alkylene chain, -C(O)-, -C(O)O-, -O-, -N(R) ｇ )-, -S--C(S)-, -C(S)-O-, -O-C(O)O-, -C(O)-N(R ｇ )-, or -O-C(O)-N(R ｇ ) - and Ring B is C ６－１２ They are aryl, 5-12 membered heteroaryl, or 4-12 membered heterocyclyl, each having 1-3 R ｊ It is arbitrarily replaced with, R ｇ However, hydrogen or C １－６ It is alkyl, Each R ｊ However, independently, halo, oxo, -CN, -OR ｃ , C １－６ Alkyl, or C １－６ The compound, its stereoisomer, or a pharmaceutically acceptable salt, which is a haloalkyl compound.

2. Each L １ , L ２ , L ３ , L ４ , L ５ , L ６ , L ７ , or L ８ However, they became independent, i) 【Chemistry 632-1】 【Chemistry 632-2】 A divalent ring portion selected from the group consisting of, ii) direct binding; iii) C １－６ Alkylene chain, or iv) -C(O)-, -O-, -(CH ２ ) ｍ -C(O)-N(R ｃ )-,-(CH ２ ) ｍ -N(R) ｃ )-, -C(O)-N(R ｃ )-(CH ２ ) ｍ - or -NH- (CH ２ ) ｍ -C(O)-,-(CH ２ ) ｍ -S(O) ２ NH- (where m is 0, 1, 2, or 3), n is 0, 1, or 2, R ｂ But, hello, -OR ｃ ,-CN,C １－６ Alkyl, or C １－６ It is a haloalkyl, R ｃ However, hydrogen, C １－６ Alkyl, C ３－６ Cycloalkyl, phenyl, or C １－６ It is a haloalkyl, C １－６ Alkyl is C １－３ The compound according to claim 1, which is optionally substituted with an alkoxy.

3. Y is a direct bond, -NHC(O)-, or -NH-, Ring B is 【Chemical Formula 633】 And in the formula, n is 0, 1, or 2, R ｊ However, halo, -CN, -O-R ｃ , C １－６ Alkyl, or C １－６ The compound according to claim 1 or claim 2, wherein it is a haloalkyl compound.

4. R ３ but, One or more C １－６ Alkyl, C １－６ Phenyl compounds optionally substituted with alkoxy or halo compounds. One or more C １－６ benzyl, optionally substituted with alkyl or halo. One or more C １－６ Pyridinyl molecules optionally substituted with alkyl groups, CN, C ３－６ Cyclopropyl, One or more C １－６ Pyrazolyls optionally substituted with alkyl groups, Tetrahydropyranil, One or more C １－６ 1,2-oxazolyl, which can be optionally substituted with alkyl groups. Pyrazolo[1,5-a]pyridinyl, or -O-R ｅ (R ｅ However, C １－６ Phenyl, C, optionally substituted with alkyl or halo ３－６ Cycloalkyl, C １－６ Alkyl, or C １－６ The compound according to any one of claims 1 to 3, wherein the compound is a pyrazolyl optionally substituted with an alkyl group.

5. R ３ However, phenyl, benzyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 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]pyridine-2-yl, 5-methyl-1,2-oxazole-3-yl, 5-isopropyl-1,2-oxazole-3-yl, 3-methyl-1,2-oxazole-5-yl, or -O-R ｅ And R ｅ The compound according to claim 4, wherein the compound is phenyl, 2-chlorophenyl, 2-methylphenyl, cyclopropyl, cyclohexyl, methyl, or 1-methyl-1H-pyrazole-3yl.

6. R １ However, it is hydrogen, R ２ The compound according to any one of claims 1 to 5, wherein the compound is hydrogen.

7. R １ However, it is hydrogen, R ２ However, it is hydrogen, Y is a direct bond, and R ３ However, -OR ｅ And W is CH, and the compound is of formula (IA1): 【Transformation 634】 It has a structure represented by the formula, in which, Ring B is 【Chemical 635】 And, n is 0, 1, or 2, R ｊ However, halo, -CN, -O-R ｃ , C １－６ Alkyl, or C １－６ It is a haloalkyl, R ｅ However, C １－６ Alkyl, C ３－１２ Cycloalkyl, C ６－１２ Aryls are 5- to 12-membered heteroaryls, each being C １－６ Optionally substituted with alkyl or halo, R ｃ However, hydrogen or C １－３ It is alkyl, L １ However, -C(O)- or -C(O)N(R ｃ ) - and L ａ but, 【Chemical Formula 636】 The compound according to any one of claims 1 to 5.

