Bifunctional azines conjogates as selective degraders of smarca2 and therapeutic uses thereof

Abstract

The present disclosure provides bifunctional compounds Formula (IA) as selective SMARCA2 degraders via ubiquitin proteosome pathway, and their therapeutic use for treating cancers.

Description

[0001] BIFUNCTIONAL SELECTIVE DEGRADERS OF SMARCA2 AND THERAPEUTIC USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 507,074, filed June 8, 2023, which application is hereby incorporated by reference in its entirety. BACKGROUND Technical Field The present invention provides novel bifunctional compounds for proteolytically degrading SMARCA2, and their therapeutic use for treating SMARCA2-mediated diseases, including cancers. Description of the Related Art Mammalian SWItch / Sucrose Non-Fermentable (mSWI / SNF) chromatin remodeling complexes contain one of two mutually exclusive and highly homologous catalytic ATPase subunits, SMARCA2 or SMARCA4. Subunit mutations within the complexes are prevalent in cancer, and SMARCA4-mutated cancers show acute sensitivity to depletion of SMARCA2, making SMARCA2 an attractive oncological target. Several groups have developed small molecule inhibitors of SMARCA2, but advancement of these molecules has been hindered by the requirement for selectivity over SMARCA4. See e.g.,Wanior, M. et al J. Med. Chem.63:14680 (2020). Kofink, C. et al Nature Commun.13:5969 (2022). Two regions of the SMARCA2 protein with well-defined binding pockets relevant for small molecule inhibitor discovery are the catalytic ATPase domain and a conserved bromodomain that can interact with acetylated chromatin. High sequence homology between the ATPase domains of these proteins makes it challenging to develop inhibitors with sufficient selectivity. Known ATPase domain ligands are dual inhibitors of SMARCA2 / 4 and exhibit dose-limiting tolerability issues. Alternatively, while the bromodomain shows more potential for selectivity, its function is dispensable, and current ligands are ineffective at inhibiting cell proliferation. While selective targeting of SMARCA2 over SMARCA4 has thus far proven challenging using inhibitors, repurposing the non-inhibitory bromodomain binders for use as targeted protein degraders holds promise. However, current degraders have shown poor selectivity in targeting SMARCA2 over SMARCA4. See e.g., WO 2021 / 083949, WO 2020 / 251971 and WO 2019 / 195201. BRIEF SUMMARY Provided herein are bifunctional compounds exhibiting both potent inhibition and selectivity against SMARCA2 while sparing SMARCA4. Provided herein are bifunctional compounds represented by Formula (I): Formula (I) or a pharmaceutically acceptable salt thereof, wherein: R1is hydrogen or C1-6 alkyl optionally substituted with 1 to 3 Ra; R2is hydrogen, halo, hydroxyl, -O-Rc, C1-6 alkyl optionally substituted with 1 to 3 Ra; R3is hydrogen, –CN, C1-6 alkyl, C6-12 aryl, C3-12 cycloalkyl, or 5-12 membered heteroaryl, each being optionally substituted with 1 to 3 Rd; L comprises up to 8 linker segments represented by –L1-L2-L3-L4-L5-L6-L7–L8–, each L1, L2, L3, L4, L5, L6, L7, or L8, being independently: i) C3-12 cycloalkyl optionally substituted with 1-3 Rb; ii) C6-12 aryl optionally substituted with 1-3 Rb; iii) 4-12 membered heterocyclyl optionally substituted with 1-3 Rb; iv) 5-12 membered heteroaryl optionally substituted with 1-3 Rb; v) direct bond; vi) C1-12 alkylene chain optionally substituted with 1-3 Rb; or vii) –(CH2)m-C(O)–, –(CH2)m-C(O)O–, –(CH2)m-O–, –(CH2)m-N(Rc)-, –(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(Rc)–, –C(O)-N(Rc)-(CH2)m–, –CH2)m-O-C(O)-N(Rc)–, –(CH2)m–O-C(O)-O–, or –NH-(CH2)m-C(O)–, wherein m is 0, 1, 2, 3, 4, 5 or 6; each Rais independently halo, or -O-Rc; each Rbis independently oxo, imino, sulfoximino, halo, nitro, -CN, C1-6 alkyl, C2-6 alkenyl, C3-15 cycloalkyl, C1-8 haloalkyl, C6-12 aryl, 5-12 membered heteroaryl, 4-12 membered heterocyclyl, -O-Rc, -C(O)-Rc, -C(O)O-Rc, -C(O)-N(Rc)( Rc), -N(Rc)(Rc), -N(Rc)C(O)- Rc, -N(Rc)C(O)O-Rc, -N(Rc)C(O)N(Rc)( Rc), -N(Rc)S(O)2(Rc), -NRcS(O)2N(Rc)( Rc), - N(Rc)S(O)2O(Rc), -OC(O)Rc, -OC(O)-N(Rc)( Rc), -Si(Rc)3, -S-Rc, -S(O)Rc, -S(O)(NH)Rc, - S(O)2Rcor -S(O)2N(Rc)( Rc), wherein each of C1-6 alkyl, C2-6 alkenyl, C3-15 cycloalkyl, C1-8 haloalkyl, C6-12 aryl, 5-12 membered heteroaryl, and 4-12 membered heterocyclyl may be optionally substituted with 1 to 3 Rd; each Rcis independently hydrogen, C1-6 alkyl, or C1-6 haloalkyl; each Rdis independently halo, -CN, -O-Rc, C1-6 alkyl, or C1-6 haloalkyl; W is –C(Rg)- or –N-; Y is direct bond, C1-4 alkylene chain, -C(O)-, -C(O)O-, -O -, -N(Rg)-, -S- -C(S)-, -C(S)-O-, -O-C(O)O-, –C(O)-N(Rg)-, or –O-C(O)-N(Rg)-; B ring is C6-12 aryl, 5-12 membered heteroaryl, or 4-12 membered heterocyclyl, each being optionally substituted with 1 to 3 Rj; Rgis hydrogen or C1-6 alkyl; and each Rjis independently halo, -CN, -O-Rc, C1-6 alkyl, C6-12 aryl or C1-6 haloalkyl. In various specific embodiments, Y is direct bond, and the bifunctional compounds of Formula (I) are represented by Formula (II): wherein, R1, R2, R3, L, W are as defined above; X is CH or N; p is 0, 1, or 2; and Rjis halo or C1-3 alkyl. In various specific embodiments, the bifunctional compounds of Formula (II) are represented by Formula (IIa), (IIb), (IIc) or (IId): Formula (IIb) Formula (IId). In more specific embodiments, R1and R2are each hydrogen, Y is direct bond, L1is - C(O)-, L’ is -L2-L3-L4-L5-L6-L7–L8–, and the bifunctional compounds are represented by the structures of Formula (III) and substructures (IIIa), (IIIb), (IIIc) and (IIId): Formula (IIIb), Formula (IIId). In even more specific embodiments, R1and R2are each hydrogen, Y is direct bond, L1 is the bifunctional compounds are represented by the structure of Formula (IV), (IVa), (IVb), and their respective substructures: Formula (IVa1) Formula (IVb1) Formula (IVb2) Formula (IVb4) In various embodiments, each of the linker segments, namely, L1, L2, L3, L4, L5, L6, L7, or L8 is independently: vi) C1-6 alkylene chain; or vii) -C(O)-, -O–, –C(O)-N(Rc)-, -(CH2)m-C(O)–, or –NH-(CH2)m-C(O)–, wherein m is 0, 1, 2 or 3; wherein, m is 0, 1, 2, or 3; n is 0, 1, or 2; Rbis halo, -CN, C1-3 alkyl, or C1-3 haloalkyl; and Rcis hydrogen or C1-3 alkyl. Also provided herein is a pharmaceutical composition comprising a compound of Formulae (I), (II), (III) and (IV), (IA), or any one of the substructures or specific compounds of Examples 1-196 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. DETAILED DESCRIPTION Specific degradation of SMARCA2 could be accomplished by using heterobifunctional small molecules to recruit SMARCA2, with high selectivity over SMARCA4, to a ubiquitin ligase and thus promoting ubiquitylation and proteasomal degradation of SMARCA2. Thus, provided herein are bifunctional compounds, each comprising a selective SMARCA2 binder, a covalent a linker moiety (L) and a ligase harness moiety (LHM) for targeting ubiquitin ligase. Preferably, the LHM targets cereblon (CRBN) proteins, which are substrate recognition subunits of two ubiquitously expressed and biologically important Cullin RING E3 ubiquitin ligase complexes. See, e.g., WO 2019 / 099926, WO 2020 / 023851, and U.S. Published Application No. 2019 / 0192668. In addition to the compounds of Formula (I)-(IV) and their substructures described herein, various embodiments further provide a compound having a structure represented by Formula (IA): Formula (IA) or a stereoisomer, pharmaceutically acceptable salt thereof, wherein: R1is hydrogen or C1-6 alkyl optionally substituted with 1 to 3 Ra; R2is hydrogen, halo, hydroxyl, -O-Rc, C1-6alkyl optionally substituted with 1 to 3 Ra; R3is hydrogen, –CN, C1-6 alkyl, C6-12 aryl, C3-12 cycloalkyl, 5-12 membered heteroaryl, each being optionally substituted with 1 to 3 Rd, or -O-Re; L comprises up to 8 linker segments represented by –L1-L2-L3-L4-L5-L6-L7–L8–, each L1, L2, L3, L4, L5, L6, L7, or L8, being independently: i) C3-12cycloalkyl optionally substituted with 1-3 Rb; ii) C6-12 aryl optionally substituted with 1-3 Rb; iii) 4-12 membered heterocyclyl optionally substituted with 1-3 Rb; iv) 5-12 membered heteroaryl optionally substituted with 1-3 Rb; v) direct bond; vi) C1-12 alkylene chain optionally substituted with 1-3 Rb; or vii) –(CH2)m-C(O)–, –(CH2)m-C(O)O–, –(CH2)m-O–,–(CH2)m-N(Rc)-, –(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(Rc)–, –C(O)-N(Rc)-(CH2)m–, –(CH2)m-O-C(O)-N(Rc)–, –(CH2)m–O-C(O)-O–, or –NH-(CH2)m-C(O)–, wherein m is 0, 1, 2, 3, 4, 5 or 6; each Rais independently halo, or -O-Rc; each Rbis independently oxo, imino, sulfoximino, halo, nitro, -CN, C1-6 alkyl, C2-6 alkenyl, C3-15cycloalkyl, C1-8haloalkyl, C6-12aryl, 5-12 membered heteroaryl, 4-12 membered heterocyclyl, -O-Rc, -C(O)-Rc, -C(O)O-Rc, -C(O)-N(Rc)( Rc), -N(Rc)(Rc), -N(Rc)C(O)- Rc, -N(Rc)C(O)O-Rc, -N(Rc)C(O)N(Rc)( Rc), -N(Rc)S(O)2(Rc), -NRcS(O)2N(Rc)( Rc), - N(Rc)S(O)2O(Rc), -OC(O)Rc, -OC(O)-N(Rc)( Rc), -Si(Rc)3, -S-Rc, -S(O)Rc, -S(O)(NH)Rc, - S(O)2Rcor -S(O)2N(Rc)( Rc), wherein each of C1-6alkyl, C2-6alkenyl, C3-15cycloalkyl, C1-8haloalkyl, C6-12 aryl, 5-12 membered heteroaryl, and 4-12 membered heterocyclyl may be optionally substituted with 1 to 3 Rd; each Rcis independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C6-12 aryl or C1-6 haloalkyl, wherein C1-6alkyl is optionally substituted with C1-3alkoxy; each Rdis independently halo, -CN, -O-Rc, C1-6 alkyl, C6-12 aryl or C1-6 haloalkyl; Reis C1-6alkyl, C3-12cycloalkyl, C6-12aryl, 5-12 membered heteroaryl, each being optionally substituted with C1-6 alkyl or halo; W is –C(Rg)- or –N-; Y is direct bond, C1-4 alkylene chain, -C(O)-, -C(O)O-, -O -, -N(Rg)-, -S- -C(S)-, -C(S)-O-, -O-C(O)O-, –C(O)-N(Rg)-, or –O-C(O)-N(Rg)-; B ring is C6-12 aryl, 5-12 membered heteroaryl, or 4-12 membered heterocyclyl, each being optionally substituted with 1 to 3 Rj; Rgis hydrogen or C1-6 alkyl; and each Rjis independently halo, oxo, -CN, -O-Rc, C1-6alkyl, or C1-6haloalkyl. In more specific embodiments, each L1, L2, L3, L4, L5, L6, L7, or L8is independently: i) a bivalent ring moiety selected from the group consisting of: ii) direct bond; iii) C1-6alkylene chain; or iv) -C(O)-, -O–,–(CH2)m–C(O)-N(Rc)–, –(CH2)m-N(Rc)-, – C(O)-N(Rc)-(CH2)m–, or –NH-(CH2)m-C(O)–, –(CH2)m-S(O)2NH–, m being 0, 1, 2 or 3; wherein, n is 0, 1, or 2; Rbis halo, -O-Rc, -CN, C1-6alkyl, or C1-6haloalkyl; and Rcis hydrogen, C1-6 alkyl, C3-6 cycloalkyl, phenyl, or C1-6 haloalkyl, wherein C1-6 alkyl is optionally substituted with C1-3alkoxy. halo, -CN, -O-Rc, C1-6alkyl, or C1-6haloalkyl. In various embodiments, R3is phenyl optionally substituted with one or more C1-6 alkyl, C1-6alkoxy, or halo; benzyl optionally substituted with one or more C1-6alkyl or halo; pyridinyl optionally substituted with one or more C1-6 alkyl; CN; C3-6 cyclopropyl; pyrazolyl optionally substituted with one or more C1-6alkyl; tetrahydropyranyl;1,2-oxazolyl optionally substituted with one or more C1-6 alkyl; pyrazolo[1,5-a]pyridinyl; or -O-Re, wherein Reis phenyl optionally substituted with C1-6alkyl or halo, C3-6cycloalkyl, C1-6alkyl, or pyrazolyl optionally substituted with C1-6 alkyl. In even more specific embodiments, R3is phenyl, benzyl, 2-pyridinyl, 3-pyridinyl, 4- pyridinyl, CN, cyclopropyl, 1-methyl-1H-pyrazol-3yl, 3-methylphenyl, 2-methylphenyl, 3- chlorophenyl, 3,4-dichlorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-fluorophenyl, 4- fluorophenyl, tetrahydropyran-4yl, 3-methyl-1H-pyrazol-1yl, 4-methyl-1H-pyrazol-1yl, 5- methyl-1H-pyrazol-1yl, 1-methyl-1H-pyrazol-3yl, 1-methyl-1H-pyrazol-4yl, 1-methyl-1H- pyrazol-5yl, pyrazolo[1,5-a]pyridin-2-yl, 5-methyl-1,2-oxazol-3-yl, 5-isopropyl-1,2-oxazol-3-yl, 3-methyl-1,2-oxazol-5-yl, or -O-Re, wherein Reis phenyl, 2-chlorophenyl, 2-methylphenyl, cyclopropyl, cyclohexyl, methyl, or 1-methyl-1H-pyrazol-3yl. In certain embodiments, R1is hydrogen, R2is hydrogen, Y is direct bond, R3is -O-Re, W is CH, and the compound has a structure represented by Formula (IA1): n is 0, 1 or 2; Rjis halo, -CN, -O-Rc, C1-6 alkyl, or C1-6 haloalkyl; Reis C1-6alkyl, C3-12cycloalkyl, C6-12aryl, 5-12 membered heteroaryl, each being optionally substituted with C1-6 alkyl or halo; Rcis hydrogen or C1-3alkyl; n is 0 or 1; Rjis fluoro or chloro; Reis C1-6alkyl, C3-12cycloalkyl, C6-12aryl, 5-12 membered heteroaryl, each substituted with C1-6 alkyl or halo; L1is -C(O)N(Rc)- where Rcis methyl or ethyl; In various embodiments, Reis C1-3 alkyl. In more specific embodiments, Reis methyl, phenyl, cyclopropyl, cyclohexyl, 1-methyl- 1H-pyrazol-3yl or phenyl substituted with chloro or methyl. In other more specific embodiments of Formula (IA1), B ring is ; n is 0, 1 or 2; Rjis fluoro or chloro; Reis methyl, ethyl, or propyl; Rcis hydrogen, methyl, or In certain embodiments, R1and R2are hydrogen, W is CH, and the compound has a structure represented by Formula (IA2): Formula (IA2) wherein, n is 0, 1, or 2; Y is direct bond, –NHC(O)-, or -NH-; X is N or CH; Rj is C1-3alkyl or halo; R3is C6-12 aryl, C3-12 cycloalkyl, 5-12 membered heteroaryl, each being optionally substituted with 1 to 3 Rd, or -O-Re; Rcis hydrogen or C1-6 methyl; each Rdis independently halo, -CN, -O-Rc, C1-6alkyl, C6-12aryl or C1-6haloalkyl; and Reis C1-6alkyl, C3-12cycloalkyl, C6-12aryl, 5-12 membered heteroaryl, each being substituted with C1-6 or halo; and In more specific embodiments of Formula (IA2), R3is phenyl, 2-fluorophenyl, 5-methyl- 1,2-oxazol-5-yl, 5-isopropyl-1,2-oxazol-5-yl, pyrazolo[1,5-a]pyridinyl, -O-Re, wherein Reis phenyl, 2-chlorophenyl, 2-methylphenyl, 1-methyl-1H-pyrazol-3yl, cyclohexyl, or methyl. In certain embodiments, R1and R2are hydrogen, W is CH, and the compound has a structure represented by Formula (IA3): Formula (IA3) wherein, n is 0, 1, or 2; Y is direct bond, –NHC(O)-, or -NH-; X is N or CH; R3is C6-12 aryl, C3-12 cycloalkyl, 5-12 membered heteroaryl, each being optionally substituted with 1 to 3 Rd, or -O-Re; Rcis hydrogen, C1-3alkyl, or C3-6 cycloalkyl; each Rdis independently halo, -CN, -O-Rc, C1-6alkyl, C6-12aryl or C1-6haloalkyl; Reis C1-6 alkyl, C3-12 cycloalkyl, C6-12 aryl, 5-12 membered heteroaryl, each being optionally substituted with C1-6alkyl or halo; Rjis C1-3alkyl or halo; and In certain embodiments, R1and R2are hydrogen, W is CH, Y is direct bond, R3is phenyl, and the compound has a structure represented by Formula (IA4): Formula (IA4) wherein, n is 0, 1, or 2; X is N or CH; Rcis hydrogen or C1-3alkyl optionally substituted with C1-3 alkoxy; Rjis C1-or halo; and In certain embodiments, R1and R2are hydrogen, W is CH, Y is direct bond, R3is phenyl, and the compound has a structure represented by Formula (IA5) Formula (IA5) wherein, n is 0, 1, or 2; X is N or CH; Q is direct bond, -N(Rc)- or -NHS(O)2-, Rcis hydrogen or C1-3alkyl; Rjis C1-3alkyl or halo; and In certain embodiments, R1and R2are hydrogen, W is CH, Y is direct bond, and the compound has a structure represented by Formula (IA6): , Formula (IA6) wherein, R3is C6-12 aryl, C3-12 cycloalkyl, 5-12 membered heteroaryl, each being optionally substituted with 1 to 3 Rd, or -O-Re; Rcis hydrogen or C1-6 alkyl; each Rdis independently halo, -CN, -O-Rc, C1-6alkyl, C6-12aryl or C1-6haloalkyl; Reis C1-6alkyl, C3-12cycloalkyl, C6-12aryl, 5-12 membered heteroaryl, each being optionally substituted with C1-6 alkyl or halo; SMARCA2 Binders Each bifunctional compound of Formulae (I) and (IA) comprises a selective SMARCA1 binder moiety, depicted as Formula (A): Formula (A) wherein, In more specific embodiments, R1and R2are each hydrogen. In other more specific embodiments, R1is C1-3 alkyl optionally substituted with 1 to 3 halo or hydroxy. In more specific embodiments, R1is -CF2H or -C(CH3)2OH, and R2is hydrogen. In various embodiments, R3is phenyl, pyridinyl, pyrazolyl, cyclopropyl, or C1-3 alkyl, each being optionally substituted with 1 to 3 Rd, wherein Rdis C1-3 alkyl, halo, or phenyl. In more specific embodiments, R3is phenyl, benzyl, 2-pyridinyl, 3-pyridinyl, -CN, 1- methyl-1H-pyrazol-3yl, 3-methylphenyl, 2-methylphenyl, 3-chlorophenyl, or 3,4- dichlorophenyl. In various embodiments, R3is phenyl optionally substituted with one or more C1-6 alkyl, C1-6 alkoxy, or halo; benzyl optionally substituted with one or more C1-6 alkyl or halo; pyridinyl optionally substituted with one or more C1-6 alkyl; CN; C3-6 cyclopropyl; pyrazolyl optionally substituted with one or more C1-6 alkyl; tetrahydropyranyl;1,2-oxazolyl optionally substituted with one or more C1-6 alkyl; pyrazolo[1,5-a]pyridinyl; or -O-Re, wherein Reis phenyl optionally substituted with C1-6 alkyl or halo, C3-6 cycloalkyl, C1-6 alkyl, or pyrazolyl optionally substituted with C1-6 alkyl. In even more specific embodiments, R3is phenyl, benzyl, 2-pyridinyl, 3-pyridinyl, 4- pyridinyl, CN, cyclopropyl, 1-methyl-1H-pyrazol-3yl, 3-methylphenyl, 2-methylphenyl, 3- chlorophenyl, 3,4-dichlorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-fluorophenyl, 4- fluorophenyl, tetrahydropyran-4yl, 3-methyl-1H-pyrazol-1yl, 4-methyl-1H-pyrazol-1yl, 5- methyl-1H-pyrazol-1yl, 1-methyl-1H-pyrazol-3yl, 1-methyl-1H-pyrazol-4yl, 1-methyl-1H- pyrazol-5yl, pyrazolo[1,5-a]pyridin-2-yl, 5-methyl-1,2-oxazol-3-yl, 5-isopropyl-1,2-oxazol-3-yl, 3-methyl-1,2-oxazol-5-yl, or -O-Re, wherein Reis phenyl, 2-chlorophenyl, 2-methylphenyl, cyclopropyl, cyclohexyl, methyl, or 1-methyl-1H-pyrazol-3yl. In a specific embodiment, R1and R2are each hydrogen, R3is phenyl, and the SMARCA2 binder moiety has the structure of Formula (A1): In another specific embodiment, R1and R2are each hydrogen, R3is -O-Re, as defined herein. Ligase Harness Moieties (LHM) The LHM moiety of the bifunctional compound of Formula (I) targets CRBN of E3 ligases. Once harnessed by the bifunctional compounds, the E3 ligases are capable of inducing ubiquitination and subsequent proteasomal degradation of SMARCA2. The LHM moiety of Formula (I) typically comprises a glutarimide or dihydrouracil moiety coupled to a ring structure, as represented by Formula (B): Formula (B) wherein, W is –C(Rg)- or –N-; Y is direct bond, C1-4 alkylene chain, -C(O)-, -C(O)O-, -O -, -N(Rg)-, -S- -C(S)-, -C(S)-O-, -O-C(O)O-, –C(O)-N(Rg)-, or –O-C(O)-N(Rg)-; B ring is C6-12 aryl, 5-12 membered heteroaryl, or 4-12 membered heterocyclyl, each being optionally substituted with 1 to 3 Rj; each Rjis independently halo, -CN, oxo, -O-Rc, C1-6 alkyl, or C1-6 haloalkyl; and Rgis hydrogen or C1-6 alkyl. In other embodiments, W is –N-, Y is direct bond; and B ring is , , whereinj R is H or C1-3alkyl. In more specific embodiments, the LHM moiety is: In other more specific embodiments, the LHM moiety is: In other more specific embodiments, the LHM moiety is: , Linker Each bifunctional compound of Formula (I) comprises a Linker (L), which is a bivalent moiety that couples the SMARCA2 Binder moiety to the LHM. The structure (e.g., length or rigidity) of the linker moiety may impact the efficiency or selectivity of the degradation process. The Linker comprises a continuous sequence of covalent bonds between the respective attachment points to the SMARCA2 Binder moiety and the LHM, inclusive of the bond indicated by a wavy line of Formulae (A) and (B) and their respective substructures. Typically, the linker moiety comprises multiple bivalent segments (i.e., – L1-L2-L3-L4-L5-L6-L7-L8–), which collectively contribute to the overall length and rigidity of the Linker, in addition to providing the respective attachment points to the SMARCA2 Binder moiety and the LHM. In various embodiments, the linker segments L1, L2, L3, L4, L5, L6, L7, L8 are each independently: i) C3-12 cycloalkyl optionally substituted with 1-3 Rb; ii) C6-12 aryl optionally substituted with 1-3 Rb; iii) 4-12 membered heterocyclyl optionally substituted with 1-3 Rb; iv) 5-12 membered heteroaryl optionally substituted with 1-3 Rb; v) direct bond; vi) C1-12 alkylene chain optionally substituted with 1-3 Rd; or vii) –(CH2)m-C(O)–, –(CH2)m-C(O)O–, –(CH2)m-O–, –(CH2)m-N(Rc)-, –(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(Rc)–, –C(O)-N(Rc)-(CH2)m–, –CH2)m-O-C(O)-N(Rc)–, –(CH2)m–O-C(O)-O–, or –NH-(CH2)m-C(O)–, wherein m is 0, 1, 2, 3, 4, 5 or 6; wherein Rd, Rcand Rdare as defined herein. It is to be understood that, unless otherwise specified and provided that the valence is satisfied, the bivalent linker segments described herein (e.g., L1or L2) are not limited to the direction in which they are expressed. For instance, for a given linker segment, e.g., -C(O)-NH-, the manner in which it is connected to the remainder of the molecule may be either direction: i.e., -C(O)-NH- or –NH-C(O)-, provided that the connection does not violate valence rules. Unless other specified, it is further to be understood that the first linker segment L1is directly coupled to the SMARCA2 Binder moiety, whereas the last linker segment L8is directly coupled to the LHM. One or more linker segments may be direct bonds. To illustrate, in a sequence of linker segments represented by –L2-L3-L4--, when L3 is a direct bond, it is effectively absent because L2 and L4 are coupled directly to each other. In another embodiment, the Linker has one or more rings, which tend to increase the linker rigidity. A combination of chain bonds and ring(s) may be used to tune the relative orientations of the bifunctional groups or the distance therebetween. In various specific embodiments, the linker (L) of compounds of Formulae (I), (II), (IIa), (IIb), (IIc) and (IId) is presented by –L1-L2-L3-L4-L5-L6-L7–L8–, each L1, L2, L3, L4, L5, L6, L7, or L8, being v) direct bond; vi) C1-6alkylene chain; or vii) -C(O)-, -O–,–C(O)-N(Rc)-, -(CH2)m-C(O)–, or –NH-(CH2)m-C(O)–, wherein m is 0, 1, 2 or 3; wherein, n is 0, 1, or 2; Rbis halo, -CN, C1-3alkyl, or C1-3haloalkyl; and Rcis hydrogen or C1-3alkyl. In more specific embodiments, one or more of the linker segments form a diamine linker moiety having one of the following structures:

[0002] In other specific embodiments, the linker (L’) of compounds of Formula (III) and its substructures Formulae (IIIa), (IIIb), (IIIc) and (IIId) may have one of the following structures:

