Bifunctional selective degraders of smarca2 and therapeutic uses thereof

Abstract

The present disclosure provides bifunctional compounds 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

[0002] This application claims the benefit of priority to U. S. Provisional Application No. 63 / 730,921, filed December 11, 2024, which application is hereby incorporated by reference in its entirety.

[0003] BACKGROUND

[0004] Technical Field

[0005] 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

[0006] 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.

[0007] 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.

[0008] 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.

[0009] BRIEF SUMMARY

[0010] Provided herein are bifunctional compounds exhibiting both potent inhibition and selectivity against SMARCA2 while sparing SMARCA4.

[0011] Provided herein are bifunctional compounds represented by Formula (I):

[0012] R1

[0013]

[0014] Formula (I) or a stereoisomer, pharmaceutically acceptable salt thereof, wherein:

[0015] t is 0 or 1;

[0016] R1is hydrogen or Ci-6 alkyl optionally substituted with 1 to 3 Ra;

[0017] R2is hydrogen, halo, hydroxyl, -O-Rc, Ci -6 alkyl optionally substituted with 1 to 3 Ra;

[0018] R3is hydrogen, -CN, Ci-6 alkyl, Ce-i2 aryl, C3-12 cycloalkyl, 5-12 membered heteroaryl, each being optionally substituted with 1 to 3 Rd, or -O-Re;

[0019] L comprises up to 8 linker segments represented by -L1-L2-L3-L4-L5-L6-L7-L8-, each Li, L2, L3, L4, L5, Le, L7, or Ls, being independently:

[0020] i) C3-12 cycloalkyl optionally substituted with 1-3 Rb;

[0021] ii) C6-12 aryl optionally substituted with 1-3 Rb;

[0022] iii) 4-12 membered heterocyclyl optionally substituted with 1-3 Rb;

[0023] iv) 5-12 membered heteroaryl optionally substituted with 1-3 Rb;

[0024] v) direct bond;

[0025] vi) C1-12 alkylene chain optionally substituted with 1-3 Rb; or

[0026] 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;

[0027] each Rais independently halo, or -O-Rc;

[0028] each Rbis independently oxo, imino, sulfoximino, halo, nitro, -CN, C1-6 alkyl, C2-6 alkenyl, C3-15 cycloalkyl, Ci-s haloalkyl, Ce-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,

[0029] -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;

[0030] each Rcis independently hydrogen, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, Ce-i2 aryl, or C1-6 haloalkyl, wherein C1-6 alkyl is optionally substituted with one or more substituents selected from C1-3 alkoxy, hydroxy, C3-6 cycloalkyl, Ce-12 aryl and amino;

[0031] each Rdis independently halo, -CN, -O-Rc, C1-6 alkyl, C 6-12 aryl or C1-6 haloalkyl,

[0032] Reis C1-6 alkyl, C3-12 cycloalkyl, Ce-12 aryl, 5-12 membered heteroaryl, each being optionally substituted with C1-6 alkyl, C1-6 haloalkyl or halo;

[0033] W is -C(R8)- or-N-;

[0034] Y is direct bond, C1-4 alkylene chain, -C(O)-, -C(O)O-, -O - -N(R8)-, -S--C(S)-, -C(S)-O-, -O-C(O)O-, -C(O)-N(R8)-, or -O-C(O)-N(R8)-;

[0035] B ring is Ce-12 aryl, 5-12 membered heteroaryl, or 4-12 membered heterocyclyl, each being optionally substituted with 1 to 3 RJ;

[0036] R8is hydrogen or C1-6 alkyl; and

[0037] each RJis independently halo, oxo, -CN, -O-Rc, C1-6 alkyl, or C1-6 haloalkyl. Also provided herein are compounds having the structure represented by Formula (II):

[0038]

[0039] Formula (II)

[0040] or a stereoisomer, pharmaceutically acceptable salt thereof, wherein:

[0041] t and q is independently 0 or 1;

[0042] Z is -N- or -C(R3)-;

[0043] R1is hydrogen or Ci-6 alkyl optionally substituted with 1 to 3 Ra;

[0044] R2is hydrogen, halo, hydroxyl, -O-Rc, Ci -6 alkyl optionally substituted with 1 to 3 Ra;

[0045] R3is hydrogen, -CN, halo (preferably F), -O-Re, Ci-6 alkyl, Ce-i2 aryl, C3-12 cycloalkyl, 5-12 membered heteroaryl, wherein each of C1-6 alkyl, Ce-12 aryl, C3-12 cycloalkyl, and 5-12 membered heteroaryl is optionally substituted with 1 to 3 Rd;

[0046] R4aand R4bare each independently hydrogen, C1-6 alkyl or C1-6 alkoxy, or

[0047] R4aand R4btogether may form a C1-3 alkylene chain; or

[0048] R4aand R3together with the carbons to which they are attached form a C3-12 cycloalkyl or 5-12 membered heterocycle,

[0049] L comprises up to 8 linker segments represented by -L1-L2-L3-L4-L5-L6-L7-L8-, each Li, L2, L3, L4, L5, Le, L7, or Ls, being independently:

[0050] i) C3-12 cycloalkyl optionally substituted with 1-3 Rb;

[0051] ii) C6-12 aryl optionally substituted with 1-3 Rb;

[0052] iii) 4-12 membered heterocyclyl optionally substituted with 1-3 Rb; iv) 5-12 membered heteroaryl optionally substituted with 1-3 Rb;

[0053] v) direct bond;

[0054] vi) C1-12 alkylene chain optionally substituted with 1-3 Rb;

[0055] vii) C1-12 alkenylene chain optionally substituted with 1-3 Rb; or

[0056] viii) -(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;

[0057] each Rais independently halo, or -O-Rc;

[0058] each Rbis independently oxo, imino, sulfoximino, halo, nitro, -CN, C1-6 alkyl, C2-6 alkenyl, C3-15 cycloalkyl, Ci-s 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(0)0-Rc, -N(RC)C(O)N(RC)( Rc), -N(RC)S(O)2(RC), -NRCS(0)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, Ci-6 alkyl, Ci-6 alkoxy, C3-6 cycloalkyl (optionally substituted with 1 or 2 halo, C1-3 alkyl or C1-3 alkoxy), Ce-12 aryl, 4-12 membered heterocyclyl optionally substituted with 1 or 2 C1-3 alkyl), 5-12 membered heteroaryl optionally substituted with 1 or 2 C1-3 alkyl or C1-3 haloalkyl) or C1-6 haloalkyl, wherein C1-6 alkyl is optionally substituted with one or more substituents selected from C1-3 alkoxy, hydroxy, C3-6 cycloalkyl (optionally further substituted with 1 or 2 halo, C1-3 alkoxy or C1-3 alkyl), CN, 5-12 membered heteroaryl (optionally further substituted with 1 or 2 halo or Ci-3 alkyl), C6-12 aryl and amino;

[0059] each Rdis independently halo, -CN, -O-Rc, C1-6 alkyl, C 6-12 aryl, C3-6 cycloalkyl 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, C1-6 alkoxy, C1-6 haloalkyl or halo;

[0060] W is -C(R8)- or-N-;

[0061] Y is direct bond, C1-4 alkylene chain, -C(O)-, -C(O)O-, -O - -N(R8)-, -S--C(S)-, -C(S)-O-, -O-C(O)O-, -C(0)-N(R8)-, or -0-C(0)-N(R8)-;

[0062] B ring is C6-12 aryl, 5-12 membered heteroaryl, or 4-12 membered heterocyclyl, each being optionally substituted with 1 to 3 RJ;

[0063] R8is hydrogen or C1-6 alkyl; and

[0064] each RJis independently halo, oxo, -CN, -O-Rc, C1-6 alkyl, or C1-6 haloalkyl.

[0065] In further more specific embodiments, t is 1, and the compound of Formula (I) has the following structure:

[0066]

[0067] Formula (IA)

[0068] In other more specific embodiments, t is 0, and the compound of Formula (I) has the following structure:

[0069]

[0070] Formula (IB) In various other more specific embodiments, compounds of Formula (II) have one of the following structures:

[0071] ; (wherein v is 1, 2 or 3)

[0072]

[0073] ; (wherein v is 1, 2 or 3) Formula (ID)

[0074]

[0075] Formula (IF).

[0076] In various more specific embodiments, each Li, L2, L3, L4, L5, Ls, L7, or Ls is independently: i) a bivalent ring moiety selected from the group consisting of:

[0077]

[0078]

[0079] ii) direct bond;

[0080] iii) Ci-6 alkylene chain optionally substituted with 1-3 Rb; or

[0081] iv) -C(O)-, -O- -(CH2)m-C(O)-N(Rc)-, -(CH2)m-C(O)- -(CH2)m-N(Rc)-,

[0082] -C(O)-N(Rc)-(CH2)m- or -NH-(CH2)m-C(O)-, -(CH2)m-S(O)2NH- m being 0, 1, 2 or 3;

[0083] wherein,

[0084] n is 0, 1, or 2;

[0085] Rbis halo, -O-Rc, -CN, Ci-6 alkyl, or Ci-6 haloalkyl; and

[0086] Rcis hydrogen, Ci-6 alkyl, Ci-6 alkoxy, C3-6 cycloalkyl, phenyl, or Ci-6 haloalkyl, wherein Ci-6 alkyl is optionally substituted with C1.3 alkoxy, hydroxy, C3-6 cycloalkyl, phenyl and amino.

[0087] In various more specific embodiments, Y is direct bond,-C(O)-N(R8)- (wherein R8is hydrogen or Ci-6 alkyl), or -NH-; and

[0088]

[0089] , RJis halo, -CN, -O-Rc, Ci-6 alkyl, or Ci-6 haloalkyl.

[0090] Also provided herein are compounds of the following substructures:

[0091] Formula (IAA3)

[0092]

[0093] Formula (IAA4) Formula (IAA5)

[0094] Formula (IB 1)

[0095] Formula (IB2)

[0096] Formula (ID 1)

[0097]

[0098] Formula (IE1)

[0099]

[0100] Formula (IF1)

[0101] Also provided herein is a pharmaceutical composition comprising a compound of Formulae (I), (II) or any one of the substructures (IA), (IB), (IC), (ID), (IE), (IF), (IAA), (IAA1), (IAA2), (IAA3), (IAA4), (IAA5), (IB1), (IB2), (IC1), (IC2), (ID1), (IE1), or (IF 1) or any one of the specific compounds of Examples 1-263 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

[0102] Further provided herein are pharmaceutical or therapeutic use of the compound and pharmaceutical composition described herein for treating SMARCA2 mediated diseases or disorders, including various types of cancers.

[0103] DETAILED DESCRIPTION

[0104] 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.

[0105] Various embodiments provide compounds having a structure represented by Formula (I):

[0106] R1

[0107]

[0108] R2

[0109] Formula (I)

[0110] or a stereoisomer, pharmaceutically acceptable salt thereof, wherein:

[0111] t is 0 or 1;

[0112] R1is hydrogen or Ci-6 alkyl optionally substituted with 1 to 3 Ra;

[0113] R2is hydrogen, halo, hydroxyl, -O-Rc, Ci.6 alkyl optionally substituted with 1 to 3 Ra;

[0114] R3is hydrogen, -CN, Ci-6 alkyl, Ce-i2 aryl, C3-12 cycloalkyl, 5-12 membered heteroaryl, each being optionally substituted with 1 to 3 Rd, or -O-Re;

[0115] L comprises up to 8 linker segments represented by -L1-L2-L3-L4-L5-L6-L7-L8-, each Li, L2, L3, L4, L5, L6, L7, or L8, being independently:

[0116] i) C3-12 cycloalkyl optionally substituted with 1-3 Rb;

[0117] ii) Ce-i2 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;

[0118] v) direct bond;

[0119] vi) Ci-12 alkylene chain optionally substituted with 1-3 Rb; or

[0120] vii) -(CH2)m-C(0)-, -(CH2)m-C(0)0- -(CH2)m-0- -(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–,

[0121] -(CH2)m-S(O)2NH-, -(CH2)m-C(0)-N(Rc)-, -C(0)-N(Rc)-(CH2)m- -(CH2)m-0-C(0)-N(Rc)--(CH2)m-0-C(0)-0-, or -NH-(CH2)m-C(0)-, wherein m is 0, 1, 2, 3, 4, 5 or 6;

[0122] each Rais independently halo, or -O-Rc;

[0123] each Rbis independently oxo, imino, sulfoximino, halo, nitro, -CN, Ci-6 alkyl, C2.6 alkenyl, C3-15 cycloalkyl, Ci-s haloalkyl, Ce-i2aryl, 5-12 membered heteroaryl, 4-12 membered heterocyclyl,

[0124] -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(0)0-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 Ci-6alkyl, C2-6 alkenyl, C3-15 cycloalkyl, Ci-s haloalkyl, Ce-i2aryl, 5-12 membered heteroaryl, and 4-12 membered heterocyclyl may be optionally substituted with 1 to 3 Rd;

[0125] each Rcis independently hydrogen, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, Ce-i2aryl, or C1-6 haloalkyl, wherein C1-6 alkyl is optionally substituted with one or more substituents selected from C1-3 alkoxy, hydroxy, C3-6 cycloalkyl, Ce-i2aryl and amino;

[0126] each Rdis independently halo, -CN, -O-Rc, C1-6 alkyl, C6-i2aryl or C1-6 haloalkyl,

[0127] Reis C1-6 alkyl, C3-i2cycloalkyl, Ce-i2aryl, 5-12 membered heteroaryl, each being optionally substituted with C1-6 alkyl, C1-6 haloalkyl or halo;

[0128] W is -C(R8)- or-N-;

[0129] Y is direct bond, C1-4 alkylene chain, -C(O)-, -C(O)O-, -O - -N(R8)-, -S--C(S)-, -C(S)-O-, -O-C(O)O-, -C(0)-N(R8)-, or -0-C(0)-N(R8)-;

[0130] B ring is Ce-i2aryl, 5-12 membered heteroaryl, or 4-12 membered heterocyclyl, each being optionally substituted with 1 to 3 RJ;

[0131] R8is hydrogen or C1-6 alkyl; and

[0132] each RJis independently halo, oxo, -CN, -O-Rc, C1-6 alkyl, or C1-6 haloalkyl.

[0133] Also provides are compounds having a structure represented by Formula (II):

[0134]

[0135] Formula (II)

[0136] or a stereoisomer, pharmaceutically acceptable salt thereof, wherein:

[0137] t and q is independently 0 or 1;

[0138] Z is -N- or -C(R3)-;

[0139] R1is hydrogen or C1-6 alkyl optionally substituted with 1 to 3 Ra; R2is hydrogen, halo, hydroxyl, -O-Rc, Ci -6 alkyl optionally substituted with 1 to 3 Ra;

[0140] R3is hydrogen, -CN, halo (preferably F), -O-Re, Ci-6 alkyl, Ce-i2 aryl, C3-12 cycloalkyl, 5-12 membered heteroaryl, wherein each of C1-6 alkyl, Ce-12 aryl, C3-12 cycloalkyl, and 5-12 membered heteroaryl is optionally substituted with 1 to 3 Rd;

[0141] R4aand R4bare each independently hydrogen, C1-6 alkyl or C1-6 alkoxy, or

[0142] R4aand R4btogether may form a C1-3 alkylene chain; or

[0143] R4aand R3together with the carbons to which they are attached form a C3-12 cycloalkyl or 5-12 membered heterocycle,

[0144] L comprises up to 8 linker segments represented by -L1-L2-L3-L4-L5-L6-L7-L8-, each Li, L2, L3, L4, L5, Le, L7, or Ls, being independently:

[0145] i) C3-12 cycloalkyl optionally substituted with 1-3 Rb;

[0146] ii) C6-12 aryl optionally substituted with 1-3 Rb;

[0147] iii) 4-12 membered heterocyclyl optionally substituted with 1-3 Rb;

[0148] iv) 5-12 membered heteroaryl optionally substituted with 1-3 Rb;

[0149] v) direct bond;

[0150] vi) C1-12 alkylene chain optionally substituted with 1-3 Rb;

[0151] vii) C1-12 alkenylene chain optionally substituted with 1-3 Rb; or

[0152] viii) -(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;

[0153] each Rais independently halo, or -O-Rc;

[0154] each Rbis independently oxo, imino, sulfoximino, halo, nitro, -CN, C1-6 alkyl, C2-6 alkenyl, C3-15 cycloalkyl, Ci-s 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(0)0-Rc, -N(RC)C(O)N(RC)( Rc), -N(RC)S(O)2(RC), -NRCS(0)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;

[0155] each Rcis independently hydrogen, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl (optionally substituted with 1 or 2 halo, C1-3 alkyl or C1-3 alkoxy), C6-12 aryl, 4-12 membered heterocyclyl optionally substituted with 1 or 2 C1-3 alkyl), 5-12 membered heteroaryl optionally substituted with 1 or 2 C1-3 alkyl or C1-3 haloalkyl) or C1-6 haloalkyl, wherein C1-6 alkyl is optionally substituted with one or more substituents selected from C1-3 alkoxy, hydroxy, C3-6 cycloalkyl (optionally further substituted with 1 or 2 halo, C1-3 alkoxy or C1-3 alkyl), CN, 5-12 membered heteroaryl (optionally further substituted with 1 or 2 halo or Ci-3 alkyl), C6-12 aryl and amino;

[0156] each Rdis independently halo, -CN, -O-Rc, C1-6 alkyl, C 6-12 aryl, C3-6 cycloalkyl 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, C1-6 alkoxy, C1-6 haloalkyl or halo;

[0157] W is -C(R8)- or-N-; Y is direct bond, C1-4 alkylene chain, -C(0)-, -C(0)0-, -O - -N(R8)-, -S--C(S)-, -C(S)-O-, -0-C(0)0-, -C(O)-N(R8)-, or -O-C(O)-N(R8)-;

[0158] B ring is Ce-12 aryl, 5-12 membered heteroaryl, or 4-12 membered heterocyclyl, each being optionally substituted with 1 to 3 RJ;

[0159] R8is hydrogen or C1-6 alkyl; and

[0160] each RJis independently halo, oxo, -CN, -O-Rc, C1-6 alkyl, or C1-6 haloalkyl.

[0161] In more specific embodiments, t is 1, and the compound of Formula (I) has the following structure:

[0162]

[0163] Formula (IA)

[0164] In other more specific embodiments, t is 0, and the compound of Formula (I) has the following structure:

[0165]

[0166] Formula (IB)

[0167] In other more specific embodiments, wherein t is 1, q is 1, R4aand R4btogether form a C1-3 alkylene chain, and the compound has one of the following structures:

[0168] (wherein v is 1, 2 or 3)

[0169]

[0170] (wherein v is 1, 2 or 3)

[0171] Formula (ID).

[0172] In other more specific embodiments, wherein t is 0, q is 1, and R4aand R3together form a methylene chain, and the compound has the following structure:

[0173]

[0174] Formula (IE).

[0175] In other more specific embodiments, wherein t is 0, and q is 0, and the compound has the following structure:

[0176]

[0177] Formula (IF).

[0178] In various embodiments, the each L1, L2, L3, L4, L5, L6, L7, or L8is independently:

[0179]

[0180]

[0181] ii) direct bond;

[0182] iii) Ci.6 alkylene chain optionally substituted with 1-3 Rb; or

[0183] iv) -C(O)-, -O- -(CH2)m-C(0)-N(Rc)-, -(CH2)m-C(O)- -(CH2)m-N(Rc)-, -C(0)-N(Rc)-(CH2)m- or -NH-(CH2)m-C(0)-, -(CH2)m-S(O)2NH- m being 0, 1, 2 or 3; wherein,

[0184] n is 0, 1, or 2;

[0185] Rbis halo, -O-Rc, -CN, Ci-6 alkyl, or Ci-6 haloalkyl; and

[0186] Rcis hydrogen, Ci-6 alkyl, Ci-6 alkoxy, C3-6 cycloalkyl, phenyl, or C1-6 haloalkyl, wherein C1-6 alkyl is optionally substituted with C1-3 alkoxy, hydroxy, C3-6 cycloalkyl, phenyl and amino.

[0187] In other more specific embodiments, Y is direct bond,-C(O)-N(R8)- (wherein Rg is hydrogen or C1-6 alkyl), or -NH-; and

[0188]

[0189] wherein p is 0, 1 or 2, RJis halo, -CN, -O-Rc, C1-6 alkyl, or C1-6 haloalkyl.

[0190] In certain more specific embodiments, R1is hydrogen and R2is hydrogen.

[0191] In certain other specific embodiments, R1is hydrogen and R2is halo (e.g., F or Cl) or C1-3 alkyl (e.g., methyl or ethyl).

[0192] In other more specific embodiments, R1is hydrogen, Lg, L7 and Ls are direct bonds, and the compound of Formula (I) has the following structure:

[0193]

[0194] Formula (IAA)

[0195] wherein,

[0196] R2is hydrogen, halo or C1.3 alkyl;

[0197] R3is halo, C3-6 cycloalkyl, Ce-i2 aryl, -O-Re(wherein Reis C3-6 cycloalkyl or Ci-6 alkyl optionally substituted with one or more Ci ^alkoxy or halo), Ci-6 alkyl optionally substituted with Ci ^alkoxy. Ce-i2 aryl, halo, or 5-12 membered heteroaryl optionally substituted with 1 or 2 Ci-6 alkyl or Ci-6 haloalkyl;

[0198] Li is -C(O)- or -C(O)-N(RC)-, wherein Rcis hydrogen, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, C3-6 cycloalkyl (optionally substituted with 1 or 2 halo, C1.3 alkyl or C1.3 alkoxy), 4-12 membered heterocyclyl (optionally substituted with 1 or 2 C1.3 alkyl), or 5-12 membered heteroaryl (optionally substituted with 1 or 2 C1.3 alkyl or C1.3 haloalkyl), wherein Ci-6 alkyl is optionally substituted with 1 or 2 substituents selected from the group consisting of C1.3 alkoxy, CN, 5-12 member heteroaryl (optionally further substituted with 1 or 2 halo or C1.3 alkyl), hydroxy, C3-6 cycloalkyl (optionally further substituted with 1 or 2 halo, C1.3 alkoxy or C1.3 alkyl), phenyl and amino;

[0199] L2is

[0200]

[0201] L3 is direct bond, -CH2-C(0)-, -(CH2)2-O-, or C1-4 alkylene chain optionally substituted with C1-3 alkyl or C2-4 alkylene chain optionally substituted with C1-3 alkyl;

[0202]

[0203] n is 0, 1 or 2, Rbis halo, C1-3 alkyl, or C’ualkoxy:

[0204] L5 is direct bond or -O-

[0205]

[0206] Y is direct bond, or -C(0)-N(Me)-; and

[0207] W is CH or N.