8. B, 【Chemical 637】 And, n is 0 or 1, R ｊ However, it is fluoro or chloro, R ｅ However, C １－６ Alkyl, C ３－１２ Cycloalkyl, C ６－１２ Aryls are 5- to 12-membered heteroaryls, each being C １－６ Optionally substituted with alkyl or halo, L １ However, -C(O)N(R ｃ ) - and R ｃ However, it is methyl or ethyl, L ａ but, 【Chemical Formula 638】 The compound according to claim 7.

9. R ｅ However, C １－３ The compound according to claim 7 or claim 8, wherein it is alkyl.

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

11. Ring B is 【Chemistry 639】 And, n is 0, 1, or 2, R ｊ However, it is fluoro or chloro, R ｅ However, it is methyl, ethyl, or propyl, R ｃ However, it is hydrogen, methyl, or ethyl, L １ However, -C(O)- or -C(O)N(R ｃ ) - and L ａ but, 【Chemical 640】 The compound according to claim 7.

12. R １ and R ２ is hydrogen, W is CH, and the compound is of formula (IA2): 【Chemistry 641】 It has a structure represented by the formula, in which, n is 0, 1, or 2, Y is a direct bond, -NHC(O)-, or -NH-, X is N or CH, Rj, C １－３ Alkyl or halo, R ３ However, C ６－１２ Ariel, C ３－１２ Cycloalkyl, 5-12 member heteroaryl, each containing 1-3 R ｄ , or -OR ｅ It is arbitrarily replaced with, R ｃ However, hydrogen or C １－６ It is methyl, Each R ｄ However, independently, Halo, -CN, -OR ｃ , C １－６ Alkyl, C ６－１２ Aryl, or C １－６ It is a haloalkyl, R ｅ However, C １－６ Alkyl, C ３－１２ Cycloalkyl, C ６－１２ Aryls are 5- to 12-membered heteroaryls, each being C １－６ Optionally substituted with alkyl or halo, L ｂ but, 【Chemistry 642-1】 【Chemistry 642-2】 The compound according to any one of claims 1 to 5.

13. R ３ However, phenyl, 2-fluorophenyl, 5-methyl-1,2-oxazole-5-yl, 5-isopropyl-1,2-oxazole-5-yl, pyrazolo[1,5-a]pyridinyl, -O-R ｅ And R ｅ The compound according to claim 12, wherein the compound is phenyl, 2-chlorophenyl, 2-methylphenyl, 1-methyl-1H-pyrazole-3-yl, cyclohexyl, or methyl.

14. R １ and R ２ is hydrogen, W is CH, and the compound is of formula (IA3): 【Chemistry 643】 It has a structure represented by the formula, in which, n is 0, 1, or 2, Y is a direct bond, -NHC(O)-, or -NH-, X is N or CH, R ３ However, C ６－１２ Ariel, C ３－１２ Cycloalkyl, 5-12 member heteroaryl, each containing 1-3 R ｄ , or -OR ｅ It is arbitrarily replaced with, R ｃ However, hydrogen, C １－３ Alkyl, or C ３－６ It is a cycloalkyl, Each R ｄ However, independently, Halo, -CN, -OR ｃ , C １－６ Alkyl, C ６－１２ Aryl, or C １－６ It is a haloalkyl, R ｅ However, C １－６ Alkyl, C ３－１２ Cycloalkyl, C ６－１２ Aryls are 5- to 12-membered heteroaryls, each being C １－６ Optionally substituted with alkyl or halo, R ｊ However, C １－３ Alkyl or halo, L ｃ but, 【Chemical 644】 The compound according to any one of claims 1 to 5.