[0003] Definitions The following description sets forth exemplary methods, parameters and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments. A dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -C(O)NH2 is attached through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in a structure indicates a point of attachment of a group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written or named. The prefix “Cu-v” indicates that the following group has from u to v carbon atoms. For example, “C1-6 alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms. Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. 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, to the term “about X” includes description of “X”. Also, the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to "the compound" includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art. “Alkyl” refers to an unbranched or branched saturated hydrocarbon chain containing no unsaturation. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C1-20 alkyl), 1 to 12 carbon atoms (i.e., C1-12 alkyl), 1 to 8 carbon atoms (i.e., C1-8 alkyl), 1 to 6 carbon atoms (i.e., C1-6 alkyl), or 1 to 4 carbon atoms (i.e., C1-4 alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; thus, for example, “butyl” includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2) and tert- butyl (i.e., -C(CH3)3); and “propyl” includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., - CH(CH3)2). “Alkylene” or “alkylene chain” refers to a unbranched or branched divalent hydrocarbon chain, linking the rest of the molecule to a radical group, containing no unsaturation and having from 1 to 20 carbon atoms, or more typically 1 to 12 carbon atoms (C1-12 alkylene), or 1 to 8 carbon atoms (C1-8 alkylene), or 1 to 3 carbon atoms (C1-3 alkylene) e.g., methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain may be attached to the rest of the molecule and to the radical group through one carbon within the chain or through any two carbons within the chain. “Alkenyl” refers to an alkyl group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C2-20 alkenyl), or more typically 2 to 12 carbon atoms (i.e., C2-12 alkenyl), 2 to 8 carbon atoms (i.e., C2-8 alkenyl), 2 to 6 carbon atoms (i.e., C2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C2-4 alkenyl). Examples of alkenyl groups include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl). “Alkenylene” and “alkenylene chain” refer to a unbranched or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, containing at least one double bond and having from 2 to 20 carbon atoms, or more typically 2 to 12 carbon atoms, or 2 to 8 carbon atoms, e.g., ethenylene, propenylene, n-butenylene, and the like. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a double bond or a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. “Alkynyl” refers to an alkyl group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C2-20 alkynyl), or more typically 2 to 12 carbon atoms (i.e., C2-12 alkynyl), or more typically 2 to 8 carbon atoms (i.e., C2-8 alkynyl), 2 to 6 carbon atoms (i.e., C2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C2-4 alkynyl). The term “alkynyl” also includes those groups having one triple bond and one double bond. “Alkynylene” and “alkynylene chain” refer to a unbranched or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, containing at least one triple bond and having from 2 to 20 carbon atoms, or more typically 2 to 12 carbon atoms, or 2 to 8 carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a double bond or a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. “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. “Haloalkoxy” refers to an alkoxy group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. “Alkylthio” refers to the group “alkyl-S-”. “Amino” refers to the group -NRyRywherein each Ryis independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl or heteroaryl, each of which is optionally substituted, as defined herein. “Aryl” refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) including fused systems. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C6-20 aryl), 6 to 15 carbon ring atoms (i.e., C6-15 aryl), or 6 to 10 carbon ring atoms (i.e., C6-10 aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl, the resulting ring system is heteroaryl. If one or more aryl groups are fused with a heterocyclyl, the resulting ring system is heterocyclyl. “Cyano” refers to the group -CN. “Keto” or “oxo” refers to a group =O. “Carbamoyl” refers to both an “O-carbamoyl” group which refers to the group –O- C(O)NRyRzand an “N-carbamoyl” group which refers to the group -NRyC(O)ORz, wherein Ryand Rzare independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each of which may be optionally substituted. “Carboxyl” or “carboxylic acid” refers to -C(O)OH. “Ester” refers to both -OC(O)R and -C(O)OR, wherein R is a substituent; each of which may be optionally substituted, as defined herein. “Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems. The term “cycloalkyl” includes cycloalkenyl groups (i.e., the cyclic group having at least one double bond). As used herein, cycloalkyl has from 3 to 15 ring carbon atoms (i.e., C3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6 cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[2.2.2]octan-1-yl. Cycloalkyl may be attached to the remainder of a molecule by a single ring atom (e.g., as a substituent) or by two ring atoms (e.g., as a linker). “Ethylene glycol unit” refers to a bivalent monomer having the structure of -CH2CH2O-, which may be repeated and extended into a longer chain. A linker segment may have up to 12 ethylene glycol units, or more typically up to 6 ethylene glycol units. “Propylene glycol unit” refers to a bivalent monomer having the structure of -CH(CH3)- CH2O-, which may be repeated and extended into a longer chain. A linker segment may have up to 12 propylene glycol units, or more typically up to 6 propylene glycol units. “Halogen” or “halo” includes fluoro, chloro, bromo, and iodo. “Haloalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include difluoromethyl (-CHF2) and trifluoromethyl (-CF3). “Heteroalkyl” refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatoms such as N, O, S, and the likes. The term “heteroalkyl” includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatoms. Heteroatomic groups include, but are not limited to, -N(R)-, -O-, -S-, -S(O)-, -S(O)2-, and the like, 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, heteroalkyl include 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. “Heteroaryl” refers to a 5-15 membered, or more typically, 5-12 membered aromatic group having a single ring, multiple rings, or multiple fused rings, with 1-3 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 3 to 12 ring carbon atoms (i.e., C3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C3-8 heteroaryl); and 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Examples of the 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, where the heteroaryl can be bound via either ring of the fused system. Any aromatic ring, having a single or multiple fused rings, containing at least one heteroatom, is considered a heteroaryl regardless of the attachment to the remainder of the molecule (i.e., through any one of the fused rings). Heteroaryl does not encompass or overlap with aryl (which has no heteroatom) or heterocyclyl (which has at least one non-aromatic ring). Heteroaryl may be attached to the remainder of a molecule by a single ring atom (e.g., as a substituent) or by two ring atoms (e.g., as a linker). “Heterocyclyl” refers to a 3-15 membered, or more typically, 5-12 membered, saturated or unsaturated cyclic alkyl group, with 1-3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. The term “heterocyclyl” includes heterocycloalkenyl groups (i.e., the heterocyclyl group having at least one double bond), bicyclic heterocyclyl groups, bridged- heterocyclyl groups, fused-heterocyclyl groups, and spiro-heterocyclyl groups. A heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the attachment (i.e., can be bound through a carbon atom or a heteroatom). Further, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring, regardless of the attachment to the remainder of the molecule. As used herein, heterocyclyl has 3 to 15 ring atoms (e.g., 3-15 membered heterocyclyl, 3-12 membered heterocyclyl, 4 to 10 membered heterocyclyl, 4-8 membered heterocyclyl or 4-6 membered heterocyclyl; having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur or oxygen. A heterocyclyl may contain one or more oxo and / or thioxo groups. Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, azetidinyl, morpholinyl, thiomorpholinyl, 4-7 membered sultam, 4-7 membered cyclic carbamate, 4-7 membered cyclic carbonate, 4-7 membered cyclic sulfide and morpholinyl. As used herein, heterocyclyl may include a bridged structure (i.e., “bridged heterocyclyl), in which a four- to ten-membered cyclic moiety connected at two non-adjacent atoms of the heterocyclyl with one or more (e.g., 1 or 2) four- to ten- membered cyclic moiety having at least one heteroatom where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. As used herein, bridged- heterocyclyl includes bicyclic and tricyclic ring systems. Also used herein, the term “spiro-heterocyclyl” refers to a ring system in which a three- to ten-membered heterocyclyl has one or more additional ring, wherein the one or more additional ring is three- to ten-membered cycloalkyl or three- to ten- membered heterocyclyl, where a single atom of the one or more additional ring is also an atom of the three- to ten-membered heterocyclyl. Examples of the 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 the fused-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, where the heterocyclyl can be bound via either ring of the fused system. As used herein, a bicyclic heterocyclyl group is a heterocyclyl group attached at two points to another cyclic group, wherein the other cyclic group may itself be a heterocyclic group, or a carbocyclic group. Heteroaryl may be attached to the remainder of a molecule by a single ring atom (e.g., as a substituent) or by two ring atoms (e.g., as a linker). “Fused” refers to a ring which is joint to an adjacent ring and share two adjacent ring atoms that form a covalent bond. “Bridged” refers to a ring fusion wherein non-adjacent atoms on a ring are joined by a divalent substituent, such as alkylenyl group, an alkylenyl group containing one or two heteroatoms, or a single heteroatom. Quinuclidinyl and admantanyl are examples of bridged ring systems. “Spiro” refers to a ring substituent which is joined by two bonds at the same carbon atom. Examples of spiro groups include 1,1-diethylcyclopentane, dimethyl-dioxolane, and 4-benzyl-4- methylpiperidine, wherein the cyclopentane and piperidine, respectively, are the spiro substituents. “Hydroxy” or “hydroxyl” refers to the group -OH. “Hydroxyalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a hydroxyl. “Nitro” refers to the group –NO2. “Imino” refers to a group that contains a C=N double bond, such as C=N-Ry, or =N- C(O)Ry, wherein Ryis selected from the group consisting of hydrogen, alkyl, aryl, cyano, haloalkyl, or heteroaryl; each of which may be optionally substituted. Imino may be a linker segment by attaching to the remainder molecule at the carbon and nitrogen respectively. “Sulfonyl” refers to the group -S(O)2R, where R is a substituent, or a defined group. “Alkylsulfonyl” refers to the group -S(O)2R, where R is a substituent, or a defined group. “Alkylsulfinyl” refers to the group -S(O)R, where R is a substituent, or a defined group. “Thiocyanate” –SCN. “Thiol” refers to the group -SR, where R is a substituent, or a defined group. “Thioxo” or “thione” refer to the group (=S) or (S). Certain commonly used alternative chemical names may be used. For example, a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc., may also be referred to as an “alkylene” group or an “alkylenyl” group, an “arylene” group or an “arylenyl” group, respectively. Also, unless indicated explicitly otherwise, where combinations of groups are referred to herein as one moiety, e.g., arylalkyl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule. The terms “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. Also, the term “optionally substituted” refers to any one or more hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen. “Optionally substituted” may be zero to the maximum number of possible substitutions, and each occurrence is independent. When the term “substituted” is used, then that substitution is required to be made at a substitutable hydrogen atom of the indicated substituent. An optional substitution may be the same or different from a (required) substitution. When a moiety is “optionally substituted,” and reference is made to a general term, such as any “alkyl,” “alkenyl,” “alkynyl,” “haloalkyl,” “cycloalkyl,” “aryl”or “heteroaryl,” then the general term can refer to any antecedent specifically recited term, such as (C1-3 alkyl), (C4-6 alkyl), -O(C1-4 alkyl), (C3-10 cycloalkyl), O-(C3-10 cycloalkyl) and the like. For example, “any aryl” includes both “aryl” and “-O(aryl) as well as examples of aryl, such as phenyl or naphthyl and the like. Also, the term “any heterocyclyl” includes both the terms “heterocyclyl” and O- (heterocyclyl),” as well as examples of heterocyclyls, such as oxetanyl, tetrahydropyranyl, morpholino, piperidinyl and the like. In the same manner, the term “any heteroaryl” includes the terms “heteroaryl” and “O-(heteroryl),” as well as specific heteroaryls, such as pyridine and the like. Some compounds of Formula (I) may exist as a “stereoisomer” or a mixture of stereoisomers. Stereoisomer refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The compounds of the disclosure, or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers (two stereoisomers whose molecules are non-superimposable mirror images of one another), diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present disclosure is meant to include all such possible isomers, as well as their racemic mixture (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 resolved using conventional techniques, such as HPLC or SFC using a chiral column. “&1” means that a compound including the “&1” notation at a particular chemical element or atom (e.g., carbon) within the compound was prepared as a mixture of two stereoisomers at the noted chemical element or atom (e.g., a diastereomeric mixture having a de or % de as described above). “&2,” if presents, denotes a second set of isomers. The disclosure also includes “deuterated analogues” of compounds of Formula (I) in which from 1 to n hydrogens attached to a carbon atom is / are replaced by deuterium, in which n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound of Formula (I) when administered to a mammal, particularly a human. 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 employing starting materials in which one or more hydrogens have been replaced by deuterium. Deuterium labelled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and / or an improvement in therapeutic index. An18F labeled compound may be useful for PET or SPECT studies. Isotopically labeled compounds of this disclosure can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in the compound of Formula (I). The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium. In many cases, the compounds of this disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto. Provided are also pharmaceutically acceptable salts, hydrates, or solvates of the compounds described herein. “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical uses. The term “pharmaceutically acceptable salt” of a given compound refers to salts that retain the biological effectiveness and properties of the given compound, and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. 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-toluene-sulfonic acid, salicylic acid, and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines (i.e., NH2(alkyl)), dialkyl amines (i.e., HN(alkyl)2), trialkyl amines (i.e., N(alkyl)3), substituted alkyl amines (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), alkenyl amines (i.e., NH2(alkenyl)), dialkenyl amines (i.e., HN(alkenyl)2), trialkenyl amines (i.e., N(alkenyl)3), substituted alkenyl amines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl) amines (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl) amines (i.e., N(substituted alkenyl)3, mono-, di- or tri- cycloalkyl amines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di- or tri- arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like. The term “substituted” means that any one or more hydrogen atoms on the designated atom or group is replaced with one or more substituents other than hydrogen, provided that the designated atom’s normal valence is not exceeded. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof. Polymers or similar indefinite structures arrived at by defining substituents with further substituents appended ad infinitum (e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended for inclusion herein. Unless otherwise noted, the maximum number of serial substitutions in compounds described herein is three. For example, serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to ((substituted aryl)substituted aryl) substituted aryl. Similarly, the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan. When used to modify a chemical group, the term “substituted” may describe other chemical groups defined herein. Unless specified otherwise, where a group is described as optionally substituted, any substituents of the group are themselves unsubstituted. For example, in some embodiments, the term “substituted alkyl” refers to an alkyl group having one or more substituents including hydroxyl, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, the one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted One skilled in the art will recognize that substituents and other moieties of the compounds of the generic formula herein should be selected in order to provide a compound which is sufficiently stable to provide a pharmaceutically useful compound which can be formulated into an acceptably stable pharmaceutical composition. Compounds which have such stability are contemplated as falling within the scope of the present invention. It should be understood by one skilled in the art that any combination of the definitions and substituents described above should not result in an inoperable species or compound. As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions. 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. Targeted SMARCA2 Degradation The compounds of the present disclosure are demonstrated by cell-based profiling to selectively degrade SMARCA2 while sparing SMARCA4. Additional biological activities, including selectivity data of compounds of Formula (I) are summarized in Table 1 herein. Pharmaceutical Composition and Use of the Bifunctional Compounds of Formula (I) The bifunctional compounds of Formula (I) are demonstrated to selectively degrade SMARCA2 and are therefore particularly useful for treating SMARCA4-deficient cancers. Various embodiments provide pharmaceutical compositions of a compound of Formula (I), or any one of the substructures or specific compounds of Examples 1-58, and a pharmaceutically acceptable carrier. Further embodiments provide methods for treating SMARCA2-mediated disease or disorder, including, for increasing T-cell activation, for treating cancer, for inhibiting the growth or proliferation of cancer cells, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), any one of the substructures or compounds of Examples 1-58. SMARCA2-mediated diseases may be cancers selected from the group consisting of acoustic neuroma, acute leukemiat, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, 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 cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, liver cancer, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's; Burkitt’s), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B — cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, malignant rhabdoid tumor (MRT), rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor. In some embodiments, a compound of Formula (I), or any one of the substructures or a compound of Examples 1-58 may be co-administered with a therapeutically effective amount of one or more additional therapeutic agents, or a pharmaceutically acceptable salt thereof. The additional therapeutic agents include, for example, chemotherapeutic agents disclosed in WO WO2021083949. Construction of Compounds of Formula (I) The synthesis or construction of the compounds of Formula (I) can be carried out in multiple steps, typically involving separately preparing building blocks of the SMARCA2 binder and the LHM moiety, followed by joining the respective building blocks through covalent bond formation. Generally speaking, either or both building blocks may be prepared with one or more linker precursors. A linker precursor comprises one or more linker segments (Ls) and has a terminal reactive group for further coupling. The two building blocks can be finally coupled (via formation of a further linker segment) to afford a compound of Formula (I). The following schemes demonstrate the general approaches of preparing building blocks. Specific examples (Examples 1-58) were synthesized and characterized by their respective physiochemical properties according to the general schemes described herein. INTERMEDIATES INTERMEDIATE 1 1-[6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL]-4-(5-METHYL-ISOXAZOL-3-YL)PIPERIDINE-4- CARBOXYLIC ACID Step 1: Synthesis of 1-(tert-butyl) 4-methyl 4-(5-methylisoxazol-3-yl)piperidine-1,4- dicarboxylate To a solution of methyl 2-(5-methylisoxazol-3-yl)acetate (28.0 g, 180 mmol, 1.00 eq) in DMF (280 mL) was added NaH (18.0 g, 451 mmol, 60% purity, 2.50 eq) at 0 – 5 °C under N2, the mixture was stirred at 0 – 5 °C for 1 hr. Then, tert-butyl bis(2-chloroethyl)carbamate (48.0 g, 198 mmol, 1.10 eq) was added at 0 – 5 °C, the mixture was heated to 60 °C and stirred at 60 °C for 15 hrs. The mixture was cooled down to 25 °C, then poured into saturated NH4Cl (500 mL) aqueous solution, then extracted with EtOAc (250 mL * 2). The combined organic layers were washed with brine (250 mL * 2), dried over Na2SO4, filtered and concentrated to give the product as a black brown liquid (57.8 g, crude). The crude product was directly used in the next step. LCMS: C16H24N2O5 requires 324.4, found: m / z = 325.2 [M+H]+. Step 2: Synthesis of methyl 4-(5-methylisoxazol-3-yl)piperidine-4-carboxylate A solution of 1-(tert-butyl) 4-methyl 4-(5-methylisoxazol-3-yl)piperidine-1,4- dicarboxylate (57.8 g, 178 mmol, 1.00 eq) in HCl / EtOAc (2 M, 578 mL, 6.49 eq) was stirred at 20 – 25 °C for 2 hrs. The reaction mixture was filtered and filter cake was dried under vacuum. The crude product was directly used in the next step. Methyl 4-(5-methylisoxazol-3- yl)piperidine-4-carboxylate (49.7 g, crude, HCl) was obtained as black brown liquid. LCMS: C11H16N2O3 requires 224.1, found: m / z = 225.1 [M+H]+. Step 3: Synthesis of methyl 1-(6-chloropyridazin-4-yl)-4-(5-methylisoxazol-3-yl)piperidine- 4-carboxylate To a solution of methyl 4-(5-methylisoxazol-3-yl)piperidine-4-carboxylate hydrochloride (47.7 g, 183 mmol, 1.00 eq, HCl) in IPA (480 mL) was added DIEA (94.6 g, 732 mmol, 127 mL, 4.00 eq) at 20 °C, then was added 3,5-dichloropyridazine (30.0 g, 201 mmol, 1.10 eq) at 20 °C. The reaction mixture was stirred at 70 °C for 12 hrs. The reaction mixture was quenched with H2O (1.00 L), then extracted with DCM (500 mL * 3). The organic layer was washed with brine (500 mL * 2), dried over Na2SO4, filtered and concentrated to give the product. The residue was purified by column chromatography (SiO2) with a gradient 30-100% ethyl acetate in petroleum ether. Methyl 1-(6-chloropyridazin-4-yl)-4-(5-methylisoxazol-3-yl)piperidine-4-carboxylate (5.10 g, 7.92 mmol, 4.16% yield, 52.3% purity) was obtained as a brown solid. LCMS: C15H17ClN4O3 requires 336.1, found: m / z = 337.1 [M+H]+. Step 4: Synthesis of methyl 1-(6-(2-methoxyphenyl)37yridazine-4-yl)-4-(5-methylisoxazol-3- yl)piperidine-4-carboxylate A mixture of methyl 1-(6-chloropyridazin-4-yl)-4-(5-methylisoxazol-3-yl)piperidine-4- carboxylate (2.54 g, 7.54 mmol, 1.00 eq), (2-methoxyphenyl)boronic acid (2.29 g, 15.0 mmol, 2.00 eq), K2CO3 (3.13 g, 22.6 mmol, 3.00 eq), RuPhos Pd G3 (630 mg, 754 μmol, 0.10 eq) in dioxane (127 mL) and H2O (12.7 mL) was degassed and purged with N2 for 3 times at 25 °C, and then the mixture was stirred at 90 °C for 12 hrs under N2 atmosphere. Then the mixture was poured into H2O (150 mL), extracted with ethyl acetate (150 mL * 3). The combined organic phase was washed with brine (150 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by RP-FC with a gradient of 25-55% MeCN in H2O. The eluent was concentrated in vacuum. The aqueous phase was lyophilized to give the product. Methyl 1-(6-(2-methoxyphenyl)pyridazine-4-yl)-4-(5-methylisoxazol-3-yl)piperidine-4- carboxylate (1.90 g, 4.50 mmol, 35.9% yield, 96.6% purity) was obtained as a light yellow solid. LCMS: C22H24N4O4 requires 408.2, found: m / z = 409.1 [M+H]+. Step 5: Synthesis of title compound To a solution of methyl 1-(6-(2-methoxyphenyl)pyridazine-4-yl)-4-(5-methylisoxazol-3- yl)piperidine-4-carboxylate (1.60 g, 3.79 mmol, 1.00 eq) in DCM (50.0 mL) was added BBr3 (2 M, 3.79 mL, 2.00 eq) at 0 °C. The reaction was stirred at 15 °C for 3 hrs. The resulting mixture was quenched by addition of HCl solution (1 N, 5.00 mL). The resulting mixture was extracted with EtOAc (10.0 mL * 3), dried over Na2SO4, concentrated under reduced pressure to give methyl 1-(6-(2-hydroxyphenyl)pyridazine-4-yl)-4-(5-methylisoxazol-3-yl)piperidine-4- carboxylate (3.80 g, crude) was as a light yellow solid. Then, to a solution of methyl 1-(6-(2- hydroxyphenyl)pyridazine-4-yl)-4-(5-methylisoxazol-3-yl)piperidine-4-carboxylate (3.10 g, 2.33 mmol, 1.00 eq) in THF (30.0 mL) and H2O (30.0 mL) was added LiOH·H2O (977 mg, 23.3 mmol, 10.0 eq), and the mixture was stirred at 15 °C for 4 hrs. The resulting mixture was quenched by addition of HCl solution (1 N, 30.0 mL), then concentrated under vacuum. This was purified by RP-FC with a gradient of 1-31% MeCN in H2O. The residue was dissolved with CAN (5.00 mL), H2O (5.00 mL), concentrated under vacuum to removed CAN, then concentrated under lyophilization.1-(6-(2-hydroxyphenyl)pyridazine-4-yl)-4-(5-methylisoxazol- 3-yl)piperidine-4-carboxylic acid (444 mg, 1.13 mmol, 30.5% yield, 96.5% purity) was obtained as a white solid. LCMS: C20H20N4O4 requires 380.1, found: 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). INTERMEDIATE 2 1-(6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL)-4-(2-METHOXYPHENYL)PIPERIDINE-4- CARBOXYLIC ACID Step 1: Synthesis of 1-(tert-butyl) 4-methyl 4-(2-methoxyphenyl)piperidine-1,4- dicarboxylate This intermediate was synthesized according to Step 1 of Intermediate 1 using methyl 2- (2-methoxyphenyl)acetate.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: C19H27NO5 requires 349.2, found: m / z = 250.1 [M-100+H]+. Step 2: Synthesis of methyl 4-(2-methoxyphenyl)piperidine-4-carboxylate 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 brown oil. LCMS: C14H19NO3requires 249.1, found: m / z = 250.1 [M+H]+. Step 3: Synthesis of methyl 1-(6-chloropyridazin-4-yl)-4-(2-methoxyphenyl)piperidine-4- carboxylate This intermediate was synthesized according to Step 3 of Intermediate 1using methyl 4- (2-methoxyphenyl)piperidine-4-carboxylate. 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 yellow oil. LCMS: C18H20ClN3O3requires 361.1, found: m / z = 362.2 [M+H]+. Step 4: Synthesis of methyl 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(2- methoxyphenyl)piperidine-4-carboxylate This intermediate was synthesized (2.5 g, crude) according to Step 4 of Intermediate 1 using methyl 1-(6-chloropyridazin-4-yl)-4-(2-methoxyphenyl)piperidine-4-carboxylate and (2- hydroxyphenyl)boronic acid. LCMS: C24H25N3O4 requires 419.2, found: m / z = 420.2 [M+H]+. Following 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). INTERMEDIATE 4 1-(6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL)-4-(TETRAHYDRO-2H-PYRAN-4-YL)PIPERIDINE-4- CARBOXYLIC ACID Step 1: Synthesis of ethyl 4-(tetrahydro-2H-pyran-4-yl)piperidine-4-carboxylate To a solution of DIPA (4.71 g, 46.6 mmol, 6.58 mL, 1.20 eq) in THF (50.0 mL) was added n-BuLi (2.50 M, 18.7 mL, 1.20 eq) at -10 °C, and stirred at -10 °C for 0.5 hr. Then, ethyl piperidine-4-carboxylate (10.0 g, 38.9 mmol, 1.00 eq) in THF (10.0 mL) was added drop wise to the reaction mixture at -10 °C, and stirred at -10 °C for 2 hr. A solution of 4-iodotetrahydro-2H- pyran (9.06 g, 42.8 mmol, 1.10 eq) in THF (10.0 mL) was added to the mixture at -10 °C and stirred at -10 °C for 1 hr. The mixture was warmed to 25 °C and stirred at 25 °C for 12 hrs. The reaction mixture was poured into saturated ice NH4Cl solution (500 mL) at 0 °C, the aqueous phase was extracted with ethyl acetate (500 mL *2). The combined organic phase was washed with H2O (500 mL), brine (500 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give a crude product. The residue was purified by column chromatography (SiO2) with 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.1H NMR: (400 MHz, MeOD) δ 4.21 (q, J = 7.2 Hz, 2H), 4.06 - 3.88 (m, 4H), 3.41 - 3.32 (m, 2H), 2.74 (br s, 2H), 2.14 (br d, J = 12.4 Hz, 2H), 1.70 - 1.62 (m, 1H), 1.61 - 1.55 (m, 2H), 1.46 - 1.44 (m, 9H), 1.43 - 1.32 (m, 4H), 1.29 (t, J = 7.2 Hz, 3H) Step 2: Synthesis of ethyl 4-(tetrahydro-2H-pyran-4-yl)piperidine-4-carboxylate 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 light yellow solid. LCMS: C13H23NO3requires 241.2, found: m / z = 242.2 [M+H]+. Step 3: Synthesis of ethyl 1-(6-chloropyridazin-4-yl)-4-(tetrahydro-2H-pyran-4- yl)piperidine-4-carboxylate This intermediate was synthesized (5.40 g, 15.0 mmol, 69.4% yield, 98.2% purity) according to Step 3 of Intermediate 1 using ethyl 4-(tetrahydro-2H-pyran-4-yl)piperidine-4- carboxylate. LCMS: C17H24ClN3O3requires 353.2, found: m / z = 354.1 [M+H]+. Step 4: Synthesis of methyl 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(2- methoxyphenyl)piperidine-4-carboxylate This intermediate was synthesized (4.50 g, 10.6 mmol, 78.1% yield, 97.1% purity) according to Step 4 of Intermediate 1using ethyl 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4- (tetrahydro-2H-pyran-4-yl)piperidine-4-carboxylate and (2-hydroxyphenyl)boronic acid. LCMS: C23H29N3O4 requires 411.2, found: m / z = 412.2 [M+H]+. Following basic hydrolysis, the title compound was obtained as a beige solid (2.43 g, 6.28 mmol, 88.7% yield, 99.1% purity). LCMS: C21H25N3O4 requires 383.2, found: m / z = 384.1 [M+H]+.1H 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) INTERMEDIATE 5 1-(6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL)-4-(3-METHYL-1H-PYRAZOL-1-YL)PIPERIDINE-4- CARBOXYLIC ACID Step 1: Synthesis of di-tert-butyl 1-(1-benzyl-4-(ethoxycarbonyl)piperidin-4-yl)hydrazine- 1,2-dicarboxylate To the solution of DIPA (15.5 g, 153 mmol, 21.6 mL, 1.40 eq) in THF (270 mL) was added n-BuLi (2.5 M, 60.9 mL, 1.39 eq) at -65 °C under N2. The reaction mixture was stirred at -65°C for 1 hr. Then ethyl 1-benzylpiperidine-4-carboxylate (27.0 g, 109 mmol, 1.00 eq) was added drop wise to the reaction mixture at -65°C and stirred at -65 °C for 1 hr. 1,2-Bis(1,1- dimethylethyl)-(1E)-1,2-diazenedicarboxylate (27.5 g, 120 mmol, 1.10 eq) 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 hrs under N2. The reaction mixture was poured into saturated NH4Cl solution (1.50 L) and extracted with ethyl acetate (600 mL * 3). The combined organic phase was washed with brine (1.50 L), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by RP-FC and purified with a gradient of 25-46% MeCN in H2O. The eluent was concentrated in vacuum to remove acetonitrile and adjusted to pH = 7 with saturated NaHCO3solution. The aqueous phase was extracted with ethyl acetate (1.00 L * 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give di-tert-butyl 1-(1-benzyl-4- (ethoxycarbonyl)piperidin-4-yl)hydrazine-1,2-dicarboxylate (48.8 g, 97.1 mmol, 88.9% yield) as a yellow solid. LCMS: C25H39N3O6requires 477.3, found: m / z = 478.1 [M+H]+. Step 2: Synthesis of ethyl 1-benzyl-4-hydrazineylpiperidine-4-carboxylate To a solution of di-tert-butyl 1-(1-benzyl-4-(ethoxycarbonyl)piperidin-4-yl)hydrazine- 1,2-dicarboxylate (48.8 g, 102 mmol, 1.00 eq) in EtOAc (50.0 mL) was added HCl / EtOAc (2 M, 500 mL, 9.79 eq) at 25 °C. The mixture was heated to 40 °C and stirred at 40 °C for 12 hrs. The reaction mixture was concentrated under vacuum to give ethyl 1-benzyl-4-hydrazineylpiperidine- 4-carboxylate (36.0 g, crude, HCl) as a white solid. LCMS: C15H23N3O2 requires 277.2, found: m / z = 278.1 [M+H]+. Step 3: Synthesis of ethyl 1-benzyl-4-(3-methyl-1H-pyrazol-1-yl)piperidine-4-carboxylate A mixture of ethyl 1-benzyl-4-hydrazineylpiperidine-4-carboxylate (39.0 g, 141 mmol, 1.00 eq) and 4,4-dimethoxybutan-2-one (18.6 g, 141 mmol, 18.7 mL, 1.00 eq) in EtOH (195 mL) and AcOH (19.5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 50 °C for 2 hrs under N2. The reaction mixture was concentrated under vacuum. The residue was purified by RP-FC with a gradient of 10-40% MeCN in H2O. The eluent was concentrated in vacuum to remove acetonitrile and H2O, the residual aqueous was lyophilized to give ethyl 1-benzyl-4-(3-methyl-1H-pyrazol-1-yl)piperidine-4-carboxylate (22.0 g, 64.4 mmol, 45.8% yield) as a yellow solid. LCMS: C19H25N3O2 requires 327.2, found: m / z = 328.1 [M+H]+. Step 4: Synthesis of ethyl 4-(3-methyl-1H-pyrazol-1-yl)piperidine-4-carboxylate To a solution of ethyl 1-benzyl-4-(3-methyl-1H-pyrazol-1-yl)piperidine-4-carboxylate (22.0 g, 67.2 mmol, 1.00 eq) in MeOH (110 mL) was added Pd / C (2.22 g, 2.08 mmol, 10% purity, 0.031 eq) under N2. The suspension was degassed under vacuum and purged with H2 three times. The mixture was stirred under H2 (50 psi) at 25 °C for 12 hrs. The reaction mixture was filtered and the filter was concentrated to give ethyl 4-(3-methyl-1H-pyrazol-1- yl)piperidine-4-carboxylate (15.6 g, 64.8 mmol, 96.5% yield) as a yellow solid.1H 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). Step 5: Synthesis of ethyl 1-(6-chloropyridazin-4-yl)-4-(3-methyl-1H-pyrazol-1- yl)piperidine-4-carboxylate This intermediate was synthesized (12.5 g, 35.5 mmol, 53.9% yield) according to Step 3 of Intermediate 1 using ethyl 4-(3-methyl-1H-pyrazol-1-yl)piperidine-4-carboxylate. LCMS: C16H20ClN5O2 requires 349.1, found: m / z = 350.0 [M+H]+. Step 6: Synthesis of ethyl 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(3-methyl-1H-pyrazol-1- yl)piperidine-4-carboxylate This intermediate was synthesized (8.50 g, 16.7 mmol, 83.4% yield) according to Step 4 of Intermediate 1using ethyl 1-(6-chloropyridazin-4-yl)-4-(3-methyl-1H-pyrazol-1-yl)piperidine- 4-carboxylate and (2-hydroxyphenyl)boronic acid. LCMS: C22H25N5O3 requires 407.2, found: m / z = 408.2 [M+H]+. Following basic hydrolysis, the title compound was obtained as a light brown solid (1.07 g, 2.75 mmol, 37.3% yield, 97.4% purity). LCMS: C20H21N5O3 requires 379.4, found: m / z = 380.1 [M+H]+.1H 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) INTERMEDIATE 6 1-(6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL)-4-(PYRIDIN-4-YL)PIPERIDINE-4-CARBOXYLIC ACID Step 1: Synthesis of 1-(tert-butyl) 4-methyl 4-(pyridin-4-yl)piperidine-1,4-dicarboxylate This intermediate was synthesized (9.20 g, 25.4 mmol, 9.84% yield, 88.4% purity) according to Step 1 of Intermediate 1 using methyl 2-(4-fluorophenyl)acetate. LCMS: C17H24 N2O4 requires 320.2, found: m / z = 321.3 [M+H]+. Step 2: Synthesis of methyl 4-(pyridin-4-yl)piperidine-4-carboxylate This intermediate was synthesized (9.20 g, crude, HCl) according to Step 2 of Intermediate 1. LCMS: C12H16N2O2requires 220.1, found: m / z = 221.1 [M+H]+. Step 3: Synthesis of methyl 1-(6-chloropyridazin-4-yl)-4-(pyridin-4-yl)piperidine-4- carboxylate This intermediate was synthesized (6.67 g, 19.8 mmol, 62.0% yield, 98.8% purity) according to Step 3 of Intermediate 1 using methyl 4-(pyridin-4-yl)piperidine-4-carboxylate. LCMS: C16H17ClN4O2 requires 332.1, found: m / z = 333.2 [M+H]+. Step 4: Synthesis of methyl 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(pyridin-4- yl)piperidine-4-carboxylate This intermediate was synthesized (4.20 g, 10.6 mmol, 63.9% yield, 98.2% purity) according to Step 4 of Intermediate 1using methyl 1-(6-chloropyridazin-4-yl)-4-(pyridin-4- yl)piperidine-4-carboxylate and (2-hydroxyphenyl)boronic acid. LCMS: C22H22N4O3 requires 390.2, found: m / z = 391.2 [M+H]+. Following 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. LCMS: C21H20N4O3 requires 376.2, found: m / z = 377.2.1H 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). INTERMEDIATE 7 1-(6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL)-4-(3-METHOXYPHENYL)PIPERIDINE-4- CARBOXYLIC ACID Step 1: Synthesis of 1-(tert-butyl) 4-methyl 4-(3-methoxyphenyl)piperidine-1,4- dicarboxylate This intermediate was synthesized (7.70 g, 11.0 mmol, 6.62% yield, 50.0% purity) according to Step 1 of Intermediate 1using methyl 2-(3-methoxyphenyl)acetate. LCMS: C19H27NO5 requires 349.2, found: m / z = 250.1 [M-100+H]+. Step 2: Synthesis of methyl 4-(3-methoxyphenyl)piperidine-4-carboxylate This intermediate was synthesized (7.40 g, crude, HCl) according to Step 2 of Intermediate 1. LCMS: C14H19NO3requires 249.1, found: m / z = 250.1 [M+H]+. Step 3: Synthesis of methyl 1-(6-chloropyridazin-4-yl)-4-(3-methoxyphenyl)piperidine-4- carboxylate This intermediate was synthesized (5.90 g, 16.0 mmol, 57.3% yield, 98.3% purity) according to Step 3 of Intermediate 1using methyl 4-(3-methoxyphenyl)piperidine-4- carboxylate. LCMS: C18H20ClN3O3requires 361.1, found: m / z = 362.2 [M+H]+. Step 4: Synthesis of methyl 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(3- methoxyphenyl)piperidine-4-carboxylate This intermediate was synthesized (3.20 g, 7.40 mmol, 59.5% yield, 97% purity) according to Step 4 of Intermediate 8using methyl 1-(6-chloropyridazin-4-yl)-4-(3- methoxyphenyl)piperidine-4-carboxylate and (2-hydroxyphenyl)boronic acid. LCMS: C24H25N3O4 requires 419.2, found: m / z = 420.1 [M+H]+. Following basic hydrolysis, the title compound (1.04 g, 2.56 mmol, 39.8% yield, 99.9% purity) was obtained as an off-white solid. LCMS: C23H23N3O4 requires 405.2, found: m / z = 406.2 [M+H]+.1H 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). INTERMEDIATE 8 4-(4-FLUOROPHENYL)-1-(6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL)PIPERIDINE-4-CARBOXYLIC ACID Step 1: Synthesis of 1-(tert-butyl) 4-methyl 4-(4-fluorophenyl)piperidine-1,4-dicarboxylate This intermediate was synthesized (8.36 g, crude) according to Step 1 of Intermediate 1using methyl 2-(4-fluorophenyl)acetate. LCMS: C18H24FNO4 requires 337.2, found: m / z = 282.2 [M-56+H]+. Step 2: Synthesis of methyl 4-(4-fluorophenyl)piperidine-4-carboxylate This intermediate was synthesized (7.64 g, crude, HCl) according to Step 2 of Intermediate 1. LCMS: C13H16FNO2 requires 237.1, found: m / z = 238.2 [M+H]+. Step 3: Synthesis of methyl 1-(6-chloropyridazin-4-yl)-4-(4-fluorophenyl)piperidine-4- carboxylate This intermediate was synthesized (2.61 g, 7.31 mmol, 41.0% yield, 98.0% purity) according to Step 3 of Intermediate 1using methyl 4-(4-fluorophenyl)piperidine-4-carboxylate. LCMS: C17H17ClFN3O2 requires 349.1, found: m / z = 350.2 [M+H]+. Step 4: Synthesis of methyl 4-(4-fluorophenyl)-1-(6-(2-hydroxyphenyl)pyridazin-4- yl)piperidine-4-carboxylate To a solution of methyl 1-(6-chloropyridazin-4-yl)-4-(4-fluorophenyl)piperidine-4- carboxylate (2.41 g, 6.75 mmol, 1.00 eq), (2-hydroxyphenyl)boronic acid (1.86 g, 13.5 mmol, 2.00 eq) and K2CO3 (2.80 g, 20.3 mmol, 3.00 eq) in dioxane (24.1 mL) and H2O (4.82 mL) was added Pd(dppf)Cl2 (494 mg, 675 μmol, 0.10 eq) under N2 atmosphere. The mixture was stirred at 110 °C for 12 hrs. The mixture was poured into H2O (100 mL) and extracted with ethyl acetate (100 mL * 3). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified by MPLC (SiO2) with a gradient of 10-50% Petroleum ether / Ethyl acetate(751 mg, 1.80 mmol, 26.6% yield, 97.6% purity). LCMS: C23H22FN3O3 requires 407.2, found: m / z = 408.2 [M+H]+. Following basic hydrolysis, the title compound (1.14 g, 2.62 mmol, 79.2% yield, 98.8% purity, HCl) was obtained as a white solid. LCMS: C22H20FN3O3 requires 393.1, found: 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).19F NMR: (400 MHz, DMSO-d6) δ -115.561. INTERMEDIATE 9 4-(2-FLUOROPHENYL)-1-(6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL)PIPERIDINE-4-CARBOXYLIC ACID Step 1: Synthesis of 1-(tert-butyl) 4-methyl 4-(2-fluorophenyl)piperidine-1,4-dicarboxylate To a solution of methyl 2-(2-fluorophenyl)acetate (28.0 g, 164 mmol) in DMF (560 mL) was added NaH (16.4 g, 411 mmol, 60.0% in mineral oil) at 0 - 5 °C under N2, the mixture was stirred at 0 - 5 °C for 1 hr. Then, tert-butyl bis(2-chloroethyl)carbamate (51.8 g, 214 mmol) was added, the mixture was heated to 60 °C and stirred until complete as judged by LCMS. Once complete, the reaction mixture was quenched with saturated NH4Cl solution (300 mL) at 0 °C. The mixture was poured into H2O (500 mL) and extracted with EtOAc (500 mL x 3). The combined organic phase was washed with H2O (500 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to afford the crude product (54.0 g) as a yellow oil which was taken forward without any further purification. LCMS C9H9FO2 requires 337.2, found 282.2 [M-56+H]+. Step 2: Synthesis of methyl 4-(2-fluorophenyl)piperidine-4-carboxylate To a solution of 1-(tert-butyl) 4-methyl 4-(2-fluorophenyl)piperidine-1,4-dicarboxylate (54.0 g, 160 mmol) in EtOAc (200 mL) was added a 1:1 mixture of conc HCl in EtOAc (300 mL). The mixture was stirred at 25 °C until complete as judged by LCMS. Once complete, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was adjusted to pH = 8 with saturated sodium bicarbonate solution and extracted with DCM (100 mL). The aqueous phase was adjusted to pH = 10 with saturated sodium carbonate solution and extracted with DCM (200 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product (16.0 g, HCl salt) as a yellow oil which was taken forward without any further purification. LCMS C17H17ClFN3O2requires 237.1, found m / z = 238.2 [M+H]+. Step 3: Synthesis of methyl 1-(6-chloropyridazin-4-yl)-4-(2-fluorophenyl)piperidine-4- carboxylate To a solution of methyl 4-(2-fluorophenyl)piperidine-4-carboxylate (16.0 g, 67.4 mmol) in IPA (160 mL) was added DIPEA (46.9 mL, 269 mmol) and 3,5-dichloropyridazine (12.0 g, 80.9 mmol). The mixture was stirred at 25 °C until complete as judged by LCMS. Once complete, the reaction mixture was filtered and concentrated under reduced pressure to give a crude residue. The residue was dissolved in minimal 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 give the crude product. The crude residue was purified by flash column chromatography (petroleum ether in ethyl acetate: 15% to 50%) to afford the desired product as a yellow solid (9.45 g, 39% yield). LCMS C17H17ClFN3O2requires 349.1, found m / z = 350.2 [M+H]+. Step 4: Synthesis of methyl 4-(2-fluorophenyl)-1-(6-(2-hydroxyphenyl)pyridazin-4- yl)piperidine-4-carboxylate 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) was added 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) under N2atmosphere at 25 °C. The mixture was then heated to 90 °C and allowed to stir until complete as judged by LCMS. Once complete, the reaction mixture was filtered through Celite (with EtOAc washing) and concentrated under reduced pressure to minimal solvent. The residue was poured into H2O (200 mL) and was extracted with EtOAc (300 mL x 3). The combined organic layer was dried over Na2SO4, filtered and concentrated to give a crude residue. The crude product was purified by flash column chromatography to afford the desired product as a yellow solid (2.75 g, 30.6% yield). LCMS C23H22FN3O3requires m / z = 407.2, found 408.3 [M+H]+. Following basic hydrolysis, the title compound was obtained as a light-yellow solid (1.97 g, 71% yield). LCMS C22H20FN3O3requires 393.2, found m / z = 394.2 [M+H]+. INTERMEDIATE 10 1-(6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL)-4-(5-ISOPROPYLISOXAZOL-3-YL)PIPERIDINE-4- CARBOXYLIC ACID Step 1: Synthesis of (5-isopropylisoxazol-3-yl)methanol To a solution of methyl 5-isopropylisoxazole-3-carboxylate (25.0 g, 148 mmol) in THF (125 mL) was added LAH (2.5 M in THF, 118 mL) at 0 °C under N2. The mixture was then allowed to warm and stirred at 25 °C under N2 until complete as judged by LCMS. Once complete, the mixture was cooled to 0 °C, followed by slow addition of 1 M HCl (800 mL) drop- wise under N2 with stirring for 30 mins. 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 afford the crude product as a yellow oil which was taken forward without any further purification (13.0 g). LCMS C7H11NO2 requires 141.1, found 142.6 [M+H]+. Step 2: Synthesis of (5-isopropylisoxazol-3-yl)methyl methanesulfonate To a solution of (5-isopropylisoxazol-3-yl)methanol (20.1 g, 142 mmol) and TEA (39.6 mL, 285 mmol) in DCM (201 mL) was added MsCl (16.6 mL, 215 mmol) drop-wise at 0 °C. The mixture was allowed to warm and stirred at 25 °C until complete as judged by LCMS. Once complete, the mixture was poured into ice-cold water (500 mL) and extracted with DCM (250 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under vacuum to afford the crude product as a yellow oil which was taken forward without any further purification (28.1 g). LCMS C8H13NO4S requires 219.1, found m / z = 220.4 [M+H]+. Step 3: Synthesis of 2-(5-isopropylisoxazol-3-yl)acetonitrile To a solution of (5-isopropylisoxazol-3-yl)methyl methanesulfonate (29.6 g, 135 mmol) in DMF (150 mL) was added NaCN (10.2 g, 208 mmol). The mixture was then heated to 60 °C and allowed to stir until complete as judged by LCMS. Once complete, the reaction mixture was diluted with saturated aqueous Na2CO3solution (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 give a crude residue. The crude residue was purified by flash column chromatography (petroleum ether in ethyl acetate - 5% to 20%) afford the desired product as a yellow oil (13.9 g, 69% yield). LCMS C8H10N2O requires 150.1, found 151.2 [M+H]+. Step 4: tert-butyl 4-cyano-4-(5-isopropylisoxazol-3-yl)piperidine-1-carboxylate This intermediate was synthesized as described for Step 1 for Intermediate 9, using 2-(5- isopropylisoxazol-3-yl)acetonitrile in place of methyl 2-(2-fluorophenyl)acetate. LCMS C17H25N3O3requires 319.2, found m / z = 220.1 [M-Boc+H]+. Step 5: Synthesis of 4-(5-isopropylisoxazol-3-yl)piperidine-4-carbonitrile This intermediate was prepared as described in Step 2 for Intermediate 9, using tert-butyl 4-cyano-4-(5-isopropylisoxazol-3-yl)piperidine-1-carboxylate (Step 7) in place of 1-(tert-butyl) 4-methyl 4-(2-fluorophenyl)piperidine-1,4-dicarboxylate (9.65 g). LCMS C12H17N3O requires 219.1, found m / z = 220.1 [M+H]+. Step 6: Synthesis of 1-(6-chloropyridazin-4-yl)-4-(5-isopropylisoxazol-3-yl)piperidine-4- carbonitrile This intermediate was prepared as described in Step 3 for Intermediate 9, using 4-(5- isopropylisoxazol-3-yl)piperidine-4-carbonitrile in place of 4-(2-fluorophenyl)piperidine-4- carboxylate (14.5 g). LCMS C16H18ClN5O requires 331.1, found m / z = 332.1 [M+H]+. Step 7: Synthesis of 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(5-isopropylisoxazol-3- yl)piperidine-4-carbonitrile To a solution of 1-(6-chloropyridazin-4-yl)-4-(5-isopropylisoxazol-3-yl)piperidine-4- carbonitrile (4.00 g, 12.1 mmol), (2-hydroxyphenyl)boronic acid (3.33 g, 24.1 mmol) in 1,4- dioxane (40 mL) and H2O (4 mL) was added K2CO3 (5.00 g, 36.2 mmol) and RuPhos Pd G3 (504 mg, 603 µmol) at 25 °C, the mixture was degassed and purged with N2 three times. The mixture was then heated to 90 °C and stirred until complete as judged by LCMS. Once complete, the residue was diluted with H2O (50.0 mL) and extracted with EtOAc (50.0 mL x 3). The combined organic layers were washed with brine (50.0 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude residue. The residue was purified by flash column chromatography (petroleum ether in ethyl acetate – 5 to 100%) to afford the desired product as a brown solid. (2.00 g, 42% yield). LCMS C22H23N5O2 requires 389.2, found m / z = 390.3 [M+H]+. Step 8: Synthesis of Title Compound To a solution of 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(5-isopropylisoxazol-3- yl)piperidine-4-carbonitrile (2.00 g, 5.14 mmol) in THF (6 mL), MeOH (6 mL) and H2O (6 mL) was added NaOH (2.05 g, 51.4 mmol) at 25 °C, the mixture was heated to 80 °C and stirred until complete as judged by LCMS. Once complete, the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude residue. The crude residue was purified by RP-FC (26.0% - 46.0%). The desired eluent was concentrated under reduced pressure to half volume, frozen at -78°C and lyophilized to dryness to afford to desired compound as a yellow solid (1.14g, 58% yield). LCMS C22H24N4O4 requires 408.2, found m / z = 409.1 [M+H]+. INTERMEDIATE 11 1-(6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL)-4-(PYRAZOLO[1,5-A]PYRIDIN-2-YL)PIPERIDINE-4- CARBOXYLIC ACID Step 1: Synthesis of ethyl 2-(pyrazolo[1,5-a]pyridin-2-yl)acetate To a solution of 2-(pyrazolo[1,5-a]pyridin-2-yl)acetic acid (23.0 g, 130 mmol) in EtOH (115 mL) was added H2SO4 (6.40 g, 65.2 mmol, 3.48 mL) at 25 °C, the reaction was then heated to 80 °C and allowed to stir util complete as judged by LCMS. Once complete, the reaction mixture was concentrated under vacuum to give a crude residue. The residue was quenched with ice-water (175 mL), followed by extraction with DCM (175 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to afford the title compound as black-brown liquid (25.4 g). LCMS C11H12N2O2 requires 204.1, found m / z = 205.1 [M+H]+. Step 2: Synthesis of 1-(tert-butyl) 4-ethyl 4-(pyrazolo[1,5-a]pyridin-2-yl)piperidine-1,4- dicarboxylate This intermediate was synthesized as described in Step 1 for Intermediate 9, using ethyl 2-(pyrazolo[1,5-a]pyridin-2-yl)acetate in place of methyl 2-(2-fluorophenyl)acetate (34.5 g). LCMS C20H27N3O4 requires 373.2, found m / z = 318.2 [M-56+H]+. Step 3: ethyl 4-(pyrazolo[1,5-a]pyridin-2-yl)piperidine-4-carboxylate This intermediate was synthesized as described in Step 2 for Intermediate 9, using 1-(tert- butyl) 4-ethyl 4-(pyrazolo[1,5-a]pyridin-2-yl)piperidine-1,4-dicarboxylate (Step 13) in place of 1-(tert-butyl) 4-methyl 4-(2-fluorophenyl)piperidine-1,4-dicarboxylate (42.9 g). LCMS C19H20ClN5O2 requires 273.2, found m / z =274.2 [M+H]+. Step 4: Synthesis of ethyl 1-(6-chloropyridazin-4-yl)-4-(pyrazolo[1,5-a]pyridin-2- yl)piperidine-4-carboxylate This intermediate was synthesized as described for Intermediate 9 Step 3, using ethyl 4- (pyrazolo[1,5-a]pyridin-2-yl)piperidine-4-carboxylate in place of 4-(2-fluorophenyl)piperidine- 4-carboxylate (11.0 g). LCMS C19H20ClN5O2 requires 385.1, found m / z = 386.2 [M+H]+. Step 5: Synthesis of ethyl 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(pyrazolo[1,5-a]pyridin- 2-yl)piperidine-4-carboxylate This intermediate was prepared as described in Step 4 for Intermediate 9, using ethyl 1- (6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(pyrazolo[1,5-a]pyridin-2-yl)piperidine-4-carboxylate in place of methyl 1-(6-chloropyridazin-4-yl)-4-(2-fluorophenyl)piperidine-4-carboxylate (42% yield over four steps). LCMS C25H25N5O3 requires 443.2, found m / z = 444.2 [M+H]+. Following basic hydrolysis, the title compound was obtained (2.50 g). LCMS C23H21N5O3 requires 415.2, found 416.2 [M+H]+. INTERMEDIATE 12 1-(6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL)-4-(1-METHYL-1H-PYRAZOL-4-YL)PIPERIDINE-4- CARBOXYLIC ACID Step 1: Synthesis of 1-(tert-butyl) 4-methyl 4-(1-methyl-1H-pyrazol-4-yl)piperidine-1,4- dicarboxylate This intermediate was synthesized as described in Step 1 for Intermediate 9, using methyl 2-(1-methyl-1H-pyrazol-4-yl)acetate in place of methyl 2-(2-fluorophenyl)acetate (80.8 g). LCMS C16H25N3O4requires 323.2, found m / z = 268.2 [M-56+H]+. Step 2: Synthesis of methyl 4-(1-methyl-1H-pyrazol-4-yl)piperidine-4-carboxylate This intermediate was synthesized as described in Step 2 for Intermediate 9, using 1-(tert- butyl) 4-methyl 4-(1-methyl-1H-pyrazol-4-yl)piperidine-1,4-dicarboxylate in place of 1-(tert- butyl) 4-methyl 4-(2-fluorophenyl)piperidine-1,4-dicarboxylate (82.5 g). LCMS C11H17N3O2requires 223.1, found m / z = 224.3 [M+H]+. Step 3: Synthesis of methyl 1-(6-chloropyridazin-4-yl)-4-(1-methyl-1H-pyrazol-4- yl)piperidine-4-carboxylate This intermediate was synthesized as in Step 3 for Intermediate 9, using methyl 4-(1- methyl-1H-pyrazol-4-yl)piperidine-4-carboxylate in place of 4-(2-fluorophenyl)piperidine-4- carboxylate (7.8 g) LCMS C15H18ClN5O2requires 335.1, found m / z = 336.2 [M+H]+. Step 4: Synthesis of methyl 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(1-methyl-1H-pyrazol- 4-yl)piperidine-4-carboxylate This intermediate was synthesized as described in Step 4 for Intermediate 9, using methyl 1-(6-chloropyridazin-4-yl)-4-(1-methyl-1H-pyrazol-4-yl)piperidine-4-carboxylate in place of methyl 1-(6-chloropyridazin-4-yl)-4-(2-fluorophenyl)piperidine-4-carboxylate (4.1 g, 44% yield over four steps). LCMS C21H23N5O3requires 393.2, found m / z = 394.2 [M+H]+. Following basic hydrolysis, the title compound was obtained (2.2 g, 79% yield). LCMS C20H21N5O3requires 379.2, found 380.2 [M+H]+. INTERMEDIATE 13 1-(6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL)-4-(3-METHYLISOXAZOL-5-YL)PIPERIDINE-4- CARBOXYLIC ACID Step 1: Synthesis of 1-(tert-butyl) 4-methyl 4-(3-methylisoxazol-5-yl)piperidine-1,4- dicarboxylate This intermediate was prepared as described in Step 1 for Intermediate 9, using methyl 2- (3-methylisoxazol-5-yl)acetate in place of methyl 2-(2-fluorophenyl)acetate (57.8 g). LCMS C16H24N2O5 requires 324.2, found m / z = 325.2 [M+H]+. Step 2: Synthesis of methyl 4-(3-methylisoxazol-5-yl)piperidine-4-carboxylate This intermediate was synthesized as described in Step 2 for Intermediate 9, using 1-(tert- butyl) 4-methyl 4-(3-methylisoxazol-5-yl)piperidine-1,4-dicarboxylate in place of 1-(tert-butyl) 4-methyl 4-(2-fluorophenyl)piperidine-1,4-dicarboxylate (49.7 g). LCMS C11H16N2O3requires 224.1, found m / z = 225.1 [M+H]+. Step 3: Synthesis of methyl 1-(6-chloropyridazin-4-yl)-4-(3-methylisoxazol-5-yl)piperidine- 4-carboxylate This intermediate was synthesized as described in Step 3 for Intermediate 9, using methyl 4-(3-methylisoxazol-5-yl)piperidine-4-carboxylate in place of methyl 4-(2- fluorophenyl)piperidine-4-carboxylate (5.1 g). LCMS C15H17ClN4O3 requires 336.1, found m / z = 337.1 [M+H]+. Step 4: Synthesis of methyl 1-(6-(2-methoxyphenyl)pyridazin-4-yl)-4-(3-methylisoxazol-5- yl)piperidine-4-carboxylate This intermediate was synthesized as described in Step 7 for Intermediate 10, using methyl 1-(6-chloropyridazin-4-yl)-4-(3-methylisoxazol-5-yl)piperidine-4-carboxylate in place of 1-(6-chloropyridazin-4-yl)-4-(5-isopropylisoxazol-3-yl)piperidine-4-carbonitrile and (2- methoxyphenyl)boronic acid in place of (2-hydroxyphenyl)boronic acid (1.90 g, 36% yield over four steps). LCMS C22H24N4O4requires 408.2, found m / z = 409.1 [M+H]+. Step 5: Synthesis of methyl 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(3-methylisoxazol-5- yl)piperidine-4-carboxylate To a solution of methyl 1-(6-(2-methoxyphenyl)pyridazin-4-yl)-4-(3-methylisoxazol-5- yl)piperidine-4-carboxylate (1.60 g, 3.79 mmol) in DCM (50 mL) was added BBr3 (2 M, 3.79 mL) at 0 °C. The reaction was then warmed to 25 °C and allowed to stir util complete as judged by LCMS. Once complete, the reaction mixture was quenched by addition of HCl solution (1 N, 5.0 mL). The resulting mixture was extracted with EtOAc (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude light-yellow solid which was taken forward without any further purification (3.80 g). LCMS C21H22N4O4 requires 394.2, found m / z = 395.2 [M+H]+. Following basic hydrolysis, the title compound was obtained (444 mgs, 31% yield). LCMS C20H20N4O4 requires 380.2, found m / z = 381.1 [M+H]+. INTERMEDIATE 14 1-(6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL)-4-(5-METHYL-1H-PYRAZOL-1-YL)PIPERIDINE-4- CARBOXYLIC ACID Step 1: Synthesis of di-tert-butyl 1-(1-benzyl-4-(ethoxycarbonyl)piperidin-4-yl)hydrazine- 1,2-dicarboxylate To a solution of LDA (2 M in THF, 44.4 mL) in THF (120 mL) was added ethyl 1- benzylpiperidine-4-carboxylate (20.0 g, 80.8 mmol) dropwise at -70 °C and the mixture was stirred at -70 °C for 0.5 hr. Then to the mixture was added a solution of di-tert-butyl (E)- diazene-1,2-dicarboxylate (19.5 g, 84.9 mmol) in THF (40.0 mL) at -70 °C. The mixture was warmed to 25 °C and allowed to stir until complete as judged by LCMS. Once complete, the reaction mixture was poured into 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 afford a crude residue. The crude product was purified by flash column chromatography (petroleum ether in EtOAc - 10% to 50%) to afford the title compound as a yellow solid (15.0 g, 39% yield). LCMS C15H21NO2 requires 477.3, found m / z = 478.4 [M+H]+. Step 2: Synthesis of ethyl 1-benzyl-4-hydrazineylpiperidine-4-carboxylate This intermediate was synthesized as described in Step 2 for Intermediate 9, using di-tert- butyl 1-(1-benzyl-4-(ethoxycarbonyl)piperidin-4-yl)hydrazine-1,2-dicarboxylate in place of 1- (tert-butyl) 4-methyl 4-(2-fluorophenyl)piperidine-1,4-dicarboxylate (12.0 g, bis-HCl salt). LCMS C15H23N3O2requires 277.2, found m / z = 278.5 [M+H]+. Step 3: Synthesis of ethyl 1-benzyl-4-(5-methyl-1H-pyrazol-1-yl)piperidine-4-carboxylate 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 hr. The mixture was cooled to 60 °C and to the mixture was added ethyl 1- benzyl-4-hydrazineylpiperidine-4-carboxylate (4.66 g, 12.04 mmol) at 60 °C. The mixture was then heated and stirred at 120 °C until complete as judged by LCMS. Once complete, the reaction mixture adjusted pH to 10 with Na2CO3 solution, then extracted with EtOAc (60.0 mL x 3). The combined organic layers were dried with anhydrous Na2SO4, filtered, and concentrated under vacuum to afford the crude product as a black / brown oil which was taken forward without any further purification (4.0 g). LCMS C19H25N3O2 requires 327.2, found m / z = 328.4 [M=H]+. Step 4: Synthesis of ethyl 4-(5-methyl-1H-pyrazol-1-yl)piperidine-4-carboxylate To a solution of ethyl 1-benzyl-4-(5-methyl-1H-pyrazol-1-yl)piperidine-4-carboxylate (5.13 g, 15.6 mmol) in EtOH (40.0 mL) was added Pd / C (516 mg, 485 μmol, 10% purity) under N2 atmosphere. The suspension was degassed and charged with H2 three times. The mixture was charged with H2 (50 psi) and allowed to stir at 25 °C until complete as judged by LCMS. Once complete, the reaction mixture was filtered through celite with EtOH washing, and the resulting filtrate was concentrated under vacuum to obtain a colorless oil which was taken forward with any further purification (3.4 g). LCMS C12H19N3O2 requires 237.2, found 238.5 [M+H]+. Step 5: Synthesis of ethyl 1-(6-chloropyridazin-4-yl)-4-(5-methyl-1H-pyrazol-1- yl)piperidine-4-carboxylate This intermediate was synthesized as in Step 3 for Intermediate 9, using ethyl 4-(5- methyl-1H-pyrazol-1-yl)piperidine-4-carboxylate in place of methyl 4-(2- fluorophenyl)piperidine-4-carboxylate (2.9 g). LCMS C16H20ClN5O2requires 349.1, found m / z = 350.3 [M+H]+. Step 6: Synthesis of ethyl 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(5-methyl-1H-pyrazol-1- yl)piperidine-4-carboxylate This intermediate was synthesized as described in Step 7 for Intermediate 10, using ethyl 1-(6-chloropyridazin-4-yl)-4-(5-methyl-1H-pyrazol-1-yl)piperidine-4-carboxylate in place of 1- (6-chloropyridazin-4-yl)-4-(5-isopropylisoxazol-3-yl)piperidine-4-carbonitrile (3.0 g). LCMS C22H25N5O3 requires 407.2, found m / z = 408.3 [M+H]+. Following Step 8 for Intermediate 10, the title compound was obtained (1.14 g, 10% yield over six steps). LCMS C20H21N5O3 requires 379.2, found 380.3 [M+H]+. INTERMEDIATE 15 SYNTHESIS OF 2-(5-(4-(AMINOMETHYL)-4-PHENYLPIPERIDIN-1-YL)PYRIDAZIN-3-YL)PHENOL Step 1: Synthesis of tert-butyl ((1-(6-chloropyridazin-4-yl)-4-phenylpiperidin-4- yl)methyl)carbamate This intermediate was synthesized as described in Step 3 for Intermediate 9using tert- butyl ((4-phenylpiperidin-4-yl)methyl)carbamate in place of methyl 4-(2- fluorophenyl)piperidine-4-carboxylate. LCMS C21H27ClN4O2 requires 402.2, found 403.2 [M+H]+. Step 2: Synthesis of tert-butyl ((1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-phenylpiperidin-4- yl)methyl)carbamate This intermediate was synthesized as described in Step 4 for Intermediate 9, using tert- butyl ((1-(6-chloropyridazin-4-yl)-4-phenylpiperidin-4-yl)methyl)carbamate in place of methyl 1-(6-chloropyridazin-4-yl)-4-(2-fluorophenyl)piperidine-4-carboxylate to afford the title compound as a yellow solid (1.13 g, 49% yield over two steps). LCMS C27H32N4O3requires 460.3, found 461.3 [M+H]+. Following basic hydrolysis, the title compound was obtained. LCMS C22H24N4O requires 360.2, found m / z = 361.2 [M+H]+. INTERMEDIATE 16 METHYL 1-[6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL]-4-(2-METHYLPHENOXY)PIPERIDINE-4- CARBOXYLATE Step 1: Synthesis of 1-[(tert-butoxy)carbonyl]-4-(2-methylphenoxy)piperidine-4-carboxylic acid o-cresol (2.500 g, 23.11 mmol, 1.0 Equiv.) was dissolved in anhydrous THF (116 ml, 0.2 M). Powdered NaOH (4.624 g, 115.591 mmol, 5.0 eq) and 1-Boc-piperidin-4-one (13.819 g, 69.355 mmol, 3.0 Equiv.) were added to the solution at 0 °C. Chloroform (9.26 ml, 115.591 mmol, 5.0 Equiv.) was added dropwise and the reaction mixture was stirred for 1 h at 0 °C, followed by overnight stirring at RT. The reaction mixture was diluted with water and ethyl acetate. Layers were separated and 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 solvents were evaporated to give 1-[(tert-butoxy)carbonyl]-4-(2- methylphenoxy)piperidine-4-carboxylic acid (0.612 g, 1.825 mmol, 8%) as a yellow solid.1H 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). Step 2: Synthesis of methyl 4-(2-methylphenoxy)piperidine-4-carboxylate hydrochloride Thionyl chloride (0.293 ml, 4.014 mmol, 2.2 eq) was added carefully to a stirred solution of 1-[(tert-butoxy)carbonyl]-4-(2-methylphenoxy)piperidine-4-carboxylic acid (0.612 g, 1,825 mmol, 1 eq) in anhydrous methanol (6.08 ml, 0.3 M). The resulting solution was stirred at reflux overnight. Next, it was cooled down to RT and volatiles were evaporated to dryness. The residue was triturated with diethyl ether, filtered, washed with diethyl ether, collected and dried under reduced pressure to give methyl 4-(2-methylphenoxy)piperidine-4-carboxylate hydrochloride (0.494 g, 1.711 mmol, 94%) as a brown solid.1H 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). Step 3: Synthesis of methyl 1-(6-chloropyridazin-4-yl)-4-(2-methylphenoxy)piperidine-4- carboxylate Mixture of 3,5-Dichloropyridazine (0.255 g, 1.711 mmol, 1.0 eq), methyl 4-(2- methylphenoxy)piperidine-4-carboxylate hydrochloride (0.494 g, 1.711 mmol, 1.0 eq) in anhydrous NMP (3.42 ml, 0.5 M) and N,N-Diisopropylethylamine (0.894 ml, 5.134 mmol, 3.0 eq) was stirred under argon in closed vial at 100 °C for 1 h. Reaction was pouring it into cold water with vigorous stirring, The formed precipitate was filtered, washed with water, collected and dried under reduced pressure to give methyl 1-(6-chloropyridazin-4-yl)-4-(2- methylphenoxy)piperidine-4-carboxylate (0.47 g, 1.234 mmol, 72%) as a off-white solid.1H 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). Step 4: Synthesis of methyl 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-(2- methylphenoxy)piperidine-4-carboxylate methyl 1-(6-chloropyridazin-4-yl)-4-(2-methylphenoxy)piperidine-4-carboxylate (0.47 g, 1.234 mmol, 1.0 eq) was placed in a pressure vessel with K2CO3(0.512 g, 3.70 mmol, 3.0 eq), 2- Hydroxyphenylboronic acid (0.255 g, 1.851 mmol, 1.5 eq) and Pd(PPh3)4(0.143 g, 0.1234 mmol, 0.1 eq), followed by addition of dioxane (6.17 ml, 0.2 M) and water (1.23 ml, 1.0 M). Argon was bubbled through the mixture was 15 min. After that reaction mixture was stirring for about overnight at 100 °C. After cooling down to RT, Celite was added and the mixture was evaporated under reduced pressure to give a dry-load for FC purification on silica gel (DCM – AcOEt 100:0 to 30:70) to give methyl 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-(2- methylphenoxy)piperidine-4-carboxylate (0.292 g, 0.696 mmol, 56%) as a off-white solid.1H 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). Following basic hydrolysis, the title compound was obtained (0.185 g, 0.443 mmol, 62%) as a white solid.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). INTERMEDIATE 17 1-{6-[2-(METHOXYMETHOXY)PHENYL]PYRIDAZIN-4-YL}-4-PHENYLPIPERIDINE-4-CARBOXYLIC ACID Step 1: Synthesis of methyl 4-phenylpiperidine-4-carboxylate hydrochloride Thionyl chloride (5.402 ml, 74.466 mmol, 1.8 eq) was added carefully at 0 C to the stirred solution of 4-phenylpiperidine-4-carboxylic acid hydrochloride (10.0 g, 41.37 mmol, 1.0 eq) in anhydrous methanol (51.71 ml, 0.8 M). The resulting solution was stirred at reflux overnight. Next, it was cooled down to RT and volatiles were evaporated. The obtained solid was triturated with MTBE and filtered. The solid was collected and dried under reduced pressure which afforded methyl 4-phenylpiperidine-4-carboxylate hydrochloride (10.5 g, 39.004 mmol, 94%) as brown solid. LCMS (m / z): [M+H]+calculated for C13H19NO2+: 220.13, found: 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). Step 2: Synthesis of methyl 1-(6-chloropyridazin-4-yl)-4-phenylpiperidine-4-carboxylate A 500 mL pressure vial equipped with a magnetic stirrer was charged with 3,5- dichloropyridazine (4.648 g, 31.203 mmol, 1.2 eq) and methyl 4-phenylpiperidine-4-carboxylate hydrochloride (7.0 g, 26.003 mmol, 1.0 eq). To this, dimethyl sulfoxide (52.01 ml, 0.5 M) and N,N-diisopropylethylamine (DIPEA) (27.176 ml, 156.018 mmol, 6.0 eq) were added. The reaction mixture was stirred at 100 °C overnight. DIPEA was evaporated and compound was precipitated in water followed by sonication, filtration, and drying which afforded methyl 1-(6- chloropyridazin-4-yl)-4-phenylpiperidine-4-carboxylate (8.5 g, 23.056 mmol, 89%) as brown solid. LCMS (m / z): [M+H]+calculated for C17H19ClN3O2+: 332.12, found: 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). Step 3: Synthesis of methyl 1-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-4- phenylpiperidine-4-carboxylate A flame dried 500 mL pressure vial equipped with magnetic stirrer and argon balloon was charged with 2-(methoxymethoxy)phenylboronic acid (1.54 g, 8.463 mmol, 1.2 eq), and methyl 1-(6-chloropyridazin-4-yl)-4-phenylpiperidine-4-carboxylate (2.6 g, 7.052 mmol, 1.0 eq). To this dioxane (70.52 ml, 0.1 M) and potassium carbonate (2.924 g, 21.157 mmol, 3.0 eq) solution in water (14.1 ml, 0.5 M) were added. Argon was bubbled through the mixture for 20 min and then tetrakis(triphenylphosphine)palladium (0.815 g, 0.705 mmol, 0.1 eq) was added. The reaction vial was purged through argon before closing the cap and reaction mixture was stirred at 100 ℃ for 7 h. The compound was purified by FC using MTBE / DCM (0 to 70%) and methyl 1-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-4-phenylpiperidine-4-carboxylate (2.56 g, 5.787 mmol, 82%) was obtained as yellow solid. LCMS (m / z): [M+H]+calculated for C25H28ClN3O4+: 434.21, found: 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). Following basic hydrolysis, the title compound was obtained (2.3 g, 5.318 mmol, 92%) as off-white solid. LCMS (m / z): [M+H]+calculated for C24H26N3O4+: 420.19, found: 420.22.1H 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). INTERMEDIATE 20 1‐[6‐(2‐HYDROXYPHENYL)PYRIDAZIN‐4‐YL]‐4‐PHENOXYPIPERIDINE‐4‐CARBOXYLIC ACID Step 1: Synthesis of 1-[(tert-butoxy)carbonyl]-4-phenoxypiperidine-4-carboxylic acid Phenol (1.50 g, 15.938 mmol) was dissolved in anhydrous tetrahydrofuran (31.88 ml, 0.5 M) and cooled to 0 °C. Powdered NaOH (3.19 g, 79.69 mmol) and 1-Boc-piperidin-4-one (9.53 g, 47.82 mmol) were added followed by addition of chloroform (6.38 ml, 79.69 mmol) dropwise and the resulting mixture was stirred for 1 h at 0 °C, followed by overnight stirring at room temperature. Once complete, the reaction mixture was diluted with water and extracted twice with ethyl acetate. The aqueous layer was acidified to pH = 2 (using 0.5 M HCl) and extracted with ethyl acetate (x2). The combined organic extracts from the acidic wash were dried over magnesium sulfate, filtered, and evaporated. The crude product was obtained as a yellow oil (2.11 g, 37%). LCMS: C17H23NO5 requires 321.3, found: m / z = 322.1 [M+H]+. 1H 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). Step 2: Synthesis of 4-phenoxypiperidine-4-carboxylic acid hydrochloride 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 and the resulting solution was stirred at room temperature for 72 h. Once complete, the solvent was removed under reduce pressure, to afford 4-phenoxypiperidine-4-carboxylic acid hydrochloride (1.59 g, 92%) as a tan solid. LCMS: C12H15NO3requires 221.7, found: m / z = 222.1 [M+H]+. 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). Step 3: Synthesis of 1‐(6‐chloropyridazin‐4‐yl)‐4‐phenoxypiperidine‐4‐carboxylic acid To a solution of 3,5-dichloropyridazine (1.72 g, 11.59 mmol) in anhydrous dimethylformamide (23.19 ml, 0.2 M) was added 4-phenoxypiperidine-4-carboxylic acid hydrochloride (1.44 g, 4.638 mmol) and DIPEA (4.85 ml, 23.83 mmol). The resulting mixture was stirred at 100 °C for 3 h. Once complete, the reaction was quenched citric acid to pH = ~5 and extracted with dichloromethane 3x. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash-chromatography (DCM / MeOH, 100:0 to 90:10) to afford 1‐(6‐chloropyridazin‐4‐yl)‐4‐phenoxypiperidine‐4‐ carboxylic acid (824 mg, 48%) as a tan powder. LCMS: C16H16ClN3O3 requires 333.7, found: m / z = 333.8 [M+H]+. 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). Step 4: Synthesis of 1‐{6‐[2‐(methoxymethoxy)phenyl]pyridazin‐4‐yl}‐4 phenoxypiperidine‐ 4‐carboxylic acid 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 vessel and under argon atmosphere. Dioxane (20.71 mL) and H2O (4.14 mL) were added sequentially, 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 to 85:15) to afford 1‐{6‐[2‐(methoxymethoxy)phenyl]pyridazin‐4‐yl}‐4 phenoxypiperidine‐4‐ carboxylic acid (503 mg, 54%). LCMS: C24H25N3O5 requires 435.4, found: m / z = 436.5 [M+H]+. 1H 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). Step 5: Synthesis of 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 at room temperature overnight. Once complete, the solvent was removed under reduced pressure and the residue was purified via RP-FC to afford the title compound (120 mg, 29%) as a trifluoroacetate salt. 1H 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). INTERMEDIATE 21 1-[6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL]-4-[(1-METHYL-1H-PYRAZOL-3- YL)OXY]PIPERIDINE-4-CARBOXYLIC ACID Step 1: Synthesis of 1-[(tert-butoxy)carbonyl]-4-[(1-methyl-1H-pyrazol-3-yl)oxy]piperidine- 4-carboxylic acid A solution of 2-methyl-1H-pyrazol-5-one (3.0 g, 30.58 mmol) in anhydrous tetrahydrofuran (152.9 ml, 0.2 M) was cooled to 0 °C and powdered NaOH (6.116 g, 152.89 mmol) and 1-Boc-piperidin-4-one (18.279 g, 91.738 mmol, 3.0 eq) were added sequentially. Chloroform anhydrous (12.249 ml, 152.897 mmol, 5.0 eq) was added dropwise to the solution and the resulting mixture was stirred overnight at room temperature. Once complete, the reaction mixture was diluted with water and extracted twice with ethyl acetate. The aqueous layer was acidified to pH = 2 (using 0.5 M HCl) and extracted with ethyl acetate (x2). The combined organic extracts from the acidic wash were dried over magnesium sulfate, filtered, and evaporated. The crude product was obtained as a yellow oil (3.60 g, 36%). LCMS: C15H23N3O5requires 325.1, found: m / z = 326.4 [M+H]+. 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). Step 2: Synthesis of methyl 4-[(1-methyl-1H-pyrazol-3-yl)oxy]piperidine-4-carboxylate hydrochloride A solution of 1-[(tert-butoxy)carbonyl]-4-[(1-methyl-1H-pyrazol-3-yl)oxy]piperidine-4- carboxylic acid (3.6 g, 11.06 mmol) in MeOH (110.64 ml, 0.1 M) was cooled to 0 °C and SOCl2(2.40 mL, 33.19 mmol) was added dropwise . The resulting solution was stirred at reflux overnight. Once complete, the reaction was cooled to room temperature and volatiles were evaporated. The obtained solid was triturated with MTBE and filtered. The solid was collected and dried under reduced pressure to afford methyl 4-[(1-methyl-1H-pyrazol-3-yl)oxy]piperidine- 4-carboxylate hydrochloride (2.88 g, 94%). LCMS: C11H17N3O3requires 239.1, found: m / z = 240.2 [M+H]+. 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). Step 3: Synthesis of methyl 1-(6-chloropyridazin-4-yl)-4-[(1-methyl-1H-pyrazol-3- yl)oxy]piperidine-4-carboxylate To a stirred solution of methyl 4-[(1-methyl-1H-pyrazol-3-yl)oxy]piperidine-4- carboxylate hydrochloride (2.88 g, 10.44 mmol) in DMSO (52.23 ml, 0.2 M) was added N,N- diisopropylethylamine (10.9 ml, 62.67 mmol), followed by 3,5-Dichloropyridazine (1.71 g, 11.49 mmol). The reaction mixture was stirred at 100 °C overnight. Once complete, the excess of DIPEA was removed under reduced pressure. Cold water was added to the solution and mixture was sonicated for 15 minutes. The resulting solid was filtered to afford methyl 1-(6- chloropyridazin-4-yl)-4-[(1-methyl-1H-pyrazol-3-yl)oxy]piperidine-4-carboxylate (3.63 g, 10.319 mmol). LCMS: C15H18ClN5O3 requires 351.1, found: m / z = 352.3 [M+H]+. 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). Step 4: Synthesis of methyl 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-[(1-methyl-1H- pyrazol-3-yl)oxy]piperidine-4-carboxylate Methyl 1-(6-chloropyridazin-4-yl)-4-[(1-methyl-1H-pyrazol-3-yl)oxy]piperidine-4- carboxylate (2.0 g, 5.685 mmol, 1.0 eq), K2CO3(2.357 g, 17.056 mmol, 3.0 eq) and 2- Hydroxyphenylboronic acid (0.863 g, 6.254 mmol, 1.1 eq) were added to a sealed vessel under argon atmosphere. Dioxane (28.43 ml, 0.2 M) and Water (5.69 ml, 1.0 M) were sequentially added and the resulting solution was degassed with an argon balloon for 15 mins. Tetrakis(triphenylphosphine)palladium (0.657 g, 0.569 mmol, 0.1 eq) was then added to the mixture and resulting solution was stirred at 100 °C for 16h. Once complete, the solvents were evaporated and the crude mixture was purified by flash chromatography (DCM / MeOH, 98:02 to 85:15) to afford methyl 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-[(1-methyl-1H-pyrazol-3- yl)oxy]piperidine-4-carboxylate (1.1 g, 42%) as yellow solid. LCMS: C21H23N5O4requires 409.4, found: m / z = 410.4 [M+H]+. 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). Following basic hydrolysis, the title compound was obtained as an off-white solid (0.116 g, 12%). LCMS: C20H21N5O4requires 395.4, found: m / z = 396.2 [M+H]+. 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). INTERMEDIATE 22 4-CYCLOPROPOXY-1-[6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL]PIPERIDINE-4-CARBOXYLIC ACID Step 1: Synthesis of benzyl 4-cyclopropoxy-4-(hydroxymethyl)piperidine-1-carboxylate A flask was charged 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 argon atmosphere. The mixture was cooled down to 15oC using an ice water bath. Boron trifluoride diethyl etherate (6.887 g, 48.53 mmol) was then added dropwise while maintaining the temperature of the bath at 15oC. After the addition was complete, the cooling bath was removed and stirring was continued for 1 h. DCM was added, followed by slow addition of water. The contents were transferred to a separatory funnel and the layers were separated. The aqueous layer was washed with DCM 3x and the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified via RP-FC column to afford benzyl 4-cyclopropoxy- 4-(hydroxymethyl)piperidine-1-carboxylate (3.07, 46%) as a colorless oil. LCMS: C17H23NO4 requires 305.3, found: m / z = 306.6 [M+H]+. 1H 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). Step 2: Synthesis of benzyl 4-cyclopropoxy-4-formylpiperidine-1-carboxylate Dess-Martin periodinane, 95% (5.543 g, 13.069 mmol) was added to a stirring 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 h. Once complete, DCM (50 mL) and water (50 M) were added, followed by sat. aq. Na2S2O3 (50 ml) and the mixture was stirred for 15 min. The contents were transferred to a separatory funnel and the layers were separated. The aqueous layer was washed with DCM 2x and the combined organic layers were washed with brine, collected, dried over Na2SO4, filtered and concentrated in vacuo to afford benzyl 4-cyclopropoxy-4-formylpiperidine-1-carboxylate (2.73 g, 81%) as a colorless oil. LCMS: C17H21NO4 requires 303.3, found: m / z = 304.2 [M+H]+. 