[0208] More specifically, in compounds of Formula (IAA), R3is -O-Re(wherein Reis C3-6 cycloalkyl or Ci.6 alkyl), Ci.6 alkyl optionally substituted with C1-3 alkoxy, 5-12 membered heteroaryl optionally substituted with 1 or 2 C1-6 alkyl or C1-6 haloalkyl;

[0209] Li is -C(O)- or -C(O)-N(RC)-, wherein Rcis hydrogen, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, or Ci.6 haloalkyl, wherein C1-6 alkyl is optionally substituted with 1 or 2 C1-3 alkoxy, hydroxy, C3-6 cycloalkyl, phenyl or amino;

[0210]

[0211] L3 is direct bond, -CH2-C(0)- or C1-2 alkylene chain optionally substituted with C1-3 alkyl;

[0212]

[0213] n is 0, 1 or 2, Rbis halo or C1.3 alkyl;

[0214] L5is direct bond or -O- O

[0215]

[0216] wherein p is 0, 1, or 2, RJis halo;

[0217] Y is direct bond, or -C(0)-N(Me)-; and

[0218] W is CH or N.

[0219] In further more specific embodiments, Y is direct bond, W is CH, and the compound of Formula (IAA) are represented by the following structure:

[0220]

[0221] Formula (IAA1)

[0222] In further more specific embodiments, Li is -C(O)- or -C(O)-N(RC)- (Rcis hydrogen, Ci-6 alkyl, Ci-6 alkoxy, C3-6 cycloalkyl, or Ci-6 haloalkyl, wherein Ci-6 alkyl is optionally substituted with 1 or 2 C1.3 alkoxy, hydroxy, C3-6 cycloalkyl, phenyl or amino), and

[0223]

[0224] In further more specific embodiments, R3is -O-Re(wherein Reis methyl, ethyl, propyl, cyclopropyl or cyclobutyl), -CH₂OCH₃, thiazol-4yl, thiazol-5yl, 1 -methyl- lH-pyrazol-5yl, 1 -ethyl- 1H-pyrazol-5yl, l,3-dimethyl-lH-pyrazol-5-yl, l,4-dimethyl-lH-pyrazol-5-yl;

[0225] Li is C(O), or -C(O)-N(RC)-, wherein Rcis hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, -OCH3, -CH2CF3, -CFFCFF-N CIfi^, -CH2CH2-OCH3, -CFF-cyclopropyl. benzyl, or l,3-dihydroxypropan-2yl; and

[0226] O

[0227]

[0228] wherein p is 0, 1, or 2, RJis F. In other more specific embodiments, Li is -C(O)- or -C(O)-N(RC)- (Rcis hydrogen, Ci-6 alkyl, Ci-6 alkoxy, C3.6 cycloalkyl, or Ci-6 haloalkyl, wherein Ci-6 alkyl is optionally substituted with 1 or 2 Ci-3alkoxy, hydroxy, C3.6 cycloalkyl, phenyl or amino),

[0229] L3is a direct bond, and

[0230] -L2-L3-L4- has the following structures:

[0231]

[0232] In yet more specific embodiments, R3is -O-Re(wherein Reis methyl, ethyl, propyl, cyclopropyl or cyclobutyl), thiazol-4yl, thiazol-5yl, 1 -methyl- lH-pyrazol-5yl, 1 -ethyl- lH-pyrazol-5yl, 1,3-dimethyl-lH-pyrazol-5-yl, l,4-dimethyl-lH-pyrazol-5-yl, l-(oxan-4-yl)-lH-pyrazol-5-yl, l-methyl-3-(trifluoromethyl)-lH-pyrazol-5-yl, or 2 -methyl -2H-indazol-3-yl;

[0233] Li is C(O), or -C(O)-N(RC)-, wherein Rcis hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, -CH2CF3, -CH2CH2-N(CH3)2, -CH2CH2-OCH3, or benzyl; and

[0234]

[0235] B is, wherein p is 0, 1, or 2, RJis halo.

[0236] In further more specific embodiments, R3is pyrazol-5yl (optionally substituted with 1 or 2 methyl, trifluoromethyl, oxan-4-yl), thiazolyl, or indazolyl (optionally substituted with 1 or 2 methyl), -CH2OCH3, or O-cyclobutyl.

[0237] According to other more specific embodiments, in compounds of Formula (IAA1): R2is hydrogen, F, Cl or methyl; R3is F, cyclopropyl, phenyl, benzyl, Ci-3haloalkyl, Ci-6 alkyl (optionally substituted 1 or 2 Ci-3alkoxy), or -O-Re(wherein Reis cyclopropyl, cyclobutyl, or Ci- 6 alkyl optionally substituted with one or more Ci.3alkoxy or halo); Li is -C(O)-N(RC)-, wherein Rcis Ci-6 alkyl, Ci-6 alkoxy, cyclopropyl (optionally substituted with methyl or methoxy), cyclobutyl (optionally substituted with 1 or 2 methyl or F), azetidinyl (optionally substituted with 1 or 2 methyl), pyrazolyl (optionally substituted with difluoromethyl), phenyl, or Ci-6 haloalkyl, wherein Ci-6 alkyl is optionally substituted with 1 or 2 Ci-3alkoxy, CN, oxazolyl, thiazolyl (optionally substituted with methyl), pyrazinyl, pyrimidinyl, 1 -methyl- 1,2, 3 -triazolyl, pyrazolyl (optionally substituted with 1 or 2 Ci-3alkyl), oxadiazolyl (optionally substituted with methyl), cyclopropyl (optionally substituted with C1-3 alkoxy), cyclobutyl, or 3,3 -difluorocyclobutyl);

[0238]

[0239] According to other more specific embodiment, in compounds of Formula (IAA1):

[0240] R2is hydrogen or F; R3is C1-6 alkyl (optionally substituted 1 or 2 C1-3 alkoxy), or -O-Re(wherein Reis C1-6 alkyl optionally substituted with one or more C1-3 alkoxy or halo); Li is -C(O)-; and

[0241]

[0242] In other various embodiments, the compounds of Formula (IAA) may be represented by the structures of Formula (IAA2) or Formula (IAA3): Formula (IAA2)

[0243]

[0244] Formula (IAA3)

[0245] wherein,

[0246] R3is -O-Re(wherein Reis C3-6 cycloalkyl or Ci-6 alkyl), C1-6 alkyl optionally substituted with C1-3 alkoxy, or 5-12 membered heteroaryl optionally substituted with 1 or 2 Ci-6 alkyl or Ci-6 haloalkyl;

[0247] Li is C(O), or -C(O)-N(RC)-, wherein Rcis hydrogen, Ci-6 alkyl, Ci-6 alkoxy, C3-6 cycloalkyl, or Ci-6 haloalkyl, wherein Ci-6 alkyl is optionally substituted with 1 or 2 C1.3 alkoxy, hydroxy, C3-6 cycloalkyl, phenyl or amino;

[0248]

[0249]

[0250] p is 0, 1, or 2; and

[0251] RJis halo.

[0252] In various more specific embodiments, Rcis Ci-6 alkoxy, C3-6 cycloalkyl, C1-6 haloalkyl, or C1-6 alkyl substituted with 1 or 2 C1-3 alkoxy, hydroxy, C3-6 cycloalkyl, phenyl or amino.

[0253] In various specific embodiments, R3is ORe, and Reis methyl, ethyl, or cyclopropyl.

[0254] In various more specific embodiments, R3is pyrazol-5yl (optionally substituted with 1 or 2 methyl, trifluoromethyl, oxan-4-yl), thiazolyl, or indazolyl (optionally substituted with 1 or 2 methyl), -CH₂OCH₃, or O-cyclobutyl.

[0255] In other various embodiments, R1is hydrogen, R2is hydrogen, L6, L7 and L8 are direct bonds, and W is N, the compound of Formula (IAA) may be represented by the structure of Formula (IAA4):

[0256]

[0257] Formula (IAA4)

[0258] wherein,

[0259] Reis Ci-6 alkyl;

[0260] Li is-C(O)-N(Rc)-, wherein Rcis hydrogen, or Ci-6 alkyl;

[0261]

[0262] In other various embodiments, R1is hydrogen, R2is hydrogen, Y is -C(O)-N(CH3)-, L6, L7 and L8 are direct bonds, the compound of Formula (IAA) may be represented by the structure of Formula (IAA5):

[0263]

[0264] Formula (IAA5)

[0265] wherein,

[0266] Reis Ci-6 alkyl;

[0267] Li is-C(O)-N(Rc)-, wherein Rcis hydrogen, or Ci-6 alkyl;

[0268]

[0269] In yet other embodiments, the compound of Formula (IB) is represented by the following structure:

[0270]

[0271] Formula (IB 1)

[0272] wherein,

[0273] Reis Ci-6 alkyl;

[0274] Li is-C(O)-N(Rc)-, wherein Rcis hydrogen, or Ci-6 alkyl;

[0275]

[0276] In more specific embodiments, compounds of Formula (II) are represented Formula (IB2):

[0277]

[0278] Formula (IB2)

[0279] wherein,

[0280] R2is hydrogen or halo;

[0281] R3is hydrogen, halo, Ce-12 aryl, Ci-6 alkyl optionally substituted with Ci-salkoxy, or -O-Re(wherein Reis C3-6 cycloalkyl, or Ci-6 alkyl optionally substituted with one or more C1-3 alkoxy or halo);

[0282] R4ais hydrogen, Ci-6 alkyl or Ci-6 alkoxy;

[0283] Li is -C(O)-, -C(O)-N(RC)- or -CH2-C(0)-N(RC)-, wherein Rcis hydrogen, Ci-6 haloalkyl, C3-6 cycloalkyl (optionally substituted with 1 or 2 halo, C1-3 alkyl or C1-3 alkoxy), or Ci-6 alkyl (optionally substituted with 1 or 2 C1-3 alkoxy or 5-12 membered heteroaryl (optionally further substituted with 1 or 2 halo or Ci -3 alkyl));

[0284]

[0285] L3 is direct bond, C1.4 alkylene chain optionally substituted with C1-3 alkyl or C2-4 alkylene chain optionally substituted with C1-3 alkyl;

[0286]

[0287] n is 0, 1 or 2, Rbis halo, C1.3 alkyl, or hydroxy;

[0288] L5is direct bond or -O-

[0289] B

[0290]

[0291] is wherein p is 0, 1, or 2, RJis halo. More specifically, R2is hydrogen or F; R3is F, C1-3 alkyl, phenyl, or -O-Re(wherein Reis cyclopropyl or C1-3 alkyl); R4ais hydrogen, or methoxy; Li is -C(O)- or -C(O)-N(RC)-, wherein Rcis hydrogen, C1-6 alkyl, C1-3 alkyl (optionally substituted with methoxy, oxazolyl, thiazolyl, pyrazinyl, pyrimidinyl, 1 -methyl- 1,2, 3 -triazolyl, pyrazolyl (optionally substituted with 1 or 2 C1-3 alkyl), oxadiazolyl (optionally substituted with methyl), or cyclopropyl (optionally substituted with 1 or 2 F, methyl, or

[0292]

[0293] In more specific embodiments, compounds of Formula (II) are represented Formula (IC1) or (IC2):

[0294]

[0295]

[0296] wherein, R2is hydrogen or halo; R3is hydrogen or C1-3 alkyl; Li is-C(O)-N(Rc)-, wherein Rcis hydrogen, C1-6 haloalkyl, C1-6 alkoxy, C3-6 cycloalkyl or C1-6 alkyl optionally substituted with C3-6 cycloalkyl, 5-7 member heteroaryl (preferably thiazolyl), or C1-6 alkoxy;

[0297]

[0298] wherein, R2is hydrogen or halo; R3is hydrogen or C1-3 alkyl; Li is-C(O)-;

[0299] L

[0300]

[0301] ’ is; and B is, wherein p is 0, 1, or 2, RJis halo. In more specific embodiments, compounds of Formula (II) are represented Formula (IE1):

[0302] O

[0303]

[0304] Formula (IE1)

[0305] wherein, R2is hydrogen or halo; Li is-C(O)-N(Rc)-, wherein Rcis hydrogen or C1-6 alkyl;

[0306] L

[0307]

[0308] ’ is, wherein p is 0, 1, or 2, RJis halo.

[0309] In more specific embodiments, compounds of Formula (II) are represented Formula (IF1)

[0310]

[0311] wherein, R2is hydrogen or halo; R3is hydrogen, Ci-6 alkyl, or -ORe(wherein R3is Ci-6 alkyl); Li is- C(O)-N(RC)-, wherein Rcis hydrogen or Ci-6 alkyl;

[0312]

[0313] L’ is; and B is, wherein p is 0, 1, or 2, RJis halo.

[0314] SMARCA2 Binders

[0315] Each bifunctional compound of Formulae (I) and (IA) comprises a selective SMARCA2 binder moiety, depicted as Formula (A):

[0316]

[0317] Formula (A)

[0318] wherein,

[0319] In more specific embodiments, R1and R2are each hydrogen.

[0320] In other more specific embodiments, R1is hydrogen, R2is halo (e.g., F or Cl) or CI-3 alkyl (e.g., methyl or ethyl).

[0321] In specific embodiments, R1is hydrogen, R2is hydrogen, F, Cl or methyl, R3is ORe(Reis defined as herein), and the SMARCA2 binder moiety has one of the following structures:

[0322] 0Re

[0323]

[0324] In other specific embodiments, R1is hydrogen, R2is hydrogen, R3is heteroaryl (e.g., pyrazol-5yl (optionally substituted with 1 or 2 methyl, trifluoromethyl, oxan-4-yl), thiazolyl, or indazolyl (optionally substituted with 1 or 2 methyl)), or alkyl optionally substituted with alkoxy. Ligase Harness Moieties (LHM)

[0325] 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.

[0326] The LHM moiety of Formula (I) typically comprises a glutarimide or dihydrouracil moiety coupled to a ring structure, as represented by Formula (B):

[0327]

[0328] Formula (B)

[0329] wherein,

[0330] W is -C(R8)- or-N-;

[0331] Y is direct bond, Ci-4 alkylene chain, -C(O)-, -C(O)O-, -O - -N(R8)-, -S--C(S)-, -C(S)-O-, -O-C(O)O-, -C(O)-N(R8)-, or -O-C(O)-N(R8)-;

[0332] B ring is Ce-i2 aryl, 5-12 membered heteroaryl, or 4-12 membered heterocyclyl, each being optionally substituted with 1 to 3 RJ;

[0333] R8is hydrogen or Ci-6 alkyl; and

[0334] each RJis independently halo, oxo, -CN, -O-Rc, Ci-6 alkyl, or Ci-6 haloalkyl.

[0335] In more specific embodiments, W is -CH- and Y is direct bond.

[0336] In more specific embodiments, B ring is:

[0337]

[0338] wherein p is 0, 1 or 2, RJis halo.

[0339] In other embodiments, W is -N-, Y is direct bond; and B ring is

[0340]

[0341] , wherein p is 0, 1 or 2, RJis halo.

[0342] In more specific embodiments, the LHM moiety is:

[0343]

[0344] Linker

[0345] Each bifunctional compound of Formula (I), Formula (II), or substructures represented by any one of Formulae (IA), (IB), (IC), (ID), (IE), (IF), (IAA), (IAA1), (IAA2), (IAA3), (IAA4), (IAA5), (IB1), (IB2), (IC1), (IC2), (ID1), (IE1), or (IF 1) 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 Formula (I) and its substructures.

[0346] 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 Li, L2, L3, L4, L5, Lg, L7, Ls are each independently:

[0347] i) C3-12 cycloalkyl optionally substituted with 1-3 Rb;

[0348] ii) C6-12 aryl optionally substituted with 1-3 Rb;

[0349] iii) 4-12 membered heterocyclyl optionally substituted with 1-3 Rb;

[0350] iv) 5-12 membered heteroaryl optionally substituted with 1-3 Rb;

[0351] v) direct bond;

[0352] vi) C1-12 alkylene chain optionally substituted with 1-3 Rb;

[0353] (vii) C1-12 alkenylene chain optionally substituted with 1-3 Rb; or

[0354] viii) -(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;

[0355] wherein Rb, Rcand Rdare as defined herein.

[0356] 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(0)-NH-, the manner in which it is connected to the remainder of the molecule may be either direction: i.e., -C(0)-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.

[0357] 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.

[0358] 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.

[0359] In various specific embodiments, the linker (L) of compounds of Formulae (I), (II), (IA), (IB), (IC), (ID), (IE), (IF), (IAA), (IAA1), (IAA2), (IAA3), (IAA4), (IAA5), (IB1), (IB2), (IC1), (IC2), (ID1), (IE1), or (IF 1) is presented by -L1-L2-L3-L4-L5-L6-L7-L8-, each L1, L2, L3, L4, L5, L6, L7, or L8, being independently:

[0360] i) a bivalent ring moiety selected from the group consisting of:

[0361]

[0362]

[0363] ii) direct bond;

[0364] iii) Ci.6 alkylene chain optionally substituted with 1-3 Rb; or

[0365] iv) -C(O)-, -O- -(CH2)m-C(0)-N(Rc)-, -(CH2)m-C(O)- -(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,

[0366] n is 0, 1, or 2;

[0367] Rbis halo, -O-Rc, -CN, Ci-6 alkyl, or Ci-6 haloalkyl; and

[0368] Rcis hydrogen, Ci-6 alkyl, Ci-6 alkoxy, C3-6 cycloalkyl, phenyl, or C1-6 haloalkyl, wherein C1-6 alkyl is optionally substituted with C1-3 alkoxy, hydroxy, C3-6 cycloalkyl, phenyl and amino.

[0369] In specific embodiments, Lg, L7, or Ls are each direct bond.

[0370] In more specific embodiments, Li is -C(O)- or -C(O)-N(RC)- (Rcis hydrogen, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, or C1-6 haloalkyl, wherein C1-6 alkyl is optionally substituted with 1 or 2 C1-3 alkoxy, hydroxy, C3-6 cycloalkyl, phenyl or amino),

[0371] L2is

[0372]

[0373] L3 is direct bond, -CH2-C(O)- or C1-2 alkylene chain optionally substituted with C1-3 alkyl;

[0374]

[0375] n is 0, 1 or 2, Rbis halo or C1-3 alkyl;

[0376] L5 is direct bond or -O- In further more specific embodiments, -L2-L3-L4- has the following structures:

[0377]

[0378] In yet other more specific embodiments, Li is -C(0)- or -C(O)-N(RC)- (Rcis hydrogen, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, or C1-6 haloalkyl, wherein C1-6 alkyl is optionally substituted with 1 or 2 Ci -3 alkoxy, hydroxy, C3-6 cycloalkyl, phenyl or amino),

[0379] L3 is a direct bond, and

[0380] -L2-L3-L4- has the following structures:

[0381]

[0382]

[0383] In other more specific embodiments, Li is -C(O)-N(RC)-, wherein Rcis Ci-6 alkyl, Ci-6 alkoxy, cyclopropyl (optionally substituted with methyl or methoxy), cyclobutyl (optionally substituted with 1 or 2 methyl or F), azetidinyl (optionally substituted with 1 or 2 methyl), pyrazolyl (optionally substituted with difluoromethyl), phenyl, or Ci-6 haloalkyl, wherein Ci-6 alkyl is optionally substituted with 1 or 2 Ci.

[0384] 3 alkoxy, CN, oxazolyl, thiazolyl (optionally substituted with methyl), pyrazinyl, pyrimidinyl, 1 -methyl -1,2,3-triazolyl, pyrazolyl (optionally substituted with 1 or 2 C1.3 alkyl), oxadiazolyl (optionally substituted with methyl), cyclopropyl (optionally substituted with C1.3 alkoxy), cyclobutyl, or 3,3-difluorocyclobutyl);

[0385]

[0386]

[0387] Definitions

[0388] 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.

[0389] A dash

[0390]

[0391] 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.

[0392] The prefix “Cu-v” indicates that the following group has from u to v carbon atoms. For example, “Ci-6 alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms.

[0393] 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.

[0394] “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., Ci-s 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, secbutyl, 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 (Ci-s alkylene), or 1 to 3 carbon atoms (C1-3 alkylene) e.g., methylene, ethylene, propylene, w-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.

[0395] “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).

[0396] “Alkenylene” and “alkenylene chain” refer to an 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, w-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.

[0397] “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.

[0398] “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.

[0399] “Alkoxy” refers to the group “alkyl-O-”. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, / c / 7-butoxy. sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0400] “Haloalkoxy” refers to an alkoxy group as defined above, wherein one or more hydrogen atoms are replaced by a halogen.

[0401] “Alkylthio” refers to the group “alkyl-S-”.

[0402] “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.

[0403] “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., Ce-i5 aryl), or 6 to 10 carbon ring atoms (i.e., Ce-io 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.

[0404] “Cyano” refers to the group -CN.

[0405] “Keto” or “oxo” refers to a group =0.

[0406] “Carbamoyl” refers to both an “O-carbamoyl” group which refers to the group -0-C(0)NRyRzand an “N-carbamoyl” group which refers to the group -NRyC(0)0Rz, wherein Ryand Rzare independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each of which may be optionally substituted.

[0407] “Carboxyl” or “carboxylic acid” refers to -C(0)0H.

[0408] “Ester” refers to both -0C(0)R and -C(0)0R, wherein R is a substituent; each of which may be optionally substituted, as defined herein.

[0409] “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-l-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).

[0410] “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.

[0411] “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.

[0412] “Halogen” or “halo” includes fluoro, chloro, bromo, and iodo.

[0413] “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).

[0414] “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(0)-, -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.