15. R ３ However, phenyl, 2-pyridinyl, 4-pyridinyl, 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-oxazole-5-yl, 5-isopropyl-1,2-oxazole-3-yl, pyrazolo[1,5-a]pyridinyl, -O-R ｅ And R ｅ The compound according to claim 14, wherein the compound is phenyl, 2-chlorophenyl, 2-methylphenyl, 1-methyl-1H-pyrazole-3-yl, cyclopropyl, cyclohexyl, or methyl.

16. R １ and R ２ However, it is hydrogen, W is CH, Y is a direct bond, and R ３ However, it is phenyl, and the compound is of formula (IA4): 【Chemical 645】 It has a structure represented by the formula, in which, n is 0, 1, or 2, X is N or CH, R ｃ However, hydrogen or C １－３ C arbitrarily substituted with alkoxy １－３ It is alkyl, R ｊ However, C １－３ Alkyl or halo, L ｄ but, 【Chemical 646】 The compound according to any one of claims 1 to 5.

17. R １ and R ２ However, it is hydrogen, W is CH, Y is a direct bond, and R ３ However, it is phenyl, and the compound is of formula (IA5): 【Chemical 647】 It has a structure represented by the formula, in which, n is 0, 1, or 2, X is N or CH, Q is directly bonded, -N(R ｃ ) - or -NHS(O) ２ - and R ｃ However, hydrogen or C １－３ It is alkyl, R ｊ However, C １－３ Alkyl or halo, L ｅ but, 【Chemical Formula 648】 The compound according to any one of claims 1 to 5.

18. R １ and R ２ is hydrogen, W is CH, Y is a direct bond, and the compound is of formula (IA6): 【Chemical 649】 It has a structure represented by the formula, in which, B, 【Chemical 650】 And, R ３ However, C ６－１２ Ariel, C ３－１２ Cycloalkyl, 5-12 member heteroaryl, each containing 1-3 R ｄ , or -OR ｅ It is arbitrarily replaced with, R ｃ However, hydrogen or C １－６ It is alkyl, Each R ｄ However, independently, Halo, -CN, -OR ｃ , C １－６ Alkyl, C ６－１２ Aryl, or C １－６ It is a haloalkyl, R ｅ However, C １－６ Alkyl, C ３－１２ Cycloalkyl, C ６－１２ Aryls are 5- to 12-membered heteroaryls, each being C １－６ Optionally substituted with alkyl or halo, L １ However, -C(O)-, -C(O)-N(R ｃ )-(CH ２ )-, or -C(O)-N(R ｃ ) - and L ｆ but, 【Chemical 651】 The compound according to any one of claims 1 to 5.

19. R ３ This is phenyl, 1-methyl-1H-pyrazole-5-yl, 5-methyl-1H-pyrazole-1-yl, or -O-R ｅ And R ｅ The compound according to claim 18, wherein the compound is 1-methyl-1H-pyrazole-3yl or methyl.