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). Step 3: Synthesis of 1-[(benzyloxy)carbonyl]-4-cyclopropoxypiperidine-4-carboxylic acid A flask was charged with benzyl 4-cyclopropoxy-4-formylpiperidine-1-carboxylate (2.73 g, 8.09 mmol) and potassium phosphate monobasic (3.30 g, 24.29 mmol). T-Butanol (80.99 ml), Water (20.25 ml) and 2-Methyl-2-butene (10.297 ml, 97.19 mmol) were then added sequentially. Sodium chlorite (2.75 g, 24.29 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. Once complete by LCMS, the reaction was diluted with DCM and the pH was adjusted to ~12 using 1M NaOH. The contents were transferred to a separatory funnel and the layers were separated. The aqueous layer was then acidified with 1 M HCl to pH ~2 and extracted with EtOAc 3x. The combined organic layers were dried over Na2SO4, filtered and evaporated to afford 1-[(benzyloxy)carbonyl]-4-cyclopropoxypiperidine-4-carboxylic acid (1.76 g, 65% yield) as a colorless oil. LCMS: C17H21NO5requires 318.3, found: m / z = 319.3 [M+H]+. 1H 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). Step 4: 1-benzyl 4-methyl 4-cyclopropoxypiperidine-1,4-dicarboxylate (Trimethylsilyl)diazomethane, (2M in hexanes) (17.02 ml, 34.03 mmol) was added dropwise to a cooled (10 °C) solution of 1-[(benzyloxy)carbonyl]-4-cyclopropoxypiperidine-4- carboxylic acid (1.76 g, 5.24 mmol) in methanol (20.94 ml, 0.25 M). Addition was continued until the light yellow color persisted in the solution. The cooling bath was then removed and the reaction was stirred at room temperature for 1 h. Once complete, acetic acid was added dropwise until the yellow color disappeared and the solution became colorless. Residual solvents were evaporated and the residue was purified by chromatography (hexane / MTBE, 100:0 to 75:25) to afford 1-benzyl 4-methyl 4-cyclopropoxypiperidine-1,4-dicarboxylate (1.39 g, 79%) as a colorless oil. LCMS: C18H23NO5 requires 333.3, found: m / z = 334.2 [M+H]+. 1H 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). Step 5: Synthesis of methyl 4-cyclopropoxypiperidine-4-carboxylate 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-neck-RBF equipped with argon balloon and hydrogen balloon. The reaction mixture was degassed with argon and Pd / C (10% by weight; 0.62 g, 5.8 mmol) was added followed again by degassing with argon and filling with hydrogen . The reaction was stirred at room temperature overnight. The reaction mixture was filtered through a celite pad and evaporated to dryness to provide methyl 4-cyclopropoxypiperidine-4-carboxylate (0.78 g, 96%) as a gray solid. 1H 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). Step 6: Synthesis of methyl 1-(6-chloropyridazin-4-yl)-4-cyclopropoxypiperidine-4- carboxylate A mixture of 3,5-Dichloropyridazine (0.55 g, 3.72 mmol), methyl 4- cyclopropoxypiperidine-4-carboxylate (0.78 g, 3.72 mmol) in N-methyl-2-pyrrolidone (7.44 ml, 0.5 M) and N,N-diisopropylethylamine (1.9 ml, 11.16 mmol) was stirred under argon atmosphere in closed vial at 100 °C for 1 h. Once complete, the reaction was quenched with cold water and extracted with ethyl acetate 3x. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to afford methyl 1-(6-chloropyridazin-4-yl)-4- cyclopropoxypiperidine-4-carboxylate (1.4 g, 87%) as a sticky brown solid that was used in next step without additional purification. LCMS: C14H18ClN3O3 requires 311.7, found: m / z = 313.0 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). Step 7: Synthesis of methyl 4-cyclopropoxy-1-[6-(2-hydroxyphenyl)pyridazin-4- yl]piperidine-4-carboxylate Methyl-1-(6-chloropyridazin-4-yl)-4-cyclopropoxypiperidine-4-carboxylate (1.4 g, 3.59 mmol) was added to a pressure vessel with 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 mins. Tetrakis(triphenylphosphine)palladium (0.415 g, 0.359 mmol, 0.1 eq) was added to the reaction mixture and the solution was stirred at 100 °C for 18h. Once complete, the reaction was concentrated in vacuo and the resulting residue was purfied by chromatography (Hexane^ / EtOAc, 0-100%) to provide methyl 4-cyclopropoxy-1-[6-(2-hydroxyphenyl)pyridazin-4-yl]piperidine-4- carboxylate (0.58 g, 44% yield) as a yellow solid. LCMS: C20H23N3O4 requires 369.4, found: m / z = 370.7 [M+H]+. 1H 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). Following basic hydrolysis, the title compound was obtained (468.4 mg, 82%) as a off- white solid. LCMS: C19H21N3O4 requires 355.3, found: m / z = 356.3 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 13.57 (s, 2H), 8.96 (d, J = 2.8 Hz, 1H), 8.11 (dd, J = 8.4, 1.7 Hz, 1H), 7.57 (d, J = 2.9 Hz, 1H), 7.34 (ddd, J = 8.5, 7.2, 1.6 Hz, 1H), 6.99 – 6.84 (m, 2H), 3.90 – 3.77 (m, 2H), 3.54 – 3.43 (m, 2H), 2.00 (t, J = 5.6 Hz, 4H), 0.61 – 0.40 (m, 4H). INTERMEDIATE 23 4-(CYCLOHEXYLOXY)-1-[6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL]PIPERIDINE-4-CARBOXYLIC ACID Step 1: Synthesis of benzyl 4-(cyclohexyloxy)-4-(hydroxymethyl)piperidine-1-carboxylate A solution of benzyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (6.0 g, 24.26 mmol) in cyclohexanol (50.523 ml, 485.252 mmol, 20.0 eq) was cooled down to +15 ℃ followed by dropwise addition of boron trifluoride diethyl etherate (6.88 g, 48.525 mmol, 2.0 eq). After addition was complete, the cooling bath was removed and stirring was continued for 1 h. DCM was added, followed by slow addition of water. The contents were transferred to a separatory funnel and the layers were separated. The aqueous layer was washed with DCM 3x. The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by RP-FC column for purification (330 g column, 80 mL flow, water / MeCN + 0.1% FA, gradient 95:5 to 35:65) to afford benzyl 4-(cyclohexyloxy)-4- (hydroxymethyl)piperidine-1-carboxylate (3.68 g, 44%) as a colorless oil.. LCMS: C20H29NO4 requires 347.2, found: m / z = 349.0 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 7.44 – 7.26 (m, 6H), 5.07 (s, 2H), 4.62 (t, J = 5.2 Hz, 1H), 3.77 – 3.67 (m, 2H), 3.55 (br s, 1H), 3.15 (br s, J = 19.2 Hz, 2H), 1.75 – 1.61 (m, 4H), 1.61 – 1.38 (m, 6H), 1.28 – 1.17 (m, 4H). Step 2: Synthesis of benzyl 4-(cyclohexyloxy)-4-formylpiperidine-1-carboxylate Dess-Martin periodinane, 95% (5.84 g, 13.76 mmol) was added to a stirring 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 h. Once complete, DCM (50 mL) and water (50 M) were added, followed by sat. aq. Na2S2O3(50 ml) and the mixture was stirred for 15 min. The contents were transferred to a separatory funnel and the layers were separated. The aqueous layer was washed with DCM 2x and the combined organic layers were washed with brine, collected, dried over Na2SO4, filtered and concentrated in vacuo to afford benzyl 4-(cyclohexyloxy)-4-formylpiperidine-1-carboxylate (3.65 g, 100%) as a colorless oil. LCMS: C20H27NO4requires 345.1, found: m / z = 346.2 [M+H]+. 1H 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). Step 3: Synthesis of 1-[(benzyloxy)carbonyl]-4-(cyclohexyloxy)piperidine-4-carboxylic acid A flask was charged with benzyl 4-(cyclohexyloxy)-4-formylpiperidine-1-carboxylate (3.65 g, 10.56 mmol) and potassium phosphate monobasic (4.31 g, 31.69 mmol). T-Butanol (106 ml), Water (26 ml) and 2-Methyl-2-butene (13.43 ml, 126.8 mmol) were then added sequentially. Sodium chlorite (3.58 g, 31.69 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. Once complete by LCMS, the reaction was diluted with DCM and the pH was adjusted to ~12 using 1M NaOH. The contents were transferred to a separatory funnel and the layers were separated. The aqueous layer was then acidified with 1 M HCl to pH ~2 and extracted with EtOAc 3x. The combined organic layers were dried over Na2SO4, filtered and evaporated to afford 1-[(benzyloxy)carbonyl]-4-(cyclohexyloxy)piperidine-4-carboxylic acid (0.77 g,17%) containing 14 wt% t-butanol. LCMS: C20H27NO5 requires 361.0, found: m / z = 362.2 [M+H]+. 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). Step 4: Synthesis of 1-benzyl 4-methyl 4-(cyclohexyloxy)piperidine-1,4-dicarboxylate (Trimethylsilyl)diazomethane, (2M in hexanes) (5.95 ml, 11.91 mmol) was added dropwise to a cooled (10 °C) solution of 1-[(benzyloxy)carbonyl]-4-(cyclohexyloxy)piperidine- 4-carboxylic acid (0.77 g, 1.83 mmol) in methanol (7.33 ml, 0.25 M). Addition was continued until the light yellow color persisted in the solution. The cooling bath was then removed and the reaction was stirred at room temperature for 1 h. Once complete, acetic acid was added dropwise until the yellow color disappeared and the solution became colorless. Residual solvents were evaporated and the residue was purified by chromatography (hexane / MTBE, 100:0 to 75:25) to afford 1-benzyl 4-methyl 4-(cyclohexyloxy)piperidine-1,4-dicarboxylate (0.64 g, 93%) as a colorless oil. 1H 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). Step 5: Synthesis of methyl 4-(cyclohexyloxy)piperidine-4-carboxylate 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-neck-RBF equipped with argon balloon and hydrogen balloon. The reaction mixture was degassed with argon and Pd / C (10% by weight; 0.18 g, 0.17 mmol) was added followed again by degassing with argon and filling with hydrogen . The reaction was stirred at room temperature overnight. The reaction mixture was filtered through a celite pad and evaporated to dryness to provide methyl 4-(cyclohexyloxy)piperidine-4- carboxylate (0.4 g, 92%) as a black solid.1H 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). Step 6: Synthesis of methyl 1-(6-chloropyridazin-4-yl)-4-(cyclohexyloxy)piperidine-4- carboxylate A mixture of 3,5-Dichloropyridazine (0.25 g, 1.73 mmol), methyl 4- (cyclohexyloxy)piperidine-4-carboxylate (0.40 g, 1.56 mmol) in DMSO (5.25 ml, 0.3 M) and N,N-diisopropylethylamine (1.65 ml, 9.45 mmol) was stirred under argon atmosphere in closed vial at 100 °C for 1 h. Once complete, the reaction was quenched with cold water and extracted with ethyl acetate 3x. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to afford methyl 1-(6-chloropyridazin-4-yl)-4-(cyclohexyloxy)piperidine- 4-carboxylate (0.50 g, 89%) as a sticky brown solid that was used in next step without additional purification. LCMS: C17H24ClN3O3 requires 353.1, found: m / z = 354.2 [M+H]+. 1H 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). Step 7: Synthesis of methyl 4-(cyclohexyloxy)-1-{6-[2-(methoxymethoxy)phenyl]pyridazin- 4-yl}piperidine-4-carboxylate A sealed vial was charged 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) under argon atmosphere.1,4-dioxane (13.99 ml, 0.1 M) was added followed by K2CO3(0.112 g, 0.814 mmol) dissolved in H2O (2.8 ml, 0.5 M). Argon was bubbled through the mixture for 20 min and the vial was sealed and stirred at 100 ℃ for 16 h. Once complete, the solvent was evaporated and the residue was purified by chromatography (EtOAc / hexane, 0 to 100%) to afford methyl 4- (cyclohexyloxy)-1-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}piperidine-4-carboxylate (0.52 g, 79%) as light yellow solid. LCMS: C25H33N3O5requires 455.2, found: m / z = 456.9 [M+H]+. 1H 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). Step 8: Synthesis of 4-(cyclohexyloxy)-1-{6-[2-(methoxymethoxy)phenyl]pyridazin-4- yl}piperidine-4-carboxylic acid 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 eq) was added in one portion. The reaction mixture was stirred at room temperature for 16 h. Once complete, the mixture was neutralized with 4M HCl and evaporated in vacuo. The residue was purified using RP-FC (ACN / water) to afford 4-(cyclohexyloxy)-1-{6-[2-(methoxymethoxy)phenyl]pyridazin-4- yl}piperidine-4-carboxylic acid (0.45 g, 87%) as yellow solid. LCMS: C24H31N3O5 requires 441.2, found: m / z = 442.1 [M+H]+. 1H 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). Synthesis of Title Compound 4-(cyclohexyloxy)-1-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}piperidine-4- carboxylic acid (0.45 g, 0.968 mmol) was dissolved in dioxane (9.68 ml, 0.1 M) and hydrogen chloride (4.0M in dioxane) (7.26 ml, 29.05 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 16 h. Once complete, the volatiles were evaporated and the residue was purified by RP-FC (ACN / water in 0.1 % formic acid, 5% / 95% to 75% / 25%)to afford 4-(cyclohexyloxy)-1-[6-(2-hydroxyphenyl)pyridazin-4-yl]piperidine-4- carboxylic acid (0.25 g, 66%) as yellow solid. LCMS: C22H27N3O4 requires 397.2, found: m / z = 398.2 [M+H]+. 1H 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). INTERMEDIATE 24 1-[6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL]-4-METHOXYPIPERIDINE-4-CARBOXYLIC ACID Step 1: Synthesis of methyl 1-(6-chloropyridazin-4-yl)-4-methoxypiperidine-4-carboxylate A mixture of 3,5-Dichloropyridazine (0.71 g, 4.76 mmol), methyl-4-methoxypiperidine- 4-carboxylate hydrochloride (1.00 g, 4.769 mmol) in N-methyl-2-pyrrolidone (9.54 ml, 0.5 M) and N,N-diisopropylethylamine (2.49 ml, 14.31 mmol) was stirred under argon atmosphere in closed vial at 100 ℃ for 1 h. Once complete, the reaction was quenched with cold water and then extracted with EtOAc 3x. The combined organic extracts were dried over Na2SO4 , filtered and concentrated in vacuo to afford methyl 1-(6-chloropyridazin-4-yl)-4-methoxypiperidine-4- carboxylate (1.09 g, 63%) as a sticky brown solid that was used in next step without additional purification. LCMS: C12H16ClN3O3 requires 285.0, found: m / z = 287.1 [M+H]+. 1H 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). Step 2: Synthesis of methyl 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxypiperidine-4- carboxylate 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 mins and tetrakis(triphenylphosphine)palladium (0.349 g, 0.302 mmol) was added in one portion. The reaction mixture was stirred for 18h at 100oC. Once complete, the solvents were evaporated and the residue was purified by flash chromatography (Hexane:EtOAc; 0-100%) to provide methyl 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4- methoxypiperidine-4-carboxylate (0.64 g, 54%) as a pale yellow solid. LCMS: C18H21N3O4requires 343.1, found: m / z = 344.6 [M+H]+.1H 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). Following basic hydrolysis, the title compound was obtained (0.30 g, 55% yield) as a pale yellow solid. LCMS: C17H19N3O4 requires 329.1, found: m / z = 330.1 [M+H]+. 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). INTERMEDIATE 25 4-(2-CHLOROPHENOXY)-1-[6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL]PIPERIDINE-4- CARBOXYLIC ACID Step 1: 1-[(tert-butoxy)carbonyl]-4-(2-chlorophenoxy)piperidine-4-carboxylic acid o-chlorophenol (2 g, 15.556 mmol, 1.0 equiv.) was dissolved in tetrahydrofuran anhydrous (27 mL, 0.5 M), cooled to 0 ℃. To this powdered NaOH (3.11 g, 77.784 mmol, 5.0 eq) and t-butyl 3-oxoazetidine-1-carboxylate (9.299 g, 46.670 mmol, 3.0 equiv.) were added to the solution at 0 ℃. Then chloroform (6.23 ml, 77.78 mmol, 5.0 equiv.) was added dropwise over the period 15 min and the reaction mixture was stirred for 1 h at 0 ℃, followed by overnight stirring at room temperature. The 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) gave yellow precipitate. The yellow precipitate was dissolved in EtOAc and aqueous layer was extracted with EtOAc thrice. The organic phase was dried over MgSO4, filtered and evaporated on rotavapor which afforded 1-[(tert-butoxy)carbonyl]-4-(2-chlorophenoxy)piperidine-4- carboxylic acid as yellow solid (5.1 g, 83%). LCMS (m / z): [M-H]−calculated for C17H21ClNO5−: 354.11 , found: 354.95.1H 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 Thionyl chloride (1.684 ml, 23.22 mmol, 1.8 eq) was added carefully to a stirred solution of 232800123-VVI01-024 (5.1 g, 12.9 mmol, 1.0 eq) in Methanol anhydrous (16.12 ml, 0.8 M) at 0 C. The resulting solution was stirred at reflux overnight. Next, it was cooled down to RT and volatiles were evaporated. The obtained solid was triturated with MTBE and filtered. The solid was collected and dried under reduced pressure and methyl 4-(2-chlorophenoxy)piperidine-4- carboxylate hydrochloride (4.0 g, 11.105 mmol, 86%) was obtained as an off white solid. LCMS (m / z): [M+H]+calculated for C13H17ClNO3+: 270.09, found: 270.50.1H NMR (300 MHz, DMSO-d6) δ 9.18 (d, J = 33.6 Hz, 2H), 7.53 (dd, J = 8.0, 1.7 Hz, 1H), 7.29 (td, J = 7.9, 1.7 Hz, 1H), 7.07 (td, J = 7.7, 1.3 Hz, 1H), 6.75 (dd, J = 8.3, 1.3 Hz, 1H), 3.79 (s, 3H), 3.25 (d, J = 13.3 Hz, 2H), 2.96 (d, J = 11.3 Hz, 2H), 2.31 (dq, J = 10.7, 6.8, 5.4 Hz, 4H). Step 3: methyl 4-(2-chlorophenoxy)-1-(6-chloropyridazin-4-yl)piperidine-4-carboxylate A 150 mL pressure vial equipped with a magnetic stirrer was charged with 3,5- dichloropyridazine (0.993 g, 6.663 mmol, 1.2 eq) and methyl 4-(2-chlorophenoxy)piperidine-4- carboxylate hydrochloride (2.0 g, 5.552 mmol, 1.0 eq). To this dimethyl sulfoxide (11.1 ml, 0.5 M) and N,N-diisopropylethylamine (DIPEA) (5.803 ml, 33.314 mmol, 6.0 eq) were added. The reaction mixture was stirred at 100 ℃ overnight. UPLC indicated full conversion. DIPEA was evaporated on rotavapor, water was added and precipitate was obtained, sonicated and then brown solid was filtered off which was DP methyl 4-(2-chlorophenoxy)-1-(6-chloropyridazin-4- yl)piperidine-4-carboxylate (1.8 g, 3.814 mmol, 69%). LCMS (m / z): [M+H]+calculated for C17H18Cl2N3O3+: 382.07, found: 383.40.1H 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). Step 4: methyl 4-(2-chlorophenoxy)-1-[6-(2-hydroxyphenyl)pyridazin-4-yl]piperidine-4- carboxylate In a pressure vial, methyl 4-(2-chlorophenoxy)-1-(6-chloropyridazin-4-yl)piperidine-4- carboxylate (1.7 g, 3.602 mmol, 1.0 eq), 2-hydroxyphenylboronic acid (0.547 g, 3.963 mmol, 1.1 eq), potassium carbonate anhydrous (1.494 g, 10.807 mmol, 3.0 eq), dioxane (36.02 ml, 0.1 M) and water (7.2 ml, 0.5 M) were added. The resulting reaction mixture was degassed with Ar for 30 min and then tetrakis(triphenylphosphine)palladium (0.416 g, 0.36 mmol, 0.1 eq) was added, stirred the reaction mixture at 100 °C for 10 h. UPLC showed full conversion. The crude mixture was purified by FC using eluent EtOAc / Cyc (0-60%) and methyl 4-(2-chlorophenoxy)-1-[6-(2- hydroxyphenyl)pyridazin-4-yl]piperidine-4-carboxylate (0.985 g, 2.15 mmol, 60%) was isolated as yellow solid. LCMS (m / z): [M+H]+calculated for C23H23ClN3O4+: 440.14, found: 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). Following basic hydrolysis, the title compound was obtained (0.425 g, 0.979 mmol, 46%). LCMS (m / z): [M+H]+calculated for C22H21ClN3O4+: 426.12, found: 426.19.1H 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). INTERMEDIATE 26 SYNTHESIS OF 1-[6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL]-4-PHENYL-N-(PIPERIDIN-4-YL)-N- PROPYLPIPERIDINE-4-CARBOXAMIDE Step 1: tert-butyl 4-(N-propyl1-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-4- phenylpiperidine-4-amido)piperidine-1-carboxylate To 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) were added 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). Mixture was stirred at 50oC for 3 days. Then reaction mixture was diluted with DCM (50 mL) and extracted with NaHCO3 (50 mL). Basic phase was then extracted once again with DCM (50 mL). Combined organic layers were extracted with water (50 mL). Organic layer was dried over MgSO4 and solvents were evaporated. Crude was purified by flash chromatography eluted by Hexane: EtOAc (0-70%) and then flushing with EtOAc:MeOH (9:1). Received impure product was purified by RP-FC to provide 0.36 g (0.531 mmol, 51% yield) of title compound. LCMS (m / z): [M+H]+calculated for C37H49N5O5: 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). To the tert-butyl 4-(N-propyl1-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-4- phenylpiperidine-4-amido)piperidine-1-carboxylate (0.36 g, 0.531 mmol, 1.0 eq) as a solution in DCM anh. (2.12 ml, 0.25 M) was added TFA (1.42 ml, 18.592 mmol, 35.0 eq). Reaction mixture was stirred for 2h at room temperature. UPLC showed full conversion of starting material to desired product. Solvents were evaporated and received crude was triturated with diethyl ether twice. After drying 0.391 g of title compound was obtained (0.484 mmol, 91% yield). LCMS (m / z): [M+H]+calculated for C30H37N5O2: 499.66, found: 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). INTERMEDIATE 27 SYNTHESIS OF N-CYCLOPROPYL-1-[6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL]-4-PHENYL-N- (PIPERIDIN-4-YL)PIPERIDINE-4-CARBOXAMIDE The Title compounds was made in analogous fashion to Synthesis of 1-[6-(2- hydroxyphenyl)pyridazin-4-yl]-4-phenyl-N-(piperidin-4-yl)-N-propylpiperidine-4-carboxamide (Intermediate 26) by replacing 1-Boc-4-propylaminopiperidine with 1-Boc-4- cyclopropylaminopiperidine. (0.118 g 94% yield) of title compound was obtained. LCMS (m / z): [M+H]+ calculated for C30H35N5O2: 497.64, found: 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). INTERMEDIATE 28 SYNTHESIS OF RAC-2-(1-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4- YL)ACETALDEHYDE Step 1: Synthesis of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine To a solution 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (65.0 g, 155 mmol), 1-bromo-4-iodobenzene (52.8 g, 186 mmol) in 1,4-dioxane (650 mL) and H2O (165 mL) was added in K2CO3(43.0 g, 311 mmol) and Pd(dppf)Cl2(11.4 g, 15.5 mmol) at 20 °C and purged with N2for 3 times. The mixture was heated and stirred at 80 °C until complete as judged by LCMS. Once complete, the reaction mixture was cooled down to room temperature and filtered through celite, with EtOAc rinsing. The collected filtrate was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a crude residue. The crude residue was purified by flash-column chromatography (petroleum ether in ethyl acetate= 0 to 100%) to afford desired product, which was then triturated by petroleum ether in ethyl acetate (50:1, 500 mL) at 25 °C for 15 mins to obtain the desired compound as a white solid. (163 g, 80% yield). LCMS C25H20BrNO2 requires 447.1, found m / z = 448.2 [M+H]+. Step 2: Synthesis of ethyl 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4- yl)acetate To a solution of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (67.0 g, 146 mmol), ethyl 2-(piperidin-4-yl)acetate (37.6 g, 219 mmol) in 2-MeTHF (670 mL) and H2O (67 mL) was added in DavePhos (11.5 g, 29.3 mmol), Cs2CO3(143 g, 439 mmol) and Pd2(dba)3(13.4 g, 14.6 mmol,) and purged with N2(3x). The mixture was stirred at 100 °C until complete as judged 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 with anhydrous Na2SO4, filtered, and concentrated to afford a crude residue. The residue was purified by flash column chromatography (petroleum ether in ethyl acetate= 0 to 100%) to afford purified material, which was triturated with MTBE (200 mL) at 20 °C for 30 mins to afford the desired product as a light-yellow solid was obtained as a light-yellow solid (76.3 g, 45% yield). LCMS C34H36N2O4requires 536.3, found m / z = 537.4 [M+H]+. Step 3: Synthesis of 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-yl)ethan-1- ol Flow Procedure: Solution 1: ethyl 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3- yl)phenyl)piperidin-4-yl)acetate (1.00 eq, 76.0 g in THF, 760 mL). Solution 2: LiAlH4 (2.00 eq, 0.707 g, 114 mL, 2.50 M). The whole flow-reaction process is performed under an inert atmosphere of N2. The volume of flow reactor 11 / 8”PFA coil was 60 mL. The residence time of flow reactor 1 was 2 min. Set the bath at 20 °C for flow reactor 1. The flow rate of Pump 1 was adjusted to 26.1 mL / min for solution 1. The flow rate of Pump 2 was adjusted to 3.9 mL / min for solution 2. The mixture was collected with a bottle quenched by Na2SO4-10H2O . The Pump 1 and Pump 2 was started and the reaction mixture was collected after running 5 mins. Once the reaction was complete as judged by LCMS, the reaction mixture was filtered through celite to remove Na2SO4 with THF (500 mL) and DCM (500 mL) rinsing. The crude filtrate was concentrated by vacuum to afford desired product as a gray solid, which was taken forward without any further purification (67.7 g). LCMS C32H34N2O3 requires 494.3, found m / z = 495.3 [M+H]+. Step 4: Synthesis of rac-3-(4-(4-(2-hydroxyethyl)piperidin-1-yl)phenyl)piperidine-2,6-dione An oven-dried flask was purged under vacuum and by backfilled with N2(3X), followed by addition of Pd / C (14.2 g, 66.7 mmol, 50% purity), Pd(OH)2(14.2 g, 50.5 mmol, 50% purity), 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-yl)ethan-1-ol (74.0 g, 149 mmol) and THF (740 mL) was added in the bottle. The suspension was purged of N2and charged with H2(3X). The reaction mixture was stirred under H2(50 psi) at 25 °C until complete as judged by LCMS. Once complete, the mixture was filtered with THF rinsing (2.00 L). The collected filtrate was refluxed at 80 °C for 15 minutes and then filtered while hot to obtain the filtrate. The collected filtrate was concentrated give a crude residue that was triturated by MTBE (60 mL) to afford the desired compound as white solid, which was taken forward without any further purification (40.0 g). LCMS C18H24N2O3requires 316.2, found m / z = 317.2 [M+H]+. Step 5: Synthesis of title compound An oven dried vial was purged and then backfilled with N2(3x), followed by addition of a solution of rac-(R)-3-(4-(4-(2-hydroxyethyl)piperidin-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 eq) was then added portion-wise, and the mixture was allowed to stir at 25 °C until complete as judged by LCMS. Once complete, the mixture was cooled to 15 °C and 2-MeTHF (300 mL) was added to prevent the precipitation of products during quenching of the reaction. H2O (500 mL) was added to quench the reaction, and the reaction mixture was then extracted by 2-MeTHF (300 mL x 3) and DCM (800 mL x 10). The combined organic layers were washed by brine (500 mL) and saturated NaHCO3solution (500 mL), dried via anhydrous Na2SO4, filtered and concentrated to give a crude residue. The residue was purified by flash column chromatography (Petroleum ether / Ethyl acetate (w / 10% DCM)= 0-33%) to afford the desired product as a green solid (26.0 g, 84% yield). LCMS C18H22N2O3requires 314.2, found m / z = 315.3 [M+H]+. INTERMEDIATE 29 (S)-2-(1-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4-YL)ACETALDEHYDE rac-2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)acetaldehyde (24.9 g, 79.4 mmol) was separated by SFC (column: DAICEL CHIRALPAK AS(250 mm * 30 mm,10 um);mobile phase: [CO2-i-PrOH / ACN];B%:70%, isocratic elution mode). The title compound (first-eluting isomer) was obtained as a yellow solid (7.00 g, 44.6% yield). LCMS C18H22N2O3 requires 314.2, found m / z = 315.3 [M+H]+. INTERMEDIATE 30 RAC-3-((4-(PIPERIDIN-4-YL)PHENYL)AMINO)PIPERIDINE-2,6-DIONE Step 1: Synthesis of rac-tert-butyl (R)-4-(4-((2,6-dioxopiperidin-3- yl)amino)phenyl)piperidine-1-carboxylate To a solution of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (23.5 g, 85.0 mmol, 1.0 eq) and NaHCO3 (21.4 g, 255.0 mmol, 3.0 eq) in DMF (250 mL) was added rac-3- bromopiperidine-2,6-dione (24.5 g, 127.5 mmol, 1.5 eq) at room temperature and the reaction mixture was stirred at 65oC until complete as judged by LCMS. Once complete, the mixture was quenched with ice water (500 mL) and stirred at room temperature for 15 min. The reaction mixture was filtered and concentrated to give crude product. The crude product was triturated with MTBE (150 mL) to give desired product as a gray solid which was taken forward without any further purification (26 g). LCMS C21H29N3O4 requires 387.2, found 386.1 [M-H]-. Step 2: Synthesis of Title Compound To a solution of rac-tert-butyl-4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-1- carboxylate (22.5 g, 58.1 mmol) in DCM (66 mL) was added 4N HCl in dioxane (43.6 mL, 174.3 mmol) at 0oC and the reaction mixture was stirred at room temperature until complete as judged by LCMS. Once complete, the mixture was concentrated to give crude product. The crude product was triturated with MTBE (100 mL) to give the desired product as a grey solid, which was taken forward without any further purification (16.0 g, HCl salt). LCMS C16H21N3O2 requires 287.2, found 288.2 [M+H]+. INTERMEDIATE 31 (1R,4R)-4-(4-((RS)-2,6-DIOXOPIPERIDIN-3-YL)PHENOXY)CYCLOHEXANE-1-CARBALDEHYDE Step 1: Synthesis of methyl (1r,4r)-4-(4-bromophenoxy)cyclohexane-1-carboxylate To a solution of methyl (1r,4r)-4-hydroxycyclohexane-1-carboxylate (20.0 g, 126 mmol) in toluene (400 mL) was added PPh3 (36.4 g, 139 mmol) and 4-bromophenol (24.0 g, 139 mmol). The mixture was then cooled to 0 °C and to the mixture was added DEAD (27.5 mL, 151 mmol). The reaction mixture was then allowed to warm to 25 °C and react until complete as judged by LCMS. Once complete, the reaction mixture was poured into petroleum ether (1000 mL) where a precipitate formed. The mixture was filtered, and the filter cake was washed with petroleum ether (200 mL x 2). The combined filtrate was washed with brine (500 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to afford a crude residue. The residue was purified by column chromatography (petroleum ether in ethyl acetate = 0 to 100%) to afford the desired compound as a white solid (23.0g, 58% yield over two steps). LCMS C14H17BrO3 requires 312.1, found m / z = 313.2 [M+H]+. Step 2: Synthesis of methyl (1r,4r)-4-(4-(2,6-bis(benzyloxy)pyridin-3- yl)phenoxy)cyclohexane-1-carboxylate This intermediate was prepared as described for intermediate 28 Step 1, using methyl (1r,4r)-4-(4-bromophenoxy)cyclohexane-1-carboxylate in place of 1-bromo-4-iodobenzene (12.0 g, 72% yield). LCMS C33H33NO5 requires 523.2, found m / z = 524.2 [M+H]+. Step 3: Synthesis of ((1r,4r)-4-(4-(2,6-bis(benzyloxy)pyridin-3- yl)phenoxy)cyclohexyl)methanol To a solution of (1r,4r)-4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenoxy)cyclohexane-1- carboxylate (6.00 g, 11.4 mmol) in THF (60 mL) was added LiBH4 (2.00 M in THF, 236 mL) at 0 °C under N2. The mixture was warmed to 25 °C and allowed to react until complete as judged by LCMS. Once complete, the reaction mixture was cooled down to 0 °C and to the mixture was added a 5% solution of NaHCO3 (100 mL) at 0 °C, slowly. The mixture was extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine (150 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated to give the desired compound as a light- yellow solid which was taken forward without any further purification (5.0 g, 87% yield). LCMS C32H33NO4 requires 495.2, found m / z = 496.3 [M+H]+. Step 4: Synthesis of (RS)-3-(4-(((1r,4R)-4- (hydroxymethyl)cyclohexyl)oxy)phenyl)piperidine-2,6-dione To a solution of ((1r,4r)-4-(4-(2,6-bis(benzyloxy)pyridin-3- yl)phenoxy)cyclohexyl)methanol (3.00 g, 5.95 mmol) in THF (30 mL) was added Pd / C (600 mg, 10% purity), Pd(OH)2 (600 mg, 20% purity) under N2 atmosphere. The suspension was degassed and purged with H23 times. The mixture was stirred under H2 (15 Psi) at 25 °C until complete as judged by LCMS. Once complete, the reaction mixture was filtered through a layer of Celite, with THF washing. The collected filtrate was concentrated under vacuum to give the desired product as yellow solid which was taken forward without any further purification (2.50 g). LCMS C18H23NO4 requires 317.2, found m / z = 318.3 [M+H]+. Step 5: Synthesis of 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) was slowly added DMP (2.58 g, 6.09 mmol) at 25 °C. The reaction was stirred at 25°C until complete as judged by LCMS. Once complete, the mixture was adjusted with saturated aqueous Na2CO3 to pH = 10 and the aqueous layer was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with half-saturated Na2S2O3 solution (50 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum toa afford a crude residue. The crude product was triturated with Petroleum ether / ethyl acetate = (3:1, 5 mL) at 25 °C for 15 mins to give to give the desired product as a white solid, which was taken forward without any further purification (0.66 g). LCMS C18H21NO4 requires 315.2, found m / z = 316.2 [M+H]+. INTERMEDIATE 32 RAC-(R)-2-(4-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)-1-OXA-4,9-DIAZASPIRO[5.5]UNDECAN-9- YL)ACETIC ACID Step 1: Synthesis of tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-1-oxa-4,9- diazaspiro[5.5]undecane-9-carboxylate To a stirred solution of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (5 g, 11.20 mmol) and tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (2.87 g, 11.20 mmol) in 1,4 dioxane (50 mL) was added cesium carbonate (7.30 g, 22.40 mmol) at room temperature. The resulting mixture was purged with N2 for 10 min. 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 min and heated to 100 °C for 16 h. Upon completion of reaction, the reaction mixture was cooled to RT and filtered through Celite, with ethyl acetate rinsing (300 mL). The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layer was dried over anhydrous sodium sulphate and concentrated under vacuum to afford the crude compound as a brown liquid. The crude compound was purified by flash-column chromatography using ethyl acetate / pet-ether (0-30%) as the eluent to afford the desired compound as pale yellow solid. (5.6 g, 77% yield). LCMS C38H43N3O5 requires 621.3, found m / z = 622.2 [M+H]+. Step 2: Synthesis of 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-1-oxa-4,9- diazaspiro[5.5]undecane This intermediate was prepared as described for the synthesis of intermediate 30 Step 2, using tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-1-oxa-4,9- diazaspiro[5.5]undecane-9-carboxylate in place of rac-tert-butyl (R)-4-(4-((2,6-dioxopiperidin- 3-yl)amino)phenyl)piperidine-1-carboxylate (4.5 g, HCl salt). LCMS C33H35N3O3 requires 521.3, found 522.4 [M+H]+. Step 3: Synthesis of tert-butyl 2-(4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-1-oxa-4,9- diazaspiro[5.5]undecan-9-yl)acetate To a solution of (4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-1-oxa-4,9- diazaspiro[5.5]undecane (4.5 g, 7.33 mmol) in MeCN (50 mL) at RT was added TEA (5.11 ml, 36.7 mmol) and tert-butyl 2-chloroacetate (3.15 mL, 22.00 mmol). The reaction mixture was stirred at 60 °C until complete as judged by LCMS. Upon completion of reaction, the reaction mixture was cooled to room temperature. Once cooled, water (100 mL) was added, and the mixture was extracted with EtOAc (2 x 250 mL). The combined organic layers were washed with water (200 mL), brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product. The crude product was purified by FCC using 30% ethyl acetate / pet-ether as eluent (isocratic elution) to afford the desired product as an off-white solid (3.0 g, 61% yield). LCMS C39H45N3O5 requires 636.3, found m / z = 637.4 [M+H]+. Step 4: Synthesis of rac-tert-butyl (R)-2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-1-oxa-4,9- diazaspiro[5.5]undecan-9-yl)acetate To a stirred solution of tert-butyl 2-(4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-1-oxa- 4,9-diazaspiro[5.5]undecan-9-yl)acetate (3 g, 4.72 mmol) in 1,4-dioxane (30 mL) was added Pd(OAc)2(0.4 g, 1.782 mmol) and 10% Pd / C (0.5 g, 4.70 mmol) under N2atmosphere at RT. The resulting mixture was stirred under H2pressure (1 atm) at RT until complete as judged by LCMS. Once complete, the reaction mixture was filtered through celite with ethyl acetate washing (100 mL). The eluent was concentrated under reduced pressure to afford crude compound, which was washed with toluene (2 x 50 mL), MTBE (2 x 30 mL) and concentrated under reduced pressure to afford the desired compound as an off-white solid which was taken forward without any further purification (1.8 g). LCMS C25H35N3O5requires 457.3, found 458.6 [M+H]+. Step 5: Synthesis of Title Compound This intermediate was prepared as described for the synthesis of Intermediate 30 step 2, using rac-tert-butyl (R)-2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-1-oxa-4,9- diazaspiro[5.5]undecan-9-yl)acetate in place of rac-tert-butyl (R)-4-(4-((2,6-dioxopiperidin-3- yl)amino)phenyl)piperidine-1-carboxylate (0.91 g, HCl salt). LCMS C21H27N3O5 requires 401.2, found 402.2 [M+H]+. INTERMEDIATE 33 2-((3AR,6AR)-5-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)HEXAHYDROPYRROLO[3,4-C]PYRROL- 2(1H)-YL)ACETIC ACID Step 1: Synthesis of tert-butyl (3aS,6aS)-5-(4-(2,6-bis(benzyloxy)pyridin-3- yl)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate 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) was added cesium carbonate (7.30 g, 22.40 mmol) at room temperature. The resulting mixture was purged with N2 for 10 min. 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 min and heated to 100 °C for 16 h. Upon completion of reaction, as confirmed by LCMS, the reaction mixture was cooled to RT and filtered through Celite pad and washed with ethyl acetate (300 mL). The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford the crude product as brown liquid. It was purified by flash chromatography with a gradient of 0-30% ethyl acetate / pet-ether to afford tert-butyl (3aS,6aS)-5-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxylate (4.5 g, 66% yield) as pale-yellow solid. LCMS: C36H39N3O4 requires 577.3, found: m / z = 578.2 [M+H]+. Step 2: Synthesis of (3aR,6aR)-2-(4-(2,6-bis(benzyloxy)pyridin-3- yl)phenyl)octahydropyrrolo[3,4-c]pyrrole To a stirred solution of tert-butyl (3aS,6aS)-5-(4-(2,6-bis(benzyloxy)pyridin-3- yl)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (4.5 g, 7.79 mmol) in DCM (20 mL) was added 4M HCl in dioxane (9.74 ml, 38.9 mmol) at 0 °C. The resulting reaction mixture was stirred at RT for 2 h. Upon completion of reaction, as confirmed by LCMS, the reaction mixture was concentrated under reduced pressure and washed with n-hexane (3 x 100 mL) and dried to afford (3aR,6aR)-2-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)octahydropyrrolo[3,4- c]pyrrole (3.5 g, 70 % yield) as off-white solid. LCMS: C31H31N3O2 requires 477.2, found: m / z = 478.2 [M+H]+. Step 3: Synthesis 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 To a solution of (3aR,6aR)-2-(4-(2,6-bis(benzyloxy)pyridin-3- yl)phenyl)octahydropyrrolo[3,4-c]pyrrole (3.5 g, 5.13 mmol) in MeCN ( 20 ml) at RT were added triethylamine (1.557 g, 15.39 mmol) and tert-butyl 2-chloroacetate (2.201 ml, 15.39 mmol). The reaction mixture was stirred at 60 °C for 2 h. Upon completion of reaction, as confirmed by LCMS, the reaction mixture was cooled to room temperature. Then water (100 mL) was added and extracted with EtOAc (2 x 250 mL), the combined organic layer was washed with water (200 mL), brine (100 mL), dried over sodium sulphate and concentrated under reduced pressure to get the crude product. The crude product was purified by flash chromatography using 30% of ethyl acetate / pet-ether as eluent to afford tert-butyl 2-((3aR,6aR)- 5-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)acetate (3.5 g, 70% yield) as off white solid. LCMS: C37H41N3O4 requires 591.3, found: m / z = 592.2 [M+H]+. Step 4: Synthesis of tert-butyl 2-((3aR,6aR)-5-(4-(2,6-dioxopiperidin-3- yl)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)acetate To 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 Pd(OAc)2 (0.200 g, 0.891 mmol) and 10% Pd / C (0.300 g, 2.82 mmol) under N2 atmosphere at RT. The resulting mixture was stirred under H2 (1 atm pressure) at RT for 16 h. Upon completion of reaction, as confirmed by LCMS, the reaction mixture was filtered through Celite bed washed with ethyl acetate (100 mL) and concentrated under reduced pressure. The crude product was washed with toluene (2 x 50 mL), MTBE (2 x 30 mL) and concentrated under reduced pressure to afford 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 off-white solid. LCMS: C23H31N3O4 requires 413.2, found: m / z = 414.1 [M+H]+. Step 5: Synthesis of the title compound To a stirred solution 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. Upon completion of reaction, as confirmed by LCMS, n-hexane (50 mL) was added, stirred for 10 min. The clear solvent layer was decanted and repeated twice. The resulting residue was concentrated, dried under reduced pressure to get the crude product. The crude product was purified by RP-FC with MeCN in H2O and the collected fraction lyophilized to afford the title compound (0.37 g, 64% yield, TFA salt) as off-white solid. LCMS: C19H23N3O4 requires 357.2, found: m / z = 358.2 [M+H]+.1H 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). INTERMEDIATE 34 7-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)-7-AZASPIRO[3.5]NONANE-2-CARBALDEHYDE Step 1: Synthesis of 7-(tert-butyl) 2-methyl 7-azaspiro[3.5]nonane-2,7-dicarboxylate 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) were added cesium carbonate (8.17 g, 25.06 mmol) followed by methyl iodide (2.85 g, 20.05 mmol). The mixture was stirred at RT for 16 h. Upon completion of reaction, as confirmed by LCMS, the reaction mixture was poured to ice cold water (100 mL) and extracted with ethyl acetate (2 x 200 mL). The organic layer was washed with brine solution (20 mL), dried over sodium sulphate and concentrated under reduced pressure to afford 7-(tert-butyl) 2-methyl 7-azaspiro[3.5]nonane-2,7-dicarboxylate (4 g, 80% yield) as yellow oil. LCMS: C15H25NO4requires 283.2, found: m / z = 184.2 [M-Boc]+. Step 2: Synthesis of methyl 7-azaspiro[3.5]nonane-2-carboxylate To a stirred solution of 7-(tert-butyl) 2-methyl 7-azaspiro[3.5]nonane-2,7-dicarboxylate (4 g, 14.12 mmol) in DCM (20 mL) was added 4M HCl in dioxane (35.3 mL, 141 mmol) at 0 °C. The resulting mixture stirred at RT for 5 h. Upon completion of reaction, as confirmed by LCMS, the reaction mixture was concentrated under reduced pressure and washed with n-hexane (3 x 100 mL) and dried to afford methyl 7-azaspiro[3.5]nonane-2-carboxylate.HCl (3 g, 95%) as yellow solid. LCMS: C10H17NO2 requires 183.2, found: m / z = 184.2 [M+H]+. Step 3: Synthesis of methyl 7-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-7- azaspiro[3.5]nonane-2-carboxylate 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) was added, cesium carbonate (22.99 g, 70.6 mmol) at room temperature. The resulting mixture was purged with N2 for 10 min. 