[0415] “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, imidazoyl, thiazolyl, oxazolyl, triazolyl, pyrazinyl, isoxazolyl 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[l,5-a]pyridinyl, and imidazo[l,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 any single ring atom (e.g., as a substituent) or by any two ring atoms (e.g., as a linker), provided that the valence is satisfied.

[0416] “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-l-azaspiro[3.3]heptanyl. Examples of the fused-heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 1-oxo-l, 2,3,4-tetrahydroisoquinolinyl, l-oxo-l,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.

[0417] 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).

[0418] “Fused” refers to a ring which is joint to an adjacent ring and share two adjacent ring atoms that form a covalent bond.

[0419] “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.

[0420] “Spiro” refers to a ring substituent which is joined by two bonds at the same carbon atom.

[0421] 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.

[0422] “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.

[0423] “Nitro” refers to the group -NO2.

[0424] “Imino” refers to a group that contains a C=N double bond, such as C=N-Ry, or =N-C(0)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.

[0425] “Sulfonyl” refers to the group -S(O)2R, where R is a substituent, or a defined group.

[0426] “Alkylsulfonyl” refers to the group -S(O)2R, where R is a substituent, or a defined group.

[0427] “Alkylsulfinyl” refers to the group -S(O)R, where R is a substituent, or a defined group.

[0428] “Thiocyanate” -SCN.

[0429] “Thiol” refers to the group -SR, where R is a substituent, or a defined group.

[0430] “Thioxo” or “thione” refer to the group (=S) or (S).

[0431] 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.

[0432] 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.

[0433] 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(Ci-4 alkyl), (C3-10 cycloalkyl), 0-(C3-io 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.

[0434] 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 ( / ?) and (. S') enantiomers) and optically pure forms. Optically active (+) and (-), ( / ?)- 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.

[0435] “&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).

[0436]

[0437] if presents, denotes a second set of isomers.

[0438] 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 pharmaceutically acceptable salts, hydrates, or solvates of the compounds described herein.

[0439] “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.

[0440] 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, alkylsulfmyl, 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.

[0441] 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.

[0442] 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.

[0443] Targeted SMARCA2 Degradation

[0444] The compounds of the present disclosure are demonstrated by cell-based profiling to selectively degrade SMARCA2 while sparing SMARCA4.

[0445] Additional biological activities, including selectivity data of compounds of Formula (I) are summarized in Table 1 herein.

[0446] Pharmaceutical Composition and Use of the Bifunctional Compounds of Formula (I)

[0447] The bifunctional compounds of Formula (I) or Formula (II) are demonstrated to selectively degrade SMARCA2 and are therefore particularly useful for treating SMARCA4-deficient cancers.

[0448] Various embodiments provide pharmaceutical compositions of a compound of Formula (I), or any one of the substructures or specific compounds of Examples 1-263, 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) or Formula (II), any one of the substructures or compounds of Examples 1-263.

[0449] 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.

[0450] In some embodiments, a compound of Formula (I), or any one of the substructures or a compound of Examples 1-263 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.

[0451] Construction of Compounds of Formula (I)

[0452] 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).

[0453] The following schemes demonstrate the general approaches of preparing building blocks. Specific examples (Examples 1-263) were synthesized and characterized by their respective physiochemical properties according to the general schemes described herein.

[0454] INTERMEDIATES INTERMEDIATE 1

[0455] LITHIUM 4-METHOXY-l-(6-(2-(METHOXYMETHOXY)PHENYL)PYRID AZIN-4- YL)PIPERIDINE-4- CARBOXYLATE

[0456] <1

[0457] otL d c.

[0458]

[0459] Step 1: Synthesis of l-(tert-butyl) 4-methyl 4-methoxypiperidine-l,4-dicarboxylate

[0460] O JI, /

[0461]

[0462] Boc

[0463] A flask was charged with 4.63 g of NaH (60% dispersion in oil) and the solid was washed with hexanes 2x. For washing procedure, add hexanes and swirl flask. Let flask sit for 2 mins and then decant hexanes using syringe 2x. Once complete, DMF (30 mL) was added to the flask under N2 and the mixture was cooled to 0 °C in an ice bath. 1 -tert-butyl 4-methyl 4-hydroxypiperidine-l,4-dicarboxylate (3.00 g, 11.5 mmol) was dissolved in 15 mL DMF and the solution was added slowly to the solution of NaH in DMF. Once complete, the reaction was allowed to stir for 30 mins. Methyl iodide (7.20 mL, 16.4 g, 115 mmol) was then added over 10 mins slowly to the reaction mixture at 0-5 °C. Slight bubbling was observed. Once complete, the reaction was stirred in the melted ice bath for 2 hours exactly. TLC of the reaction mixture (3:7 EA: Hex, ninhydrin stain) indicates all SM is consumed and clear conversion to product. The reaction was chilled in a new ice bath at °C. To prevent hydrolysis of ester during quench, 3 mL of MeOH was slowly added to the reaction mixture and H2gas evolved. Then, sat. NH4CI was added slowly. The mixture was transferred to a separatory funnel and extracted 3x with EtOAc. The organic phases were combined, dried and concentrated in vacuo. The residue was purified via chromatography (EA: Hex gradient) to yield the desired product (2.82 g, 89% yield) as a clear oil. LCMS: C13H23NO5 requires: 273.1, found: m / z = 274.4 [M+H]+

[0464] Step 2: Synthesis of methyl 4-methoxypiperidine-4-carboxylate hydrochloride

[0465]

[0466] HHCI 1 -tert-butyl 4-methyl 4-methoxypiperidine-l,4-dicarboxylate (3.88 g, 14.1 mmol) was dissolved in 4M HC1 in dioxane (25.00 mL) and stirred at RT. After 1 hr, the reaction was checked by LCMS and solid has precipitated out. Once complete, the reaction is concentrated in vacuo to give a white powder. The resulting solid is dried further on a high vacuum system to yield the product (2.88 g, 96% yield) as a while solid. LCMS: C8H15NO3requires: 173.1, found: m / z = 174.3 [M+H]+

[0467] Step 3: Synthesis of methyl l-(6-chloropyridazin-4-yl)-4-methoxypiperidine-4-carboxylate

[0468]

[0469] Methyl 4-methoxypiperidine-4-carboxylate hydrochloride (2.88 g, 13.7 mmol) and 3,5-dichloropyridazine (2.05 g, 13.7 mmol) were dissolved in DMSO (30 mL) under argon atmosphere. N, N-diisopropylethylamine (12.0 mL, 8.88 g, 68.6 mmol) was then added and the resulting solution was stirred at 100 °C for 12 hours. The reaction was monitored via LCMS. Once complete, the reaction was concentrated in vacuo to remove excess DIPEA and then quenched with H2O and extracted with EtOAc 3 times. The organic phases were combined, dried and concentrated in vacuo. The residue was purified via chromatography (EA:hexane, gradient) to produce a red oil. Diethyl ether (10 mL) was added to the red oil and a pink solid was precipitated out. The solid was collected and further dried to yield the product (3.21 g, 81% yield) as a pink solid. LCMS: C12H16CIN3O3 requires: 285.0, found: m / z = 285.3 [M+H]+Step 4: Synthesis of methyl 4-methoxy-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperidine-4-carboxylate

[0470]

[0471] A flask was charged with methyl l-(6-chloropyridazin-4-yl)-4-methoxypiperidine-4-carboxylate (850 mg, 2.97 mmol), potassium carbonate (1.23 g, 8.92 mmol), and 2-(methoxymethoxy)phenylboronic acid (812 mg, 4.46 mmol) under N2 atmosphere. 1,4-dioxane (12.00 mL) and water (3.00 mL) were sequentially added to the flask. The resulting solution was degassed with an Argon balloon for 15 mins and then tetrakis(triphenylphosphine)palladium(0) (343 mg, 0.297 mmol) was added in one portion. The flask was sealed and the resulting mixture was stirred at 100 °C for 12 h. Upon completion, the flask was diluted in EtOAc and sat. NH4CI was added. The mixture was extracted 3x with EtOAc and the organic phases were concentrated in vacuo. The residue was purified via chromatography (EA:hexane, gradient) to give the desired product (0.512 g, 44% yield) as an orange oil. LCMS: C20H25N3O5 requires: 387.1, found: m / z = 387.4 [M+H]+

[0472] Step 5: Synthesis of title compound

[0473] methyl 4-methoxy-l-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}piperidine-4-carboxylate (512 mg, 1.32 mmol) was dissolved in 6 mL of a 1: 1 THF / H2O mixture and lithium hydroxide monohydrate (55.4 mg, 1.32 mmol) was added in one portion. The reaction was stirred at RT until complete by LCMS. Once complete, the reaction mixture is concentrated in vacuo and lyophilized to afford the desired lithium salt (510 mg, 101% yield) as a yellow powder. LCMS: C19H22N3O5 requires: 372.1, found: m / z = 373.1 [M+H]+

[0474] INTERMEDIATE 2

[0475] LITHIUM l-(6-(5-FLUORO-2-OXIDOPHENYL)PYRID AZIN-4- YL)-4-METHOXYPIPERIDINE-4- CARBOXYLATE

[0476] OLi

[0477]

[0478] Step 1: Synthesis of methyl l-(6-(5-fluoro-2-hydroxyphenyl)pyridazin-4-yl)-4-methoxypiperidine-4-carboxylate

[0479]

[0480] A flask was charged with methyl l-(6-chloropyridazin-4-yl)-4-methoxypiperidine-4-carboxylate (500 mg, 1.74 mmol), potassium carbonate (725 mg, 5.24 mmol), and 5-fluoro-2-hydroxyphenylboronic acid (409 mg, 2.62 mmol). 1,4-dioxane (9.00 mL) and water (2.00 mL) were sequentially added to the flask. The resulting solution was degassed with an Argon balloon for 5 mins and then tetrakis(triphenylphosphine)palladium(0) (202 mg, 0.175 mmol) was added in one portion. The flask was sealed and the resulting mixture was stirred at 100°C for 18 h. Upon completion, the flask was diluted in EtOAc and sat. NH4CI was added. The mixture was extracted 3x with EtOAc and the organic phases were concentrated in vacuo. The residue was purified via chromatography (EA:hexane, gradient) to give the desired product (0.503 g, 79% yield) as an orange oil. LCMS: C18H20FN3O4 requires: 361.1, found: m / z = 362.2 [M+H]+

[0481] Step 2: Synthesis of the title compound

[0482] methyl l-[6-(5-fluoro-2-hydroxyphenyl)pyridazin-4-yl]-4-methoxypiperidine-4-carboxylate (210 mg, 0.581 mmol) was dissolved in THF: H2O (5 mL:5 mL) and lithium hydroxide monohydrate (48.7 mg, 1.16 mmol) was added in one portion. The reaction was stirred at RT until complete by LCMS. Once complete, the reaction mixture was concentrated in vacuo and lyophilized to afford the desired di-lithium salt (241 mg, 115%). LCMS: C17H16FN3O4 requires: 345.1, found: m / z = 346.1 [M+H]+ INTERMEDIATE 3

[0483] LITHIUM l-(6-(3-FLUORO-2-OXIDOPHENYL)PYRID AZIN-4- YL)-4-METHOXYPIPERIDINE-4- CARBOXYLATE

[0484]

[0485] A flask was charged with methyl l-(6-chloropyridazin-4-yl)-4-methoxypiperidine-4-carboxylate (500 mg, 1.74 mmol), potassium carbonate (725 mg, 5.24 mmol), and 3-fluoro-2-hydroxyphenylboronic acid (409 mg, 2.62 mmol). 1,4-dioxane (9.00 mL) and water (2.00 mL) were sequentially added to the flask. The resulting solution was degassed with an Argon balloon for 5 mins and then tetrakis(triphenylphosphine)palladium(0) (202 mg, 0.175 mmol) was added in one portion. The flask was sealed and the resulting mixture was stirred at 100°C for 18 h. Upon completion, the flask was diluted in EtOAc and sat. NH4CI was added. The mixture was extracted 3x with EtOAc and the organic phases were concentrated in vacuo. The residue was purified via chromatography (EA:hexane, gradient) to give the desired product (0.305 g, 48% yield) as an orange oil. LCMS: C18H20FN3O4 requires: 361.1, found: m / z = 362.2 [M+H]+

[0486] Step 2: Synthesis of the title compound

[0487] Methyl l-[6-(3-fluoro-2-hydroxyphenyl)pyridazin-4-yl]-4-methoxypiperidine-4-carboxylate (287 mg, 0.794 mmol) was dissolved in THF:H2O (5 mL:5 mL) and lithium hydroxide monohydrate (66.6 mg, 1.58 mmol) was added in one portion. The reaction was stirred at RT until complete by LCMS. Once complete, the reaction mixture was concentrated in vacuo and lyophilized to afford the desired di-lithium salt (312 mg, 109%). LCMS: C17H16FN3O4requires: 345.1, found: m / z = 346.1 [M+H]+

[0488] INTERMEDIATE 4

[0489] LITHIUM 4-ETHOXY-l-(6-(2-OXIDOPHENYL)PYRID AZIN-4- YL)PIPERIDINE-4- CARBOXYLATE

[0490]

[0491] Step 1: Synthesis of l-(tert-butyl) 4-methyl 4-ethoxypiperidine-l,4-dicarboxylate

[0492] O

[0493]

[0494] Boc

[0495] A flask was charged with 1.55g of NaH (60% dispersion in oil) and the solid was washed with hexanes 2x. For washing procedure, add hexanes and swirl flask. Let flask sit for 2 mins and then decant hexanes using syringe 2x. Once complete, DMF (5 mL) was added to the flask under N2 and the mixture was cooled to 0 °C in an ice bath. 1 -tert-butyl 4-methyl 4-hydroxypiperidine-l,4-dicarboxylate (1.00 g, 3.85 mmol) was dissolved in 10 mL DMF and the solution was added slowly to the solution of NaH in DMF. Once complete, the reaction was allowed to stir for 30 mins. Ethyl iodide (3.10 mL, 6.01 g, 38.5 mmol) was then added over 10 mins slowly to the reaction mixture at 0-5 °C. Slight bubbling was observed. Once complete, the reaction was stirred in the melted ice bath for 2 hours exactly. TLC of the reaction mixture (3:7 EA: Hex, ninhydrin stain) indicates all SM is consumed and clear conversion to product. The reaction was chilled in a new ice bath at 0 °C. To prevent hydrolysis of ester during quench, 3 mL of MeOH was slowly added to the reaction mixture and H2 gas evolved. Then, sat. NH₄Cl was added slowly. The mixture was transferred to a separatory funnel and extracted 3x with EtOAc. The organic phases were combined, dried and concentrated in vacuo. The residue was purified via chromatography (EA: Hex gradient) to yield the desired product (475 mg, 42.8% yield) as a clear oil. LCMS: C14H25NO5 requires: 287.1, found: m / z = 288.2 [M+H]+

[0496] Step 2: Synthesis of methyl 4-ethoxypiperidine-4-carboxylate hydrochloride

[0497] O

[0498]

[0499] HHCI

[0500] 1-tert-butyl 4-methyl 4-ethoxypiperidine-l,4-dicarboxylate (475 mg, 1.65 mmol) was dissolved in 4M HCI in dioxane (4.00 mL) and stirred at RT. After 1 hr, the reaction was checked by LCMS and solid has precipitated out. Once complete, the reaction is concentrated in vacuo to give a white powder. The resulting solid is dried further on a high vacuum system to yield the product (350 mg, 94.6% yield) as a while solid. LCMS: C9H17NO3 requires: 223.1, found: m / z = 224.1 [M+H]+

[0501] Step 3: Synthesis of methyl l-(6-chloropyridazin-4-yl)-4-ethoxypiperidine-4-carboxylate

[0502]

[0503] Methyl 4-ethoxypiperidine-4-carboxylate hydrochloride (342 mg, 1.52 mmol) and 3,5-dichloropyridazine (227 mg, 1.52 mmol) were dissolved in DMSO (3.0 mL) under argon atmosphere. N, N-diisopropylethylamine (DIPEA) (987 mg, 7.64 mmol) was then added and the resulting solution was stirred at 100 C for 12 hours. The reaction was monitored via LCMS. Once complete, the reaction was concentrated in vacuo to remove excess DIPEA and then quenched with H2O and extracted with EtOAc 3 times. The organic phases were combined, dried and concentrated in vacuo. The residue was purified via chromatography (EA:hexane, gradient) to produce a red oil. Diethyl ether (10 mL) was added to the red oil and a pink solid was precipitated out. The solid was collected and further dried to yield the product (423 mg, 92.3% yield) as a pink solid. LCMS: C13H18CIN3O3 requires: 299.0, found: m / z = 300.1 [M+H]+Step 4: Synthesis of methyl 4-ethoxy-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)piperidine-4-carboxylate

[0504]

[0505] A flask was charged with methyl l-(6-chloropyridazin-4-yl)-4-ethoxypiperidine-4-carboxylate (423 mg, 1.41 mmol), potassium carbonate (585 mg, 4.23 mmol), and 2-hydroxyphenylboronic acid (291 mg, 2.11 mmol). 1,4-dioxane (5.60 mL) and water ( 1.20 mL) were sequentially added to the flask. The resulting solution was degassed with an argon balloon for 5 mins and then tetrakis(triphenylphosphine)palladium(0) (163 mg, 0.141 mmol) was added in one portion. The flask was sealed and the resulting mixture was stirred at 100°C for 18 h. Upon completion, the flask was diluted in EtOAc and sat. NH4CI was added. The mixture was extracted 3x with EtOAc and the organic phases were concentrated in vacuo. The residue was purified via chromatography (EA:hexane, gradient) to give the desired product (440 mg, 87% yield) as an orange oil. LCMS: C20H25N3O5 requires: 357.1, found: m / z = 358.2 [M+H]+

[0506] Step 5: Synthesis of the title compound

[0507] Methyl 4-ethoxy-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]piperidine-4-carboxylate (169 mg, 0.472 mmol) was dissolved in THF (2.50 mL) and H2O (2.50 mL). Lithium hydroxide monohydrate (39.6 mg, 0.945 mmol) was added in one portion. The reaction was stirred at RT until complete by LCMS. Once complete, the reaction mixture is concentrated in vacuo and lyophilized to afford the desired lithium salt (190 mg, 113% yield) as a yellow powder. LCMS: C18H19N3O4 requires: 342.1, found: m / z = 343.1 [M+H]+

[0508] INTERMEDIATE 5

[0509] 7MC-(R)-3-METHOXY-l-(6-(2-(METHOXYMETHOXY)PHENYL)PYRID AZIN-4- YL)PYRROLIDINE-3- CARBOXYLIC ACID

[0510] &1

[0511]

[0512] Step 1: Synthesis of rac-methyl (R)-l-(6-chloropyridazin-4-yl)-3-methoxypyrrolidine-3-carboxylate

[0513]

[0514] This compound was prepared as described for the synthesis of Intermediate 1 Step 3, using rac-methyl (R)-3 -methoxypyrrolidine-3 -carboxylate to afford the desired compound (906.1 mgs, 65% yield) as a yellow oil. LCMS C11H14CIN3O3 requires 271.2 found m / z = 272.2 [M+H]+.

[0515] Step 2: Synthesis of rac-methyl ( / ?)-3-methoxy-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)pyrrolidine-3-carboxylate

[0516]

[0517] This compound was prepared as described for the synthesis of Intermediate 1 Step 4, using rac-methyl (R)- l-(6-chloropyridazin-4-yl)-3-methoxypyrrolidine-3-carboxylate to afford the desired compound (813.9 mg, 65% yield) as a yellow oil. LCMS C19H23N3O5 requires 373.2, found m / z = 374.2 [M+H]+.

[0518] Step 3: Synthesis of title intermediate

[0519] The title intermediate compound was prepared as described for Intermediate 1 Step 5, using rac-methyl (A)-3-methoxy-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)pyrrolidine-3-carboxylate. An additional acidification step to pH 7 with 3M HC1 was performed followed by evaporation to dryness to isolate the title compound as the free acid in quantitative yield as a yellow oil. LCMS C18H21N3O5 requires 359.2, found m / z = 360.2 [M+H]+.

[0520] INTERMEDIATE 6

[0521] 2-(l-(2-(2,6-DIOXOPIPERIDIN-3-YL)-l,3-DIOXOISOINDOLIN-5-YL)PIPERIDIN-4-YL)ACETALDEHYDE

[0522]

[0523] Step 1: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-l, 3-dione

[0524] O O

[0525]

[0526] o'

[0527] A mixture of 5-fluoro-l,3-dihydro-2-benzofuran-l, 3-dione (5.00 g, 30.10 mmol),

[0528] 3-aminopiperidine-2, 6-dione hydrochloride (6.90 g, 42.14 mmol) and NaOAc (4.20 g, 51.17 mmol) in HO Ac (50 mL) was stirred at 120°C for 5 h before concentrated under vacuum. The residue was washed with water and the solid was collected by fdtration. The crude product was washed with water twice and ethyl acetate twice and dried under oven to afford 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-l,3-dione (7.70 g, 92%) as a light brown solid. ’H NMR (300 MHz, DMSO-6) 5 11.16 (s, 1H), 8.03 - 8.00 (m, 1H), 7.87 - 7.85 (m, 1H), 7.75 - 7.70 (m, 1H), 5.19 - 5.15 (m, 1H), 2.94 - 2.86 (m, 1H), 2.63 - 2.48 (m, 2H), 2.12 - 2.06 (m, 1H). F NMR (300 MHz, DMSO-6) 5 -102.078.

[0529] Step 2: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-hydroxyethyl)piperidin-l-yl)isoindoline-l,3-dione

[0530]

[0531] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydro-lH-isoindole-l, 3-dione (1.00 g, 3.62 mmol) in N-Methyl pyrrolidone (10.00 mL) were added 2-(piperidin-4-yl)ethan-l-ol (3.60 mmol) and DIEA (1.40 g, 10.83 mmol). The resulting solution was stirred at 80°C for 16 h. The reaction mixture was cooled down to room temperature and purified by reverse phase flash chromatography to afford 2-(2, 6-dioxopiperidin-3-yl)-5-(4-(2-hydroxyethyl)piperidin-l-yl)isoindoline-l, 3-dione (822.80 mg, 59%) as a yellow solid. 'H NMR (300 MHz, DMSO-tL) 511.09 (s, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 2.4 Hz, 1H), 7.23 (dd, J = 8.4, 2.4 Hz, 1H), 5.07 (dd, J= 12.6, 5.4 Hz, 1H), 4.40 (t, J = 5.1 Hz, 1H), 4.04 (d, J = 13.2 Hz, 2H), 3.64 - 3.40 (m, 2H), 3.09 - 2.79 (m, 3H), 2.70 - 2.51 (m, 2H), 2.07 - 1.94 (m, 1H), 1.77 - 1.66 (m, 3H), 1.41 - 1.34 (m, 2H), 1.24 - 1.12 (m, 2H). MS (ESI) C20H23N3O5 [M+H]+requires: 386.2; found 386.1.