20. Equation (I): 【Chemical 652】 A compound having a structure represented by the formula, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the formula is R １ However, 1 to 3 R ａ Hydrogen or C which can be optionally substituted. １－６ It is alkyl, R ２ However, 1 to 3 R ａ Hydrogen, halo, hydroxyl, -O-R are arbitrarily substituted. ｃ , C １－６ It is alkyl, R ３ However, hydrogen, -CN, C １－６ Alkyl, C ６－１２ Ariel, C ３－１２ Cycloalkyl or 5-12 member heteroaryl, each having 1-3 R ｄ It is arbitrarily replaced with, L is -L １ -L ２ -L ３ -L ４ -L ５ -L ６ -L ７ -L ８ It includes up to 8 linker segments represented by -, each L １ , L ２ , L ３ , L ４ , L ５ , L ６ , L ７ , or L ８ However, they became independent, i) 1 to 3 R ｂ C is arbitrarily replaced by ３－１２ Cycloalkyl, ii) 1 to 3 R ｂ C is arbitrarily replaced by ６－１２ Ariel, iii) 1 to 3 R ｂ A 4-12 member heterocycline that is arbitrarily substituted, iv) 1 to 3 R ｂ A 5-12 member heteroaryl that can be arbitrarily substituted, v) direct binding; vi) 1 to 3 R ｂ C is arbitrarily replaced by １－１２ Alkylene chain, or vii) - (CH ２ ) ｍ -C(O)-,-(CH ２ ) ｍ -C(O)O-, -(CH ２ ) ｍ -O-, -(CH ２ ) ｍ -N(R) ｃ )-,-(CH ２ ) ｍ -S-, -(CH ２ ) ｍ -C(S)-,-(CH ２ ) ｍ -C(S)-O-, -(CH ２ ) ｍ -S(O) ２ -, - (CH ２ ) ｍ -S(O)=N-, -(CH ２ ) ｍ -S(O) ２ NH-,-(CH ２ ) ｍ -C(O)-N(R ｃ )-, -C(O)-N(R ｃ )-(CH ２ ) ｍ -ien-CH ２ ) ｍ -O-C(O)-N(R ｃ )-,-(CH ２ ) ｍ -O-C(O)-O-, or -NH-(CH ２ ) ｍ -C(O)- (where m is 0, 1, 2, 3, 4, 5, or 6), Each R ａ However, independently, halo, or -OR ｃ And, Each R ｂ However, independently, oxo, imino, sulfoxyimino, halo, nitro, -CN, C １－６ Alkyl, C ２－６ Alkenil, C ３－１５ Cycloalkyl, C １－８ Haloalkyl, C ６－１２ Aryl, 5-12 member heteroaryl, 4-12 member heterocyclyl, -O-R ｃ , -C(O)-R ｃ , -C(O)O-R ｃ , -C(O)-N(R ｃ ) (Caution ｃ ), -N(R ｃ ) (Caution ｃ ), -N(R ｃ ) C(O)-R ｃ , -N(R ｃ ) C(O)O-R ｃ , -N(R ｃ ) C(O)N(R ｃ ) (Caution ｃ ), -N(R ｃ ) S(O) ２ (R ｃ ), -NR ｃ S(O) ２ N(R) ｃ ) (Caution ｃ ), -N(R ｃ ) S(O) ２ O(R) ｃ ), -OC(O)R ｃ , -OC(O)-N(R ｃ ) (Caution ｃ ), -Si(R ｃ ) ３ , -S-R ｃ , -S(O)R ｃ , -S(O)(NH)R ｃ , -S(O) ２ R ｃ , or -S(O) ２ N(R) ｃ ) (Caution ｃ ) and C １－６ Alkyl, C ２－６ Alkenil, C ３－１５ Cycloalkyl, C １－８ Haloalkyl, C ６－１２ Each of the aryl, 5-12 member heteroaryl, and 4-12 member heterocyclyl has 1-3 R ｄ It can be arbitrarily replaced with, Each R ｃ However, independently, hydrogen, C １－６ Alkyl, or C １－６ It is a haloalkyl, Each R ｄ However, independently, Halo, -CN, -OR ｃ , C １－６ Alkyl, C ６－１２ Aryl, or C １－６ It is a haloalkyl, W is -C(R ｇ ) - or -N-, Y is directly bonded, C １－４ Alkylene chain, -C(O)-, -C(O)O-, -O-, -N(R) ｇ )-, -S--C(S)-, -C(S)-O-, -O-C(O)O-, -C(O)-N(R ｇ )-, or -O-C(O)-N(R ｇ ) - and Ring B is C ６－１２ They are aryl, 5-12 membered heteroaryl, or 4-12 membered heterocyclyl, each having 1-3 R ｊ It is arbitrarily replaced with, R ｇ However, hydrogen or C １－６ It is alkyl, Each R ｊ However, independently, Halo, -CN, -OR ｃ , C １－６ Alkyl, or C １－６ The compound, its stereoisomer, or a pharmaceutically acceptable salt, which is a haloalkyl compound.

21. Y is a direct bond or -NHC(O)-, Ring B is 【Chemical 653】 And in the formula, n is 0, 1, or 2, R ｊ However, halo, -CN, -O-R ｃ , C １－６ Alkyl, or C １－６ The compound according to claim 20, which is a haloalkyl compound.

22. Formula (II): 【Chemical 654】 It has a structure represented by the formula, in which, W is either CN or N, X is CH or N, p is 0, 1, or 2, R ｊ However, Halo or C １－３ The compound according to claim 21, wherein it is alkyl.