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 min and heated the reaction mixture to 100 °C for 16 h. Upon completion of reaction, as confirmed by LCMS, the reaction mixture was cooled to RT and filtered through Celite pad and washed with ethyl acetate (300 mL). The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product as brown liquid. The crude product was purified by flash chromatography using a gradient of 0-25% ethyl acetate / pet-ether to afford methyl 7-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)spiro[3.5]nonane-2-carboxylate (5.3 g, 52% yield) as pale yellow solid. LCMS: C35H36N2O4 requires 548.3, found: m / z = 549.2 [M+H]+. Step 4: Synthesis of (7-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-7-azaspiro[3.5]nonan-2- yl)methanol To a stirred solution of methyl 7-(4-(2,6-bis(benzyloxy)pyridin-3- yl)phenyl)spiro[3.5]nonane-2-carboxylate (5.3 g, 9.68 mmol) in THF (50 mL), LiAlH4(1 M soln. in THF, 9.68 mL, 19.35 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at RT for 2 h. Upon completion of reaction, as confirmed by LCMS, the mixture was quenched with ethyl acetate (25 mL), followed by saturated solution of sodium sulphate (20 mL). The reaction mixture was filtered through Celite pad, the filtrate was diluted with ethyl acetate (200 mL) and washed with water (2 x 100 mL), brine (50 mL), the organic layer was dried over sodium sulphate and concentrated under reduced pressure to get the crude product (5 g). The crude product was triturated with a mixture of DCM (50 mL) and hexane (40 mL) to afford (7- (4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)spiro[3.5]nonan-2-yl)methanol (4.3 g, 80% yield) as green gum. LCMS: C34H36N2O3requires 520.3, found: m / z = 521.3 [M+H]+. Step 5: Synthesis of 3-(4-(2-(hydroxymethyl)-7-azaspiro[3.5]nonan-7-yl)phenyl)piperidine- 2,6-dione To a stirred solution of (7-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)spiro[3.5]nonan-2- yl)methanol (4.3 g, 8.27 mmol) in 1,4-dioxane (40 mL) were added Pd(OAc)2(0.4 g, 1.782 mmol) and 10% Pd / C (0.8 g, 7.52 mmol) under N2atmosphere at RT. The resulting reaction mixture stirred under H2pressure (1 atm) at RT for 16 h. Upon completion of reaction, as confirmed by LCMS, the reaction mixture was filtered through Celite bed washed with ethyl acetate (100 mL) and concentrated under reduced pressure. The crude was washed with toluene (2 x 50 mL), MTBE (2 x 30 mL) and concentrated under reduced pressure to afford 3-(4-(2- (hydroxymethyl)-7-azaspiro[3.5]nonan-7-yl)phenyl)piperidine-2,6-dione (2.5 g, 83% yield) as off-white solid. LCMS: C20H26N2O3requires 342.2, found: m / z = 343.2 [M+H]+. Step 6: Synthesis of the title compound To a stirred solution of 3-(4-(2-(hydroxymethyl)-7-azaspiro[3.5]nonan-7- yl)phenyl)piperidine-2,6-dione (2.5 g, 7.30 mmol) in DMSO (5 mL) was added Dess-Martin periodinane (4.64 g, 10.95 mmol) under N2atmosphere at 0 °C. The resulting reaction mixture was stirred at RT for 2 h. Upon completion of reaction, as confirmed by LCMS, the reaction mixture was quenched by sodium thiosulphate solution (20mL) and extracted with ethyl acetate (2 x 50 mL). The organic layer was washed with sodium bicarbonate (20 mL), brine (20 mL), dried over sodium sulphate and concentrated under reduced pressure to get the crude product. The crude product was purified by RP-FC with MeCN in H2O. The collected fraction was lyophilized to afford the title compound (0.903 g, 25% yield, as TFA.salt) as off-white solid. LCMS: C20H24N2O3requires 340.2, found: m / z = 341.3 [M+H]+.1H 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). INTERMEDIATE 35 SYNTHESIS OF 2-(1-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)-4-METHYLPIPERIDIN-4- YL)ACETALDEHYDE Step 1: Synthesis of 2-(4-methylpiperidin-4-yl)ethan-1-ol To a stirred solution of tert-butyl 4-(2-hydroxyethyl)-4-methylpiperidine-1-carboxylate (1 g, 4.11 mmol) in DCM (10 mL) was added 4M HCl in dioxane (0.027 mL, 4.11 mmol) at 0 °C. The resulting mixture stirred at RT for 5 h. Upon completion of reaction, as confirmed by LCMS, the reaction mixture was concentrated under reduced pressure and washed with n-hexane (3 x 100 mL) and dried to afford 2-(4-methylpiperidin-4-yl)ethan-1-ol (HCl salt) as colorless gum. LCMS: C8H17NO requires 143.1, found: m / z = 144.2 [M+H]+. Step 2: Synthesis of 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-4-methylpiperidin-4- yl)ethan-1-ol To a stirred solution of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (1.5 g, 3.36 mmol) and 2-(4-methylpiperidin-4-yl)ethan-1-ol HCl (0.604 g, 3.36 mmol) in 1,4 dioxane (50 mL) was added, cesium carbonate (5.47 g, 16.80 mmol) at room temperature. The resulting mixture was purged with N2for 10 min. 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 N2for 5 min and heated the reaction mixture to 100 °C for 16 h. Upon completion of reaction, as confirmed by LCMS, the reaction mixture was cooled to RT and filtered through Celite pad and washed with ethyl acetate (300 mL). The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layer was dried over sodium sulphate and concentrated under vacuum to afford crude compound as brown liquid. Similarly, an additional 1.5 g batch was performed to get 0.5 g of the crude product. The crude product from both batches were mixed and purified by flash chromatography with a gradient of 0-30% ethyl acetate / pet-ether to afford 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-4-methylpiperidin-4- yl)ethan-1-ol (1 g, 30%) as pale yellow solid. LCMS: C33H36N2O3requires 508.3, found: m / z = 509.4 [M+H]+. Step 3: Synthesis of 3-(4-(4-(2-hydroxyethyl)-4-methylpiperidin-1-yl)phenyl)piperidine-2,6- dione To a stirred solution of 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-4- methylpiperidin-4-yl)ethan-1-ol (1 g, 1.966 mmol) in 1,4-dioxane (10 mL) were added Pd(OAc)2 (0.1 g, 0.445 mmol) and 10% Pd / C (0.2 g, 1.879 mmol) under N2 atmosphere at RT. The resulting mixture stirred under H2 bladder pressure at RT for 16 h. Upon completion of reaction, as confirmed by LCMS, the reaction mixture was filtered through Celite bed washed with ethyl acetate (100 mL) and concentrated under reduced pressure. The crude was washed with toluene (2 x 50 mL), MTBE (2 x 30 mL) and concentrated under reduced pressure to afford 3-(4-(4-(2- hydroxyethyl)-4-methylpiperidin-1-yl)phenyl)piperidine-2,6-dione (0.5 g, 74%) as off-white solid. LCMS: C19H26N2O3 requires 330.2, found: m / z = 331.2 [M+H]+. Step 4: Synthesis of the title compound To a stirred solution of 3-(4-(4-(2-hydroxyethyl)-4-methylpiperidin-1- yl)phenyl)piperidine-2,6-dione (0.45 g, 1.362 mmol) in DMSO (5 mL) was added Dess-Martin periodinane (0.866 g, 2.043 mmol) under N2 atmosphere at 0 °C. The resulting reaction mixture was stirred at RT for 2 h. Upon completion of reaction, as confirmed by LCMS, the reaction mixture was quenched by sodium thiosulphate solution (20 mL) and extracted with ethyl acetate (2 x 50mL). The organic layer was washed with sodium bicarbonate (20 mL), brine solution (20 mL), dried over sodium sulphate and concentrated under reduced pressure to get the crude product. The crude product was purified by RP-FC with MeCN in H2O. The collected fraction was lyophilized to afford 2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)-4-methylpiperidin-4- yl)acetaldehyde (0.11 g, 20% yield, TFA salt) as off-white solid. LCMS: C19H24N2O3 requires 328.2, found: m / z = 329.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.89-10.79 (m, 1H), 9.86-9.73 (m, 1H), 7.38-6.81 (m, 4H), 3.73-3.62 (m, 1H), 3.41-3.31 (m, 2H), 3.28-3.17 (m, 2H), 2.70-2.63 (m, 1H), 2.50-2.45 (m, 3H), 2.25-1.99 (m, 2H), 1.82-1.69 (m, 2H), 1.67-1.56 (m, 2H), 1.14 (s, 3H) INTERMEDIATE 36 3-(4-(2-OXO-6-AZASPIRO[3.4]OCTAN-6-YL)PHENYL)PIPERIDINE-2,6-DIONE Step 1: Synthesis of 6-azaspiro[3.4]octan-2-one 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) was added 4M HCl in dioxane (27.7 mL, 111 mmol) at 0 °C. The resulting reaction mixture was stirred at RT for 2 h. Upon completion of the reaction, as confirmed by LCMS, the reaction mixture was concentrated under reduced pressure and washed with n-hexane (3 x 100 mL) and dried to afford 6-azaspiro[3.4]octan-2-one (2.89 g, 94% yield, HCl salt) as brown gum. LCMS: C7H11NO requires 125.1, found: m / z = 126.2 [M+H]+. Step 2: Synthesis of 6-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-6-azaspiro[3.4]octan-2-one To a stirred solution of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (4.3 g, 9.641mmol) and 6-azaspiro[3.4]octan-2-one HCl (1.55 g, 9.641 mmol) in 1,4 dioxane (50 mL) was added cesium carbonate (14.02 g, 43.0 mmol) at room temperature. The resulting mixture was purged with N2 for 10 min. Then, Pd2(dba)3 (0.492 g, 0.538 mmol) and RuPhos (0.502 g, 1.075 mmol) were added. The resulting mixture was purged with N2 for 5 min and heated to 100 °C for 16 h. Upon completion of reaction, as confirmed by LCMS, the reaction mixture was cooled to RT and filtered through Celite pad and washed with ethyl acetate (300 mL). The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layer was dried over sodium sulphate and concentrated under vacuum to afford crude compound as brown liquid. The crude compound was purified by flash chromatography with a gradient of 0-30% ethyl acetate / pet-ether to afford 6-(4-(2,6- bis(benzyloxy)pyridin-3-yl)phenyl)-6-azaspiro[3.4]octan-2-one (1 g, 75% purity) as pale yellow solid. LCMS: C32H30N2O3 requires 490.2, found: m / z = 491.1 [M+H]+. Step 3: Synthesis of the title compound To a stirred solution of 6-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-6- azaspiro[3.4]octan-2-one (1 g, 2.038 mmol) in 1,4-dioxane (10 mL) was added Pd(OAc)2 (0.1 g, 0.445 mmol) and 10% Pd / C (0.2 g, 1.879 mmol)) under N2 atmosphere at RT. The resulting reaction mixture was stirred under H2 pressure (1 atm) at RT for 16 h. Upon completion of reaction, as confirmed by LCMS, the reaction mixture was filtered through Celite bed washed with ethyl acetate (100 mL) and concentrated under reduced pressure. The crude was washed with toluene (2 x 50 mL), MTBE (2 x 30 mL) and concentrated under reduced pressure The crude product was purified by RP-FC with MeCN in H2O. The collected fraction was lyophilized to afford 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 off-white solid. LCMS: C18H20N2O3 requires 312.1, found: m / z = 313.3 [M+H]+.1H 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). INTERMEDIATE 37 8-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)-2-OXA-8-AZASPIRO[4.5]DECANE-3- CARBALDEHYDE Step 1: Synthesis of tert-butyl 4-allyl-4-formylpiperidine-1-carboxylate To stirred solution of tert-butyl 4-formylpiperidine-1-carboxylate (5 g, 23.44 mmol) in THF (50 ml) at -25 °C was added 3-bromoprop-1-ene (2.431 ml, 28.1 mmol) and t-BuOK (3.16 g, 28.1 mmol) portion wise. The reaction mixture was stirred between -25 °C to -15 °C for 1 h. Upon completion of reaction, as confirmed by LCMS, the reaction mixture was cooled to RT. The reaction mixture was quenched by saturated ammonium chloride solution (200 mL) and extracted with ethyl acetate (2 x 200 mL). The organic layer was washed by brine (50 mL), dried over sodium sulphate, and concentrated to get the crude product. The crude compound was purified by flash chromatography with a gradient of 0-25% ethyl acetate / pet-ether to afford tert- butyl 4-allyl-4-formylpiperidine-1-carboxylate (3 g, 50% yield) as colorless oil. LCMS: C14H23NO3 requires 253.2, found: m / z = 153.1 [M-Boc]-. Step 2: Synthesis of tert-butyl 4-allyl-4-(hydroxymethyl)piperidine-1-carboxylate To stirred solution of tert-butyl 4-allyl-4-formylpiperidine-1-carboxylate (3 g, 11.84 mmol) in THF (30 mL) at 0 °C was added NaBH4(0.896 g, 23.68 mmol) portion wise. The reaction mixture was stirred at RT for 2 h. Upon completion of reaction, as confirmed by TLC, the reaction mixture was cooled to room temperature. Then water (100 mL) was added and extracted with EtOAc (2 x 250 mL), the combined organic layer was washed with brine (100 mL), dried over sodium sulphate and concentrated under reduced pressure to afford tert-butyl 4- allyl-4-(hydroxymethyl)piperidine-1-carboxylate (3 g, 90% yield) as colorless oil. LCMS: C14H25NO3requires 255.2, found: m / z = 156.2 [M-Boc]-. Step 3: Synthesis of tert-butyl 3-(hydroxymethyl)-2-oxa-8-azaspiro[4.5]decane-8- carboxylate To stirred solution of tert-butyl 4-allyl-4-(hydroxymethyl)piperidine-1-carboxylate (3 g, 11.75 mmol) in DCM (30 mL) was added m-CPBA (8.11 g, 47.0 mmol) at 0 °C, the reaction mixture was stirred at RT for 16 h. Upon completion of reaction, as confirmed by TLC, the reaction mixture was cooled to room temperature. Then reaction mixture was quenched with sodium sulfite (100 mL), extracted with EtOAc (2 x 250 mL) and the combined organic layer was washed with sodium bicarbonate (100 mL), brine (100 mL), dried over sodium sulphate and concentrated under reduced pressure to get the crude product. The crude product was purified by flash chromatography with 20% of ethyl acetate in pet-ether to afford tert-butyl 3- (hydroxymethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (2 g, 62% yield) as a colorless oil. LCMS: C14H25NO4requires 271.2, found: m / z = 172.1 [M-Boc]-. Step 4: Synthesis of (2-oxa-8-azaspiro[4.5]decan-3-yl)methanol 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) was added 4M HCl in dioxane (18.43 mL, 73.7 mmol) at 0 °C. The resulting mixture stirred at RT for 2 h. Upon completion of reaction, as confirmed by LCMS, the reaction mixture was concentrated under reduced pressure and washed with n-hexane (3 x 100 mL), dried and lyophilized to afford (2-oxa-8-azaspiro[4.5]decan-3- yl)methanol (1.7 g, 97% yield, HCl salt) as off-white gummy solid. LCMS: C9H17NO2 requires 171.1, found: m / z = 172.2 [M+H]+. Step 5: Synthesis of (8-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-2-oxa-8- azaspiro[4.5]decan-3-yl)methanol To a stirred solution of (2-oxa-8-azaspiro[4.5]decan-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) was added cesium carbonate (7.30 g, 22.40 mmol) at room temperature. The resulting mixture was purged with N2for 10 min. 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 N2for 5 min and heated the reaction mixture to 100 °C for 16 h. Upon completion of reaction, as confirmed by LCMS, the reaction mixture was cooled to RT and filtered through Celite pad and washed with ethyl acetate (300 mL). The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layer was dried over sodium sulphate and concentrated under vacuum to afford crude compound as brown liquid. The crude compound was purified by flash chromatography with a gradient of 0-30% ethyl acetate / pet-ether to afford (8- (4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-2-oxa-8-azaspiro[4.5]decan-3-yl)methanol (0.6 g, 50% yield) as pale yellow solid. LCMS: C34H36N2O4requires 536.3, found: m / z = 537.3 [M+H]+. Step 6: Synthesis of 3-(4-(3-(hydroxymethyl)-2-oxa-8-azaspiro[4.5]decan-8- yl)phenyl)piperidine-2,6-dione To a stirred solution of (8-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-2-oxa-8- azaspiro[4.5]decan-3-yl)methanol (0.6 g, 1.118 mmol) in 1,4-dioxane (10 mL) were added Pd(OAc)2 (0.05 g, 0.223 mmol) and 10% Pd / C (0.1 g, 0.940 mmol) under N2 atmosphere at RT. The resulting mixture stirred under H2 pressure (1 atm) at RT for 16 h. Upon completion of reaction, as confirmed by LCMS, the reaction mixture was filtered through Celite bed washed with ethyl acetate (100 mL) and concentrated under reduced pressure. The crude was washed with toluene (2 x 50 mL), MTBE (2 x 30 mL) and concentrated under reduced pressure to afford 3-(4-(3-(hydroxymethyl)-2-oxa-8-azaspiro[4.5]decan-8-yl)phenyl)piperidine-2,6-dione (0.4 g, 90% yield) as off-white solid. LCMS: C20H26N2O4 requires 358.2, found: m / z = 359.1 [M+H]+. Step 7: Synthesis of the title compound To a stirred solution of 3-(4-(3-(hydroxymethyl)-2-oxa-8-azaspiro[4.5]decan-8- yl)phenyl)piperidine-2,6-dione (0.4 g, 1.116 mmol) in DMSO (5 mL) was added Dess-Martin periodinane (0.710 g, 1.674 mmol) under N2 atmosphere at 0 °C. The resulting mixture was stirred at RT for 4 h. Upon completion of reaction, as confirmed by LCMS, the reaction mixture was quenched with sodium thiosulphate solution (20 mL) and extracted with ethyl acetate (2 x 50 mL). The organic layer was washed with sodium bicarbonate (20 mL), brine solution (20 mL) dried over sodium sulphate concentrated under reduced pressure. The crude product was purified by RP-FC with MeCN in H2O. The collected fraction was lyophilized to afford 8-(4-(2,6- dioxopiperidin-3-yl)phenyl)-2-oxa-8-azaspiro[4.5]decane-3-carbaldehyde (0.124 g, TFA salt) as off-white solid. LCMS: C20H24N2O4 requires 356.2, found: m / z = 357.2 [M+H]+.1H 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). INTERMEDIATE 38 RAC-(4-{4-[(3R)-2,6-DIOXOPIPERIDIN-3-YL]PHENYL}PIPERAZIN-1-YL)ACETIC ACID Step-1: Synthesis of tert-butyl 2-[4-(4-bromophenyl)piperazin-1-yl]acetate To a mixture of tert-butyl 2-(piperazin-1-yl)acetate (500 mg, 2.496 mmol, 1 equiv) in toluene (5 mL) was added dibromobenzene (588 mg, 2.496 mmol, 1 equiv), Pd2(dba)3(228 mg, 0.250 mmol, 0.1 equiv), BINAP (310 mg, 0.499 mmol, 0.2 equiv) and Cs2CO3(2440 mg, 7.488 mmol, 3 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2h at 100°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 1) to afford tert-butyl 2-[4-(4-bromophenyl)piperazin-1-yl]acetate (300 mg, 33.82%) as a yellow oil. LCMS: (C16H23BrN2O2) desired mass = 355.1; observed mass = 355.1 [M+H]+. Step-2: Synthesis of tert-butyl 2-(4-{4-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}piperazin-1- yl)acetate To a mixture of tert-butyl 2-[4-(4-bromophenyl)piperazin-1-yl]acetate (1 g, 2.815 mmol, 1 equiv) in dioxane (50 mL) was added 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 equiv), XPhos Pd G2 (0.44 g, 0.563 mmol, 0.2 equiv), K3PO4 (1.79 g, 8.445 mmol, 3 equiv) in H2O (10 mL). The resulting mixture was stirred for 2 h at 60°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 2) to afford tert-butyl 2-(4-{4-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}piperazin-1- yl)acetate (650 mg, 36.74%) as a yellow solid. LCMS: (C35H39N3O4) desired mass = 566.3; observed mass = 566.3 [M+H]+. Step-3: Synthesis of tert-butyl 2-{4-[4-(2,6-dioxopiperidin-3-yl)phenyl]piperazin-1- yl}acetate To mixture of tert-butyl 2-(4-{4-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}piperazin-1- yl)acetate (650 mg, 1.149 mmol, 1 equiv) in THF (25 mL) was added Pd / C (650 mg) at room temperature. The resulting mixture was stirred overnight at room temperature under hydrogen atmosphere. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. This resulted in tert-butyl 2-{4-[4-(2,6-dioxopiperidin-3-yl)phenyl]piperazin-1- yl}acetate (400 mg, crude) as a light yellow solid. LCMS: (C21H29N3O4) desired mass = 388.2; observed mass = 388.2 [M+H]+. Step 4: Synthesis of rac-(4-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperazin-1-yl)acetic acid A mixture of tert-butyl 2-{4-[4-(2,6-dioxopiperidin-3-yl)phenyl]piperazin-1-yl}acetate (2 g, 5.162 mmol, 1 equiv) in HCl (gas) / 1,4-dioxane (20 mL, 4M) was stirred for 2h at room temperature. The resulting mixture was concentrated under vacuum and further lyophilized. The crude product was purified by trituration with n-hexane. This result in rac-(4-{4-[(3R)-2,6- dioxopiperidin-3-yl]phenyl}piperazin-1-yl)acetic acid (1.5316 g, 81.58%) as an off-white solid. LCMS: (C17H21N3O4) desired mass = 332.2; observed mass = 332.2 [M+H]+. 1H 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). INTERMEDIATE 39 3-(4-(3-OXO-1-OXA-8-AZASPIRO[4.5]DECAN-8-YL)PHENYL)PIPERIDINE-2,6-DIONE Step 1: Synthesis of 8-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-1-oxa-8- azaspiro[4.5]decan-3-one To a stirred solution of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine 1 (5 g, 11.2 mmol), 1-oxa-8-azaspiro[4.5]decan-3-one.HCl 2 (2.141 g, 11.2 mmol) in dioxane (60 mL) was added cesium carbonate (18.2 g, 56 mmol) at room temperature. The resulting mixture was purged with N2 for 10 min. 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 min and heated the reaction mixture to 100 °C for 16 h. Upon completion of reaction, as confirmed by LCMS, the reaction mixture was cooled to RT and filtered through Celite pad and washed with ethyl acetate (300 mL). The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layer was dried over sodium sulphate and concentrated under vacuum to afford the crude compound as brown liquid. The crude compound was purified by Biotage- Isolera (silica-gel: 230-400 mesh) using ethyl acetate / pet-ether (0-30%) as eluent to get the crude product (2g) as yellow solid. The crude product was purified by prep-HPLC purification using - Column: Xselect C18250 mm, Method: 0.1% TFA in water / MeCN, Flow rate:12mL / min. The collected fraction was lyophilized to afford 8-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-1-oxa- 8-azaspiro[4.5]decan-3-one (1.1 g 13% yield) as pale yellow solid: LCMS: m / z = 522.1 [M+H]+. 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). Step 2: Synthesis of Title Compound To a stirred solution of 8-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-1-oxa-8- azaspiro[4.5]decan-3-one 3 (1.1 g, 2.113 mmol in 1,4-dioxane (30 mL) was added Pd(OAc)2 (0.150 g, 0.668 mmol)and 10% Pd / C (0.200 g, 1.879 mmol) under N2 atmosphere at RT. The resulting mixture was stirred under H2 pressure (1 atm) at RT for 16 h. Upon completion of the reaction, as confirmed by LCMS, the reaction mixture was filtered through Celite bed washed with ethyl acetate (100 mL) and concentrated under reduced pressure. The crude compound was washed with toluene (2 x 50 mL), MTBE (2 x 30 mL), the resulting residue was concentrated under reduced pressure and lyophilized to afford the title compound (0.504 g, 52% yield, TFA salt) as off-white solid. LCMS: m / z = 343.2 [M+H]+. 1H 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). INTERMEDIATE 40 RAC-(R)-1-(4-(2,6-DIOXOPIPERIDIN-3-YL)-2,3-DIFLUOROPHENYL)PIPERIDINE-4- CARBALDEHYDE Step 1: Synthesis of 1-(4-bromo-2,3-difluorophenyl)-4-(dimethoxymethyl)piperidine To a solution of 1-bromo-2,3-difluoro-4-iodobenzene (20.0 g, 62.7 mmol, 1.00 eq), 4- (dimethoxymethyl)piperidine (10.9 g, 68.9 mmol, 1.10 eq), BINAP (1.56 g, 2.51 mmol, 0.04 eq), t-BuONa (12.0 g, 125 mmol, 2.00 eq) and Pd2(dba)3(1.15 g, 1.25 mmol, 0.02 eq) was added in toluene (200 mL) at 20 °C and purged with N2for 3 times. The mixture was stirred at 100 °C for 16 hrs. LCMS showed 28.9% of the desired MS was detected. The mixture was concentrated directly by 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). Then the fraction was concentrated under vacuum to give the title compound (14.0 g, 31.5 mmol, 50.3% yield, 79.0% purity) was obtained as a yellow solid. δ 7.21 - 7.12 (m, 1H), 6.67 - 6.55 (m, 1H), 4.10 (d, J = 7.1 Hz, 1H), 3.46 (br d, J = 12.0 Hz, 2H), 3.38 (s, 6H), 2.73 - 2.60 (td, 2H), 1.85 (br d, J = 13.9 Hz, 2H), 1.56 - 1.43 (m, 2H), 1.26 (t, 1H) Step 2: Synthesis of 2,6-bis(benzyloxy)-3-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2,3- difluorophenyl)pyridine To a solution of 1-(4-bromo-2,3-difluorophenyl)-4-(dimethoxymethyl)piperidine (13.0 g, 29.7 mmol, 1.00 eq), 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 eq), Cs2CO3(24.1 g, 74.2 mmol, 2.50 eq) and Pd(dppf)Cl2.CH2Cl2(1.21 g, 1.48 mmol, 0.05 eq) was added in dioxane (260 mL) and H2O (52.0 mL) at 20 °C and purged with N2for 3 times. The mixture was stirred at 100 °C for 16 hrs under N2atmosphere. The residue was added to water (200 mL) and extracted with ethyl acetate (60.0 mL x 3). The combined organic layers were washed with brine (100 mL x 1), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, Ethyl acetate / Petroleum ether=0 / 1 to 1 / 20, Ethyl acetate / Petroleum ether = 1 / 10, Rf = 0.25). Then the fraction was concentrated under vacuum. The desired product 2,6-bis(benzyloxy)-3-(4-(4- (dimethoxymethyl)piperidin-1-yl)-2,3-difluorophenyl)pyridine (8.80 g, 13.8 mmol, 46.5% yield, 88.0% purity) was obtained as a yellow solid. NMR: (400 MHz, CDCl3) δ 7.56 - 7.29 (m, 11H), 7.10 - 6.95 (m, 1H), 6.46 (d, J = 8.1 Hz, 1H), 5.46 - 5.23 (m, 4H), 4.12 (d, J = 7.2 Hz, 1H), 3.54 (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) Step 3: Synthesis of rac-(R)-3-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2,3- difluorophenyl)piperidine-2,6-dione To a solution of rac-(R)-3-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2,3- difluorophenyl)piperidine-2,6-dione (43.0 g, 76.7 mmol, 1.00 eq) in THF (430 mL) was added Pd / C (12.9 g, 12.1 mmol, 10% purity) and Pd(OH)2(12.9 g, 27.5 mmol, 30% purity) under N2atmosphere. The suspension was degassed and purged with H2for 3 times. The mixture was stirred under H2(50 psi) at 25 °C for 6 hrs at which time the mixture was filtered and concentrated. The crude was triturated by MTBE (20.0 mL) at 25 °C for 30 mins, and filtered and the cake was dried under reduced pressure to give rac-(R)-3-(4-(4- (dimethoxymethyl)piperidin-1-yl)-2,3-difluorophenyl)piperidine-2,6-dione (8.00 g, 20.9 mmol, 88.8% yield) was obtained as a white solid.1H 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) Step 4: Synthesis of Title Compound To a solution of rac-(R)-3-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2,3- difluorophenyl)piperidine-2,6-dione (4.00 g, 10.4 mmol, 1.00 eq) in THF (93.0 mL) was added dropwise slowly in HCl (2.00 M, 93.1 mL, 17.8 eq). After addition, the reaction solution was stirred at 70 °C for 1 hr. To the reaction mixture was then added saturated NaHCO3solution until pH = 7, then extracted with EtOAc (30.0 mL x 3), dried over Na2SO4, filtered and concentrated to get the crude. The crude was triturated with EtOAc (10.0 mL) at 25 °C for 30 mins to give 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)+ 1H NMR:(400 MHz, DMSO-d6)δ 10.88 (s, 1H), 9.64 (s, 1H), 6.99 (br t, J = 7.5 Hz, 1H), 6.82 (br t, J = 7.9 Hz, 1H), 4.12 - 3.94 (m, 1H), 3.35 - 3.26 (m, 2H), 2.88 - 2.67 (m, 3H), 2.55 (br d, J = 3.1 Hz, 1H), 2.49 - 2.43 (m, 1H), 2.26 - 2.09 (m, 1H), 2.05 - 1.88 (m, 3H), 1.73 - 1.56 (m, 2H) INTERMEDIATE 41 SYNTHESIS OF RAC-(R)-2-(1-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)-4-FLUOROPIPERIDIN-4- YL)ACETALDEHYDE Step 1: Synthesis of tert-butyl 4-fluoro-4-(2-hydroxyethyl)piperidine-1-carboxylate A mixture of tert-butyl 4-(2-ethoxy-2-oxoethyl)-4-fluoropiperidine-1-carboxylate (10.5 g, 36.3 mmol, 1.00 eq) in THF (105 mL) was degassed under vacuum and purged with N2several times. The mixture was cooled to -20~0 °C, then LiAlH4(2.50 M, 29.0 mL, 2.00 eq) was added to the mixture dropwise at -20~0 °C under N2. The resulting mixture was stirred at -20~0 °C for 2 hrs under N2. H2O (5.00 mL) was added to the reaction mixture dropwise at -20~0 °C to quench the reaction under N2flow, then the mixture was dried with Na2SO4, filtered and concentrated under vacuum. The crude product tert-butyl 4-fluoro-4-(2- hydroxyethyl)piperidine-1-carboxylate (9.00 g, crude) as a colorless oil was used into the next step without further purification.1H NMR (400 MHz, CDCl3) δ 4.00 - 3.79 (m, 4H), 3.08 (br t, J = 12.0 Hz, 2H), 1.95 - 1.83 (m, 5H), 1.70 - 1.50 (m, 2H), 1.45 (s, 9H) Step 2: Synthesis of 2-(4-fluoropiperidin-4-yl)ethan-1-ol hydrochloride To mixture of tert-butyl 4-fluoro-4-(2-hydroxyethyl)piperidine-1-carboxylate (10.6 g, 43.1 mmol, 1.00 eq) in dioxane (11.0 mL) was added HCl / dioxane (2.00 M, 53.2 mL, 2.47 eq) at 10-20 °C. The resulting mixture was stirred at 10-20 °C for 12 hrs. The mixture was concentrated under vacuum. The crude 2-(4-fluoropiperidin-4-yl)ethan-1-ol hydrochloride (7.92 g, 43.1 mmol, 100% yield, HCl) as a white solid was used into 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) Step 3: Synthesis of 2-(1-(4-bromophenyl)-4-fluoropiperidin-4-yl)ethan-1-ol To a mixture of 1-bromo-4-iodobenzene (11.7 g, 41.4 mmol, 1.10 eq), 2-(4- fluoropiperidin-4-yl)ethan-1-ol hydrochloride (6.92 g, 37.7 mmol, 1.00 eq, HCl) in DMSO (82.0 mL) was added K2CO3(15.6 g, 113 mmol, 3.00 eq), CuI (1.44 g, 7.54 mmol, 0.20 eq), L- PROLINE (1.74 g, 15.0 mmol, 0.40 eq) under N2at 15-25 °C. The resulting mixture was stirred at 75-80 °C for 16 hrs under N2. The mixture was poured into H2O (200 mL), extracted with ethyl acetate (80.0 mL * 3), the combined organic layers were washed with 3.00% NH3·H2O solution (50.0 mL), brine (50.0 mL), dried with Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 3 / 1, Petroleum ether / Ethyl acetate = 2 / 1, Rf = 0.21), concentrated in vacuum. The crude compound 2-(1-(4-bromophenyl)-4-fluoropiperidin-4-yl)ethan-1-ol (5.70 g, 18.2 mmol, 48.4% yield, 96.7% purity) was obtained as a yellow solid. LCMS: C13H17BrFNO requires: 301.0, found: m / z = 304.1 (M+H)+. Step 4: Synthesis of 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-4-fluoropiperidin-4- yl)ethan-1-ol To a mixture of 2-(1-(4-bromophenyl)-4-fluoropiperidin-4-yl)ethan-1-ol (5.70 g, 18.8 mmol, 1.00 eq) in dioxane (114 mL) and H2O (22.8 mL) was added 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 eq), Cs2CO3 (15.4 g, 47.2 mmol, 2.50 eq), the suspension was degassed under vacuum and purged with N2 several times. Then Pd(dppf)Cl2.CH2Cl2 (1.54 g, 1.89 mmol, 0.10 eq) was added to the mixture under N2. The resulting mixture was stirred at 100 °C for 16 hrs. The reaction mixture was poured into water (400 mL) and extracted with ethyl acetate (200 mL * 3), the organic phase was washed with brine (200 mL), dried over Na2SO4, concentrated under vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 3 / 1, Petroleum ether / Ethyl acetate = 2 / 1, Rf = 0.21), concentrated in vacuum. 2-(1-(4-(2,6- bis(benzyloxy)pyridin-3-yl)phenyl)-4-fluoropiperidin-4-yl)ethan-1-ol (7.10 g, 13.7 mmol, 72.8% yield, 99.1% purity) was obtained as a yellow solid. LCMS: C32H33FN2O3 requires: 512.2, found: 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) Step 5: Synthesis of rac-(R)-3-(4-(4-fluoro-4-(2-hydroxyethyl)piperidin-1- yl)phenyl)piperidine-2,6-dione To a mixture of 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-4-fluoropiperidin-4- yl)ethan-1-ol (6.60 g, 12.9 mmol, 1.00 eq) in THF (200 mL) was added Pd / C (1.98 g, 1.86 mmol, 10% purity, 0.145 eq) , then Pd(OH)2 (1.98 g, 2.82 mmol, 20% purity, 0.219 eq) under N2. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (50 Psi) at 25 °C for 14 hrs. The mixture was filtered through a pad of celite to get the filtrate. The filter cake was washed with THF (200 mL * 3), the combined filtrate was concentrated in vacuum. The residue was triturated with MTBE (30.0 mL) at 20-25oC for 30 mins, filtered, the filter cake was washed with MTBE (8.00 mL * 3), dried in vacuum. rac-(R)-3-(4-(4-fluoro-4-(2- hydroxyethyl)piperidin-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: C18H23FN2O3 requires: 334.2, found: m / z = 335.2 (M+H)+ 1H 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) Step 6: Synthesis of title compound To a mixture of rac-(R)-3-(4-(4-fluoro-4-(2-hydroxyethyl)piperidin-1- yl)phenyl)piperidine-2,6-dione (3.40 g, 10.17 mmol, 1.00 eq) in DMSO (34.0 mL) was added IBX (4.27 g, 15.2 mmol, 1.50 eq) at 20-25 °C and the resulting mixture was stirred at 20-25 °C for 4hrs. The mixture was poured into H2O (150 mL), extracted with ethyl acetate (100 mL * 4), the combined organic layers were washed with sat.NaHCO3 (50.0 mL), brine (150 mL), dried with Na2SO4, filtered and concentrated in vacuum. The crude product was triturated with ethyl acetate ( 50.0 mL) at 25oC for 30 mins, filtered, the filter cake was washed with ethyl acetate (5.00 mL * 3), dried in vacuum. rac-(R)-2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)-4- fluoropiperidin-4-yl)acetaldehyde (2.65 g, 7.75 mmol, 76.2% yield, 97.2% purity) was obtained as a yellow solid. LCMS: C18H21FN2O3 requires: 332.2, found: m / z = 333.2 (M+H)+. 1H NMR (400 MHz, DMSO) δ 10.77 (s, 1H), 9.79 (br d, J = 1.2 Hz, 1H), 7.06 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 3.73 (dd, J = 4.8, 11.0 Hz, 1H), 3.58 - 3.45 (m, 2H), 3.08 - 2.91 (m, 2H), 2.87 - 2.75 (m, 2H), 2.69 - 2.57 (m, 1H), 2.49 - 2.41 (m, 1H), 2.20 - 2.06 (m, 1H), 2.05 - 1.80 (m, 5H) INTERMEDIATE 42 REL-(R)-1-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDINE-4-CARBOXYLIC ACID Step1: Synthesis of tert-butyl 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidine-4- carboxylate A mixture of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (170 g, 380 mmol), tert- butyl piperidine-4-carboxylate (84.6 g, 457 mmol), K3PO4 (242 g, 1.14 mol) and XPhos Pd G3 (32.2 g, 38.0 mmol) in DMF (1000 mL) was stirred at 100 °C until complete as judged by LCMS . Once complete, to the mixture was added H2O (2.00 L) and extracted with ethyl acetate (700 mL x 2). The organic layers were washed with brine (700 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated to give a crude residue. The residue was purified by column chromatography (Petroleum ether in Ethyl acetate = 100:1 to 20:1) to give the desired compound as a yellow solid (160 g, mmol, 71% yield). LCMS C35H38N2O4 requires 550.3, found m / z = 551.3 [M+H]+. Step 2: Synthesis of rac-tert-butyl (R)-1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4- carboxylate A mixture of tert-butyl 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidine-4- carboxylate (75.0 g, 136.1 mmol) and Pd / C (15.0 g, 14.1 mmol, 10% purity), and Pd(OH)2(15.0 g, 21.3 mmol, 20% purity) in THF (750 mL) was purged of air and back filled with N2(3x).The vessel was then purged of N2and backfilled with H2(3x), then stirred at 50 °C until complete as judged by LCMS. Once complete, the mixture was filtered through celite, and the filtrate was concentrated under vacuum afford the desired compound, which was taken forward without any further purification (96 g). LCMS C21H28N2O4requires 372.2, found m / z = 373.3 [M+H]+. Step 3: Synthesis of rac-(R)-1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carboxylic acid To a solution of rac-tert-butyl (R)-1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4- carboxylate (45.0 g, 120 mmol) in DCM (500 mL) was slowly added TFA (179 mL, 2.42 mol) at 0 °C, and the mixture was stirred at 30 °C until complete as judged by LCMS. Once complete, the mixture was concentrated to give a crude residue. The residue was purified by RP-FC (5- 95%) to afford the desired compound as an off-white solid (40.3 g, 75% yield over two steps). LCMS C17H20N2O4 requires 316.2, found m / z = 317.1 [M+H]+. Step 4: Synthesis of rel-tert-butyl (R)-1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4- carboxylate rac-tert-butyl (R)-1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carboxylate was purified by SFC (DAICEL CHIRALPAK AS (250mm*30mm,10um); mobile phase: [CO2-i- PrOH / ACN]; B%:35%, isocratic elution mode). The desired compound was obtained as a white solid (first-eluting isomer, 20.0 g, 40% yield). LCMS C21H28N2O4 requires 372.2, found 373.4 [M+H]+. Step 5: Synthesis of rel-tert-butyl (R)-1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4- carboxylate rac-tert-butyl (R)-1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carboxylate was purified by SFC (DAICEL CHIRALPAK AS (250mm*30mm,10um); mobile phase: [CO2-i- PrOH / ACN]; B%:35%, isocratic elution mode). The desired compound was obtained as a white solid (second-eluting isomer, 19.0 g, 37% yield). LCMS C21H28N2O4requires 372.2, found 373.4 [M+H]+. Step 6: Synthesis of rel-(R)-1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carboxylic acid This compound was prepared as described in Step 3 for Intermediate 41, using rel-tert- butyl (R)-1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carboxylate in place of rac-tert- butyl (R)-1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carboxylate (22 g, 93% yield). LCMS C17H20N2O4 requires 316.1, found m / z =317.2 [M+H]+. Synthesis of title compound This compound was prepared as described in Step 3 for Intermediate 41, using rec-tert- butyl (R)-1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carboxylate in place of rac-tert- butyl (R)-1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carboxylate (14.2 g, 94% yield). LCMS C17H20N2O4 requires 316.1, found m / z =317.2 [M+H]+. EXAMPLES Purification Procedures Preparative-scale HPLC was performed using columns such as SunFire Prep C18 OBD, XBridge Prep OBD C18 and Xbridge Shield RP18 OBD, using solvent systems such as (water- 0.1% formic acid) / acetonitrile, (water-10 mmol / L NH4HCO3) / acetonitrile, or (water-10 mmol / L NH4HCO3) / acetonitrile. Chromatography A refers to purification over silica gel, typically in pre- packed cartridges, eluting with mixtures of EtOAc in hexanes or petroleum ether; Chromatography B refers to elution with mixtures of MeOH in DCM; Chromatography C refers to use of C18 reverse-phase silica gel, eluting with mixtures of acetonitrile in water. Compounds drawn without stereochemistry were tested as racemic or diasteromeric mixtures in the Biological Examples. Abbreviations Abbreviations used in the Examples include the following: BOP (Benzotriazol-1- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; BINAP (2,2- bis(diphenylphosphino)-1,1-binaphthyl); Bn (benzyl), Boc (tert-butoxycarbonyl); CBz: (benzyloxycarbonyl), HATU (N-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1- ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide); DMSO (dimethyl sulfoxide); THF (tetrahydrofuran); EtOAc (ethyl acetate); ACN (acetonitrile); Et2O (diethyl ether); DCM (dichloromethane); MeOH (methanol); EtOH (ethanol); DCE (1,2-dichloroethane); TEA (trimethylamine); TFA (trifluoroacetic acid); DIEA (N,N-diisopropylethlamine); DIPEA (N,N-Diisopropylethylamine); DMF (N,N-dimethylformamide); NMP (N-methyl-2-pyrrolidone); N,N-dimethylacetamide (DMA); EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide); HFIP (hexafluoroisopropanol); HOBT (hydroxybenzotriazole); STAB (sodium triacetoxyborohydride); Pd2(dba)3 (tris(dibenzylideneacetone)dipalladium); Pd(dppf)Cl2 ([1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II)); PE (petroleum ether); RuPhos (palladacycle Gen.3: 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 (anhydrous); eq. or equiv. (equivalent), FC (flash chromatography). EXAMPLE 1 RAC-N-[(3R)-2,6-DIOXOPIPERIDIN-3-YL]-4-(4-{1-[6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL]-4- PHENYLPIPERIDINE-4-CARBONYL}PIPERAZIN-1-YL)PYRIDINE-2-CARBOXAMIDE Step 1: Synthesis of methyl 1-(6-chloropyridazin-4-yl)-4-phenylpiperidine-4-carboxylate A vial was charged 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 to 120C overnight and then purified directly via RP-FC to yield the title compound (750 mg, 86%). LCMS: C17H18ClN3O2 requires: 331.2, found: m / z = 332.4 [M+H]+. Step 2: Synthesis of methyl 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-phenylpiperidine-4- carboxylate To a flask equipped with a stir bar was added 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). To these dry powders was added 12 mL of dry and pre-sparged 1,4-dioxane. The vial was sealed and allowed to heat to 95C overnight. Upon completion, the crude mixture was filtered through celite and purified by RP-FC to furnish the title compound (70mg, 12%). LCMS: C23H23N3O3requires: 389.5, found: m / z = 390.5 [M+H]+. Step 3: Synthesis of 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-phenylpiperidine-4-carboxylic acid Dissolve methyl 1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-phenylpiperidine-4- carboxylate (200 mg, 0.5135 mmol) in 2mL of 1:1 Dioxane:1M NaOH. Stir until complete, about 3 hours, then filter and purify directly via RP-FC to furnish the title compound in quantitative yield. LCMS: C22H21N3O3requires: 375.4, found: m / z = 376.4 [M+H]+. Step 4: Synthesis of 4-fluoropicolinic acid To a solution of methyl 4-fluoropicolinate (10.0 g, 64.4 mmol, 1.00 eq) in THF (100 mL) and H2O (50.0 mL) was added NaOH (3.87 g, 96.7 mmol, 1.50 eq) at 25 °C. Then the mixture was stirred at 25 °C for 2 hrs. 