[0532] Step 3: Synthesis of title compound

[0533] To a mixture of the 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-hydroxyethyl)piperidin-l-yl)isoindoline- 1, 3-dione (1.06 mmol) in CH2CI2 (10 mL) was added Dess-Martin periodinane (2.12 mmol). The mixture was allowed to stir at room temperature for 1 h. The mixture was purified by column chromatography to afford the title compound as a clear oil. LCMS C20H21N3O5 requires: 383, found: m / z = 384 [M+H]+.

[0534] INTERMEDIATE 7

[0535] l-(4-(2,4-DIOXOTETRAHYDROPYRIMIDIN-l(2H)-YL)PHENYL)PIPERIDINE-4-CARB ALDEHYDE

[0536]

[0537] Step 1: Synthesis of l-(4-bromophenyl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione

[0538]

[0539] To a 40 mL vial was added l-(4-bromophenyl)-l,3-diazinane-2, 4-dione (6.40 g, 24.00 mmol), cesium carbonate (9.30 g, 28.50 mmol), and DMF (60.00 mL). To the reaction mixture was added 4-methoxybenzyl chloride (4.17 mL, 4.84 g, 30.90 mmol). The reaction mixture was stirred overnight, then quenched with water. The product was extracted with DCM (3x), dried over Na2SO4, then concentrated. The resulting residue was purified by FC (330 g silica, 0-50% EtOAc / DCM). The resulting purified residue was concentrated under reduced pressure into an amorphous solid and triturated with hexanes to yield l-(4-bromophenyl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione as a white solid (9.26 g, quantitative yield). LCMS: CisHnBr^Os requires: 388.0, found: m / z = 389.2 [M+H]+.

[0540] Step 2: Synthesis of l-(4-(4-(l,3-dioxolan-2-yl)piperidin-l-yl)phenyl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione

[0541] N

[0542]

[0543] To a 2 dram vial was added l-(4-bromophenyl)-3-[(4-methoxyphenyl)methyl]-l,3-diazinane-2,4-dione (550.00 mg, 1.41 mmol), 4-(l,3-dioxolan-2-yl)piperidine (666.00 mg, 4.24 mmol), di-tert-butyl({2',4',6'-triisopropyl-[l,r-biphenyl]-2-yl})phosphane (240 mg, 0.57 mmol), palladium (II) acetate (63.00 mg, 0.28 mmol), cesium carbonate (1.38 g, 4.24 mmol), and dioxane (5.00 mL). The reaction mixture was sparged with N2 for 10 min, then stirred at 95 °C overnight. The crude reaction mixture was diluted with DCM and water, then filtered through celite. The product was extracted with DCM (3x), dried over MgSCfi. then concentrated. The resulting residue was purified by FC (40 g silica, 0-100% EtOAc / hex) to yield l-(4-(4-(l,3-dioxolan-2-yl)piperidin-l-yl)phenyl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione as a white solid (395.00 mg, 60%). LCMS:

[0544] C26H31N3O5 requires: 465.2, found: m / z = 466.4 [M+H]+.

[0545] Step 3: Synthesis of title compound

[0546] To a 20 mL vial was added l-{4-[4-(l,3-dioxolan-2-yl)piperidin-l-yl]phenyl}-3-[(4-methoxyphenyl)methyl]-l,3-diazinane-2, 4-dione (395.00 mg, 0.85 mmol) and TFA (5.00 mL). To the reaction mixture was added trifluoromethanesulfonic acid (374.00 uL, 636.00 mg, 4.24 mmol). Full conversion after 10 min. The reaction mixture was diluted with minimal water, then purified by RP-FC (415 g C18 silica, 0-50% MeCN / water +0.1% TFA) to yield l-(4-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)phenyl)piperidine-4-carbaldehyde as a white solid (40.00 mg, 16%). LCMS: C16H21N3O3 requires: 301.1, found: m / z = 302.2 [M+H]+. INTERMEDIATE 8

[0547] 2-(l-(5-(2,6-DIOXOPIPERIDIN-3-YL)PYRIDIN-2-YL)PIPERIDIN-4-YL)ACETALDEHYDE

[0548]

[0549] Step 1: Synthesis of 2-(l-(5-bromopyridin-2-yl)piperidin-4-yl)ethan-l-ol

[0550] / — \N—V >7

[0551] HB

[0552]

[0553] O—' ' - fr

[0554] To a solution of 5 -bromo-2 -fluoropyridine (25.00 g, 142.00 mmol, 14.60 mL, 1.00 eq) and 2-(piperidin-4-yl)ethan-l-ol (27.50 g, 213.00 mmol, 1.50 eq) in ACN (250 mL) was added K2CO3 (58.90 g, 426.00 mmol, 3.00 eq). The mixture was stirred at 80 °C for 12 hrs. The mixture was poured into water and extracted with ethyl acetate, the combined organic layer was washed with brine, dried over Na2SO4, filter and concentrated under vacuum to get the crude product. The crude product was purified by chromatography on silica gel with petroleum ether: ethyl acetate = 100: 1 to 1:1. (Product: petroleum ether: ethyl acetate = 0: 1, Rf = 0.40). 2-(l-(5-bromopyridin-2-yl)piperidin-4-yl)ethan-l-ol (44.00 g, 150.00 mmol, 75.8% yield, 97.8% purity) was obtained as a white solid. LCMS C11H14BrNO requires: 284.0, found: 285.2 [M+H]+.

[0555] Step 2: Synthesis of 2-(l-(2',6'-bis(benzyloxy)-[3,3'-bipyridin]-6-yl)piperidin-4-yl)ethan-l-ol

[0556]

[0557] To a solution of 2-(l-(5-bromopyridin-2-yl)piperidin-4-yl)ethan-l-ol (22.00 g, 75.40 mmol, 1.00 eq) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (33.00 g, 79.20 mmol, 1.05 eq) in dioxane (220 mL) and H2O (44.0 mL) was added K2CO3 (31.20 g, 226.00 mmol, 3.00 eq), then Pd(dppf)C12 (2.76 g, 3.77 mmol, 0.05 eq) was added to the mixture under N2. The reaction mixture was stirred at 100°C for 12 hrs. The mixture was poured into water and extracted with ethyl acetate, the combined organic layer was washed with brine, dried over Na2SO4, filter and concentrated under vacuum to get the crude product. The residue was purified by column chromatography (SiO2, petroleum ether: Ethyl acetate = 1: 10 to 0: 1, petroleum ether: ethyl acetate = 1: 1, Rf = 0.30). 2-(l-(2',6'-bis(benzyloxy)-[3,3'-bipyridin]-6-yl)piperidin-4-yl)ethan-l-ol (60.00 g, 113.00 mmol, 74.9% yield, 93.4% purity) was obtained as a yellow solid. LCMS C31H33N3O3 requires: 495.2, found: 496.3 [M+H]+. Step 3: Synthesis of 3-(6-(4-(2-hydroxyethyl)piperidin-l-yl)pyridin-3-yl)piperidine-2, 6-dione

[0558]

[0559] To a solution of 2-(l-(2',6'-bis(benzyloxy)-[3,3'-bipyridin]-6-yl)piperidin-4-yl)ethan-l-ol (30.00 g, 56.50 mmol, 1.00 eq) in THF (150.00 mL) and EtOH (150.00 mL) was added Pd / C (9.00 g, 10% purity) and Pd(OH)2 (9.00 g, 20% purity) 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 12 hrs. The mixture was filtered to get the filtrate. The filtrate was concentrated. The crude product was triturated with ethyl acetate (3 V, 90.00 mL) at 25°C for 30 mins. 3-(6-(4-(2-hydroxyethyl)piperidin-l-yl)pyridin-3-yl)piperidine-2, 6-dione (11.00 g, 32.60 mmol, 57.6% yield, 94.1% purity) was obtained as a yellow solid. LCMS C17H23N3O3 requires: 317.2, found: 318.2 [M+H]+.

[0560] Step 4: Synthesis of title compound

[0561] To a solution of 3-(6-(4-(2-hydroxyethyl)piperidin-l-yl)pyridin-3-yl)piperidine-2, 6-dione (7.00 g, 20.70 mmol, 1.00 eq), DIEA (8.05 g, 62.20 mmol, 10.80 mL, 3.00 eq) and DMSO (3.24 g, 41.50 mmol, 3.24 mL, 2.00 eq) in DCM (130 mL) was added slowly SO3.Py (6.61 g, 41.50 mmol, 2.00 eq) at 0 °C. The reaction was stirred at 0~5 °C for 1 hr. The reaction mixture was concentrated under the vacuum. The residue was purified by column chromatography (SiO2, petroleum ether: Ethyl acetate to Dichloromethane: Methanol = 10: 1 to 10: 1) (Ethyl acetate: Methanol = 5: 1, Rf = 0.60). 2-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)acetaldehyde (8.78 g, 26.60 mmol, 64.1% yield, 95.7% purity) was obtained as a pink solid. LCMS C17H21N3O3 requires: 315.2, found: m / z = 316.2 [M+H]+.

[0562] INTERMEDIATE 9

[0563] l-(5-(2,6-DIOXOPIPERIDIN-3-YL)PYRIMIDIN-2-YL)PIPERIDINE-4-CARB ALDEHYDE

[0564] O

[0565]

[0566] Step 1: Synthesis of (l-(5-chloropyrimidin-2-yl)piperidin-4-yl)methanol

[0567] HO

[0568]

[0569] To a solution piperidin-4-ylmethanol (18.00 g, 156.00 mmol, 1.00 eq) and 2,5 -dichloropyrimidine (23.20 g, 156.00 mmol, 1.00 eq) in ACN (180 mL) was added TEA (63.2 g, 625.00 mmol, 87.00 mL, 4.00 eq) at 20 °C. The reaction was stirred at 90 °C for 12 hrs. The mixture was cooled to 20 °C and filtered. The filtrate was concentrated. The crude product was triturated with petroleum ether / Ethyl acetate = 10 / 1 (200 mL) at 20 °C for 12 hrs. The crude product was triturated with H2O (200 mL) at 20 °C for 30 mins. (l-(5-chloropyrimidin-2-yl)piperidin-4-yl)methanol (30.00 g, 131.00 mmol, 83.9% yield, 99.6% purity) was obtained as white solid. LCMS C10H14CIN3O requires: 227.1, found: m / z = 228.0 [M+H]+.

[0570] Step 2: Synthesis of (l-(5-(2,6-bis(benzyloxy)pyridin-3-yl)pyrimidin-2-yl)piperidin-4-yl)methanol

[0571]

[0572] To a solution of (l-(5-chloropyrimidin-2-yl)piperidin-4-yl)methanol (10.00 g, 43.70 mmol, 99.6% purity, 1.00 eq) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (18.20 g, 43.70 mmol, 1.00 eq) in dioxane (100.00 mL) and H2O (33.00 mL) was added K2CO3 (15.10 g, 109.00 mmol, 2.50 eq) and SPhos Pd G2 (1.58 g, 2.19 mmol, 0.05 eq) at 20 °C under N2. The reaction was stirred at 100 °C for 2 hrs under N2. The reaction was cooled to 20 °C and concentrated. The residue was poured into water. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by reversed-phase HPLC (0.1% FA condition). The product was concentrated under vacuum. The residue was extracted with ethyl acetate. The combined layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was triturated with petroleum ether / Ethyl acetate (1 / 1, 150 mL) at 20 °C for 20 mins. (l-(5-(2,6-bis(benzyloxy)pyridin-3-yl)pyrimidin-2-yl)piperidin-4-yl)methanol (14.00 g, 28.30 mmol, 64.7% yield, 97.6% purity) was obtained as white solid. LCMS C29H30N4O3 requires: 482.2, found: m / z = 483.2 [M+H]+.

[0573] Step 3: Synthesis of 3-(2-(4-(hydroxymethyl)piperidin-l-yl)pyrimidin-5-yl)piperidine-2, 6-dione HO

[0574]

[0575] To a solution of (l-(5-(2,6-bis(benzyloxy)pyridin-3-yl)pyrimidin-2-yl)piperidin-4-yl)methanol (4.00 g, 8.09 mmol, 97.6% purity, 1.00 eq) in THF (110 mL) was added Pd / C (4.00 g, 10% purity) under N2. The suspension was degassed under vacuum and purged with H2several times. The mixture was stirred under H2(15 psi) at 20 °C for 12 hrs. The mixture was filtered without diatomite and the combined filtrate was concentrated atN2. 3-(2-(4-(hydroxymethyl)piperidin-l-yl)pyrimidin-5-yl)piperidine-2,6-dione (3.90 g, crude) was obtained as light yellow solid without purification. LCMS C15H20N4O3 requires: 304.1, found: m / z = 305.2 [M+H]+.

[0576] Step 4: Synthesis of title compound

[0577] To a solution of 3-(2-(4-(hydroxymethyl)piperidin-l-yl)pyrimidin-5-yl)piperidine-2, 6-dione (1.30 g, 3.17 mmol, 74.2% purity, 1.00 eq) in DMSO (36.0 mL) was slowly added DMP (3.62 g, 8.54 mmol, 2.64 mL, 2.00 eq) at 20 °C. The reaction was stirred at 20 °C for 1 hr. The mixture was poured into ice- water (200 mL) and adjusted with saturated aqueous Na2CO3until pH = 10 at 0 °C and the aqueous layer was extracted with Ethyl acetate (1200 mL * 3). The combined organic layers were washed with Na2S2O3solution (500 mL * 2) and brine (1000 mL * 2), dried over Na2SO4, concentrated under vacuum. The crude product was triturated with ethyl acetate (20.0 mL) at 20 °C for 12 hrs. l-(5-(2,6-dioxopiperidin-3-yl)pyrimidin-2-yl)piperidine-4-carbaldehyde (0.95 g, 3.12 mmol, 24.3% yield, 99.4% purity) was obtained as white solid. LCMS C15H18N4O3 requires: 302.1, found: m / z = 301.1 [M-H]+. ’HNMR: 400 MHz, DMSO- e 5 10.86 (s, 1H), 9.62 (s, 1H), 8.23 (s, 2H), 4.47 - 4.39 (m, 2H), 3.77 - 3.70 (m, 1H), 3.19 - 3.10 (m, 2H), 2.56 (t, J= 3.6 Hz, 3H), 2.29 - 2.16 (m, 1H), 2.02 - 1.94 (m, 1H), 1.93 - 1.85 (m, 2H), 1.49 - 1.38 (m, 2H).

[0578] INTERMEDIATE 10

[0579] l-(3-(2,6-DIOXOPIPERIDIN-3-YL)-4-FLUOROPHENYL)PIPERIDINE-4-CARB ALDEHYDE

[0580]

[0581] H

[0582] Step 1: Synthesis of l-(3-bromo-4-fluorophenyl)-4-(dimethoxymethyl)piperidine

[0583]

[0584] To a solution of 2-bromo-l-fluoro-4-iodobenzene (40.00 g, 133.00 mmol, 1.00 eq), 4-(dimethoxymethyl)piperidine (23.30 g, 146.00 mmol, 1.10 eq), L-PROLINE (6.12 g, 53.20 mmol, 0.40 eq) and CS2CO3 (86.60 g, 266.00 mmol, 2.00 eq) in DMSO (280 mL) was added Cui (5.06 g, 26.60 mmol, 0.200 eq), then stirred at 80 °C for 12 hrs. The mixture was diluted with H2O, extracted with MTBE, the combined organic layer was washed with 3% NH3. H2O and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford l-(3-bromo-4-fluorophenyl)-4-(dimethoxymethyl)piperidine (25.50 g, 68.20 mmol, 51.3% yield, 88.9% purity) as an yellow oil, which was used for next step without further purification. LCMS C14H19BrFNO2requires: 333.0, found: m / z = 334 [M+H]+.

[0585] Step 2: Synthesis of 2,6-bis(benzyloxy)-3-(5-(4-(dimethoxymethyl)piperidin-l-yl)-2-fluorophenyl)pyridine

[0586]

[0587] To a solution of l-(3-bromo-4-fluorophenyl)-4-(dimethoxymethyl)piperidine (25.50 g, 68.20 mmol, 1.00 eq) in dioxane (500.00 mL) and H2O (100.00 mL) was added 2,6-bis(benzyloxy)-3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (40.30 g, 88.70 mmol, 1.30 eq), CS2CO3 (55.60 g, 171.00 mmol, 2.50 eq) and Pd(dppf)C12*CH2C12 (2.79 g, 3.41 mmol, 0.05 eq) at 25 °C under N2. The reaction mixture was stirred at 100 °C for 12 hrs. The mixture was poured into H2O, extracted with EtOAc, the combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by MPLC (SiCL, petroleum ether: Ethyl acetate = 1:0 to 10:1, petroleum ether: Ethyl acetate = 5:1, Rf = 0.4), concentrated to afford 2,6-bis(benzyloxy)-3-(5-(4-(dimethoxymethyl)piperidin-l-yl)-2-fluorophenyl)pyridine (36.00 g, 64.80 mmol, 95.0% yield, 97.7% purity) as a yellow oil. LCMS C33H35FN2O4 requires: 542.2, found: m / z = 543.4 [M+H]+.

[0588] Step 3: Synthesis of 3-(5-(4-(dimethoxymethyl)piperidin-l-yl)-2-fluorophenyl)piperidine-2, 6-dione

[0589]

[0590] A solution of 2,6-bis(benzyloxy)-3-(5-(4-(dimethoxymethyl)piperidin-l-yl)-2-fluorophenyl)pyridine (1.00 eq, 36.00 g) in dioxane (1.80 L) was stirred at 20 °C until becoming a clear solution. The fixed bed (named FLR1, volume 50 mL) was packed with granular catalyst 5%Pd / C (WXC1030), then heated to 40-55 °C. The H2back pressure regulator was adjusted to 0.3 MPa. The above solution was pumped into the fixed bed { FLR1,5 min} at a flow rate of {2 mL / min}, and the flow rate of H2was 98 mL / min. The reaction mixture was collected after running 30 mins. After the reaction was completed, the fixed bed was washed by extra { dioxane, 100 mL }. The solution was concentrated under reduced pressure to obtain the crude material, which was triturated with petroleum ether: Ethyl acetate = 5:1 (100 mL) at 25 °C for 1 hr, filtered and the cake was dried under reduced pressure to afford 3-(5-(4-(dimethoxymethyl)piperidin-l-yl)-2-fluorophenyl)piperidine-2, 6-dione (19.40 g, 49.30 mmol, 76.1% yield, 92.6% purity) as a white solid. LCMS C19H25FN2O4 requires: 364.2, found: m / z = 365.3 [M+H]+.

[0591] Step 4: Synthesis of title compound

[0592] To a solution of 3-(5-(4-(dimethoxymethyl)piperidin-l-yl)-2-fluorophenyl)piperidine-2, 6-dione (10.00 g, 25.40 mmol, 1.00 eq) in THF (250.00 mL) was added HC1 (2 M, 226.00 mL, 17.80 eq). After addition, the reaction solution was stirred at 70 °C for 1 hr. The reaction mixture was cooled to 25 °C, then added saturated NaHC’CF solution until pH reached 7, then extracted with EtOAc, the combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to get the crude. The crude was triturated with MTBE (30.00 mL) at 25 °C for 0.5 hr, filtered and the cake was dried under reduced pressure. The residue was diluted with DCM until the mixture turned to clear and concentrated to afford l-(3-(2,6-dioxopiperidin-3-yl)-4-fluorophenyl)piperidine-4-carbaldehyde (5.55 g, 17.10 mmol, 67.1% yield, 97.8% purity) as an off-white solid. LCMS C17H19FN2O3 requires: 318.1, found: m / z = 337.1 [M+H20+H]+. ’HNMR: (400 MHz, CDCI3) S 9.70 (s, 1H), 8.42 (br s, 1H), 7.03 - 6.95 (m, 1H), 6.90 -6.82 (m, 1H), 6.74 (dd, J = 2.8, 6.0 Hz, 1H), 3.84 (dd, J = 5.2, 11.2 Hz, 1H), 3.50 - 3.45 (m, 2H), 2.87 -2.59 (m, 4H), 2.44 - 2.33 (m, 1H), 2.32 - 2.15 (m, 2H), 2.10 - 1.98 (m, 2H), 1.84 - 1.72 (m, 2H). INTERMEDIATE 11

[0593] 2-(4-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)-l-OXA-4,9-DIAZASPIRO[5.5]UNDECAN-9-YL)ACETIC

[0594]

[0595] Step 1: Synthesis of tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-l-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate

[0596]

[0597] To a stirred solution of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (5.00 g, 11.20 mmol) and tert-butyl l-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (2.87 g, 11.20 mmol) in 1,4 dioxane (50.00 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(0.51 g, 0.56 mmol) and RuPhos (0.52 g, 1.12 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 and extracted with ethyl acetate. 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 afford tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-l-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (5.60 g, 77% yield) as pale yellow solid. 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)-l-oxa-4,9-diazaspiro[5.5]undecane

[0598]

[0599] To a stirred solution of tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-l-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (5.60 g, 9.01 mmol) in DCM (30.00 mL) was added 4M HC1 in dioxane (11.26 mL, 45.00 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 and dried to afford 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-l-oxa-4,9-diazaspiro[5.5]undecane (4.50 g, 81% yield, HC1 salt) as off-white solid. LCMS C33H35N3O3 requires: 521.3, found: m / z = 522.4 [M+H]+.