23. Formulas (IIa), (IIb), (IIc), or (IId): 【Chemical Formula 655】 The compound according to claim 22, having the structure represented by the formula.

24. Each L １ , L ２ , L ３ , L ４ , L ５ , L ６ , L ７ , or L ８ However, they became independent, i) 【Chemical 656】 A divalent ring portion selected from the group consisting of, ii) direct binding; iii) C １－６ Alkylene chain, or iv) -C(O)-, -O-, -C(O)-N(R ｃ )-,-(CH ２ ) ｍ -C(O)- or -NH-(CH ２ ) ｍ -C(O)- (where m is 0, 1, 2, or 3), n is 0, 1, or 2, R ｂ However, halo, -CN, C １－３ Alkyl, or C １－３ It is a haloalkyl, R ｃ However, hydrogen or C １－３ The compound according to any one of claims 20 to 23, wherein it is alkyl.

25. R １ However, C is substituted with hydrogen or 1 to 3 fluoro or hydroxyl atoms. １－６ The compound according to any one of claims 20 to 24, wherein it is alkyl.

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

27. R １ However, it is hydrogen, R ２ The compound according to any one of claims 20 to 26, wherein the compound is hydrogen.

28. Formula (III) 【Chemical Formula 657】 It has a structure represented by the formula, in which, W is N or CH, X is N or CH, L' is -L ２ -L ３ -L ４ -L ５ -L ６ -L ７ -L ８ - and R ３ However, CN, cyclopropyl, C １－３ Alkyl, one or two halos or C １－３ Phenyl or C compounds optionally substituted with alkyl groups. １－３ The compound according to claim 27, wherein the pyrazolyl is optionally substituted with an alkyl group.

29. Formulas (IIIa), (IIIb), (IIIc), or (IIId): 【Chemical Formula 658】 It has a structure represented by, In the formula, L' is 【Chemistry 659-1】 【Chemistry 659-2】 【Chemistry 659-3】 The compound according to claim 28.

30. Formula (IV): 【Chemical Formula 660】 It has a structure represented by the formula, in which, W is N or CH, X is N or CH, V is N or CH, L'' is -L ２ -L ３ -L ４ -L ５ -L ６ -L ７ - and R ３ However, CN, cyclopropyl, C １－３ Alkyl, one or two halos or C １－３ Phenyl or C compounds optionally substituted with alkyl groups. １－３ The compound according to claim 27, wherein the pyrazolyl is optionally substituted with an alkyl group.

31. Formulas (IVa1), (IVa2), (IVa3), (IVa4), (IVb1), (IVb2), (IVb3), (IVb4): 【Chemistry 661-1】 【Chemistry 661-2】 It has a structure that can be represented by any one of the following, where L'' is 【Chemistry 662-1】 【Chemistry 662-2】 The compound according to claim 30.

32. A compound according to claim 1, selected from the group consisting of compounds from Examples 1 to 196.

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

34. The pharmaceutical composition according to claim 33, further comprising one or more additional therapeutic agents or pharmaceutically acceptable salts thereof.

35. A compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 33 or claim 34, for use in therapeutic purposes.

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

37. The aforementioned SMARCA2-mediated diseases include 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, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic lung cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, and diffuse leukemia. Large B-cell lymphoma, dysproliferative changes (dysplasia and metaplasia), embryonic carcinoma, endometrial cancer, endosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, liver cancer, lung cancer, intralymphatic sarcoma, lymphangiosarcoma, lymphoblastic Leukemia, lymphoma (Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma), malignancies of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin, and uterus, as well as hyperproliferative disorders, T-cell or B-cell derived lymphoid malignancies, 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 carcinoma, papillary carcinoma A compound or pharmaceutical composition for use according to claim 36, which is a cancer selected from the group consisting of pineal tumor, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, malignant rhabdoid tumor (MRT), rhabdomyosarcoma, sarcoma, sebaceous carcinoma, seminomas, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synoviomas, sweat gland carcinoma, thyroid cancer, Waldenström macroglobulinemia, testicular tumor, uterine cancer, and Wilms' tumor.

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