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 requires: 141.0, found: m / z = 141.1 [M+H]+.1H 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). Step 5: Synthesis of rac-(R)-N-(2,6-dioxopiperidin-3-yl)-4-fluoropicolinamide A solution of 4-fluoropicolinic acid (9.00 g, 61.1 mmol, 95.8% purity, 1.00 eq) in SOCl2 (147 g, 1.24 mol, 90.0 mL, 20.3 eq) was stirred at 90 °C for 1 hr. The mixture was concentrated to remove SOCl2. The residue was dissolved in DCM (200 mL). The mixture was added dropwise to a solution of 3-aminopiperidine-2,6-dione (10.1 g, 61.1 mmol, 1.00 eq, HCl) and NEt3 (30.9 g, 305 mmol, 42.5 mL, 5.00 eq) in DCM (200 mL) at 0 °C. Then the mixture was stirred at 25 °C for 12 hrs. The mixture was concentrated under vacuum to obtain the crude product without purification. rac-(R)-N-(2,6-dioxopiperidin-3-yl)-4-fluoropicolinamide (19.0 g, 58.1 mmol, 95.1% yield, 76.8% purity) was obtained as a blue solid. LCMS C11H10FN3O3 requires: 251.1, found: m / z = 252.0 [M+H]+.1H 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). Step 6: Synthesis of rac-tert-butyl (R)-4-(2-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-4- yl)piperazine-1-carboxylate To a solution of rac-(R)-N-(2,6-dioxopiperidin-3-yl)-4-fluoropicolinamide (17.0 g, 51.9 mmol, 76.8% purity, 1.00 eq) and tert-butyl piperazine-1-carboxylate (9.68 g, 51.9 mmol, 1.00 eq) in DMF (170 mL) was added DIEA (26.8 g, 207 mmol, 36.2 mL, 4.00 eq). Then the mixture was stirred at 100 °C for 12 hrs. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (3 x 250 mL). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum to get the crude product. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 1 / 1). rac-tert-butyl (R)-4-(2-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-4-yl)piperazine-1- carboxylate (1.86 g, 3.98 mmol, 7.66% yield, 89.3% purity) was obtained as a yellow solid. LCMS C20H27N5O5requires: 417.2, found: m / z = 418.3 [M+H]+. 1H 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) Step 7: Synthesis of rac-(R)-N-(2,6-dioxopiperidin-3-yl)-4-(piperazin-1-yl)picolinamide To a solution of rac-tert-butyl (R)-4-(2-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-4- yl)piperazine-1-carboxylate (1.86 g, 3.98 mmol, 89.3% purity, 1.00 eq) in DCM (18.0 mL) was added HCl / dioxane (4.00 M, 19.6 mL, 19.7 eq) at 25 °C. Then the mixture was stirred at 25 °C for 12 hrs. The mixture was filtered and the cake was concentrated to get the crude product without purification. rac-(R)-N-(2,6-dioxopiperidin-3-yl)-4-(piperazin-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 C15H19N5O3requires: 317.1, found: m / z = 318.1 [M+H]+. 1H 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). Step 8: Synthesis of the title compound Stirred 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]pyridin-3- yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (20.26 mg, 0.0533 mmol), and N,N-diisopropylethylamine (13.77 mg, 0.1065 mmol) in DMF. Added rac-(R)-N- (2,6-dioxopiperidin-3-yl)-4-(piperazin-1-yl)picolinamide (8.45 mg, 0.0266 mmol) and let stir at r.t. until complete by LCMS. The solution was injected onto RP-FC and purified with a gradient of 0-70% MeCN in H2O to furnish the title compound (2.7mg, 15%). LCMS: C37H38N8O5requires: 674.3, found: m / z = 675.3 [M+H]+. EXAMPLE 2 (3RS)-3-{4-[(1S)-1-(1-{1-[6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL]-4-PHENYLPIPERIDINE-4- CARBONYL}PIPERIDIN-4-YL)ETHOXY]PHENYL}PIPERIDINE-2,6-DIONE Step 1: Synthesis of tert-butyl (S)-4-(1-(4-(2,6-bis(benzyloxy)pyridin-3- yl)phenoxy)ethyl)piperidine-1-carboxylate To a 20 mL vial was added 4-[2,6-bis(benzyloxy)pyridin-3-yl]phenol (500.00 mg, 1.3040 mmol) synthesized as described for compound 3 in 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). The reaction mixture was cooled to 0 C, then diisopropyl azodicarboxylate (0.77 mL, 0.79 g, 3.9119 mmol) was added in a dropwise fashion. The reaction mixture was stirred warming to RT for 16 h, then concentrated. The resulting residue was purified by FC (80 g silica, 0-25% EtOAc / hex) to yield the title compound as a colorless oil (415 mg, 54%). LCMS: C37H42N2O5requires: 594.7, found: m / z = 595.7 [M+H]+. Step 2: Synthesis of (3RS)-3-{4-[(1S)-1-(piperidin-4-yl)ethoxy]phenyl}piperidine-2,6-dione To a 20 mL vial was added tert-butyl 4-[(1S)-1-{4-[2,6-bis(benzyloxy)pyridin-3- yl]phenoxy}ethyl]piperidine-1-carboxylate (415.00 mg, 0.6978 mmol), Pd / C (400.00 mg, mmol), EtOH (5.00 mL), and THF (5.00 mL). The reaction mixture was sparged with H2 for 10 min, then stirred under H2 atmosphere (balloon) for 16 h. The reaction mixture was then filtered through a pad of celite, then concentrated. The crude material was dissolved in TFA / DCM 1:1 and stirred for 30 minutes, then concentrated and lyophilized to yield the title compound as a white solid (247 mg, 85%). LCMS: C18H24N2O3 requires: 316.2, found: m / z = 317.5 [M+H]+. Step 3: Synthesis of the title compound Stirred 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]pyridin-3- yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (20.26 mg, 0.0533 mmol), and N,N-diisopropylethylamine (13.77 mg, 0.1065 mmol) in DMF. Add rac-N-[(3R)- 2,6-dioxopiperidin-3-yl]-4-(piperazin-1-yl)pyridine-2-carboxamide (8.45 mg, 0.0266 mmol) and let stir at r.t. until complete by LCMS. The solution was injected onto RP-FC and purified with a gradient of 0-70% MeCN in H2O to furnish the title compound (6.5 mg, 33%). LCMS: C40H43N5O5 requires: 673.3, found: m / z = 674.3 [M+H]+. EXAMPLE 3 (3RS)-3-{4-[(1R)-1-(1-{1-[6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL]-4-PHENYLPIPERIDINE-4- CARBONYL}PIPERIDIN-4-YL)ETHOXY]PHENYL}PIPERIDINE-2,6-DIONE Stirred 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]pyridin-3- yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (22.28 mg, 0.0586 mmol), and N,N-diisopropylethylamine (20.47 μL, 15.15 mg, 0.1172 mmol) in DMF. Add (3RS)-3-{4-[(1R)-1-(piperidin-4-yl)ethoxy]phenyl}piperidine-2,6-dione (9.27 mg, 0.0293 mmol), prepared according to the inversed methyl diastereomer of Step 2, Example 2, and let stir at r.t. until complete by LCMS. The solution was injected onto RP-FC and purified with a gradient of 0-70% MeCN in H2O to furnish the title compound (4.6 mg, 23%). LCMS: C40H43N5O5 requires: 673.3, found: m / z = 674.3 [M+H]+. EXAMPLE 4 RAC-(3R)-3-{4-[(1-{1-[6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL]-4-PHENYLPIPERIDINE-4- CARBONYL}PIPERIDIN-4-YL)OXY]PHENYL}PIPERIDINE-2,6-DIONE Step 1: Synthesis of 4-(2,6-bis(benzyloxy)pyridin-3-yl)phenol Dissolved 2,6-bis(benzyloxy)-3-bromopyridine (290 g, 783 mmol, 1.00 eq) and (4- hydroxyphenyl)boronic acid (118 g, 861 mmol, 1.10 eq) in dioxane (2.90 L). Charged K2CO3 (216 g, 1.57 mol, 2.00 eq) and H2O (580 mL) into the reactor under N2. The suspension was degassed under vacuum and purged with N2 several times. Charged Pd(dppf)Cl2 (28.6 g, 39.1 mmol, 0.05 eq) into the reactor under N2. The suspension was degassed under vacuum and purged with N2 several times. Stirred for 12 hrs at 110 °C. The reaction solution was concentrated under reduced pressure, then diluted with water (500 mL) and extracted with ethyl acetate (3 x 500 mL). The organic layer was washed twice with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, N-heptane / ethyl acetate = 100 / 1 to 10 / 1). 4-(2,6- bis(benzyloxy)pyridin-3-yl)phenol (240 g, 597 mmol, 76.3% yield, 95.5% purity) was obtained as an off-white solid. 1H 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). Step 2: Synthesis of benzyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenoxy)piperidine-1- carboxylate Charged 4-(2,6-bis(benzyloxy)pyridin-3-yl)phenol (120 g, 313 mmol, 1.00 eq) into THF (840 mL) in a reactor R-1 (2.00 L bottle, in parallel) set up with an agitator. Charged benzyl 4- hydroxypiperidine-1-carboxylate (77.3 g, 328 mmol, 1.05 eq) into R-1. Charged PPh3(86.1 g, 328 mmol, 1.05 eq) into R-1. Added DEAD (57.2 g, 328 mmol, 59.7 mL, 1.05 eq) at 0 °C under nitrogen atmosphere. Stirred the mixture at 25 °C for 12 hrs under N2. The reaction solution was concentrated under reduced pressure. The crude product was triturated with MTBE (500 mL) at 20 °C for 1 hr. The filtrate was concentrated under vacuum at 40 ~ 45 °C. Then the crude product was purified by prep-HPLC (column: Phenomenex luna C18 (250 × 70 mm, 10 um); mobile phase: [water (HCl)-ACN]; B%: 100-100% 40min). benzyl 4-(4-(2,6- bis(benzyloxy)pyridin-3-yl)phenoxy)piperidine-1-carboxylate (260 g, 427 mmol, crude) was obtained as a yellow oil. LCMS: C38H36N2O5requires: 600.3, found: m / z = 601.4 [M+H]+. 1H 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). Step 3: Synthesis of 5-(4-(piperidin-4-yloxy)phenyl)pyridine-2,6(1H,3H)-dione Charged benzyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenoxy)piperidine-1-carboxylate (100 g, 166 mmol, 1.00 eq) into DCM (500 mL) in a reactor R-1 (2.00 L bottle, in parallel) set up with an agitator. Charged HBr (521 g, 2.13 mol, 350 mL, 33% purity, 12.7 eq) at 20 °C into R-1. Stirred the mixture at 50 °C for 12 hrs under N2. The reaction solution was concentrated under reduced pressure.5-(4-(piperidin-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: C16H18N2O3 requires: 286.1, found: m / z = 286.9 [M+H]+. Step 4: Synthesis of rac-(R)-3-(4-(piperidin-4-yloxy)phenyl)piperidine-2,6-dione Set up a reactor R-1 (2.00 L bottle) with an agitator. Blew argon into the bottle for 2 min. Added Pd(OH)2(20.0 g, 14.2 mmol, 10% purity, 0.12 eq) and Pd / C (20.0 g, 18.7 mmol, 10% purity, 0.13 eq) soaked with MeOH (100 mL) into R-1. Charged 5-(4-(piperidin-4- yloxy)phenyl)pyridine-2,6(1H,3H)-dione (40.0 g, 139mmol, 1.00 eq) with MeOH (700 mL) into R-1. Hydrogen was replaced three times and stirred at 50 °C for 12 hrs. The reaction was filtered and washed with MeOH (2.00 L). HCl / EA (120 mL) was added dropwise. rac-(R)-3-(4- (piperidin-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.. LCMS: C16H20N2O3requires: 288.1, found: m / z = 288.9 [M+H]+.1H NMR: (400 MHz, DMSO) δ ppm 10.7 (s, 1H) 9.18 - 9.39 (m, 2H) 7.14 (d, J = 8.58 Hz, 2H) 6.95 (d, J = 8.70 Hz, 2H) 4.63 (dt, J = 7.12, 3.77 Hz, 1H) 3.79 (dd, J = 11.5, 4.83 Hz, 1H) 3.12 - 3.28 (m, 2H) 2.98 - 3.11 (m, 2H) 2.60 - 2.72 (m, 1H) 2.45 (br t, J = 3.99 Hz, 1H) 2.06 - 2.22 (m, 3H) 1.95 - 2.04 (m, 1H) 1.80 - 1.90 (m, 2H) Step 5: Synthesis of the title compound Stirred 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]pyridin-3- yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (10.13 mg, 0.0266 mmol), and N,N-diisopropylethylamine (9.30 μL, 6.89 mg, 0.0533 mmol) in DMF. Added rac- (3R)-3-[4-(piperidin-4-yloxy)phenyl]piperidine-2,6-dione (3.84 mg, 0.0133 mmol) and let stir at r.t. until complete by LCMS. The solution was injected onto RP-FC and purified with a gradient of 0-70% MeCN in H2O to furnish the title compound (2.0 mg, 14%). LCMS: C38H39N5O5requires: 645.3, found: m / z = 646.3 [M+H]+. EXAMPLE 5 RAC-(3R)-3-{4-[(1-{1-[6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL]-4-PHENYLPIPERIDINE-4- CARBONYL}PIPERIDIN-4-YL)METHOXY]PHENYL}PIPERIDINE-2,6-DIONE Step 1: Synthesis of tert-butyl 4-((4-(2,6-bis(benzyloxy)pyridin-3- yl)phenoxy)methyl)piperidine-1-carboxylate To a 20 mL vial was added 4-[2,6-bis(benzyloxy)pyridin-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). The reaction mixture was cooled to 0 C, then diisopropyl azodicarboxylate (0.31 mL, 0.32 g, 1.5648 mmol) was added in a dropwise fashion. The reaction mixture was stirred warming to RT for 16 h, then concentrated. The resulting residue was purified by FC (40 g silica, 0-25% EtOAc / hex) to furnish the title compound as a colorless oil (277 mg, 92%): C36H40N2O5requires: 580.6, found: m / z = 581.5 [M+H]+. Step 2: Synthesis of rac-(R)-3-(4-(piperidin-4-ylmethoxy)phenyl)piperidine-2,6-dione To a 20 mL vial was added tert-butyl 4-{4-[2,6-bis(benzyloxy)pyridin-3- yl]phenoxymethyl}piperidine-1-carboxylate (277.00 mg, 0.4770 mmol), Pd / C (100.00 mg, mmol), EtOH (2.00 mL), and THF (2.00 mL). The reaction mixture was sparged with H2for 10 min, then stirred under H2atmosphere (balloon) for 16 h. The reaction mixture was then filtered through a pad of celite, then concentrated. To the crude product was added 4N hydrogen chloride in dioxane (1.00 mL, 0.15 g, 4.0000 mmol). The reaction mixture was stirred for 1 h, then concentrated. LCMS: C17H22N2O3requires: 302.2, found: m / z = 303.3 [M+H]+. Step 3: Synthesis of the title compound Stirred 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]pyridin-3- yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (10.13 mg, 0.0266 mmol), and N,N-diisopropylethylamine (9.30 μL, 6.89 mg, 0.0533 mmol) in DMF. Add rac- (3R)-3-[4-(piperidin-4-ylmethoxy)phenyl]piperidine-2,6-dione (4.03 mg, 0.0133 mmol) and let stir at r.t. until complete by LCMS. The solution was injected onto RP-FC and purified with a gradient of 0-70% MeCN in H2O to furnish the title compound (1.2 mg, 14%). LCMS: C39H41N5O5requires: 659.3, found: m / z = 660.3 [M+H]+. EXAMPLE 6 RAC-(3R)-3-(4-{4-[(4-{1-[6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL]-4-PHENYLPIPERIDINE-4- CARBONYL}PIPERAZIN-1-YL)METHYL]PIPERIDIN-1-YL}PHENYL)PIPERIDINE-2,6-DIONE Stirred 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]pyridin-3- yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (10.13 mg, 0.0266 mmol), and N,N-diisopropylethylamine (9.30 μL, 6.89 mg, 0.0533 mmol) in DMF. Added rac- (3R)-3-{4-[4-(piperazin-1-ylmethyl)piperidin-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, and let stir at r.t. until complete by LCMS. The solution was injected onto RP- FC and purified with a gradient of 0-70% MeCN in H2O to furnish the title compound (1.0 mg, 9%). LCMS: C43H49N7O4 requires: 727.3, found: m / z = 728.4 [M+H]+. EXAMPLE 7 RAC-(3R)-3-[4-(4-{[(1-{1-[6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL]-4-PHENYLPIPERIDINE-4- CARBONYL}PIPERIDIN-4-YL)AMINO]METHYL}PIPERIDIN-1-YL)PHENYL]PIPERIDINE-2,6-DIONE Step 1: Synthesis of rac-(R)-3-(4-(4-((piperidin-4-ylamino)methyl)piperidin-1- yl)phenyl)piperidine-2,6-dione rac-1-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidine-4-carbaldehyde (100.00 mg, 0.3329 mmol), synthesized as described for compound HCB62 in Example 59 of PCT publication WO2022 / 235715, and tert-butyl 4-aminopiperidine-1-carboxylate (66.68 mg, 0.3329 mmol) were dissolved in DCE and N,N-diisopropylethylamine (297.61 μL, 226.18 mg, 1.7500 mmol) was added and the reaction stirred for 30 min. Added sodium triacetoxyborohydride (211.69 mg, 0.9988 mmol) and stirred overnight at room temperature. The reaction was concentrated and crude purified via RP-FC to yield tert-butyl rac-(R)-3-(4-(4-((piperidin-4- ylamino)methyl)piperidin-1-yl)phenyl)piperidine-2,6-dione (146 mg, 83%). The material was dissolved in 1:1 TFA:DCM, stirred for 1h, then concentrated and purified by RP-FC to furnish the title compound, which was used crude without additional purification. LCMS: C27H40N4O4 requires: 384.5, found: m / z = 385.6 [M+H]+. Step 2: Synthesis of the title compound Stirred 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]pyridin-3- yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (10.13 mg, 0.0266 mmol), and N,N-diisopropylethylamine (9.30 μL, 6.89 mg, 0.0533 mmol) in DMF. Add rac- (3R)-3-(4-{4-[(piperidin-4-ylamino)methyl]piperidin-1-yl}phenyl)piperidine-2,6-dione (5.63 mg, 0.0146 mmol) and let stir at r.t. until complete by LCMS. The solution was injected onto RP-FC and purified with a gradient of 0-70% MeCN in H2O to furnish the title compound (0.8 mg, 8%). LCMS: C44H51N7O4 requires: 741.4, found: m / z = 742.4 [M+H]+. 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]PIPERIDIN-1-YL}PHENYL)PIPERIDINE- 2,6-DIONE Step 1: Synthesis of (S)-3-(4-(4-((2,6-diazaspiro[3.3]heptan-2-yl)methyl)piperidin-1- yl)phenyl)piperidine-2,6-dione This intermediate was synthesized according to Step 1 of Example 7 using tert-butyl 2,6- diazaspiro[3.3]heptane-2-carboxylate. LCMS: C22H30N4O2requires: 382.5, found: m / z = 383.4 [M+H]+. Step 2: Synthesis of the title compound Stirred 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]pyridin-3- yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (60.77 mg, 0.1598 mmol) and N,N-diisopropylethylamine (0.06 mL, 41.31 mg, 0.3196 mmol) in DMF. Add (3S)-3- [4-(4-{2,6-diazaspiro[3.3]heptan-2-ylmethyl}piperidin-1-yl)phenyl]piperidine-2,6-dione (33.62 mg, 0.0879 mmol) and let stir at r.t. until complete by LCMS. The solution was injected onto RP-FC and purified with a gradient of 0-70% MeCN in H2O to furnish the title compound (10.1 mg, 16%). LCMS: C44H49N7O4 requires: 739.4, found: m / z = 740.4 [M+H]+. 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]PIPERIDIN-1-YL}PHENYL)PIPERIDINE- 2,6-DIONE Step 1: (S)-3-(4-(4-((2,6-diazaspiro[3.4]octan-6-yl)methyl)piperidin-1-yl)phenyl)piperidine- 2,6-dione This intermediate was synthesized according to Step 1 of Example 7 using tert-butyl 2,6- diazaspiro[3.4]octane-2-carboxylate. LCMS: C23H32N4O2requires: 396.5, found: m / z = 397.5 [M+H]+. Step 2: Synthesis of the title compound Stir 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]pyridin-3- yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (16.20 mg, 0.0426 mmol), and N,N-diisopropylethylamine (14.89 μL, 11.02 mg, 0.0852 mmol) in DMF. Add (3S)- 3-[4-(4-{2,6-diazaspiro[3.4]octan-6-ylmethyl}piperidin-1-yl)phenyl]piperidine-2,6-dione (9.29 mg, 0.0234 mmol) and let stir at r.t. until complete by LCMS. The solution was injected onto RP-FC and purified with a gradient of 0-70% MeCN in H2O to furnish the title compound (3.4 mg, 21%). LCMS: C45H51N7O4requires: 753.4, found: m / z = 754.4[M+H]+. EXAMPLE 10 N-({1-[(1-{4-[(3S)-2,6-DIOXOPIPERIDIN-3-YL]PHENYL}PIPERIDIN-4-YL)METHYL]PIPERIDIN-3- YL}METHYL)-1-[6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL]-4-PHENYLPIPERIDINE-4- CARBOXAMIDE Step 1: (3S)-3-(4-(4-((3-(aminomethyl)piperidin-1-yl)methyl)piperidin-1- yl)phenyl)piperidine-2,6-dione This intermediate was synthesized according to Step 1 of Example 7 using tert-butyl (piperidin-3-ylmethyl)carbamate. LCMS: C23H34N4O2 requires: 398.5, found: m / z = 399.5 [M+H]+. Step 2: Synthesis of the title compound Stirred 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]pyridin-3- yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (16.20 mg, 0.0426 mmol), and N,N-diisopropylethylamine (14.89 μL, 11.02 mg, 0.0852 mmol) in DMF. Add (3S)- 3-[4-(4-{[3-(aminomethyl)piperidin-1-yl]methyl}piperidin-1-yl)phenyl]piperidine-2,6-dione (9.34 mg, 0.0234 mmol) and let stir at r.t. until complete by LCMS. The solution was injected onto RP-FC and purified with a gradient of 0-70% MeCN in H2O to furnish the title compound (0.8 mg, 5%). LCMS: C45H51N7O4 requires: 755.4, found: m / z = 756.4 [M+H]+. EXAMPLE 11 RAC-(3R)-3-[4-({1-[(1-{1-[6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL]-4-PHENYLPIPERIDINE-4- CARBONYL}PIPERIDIN-4-YL)METHYL]PIPERIDIN-4-YL}METHOXY)PHENYL]PIPERIDINE-2,6- DIONE Step 1: Synthesis of rac-(R)-3-(4-(piperidin-4-ylmethoxy)phenyl)piperidine-2,6-dione To a 20 mL vial was added tert-butyl 4-{4-[2,6-bis(benzyloxy)pyridin-3- yl]phenoxymethyl}piperidine-1-carboxylate (277.00 mg, 0.4770 mmol), Pd / C (100.00 mg, mmol), EtOH (2.00 mL), and THF (2.00 mL). The reaction mixture was sparged with H2 for 10 min, then stirred under H2 atmosphere (balloon) for 16 h. The reaction mixture was then filtered through a pad of celite, then concentrated to furnish the Boc intermediate (162 mg, 84%) which was dissolved in 1:1 TFA:DCM for 1h then concentrated and lyophilized to yield the title compound. LCMS: C17H22N2O3 requires: 302.4, found: m / z = 303.3 [M+H]+. Step 2: Synthesis of rac-(R)-3-(4-((1-(piperidin-4-ylmethyl)piperidin-4- yl)methoxy)phenyl)piperidine-2,6-dione rac-(R)-3-(4-(piperidin-4-ylmethoxy)phenyl)piperidine-2,6-dione and tert-butyl 4- formylpiperidine-1-carboxylate were dissolved in dry DCE. N,N-diisopropylethylamine (72.20 μL, 53.43 mg, 0.4134 mmol) was added and reaction stirred for 30 min. Added sodium triacetoxyborohydride (52.57 mg, 0.2480 mmol). Stirred overnight at r.t. then and purified via RP-FC to furnish the Boc protected intermediate (30 mg, 66%). This material was dissolved in 1:1 TFA:DCM, stirred for 1h at room temperature, then concentrated and used in the next step without additional purification. LCMS: C23H33N3O3 requires: 399.3, found: m / z = 400.4 [M+H]+. Step 3: Synthesis of the title compound Stir 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]pyridin-3- yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (30.38 mg, 0.0799 mmol), and N,N-diisopropylethylamine (27.91 μL, 20.66 mg, 0.1598 mmol) in DMF. Add rac- (3R)-3-(4-{[1-(piperidin-4-ylmethyl)piperidin-4-yl]methoxy}phenyl)piperidine-2,6-dione (17.56 mg, 0.0439 mmol) and let stir at r.t. until complete by LCMS. The solution was injected onto RP-FC and purified with a gradient of 0-70% MeCN in H2O to furnish the title compound (1.2 mg, 4%). LCMS: C45H52N6O5 requires: 756.4, found: m / z = 757.4 [M+H]+. EXAMPLE 12 RAC-(3R)-3-[4-({1-[(1-{1-[6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL]-4-PHENYLPIPERIDINE-4- CARBONYL}PIPERIDIN-4-YL)METHYL]PIPERIDIN-4-YL}OXY)PHENYL]PIPERIDINE-2,6-DIONE Step 1: Synthesis of rac-(R)-3-(4-((1-(piperidin-4-ylmethyl)piperidin-4- yl)oxy)phenyl)piperidine-2,6-dione rac-(3R)-3-[4-(piperidin-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 reaction stirred for 30 min. Added sodium triacetoxyborohydride (52.57 mg, 0.2480 mmol). Stirred overnight at r.t. then concentrated and purified via RP-FC to yield the Boc intermediate (30mg, 69%) which was then dissolved in 1:1 TFA:DCM and stirred for 1h, then concentrated and lyophilized. LCMS: C27H39N3O5requires: 485.6, found: m / z = 486.6 [M+H]+. Step 2: Synthesis of the title compound Stir 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]pyridin-3- yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (60.77 mg, 0.1598 mmol), and N,N-diisopropylethylamine (55.83 μL, 41.31 mg, 0.3196 mmol) in DMF. Add rac- (3R)-3-(4-{[1-(piperidin-4-ylmethyl)piperidin-4-yl]oxy}phenyl)piperidine-2,6-dione (33.89 mg, 0.0879 mmol) and let stir at r.t. until complete by LCMS. The solution was injected onto RP-FC and purified with a gradient of 0-70% MeCN in H2O to furnish the title compound (3.4 mg, 6%). LCMS: C44H50N6O5requires: 742.4, found: m / z = 743.4 [M+H]+. EXAMPLE 13 RAC-(3R)-3-(4-{[1-(1-{1-[6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL]-4-PHENYLPIPERIDINE-4- CARBONYL}PIPERIDINE-4-CARBONYL)PIPERIDIN-4-YL]OXY}PHENYL)PIPERIDINE-2,6-DIONE Step 1: Synthesis of rac-(R)-3-(4-((1-(piperidine-4-carbonyl)piperidin-4- yl)oxy)phenyl)piperidine-2,6-dione Stir rac-(3R)-3-[4-(piperidin-4-yloxy)phenyl]piperidine-2,6-dione (45.00 mg, 0.1561 mmol) , [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3- yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (118.68 mg, 0.3121 mmol), and N,N-diisopropylethylamine (80.68 mg, 0.6242 mmol) in DMF. Add 1-(tert- butoxycarbonyl)piperidine-4-carboxylic acid (35.78 mg, 0.1561 mmol) and let stir at r.t. until complete by LCMS. Inject directly and purify using RP FC to yield the Boc protected intermediate (28mg, 36%). This material was then dissolved in 1:1 TFA:DCM and stirred 1h at r.t. then concentrated and used in the next step. LCMS: C22H29N3O4requires: 399.5, found: m / z = 400.5 [M+H]+. Step 2: Synthesis of the title compound Stir 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]pyridin-3- yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (44.56 mg, 0.1172 mmol), and N,N-diisopropylethylamine (40.94 μL, 30.30 mg, 0.2344 mmol) in DMF. Add rac- (3R)-3-(4-{[1-(piperidine-4-carbonyl)piperidin-4-yl]oxy}phenyl)piperidine-2,6-dione (25.75 mg, 0.0645 mmol) and let stir at r.t. until complete by LCMS. The solution was injected onto RP-FC and purified with a gradient of 0-70% MeCN in H2O to furnish the title compound (7.2 mg, 15%). LCMS: C44H48N6O5requires: 756.4, found: m / z = 757.2 [M+H]+. EXAMPLE 14 RAC-(3R)-3-(4-{[1-(1-{1-[6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL]-4-PHENYLPIPERIDINE-4- CARBONYL}PIPERIDINE-4-CARBONYL)PIPERIDIN-4-YL]METHOXY}PHENYL)PIPERIDINE-2,6- DIONE Step 1: Synthesis of rac-(R)-3-(4-((1-(piperidine-4-carbonyl)piperidin-4- yl)methoxy)phenyl)piperidine-2,6-dione Stir rac-(3R)-3-[4-(piperidin-4-ylmethoxy)phenyl]piperidine-2,6-dione (45.00 mg, 0.1488 mmol) , [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3- yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (113.17 mg, 0.2976 mmol), and N,N-diisopropylethylamine (103.97 μL, 76.94 mg, 0.5953 mmol) in DMF. Add 1- (tert-butoxycarbonyl)piperidine-4-carboxylic acid (34.12 mg, 0.1488 mmol) and let stir at r.t. until complete by LCMS. Direct inject to RP-FC and isolate Boc protected intermediate (45 mg, 58%). Concentrate and dissolve in 1:1 TFA:DCM and stir for 1h, then concentrate and lyophilize to use in next step. LCMS: C23H31N3O4 requires: 413.6, found: m / z = 414.6 [M+H]+. Step 2: Synthesis of the title compound Stirred 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]pyridin-3- yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (44.56 mg, 0.1172 mmol), and N,N-diisopropylethylamine (40.94 μL, 30.30 mg, 0.2344 mmol) in DMF. Add rac- (3R)-3-(4-{[1-(piperidine-4-carbonyl)piperidin-4-yl]methoxy}phenyl)piperidine-2,6-dione (26.66 mg, 0.0645 mmol) and let stir at r.t. until complete by LCMS. The solution was injected onto RP-FC and purified with a gradient of 0-70% MeCN in H2O to furnish the title compound (2.4 mg, 5%). LCMS: C45H50N6O4 requires: 770.4, found: m / z = 771.4 [M+H]+. 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]PIPERIDIN-1-YL}PHENYL)PIPERIDINE- 2,6-DIONE Step 1: Synthesis of (1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-phenylpiperidin-4-yl)(2,6- diazaspiro[3.3]heptan-2-yl)methanone Stir 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]pyridin-3- yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (20.26 mg, 0.0533 mmol), and N,N-diisopropylethylamine (18.61 μL, 13.77 mg, 0.1065 mmol) in DMF. Add tert- butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (5.81 mg, 0.0293 mmol) and let stir at r.t. until complete by LCMS. Inject directly and purify via RP-FC to yield the Boc intermediate (6.2mg, 37%). This material was dissolved in 1:1 TFA:DCM and stirred 1h at r.t. then concentrated, lyophilized and used without further purification. LCMS: C27H29N5O2 requires: 455.3, found: m / z = 456.5 [M+H]+. Step 2: Synthesis of the title compound To a scintillation vial was added 2-[5-(4-{2,6-diazaspiro[3.3]heptane-2-carbonyl}-4- phenylpiperidin-1-yl)pyridazin-3-yl]phenol (42.00 mg, 0.0922 mmol), triethylamine (63.04 μL, 46.65 mg, 0.4610 mmol), 1-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidine-4-carbaldehyde (33.23 mg, 0.1106 mmol) and DCE (3.00 mL) Stir at r.t. and add sodium triacetoxyborohydride (68.39 mg, 0.3227 mmol) . Stir until complete consumption of starting material by MS. This reaction was complete and clean after 90 minutes. Quench the reaction by adding bicarbonate solution and extract with EtOAc. Dry the organic layer with brine and then over Na2SO4. Concentrated and the solution was injected onto RP-FC and purified with a gradient of 0-70% MeCN in H2O to furnish the title compound (27.4 mg, 40%). LCMS: C44H49N7O4 requires: 739.4, found: m / z = 740.4 [M+H]+. 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). 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]PIPERIDIN-1-YL}PHENYL)PIPERIDINE- 2,6-DIONE Step 1: Synthesis of (1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-phenylpiperidin-4-yl)(2,6- diazaspiro[3.4]octan-6-yl)methanone Stir 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]pyridin-3- yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (250.67 mg, 0.6592 mmol), and N,N-diisopropylethylamine (230.29 μL, 170.41 mg, 1.3185 mmol) in DMF. Add tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (75.57 mg, 0.3560 mmol) and let stir at r.t. until complete by LCMS. Inject and purify directly via RP-FC to furnish the Boc intermediate (170mg, 99%). Dissolve this material in 1:1 TFA:DCM and stir for 1h at r.t. then concentrate and lyophilize to use in the next step. LCMS: C28H31N5O2requires: 469.3, found: m / z = 470.5 [M+H]+. Step 2: Synthesis of the title compound To a scintillation vial was added 2-[5-(4-{2,6-diazaspiro[3.4]octane-6-carbonyl}-4- phenylpiperidin-1-yl)pyridazin-3-yl]phenol (42.00 mg, 0.0922 mmol), triethylamine (63.04 μL, 46.65 mg, 0.4610 mmol), 1-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidine-4-carbaldehyde (33.23 mg, 0.1106 mmol) and DCE (3.00 mL) Stir at r.t. and add sodium triacetoxyborohydride (68.39 mg, 0.3227 mmol) . Stir until complete consumption of starting material by MS. This reaction was complete and clean after 90 minutes. Quench the reaction by adding bicarbonate solution and extract with EtOAc. Dry the organic layer with brine and then over Na2SO4. Concentrated and the solution was injected onto RP-FC and purified with a gradient of 0-70% MeCN in H2O to furnish the title compound (19.8 mg, 29%). LCMS: C45H51N7O4 requires: 753.4, found: m / z = 754.4 [M+H]+. 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: C45H51N7O4 requires: 753.4, found: m / z = 754.8 [M+H]+. 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]PIPERIDIN-1-YL}PHENYL)PIPERIDINE- 2,6-DIONE Step 1: Synthesis of (1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-phenylpiperidin-4-yl)(2,6- diazaspiro[3.4]octan-2-yl)methanone Stir 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]pyridin-3- yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (250.67 mg, 0.6592 mmol), and N,N-diisopropylethylamine (230.29 μL, 170.41 mg, 1.3185 mmol) in DMF. Add tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate (75.57 mg, 0.3560 mmol) and let stir at r.t. until complete by LCMS. Inject and purify directly via RP-FC to furnish the Boc intermediate (170mg, 99%). Dissolve this material in 1:1 TFA:DCM and stir for 1h at r.t. then concentrate and lyophilize to use in the next step. LCMS: C28H31N5O2 requires: 469.3, found: m / z = 470.5 [M+H]+. Step 2: Synthesis of the title compound To a scintillation vial was added 2-[5-(4-{2,6-diazaspiro[3.4]octane-2-carbonyl}-4- phenylpiperidin-1-yl)pyridazin-3-yl]phenol (42.00 mg, 0.0922 mmol), triethylamine (63.04 μL, 46.65 mg, 0.4610 mmol), 1-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidine-4-carbaldehyde (33.23 mg, 0.1106 mmol) and DCE (3.00 mL) Stir at r.t. and add sodium triacetoxyborohydride (68.39 mg, 0.3227 mmol) . Stir until complete consumption of starting material by MS. This reaction was complete and clean after 90 minutes. Quench the reaction by adding bicarbonate solution and extract with EtOAc. Dry the organic layer with brine and then over Na2SO4. Concentrated and the solution was injected onto RP-FC and purified with a gradient of 0-70% MeCN in H2O to furnish the title compound (24.0 mg, 31%). LCMS: C45H51N7O4 requires: 753.4, found: m / z = 754.4 [M+H]+. 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). EXAMPLE 18 RAC-(3R)-3-(4-{4-[2-(1-{1-[6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL]-4-PHENYLPIPERIDINE-4- CARBONYL}PIPERIDIN-4-YL)ACETYL]PIPERAZIN-1-YL}PHENYL)PIPERIDINE-2,6-DIONE Step 1: Synthesis of (1-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4- carbonyl}piperidin-4-yl)acetic acid Stir 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]pyridin-3- yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (177.24 mg, 0.4661 mmol), and N,N-diisopropylethylamine (162.83 μL, 120.49 mg, 0.9323 mmol) in DMF. Add tert-butyl 2-(piperidin-4-yl)acetate (49.09 μL, 46.63 mg, 0.2517 mmol) and let stir at r.t. until complete by LCMS. Inject directly on RP-FC and purify to isolate the t-Bu protected intermediate (80 mg, 69%). Dissolve this material in 1:1 TFA:DCM and stir for 1h at r.t. LCMS: C29H32N4O4requires: 500.6, found: m / z = 501.4 [M+H]+. Step 2: Synthesis of the title compound Stirred (1-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4- carbonyl}piperidin-4-yl)acetic acid (10.00 mg, 0.0200 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (18.99 mg, 0.0499 mmol), and N,N-diisopropylethylamine (17.44 μL, 12.91 mg, 0.0999 mmol) in DMF. Added rac-(3R)-3-[4-(piperazin-1- yl)phenyl]piperidine-2,6-dione (6.55 mg, 0.0240 mmol), synthesized as described for compound 5 in PCT publication WO2023 / 018238, and let stir at r.t. until complete by LCMS. The solution was injected onto RP-FC and purified with a gradient of 0-70% MeCN in H2O to furnish the title compound (4.3 mg, 29%). LCMS: C44H49N7O5requires: 755.4, found: m / z = 756.7 [M+H]+. 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]PIPERIDIN-1- YL}PYRIDIN-3-YL)PIPERIDINE-2,6-DIONE Step 1: Synthesis of (4-fluoro-1-(5-iodopyridin-2-yl)piperidin-4-yl)methanol To a solution of 2-bromo-5-iodopyridine (5.92 g, 26.5 mmol, 1.00 eq) in DMF (45.0 mL) was added (4-fluoropiperidin-4-yl)methanol (4.50 g, 26.5 mmol, 1.00 eq, HCl) and K2CO3(12.8 g, 92.9 mmol, 3.50 eq) at 20 ℃. The mixture was heated to 90 ℃ and stirred at 90 ℃ for 16 hrs. The reaction mixture was poured into water (225 mL), stirred at 20 ℃ for 5 mins, filtered, and the filter cake was concentrated under vacuum. The crude product was triturated with petroleum ether:ethyl acetate = 3:1 (25.0 mL) at 25 ℃ for 2 hrs, filtered, and the filter cake was concentrated under vacuum. The filtrate was concentrated under vacuum, then purified by silica gel chromatography (SiO2, petroleum ether:ethyl acetate =12:1 to 5:1). (4-fluoro-1-(5- iodopyridin-2-yl)piperidin-4-yl)methanol (4.04 g, crude) was obtained as a white solid. LCMS: C11H14FIN2O requires: 336.0, found: m / z = 337.0 [M+H]+.1H 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). Step 2: Synthesis of (1-(2',6'-bis(benzyloxy)-[3,3'-bipyridin]-6-yl)-4-fluoropiperidin-4- yl)methanol To a solution of (4-fluoro-1-(5-iodopyridin-2-yl)piperidin-4-yl)methanol (3.60 g, 10.7 mmol, 1.10 eq) and 2,6-bis(benzyloxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4.06 g, 9.74 mmol, 1.00 eq) in dioxane (32.4 mL) and H2O (3.60 mL) was added XPhos Pd G3 (824 mg, 974 µmol, 0.10 eq). K3PO4(5.17 g, 24.3 mmol, 2.50 eq) was added to the mixture at 20 ℃ under N2, then the mixture was degassed and purged with N23 times, and then the mixture was stirred at 90 ℃ for 12 hrs under N2atmosphere. 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'-bipyridin]-6-yl)-4-fluoropiperidin- 4-yl)methanol (3.64 g, 7.25 mmol, 74.5% yield, 99.6% purity) was obtained as a white solid. LCMS: C30H30FN3O3requires: 499.2, found: m / z = 500.2 [M+H]+.1H 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). Step 3: Synthesis of rac-(R)-3-(6-(4-fluoro-4-(hydroxymethyl)piperidin-1-yl)pyridin-3- yl)piperidine-2,6-dione To a solution of (1-(2',6'-bis(benzyloxy)-[3,3'-bipyridin]-6-yl)-4-fluoropiperidin-4- yl)methanol (2.60 g, 5.20 mmol, 1.00 eq) in THF (13.0 mL) and EtOH (13.0 mL) was added AcOH (313 mg, 5.20 mmol, 298 μL, 1.00 eq) and Pd / C (1.30 g, 10.0% purity) under N2 atmosphere at 20 °C. The suspension was degassed and purged with H23 times, then the mixture was stirred under H2 (50.0 Psi) at 50 °C for 2 hrs. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The crude product was purified by silica gel chromatography (SiO2, dichloromethane:methanol = 15:1 to 10:1). rac-(R)-3-(6-(4-fluoro-4- (hydroxymethyl)piperidin-1-yl)pyridin-3-yl)piperidine-2,6-dione (1.17 g, 3.64 mmol, 70.0 % yield) was obtained as an off-white solid.1H 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). Step 4: Synthesis of rac-(R)-1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)-4-fluoropiperidine- 4-carbaldehyde rac-(R)-3-(6-(4-fluoro-4-(hydroxymethyl)piperidin-1-yl)pyridin-3-yl)piperidine-2,6-dione To a solution of rac-(R)-3-(6-(4-fluoro-4-(hydroxymethyl)piperidin-1-yl)pyridin-3- yl)piperidine-2,6-dione (1.20 g, 3.72 mmol, 1.00 eq) in DCM (24.0 mL) cooled to 0 °C was added Dess-Martin periodinane(3.16 g, 7.45 mmol, 2.31 mL, 2.00 eq), and the mixture was stirred at 20 °C for 12 hrs. The mixture was quenched with saturated Na2SO3 solution (50.0 mL), extracted with DCM:EtOH = 10:1 (4 x 50.0 mL), then the organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by Prep-HPLC (column: Phenomenex luna C18150*25mm*10um; mobile phase: [water(FA)-ACN]; B%: 4%- 34%, 10min), then concentrated under vacuum to remove ACN and concentrated by lyophilization to yield the product rac-(R)-1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)-4- fluoropiperidine-4-carbaldehyde (265 mg, 822 umol, 26.2% yield, 99.0% purity) as a white solid. LCMS: C16H18FN3O3 requires: 319.1, found: 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, 2 H), 2.27 – 2.23 (m, 2H), 1.95 – 1.88 (m, 4H). Step 5: Synthesis of the title compound To a scintillation vial was added 2-[5-(4-{2,6-diazaspiro[3.4]octane-2-carbonyl}-4- phenylpiperidin-1-yl)pyridazin-3-yl]phenol (15.00 mg, 0.0381 mmol), triethylamine (26.06 μL, 0.1906 mmol), 1-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidine-4-carbaldehyde (13.74 mg, 0.0457 mmol) and DCE (3.00 mL) Stir at r.t. and add sodium triacetoxyborohydride (28.28 mg, 0.1334 mmol) . Stir until complete consumption of starting material by MS. This reaction was complete and clean after 90 minutes. Quench the reaction by adding bicarbonate solution and extract with EtOAc. Dry the organic layer with brine and then over Na2SO4. Concentrated and the solution was injected onto RP-FC and purified with a gradient of 0-70% MeCN in H2O to furnish the title compound (7.7 mg, 44%). LCMS: C43H47N8O4F requires: 758.4, found: m / z = 759.4 [M+H]+. EXAMPLE 20 RAC-(3R)-3-{4-[4-(6-{1-[6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL]-4-PHENYLPIPERIDINE-4- CARBONYL}-2,6-DIAZASPIRO[3.3]HEPTANE-2-CARBONYL)PIPERIDIN-1- YL]PHENYL}PIPERIDINE-2,6-DIONE Step 1: Synthesis of tert-butyl 1-(4-bromophenyl)piperidine-4-carboxylate To a solution of 1-bromo-4-iodobenzene (50.0 g, 176 mmol, 1.00 eq) and tert-butyl piperidine-4-carboxylate (36.0 g, 194 mmol, 1.10 eq) in DMSO (500 mL) was added L- hydroxyproline (9.27 g, 70.7 mmol, 0.400 eq), K2CO3(48.8 g, 353 mmol, 2.00 eq) and CuI (6.73 g, 35.3 mmol, 0.200 eq) under N2. The reaction was stirred at 90 °C for 12 hrs. The reaction mixture was poured into H2O (500 mL), then was extracted with ethyl acetate (3 x 500 mL). The combined organic layer was washed with brine (2 x 500 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether / ethyl acetate = 100 / 1 - 50 / 1 - 40 / 1). tert-butyl 1-(4-bromophenyl)piperidine-4-carboxylate (43.0 g, 107 mmol, 50.6% yield, 84.9% purity) was obtained as a white solid. LCMS: C16H22BrNO2requires: 339.1, found: m / z = 340.1 [M+H]+.1H 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). Step 2: Synthesis of tert-butyl 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidine-4- carboxylate To a solution of (2,6-bis(benzyloxy)pyridin-3-yl)boronic acid (47.5 g, 114 mmol, 1.20 eq) in dioxane (400 mL) and H2O (80 mL) was added tert-butyl 1-(4-bromophenyl)piperidine-4- carboxylate (38.0 g, 94.8 mmol, 84.9% purity, 1.00 eq), K2CO3(39.3 g, 284 mmol, 3.00 eq), and Pd(dppf)Cl2(3.47 g, 4.74 mmol, 0.05 eq) at 20 °C. The reaction mixture was stirred at 90 °C for 12 hrs. The reaction mixture was poured into H2O (500 mL), then was extracted with ethyl acetate (3 x 500 mL). The combined organic layer was washed with brine (2 x 500 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 - 50 / 1 - 40 / 1). tert-butyl 1-(4-(2,6- bis(benzyloxy)pyridin-3-yl)phenyl)piperidine-4-carboxylate (46.0 g, 81.2 mmol, 75.8% yield, 97.2% purity) was obtained as a white solid. LCMS: C35H38N2O4requires: 550.3, found: m / z = 551.2 [M+H]+.1H 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). Step 3: Synthesis of rac-tert-butyl (R)-1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4- carboxylate To a solution of tert-butyl 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidine-4- carboxylate (41.0 g, 72.4 mmol, 97.2% purity, 1.00 eq) in THF (410 mL) was added Pd / C (10.0 g, 72.4 mmol, 10.0% purity, 1.00 eq) under N2. The suspension was degassed under vacuum and purged with H23 times. The reaction mixture was stirred under H2 (50 psi) at 25 °C for 12 hrs. The suspension was filtered through a pad of celite and the pad was washed with THF (4 x 500 mL). The solution was concentrated under reduced pressure using a rotary evaporator. rac-tert- butyl (R)-1-(4-(2,6-dioxopiperidin-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: C21H28N2O4 requires: 372.2, found: m / z = 373.2 [M+H]+.1H 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). Step 4: Synthesis of rac-(R)-1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carboxylic acid To a solution of rac-tert-butyl (R)-1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4- carboxylate (10.0 g, 25.8 mmol, 96.3% purity, 1.00 eq) in DCM (270 mL) was added TFA (29.5 g, 258 mmol, 19.1 mL, 10.0 eq) at 25 °C. Then the reaction mixture was stirred at 25 °C for 12 hrs. 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 mins, then filtered, and the filter cake was concentrated under vacuum. rac-(R)-1-(4-(2,6-dioxopiperidin-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: C17H20N2O4 requires: 316.1, found: m / z = 317.2 [M+H]+.1H 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). Step 5: Synthesis of the title compound Stirred 2-[5-(4-{2,6-diazaspiro[3.3]heptane-2-carbonyl}-4-phenylpiperidin-1- yl)pyridazin-3-yl]phenol (10.00 mg, 0.0220 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5- b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (20.87 mg, 0.0549 mmol), and N,N-diisopropylethylamine (19.17 μL, 14.19 mg, 0.1098 mmol) in DMF. Add rac-1-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidine-4-carboxylic acid and let stir at r.t. until complete by LCMS. the solution was injected onto RP-FC and purified with a gradient of 0-70% MeCN in H2O to furnish the title compound (4.6 mg, 28%). LCMS: C44H47N7O4 requires: 753.4, found: m / z = 754.4 [M+H]+. EXAMPLE 21 RAC-(3R)-3-{4-[4-(1-{1-[6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL]-4-PHENYLPIPERIDINE-4- CARBONYL}-4-METHYLPIPERIDINE-4-CARBONYL)PIPERAZIN-1-YL]PHENYL}PIPERIDINE-2,6- DIONE Step 1: Synthesis of methyl 1-(1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-phenylpiperidine-4- carbonyl)-4-methylpiperidine-4-carboxylate Stir 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]pyridin-3- yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (179.77 mg, 0.4728 mmol), and N,N-diisopropylethylamine (165.15 μL, 122.21 mg, 0.9456 mmol) in DMF. Add methyl 4-methylpiperidine-4-carboxylate (27.87 μL, 40.14 mg, 0.2553 mmol) and let stir at r.t. until complete by LCMS. Directly injected onto RP-FC and purified to furnish the title compound (80mg, 73%) LCMS: C30H34N4O4 requires: 514.6 found: m / z = 515.5 [M+H]+. Step 2: Synthesis of 1-{1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4- carbonyl}-4-methylpiperidine-4-carboxylic acid 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 for 2h at r.t. The mixture was then acidified to pH = 5 with HCl and extracted with EtoAC x 3. The combined org washed with brine, dried over Na2SO4 and concentrated. Crude used in next step without further purification. Step 3: Synthesis of the title compound Stirred 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]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (19.18 mg, 0.0504 mmol), and N,N-diisopropylethylamine (17.62 μL, 13.04 mg, 0.1009 mmol) in DMF. Add rac-(3R)-3-[4-(piperazin-1- yl)phenyl]piperidine-2,6-dione (6.62 mg, 0.0242 mmol) and let stir at r.t. until complete by LCMS. The solution was injected onto RP-FC and purified with a gradient of 0-70% MeCN in H2O to furnish the title compound (5.9 mg, 35%). LCMS: C44H49N7O4 requires: 755.4, found: m / z = 756.4 [M+H]+. EXAMPLE 22 RAC-(3R)-3-(4-{4-[4-(4-{1-[6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL]-4-PHENYLPIPERIDINE-4- CARBONYL}PIPERAZIN-1-YL)BUTANOYL]PIPERAZIN-1-YL}PHENYL)PIPERIDINE-2,6-DIONE Step 1: Synthesis of 4-(4-(1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-phenylpiperidine-4- carbonyl)piperazin-1-yl)butanoic acid Stir 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carboxylic acid (17.00 mg, 0.0453 mmol), [chloro(dimethylamino)methylidene]dimethylazanium; hexafluoro-lambda5- phosphanuide (25.41 mg, 0.0906 mmol), and 1-methylimidazole (14.87 mg, 0.1811 mmol) in DMF. Add ethyl 4-(piperazin-1-yl)butanoate (9.98 mg, 0.0498 mmol) and let stir at r.t. until complete by LCMS. Directly inject onto RP-FC, purify to isolate the ester protected product, then dissolve with 1.2 equivalents of LiOH monohydrate in THF and concentrate to yield the final product. (25mg, 90%) LCMS: C30H35N5O4 requires: 529.6, found: m / z = 530.5 [M+H]+. Step 2: Synthesis of the title compound Stirred 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]pyridin-3- yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (8.97 mg, 0.0236 mmol), and N,N-diisopropylethylamine (8.24 μL, 6.10 mg, 0.0472 mmol) in DMF. Add 4-(4-{1- [6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carbonyl}piperazin-1-yl)butanoic acid (5.00 mg, 0.0094 mmol) and let stir at r.t. until complete by LCMS. The solution was injected onto RP-FC and purified with a gradient of 0-70% MeCN in H2O to furnish the title compound (1.2 mg, 15%). LCMS: C45H52N8O5 requires: 784.4, found: m / z = 785.4 [M+H]+. 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]PIPERIDIN-1-YL}PHENYL)PIPERIDINE- 2,6-DIONE Step 1: Synthesis of (1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methylpiperidin-4-yl)(2,6- diazaspiro[3.3]heptan-2-yl)methanone Stir 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]pyridin-3- yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (24.27 mg, 0.0638 mmol), and N,N-diisopropylethylamine (22.30 μL, 16.50 mg, 0.1276 mmol) in DMF. Add tert- butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (6.33 mg, 0.0319 mmol) and let stir at r.t. until complete by LCMS. Directly purify Boc protected intermediate (6.1mg, 38%) by RP-FC then dissolve in 1:1 TFA:DCM and stir for 30m at r.t. Concentrate to yield product and carry to next step. LCMS: C22H27N5O2 requires: 393.3, found: m / z = 394.3[M+H]+. Step 2: Synthesis of the title compound To a scintillation vial was added 2-[5-(4-{2,6-diazaspiro[3.4]octane-2-carbonyl}-4- phenylpiperidin-1-yl)pyridazin-3-yl]phenol (15.00 mg, 0.0381 mmol), triethylamine (26.06 μL, 0.1906 mmol), 1-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidine-4-carbaldehyde (13.74 mg, 0.0457 mmol) and DCE (3.00 mL) Stir at r.t. and add sodium triacetoxyborohydride (28.28 mg, 0.1334 mmol) . Stir until complete consumption of starting material by MS. This reaction was complete and clean after 90 minutes. Quench the reaction by adding bicarbonate solution and extract with EtOAc. Dry the organic layer with brine and then over Na2SO4. Concentrated and the solution was injected onto RP-FC and purified with a gradient of 0-70% MeCN in H2O to furnish the title compound (7.4 mg, 29%). LCMS: C43H47N8O4F requires: 677.4, found: m / z = 678.4 [M+H]+. 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]PIPERIDIN-1-YL}PHENYL)PIPERIDINE- 2,6-DIONE Step 1: Synthesis of (4-cyclopropyl-1-(6-(2-hydroxyphenyl)pyridazin-4-yl)piperidin-4- yl)(2,6-diazaspiro[3.3]heptan-2-yl)methanone Stir 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]pyridin-3- yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (22.41 mg, 0.0589 mmol), and N,N-diisopropylethylamine (20.58 μL, 15.23 mg, 0.1179 mmol) in DMF. Add tert- butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (5.84 mg, 0.0295 mmol) and let stir at r.t. until complete by LCMS. Directly inject and purify Boc intermediate via RP-FC (4.9mg, 31%) then dissolve in 1:1 TFA:DCM and stir for 1h at r.t., then concentrate and lyophilize to use in the next step. LCMS: C24H29N5O2requires: 419.2, found: m / z = 420.3 [M+H]+. Step 2: Synthesis of the title compound To a scintillation vial was added 2-[5-(4-{2,6-diazaspiro[3.4]octane-2-carbonyl}-4- phenylpiperidin-1-yl)pyridazin-3-yl]phenol (15.00 mg, 0.0358 mmol), triethylamine (24.5 μL, 0.1788 mmol), 1-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidine-4-carbaldehyde (13.0 mg, 0.0429 mmol) and DCE (3.00 mL) Stir at r.t. and add sodium triacetoxyborohydride (26.5 mg, 0.1251 mmol) . Stir until complete consumption of starting material by MS. This reaction was complete and clean after 90 minutes. Quench the reaction by adding bicarbonate solution and extract with EtOAc. Dry the organic layer with brine and then over Na2SO4. Concentrated and the solution was injected onto RP-FC and purified with a gradient of 0-70% MeCN in H2O to furnish the title compound (8.0 mg, 31%). LCMS: C43H47N8O4F requires: 704.4, found: m / z = 705.4 [M+H]+. 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]PIPERIDIN-1- YL}PHENYL)PIPERIDINE-2,6-DIONE Step 1: Synthesis of (8-fluoro-2,6-diazaspiro[3.4]octan-2-yl)(1-(6-(2- hydroxyphenyl)pyridazin-4-yl)-4-phenylpiperidin-4-yl)methanone Stir 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]pyridin-3- yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (101.28 mg, 0.2664 mmol), and N,N-diisopropylethylamine (93.04 μL, 68.85 mg, 0.5327 mmol) in DMF. Add tert- butyl 8-fluoro-2,6-diazaspiro[3.4]octane-6-carboxylate (33.12 mg, 0.1438 mmol) and let stir at r.t. until complete by LCMS. Directly inject onto RP-FC and isolate the Boc intermediate (70mg, 91%) and then dissolve in 1:1 TFA:DCM, stir for 1h at r.t. and concentrate to yield the title product LCMS: C27H29N5O2F requires: 487.6, found: m / z = 488.5 [M+H]+. Step 2: Synthesis of the title compound To a scintillation vial was added 2-[5-(4-{8-fluoro-2,6-diazaspiro[3.4]octane-2- carbonyl}-4-phenylpiperidin-1-yl)pyridazin-3-yl]phenol (130 mg, 0.26 mmol), triethylamine (182 μL, 1.33 mmol), 1-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidine-4-carbaldehyde (96 mg, 0.32 mmol) and DCE (3.00 mL) Stir at r.t. and add sodium triacetoxyborohydride (198 mg, 0.93 mmol) . Stir until complete consumption of starting material by MS. This reaction was complete and clean after 90 minutes. Quench the reaction by adding bicarbonate solution and extract with EtOAc. Dry the organic layer with brine and then over Na2SO4. Concentrated and the solution was injected onto RP-FC and purified with a gradient of 0-70% MeCN in H2O to furnish the title compound (84 mg, 40%). LCMS: C45H50N7O4F requires: 771.4, found: m / z = 772.6 [M+H]+. 1H NMR (500 MHz, DMSO) δ 10.70 (s, 1H), 9.57 (s, 1H), 8.89 (d, J = 2.9 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 2.9 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.31 – 7.24 (m, 3H), 7.00 – 6.94 (m, 3H), 6.89 – 6.79 (m, 4H), 5.69 (s, 1H), 4.09 – 3.90 (m, 2H), 3.68 – 3.62 (m, 2H), 3.57 (d, J = 12.2 Hz, 1H), 3.50 (dt, J = 12.6, 4.1 Hz, 2H), 3.39 – 3.21 (m, 2H), 2.74 (td, J = 11.7, 2.9 Hz, 2H), 2.59 – 2.49 (m, 4H), 2.39 (dt, J = 16.9, 4.5 Hz, 3H), 2.31 (s, 2H), 2.10 – 2.01 (m, 2H), 1.97 – 1.90 (m, 3H), 1.88 – 1.82 (m, 3H), 1.66 (dd, J = 30.0, 8.2 Hz, 1H), 1.51 (dtd, J = 14.4, 10.9, 3.9 Hz, 3H), 1.28 – 0.99 (m, 2H). EXAMPLE 26 RAC-(3R)-3-(4-{4-[(6-{4-BENZYL-1-[6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL]PIPERIDINE-4- CARBONYL}-2,6-DIAZASPIRO[3.3]HEPTAN-2-YL)METHYL]PIPERIDIN-1-YL}PHENYL)PIPERIDINE- 2,6-DIONE Step 1: Synthesis of 1-(tert-butyl) 4-ethyl 4-benzylpiperidine-1,4-dicarboxylate To a stirring solution of 1-(tert-butyl) 4-ethyl piperidine-1,4-dicarboxylate (10.0 g, 38.9 mmol, 1.00 eq) in THF (100 mL) was cooled to -78 °C and LDA (2.00 M, 23.3 mL, 1.20 eq) was added. The reaction was allowed to stir for 0.5 hr. The reaction mixture was heated to 20 °C and benzyl bromide (6.65 g, 38.9 mmol, 4.62 mL, 1.00 eq) was added. The mixture was stirred at 20 °C for 2 hrs. The reaction was washed with saturated NH4Cl solution (100 mL). The aqueous layers were extracted with EtOAc (2 x 120 mL). The organics were combined, washed with brine (250 mL) and dried over Na2SO4. The solution was filtered and evaporated under reduced pressure to a yellow oil. The crude product was used in the next step without further purification. LCMS: C20H29NO4 requires: 347.2, found: m / z = 248.2 [M-Boc+H]+. Step 2: Synthesis of ethyl 4-benzylpiperidine-4-carboxylate To a solution of 1-(tert-butyl) 4-ethyl 4-benzylpiperidine-1,4-dicarboxylate (13.5 g, 38.9 mmol, 1.00 eq) in EtOAc (10.0 mL) was added HCl / EtOAc (4.00 M, 9.73 mL, 1.00 eq). The mixture was stirred at 20 °C for 2 hrs. The solution was filtered and evaporated under reduced pressure to a yellow oil. The crude product was used in the next step without further purification. LCMS: C15H21NO2 requires: 247.2, found: m / z = 248.4 [M+H]+. Step 3: Synthesis of ethyl 4-benzyl-1-(6-chloropyridazin-4-yl)piperidine-4-carboxylate To a solution of ethyl 4-benzylpiperidine-4-carboxylate (5.52 g, 22.3 mmol, 1.00 eq) and 3,5-dichloropyridazine (6.48 g, 43.5 mmol, 1.95 eq) in IPA (90.0 mL) was added DIPEA (14.4 g, 111 mmol, 19.4 mL, 5.00 eq) at 20 °C. The mixture was stirred at 70 °C for 16 hrs. The residue was diluted with H2O (250 mL) and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (3 x 500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 0 / 1, Rf = 0.20) to furnish the title compound as a yellow solid (3.44 g, 9.17 mmol, 41.1% yield, 96.4% purity). LCMS: C19H22ClN3O2 requires: 359.1, found: m / z = 360.2 [M+H]+. Step 4: Synthesis of ethyl 4-benzyl-1-(6-(2-hydroxyphenyl)pyridazin-4-yl)piperidine-4- carboxylate To a solution of ethyl 4-benzyl-1-(6-chloropyridazin-4-yl)piperidine-4-carboxylate (2.00 g, 5.56 mmol, 1.00 eq), (2-hydroxyphenyl)boronic acid (1.53 g, 11.1 mmol, 2.00 eq) and Pd(dppf)Cl2 (610 mg, 834 μmol, 0.150 eq) in dioxane (20.0 mL) was added K2CO3 (2.30 g, 16.6 mmol, 3.00 eq) in H2O (2.00 mL) at 20 °C. The mixture was stirred at 110 °C for 16 hrs. The residue was diluted with H2O (20.0 mL) and extracted with EtOAc (3 x 30.0 mL). The combined organic layers were washed with brine (50.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / EtOAc = 6 / 1 to 3 / 1) to furnish the title compound as a yellow solid (1.20 g, 2.87 mmol, 51.7% yield). LCMS: C25H27N3O3 requires: 417.2, found: m / z = 418.3 [M+H]+. Step 5: Synthesis of 4-benzyl-1-(6-(2-hydroxyphenyl)pyridazin-4-yl)piperidine-4-carboxylic acid To a solution of ethyl 4-benzyl-1-(6-(2-hydroxyphenyl)pyridazin-4-yl)piperidine-4- carboxylate (500 mg, 1.20 mmol, 1.00 eq) in THF (2.50 mL) and MeOH (2.50 mL) was added LiOH•H2O (603 mg, 14.4 mmol, 12.0 eq) in H2O (2.50 mL) at 20 °C. The mixture was stirred at 50 °C for 20 hrs. The reaction mixture was cooled down to room temperature and filter under reduced pressure with MTBE (30.0 mL). H2O (15.0 mL) was added and pH was adjusted to 5 with 1 M HCl (7.00 mL), filtered, and concentrated under reduced pressure to give a residue. The title compound was obtained as a pink solid (603 mg, 1.52 mmol, 61.8% yield, 98.8% purity). LCMS: C23H23N3O3requires: 389.2, found: m / z = 390.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 13.51 - 13.30 (m, 1H), 8.93 (d, J = 2.0 Hz, 1H), 8.00 (br d, J = 7.6 Hz, 1H), 7.53 (br d, J = 2.4 Hz, 1H), 7.34 (br t, J = 7.6 Hz, 1H), 7.27 - 7.24 (m, 3H), 7.13 (br d, J = 7.2 Hz, 2H), 6.96 - 6.93 (m, 2H), 4.14 (br d, J = 13.2 Hz, 2H), 3.12 (br t, J = 12.0 Hz, 2H), 2.85 (s, 2H), 2.10 - 1.96 (m, 2H), 1.57 (br t, J = 10.4 Hz, 2H). Step 6: Synthesis of the title compound 4-benzyl-1-[6-(2-hydroxyphenyl)pyridazin-4-yl]piperidine-4-carboxylic acid (20.00 mg, 0.0514 mmol), PyBOP; hexafluoro-lambda5-phosphanuide (34.74 mg, 0.0668 mmol), and N,N- diisopropylethylamine (44.85 μL, 33.19 mg, 0.2568 mmol) were stirred in dimethylformamide (0.50 mL, 0.47 g, 6.4300 mmol) at room temperature for 1 h. rac-(3R)-3-[4-(4-{2,6- diazaspiro[3.3]heptan-2-ylmethyl}piperidin-1-yl)phenyl]piperidine-2,6-dione (25.54 mg, 0.0668 mmol) was added and the reaction stirred overnight. The solution was injected onto RP-FC and purified with a gradient of 0-70% MeCN in H2O to furnish the title compound (8.6 mg, 22%). LCMS: C45H51N7O4requires: 753.4, found: m / z = 754.4 [M+H]+. EXAMPLE 27 RAC-(3R)-3-{4-[4-({6-[4-(3-CHLOROPHENYL)-1-[6-(2-HYDROXYPHENYL)PYRIDAZIN-4- YL]PIPERIDINE-4-CARBONYL]-2,6-DIAZASPIRO[3.3]HEPTAN-2-YL}METHYL)PIPERIDIN-1- YL]PHENYL}PIPERIDINE-2,6-DIONE Step 1: Synthesis of 1-(tert-butyl) 4-methyl 4-(3-chlorophenyl)piperidine-1,4-dicarboxylate To a solution of methyl 2-(3-chlorophenyl)acetate (5.00 g, 27.1 mmol, 1.00 eq) in DMF (50.0 mL) was added NaH (2.38 g, 59.6 mmol, 60% purity, 2.20 eq) at 0 °C under N2, the mixture was stirred at 0 °C for 0.5 hr. Then tert-butyl bis(2-chloroethyl)carbamate (7.87 g, 32.5 mmol, 1.20 eq) was added, the mixture was heated to 60 °C and stirred at 60 °C for 2 hrs. The mixture was cooled down to 25 °C, then poured into saturated NH4Cl (100 mL) aqueous solution, then extracted with DCM (3 x 50.0 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over Na2SO4, filtered, and concentrated to give the product. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 5 / 1, Rf = 0.43) to furnish the title compound as a yellow solid (4.70 g, 12.4 mmol, 45.9% yield, 93.5% purity). LCMS: C18H24ClNO4 requires: 353.1, found: m / z = 298.1 [M-55]+.1H NMR (400 MHz, CDCl3) δ 7.36 (s, 1H), 7.27 (br s, 3H), 3.99 (br d, J = 12.0 Hz, 2H), 3.70 (s, 3H), 3.01 (br t, J = 12.0 Hz, 2H), 2.51 (br d, J = 12.8 Hz, 2H), 1.91 - 1.74 (m, 2H), 1.47 (s, 9H). Step 2: Synthesis of methyl 4-(3-chlorophenyl)piperidine-4-carboxylate A solution of 1-(tert-butyl) 4-methyl 4-(3-chlorophenyl)piperidine-1,4-dicarboxylate (4.70 g, 12.4 mmol, 1.00 eq) in HCl / EtOAc (4 M, 23.5 mL, 7.57 eq) was stirred at 25 °C for 12 hrs. The mixture was concentrated. The title compound was obtained as a white solid (3.40 g, 11.7 mmol, 94.3% yield, HCl). LCMS: C13H16ClNO2 requires: 253.1, found: m / z = 254.4 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.96 (br s, 2H), 7.47 - 7.31 (m, 4H), 3.65 (s, 3H), 3.22 (br d, J = 12.8 Hz, 2H), 2.95 (br d, J = 4.8 Hz, 2H), 2.55 (br d, J = 14.8 Hz, 2H), 2.16 (br t, J = 11.6 Hz, 2H). Step 3: Synthesis of methyl 4-(3-chlorophenyl)-1-(6-chloropyridazin-4-yl)piperidine-4- carboxylate To a solution of methyl 4-(3-chlorophenyl)piperidine-4-carboxylate (3.20 g, 11.0 mmol, 1.00 eq, HCl) in IPA (32.0 mL) was added DIEA (5.70 g, 44.1 mmol, 7.68 mL, 4.00 eq) at 25 °C, then 3,5-dichloropyridazine (1.97 g, 13.2 mmol, 1.20 eq) was added, the mixture was heated to 70 °C and stirred at 70 °C for 2 hrs. The mixture was concentrated, then dissolved with DCM (30.0 mL). The mixture was washed with saturated aqueous NH4Cl solution (4 x 50.0 mL) and brine (2 x 50.0 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 0 / 1, Petroleum ether / Ethyl acetate = 0 / 1, Rf = 0.50), and to furnish the title compound as a yellow solid (2.40 g, 6.55 mmol, 59.4% yield). LCMS: C17H17Cl2N3O2 requires: 365.1, found: m / z = 366.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.98 (d, J = 2.4 Hz, 1H), 7.50 - 7.26 (m, 4H), 7.11 (d, J = 2.4 Hz, 1H), 3.99 (br d, J = 13.6 Hz, 2H), 3.66 (s, 3H), 3.14 (br t, J = 11.2 Hz, 2H), 2.46 (br s, 2H), 2.05 - 1.84 (m, 2H). Step 4: Synthesis of methyl 4-(3-chlorophenyl)-1-(6-(2-hydroxyphenyl)pyridazin-4- yl)piperidine-4-carboxylate To a solution of methyl 4-(3-chlorophenyl)-1-(6-chloropyridazin-4-yl)piperidine-4- carboxylate (2.20 g, 6.01 mmol, 1.00 eq) and (2-hydroxyphenyl)boronic acid (911 mg, 6.61 mmol, 1.10 eq) in dioxane (22.0 mL) and H2O (2.20 mL) was added K2CO3(2.49 g, 18.0 mmol, 3.00 eq) and BrettPhos Pd G3(272 mg, 300 μmol, 0.05 eq) at 25 °C, then the mixture was heated to 80 °C and stirred for 12 hrs. The mixture was cooled down to 25 °C, BrettPhos Pd G3(272 mg, 300 μmol, 0.05 eq) was added, then the mixture was heated to 80 °C and stirred at 80 °C for 12 hrs. The mixture was filtered, then the filtrate was poured into H2O (100 mL) and extracted with EtOAc (3 x 50.0 mL). The organic layers were washed with brine (2 x 200 mL), dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 1 / 1, Rf= 0.50) and concentrated to afford the title compound as a yellow solid (1.00 g, 2.36 mmol, 39.3% yield). LCMS: C23H22ClN3O3 requires: 423.1, found: m / z = 424.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 14.57 (s, 1H), 8.98 (d, J = 2.8 Hz, 1H), 8.16 - 8.04 (m, 1H), 7.58 (d, J = 2.4 Hz, 1H), 7.46 - 7.28 (m, 5H), 6.92 (d, J = 8.4 Hz, 2H), 4.16 (br d, J = 14.0 Hz, 2H), 3.68 (s, 3H), 3.22 (br t, J = 11.6 Hz, 2H), 2.55 (br d, J = 6.0 Hz, 2H), 2.09 - 2.00 (m, 2H). Step 5: Synthesis of 4-(3-chlorophenyl)-1-(6-(2-hydroxyphenyl)pyridazin-4-yl)piperidine-4- carboxylic acid To a solution of methyl 4-(3-chlorophenyl)-1-(6-(2-hydroxyphenyl)pyridazin-4- yl)piperidine-4-carboxylate (900 mg, 2.12 mmol, 1.00 eq) in MeOH (9.00 mL) was added NaOH (1 M, 6.37 mL, 3.00 eq) at 25 °C, then the mixture was heated to 50 °C and stirred for 12 hrs. The pH of the mixture was adjusted to 4 with 4 M HCl aqueous solution, then filtered and concentrated. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 * 25 mm * 10um; mobile phase: [water (FA) -ACN]; gradient:18%-48% B over 10 min), concentrated and lyophilized to afford the title compound as a yellow solid (402 mg, 938 μmol, 44.2% yield, 95.6% purity). LCMS: C22H20ClN3O3requires: 409.1, found: m / z = 410.1 [M+H]+.1H NMR (400 MHz, MeOD) δ 8.83 (d, J = 2.8 Hz, 1H), 7.79 (br d, J = 7.6 Hz, 1H), 7.52 - 7.46 (m, 2H), 7.45 - 7.26 (m, 4H), 7.04 - 6.94 (m, 2H), 4.20 (br d, J = 14.0 Hz, 2H), 3.44 (br t, J = 12.0 Hz, 2H), 2.71 (br d, J = 13.2 Hz, 2H), 2.10 - 1.95 (m, 2H). Step 6: Synthesis of the title compound 4-(3-chlorophenyl)-1-[6-(2-hydroxyphenyl)pyridazin-4-yl]piperidine-4-carboxylic acid (20.00 mg, 0.0488 mmol), PyBOP; hexafluoro-lambda5-phosphanuide (33.01 mg, 0.0634 mmol), and N,N-diisopropylethylamine (42.61 μL, 31.53 mg, 0.2440 mmol) stirred in dimethylformamide (0.50 mL, 0.47 g, 6.4300 mmol) at rt for 1 h. Added rac-(3R)-3-[4-(4-{2,6- diazaspiro[3.3]heptan-2-ylmethyl}piperidin-1-yl)phenyl]piperidine-2,6-dione (24.26 mg, 0.0634 mmol) and stirred overnight. The solution was injected onto RP-FC and purified with a gradient of 0-70% MeCN in H2O to furnish the title compound (4.0 mg, 10%). LCMS: C44H48N7O4Cl requires: 773.3, found: m / z = 774.3 [M+H]+. EXAMPLE 28 1-[6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL]-4-PHENYL-N-[(1R*,4R*)-4-(4-{4-[(3RS)-2,6- DIOXOPIPERIDIN-3-YL]PHENYL}PIPERAZINE-1-CARBONYL)CYCLOHEXYL]PIPERIDINE-4- CARBOXAMIDE Step 1: Synthesis of (3RS)-3-(4-{4-[(1r*,4r*)-4-aminocyclohexanecarbonyl]piperazin-1- yl}phenyl)piperidine-2,6-dione rac-(3R)-3-[4-(piperazin-1-yl)phenyl]piperidine-2,6-dione (94.37 mg, 0.3452 mmol) , [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (273.49 mg, 0.7193 mmol), and N,N-diisopropylethylamine (251.25 μL, 185.93 mg, 1.4385 mmol) were stirred in DMF. Added (1s,4s)-4-[(tert- butoxycarbonyl)amino]cyclohexane-1-carboxylic acid (70.00 mg, 0.2877 mmol) and let stir at room temperature until complete by LCMS. Directly injected on RP-FC and purify with a gradient of 5-80% MeCN in H2O to yield the Boc-protected intermediate (80 mg, 56%). This material was dissolved in 1:1 TFA:DCM and stirred for 1h at room temperature, then concentrated and lyophilized to use in the next step. LCMS: C22H30N4O3 requires: 398.2, found: m / z = 398.3 [M+H]+. Step 2: Synthesis of the title compound 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carboxylic acid (50.00 mg, 0.1332 mmol), PyBOP; hexafluoro-lambda5-phosphanuide (103.96 mg, 0.1998 mmol), and N,N- diisopropylethylamine (116.31 μL, 86.07 mg, 0.6659 mmol) were stirred in DMF for 1 hour at room temperature. (3RS)-3-(4-{4-[(1r*,4r*)-4-aminocyclohexanecarbonyl]piperazin-1- yl}phenyl)piperidine-2,6-dione (69.00 mg, 0.1731 mmol) was then added and the reaction was stirred overnight. The solution was injected onto RP-FC and purified with a gradient of 0-70% MeCN in H2O to furnish the title compound (80.3 mg, 78%). LCMS: C44H49N7O5 requires: 755.4, found: m / z = 756.8 [M+H]+. EXAMPLE 29 RAC-(3R)-3-{4-[4-(5-{1-[6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL]-4-PHENYLPIPERIDINE-4- CARBONYL}-5-AZASPIRO[2.4]HEPTANE-1-CARBONYL)PIPERAZIN-1-YL]PHENYL}PIPERIDINE- 2,6-DIONE Step 1: Synthesis of rac-(3R)-3-[4-(4-{5-azaspiro[2.4]heptane-1-carbonyl}piperazin-1- yl)phenyl]piperidine-2,6-dione Stirred rac-(3R)-3-[4-(piperazin-1-yl)phenyl]piperidine-2,6-dione (95.16 mg, 0.3481 mmol) , [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3- yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (275.78 mg, 0.7253 mmol), and N,N-diisopropylethylamine (253.35 μL, 187.48 mg, 1.4506 mmol) in DMF. Added 5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-1-carboxylic acid (70.00 mg, 0.2901 mmol) and stirred at room temperature until complete by LCMS. Directly injected on RP-FC and purified with a gradient of 5-80% MeCN in H2O to yield the Boc-protected intermediate (100 mg, 69%). Dissolved this material in 1:1 TFA:DCM and stirred for 1 h at room temperature, then concentrated and lyophilized to use in the next step. LCMS: C22H28N4O3requires: 396.2, found: m / z = 397.3 [M+H]+. Step 2: Synthesis of the title compound 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carboxylic acid (50.00 mg, 0.1332 mmol), PyBOP; hexafluoro-lambda5-phosphanuide (103.96 mg, 0.1998 mmol), and N,N- diisopropylethylamine (116.31 μL, 86.07 mg, 0.6659 mmol) were stirred in DMF for 1 hour at room temperature. rac-(3R)-3-[4-(4-{5-azaspiro[2.4]heptane-1-carbonyl}piperazin-1- yl)phenyl]piperidine-2,6-dione (68.65 mg, 0.1731 mmol) was then added and the reaction was stirred overnight. The solution was injected onto RP-FC and purified with a gradient of 0-70% MeCN in H2O to furnish the title compound (29.3 mg, 25%) LCMS: C44H47N7O5requires: 753.4, found: m / z = 754.8 [M+H]+. EXAMPLE 30 RAC-(3R)-3-{4-[4-(1-{1-[6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL]-4-PHENYLPIPERIDINE-4- CARBONYL}PIPERIDINE-4-CARBONYL)PIPERAZIN-1-YL]PHENYL}PIPERIDINE-2,6-DIONE Step 1: Synthesis of rac-(3R)-3-{4-[4-(piperidine-4-carbonyl)piperazin-1- yl]phenyl}piperidine-2,6-dione Stirred rac-(3R)-3-[4-(piperazin-1-yl)phenyl]piperidine-2,6-dione (100.14 mg, 0.3664 mmol), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3- yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (290.22 mg, 0.7633 mmol), and N,N-diisopropylethylamine (266.62 μL, 197.30 mg, 1.5265 mmol) in DMF. Added 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (70.00 mg, 0.3053 mmol) and stirred at room temperature until complete by LCMS. Directly injected on RP-FC and purified with a gradient of 5-80% MeCN in H2O to yield the Boc-protected intermediate (100 mg, 68%). Dissolved this material in 1:1 TFA:DCM and stirred for 1 h at room temperature, then concentrated and lyophilized to use in the next step. LCMS: C21H28N4O3 requires: 384.2, found: m / z = 385.3 [M+H]+. Step 2: Synthesis of the title compound 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carboxylic acid (50.00 mg, 0.1332 mmol), PyBOP; hexafluoro-lambda5-phosphanuide (103.96 mg, 0.1998 mmol), and N,N- diisopropylethylamine (116.31 μL, 86.07 mg, 0.6659 mmol) were stirred in DMF for 1 hour at room temperature. rac-(3R)-3-{4-[4-(piperidine-4-carbonyl)piperazin-1-yl]phenyl}piperidine- 2,6-dione (68.65 mg, 0.1731 mmol) was then added and the reaction was stirred overnight. The solution was injected onto RP-FC and purified with a gradient of 0-70% MeCN in H2O to furnish the title compound (7.3 mg, 7%). LCMS: C43H47N7O5 requires: 741.4, found: m / z = 742.3 [M+H]+. EXAMPLE 31 RAC-(3R)-3-{4-[4-(6-{1-[6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL]-4-PHENYLPIPERIDINE-4- CARBONYL}-6-AZASPIRO[3.4]OCTANE-2-CARBONYL)PIPERAZIN-1-YL]PHENYL}PIPERIDINE-2,6- DIONE Step 1: Synthesis of rac-(3R)-3-[4-(4-{6-azaspiro[3.4]octane-2-carbonyl}piperazin-1- yl)phenyl]piperidine-2,6-dione Stirred rac-(3R)-3-[4-(piperazin-1-yl)phenyl]piperidine-2,6-dione (89.93 mg, 0.3290 mmol) , [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3- yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (260.62 mg, 0.6854 mmol), and N,N-diisopropylethylamine (239.43 μL, 177.18 mg, 1.3709 mmol) in DMF. Added 6-(tert-butoxycarbonyl)-6-azaspiro[3.4]octane-2-carboxylic acid (70.00 mg, 0.2742 mmol) and stirred at room temperature until complete by LCMS. Directly injected on RP-FC and purified with a gradient of 5-80% MeCN in H2O to yield the Boc-protected intermediate (100 mg, 68%). Dissolved this material in 1:1 TFA:DCM and stirred for 1 h at room temperature, then concentrated and lyophilized to use in the next step. LCMS: C23H30N4O3requires: 410.2, found: m / z = 411.3 [M+H]+. Step 2: Synthesis of the title compound 1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-phenylpiperidine-4-carboxylic acid (50.00 mg, 0.1332 mmol), PyBOP; hexafluoro-lambda5-phosphanuide (103.96 mg, 0.1998 mmol), and N,N- diisopropylethylamine (116.31 μL, 86.07 mg, 0.6659 mmol) were stirred in DMF for 1 hour at room temperature. rac-(3R)-3-{4-[4-(piperidine-4-carbonyl)piperazin-1-yl]phenyl}piperidine- 2,6-dione (68.65 mg, 0.1731 mmol) was then added and the reaction was stirred overnight. The solution was injected onto RP-FC and purified with a gradient of 0-70% MeCN in H2O to furnish the title compound (51.7 mg, 46%) LCMS: C45H49N7O5requires: 767.4, found: m / z = 768.8 [M+H]+. EXAMPLE 32 RAC-(3R)-3-{4-[4-({6-[4-(3,4-DICHLOROPHENYL)-1-[6-(2-HYDROXYPHENYL)PYRIDAZIN-4- YL]PIPERIDINE-4-CARBONYL]-2,6-DIAZASPIRO[3.3]HEPTAN-2-YL}METHYL)PIPERIDIN-1- YL]PHENYL}PIPERIDINE-2,6-DIONE Step 1: Synthesis of 1-(tert-butyl) 4-methyl 4-(3,4-dichlorophenyl)piperidine-1,4- dicarboxylate To a solution of methyl 2-(3,4-dichlorophenyl)acetate (10.0 g, 45.1 mmol, 1.00 eq) in DMF (100 mL) was added NaH (4.52 g, 112 mmol, 60.0% purity, 2.50 eq) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hr, then was added tert-butyl bis(2-chloroethyl)carbamate (12.0 g, 49.7 mmol, 1.10 eq) dropwise at 20 °C. The reaction mixture was stirred at 60 °C for 3 hrs. The mixture was quenched with saturated aqueous NH4Cl solution (200 mL), then extracted with EtOAc (2 x 100 mL). The organic layers were washed with brine (2 x 100 mL), dried over Na2SO4, filtered, and concentrated to give the title compound as a yellow oil (23.5 g, crude). LCMS: C18H23Cl2NO4requires: 387.1, found: m / z = 288.1 [M-100+H]+. Step 2: Synthesis of methyl 4-(3,4-dichlorophenyl)piperidine-4-carboxylate A solution of 1-(tert-butyl) 4-methyl 4-(3,4-dichlorophenyl)piperidine-1,4-dicarboxylate (23.0 g, 59.2 mmol, 1.00 eq) in HCl / EtOAc (4.00 M, 100 mL, 6.75 eq) was stirred at 25 °C for 12 hrs. The reaction mixture was concentrated under vacuum to give the title compound as a yellow oil (19.0 g, crude, HCl). LCMS: C13H15Cl2NO2 requires: 287.0, found: m / z = 288.1 [M+H]+. Step 3: Synthesis of methyl 1-(6-chloropyridazin-4-yl)-4-(3,4-dichlorophenyl)piperidine-4- carboxylate To a solution of methyl 4-(3,4-dichlorophenyl)piperidine-4-carboxylate (17.0 g, 52.3 mmol, 1.00 eq, HCl) in IPA (170 mL) was added DIPEA (27.0 g, 209 mmol, 36.4 mL, 4.00 eq) at 20 °C, then was added 3,5-dichloropyridazine (8.58 g, 57.6 mmol, 1.10 eq) at 20 °C. The reaction mixture was concentrated under vacuum to give the residue, then was quenched with H2O (200 mL), then extracted with DCM (3 x 100 mL). The organic layers were washed with brine (2 x 100 mL), dried over Na2SO4, filtered, and concentrated to give the product. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 2 / 1) to afford the title compound as a yellow solid (2.20 g, 5.01 mmol, 9.56% yield, 91.2% purity). LCMS: C17H16Cl3N3O2requires: 399.0, found: m / z = 400.1 [M+H]+.1H NMR (400 MHz, MeOD) δ 8.87 (d, J = 2.8 Hz, 1H), 7.59 - 7.53 (m, 2H), 7.39 (dd, J = 2.3, 8.6 Hz, 1H), 7.09 (d, J = 2.8 Hz, 1H), 4.03 - 3.99 (m, 2H), 3.73 (s, 3H), 3.33 - 3.24 (m, 2H), 2.67 (br d, J = 13.2 Hz, 2H), 2.07 - 1.99 (m, 2H). Step 4: Synthesis of methyl 4-(3,4-dichlorophenyl)-1-(6-(2-hydroxyphenyl)pyridazin-4- yl)piperidine-4-carboxylate To a solution of methyl 1-(6-chloropyridazin-4-yl)-4-(3,4-dichlorophenyl)piperidine-4- carboxylate (2.20 g, 5.01 mmol, 1.00 eq) in dioxane (22.0 mL) and H2O (2.20 mL) was added K2CO3 (3.46 g, 25.0 mmol, 5.00 eq), (2-hydroxyphenyl)boronic acid (1.38 g, 10.0 mmol, 2.00 eq) and Pd(PPh3)2Cl2 (527 mg, 751 μmol, 0.150 eq) under N2 atmosphere at 20 °C. The reaction mixture was stirred at 110 °C for 12 hrs. The reaction mixture was concentrated under vacuum, then was diluted with water (100 mL), extracted with DCM 30.0 mL (2 x 15.0 mL). The combined organic layers were washed with brine (2 x 50.0 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 1 / 1) to yield the title compound as a yellow solid (786 mg, 1.54 mmol, 28.2% yield, 89.8% purity). LCMS: C23H21Cl2N3O3 requires: 457.1, found: m / z = 458.2 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.74 (d, J = 2.8 Hz, 1H), 7.67 (dd, J = 1.2, 8.0 Hz, 1H), 7.49 - 7.45 (m, 2H), 7.37 - 7.33 (m, 1H), 7.25 (dd, J = 2.4, 8.4 Hz, 1H), 7.16 (d, J = 2.8 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.95 - 6.91 (m, 1H), 3.95 (br d, J = 13.6 Hz, 2H), 3.76 (s, 3H), 3.30 - 3.23 (m, 2H), 2.73 (br d, J = 13.6 Hz, 2H), 2.04 - 2.00 (m, 2H). Step 5: Synthesis of 4-(3,4-dichlorophenyl)-1-(6-(2-hydroxyphenyl)pyridazin-4- yl)piperidine-4-carboxylic acid To a solution of methyl 4-(3,4-dichlorophenyl)-1-(6-(2-hydroxyphenyl)pyridazin-4- yl)piperidine-4-carboxylate (786 mg, 1.54 mmol, 1.00 eq) in MeOH (4.00 mL), THF (4.00 mL) and H2O (2.00 mL) was added NaOH (615 mg, 15.4 mmol, 10.0 eq) at 20 - 25 °C. The reaction mixture was stirred at 80 °C for 12 hrs. The reaction mixture was evaporated under reduced pressure to remove the solvent, then the mixture was adjusted to pH = 3 with 4 N HCl. Then filtered and collected the precipitate. The crude product was purified by prep-HPLC (column: Phenomenex luna C18150 * 40 mm * 15um; mobile phase: [water (HCl) -ACN]; gradient: 20% - 50% B over 10 min) to afford the title compound as a yellow solid (374 mg, 779 μmol, 50.6% yield, 100% purity, HCl). LCMS: C22H19Cl2N3O3requires: 443.1, found: m / z = 444.2 [M+H]+.1H NMR (400 MHz, MeOD) δ 8.85 (br s, 1H), 7.62 (br s, 2H), 7.54 - 7.41 (m, 4H), 7.07 - 7.02 (m, 2H), 4.31 (br d, J = 14.0 Hz,...