[0600] Step 3: Synthesis of tert-butyl 2-(4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-l-oxa-4,9-diazaspir 0 [5.5] undecan-9-yl)acetate

[0601]

[0602] To a solution of (4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-l-oxa-4,9-diazaspiro[5.5]undecane (4.50 g, 7.33 mmol) in MeCN (50.00 mL) at RT were added triethylamine (5.11 ml, 36.70 mmol) and tert-butyl 2-chloroacetate (3.15 mL, 22.00 mmol). The reaction mixture was stirred at 60 °C for 16 h. Upon completion of reaction, as confirmed by LCMS, the reaction mixture was cooled to room temperature. Then water was added and extracted with EtOAc. The combined organic layer was washed with water, brine, dried over sodium sulphate and concentrated under reduced pressure to get the crude product. The crude product was purified by Biotage -Isolera (Silica gel: 230-400 mesh) using 30% of ethyl acetate / pet-ether as eluent to afford tert-butyl 2-(4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-l-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetate (3.00 g, 61% yield) as off white solid. LCMS C39H45N3O5 requires: 635.3, found: m / z = 637.4 [M+H]+. Step 4: Synthesis of tert-butyl 2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-l-oxa-4,9-diazaspir o [5.5] undecan-9-yl)acetate

[0603]

[0604] To a stirred solution of tert-butyl 2-(4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-l-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetate (3.00 g, 4.72 mmol) in 1,4-dioxane (30 mL) was added Pd(OAc)2 (0.40 g, 1.78 mmol) and 10% Pd / C (0.50 g, 4.70 mmol) under N2 atmosphere at RT. The resulting mixture was stirred under H2pressure (1 atm) at RT for 24 h. Upon completion of the reaction, as confirmed by LCMS, the reaction mixture was filtered through Celite bed washed with ethyl acetate and concentrated under reduced pressure. The crude compound was washed with toluene, MTBE and concentrated under reduced pressure to afford tert-butyl 2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetate (1.80 g, 83%) as off-white solid. LCMS C25H35N3O5 requires: 457.2, found: m / z = 458.6 [M+H]+.

[0605] Step 5: Synthesis of title compound

[0606] To a stirred solution tert-butyl 2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-1-oxa-4, 9-diazaspiro[5.5]undecan-9-yl)acetate (1.80 g, 3.93 mmol) in DCM ( 6.50 ml) at 0 °C was added HC1 (4M soln, in dioxane, 9.83 ml, 39.30 mmol). The reaction mixture was stirred at RT for 4 h. Then n-hexane was added, stirred for 10 min and decanted and repeated twice. The resulting residue was concentrated, dried under reduced pressure The crude product was purified by prep-HPLC purification using: column:: X-Select C18 19 x 250, method: HCPMeCN, Flow rate: 12 ml / min. collected fraction lyophilized to afford 2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-l-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetic acid (0.92 g, 64% yield, HC1 salt) as an off-white solid LCMS C21H27N3O5 requires: 401.2, found: m / z = 402.2 [M+H]+.

[0607] INTERMEDIATE 12

[0608] 3-(4-(PIPERAZIN-l-YL)PHENYL)PIPERIDINE-2, 6-DIONE

[0609]

[0610] Step 1: Synthesis of tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperazine-l-carboxylate

[0611]

[0612] 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (79.20 g, 177.44 mmol, 1.0 eq), tert-Butyl 1-piperazinecarboxylate (39.66 g, 212.93 mmol, 1.20 eq), CS2CO3 (289.07 g, 887.20 mmol, 5.0 eq), Pd2(dba)3(12.19 g, 13.31 mmol, 0.075 eq), Ruphos (12.43 g, 26.62 mmol, 0.15 eq) were added successively into 1,4-dioxane (800mL). The mixture was heated to 100°C under argon and stirred for 16h. The mixture was filtered through a Celite pad, and the filtrate was concentrated to give the crude product. The reaction mixture was diluted with water and extracted with EA. The organic layer was washed with saturated brine. The organic layer was dried over Na2SO4. The mixture was concentrated to afford the crude product. The crude product was purified by column chromatography on silica gel eluted with (PE / EA 8: 1) to give a yellow solid. The yellow solid was recrystallized from PE / EA (8: 1) and filtered to afford tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperazine-l-carboxylate (48.10 g, 60.7%) a white solid.

[0613] Step 2: Synthesis of tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-l-carboxylate

[0614]

[0615] A mixture of tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperazine-l-carboxylate (45.00 g, 81.60 mmol, 1.0 eq), Pd / C (9.00 g, 20% wt / wt ) and Pd / (OAc)2(7.20 g) in 1,4-dioxane (450 mL) was hydrogenated under 50 Psi of hydrogen pressure overnight at room temperature. The mixture was filtered and concentrated to afford tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-l-carboxylate (27.90 g, 91.5%) as a grey solid. LCMS C20H27N3O4 requires: 373.2, found: m / z = 374.9 [M+H]+.

[0616] Step 3: Synthesis of title compound

[0617]

[0618] To a solution of tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-l -carboxylate (27.90 g, 74.70 mmol, 1.00 eq) in DCM (300 mL) was added 4M HC1 in dioxane (261.50 mL, 1045.80 mmol, 14.0 eq). Then the reaction mixture was stirred for 2h at room temperature. After that the mixture was filtered and the filter cake was triturated with PE / EA = 10:1 (200 mL) and filtered to afford 3-(4-(piperazin-l-yl)phenyl)piperidine-2, 6-dione (21.00 g, 91.3%) as an off-white solid. LCMS C15H19N3O2 requires: 273.1, found: m / z = 274.0 [M+H]+.

[0619] INTERMEDIATE 13

[0620] l-(6-(2-(METHOXYMETHOXY)PHENYL)PYRID AZIN-4- YL)-4-(METHOXYMETHYL)PIPERIDINE-4- CARBOXYLIC ACID

[0621]

[0622] Step 1: Synthesis of ethyl l-(6-chloropyridazin-4-yl)-4-(methoxymethyl)piperidine-4-carboxylate

[0623]

[0624] This compound was prepared as described for the synthesis of Intermediate 1 Step 3, using ethyl 4-(methoxymethyl)piperidine-4-carboxylate (1.00 g, 4.97 mmol), affording the desired product (1.16 g, 75%yield) as ayellow oil. LCMS C14H20CIN3O3 requires 313.2, found m / z = 314.2 [M+H]+.

[0625] Step 2: Synthesis of ethyl l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-4-(methoxymethyl)piperidine-4-carboxylate

[0626]

[0627] This compound was prepared as described for the synthesis of Intermediate 1 Step 4, using ethyl l-(6-chloropyridazin-4-yl)-4-(methoxymethyl)piperidine-4-carboxylate (1.16 g, 3.70 mmol), affording the desired product (1.55 g, 96% yield) as a yellow oil. LCMS C22H29N3O5 requires 415.2, found m / z = 416.2 [M+H]+.

[0628] Step 3: Synthesis of title intermediate compound

[0629] The title intermediate compound was prepared as described for the synthesis of Intermediate 1 Step 5, using ethyl l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-4-(methoxymethyl)piperidine-4-carboxylate (573.6 mg, 1.38 mmol). An additional acidification step to pH 7 with 3M HC1 was performed followed by evaporation to dryness to isolate the title compound as the free acid which was taken forward without any further purification. LCMS C20H25N3O5 requires 387.2, found [M+H]+.

[0630] INTERMEDIATE 14

[0631] (lR,4R)-4-(3-((RS)-2,6-DIOXOPIPERID IN-3- YL)PHENOXY)CYCLOHEXANE-1-CARB ALDEHYDE

[0632]

[0633] Step 1: Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)phenol

[0634]

[0635] To a stirred solution of 3-hydroxyphenylboronic acid (15.00 g, 108.75 mmol, 1.00 equiv) and 2,6-bis(benzyloxy)-3 -bromopyridine (52.34 g, 141.38 mmol, 1.30 equiv) in dioxane (50.00 mL) / H20 (5.00 mL) were added K2CO3 (45.09 g, 326.25 mmol, 3.00 equiv) and Pd^ppQCECEECE (17.72 g, 21.75 mmol, 0.20 equiv). The resulting mixture was stirred at 90°C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8; mobile phase, acetonitrile in water (0.5% HCOOH), 40% to 50% gradient in 10 min; detector, UV 254 nm to afford 3-[2,6-bis(benzyloxy)pyridin-3-yl]phenol (7.00 g, 16.79%) as a brown solid. MS (ESI) calc’d for (C25H21NO3) [M+H]+, 384.1; found 384.1.

[0636] Step 2: Synthesis of methyl (lr,4r)-4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)phenoxy)cyclohexane-l-carboxylate

[0637] O

[0638]

[0639] To a stirred mixture of 3-[2,6-bis(benzyloxy)pyridin-3-yl]phenol (7.00 g, 18.25 mmol, 1.00 equiv) and methyl (ls,4s)-4-hydroxycyclohexane-l -carboxylate (9.90 mg, 0.06 mmol, 1.20 equiv) in THF (50.00 mL) were added PPI13 (9.58 g, 36.51 mmol, 2.00 equiv) and DIAD (7.38 g, 36.51 mmol, 2.00 equiv) at 0°C. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA=2 / 1 to afford methyl (lr,4r)-4-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxy}cyclohexane-l-carboxylate (3.00 g, 31.38%) as abrown oil. MS (ESI) calc’d for (C33H33NO5) [M+H]+, 524.2; found 524.2.

[0640] Step 3: Synthesis of ((lr,4r)-4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)phenoxy)cyclohexyl)methanol

[0641]

[0642] To a stirred mixture of methyl (lr,4r)-4-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxy}cyclohexane-l-carboxylate (3.00 g, 5.73 mmol, 1.00 equiv) in THF (20 mb) was added LiAlFU (0.43 g, 11.46 mmol, 2.00 equiv). The resulting mixture was stirred at room temperature for 1.5 h under nitrogen atmosphere. The mixture was quenched with water. The resulting mixture was extracted with ethyl acetate. The organic layers were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA=1 / 1 to afford [(lr,4r)-4-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxy}cyclohexyl]methanol (1.30 g, 45.78%) as a white solid. MS (ESI) calc’d for (C32H33NO4) [M+H]+, 496.2; found 496.2.

[0643] Step 4: Synthesis of (lr,4r)-4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)phenoxy)cyclohexane-l-carbaldehyde

[0644]

[0645] To a stirred mixture of [(lr,4r)-4-{3-[2,6-bis(benzyloxy)pyridin-3-yl]

[0646] phenoxy} cyclohexyl] methanol (1.30 g, 2.62 mmol, 1.00 equiv) in DCM (20 mb) was added Dess-Martin (2.23 g, 5.25 mmol, 2.00 equiv). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was washed with water. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA=1 / 1 to afford (lr,4r)-4-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxy}cyclohexane-l-carbaldehyde (900 mg, 69.51%) as a yellow oil. MS (ESI) calc’d for (C32H31NO4) [M+H]+, 494.2; found 494.2.

[0647] Step 5: Synthesis of 2,6-bis(benzyloxy)-3-(3-(((lr,4r)-4-(dimethoxymethyl)cyclohexyl)oxy)phenyl)pyridine

[0648]

[0649] To a stirred mixture of (lr,4r)-4-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxy}cyclohexane-l-carbaldehyde (900.00 mg, 1.82 mmol, 1.00 equiv) and trimethyl orthoformate (2.90 g, 27.35 mmol, 15.00 equiv) in MeOH (15 mb) was added H2SO4 (2 mb). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA=2 / 1 to afford 2,6-bis(benzyloxy)-3-(3-{[(lr,4r)-4-(dimethoxymethyl)cyclohexyl]oxy}phenyl)pyridine (800.00 mg, 81.30%) as a yellow solid. MS (ESI) calc’d for (C34H37NO5) [M+H]+, 540.2; found 540.2. Step 6: Synthesis of (RS)-3-(3-(((lr,4R)-4-(dimethoxymethyl)cyclohexyl)oxy)phenyl)piperidine-2,6-dione

[0650]

[0651] To a stirred solution of 2,6-bis(benzyloxy)-3-(3-{[(lr,4r)-4-(dimethoxymethyl)cyclohexyl] oxy} phenyl) pyridine (800.00 mg, 1.48 mmol, 1.00 equiv) in THF (10 mb) and Isopropanol (2 mL) was added Pd / C (10%, 800.00 mg) and Pd(OH)2 / C (160.00 mg). The resulting mixture was stirred at room temperature for 2 h under hydrogen atmosphere. The solids were filtered off. The filtrate was concentrated under vacuum to afford 3-(3-{[(lr,4r)-4-(dimethoxymethyl) cyclohexyl]oxy}phenyl)piperidine-2, 6-dione (400.00 mg, 74.66%) as a white solid. MS (ESI) calc’d for (C2OH27N05) [M+H]+, 362.1; found 362.1.

[0652] Step 7: Synthesis of title compound

[0653] The resulting solution of 3-(3-{[(lr,4r)-4-(dimethoxymethyl)cyclohexyl]oxy}phenyl)piperidine-2, 6-dione (400.00 mg, 1.11 mmol, 1.00 equiv) in FA (5 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure to afford (lr,4r)-4-{3-[(3RS)-2,6-dioxopiperidin-3-yl]phenoxy}cyclohexane-l-carbaldehyde (258.10 mg, 70.25%) as a white solid. MS (ESI) calc’d for (CI8H2INO4) [M+l]+, 316.15; found, 316.15. ’HNMR (400 MHz, DMSO-6) 5 10.81 (s, 1H), 9.62 (s, 1H), 7.34 - 7.13 (m, 1H), 6.95 - 6.57 (m, 3H), 4.38 - 4.17 (m, 1H), 3.95 - 3.65 (m, 1H), 2.73 - 2.60 (m, 1H), 2.47 - 2.42 (m, 1H), 2.39 - 2.30 (m, 1H), 2.27 - 2.16 (m, 1H), 2.12 - 1.93 (m, 5H), 1.52 - 1.32 (m, 4H).

[0654] INTERMEDIATE 15

[0655] 4-(l-ETHYL-17 / -PYRAZOL-5-YL)-l-(6-(2-(METHOXYMETHOXY)PHENYL)PYRID AZIN-4- YL)PIPERIDINE- 4-CARBOXYLIC ACID

[0656]

[0657] Step 1: Synthesis of tert-butyl 4-cyano-4-(l-ethyl-l / / -pyrazol-5-yl)piperidine-l -carboxylate

[0658] bU

[0659] [ p" CN

[0660] / N. J

[0661] Boo

[0662]

[0663] To a solution of 2-( l-cthyl-l / / -pyrazol-5-yl)acctonitrilc (1.50 g, 11.1 mmol, 1.00 eq) in DMF (15.0 mL) was added NaH (1.11 g, 27.7 mmol, 60% purity, 2.50 eq) at 0 °C under N2atmosphere and stirred at 25 °C for 30 mins, then tert-butyl bis(2-chloroethyl)carbamate (3.22 g, 13.3 mmol, 1.20 eq) was added to the mixture, and the mixture was heated to 60 °C and stirred until complete as judged by LCMS. Once complete, the reaction mixture was quenched by addition saturated NILC1 solution (50.0 mL) at 0°C under N2, and then diluted with water (50 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated to afford the title compound a yellow oil (3.38 g) which was taken forward crude without any further purification. LCMS C16H24N4O2 requires 304.1, found m / z = 305.1 [M+H]+.

[0664] Step 2: Synthesis of 4-(l-ethyl-LH-pyrazol-5-yl)piperidine-4-carbonitrile hydrochloride

[0665]

[0666] The title compound was prepared as described for Intermediate 1 Step 2, using tert-butyl 4-cyano-4-(l -ethyl- l / / -pyrazol-5-yl)pipcridinc- 1 -carboxylate (3.38 g, 11.1 mmol), affording the title compound as a yellow solid (3.00 g) which was taken forward crude without any further purification. LCMS C11H16N4 requires 204, found m / z = 205.1 [M+H]+.

[0667] Step 3: Synthesis of l-(6-chloropyridazin-4-yl)-4-(l-ethyl-LH-pyrazol-5-yl)piperidine-4-carbonitrile

[0668]

[0669] The title compound was prepared as described for Intermediate 1 Step 3, using 4-(l -ethyl- 1H-pyrazol-5-yl)piperidine-4-carbonitrile hydrochloride (3.00 g, 12.5 mmol), affording the title compound (2.50 g, 77% yield over three steps) as a brown solid. LCMS C15H17CIN6 requires 316.1, found m / z = 317.1 [M+H]+.

[0670] Step 4: Synthesis of 4-(l-ethyl-LH-pyrazol-5-yl)-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperidine-4-carbonitrile

[0671]

[0672] The title compound was prepared as described for Intermediate 1 Step 4, using l-(6-chloropyridazin-4-yl)-4-(l-ethyl-lH-pyrazol-5-yl)piperidine-4-carbonitrile (2.3 g, 7.26 mmol), affording the title compound (3.30 g, 97% yield) as a yellow oil. LCMS C23H26N6O2 requires 418.2, found m / z = 419.2 [M+H]+. Step 5: Synthesis of the title compound

[0673] The title intermediate compound was prepared as described for Intermediate 1 Step 5, using 4-(l-ethyl-lH-pyrazol-5-yl)-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperidine-4-carbonitrile (3.30 g, 7.07 mmol). An additional adjustment of pH to ~7 with 2N HC1 was performed, followed by concentration under reduced pressure. The resulting residue was purified by prep-HPLC (column:

[0674] Kromasil Eternity XT 250*80mm* lOum; mobile phase: [H2O (0.05% NLLOHj-ACN] gradient: 0%-25% B over 20.0 min) to afford the title compound (2.01 g, 65% yield) as a brown solid. LCMS C23H27N5O4 requires 437.2, found m / z = 438.2 [M+H]+.

[0675] INTERMEDIATE 16

[0676] 4-(l,3-DIMETHYL-l / / -PYRAZOL-5-YL)-l-(6-(2-(METHOXYMETHOXY)PHENYL)PYRIDAZIN-4- YL)PIPERIDINE-4-CARBOXYLIC ACID

[0677]

[0678] Step 1: Synthesis of tert-butyl 4-cyano-4-(l,3-dimethyl-LH-pyrazol-5-yl)piperidine-l-carboxylate

[0679]

[0680] The title compound was prepared as described for Intermediate 15 Step 1, using 2-(l,3-dimethyl- l / / -pyrazol-5-yl)acctonitrilc (1.50 g, 11.1 mmol), affording the title compound (3.38 g), as a yellow oil which was taken forward crude without further purification. LCMS C16H24N4O2 requires 304.2, found m / z = 305.2 [M+H]+.

[0681] Step 2: Synthesis of 4-(l,3-dimethyl-l / f-pyrazol-5-yl)piperidine-4-carbonitrile hydrochloride

[0682]

[0683] The title compound was prepared as described for the synthesis of Intermediate 1 Step 2, using tert-butyl 4-cyano-4-( 1, 3-dimethyl- 1 H-pyrazol-5-yl)pipcridinc- 1 -carboxylate (3.38 g, 11.1 mmol), affording the title compound (3.00 g) as a yellow solid which was taken forward crude without any further purification. LCMS C11H16N4 requires 204.1, found m / z = 205.1 [M+H]+. Step 3: Synthesis of l-(6-chloropyridazin-4-yl)-4-(l,3-dimethyl-LH-pyrazol-5-yl)piperidine-4-carbonitrile

[0684]

[0685] The title compound was prepared as described for Intermediate 1 Step 3, using 4-(l,3-dimethyl-lH-pyrazol-5-yl)piperidine-4-carbonitrile hydrochloride (3.00 g, 12.5 mmol), affording the title compound (2.00g, 57% yield over three steps) as a brown solid. LCMS C15H17CIN6 requires 316.1, found m / z = 317.1 [M+H]+.

[0686] Step 4: Synthesis of 4-(l,3-dimethyl-l / f-pyrazol-5-yl)-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperidine-4-carbonitrile

[0687]

[0688] The title compound was prepared as described for Intermediate 1 Step 4, using l-(6-chloropyridazin-4-yl)-4-(l,3-dimethyl-lH-pyrazol-5-yl)piperidine-4-carbonitrile (1.80 g, 5.68 mmol), affording the title compound (2.40 g, 91% yield) as a yellow oil. LCMS C23H26N6O2 requires 418.2, found m / z = 419.2 [M+H]+.

[0689] Step 5: Synthesis of title compound

[0690] The title compound was prepared as described for Intermediate 1 Step 5, using 4-(l,3-dimethyl-lH-pyrazol-5-yl)- l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperidine-4-carbonitrile (2.40 g, 5.16 mmol). An additional adjustment of pH to ~7 with 2N HC1 was performed, followed by concentration under reduced pressure. The resulting residue was purified by prep-HPLC (column: Kromasil Eternity XT 250*80mm* lOum; mobile phase: [H2O (0.05% NELOHj-ACN] gradient: 0%-25% B over 20.0 min) to afford the title compound (1.52 g, 67% yield) as a brown solid. LCMS C23H27N5O4 requires 437.2, found m / z = 438.2 [M+H]+.

[0691] INTERMEDIATE 17

[0692] l-(6-(2-(METHOXYMETHOXY)PHENYL)PYRID AZIN-4- YL)-4-(THIAZOL-4-YL)PIPERIDINE-4- CARBOXYLIC ACID

[0693]

[0694] Step 1: Synthesis of 4-(thiazol-4-yl)piperidine-4-carbonitrile

[0695]

[0696] To a solution of tert-butyl 4-cyano-4-(thiazol-4-yl)piperidine-l -carboxylate (CAS 1522499-80-4, Enamine) (1.86 g, 6.34 mmol, 1.00 eq) in HCl / EtOAc (2 M, 20.00 mL, 6.31 eq) was stirred at 25 °C for 2 hrs. The mixture was concentrated in vacuum. 4-(thiazol-4-yl)piperidine-4-carbonitrile (1.46 g, crude, HC1) was obtained as a brown oil. LCMS: C9H11N3S requires 193.1, found: m / z = 194.0 [M+H]+.

[0697] Step 2: Synthesis of l-(6-chloropyridazin-4-yl)-4-(thiazol-4-yl)piperidine-4-carbonitrile

[0698]

[0699] To a solution of 4-(thiazol-4-yl)piperidine-4-carbonitrile (1.46 g, 6.36 mmol, 1.00 eq, HC1) and 3,5-dichloropyridazine (1.42 g, 9.53 mmol, 1.50 eq) in IPA (120.00 mL) was added DIPEA (3.29 g, 25.40 mmol, 4.43 mL, 4.00 eq) under N2 atmosphere, and the mixture was stirred at 70 °C for 12 hrs. The mixture was concentrated to remove most IPA in vacuum. The crude product was purified by reversed-phase HPLC (column: Kromasil Eternity XT 250*80mm* 10um;mobile phase: [water (ammonia hydroxide v / v)-ACN] gradient: 10%-40% B over 20 min). l-(6-chloropyridazin-4-yl)-4-(thiazol-4-yl)piperidine-4-carbonitrile (1.43 g, 4.12 mmol, 44.0% yield, 88.0% purity) was obtained as a brown solid. LCMS: C13H12CIN5S requires 305.1, found: m / z = 306.0 [M+H]+.

[0700] Step 3: Synthesis of l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-4-(thiazol-4-yl)piperidine-4-carbonitrile

[0701]

[0702] To a solution of l-(6-chloropyridazin-4-yl)-4-(thiazol-4-yl)piperidine-4-carbonitrile (1.17 g, 3.37 mmol, 1.00 eq), (2-(methoxymethoxy)phenyl)boronic acid (1.23 g, 6.73 mmol, 2.00 eq) and K2CO3 (1.40 g, 10.10 mmol, 3.00 eq) in dioxane (50.00 mL) and H2O (10.00 mL) was added Pd(dppf)C12. CH2C12 (274.00 mg, 336.00 pmol, 0.10 eq) at 25 °C under N2 atmosphere, and the mixture was stirred at 110 °C for 6 hrs. The reaction mixture was cooled to 40 °C and diluted with water (100 mL) and extracted with EtOAc, and the combined organic layers were washed with brine, dried over Na2SO4and concentrated to obtain crude product under vacuum. The residue was triturated with MTBE / Ethyl acetate (10 / 1, 10.00 mL), at 25 °C for 20 mins, filtered and the filter cake was washed with MTBE (5.00 mL * 2), dried in vacuum. 1 -(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-4-(thiazol-4-yl)piperidine-4-carbonitrile ( 1.20 g, 2.64 mmol, 78.3% yield, 89.6% purity) was obtained as a black brown solid. LCMS: C21H21N5O2S requires 407.1, found: m / z = 408.2 [M+H]+. Step 4: Synthesis of the title compound

[0703] To a solution of l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-4-(thiazol-4-yl)piperidine-4-carbonitrile (1.20 g, 2.64 mmol, 1.00 eq) in MeOH (10.00 mL), THF (10.00 mL) and H2O (10.00 mL) was added NaOH (1.58 g, 39.58 mmol, 15.00 eq) at 25 °C. Then the mixture reaction was stirred at 80 °C for 12 hrs. The mixture was concentrated in vacuum, adjusted pH to about 7.00 with 2N HC1, concentrated in vacuum. The crude product was purified by reversed-phase HPLC (column: Waters Xbridge 150*25mm* 5um; mobile phase: [water (NH3H2O)-ACN] gradient: 0%-30% B over 11 min). 1-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-4-(thiazol-4-yl)piperidine-4-carboxylic acid (803.00 mg, 1.88 mmol, 71.2% yield, 99.8% purity) was obtained as a red solid. LCMS: C21H22N4O4S requires 426.1, found: m / z = 427.2 [M+H]+.

[0704] INTERMEDIATE 18

[0705] (R)-2-(1-(4-(2,6-DIOXOPIPERIDIN-3-YL)-3-FLUOROPHENYL)PIPERIDIN-4-YL)ACETALDEHYDE

[0706]

[0707] Step 1: Synthesis of 2,6-bis(benzyloxy)-3-(4-bromo-2-fluorophenyl)pyridine

[0708]

[0709] To a solution of 4-bromo-2 -fluoro- 1 -iodobenzene (200 g, 664 mmol, 1.0 eq) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (305 g, 731 mmol, 1.1 eq) in 1,4-dioxane (2.0 L) and H2O (200 mL) was added K2CO3 (275 g, 1.99 mol, 3.0 eq) and Pd(dppf)C12-DCM (27.1 g, 33.2 mmol, 0.05 eq). The mixture was stirred at 80 °C for 4 h. The reaction was allowed to cooled to room temperature, added water (1.0 L) and extracted by EtOAc (2.0 L x 2), the combined organic phase was washed with brine (1.5 L x 2), dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (petroleum ether / EtOAc = 50: 1) to yield the product (220 g, yield 71.3%) as a white solid. ’HNMR (300 MHz, DMSO-6): d 7.72 - 7.56 (m, 2H), 7.51 - 7.22 (m, 12H), 6.56 (d, J= 8.1 Hz, 1H), 3.32 (s, 4H). LCMS: 464.2, 466.0 ([M+H]+).

[0710] Step 2: Synthesis of 2-(l-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3-fluorophenyl)piperidin-4-yl)ethan-l-ol

[0711]

[0712] To a solution of 2,6-bis(benzyloxy)-3-(4-bromo-2-fluorophenyl)pyridine (245 g, 527 mmol, 1.0 eq) and 2-(piperidin-4-yl)ethan-l-ol (75.0 g, 580 mmol, 1.1 eq) in Toluene (2.5 L) was added t-BuONa (101 g, 1.06 mol, 2.0 eq), BINAP (64.7 g, 104 mmol, 0.2 eq) and Pd (0Ac)2 (12.3 g, 54.9 mmol, 0.1 eq). The mixture was stirred at 100 °C for 4 h. The reaction was allowed to cooled to room temperature, added water (1.0 L) and extracted by EtOAc (2.0 L x 2), the combined organic phase was washed with brine (1.5 L x 2), dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (petroleum ether / EtOAc = 10: 1-3:1) to give the product (83.0 g, yield 30.6%) as a yellow solid. ’H NMR (400 MHz, CDC13): S 7.52 (dd, J= 8.0, 0.8 Hz, 1H), 7.48 - 7.20 (m, 11H), 6.80 - 6.60 (m, 2H), 6.44 (d, J= 8.0 Hz, 1H), 5.40 (s, 2H), 5.33 (s, 2H), 3.83 - 3.67 (m, 4H), 2.87 - 2.70 (m, 2H), 1.89 - 1.77 (m, 2H), 1.70 - 1.56 (m, 3H), 1.48 - 1.30 (m, 2H).

[0713] Step 3: Synthesis of 3-(2-fluoro-4-(4-(2-hydroxyethyl)piperidin-l-yl)phenyl)piperidine-2, 6-dione

[0714]

[0715] The reaction mixture of 2-(l-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3-fluorophenyl)piperidin-4-yl)ethan-l-ol (63.0 g, 37.2 mmol, 1.0 eq), Pd / C (15.7 g) and Pd(OH)2(15.7 g) in 1,4-dioxane (650 mb) was stirred under H2 at 60 °C for 36 h. LCMS and TLC showed the reaction was completed. The mixture was filtered, and the filtrate was concentrated to give the crude, which was triturated with EtOAc (250 mb) at 25 °C for 15 min and filtered to give the product (25.0 g, yield 60.8%) as a grey solid. ’H NMR (400 MHz, DMSO-d6): d 10.79 (brs, 1H), 7.03 (t, J= 8.8 Hz, 1H), 6.77 - 6.62 (m, 2H), 4.35 (t, J= 4.8 Hz, 1H), 3.87 (dd, J= 12.3, 4.8 Hz, 1H), 3.79 - 3.60 (m, 2H), 3.50 - 3.40 (m, 2H), 2.80 - 2.60 (m, 3H), 2.22 - 2.08 (m, 1H), 2.07 - 1.90 (m, 1H), 1.80 - 1.63 (m, 2H), 1.62 - 1.48 (m, 1H), 1.38 (q, J = 6.8 Hz, 2H), 1.30 - 1.10 (m, 2H). LCMS: 335.2 ([M+H]+).

[0716] Step 4: Synthesis of the title compound

[0717] To a solution of 3-(2-fluoro-4-(4-(2-hydroxyethyl)piperidin-l-yl)phenyl)piperidine-2, 6-dione (31.5 g, 94.2 mmol, 1.0 eq) in DMSO (315 mb) was added IBX (53.1 g, 188 mmol, 2.0 eq), then the reaction mixture was stirred at room temperature for 3 h. LCMS showed the reaction was completed. The reaction mixture was dropwise into saturated Na2COs aqueous solution (600 mL) at 0 °C and extracted with DCM (500 mL x 2). The combined organic phases were washed with saturated Na2S2O3aqueous solution (300 mL x 3), dried over Na2SO4and concentrated to give a crude. The crude was added DCM (400 mL) and NaHSOs aqueous solution (200 mL, 1.2M), and then stirred at room temperature for 1 h. After that, the aqueous phase was extracted with DCM (200 mL x 2). The aqueous phase was added Na2COs aqueous solution (600 mL, 0.6M) and extracted with DCM (500 mL x 2), the combined organic phase was washed with brine (200 mL x 3), dried over Na2SO4and concentrated in vacuo to give the product (11.3 g, yield 36.1%) as a yellow solid. ’H NMR (300 MHz, DMSO-6): d 10.80 (brs, 1H), 9.69 (brs, 1H), 7.06 (t, J= 8.7 Hz, 1H), 6.80 - 6.60 (m, 2H), 3.87 (dd, J= 12.3, 4.8 Hz, 1H), 3.80 - 3.60 (m, 2H), 2.82 - 3.62 (m, 3H), 2.46 - 2.34 (m, 2H), 2.24 - 1.87 (m, 4H), 1.80 - 1.60 (m, 2H), 1.40 - 1.16 (m, 2H). LCMS: 333.2 ([M+H]+). INTERMEDIATE 19

[0718] 2-(l-(4-(2,6-DIOXOPIPERIDIN-3-YL)-3,5-DIFLUOROPHENYL)PIPERIDIN-4-YL)ACETALDEHYDE

[0719]

[0720] Step 1: Synthesis of 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine

[0721]

[0722] Br

[0723] To a solution of 5-bromo-l,3-difluoro-2 -iodobenzene (167 g, 525 mmol, 1.0 eq) in DMF (3344 mL) and H2O (334 mL) was added 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (225 g, 539.4 mmol, 1.03 eq), CsF (159 g, 1051.0 mmol, 2.0 eq) and Pd(dtbpf)C12 (33.8 g, 52.5 mmol, 0.1 eq) at room temperature under N2. The mixture was purged with N2 three times. The reaction mixture was stirred at 85 °C for 12 h. HPLC showed the reaction was complete. After cooled to room temperature, water (3000 mL) was added. The mixture was extracted with EtOAc (2000 mL x 3). The combined organic phases were washed with brine (1500 mL x 5), dried over Na2SO4 and concentrated to give crude product. The residue was triturated with petroleum ether (450 mL) to afford Compound 2 (115.0 g, 45.5%) as a white solid. 1H NMR (300 MHz, CDC13): 57.38-7.35 (m, 1H), 7.33-7.13 (m, 10H), 7.06-6.99 (m, 2H), 6.38 (d, J = 8.1 Hz, 1H), 5.27-5.23 (m, 4H).

[0724] Step 2: Synthesis of 2-(l-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)piperidin-4-yl)ethan-l-ol

[0725]

[0726] HO

[0727] To a solution of 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine (46.0 g, 95.4 mmol, 1.0 eq) in toluene (460 mL) was added 2-(piperidin-4-yl)ethan-l-ol (13.6 g, 104.9 mmol, 1.1 eq), t-BuONa (18.3 g, 190 mmol, 2.0 eq), BINAP (11.9 g, 19.1 mmol, 0.2 eq) and Pd(OAc)2 (2.1 g, 9.5 mmol, 0.1 eq) at room temperature under N2. The mixture was purged with N2three times. The reaction mixture was stirred at 110°C for 12 h. HPLC showed the reaction was complete. After cooled to room temperature, water (300 mL) was added. The mixture was extracted with EtOAc (300 mL x 2). The combined organic phases were washed with brine (400 mL x 2), dried over Na2SO4 and concentrated to give crude product, which was purified by silica gel column chromatography with (petroleum ether: EtOAc = 20: 1) to give Compound 3 (26.0 g, 51.3%) as a white oil. ’H NMR (400 MHz, CDC13): 57.42-7.18 (m, 11H), 6.41-6.35 (m, 3H), 5.31 (s, 2H), 5.24 (s, 2H), 5.22 (s, 2H), 3.66-3.60 (m, 4H), 2.74-2.68 (m, 2H), 1.74-1.70 (m, 2H), 1.50-1.44 (m, 2H), 1.32-1.24 (m, 2H). Step 3: Synthesis of 3-(2,6-difluoro-4-(4-(2-hydroxyethyl)piperidin-l-yl)phenyl)piperidine-2, 6-dione

[0728]

[0729] To a solution of 2-(l-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)piperidin-4-yl)ethan-l-ol (23.6 g, 44.5 mmol, 1.0 eq) in dioxane (236 mL) was added Pd / C (11.8 g) and Pd(OH)2 (11.8 g) at room temperature. The mixture was purged with H2 three times. The mixture was stirred at 40°C for 24 h. HPLC showed the reaction was complete. The reaction mixture was filtered and the filtrate was concentrated to give crude product, which was triturated with MTBE (40 mL) to afford the desired product (8.8 g, 56.1%) as ablue solid. ’HNMR(300 MHz, DMSO-6): d 10.85 (s, 1H), 6.62 (d, J= 12.8 Hz, 2H), 4.36 (t, J= 5.1 Hz, 1H), 4.06-4.00 (m, 1H), 3.75-3.71 (m, 2H), 3.49-3.43 (m, 2H), 2.84-2.65 (m, 3H), 2.53-2.51 (m, 1H), 2.15-1.92 (m, 2H), 1.72-1.68 (m, 2H), 1.61-1.51 (m, 1H), 1.41-1.34 (m, 2H), 1.22-1.09 (m, 2H). LCMS: 353.2 ([M+H]+).

[0730] Step 4: Synthesis of the title compound

[0731] To a solution of 3-(2,6-difluoro-4-(4-(2-hydroxyethyl)piperidin-l-yl)phenyl)piperidine-2, 6-dione (8.8 g, 25.0 mmol, 1.0 eq) in DMSO (85 mL) was added IBX (10.6 g, 37.5 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for 3 h. A saturated sodium thiosulfate solution (100 mL) was added, and the mixture was extracted with EtOAc (100 mL x 2). The combined organic phases were washed with brine (100 mL x 4), dried over Na2SO4and concentrated to give crude product. The crude product was triturated with MTBE (30 mL) and filtered to give the desired product (6.0 g, 68.6%) as a yellow solid. ’HNMR(300 MHz, DMSO-6): d 10.85 (s, 1H), 9.70-9.69 (m, 1H), 6.63 (s, 1H), 6.59 (s, 1H), 4.06-4.01 (m, 1H), 3.75-3.71 (m, 2H), 2.75-2.72 (m, 3H), 2.54-2.53 (m, 1H), 2.41-2.38 (m, 2H), 2.11-1.92 (m, 3H), 1.71-1.67 (m, 2H), 1.30-1.16 (m, 2H). LCMS: 351.1 ([M+H]+).

[0732] INTERMEDIATE 20

[0733] l-(l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-(l-METHYL-lH-PYRAZOI^4-YL)PIPERIDIN-4- YL)ETHAN-1-ONE

[0734]

[0735] Step 1: Synthesis of 4-(chloromethyl)-l-methyl-lH-pyrazole

[0736]

[0737] '--CI

[0738] To a solution of (1 -methyl- lH-pyrazol-4-yl)methanol (25.0 g, 222 mmol, 1.00 eq) in DCM (250 mL) was added SOCI2 (66.3 g, 557 mmol, 40.4 mL) dropwise. The mixture was stirred at 25 °C for 12 hrs. The mixture was directly filtered and concentrated under vacuum to give the desired product (34.1 g, crude) as a white solid, m / z = 131.2 (M+H)+

[0739] Step 2: Synthesis of 4-(chloromethyl)-l-methyl-lH-pyrazole

[0740]

[0741] CN

[0742] To a solution of 4-(chloromethyl)-l -methyl- IH-pyrazole (33.9 g, 259 mmol) in ACN (180 mL) and H2O (37.0 mL) was added KCN (27.9 g, 428 mmol, 18.3 mL) at 25 °C. The mixture was heated to 50 °C and stirred for 12 hrs. The mixture was then cooled down to 25 °C and adjusted the pH to 9 with saturated NaHCOs aqueous solution (800 mL). Then the mixture was extracted with EtOAc (900 mL * 3). The organic layers were washed with brine (800 mL * 2), dried over Na2SO4, filtered and concentrated to give the product. The residue was purified by column chromatography (SiCL. petroleum ether / Ethyl acetate = 20 / 1 to 0 / 1, Rf = 0.20, petroleum ether / Ethyl acetate = 5 / 1, PMA). The mixture was concentrated to give the desired product (23.0 g, 186 mmol, 71.9% yield) as yellow oil. m / z = 122.2 (M+H)+

[0743] Step 3: Synthesis of tert-butyl 4-cyano-4-(l-methyl-lH-pyrazol-4-yl)piperidine-l-carboxylate

[0744]

[0745] To a solution of 2-(l -methyl- lH-pyrazol-4-yl)acetonitrile (23.0 g, 186 mmol) in DMF (460 mL) was added NaH (18.6 g, 467 mmol) at 0 °C, the mixture was stirred at 0 °C for 0.5 hr. Then tert-butyl bis(2-chloroethyl)carbamate (49.7 g, 205 mmol, 1.10 eq) was added, the mixture was heated to 60 °C and stirred for 2 hrs. The mixture was cooled down to 25 °C, and poured into a saturated NH4CI aqueous solution (1.00 L), and then extracted with EtOAc (800 mL *3). The combined organic phases were washed with brine (500 mL), dried overNa2SO4, filtered and concentrated under vacuum to give the product (52.1 g, 144 mmol, 77.2% yield) as a black brown oil. m / z = 291.3 (M+H)+

[0746] Step 4: Synthesis of 4-(l-methyl-lH-pyrazol-4-yl)piperidine-4-carbonitrile

[0747]

[0748] To a solution of tert-butyl 4-cyano-4-(l -methyl- lH-pyrazol-4-yl)piperidine-l -carboxylate (52.1 g, 128 mmol) in EtOAc (100 mL) was added HCl / EtOAc (2 M, 961 mL) at 25 °C and the mixture was stirred for 12 hrs. The mixture was filtered and the filtrate was concentrated under vacuum to give the desired product (22.5 g, 111 mmol, 78.3% yield) as a black brown solid, m / z = 191.2 (M+H)+ Step 5: Synthesis of l-(6-chloropyridazin-4-yl)-4-(l-methyl-lH-pyrazol-4-yl)piperidine-4-carbonitrile

[0749] \-N

[0750]

[0751] To a solution of 4-(l -methyl- lH-pyrazol-4-yl)piperidine-4-carbonitrile (22.5 g, 93.4 mmol) and 3,5-dichloropyridazine (16.7 g, 112 mmol) in IPA (600 mL) was added DIEA (60.4 g, 467 mmol, 81.4 mL) at 25 °C and the resulting mixture was stirred at 70 °C for 12 hrs. The mixture was poured into H2O (2.00 L) and extracted with ethyl acetate (900 mL * 3). The combined organic phase was washed with brine (2.00 L), dried over ISfeSCE, filtered and concentrated under vacuum to give the desired product (28.5 g, 83.0 mmol, 88.8% yield) as a yellow solid, m / z = 303.2 (M+H)+

[0752] Step 6: l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(l-methyl-lH-pyrazol-4-yl)piperidine-4-carbonitrile

[0753] \-N

[0754]

[0755] To a solution of l-(6-chloropyridazin-4-yl)-4-(l -methyl- lH-pyrazol-4-yl)piperidine-4-carbonitrile (8.50 g, 27.6 mmol), (2-hydroxyphenyl)boronic acid (7.64 g, 55.3 mmol), K2CO3 (11.4 g, 83.0 mmol) in dioxane (85.0 mL) and H2O (17.0 mL) was added Pd(dppf)C12 (4.05 g, 5.54 mmol) at 25 °C, 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 phases were washed with brine (100 mL), dried over Na2SO4, the mixture was concentrated under vacuum. The residue was purified by column chromatography (SiC>2, Dichloromethane / Methanol = 20 / 1 to 1 / 1, Dichloromethane / Methanol = 20 / 1, Rf = 0.15, PMA) to afford the desired compound (3.50 g, 9.56 mmol, 34.5% yield) as a white solid, m / z = 361.1 (M+H)+

[0756] Step 7: Synthesis of the title compound

[0757] To a solution of l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(l -methyl- lH-pyrazol-4-yl)piperidine-4-carbonitrile (3.50 g, 9.24 mmol) in MeOH (20.0 mL), THP (20.0 mL), H2O (20.0 mL) was added NaOH (3.70 g, 92.4 mmol) at 25 °C and then the resulting mixture was stirred at 80 °C for 12 hrs. Once complete, the mixture was concentrated under vacuum. Then the mixture was adjusted to pH = 5 with IM HC1 and extracted with ethyl acetate (500 mL * 3). The combined organic phases were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by prep-HPLC to afford the desired product (2.10 g, 5.51 mmol, 59.6% yield) as a yellow solid. INTERMEDIATE 21

[0758] l-{6-[2-(METHOXYMETHOXY)PHENYL]PYRIDAZIN-4-YL}-4-[2-(OXAN-4-YL)PYRAZOL-3- YL]PIPERIDINE-4-CARBOXYLIC ACID

[0759]

[0760] Step 1: Synthesis of l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazole

[0761]

[0762] To a solution of tetrahydro-2H-pyran-4-ol (20.0 g, 196 mmol, 19.6 mL, 1.00 eq) and pyrazole (13.3 g, 196 mmol, 1.00 eq) in Tol (200 mL) was added (cyanomethylene)tributylphosphorane (70.9 g, 294 mmol, 1.50 eq). The mixture was stirred at 115 °C for 12 hrs. The reaction mixture was cooled to 25 °C and washed with brine (500 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by prep-HPLC (column: Phenomenex luna cl8

[0763] 250mm* 100mm* 10um;mobile phase: [LLOQOmM NH4HCO3)-ACN] gradient: 10%-30% B over 20.0 min), extracted with DCM (600 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure (below 40 °C) to get l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazole (9.50 g, 62.4 mmol, 31.9% yield, 100% purity) as an off-white solid. LCMS: C8H12N2O requires 152.1, found: m / z = 153.1 (M+H)+. ’H NMR (400 MHz, CDCl3) S 7.50 (d, J= 1.2 Hz, 1H), 7.42 (d, J= 2.4 Hz, 1H), 6.25 (t, J= 2.0 Hz, 1H), 4.41 - 4.29 (m, 1H), 4.19 - 4.03 (m, 2H), 3.62 - 3.46 (m, 2H), 2.19 - 2.01 (m, 4H)

[0764] Step 2: Synthesis of 5-iodo-l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazole

[0765]

[0766] To a solution of l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazole (8.50 g, 55.9 mmol, 1.00 eq) in THF (85.0 mL) was added n-BuLi (2.5 M, 33.5 mL, 1.50 eq) drop-wise at -70 — 60 °C under N2, then stirred at -70 °C for 1 hr. A solution of L (21.3 g, 83.8 mmol, 1.50 eq) in THF (85.0 mL) was added drop-wise and stirred at -70—60 °C for another 1 hr. The mixture was quenched by 10% Na2SOs solution (300 mL) extracted with EtOAc (300 mL * 2), the combined organic layer was washed with brine (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by prep-HPLC (column: Phenomenex luna cl8250mm* 100mm* 10um;mobile phase: [H2O(0.1%TFA)-ACN] gradient: 30%-50% B over 20.0 min), concentrated to remove most ACN, then extracted with EtOAc (300 mL * 3), the combined organic layer was washed with brine (500 mL), dried over Na2SO4, filtered and concentrated to obtain 5-iodo-l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazole (11.2 g, 65.9% yield) as a yellow solid. LCMS: C8H11IN2O requires 278.0, found: m / z = 279.0 (M+H)+. ’HNMR: (400 MHz, CDCl3) S 7.50 (d, J= 1.2 Hz, 1H), 7.42 (d, J= 2.4 Hz, 1H), 6.25 (t, J= 2.0 Hz, 1H), 4.41 - 4.29 (m, 1H), 4.19 - 4.03 (m, 2H), 3.62 - 3.46 (m, 2H), 2.19 - 2.01 (m, 4H) Step 3: Synthesis of 2-(l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-5-yl)acetonitrile

[0767]

[0768] Five batches were carried out in parallel.