Claims

CLAIMS 1. A compound having a structure represented by Formula (IA):Formula (IA) or a stereoisomer, pharmaceutically acceptable salt thereof, wherein: R1is hydrogen or C1-6 alkyl optionally substituted with 1 to 3 Ra; R2is hydrogen, halo, hydroxyl, -O-Rc, C1-6 alkyl optionally substituted with 1 to 3 Ra; R3is hydrogen, –CN, C1-6 alkyl, C6-12 aryl, C3-12 cycloalkyl, 5-12 membered heteroaryl, each being optionally substituted with 1 to 3 Rd, or -O-Re; L comprises up to 8 linker segments represented by –L1-L2-L3-L4-L5-L6-L7–L8–, each L1, L2, L3, L4, L5, L6, L7, or L8, being independently: i) C3-12 cycloalkyl optionally substituted with 1-3 Rb; ii) C6-12 aryl optionally substituted with 1-3 Rb; iii) 4-12 membered heterocyclyl optionally substituted with 1-3 Rb; iv) 5-12 membered heteroaryl optionally substituted with 1-3 Rb; v) direct bond; vi) C1-12 alkylene chain optionally substituted with 1-3 Rb; or vii) –(CH2)m-C(O)–, –(CH2)m-C(O)O–, –(CH2)m-O–, –(CH2)m-N(Rc)-, –(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(Rc)–, –C(O)-N(Rc)-(CH2)m–, –(CH2)m-O-C(O)-N(Rc)–, –(CH2)m–O-C(O)-O–, or –NH-(CH2)m-C(O)–, wherein m is 0, 1, 2, 3, 4, 5 or 6; each Rais independently halo, or -O-Rc; each Rbis independently oxo, imino, sulfoximino, halo, nitro, -CN, C1-6 alkyl, C2-6 alkenyl, C3-15 cycloalkyl, C1-8 haloalkyl, C6-12 aryl, 5-12 membered heteroaryl, 4-12 membered heterocyclyl, -O-Rc, -C(O)-Rc, -C(O)O-Rc, -C(O)-N(Rc)( Rc), -N(Rc)(Rc), -N(Rc)C(O)- Rc, -N(Rc)C(O)O-Rc, -N(Rc)C(O)N(Rc)( Rc), -N(Rc)S(O)2(Rc), -NRcS(O)2N(Rc)( Rc), - N(Rc)S(O)2O(Rc), -OC(O)Rc, -OC(O)-N(Rc)( Rc), -Si(Rc)3, -S-Rc, -S(O)Rc, -S(O)(NH)Rc, - S(O)2Rcor -S(O)2N(Rc)( Rc), wherein each of C1-6 alkyl, C2-6 alkenyl, C3-15 cycloalkyl, C1-8 haloalkyl, C6-12 aryl, 5-12 membered heteroaryl, and 4-12 membered heterocyclyl may be optionally substituted with 1 to 3 Rd; each Rcis independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C6-12 aryl or C1-6 haloalkyl, wherein C1-6 alkyl is optionally substituted with C1-3 alkoxy; each Rdis independently halo, -CN, -O-Rc, C1-6 alkyl, C6-12 aryl or C1-6 haloalkyl;Reis C1-6 alkyl, C3-12 cycloalkyl, C6-12 aryl, 5-12 membered heteroaryl, each being optionally substituted with C1-6 alkyl or halo; W is –C(Rg)- or –N-; Y is direct bond, C1-4 alkylene chain, -C(O)-, -C(O)O-, -O -, -N(Rg)-, -S- -C(S)-, -C(S)-O-, -O-C(O)O-, –C(O)-N(Rg)-, or –O-C(O)-N(Rg)-; B ring is C6-12 aryl, 5-12 membered heteroaryl, or 4-12 membered heterocyclyl, each being optionally substituted with 1 to 3 Rj; Rgis hydrogen or C1-6 alkyl; and each Rjis independently halo, oxo, -CN, -O-Rc, C1-6 alkyl, or C1-6 haloalkyl.

2. The compound of claim 1, wherein each L1, L2, L3, L4, L5, L6, L7, or L8 is independently: i) a bivalent ring moiety selected from the group consisting of:ii) direct bond; iii) C1-6alkylene chain; or iv) -C(O)-, -O–,–(CH2)m–C(O)-N(Rc)–, –(CH2)m-N(Rc)-, – C(O)-N(Rc)-(CH2)m–, or –NH-(CH2)m-C(O)–, –(CH2)m-S(O)2NH–, m being 0, 1, 2 or 3; wherein, n is 0, 1, or 2; Rbis halo, -O-Rc, -CN, C1-6alkyl, or C1-6haloalkyl; and Rcis hydrogen, C1-6alkyl, C3-6cycloalkyl, phenyl, or C1-6haloalkyl, wherein C1-6alkyl is optionally substituted with C1-3alkoxy.

3. The compound of claim 1 or claim 2, wherein,halo, -CN, -O-Rc, C1-6alkyl, or C1-6haloalkyl.

4. The compound of any one of claims 1-3, wherein R3is: phenyl optionally substituted with one or more C1-6alkyl, C1-6alkoxy, or halo; benzyl optionally substituted with one or more C1-6alkyl or halo; pyridinyl optionally substituted with one or more C1-6alkyl; CN; C3-6cyclopropyl; pyrazolyl optionally substituted with one or more C1-6alkyl; tetrahydropyranyl, 1,2-oxazolyl optionally substituted with one or more C1-6alkyl;pyrazolo[1,5-a]pyridinyl; or -O-Re, wherein Reis phenyl optionally substituted with C1-6 alkyl or halo, C3-6 cycloalkyl, C1-6 alkyl, or pyrazolyl optionally substituted with C1-6 alkyl.

5. The compound of claim 4, wherein R3is phenyl, benzyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, CN, cyclopropyl, 1-methyl-1H-pyrazol-3yl, 3-methylphenyl, 2-methylphenyl, 3- chlorophenyl, 3,4-dichlorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-fluorophenyl, 4- fluorophenyl, tetrahydropyran-4yl, 3-methyl-1H-pyrazol-1yl, 4-methyl-1H-pyrazol-1yl, 5- methyl-1H-pyrazol-1yl, 1-methyl-1H-pyrazol-3yl, 1-methyl-1H-pyrazol-4yl, 1-methyl-1H- pyrazol-5yl, pyrazolo[1,5-a]pyridin-2-yl, 5-methyl-1,2-oxazol-3-yl, 5-isopropyl-1,2-oxazol-3-yl, 3-methyl-1,2-oxazol-5-yl, or -O-Re, wherein Reis phenyl, 2-chlorophenyl, 2-methylphenyl, cyclopropyl, cyclohexyl, methyl, or 1-methyl-1H-pyrazol-3yl.

6. The compound of any one of claims 1-5, wherein R1is hydrogen and R2is hydrogen.

7. The compound of any one of claims 1-5, wherein R1is hydrogen, R2is hydrogen, Y is direct bond, R3is -O-Re, W is CH, and the compound has a structure represented by Formula (IA1):Rjis halo, -CN, -O-Rc, C1-6alkyl, or C1-6haloalkyl; Reis C1-6alkyl, C3-12cycloalkyl, C6-12aryl, 5-12 membered heteroaryl, each being optionally substituted with C1-6alkyl or halo; Rcis hydrogen or C1-3alkyl; L1is -C(O)-, or -C(O)N(Rc)-; and8. The compound of claim 7, wherein B isn is 0 or 1; Rjis fluoro or chloro; Reis C1-6alkyl, C3-12cycloalkyl, C6-12aryl, 5-12 membered heteroaryl, each being optionally substituted with C1-6alkyl or halo; methyl or ethyl; and9. The compound of claim 7 or claim 8, wherein Reis C1-3alkyl.

10. The compound of any one of claims 7-9, wherein Reis methyl, phenyl, cyclopropyl, cyclohexyl, 1-methyl-1H-pyrazol-3yl or phenyl substituted with chloro or methyl.

11. The compound of claim 7, wherein B ring isn is 0, 1 or 2; Rjis fluoro or chloro; Reis methyl, ethyl, or propyl;Rcis hydrogen, methyl, or ethyl;12. The compound of any one of claims 1-5, wherein R1and R2are hydrogen, W is CH, and the compound has a structure represented by Formula (IA2):Formula (IA2) wherein, n is 0, 1, or 2; Y is direct bond, –NHC(O)-, or -NH-; X is N or CH; Rj is C1-3alkyl or halo; R3is C6-12aryl, C3-12cycloalkyl, 5-12 membered heteroaryl, each being optionally substituted with 1 to 3 Rd, or -O-Re; Rcis hydrogen or C1-6methyl; each Rdis independently halo, -CN, -O-Rc, C1-6alkyl, C6-12aryl or C1-6haloalkyl; and Reis C1-6alkyl, C3-12cycloalkyl, C6-12aryl, 5-12 membered heteroaryl, each being substituted with C1-6or halo; and13. The compound of claim 12, wherein R3is phenyl, 2-fluorophenyl, 5-methyl-1,2- oxazol-5-yl, 5-isopropyl-1,2-oxazol-5-yl, pyrazolo[1,5-a]pyridinyl, -O-Re, wherein Reis phenyl, 2-chlorophenyl, 2-methylphenyl, 1-methyl-1H-pyrazol-3yl, cyclohexyl, or methyl.

14. The compound of any one of claims 1-5, wherein R1and R2are hydrogen, W is CH, and the compound has a structure represented by Formula (IA3):Formula (IA3) wherein, n is 0, 1, or 2; Y is direct bond, –NHC(O)-, or -NH-; X is N or CH; R3is C6-12aryl, C3-12cycloalkyl, 5-12 membered heteroaryl, each being optionally substituted with 1 to 3 Rd, or -O-Re;Rcis hydrogen, C1-3alkyl, or C3-6 cycloalkyl; each Rdis independently halo, -CN, -O-Rc, C1-6 alkyl, C6-12 aryl or C1-6 haloalkyl; Reis C1-6 alkyl, C3-12 cycloalkyl, C6-12 aryl, 5-12 membered heteroaryl, each being optionally substituted with C1-6 alkyl or halo; Rjis C1-3alkyl or halo; and15. The compound of claim 14, wherein R3is phenyl, 2-pyridinyl, 4-pyridinyl, 2- fluorophenyl, 4-fluorophenyl, 3-methyl-1H-pyrazol-1yl, 4-methyl-1H-pyrazol-1yl, 5-methyl-1H- pyrazol-1yl, 1-methyl-1H-pyrazol-4yl, 1-methyl-1H-pyrazol-5yl, tetrahydropyran-4yl, 3-methyl- 1,2-oxazol-5-yl, 5-isopropyl-1,2-oxazol-3-yl, pyrazolo[1,5-a]pyridinyl, -O-Re, wherein Reis phenyl, 2-chlorophenyl, 2-methylphenyl, 1-methyl-1H-pyrazol-3yl, cyclopropyl, cyclohexyl, or methyl.

16. The compound of any one of claims 1-5, wherein R1and R2are hydrogen, W is CH, Y is direct bond, R3is phenyl, and the compound has a structure represented by Formula (IA4):Formula (IA4) wherein, n is 0, 1, or 2; X is N or CH; Rcis hydrogen or C1-3alkyl optionally substituted with C1-3 alkoxy; Rjis C1- or halo; and17. The compound of any one of claims 1-5, wherein R1and R2are hydrogen, W is CH, Y is direct bond, R3is phenyl, and the compound has a structure represented by Formula (IA5)Formula (IA5) wherein, n is 0, 1, or 2; X is N or CH; Q is direct bond, -N(Rc)- or -NHS(O)2-, Rcis hydrogen or C1-3alkyl; Rjis C1-3alkyl or halo; and18. The compound of any one of claims 1-5, wherein R1and R2are hydrogen, W is CH, Y is direct bond, and the compound has a structure represented by Formula (IA6):, Formula (IA6) wherein,R3is C6-12 aryl, C3-12 cycloalkyl, 5-12 membered heteroaryl, each being optionally substituted with 1 to 3 Rd, or -O-Re; Rcis hydrogen or C1-6 alkyl; each Rdis independently halo, -CN, -O-Rc, C1-6 alkyl, C6-12 aryl or C1-6 haloalkyl; Reis C1-6 alkyl, C3-12 cycloalkyl, C6-12 aryl, 5-12 membered heteroaryl, each being optionally substituted with C1-6 alkyl or halo;19. The compound of claim 18, wherein, R3is phenyl, 1-methyl-1H-pyrazol-5yl, 5- methyl-1H-pyrazol-1yl, or -O-Re, wherein Reis 1-methyl-1H-pyrazol-3yl, or methyl.

20. A compound having a structure represented by Formula (I):Formula (I) or a stereoisomer, pharmaceutically acceptable salt thereof, wherein: R1is hydrogen or C1-6 alkyl optionally substituted with 1 to 3 Ra; R2is hydrogen, halo, hydroxyl, -O-Rc, C1-6 alkyl optionally substituted with 1 to 3 Ra; R3is hydrogen, –CN, C1-6 alkyl, C6-12 aryl, C3-12 cycloalkyl, or 5-12 membered heteroaryl, each being optionally substituted with 1 to 3 Rd; L comprises up to 8 linker segments represented by –L1-L2-L3-L4-L5-L6-L7–L8–, each L1, L2, L3, L4, L5, L6, L7, or L8, being independently: i) C3-12 cycloalkyl optionally substituted with 1-3 Rb; ii) C6-12 aryl optionally substituted with 1-3 Rb; iii) 4-12 membered heterocyclyl optionally substituted with 1-3 Rb; iv) 5-12 membered heteroaryl optionally substituted with 1-3 Rb; v) direct bond; vi) C1-12 alkylene chain optionally substituted with 1-3 Rb; or vii) –(CH2)m-C(O)–, –(CH2)m-C(O)O–, –(CH2)m-O–, –(CH2)m-N(Rc)-, –(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(Rc)–, –C(O)-N(Rc)-(CH2)m–, –CH2)m-O-C(O)-N(Rc)–, –(CH2)m–O-C(O)-O–, or –NH-(CH2)m-C(O)–, wherein m is 0, 1, 2, 3, 4, 5 or 6; each Rais independently halo, or -O-Rc; each Rbis independently oxo, imino, sulfoximino, halo, nitro, -CN, C1-6 alkyl, C2-6 alkenyl, C3-15 cycloalkyl, C1-8 haloalkyl, C6-12 aryl, 5-12 membered heteroaryl, 4-12 membered heterocyclyl, -O-Rc, -C(O)-Rc, -C(O)O-Rc, -C(O)-N(Rc)( Rc), -N(Rc)(Rc), -N(Rc)C(O)- Rc, -N(Rc)C(O)O-Rc, -N(Rc)C(O)N(Rc)( Rc), -N(Rc)S(O)2(Rc), -NRcS(O)2N(Rc)( Rc), - N(Rc)S(O)2O(Rc), -OC(O)Rc, -OC(O)-N(Rc)( Rc), -Si(Rc)3, -S-Rc, -S(O)Rc, -S(O)(NH)Rc, - S(O)2Rcor -S(O)2N(Rc)( Rc), wherein each of C1-6 alkyl, C2-6 alkenyl, C3-15 cycloalkyl, C1-8 haloalkyl, C6-12 aryl, 5-12 membered heteroaryl, and 4-12 membered heterocyclyl may be optionally substituted with 1 to 3 Rd; each Rcis independently hydrogen, C1-6 alkyl, or C1-6 haloalkyl; each Rdis independently halo, -CN, -O-Rc, C1-6 alkyl, C6-12 aryl or C1-6 haloalkyl; W is –C(Rg)- or –N-; Y is direct bond, C1-4 alkylene chain, -C(O)-, -C(O)O-, -O -, -N(Rg)-, -S- -C(S)-, -C(S)-O-, -O-C(O)O-, –C(O)-N(Rg)-, or –O-C(O)-N(Rg)-;B ring is C6-12 aryl, 5-12 membered heteroaryl, or 4-12 membered heterocyclyl, each being optionally substituted with 1 to 3 Rj; Rgis hydrogen or C1-6 alkyl; and each Rjis independently halo, -CN, -O-Rc, C1-6 alkyl, or C1-6 haloalkyl.

21. The compound of claim 20, wherein,is 0, 1 or 2, Rjis halo, -CN, -O-Rc, C1-6alkyl, or C1-6haloalkyl.

22. The compound of claim 21, having a structure represented by Formula (II):Formula (II) wherein, W is CN or N; X is CH or N; p is 0, 1, or 2; and Rjis halo or C1-3 alkyl.

23. The compound of claim 22, having a structure represented by Formulae (IIa), (IIb), (IIc) or (IId):Formula (IIa),24. The compound of any one of claims 20-23, wherein each L1, L2, L3, L4, L5, L6, L7, or L8is independently: i) a bivalent ring moiety selected from the group consisting of:ii) direct bond; iii) C1-6 alkylene chain; or iv) -C(O)-, -O–, –C(O)-N(Rc)-, -(CH2)m-C(O)–, or –NH-(CH2)m-C(O)–, wherein m is 0, 1, 2 or 3; wherein, n is 0, 1, or 2; Rbis halo, -CN, C1-3 alkyl, or C1-3 haloalkyl; and Rcis hydrogen or C1-3 alkyl.

25. The compound of any one of claims 20-24, wherein R1is hydrogen or C1-6 alkyl substituted with 1 to 3 fluoro or hydroxyl.

26. The compound of any one of claims 20-25, wherein R3is phenyl, benzyl, 2- pyridinyl, 3-pyridinyl, CN, cyclopropyl, 1-methyl-1H-pyrazol-3yl, 3-methylphenyl, 2- methylphenyl, 3-chlorophenyl, or 3,4-dichlorophenyl.

27. The compound of any one of claims 20-26, wherein R1is hydrogen and R2is hydrogen.

28. The compound of claim 27, having a structure represented by Formulae (III),Formula (III) wherein W is N or CH; X is N or CH;L’ is –L2-L3-L4-L5-L6-L7–L8–; and R3is CN, cyclopropyl, C1-3 alkyl, phenyl optionally substituted with one or two halo or C1-3 alkyl, or pyrazolyl optionally substituted with C1-3 alkyl.

29. The compound of claim 28, having a structure represented by Formulae (IIIa), (IIIb), (IIIc) or (IIId):Formula (IIIc), or,,30. The compound of claim 27, having a structure represented by Formulae (IV):Formula (IV) wherein W is N or CH; X is N or CH; V is N or CH; L’’ is –L2-L3-L4-L5-L6-L7–; and R3is CN, cyclopropyl, C1-3alkyl, phenyl optionally substituted with one or two halo or C1-3alkyl, or pyrazolyl optionally substituted with C1-3alkyl.

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

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

34. The pharmaceutical composition of claim 33, further comprising one or more additional therapeutic agents, or a pharmaceutically acceptable salt thereof.

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

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

37. The compound or the pharmaceutical composition for use according to claim 36 wherein the SMARCA2-mediated diseases are cancers selected from the group consisting of acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, 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 cancer, hormoneinsensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, liver cancer, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's; Burkitt’s), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B — cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, malignant rhabdoid tumor (MRT), rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor.

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