[0769] To a mixture of 5-iodo-l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazole (1.00 g, 3.60 mmol, 1.00 eq), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoxazole (1.05 g, 5.39 mmol, 1.50 eq) and KF (627 mg, 10.8 mmol, 3.00 eq) in dioxane (10.0 mL) and H2O (2.50 mL) was added 4-ditert-butylphosphanyl-N, N-dimethyl-aniline; dichloropalladium (CAS: 26-37-60) (127 mg, 180 pmol, 127 pL, 0.05 eq) under N2. The resulting mixture was degassed and purged with N2 for 3 times and then the mixture was stirred at 80-90 °C for 12 hrs under N2 atmosphere. The reaction mixture was cooled to 25 °C and concentrated under reduced pressure. The residue was purified by column chromatography (SiCL, petroleum ether / Ethyl acetate = 10 / 1 to 1 / 1, petroleum ether / Ethyl acetate = 1 / 1, Rf = 0.4), concentrated to get a brown oil, which was further purified by prep-HPLC (column: Welch Ultimate XB-CN 250*70mm* 10um;mobile phase: [Heptane-EtOH(0.1%NH3H2O)] gradient: 5 %-45% B over 15.0 min), concentrated under reduced pressure to get 2-(l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-5-yl)acetonitrile (2.30 g, 11.9 mmol, 55.1% yield, 98.8% purity) as ayellow oil. LCMS: C10H13N3O requires 191.1, found: m / z = 192.1 (M+H)+. ’H NMR: (400 MHz, CDC13) <57.52 (d, J= 1.6 Hz, 1H), 6.28 (d, J= 1.6 Hz, 1H), 4.27 - 4.10 (m, 3H), 3.81 (s, 2H), 3.60 - 3.50 (m, 2H), 2.40 - 2.30 (m, 2H), 1.96 - 1.83 (m, 2H)

[0770] Step 4: Synthesis of tert-butyl 4-cyano-4-(l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-5-yl)piperidine-1-carboxylate

[0771]

[0772] To a solution of 2-(l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-5-yl)acetonitrile (2.30 g, 12.0 mmol, 1.00 eq) in DMF (20.0 mL) was added NaH (1.20 g, 30.1 mmol, 60% purity, 2.50 eq) at 0-10 °C under N2 atmosphere and stirred at 25 °C for 30 mins, then a solution of tert-butyl bis(2-chloroethyl)carbamate (3.49 g, 14.4 mmol, 1.20 eq) in DMF (3.00 mL) was added to the mixture, and the mixture was heated to 60 °C and stirred at 60 °C for 2 hrs. The reaction mixture was quenched by addition saturated NH4CI solution (100 mL) at 0-10 °C under N2, and extracted with EtOAc (50.0 mL * 3). The combined organic layers were washed with brine (30.0 mL * 3), dried over Na2SO4, filtered and concentrated under vacuum to get tert-butyl 4-cyano-4-(l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-5-yl)piperidine-l -carboxylate (4.5 g, crude) as ayellow solid. LCMS: C19H28N4O3 requires 360.2, found: m / z = 361.3 (M+H)+. Step 5: Synthesis of 4-(l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-5-yl)piperidine-4-carbonitrile hydrochloride

[0773]

[0774] A mixture of tert-butyl 4-cyano-4-(l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-5-yl)piperidine-l-carboxylate (4.50 g, 12.5 mmol, 1.00 eq) in HCl / EtOAc (2 M, 50.0 mL) was stirred at 25 °C for 1 hr. The mixture was concentrated under reduced pressure to get 4-(l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-5-yl)piperidine-4-carbonitrile hydrochloride (3.70 g, crude, HC1) as a yellow solid. LCMS: C14H20N4O requires 260.2, found: m / z = 261.2 (M+H)+.

[0775] Step 6: Synthesis of l-(6-chloropyridazin-4-yl)-4-(l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-5-yl)piperidine-4-carbonitrile

[0776]

[0777] To a solution of 4-(l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-5-yl)piperidine-4-carbonitrile hydrochloride (3.70 g, 12.5 mmol, 1.00 eq, HC1) and 3,5-dichloropyridazine (1.86 g, 12.5 mmol, 1.00 eq) in IPA (20.0 mL) was added DIEA (6.44 g, 49.9 mmol, 8.69 mL, 4.00 eq) under N2 atmosphere, and the mixture was stirred at 70-80 °C for 12 hrs. The reaction mixture was cooled to 25 °C and concentrated under reduced pressure. The crude was purified by pre-HPLC (column: Kromasil Eternity XT 250*80mm* 10um;mobile phase: [H20(0.05% NEEEEO^ACN] gradient: 10%-40% B over 20.0 min), concentrated to remove most ACN, then extracted with EtOAc (300 mL * 3), the combined organic layer was washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to get l-(6-chloropyridazin-4-yl)-4-(l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-5-yl)piperidine-4-carbonitrile (3.00 g, 63.7% yield over three steps) as a brown solid. LCMS: C fEiCIM. O requires 372.1, found: m / z = 373.1 (M+H)+.’HNMR: (400 MHz, DMSO) d 9.03 (d, J= 2.0 Hz, 1H), 7.52 (s, 1H), 7.18 (d, J= 1.6 Hz, 1H), 6.25 (s, 1H), 4.75 - 4.64 (m, 1H), 4.25 (br d, J= 14.4 Hz, 2H), 3.97 (br dd, J= 3.6, 11.6 Hz, 2H), 3.55 (brt, J= 11.6 Hz, 2H), 3.28 (brt, J= 13.2 Hz, 2H), 2.45 (br s, 2H), 2.15 (dq, J= 4.4, 12.0 Hz, 2H), 2.08 - 1.99 (m, 2H), 1.80 (br d, J= 10.4 Hz, 2H)

[0778] Step 7: Synthesis of l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-4-(l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-5-yl)piperidine-4-carbonitrile

[0779]

[0780] To a solution of l-(6-chloropyridazin-4-yl)-4-(l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-5-yl)piperidine-4-carbonitrile (3.00 g, 8.05 mmol, 1.00 eq), (2-(methoxymethoxy)phenyl)boronic acid (2.93 g, 16.1 mmol, 2.00 eq) and K2CO3 (3.34 g, 24.1 mmol, 3.00 eq) in dioxane (30.0 mL) and H2O (6.00 mL) was added Pd(dppf)C12. CH2C12 (657 mg, 805 pmol, 0.100 eq) under N2 atmosphere and the mixture was stirred at 110 °C for 12 hrs. The mixture was cooled to 25 °C and poured into H2O (50.0 mL) extracted with EtOAc (30.0 mL * 3), the combined organic layer was washed with brine (50.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by column chromatography (SiCL. hexane / Ethyl acetate = 1 / 1 to 0 / 1, petroleum ether / Ethyl acetate = 0 / 1, Rf = 0.1) to get l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-4-(l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-5-yl)piperidine-4-carbonitrile (2.50 g, 62.4% yield) as a light yellow solid. LCMS: C26H30N6O3 requires 474.2, found: m / z = 475.2 (M+H)+,’H NMR: (400 MHz, DMSO) d 9.04 (d, J= 2.8 Hz, 1H), 7.63 (dd, J = 1.6, 7.6 Hz, 1H), 7.52 (d, J= 1.6 Hz, 1H), 7.46 - 7.39 (m, 1H), 7.31 (d, J = 2.8 Hz, 1H), 7.24 (d, J= 8.0 Hz, 1H), 7.13 (t, J= 7.2 Hz, 1H), 6.27 (d, J= 1.6 Hz, 1H), 5.21 (s, 2H), 4.74 - 4.63 (m, 1H), 4.22 (brd, J = 14.0 Hz, 2H), 3.98 (br dd, J= 4.0, 11.6 Hz, 2H), 3.55 (brt, J= 11.6 Hz, 2H), 3.34 - 3.21 (m, 5H), 2.48 (br s, 2H), 2.22 - 2.00 (m, 4H), 1.81 (brd, J= 10.4 Hz, 2H).

[0781] Step 8: Synthesis of l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-4-(l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-5-yl)piperidine-4-carboxylic acid

[0782]

[0783] To a solution of l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-4-(l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-5-yl)piperidine-4-carbonitrile (2.50 g, 5.27 mmol, 1.00 eq) in THF (10.0 mL), MeOH (10.0 mL) and H2O (10.0 mL) was added KOH (5.91 g, 105 mmol, 20.0 eq) at 25 °C, then the mixture was stirred at 80 °C for 100 hrs. The mixture was concentrated in vacuum, adjusted pH to about 7 with 2N HC1 (keep temperature below 25 °C), then concentrated under reduced pressure. The crude was purified by pre-HPLC (column: Kromasil Eternity XT 250*80mm* lOum; mobile phase: [H20(0.05% NH3H2O)-ACN] gradient: 0%-25% B over 20.0 min) and lyophilization. l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-4-(l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-5-yl)piperidine-4-carboxylic acid (1.53 g, 57.9% yield) was obtained as a yellow solid. LCMS: C26H31N5O5 requires 493.2, found: m / z = 494.3 (M+H)+. 'H NMR: (400 MHz, DMSO) d 9.04 (d, J= 2.8 Hz, 1H), 7.63 (dd, J= 1.6, 7.6 Hz, 1H), 7.52 (d, J= 1.6 Hz, 1H), 7.46 - 7.39 (m, 1H), 7.31 (d, J= 2.8 Hz, 1H), 7.24 (d, J= 8.0 Hz, 1H), 7.13 (t, J= 7.2 Hz, 1H), 6.27 (d, J= 1.6 Hz, 1H), 5.21 (s, 2H), 4.74 - 4.63 (m, 1H), 4.22 (br d, J= 14.0 Hz, 2H), 3.98 (br dd, J= 4.0, 11.6 Hz, 2H), 3.55 (brt, J= 11.6 Hz, 2H), 3.34 - 3.21 (m, 5H), 2.48 (br s, 2H), 2.22 - 2.00 (m, 4H), 1.81 (br d, J= 10.4 Hz, 2H). INTERMEDIATE 22

[0784] l-(6-(2-(ME THOXYMETHOXY)PHENYL)PYRID AZIN-4- YL)-4-(l-METHYL- 3-(TRIFLUOROME THYL)-1H- PYRAZOL-5-YL)PIPERIDINE-4-CARBOXYLIC ACID

[0785]

[0786] The title compound was made as described for intermediate 21 beginning at step 3 and using 5-bromo-l-methyl-3-(trifluoromethyl)-lH-pyrazole to afford l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-4-(l-methyl-3-(trifluoromethyl)-lH-pyrazol-5-yl)piperidine-4-carboxylic acid as a white solid. LCMS: C23H24F3N5O4 requires 491.2, found: m / z = 492.2 (M+H)+. ’HNMR: (400 MHz, DMSO-d6) S 8.94 (br d, J= 2.8 Hz, 1H), 7.62 (br d, J= 7.6 Hz, 1H), 7.41 (brt, J= 7.2 Hz, 1H), 7.26 - 7.17 (m, 2H), 7.11 (brt, J= 7.6 Hz, 1H), 6.58 (s, 1H), 5.20 (s, 2H), 3.91 (s, 3H), 3.79 (brd, J= 13.2 Hz, 2H), 3.40 -3.34 (m, 2H), 3.31 (s, 3H), 2.42 (brd, J= 13.2 Hz, 2H), 1.83 (brt, J= 10.4 Hz, 2H).

[0787] INTERMEDIATE 23

[0788] 4-(l,4-DIMETIIYL-lH-PYRAZOL-5-YL)-l-(6-(2-(METHOXYMETHOXY)PIIENYL)PYRIDAZIN-4- YL)PIPERIDINE-4-CARBOXYLIC ACID

[0789] I

[0790]

[0791] The title compound was made as described for intermediate 16 beginning at step 1 and using 2-(l,4-dimethyl-lH-pyrazol-5-yl)acetonitrile to afford 4-(l,4-dimethyl-lH-pyrazol-5-yl)-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperidine-4-carboxylic acid as a yellow solid. LCMS:

[0792] C23H27N5O4 requires 437.2, found: m / z = 438.2 (M+H)+. ’H NMR: (400 MHz, DMSO) d 8.92 (d, J= 3.2 Hz, 1H), 7.62 (d, J= 1.8, 7.6Hz, 1H), 7.46 - 7.37 (m, 1H), 7.23 (dd, J= 0.8, 8.4 Hz, 1H), 7.18 (d, J= 3.2 Hz, 1H), 7.12 (d, J= 1.2, 7.6 Hz, 1H), 6.98 (s, 1H), 5.21 (s, 2H), 3.88 - 3.81 (m, 5H), 3.32 (s, 3H), 3.32 -3.24 (m, 2H), 2.48 - 2.44 (m, 1H), 2.07 (s, 3H), 1.89 (dt, J= 4.0, 12.4 Hz, 2H)

[0793] INTERMEDIATE 24

[0794] l-(6-(2-(METHOXYMETHOXY)PHENYL)PYRID AZIN-4- YL)-4-(2-METHYL-2H-INDAZOL-3- YL)PIPERIDINE-4-CARBOXYLIC ACID

[0795]

[0796] The title compound was made as described for intermediate 21 beginning at step 3 and using 3-bromo-2 -methyl -2H-indazole to afford l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-4-(2-methyl-2H-indazol-3-yl)piperidine-4-carboxylic acid as a white solid. LCMS: C23H27N5O4 requires 437.2, found: m / z = 474.2 (M+H)+. ’H NMR: (400 MHz, DMSO-6) S 8.98 (d, J= 3.2 Hz, 1H), 7.86 (d, J= 8.8 Hz, 1H), 7.61 (dd, J= 1.6, 7.6 Hz, 1H), 7.51 (d, J = 8.7 Hz, 1H), 7.44 - 7.39 (m, 1H), 7.26 - 7.22 (m, 2H), 7.17 (dd, J = 6.7, 8.6 Hz, 1H), 7.12 (dt, J = 1.0, 7.5 Hz, 1H), 6.96 (ddd, J = 0.8, 7.2, 8.2 Hz, 1H), 5.20 (s, 2H), 4.17 (s, 3H), 3.92 (br d, J = 13.3 Hz, 2H), 3.39 (br s, 2H), 3.31 (s, 3H), 2.73 (br d, J = 13.4 Hz, 2H), 2.42 - 2.33 (m, 2H).

[0797] INTERMEDIATES 25-1 AND 25-2

[0798] (7?)-3-METHOXY-1-(6-(2-(METHOXYMETHOXY)PHENYL)PYRID AZIN-4- YL)PYRROLIDINE-3- CARBOXYLIC ACID (22-1) AND (A)-3-METHOXY-l-(6-(2-(METHOXYMETHOXY)PHENYL)PYRIDAZIN-4- YL)PYRROLIDINE-3-CARBOXYLIC ACID (22-2)

[0799]

[0800] rac-(R)-3 -methoxy- 1 -(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)pyrrolidine-3 -carboxylic acid (Intermediate 5) was subjected to SFC chromatography (Column: CELLULOSE-4 (30.0mm*300mmL; 5u) A: CO2 =75%, B: Cosolvent = 0.1% AH in MeOH 25%). The separated isomers were collected and concentrated, affording Intermediate 25-1 (second-eluting isomer, RT= 14.4 min, 950 mg, 45% yield) and Intermediate 25-2 (first-eluting isomer, RT= 11.4 min, 950 mg, 45% yield) as white solids. Intermediate 25-1: LCMS C18H21N3O5 requires 359.2, found m / z = 360.2 [M+H]+. Intermediate 25-2: LCMS CI8H2IN3O5 requires 359.2, found m / z = 360.2 [M+H]+.

[0801] INTERMEDIATE 26

[0802] R4C-(R)-3-ETHOXY-l-(6-(2-(METHOXYMETHOXY)PHENYL)PYRID AZIN-4- YL)PYRROLIDINE-3- CARBOXYLIC ACID, LITHIUM SALT

[0803] xo

[0804]

[0805] Step 1: Synthesis of methyl 2-eth oxyacrylate:

[0806] O

[0807]

[0808] To a stirred solution of methyl 2-methoxyacrylate (3 g, 25.8 mmol) in EtOH (10 mL) were added CuCl2(195 mg, 1.45 mmol), NaH2PC>4 (1.05 g, 8.76 mmol) and bis(benzonitrile)palladium(II) dichloride (496 mg, 1.29 mmol). The reaction was stirred at RT for 16 h. After completion of reaction (monitored by TLC), charcoal (2 g) was added and stirred at RT for 30 min. The reaction mixture was then filtered through a fritted funnel and washed with Et20 (40 mL). The filtrate layer was concentrated under reduced pressure (below 40°C). The crude material was diluted with water (20 mL) and extracted with Et20 (2 x 50 mL). The combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure (below 40°C) to give the desired title compound as a colorless liquid (1.5 g, 45% yield). ’H NMR (400 MHz, CDCl3): S 5.32 (d, J= 2.0 Hz, 1H), 4.61 (d, J= 2.0 Hz, 1H), 3.87-3.85 (m, 2H), 3.79 (s, 3H), 1.37 (t, J= 7 Hz, 3H).

[0809] Step 2: Synthesis of rac-methyl (7?)-l-benzyl-3-ethoxypyrrolidine-3-carboxylate (4):

[0810]

[0811] To a stirred solution of methyl 2-ethoxyacrylate (Step 1, 800 mg, 6.15 mmol) and N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (1.89 mL, 7.38 mmol) in DCM (10 mL) was added TEA (0.007 mL, 0.092 mmol) at 0°C. The resulting reaction mixture was stirred at RT for 16 h. After completion of reaction (monitored by TLC and LCMS). The reaction mixture was directly concentrated under reduced pressure. The crude was purified by flash column chromatography (5% EtOAc in heptane) to get the desired title compound as a colorless sticky gum (450 mg, 27% yield). LCMS C15H21NO3 requires 263.2, found m / z=264.40 [M+H]+.

[0812] Step 3: Synthesis of rac-methyl (7?)-3-ethoxypyrrolidine-3-carboxylate

[0813]

[0814] To a stirred solution of rac-methyl (R)-1-benzyl-3-ethoxypyrrolidine-3-carboxylate (450 mg, 1.71 mmol) in EtOH (10 mL) was added 10% Pd / C (225 mg, 50% w / w). The reaction mixture was degassed two times under H2 atmosphere and stirred under hydrogen atmosphere for 16 h. After completion of the reaction (monitored by TLC and LCMS), the reaction mixture was filtered through a celite bed and washed with EtOH (50 mL). The filtrate was concentrated under reduced pressure to afford the title compound as a colorless viscous liquid (290 mg, 98% yield). LCMS C8H15NO3requires 173.1, found m / z = 174.11 [M+H]+.

[0815] Step 4: Synthesis of rac-methyl (7?)-3-ethoxy-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)pyrrolidine-3-carboxylate

[0816] &1

[0817]

[0818] To a stirred solution of methyl rac-methyl (R)-3 -ethoxypyrrolidine-3 -carboxylate (290 mg, 1.67 mmol) in DMSO (3 mL) was added DIPEA (0.877 mL, 5.02 mmol) and 5-chloro-3-(2-(methoxymethoxy)phenyl)pyridazine (630 mg, 2.51 mmol), the reaction mixture was stirred at 90°C for 16 h. After completion of reaction (monitored by LCMS), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography (3% MeOH in DCM) to afford the title compound as a yellow sticky gum (300 mg, 46%). LCMS C20H25N3O5 requires 387.2, found m / z = 388.4 [M+H]+.

[0819] Step 5: Synthesis of the title compound (Intermediate 26):

[0820] To a stirred solution of rac-methyl (R)-3 -ethoxy- l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)pyrrolidine-3-carboxylate (300 mg, 0.774 mmol) in THE (10 mL) was added solution of lithium hydroxide (18.5 mg, 0.774 mmol) in water (5 mL). The resultant reaction mixture was stirred at RT for 16 h. After completion of reaction (monitored by TLC). Reaction mixture was concentrated under reduced pressure, diluted with 25% IPA in CHCI3 (50 mL) and filtered through sintered funnel. Filtrate was concentrated under reduced pressure to afford the title compound as an off-white solid (263 mg, 91%).

[0821] LCMS C19H23N3O5 requires 373.2, found m / z = 374.2 [M+H]+.

[0822] INTERMEDIATE 27

[0823] RAC-(R)-1-(6-(5-FLUORO-2-(METHOXYMETHOXY)PHENYL)PYRIDAZIN-4-YL)-3-METHOXYPYRROLIDINE-3-CARBOXYLIC ACID

[0824] &1

[0825] N

[0826]

[0827] Step 1: Synthesis of rac-methyl (R)-l-(6-(5-fluoro-2-(meth oxymeth oxy)phenyl)pyridazin-4-yl)-3-methoxypyrrolidine-3-carboxylate

[0828] &1

[0829] N

[0830]

[0831] The title compound was prepared as described for Intermediate 1, Step 4, using rac-methyl ( / ?)- 1-(6-chloropyridazin-4-yl)-3-methoxypyrrolidine-3-carboxylate (Intermediate 5, Step 1) and (5-fluoro-2-(methoxymethoxy)phenyl)boronic acid to afford the title compound (407.3 mg, 52% yield) as a yellow foam. LCMS C19H22FN3O5 requires 391.2, found m / z = 392.2 [M+H]+.

[0832] Step 2: Synthesis of title compound (Intermediate 27)

[0833] The title compound was prepared as described for Intermediate 1, Step 5, using rac-methyl ( / ?)- 1-(6-(5-fluoro-2-(methoxymethoxy)phenyl)pyridazin-4-yl)-3-methoxypyrrolidine-3-carboxylate to afford the title compound. An additional acidification step to pH 7 with 3M HC1 was performed followed by evaporation to dryness to isolate the title compound as the free acid in quantitative yield as a yellow oil. LCMS C18H20FN3O5requires 377.2, found m / z = 378.2. [M+H]+.

[0834] INTERMEDIATE 28

[0835] RAC-(R)-3-FLUORO-1-(6-(2-(METHOXYMETHOXY)PHENYL)PYRIDAZIN-4-YL)PYRROLIDINE-3-CARBOXYLIC ACID

[0836]

[0837] Step 1: Synthesis of rac-methyl (R)-l-(6-chloropyridazin-4-yl)-3-fluoropyrrolidine-3-carboxylate Cl F 0

[0838]

[0839] The title compound was synthesized as described for Intermediate 1, Step 3, using rac-methyl (R)-3-fluoropyrrolidine-3-carboxylate to afford the title compound (1.4 g, 40% yield) as a brown oil. LCMS C10H11CIFN3O2 requires 259.1, found m / z = 260.2. [M+H]+.

[0840] Step 2: Synthesis of the title compound (Intermediate 28)

[0841] rac-methyl (R)-1-(6-chloropyridazin-4-yl)-3-fluoropyrrolidine-3-carboxylate (1.4 g, 5.39 mmol) and potassium carbonate (5.39 mL, 2.2 g, 16.2 mmol) were combined and dissolved in 1,4 dioxane (21.60 mL), followed by sparging with N2for 10 minutes. Next, tetrakis(triphenylphosphine)palladium(0) (623 mg, 0.54 mmol) was added and the reaction mixture was placed in a pre-heated plate at 100 °C and stirred at this temperature until complete as judged by LCMS. After that, the reaction mixture was cooled down to room temperature and filtered to remove the precipitate formed upon cooling, with 10% MeOH in EA rinsing. The collected organic layer was washed with water (50 ml) and brine (50 ml), dried with anhydrous Na2SC>4, filtered and then concentrated to a crude oil. The crude residue was purified via flash chromatography (0-100% EtOAc / Hex, then 40% MeOH in DCM) to afford the title compound (484.7 mg, 26% yield), as a yellow oil. LCMS C17H18FN3O4 requires 347.1, found m / z = 348.2 [M+H]+.

[0842] INTERMEDIATE 29

[0843] RAC-(R)-2-(1-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)-4-HYDROXYPIPERIDIN-4-YL)ACETALDEHYDE

[0844]

[0845] Step 1: Synthesis of l-(4-nitrophenyl)piperidin-4-one

[0846]

[0847] To a solution of piperidin-4-one hydrochloride (100.0 g, 737.5 mmol) in DMF (500 mL) was added 4-Fluoronitrobenzene (83.3 g, 590.0 mmol) and DIPEA (286.0 g, 2212.5 mmol), then the reaction mixture was stirred at 80°cfor 5 h. The reaction mixture was then poured into water (1500 mL). The formed precipitate was collected by filtration, washed with water (800 mL) and dried to give a residue. The residue was triturated with Petroleum ether / EtOAc = 5:1 (800 mL) and filtered to afford the title compound (110.0 g, 68% yield) as a yellow solid. LCMS C11H12N2O requires 220.08, found m / z = 221.1 [M+H]+.

[0848] Step 2: Synthesis of tert-butyl 2-(4-hydroxy-l-(4-nitrophenyl)piperidin-4-yl)acetate

[0849] OH

[0850]

[0851] To a solution of tert-butyl acetate (53.8 g, 463.2 mmol) in THF (640 mL) was added LDA (2M in THF) (386 mL, 771.9 mmol) dropwise at -78°C. And the reaction mixture was stirred at -78°C for 30 min, then the mixture was added l-(4-nitrophenyl)piperidin-4-one (Intermediate 30 Step 1, 85.0 g, 386.0 mmol) in THF (1280 mL) dropwise at -78°C, and the reaction mixture was stirred at -10°C for 2 h. The reaction mixture was then quenched by the addition of saturated aqueous NH4Cl solution (350 mL) and extracted with EtOAc (1000 mL x 3). The combined organic phases were washed with brine (800 mL), dried over Na2SO4and concentrated to afford the title compound (120.0 g, crude) as a brown solid, which was used for next step without any further purification. LCMS C17H24N2O5 requires 336.2, found m / z = 337.2 [M+H]+.

[0852] Step 3: Synthesis of tert-butyl 2-(l-(4-aminophenyl)-4-hydroxypiperidin-4-yl)acetate

[0853] OH

[0854]

[0855] To a solution of (tert-butyl 2-(4-hydroxy-l-(4-nitrophenyl)piperidin-4-yl)acetate (Intermediate 29 Step 2, 105.0 g, 312.1 mmol) in EtOH (2000 mL) and H2O (400 mL) was added Fe powder (34.9 g, 624.0 mmol) and NH4CI (83.5 g, 1560.7 mmol) at room temperature. The mixture was stirred at 100 °C for 1 h. The mixture was then cooled to room temperature and filtered with EtOH rinsing, and the recovered filtrate was concentrated under reduced pressure to afford a crude residue. The residue was then dissolved in EtOAc (2000 mL) and washed with brine (500 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (Petroleum ether / EtOAc = 2: 1-1:1) to afford the title compound (70.0 g, 68% yield over two steps) as a yellow solid. LCMS C17H26N2O3 requires 306.2, found m / z = 307.1 [M+H]+. Step 4: Synthesis of tert-butyl 2-(4-hydroxy-l-(4-iodophenyl)piperidin-4-yl)acetate

[0856] OH

[0857]

[0858] To a solution of p-Toluenesulfonic acid monohydrate (117.4 g, 617.3 mmol) in / -BuOH (700 mL) was added tert-butyl 2-(l-(4-aminophenyl)-4-hydroxypiperidin-4-yl)acetate (Intermediate 30 Step 3, 70.0 g, 228.6 mmol) in ACN (350 mL) dropwise at 25°C. Then to the reaction mixture was added NaNCL (31.5 g, 456.9 mmol) and KI (94.9 g, 571.5 mmol) in H2O (350 mL) dropwise at 25°C, and the reaction mixture was stirred at 60°C for 4 h. To the mixture was added H2O (5000 mL) and extracted with EtOAc (800 mL x 3), the combined organic layers were washed with brine (500 mL), dried overNa2SO4and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (Petroleum ether / EtOAc = 10: 1-5:1) to afford the title compound (54.2 g, 57% yield) as a yellow solid. LCMS C17H24INO3 requires 417.1, found m / z = 418.0 [M+H]+.

[0859] Step 5: Synthesis of tert-butyl 2-(l-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-4-hydroxypiperidin-4-yl)acetate

[0860] OH

[0861]

[0862] To a solution of tert-butyl 2-(4-hydroxy-l-(4-iodophenyl)piperidin-4-yl)acetate (Intermediate 29, Step 4, 50.0 g, 119.8 mmol) in 1,2-dioxane (250 mL) and H2O (50 mL) was added 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) pyridine (62.5 g, 149.8 mmol), CS2CO3 (78.2 g, 239.9 mmol, and Pd(dppf)C12 (2.5 g, 3.8 mmol, at room temperature. The mixture was stirred at 100 °C for 3 h. The mixture was then cooled to room temperature and filtered, the filtrate was concentrated to give a residue, then the residue was diluted with EtOAc (900 mL). The combined organic layers were washed with brine (400 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (Petroleum ether / EtOAc = 8: 1-1:1) afford the title compound (58.0 g, 84% yield) as a yellow solid. LCMS C36H40N2O5 requires 580.3, found m / z = 581.1 [M+H]+.

[0863] Step 6: Synthesis of l-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-4-(2-hydroxyethyl)piperidin-4-ol

[0864]

[0865] To a solution of tert-butyl 2-(l-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-4-hydroxypiperidin-4-yl)acetate (Intermediate 29 Step 5, 30.0 g, 51.7 mmol) in THF (600 mL) was added LiAlEL (IM in THF) (103 mL, 103.3 mmol) dropwise at 0°cunder N2, then the reaction mixture was stirred at room temperature for 12 h. Once complete, the reaction mixture was cooled to 0°C, and the reaction mixture was quenched via addition of H2O (4 mL), followed by 15% aqueous NaOH (4 mL) dropwise. After quenching, the reaction was diluted with H2O (12 mL), and the mixture was filtered through a celite pad. The filtrate was concentrated to dryness to give a residue. The residue was purified by silica gel column chromatography (Petroleum ether / EtOAc = 1: 1) to afford the title compound (21.0 g, 80% yield) as a white solid. LCMS C32H34N2O4 requires 510.3, found m / z = 511.5 [M+H]+.

[0866] Step 7: Synthesis of rac-(R)-3-(4-(4-hydroxy-4-(2-hydroxyethyl)piperidin-l-yl)phenyl)piperidine-2, 6-dione

[0867]

[0868] A mixture of l-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-4-(2-hydroxyethyl)piperidin-4-ol (Intermediate 29, Step 6, 19.0 g, 37.2 mmol) and Pd / C (7.6 g, 0.4 V) in DCM (285 mL) and MeOH (285 mL) was stirred under H2 at room temperature for 12 h. Once complete, the mixture was filtered, and the filtrate was concentrated to afford the title compound (12.0 g, crude) as a white solid, which was used for next step without any further purification. LCMS C18H24N2O4 requires 332.2, found m / z = 333.0 [M+H]+.

[0869] Step 8: Synthesis of the title compound (Intermediate 29)

[0870] To a solution of rac-(A)-3-(4-(4-hydroxy-4-(2-hydroxyethyl)piperidin- l-yl)phenyl)piperidine-2, 6-dione (Intermediate 29 Step 7, 10.5 g, 31.6 mmol) in DMSO (105 mL) was added IBX (17.9 g, 63.2 mmol), then the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was added dropwise into saturated aqueous Na2CC>3 solution (210 mL) at 0°C and extracted with DCM (500 mL x 4). The combined organic phases were washed with saturated aqueous Na2S2C>3 solution (300 mL x 3), dried over Na2SO4and concentrated to give a residue. The residue was triturated with EtOAc (40 mL) and filtered to afford the title compound (5.4 g, 50% yield over two steps) as a yellow solid. LCMS C18H22N2O4 requires 330.2, found m / z = 331.0 [M+H]+.

[0871] INTERMEDIATE 30

[0872] RAC-(R)-3-(4-(2-OXO-7-AZASPIRO[3.5]NONAN-7-YL)PHENYL)PIPERIDINE-2,6-DIONE

[0873] O

[0874]

[0875] Step 1: Synthesis of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine

[0876] BnO

[0877] / =\ \=N

[0878] Br — d d OBn

[0879]

[0880] To a mixture of 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (6.00 g, 14.3 mmol), l-bromo-4-iodobenzene (4.88 g, 17.2 mmol) in dioxane (60.0 mL) and H2O (12.0 mL) was added K2CO3 (3.97 g, 28.7 mmol), Pd(dppf)C12. CH2C12 (1.17 g, 1.44 mmol) at 15 - 25 °C under N2. The resulting mixture was heated to 80 °C and stirred until complete as judged by LCMS. Once complete, mixture was poured into H2O (150 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50.0 mL), dried with Na2SO4, filtered and concentrated in vacuo to a crude residue. The residue was purified by column chromatography (Petroleum ether / Ethyl acetate = 70 / 1 to 10 / 1) to afford the title compound (4.70 g, 71% yield) as a white solid. LCMS C25H20BrNO2requires 445.1, found m / z = 446.1 [M+H]+.

[0881] Step 2: Synthesis of 7-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-7-azaspiro[3.5]nonan-2-one

[0882] BnO

[0883]

[0884] To a mixture of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (4.30 g, 9.63 mmol), 7-azaspiro[3.5]nonan-2-one hydrochloride (2.20 g, 12.5 mmol) in 2-methyltetrahydrofuran (43.0 mL) was added CS2CO3 (12.5 g, 38.5 mmol), DavePhos (758 mg, 1.93 mmol), Pd2(dba)s (882 mg, 963 pmol) at 15 - 25 °C under N2. The resulting mixture was stirred at 80 °C. After 16h, the mixture was cooled to 15 -25°C, and more Pd2(dba)s (1.32 g, 1.45 mmol), DavePhos (1.14 g, 2.89 mmol) was added under N2. Then the resulting mixture was stirred at 80 °C until complete as judged by LCMS. Once complete, the reaction mixture was cooled to RT and the mixture was poured into H2O (80.0 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried with Na2SO4, filtered and concentrated in vacuo to afford a crude residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 5 / 1). Then the purified residue was triturated with MeCN (15 mL) at 25°C for 30 mins, then filtered with MeCN rinsing. The filtrate was concentrated under reduced pressure to afford a purified residue. The purified material was subjected to prep-HPLC (Phenomenex Luna C18 (250*70mm,10 um), H2O / ACN with 0.1% FA, 70%-99%), and desired material was collected and concentrated under reduced pressure to remove MeCN. The remaining aqueous layer was adjusted pH to 7 - 8 with NaHCCL (solid), extracted with ethyl acetate (50.0 mL x 3), and the combined organic layers were washed with brine (50.0 mL), dried with Na2SO4, filtered and concentrated in vacuum to afford the desired product (1.9 g, 38% yield) was obtained as a yellow solid. LCMS C33H32N2O3 requires 504.2, found m / z = 505.2 [M+H]+.

[0885] Step 3: Synthesis of the title compound (Intermediate 30)

[0886] To amixture of 7-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-7-azaspiro[3.5]nonan-2-one (1.80 g, 3.57 mmol) in THF (45.0 mL) was added Pd / C (540 mg, 507 pmol, 10% purity), then Pd(OH)2 (540 mg, 769 pmol, 20% purity) under N2. The suspension was degassed and purged with H23 times. The mixture was stirred under H2 (50 psi) at 25 °C until complete as judged by LCMS. The mixture was filtered through a pad of celite with cold THF rinsing and the combined filtrate was concentrated under reduced pressure to give a crude residue. The residue was purified by prep-HPLC (Waters Xbridge Cl 8 150*50mm* lOum, mobile phase: [water(NH4HCO3)-ACN]; gradient: 18%-48%) then lyophilized to afford the title compound (750 mg, 63% yield) as a white solid. LCMS C19H22N2O3 requires 326.2 found m / z = 327.2 [M+H]+. INTERMEDIATE 31

[0887] 4-(DIFLUOROMETHOXY)-l-(6-(2-(METHOXYMETHOXY)PHENYL)PYRID AZIN-4- YL)PIPERIDINE-4- CARBOXYLIC ACID F

[0888] F

[0889]

[0890] Step 1: tert-butyl 4-((benzyloxy)methyl)-4-hydroxypiperidine-l-carboxylate

[0891] BnO

[0892]

[0893] Boc

[0894] To a solution of BnOH (17.2 g, 159 mmol, 16.5 mL, 1.70 eq) in DMF (120 mL) was added NaH (7.50 g, 187 mmol, 60% purity, 2.00 eq) under N2 at 0 °C and the reaction mixture was stirred at 25 °C for 0.5 hr. tert-butyl l-oxa-6-azaspiro[2.5]octane-6-carboxylate (20.0 g, 93.7 mmol, 1.00 eq) in DMF (80.0 mL) was dropwise added to the above solution under N2 at 0 °C and the reaction mixture was stirred at 25 °C for 2 hrs. The reaction mixture was quenched slowly by saturated NH4CI (150 mL) under N2 at 0 °C. The organic layers was extracted with ethyl acetate (150 mL * 2), washed with brine (200 mL), dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate = 1 / 0 ~ 5 / 1, Petroleum ether / Ethyl acetate = 3 / 1, Rf = 0.30, PMA) and concentrated. Tert-butyl 4-((benzyloxy)methyl)-4-hydroxypiperidine-l -carboxylate (9.30 g, 24.6 mmol, 26.2% yield, 85.2% purity) was obtained as a yellow oil. LCMS: RT = 0.548 min, m / z = 322.3 (M+H)+’HNMR (400 MHz, CDCl3): S 7.38 - 7.31 (m, 5H), 4.56 (s, 2H), 3.82 (s, 2H), 3.32 (s, 2H), 3.21 - 3.15 (m, 2H), 1.65 - 1.62 (m, 2H), 1.52 - 1.47 (m, 2H), 1.45 (s, 9H).

[0895] Step 2: tert-butyl 4-((benzyloxy)methyl)-4-(difluoromethoxy)piperidine-l-carboxylate

[0896]

[0897] Boc

[0898] To a solution of tert-butyl 4-((benzyloxy)methyl)-4-hydroxypiperidine-l -carboxylate (7.30 g, 22.7 mmol, 1.00 eq) and Cui (865 mg, 4.54 mmol, 0.20 eq) in ACN (70.0 mL) was dropwise added 2,2-difluoro-2-(fluorosulfonyl)acetic acid (16.1 g, 90.8 mmol, 9.39 mL, 4.00 eq) in ACN (20.0 mL) at 55 °C and the reaction mixture was stirred at 55 °C for 4 hrs. Additional 2,2-difluoro-2-(fluorosulfonyl)acetic acid (8.09 g, 45.4 mmol, 4.70 mL, 2.00 eq) was dropwise added to the above solution and the reaction mixture was stirred at 55 °C for 2 hrs. The reaction mixture was poured into saturated NaHC’CF solution (200 mL) and extracted with EtOAc (150 mL * 2). The organic layer was washed with brine (200 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate = 1 / 0 ~ 5 / 1, Petroleum ether / Ethyl acetate = 3 / 1, Rf = 0.43, PMA) and concentrated. The crude was purified by Prep-HPLC (column: Phenomenex luna C18 (250 * 70 mm, 10 um); mobile phase: [H2O (0.05% HC1) - ACN]; gradient: 45% - 85% B over 30.0 mins) and adjust to pH = 8 ~ 9 with saturated NaHCOs solution. The organic layers were extracted with EtOAc (100 mL * 2), washed with brine (150 mL), dried over Na₂SO₄, filtered and concentrated. Tert-butyl 4-((benzyloxy)methyl)-4-(difluoromethoxy)piperidine-l-carboxylate (1.10 g, 2.87 mmol, 12.6% yield, 96.8% purity) was obtained as yellow oil. LCMS: RT = 0.631 min, m / z = 272.1 (M-t-Bu+H). 'H NMR (400 MHz, DMSO): d 7.38 - 7.27 (m, 5H), 6.91 (t, J= 75.6 Hz, 1H), 4.50 (s, 2H), 3.67 - 3.64 (m, 2H), 3.57 (s, 2H), 3.02 (s, 2H), 1.82 - 1.79 (m, 2H), 1.62 - 1.55 (m, 2H), 1.38 (s, 9H).

[0899] Step 3: tert-butyl 4-((benzyloxy)methyl)-4-(difluoromethoxy)piperidine-l-carboxylate

[0900]

[0901] To a solution of tert-butyl 4-((benzyloxy)methyl)-4-(difluoromethoxy)piperidine-l -carboxylate (1.10 g, 2.96 mmol, 1.00 eq) in DCM (10.0 mL) was added TFA (1.69 g, 14.8 mmol, 1.10 mb, 5.00 eq) and the reaction mixture was stirred at 25 °C for 3 hrs. The reaction mixture was adjusted to pH = 8 ~ 9 with sat. NaHCOs solution and extracted with DCM (50.0 mL * 2). The organic layer was washed with brine (80.0 mL), dried over Na₂SO₄, filtered and concentrated. Tert-butyl 4-((benzyloxy)methyl)-4-(difluoromethoxy)piperidine-1-carboxylate (800 mg, 2.95 mmol, 99.56% yield) was obtained as yellow oil. ’H NMR (400 MHz, DMSO): d 7.37 - 7.29 (m, 5H), 6.89 (t, J= 75.6 Hz, 1H), 4.51 (s, 2H), 3.55 (s, 2H), 2.86 - 2.75 (m, 4H), 1.83 - 1.80 (m, 2H), 1.73 - 1.66 (m, 2H)

[0902] Step 4: (4-(difluoromethoxy)piperidin-4-yl)methanol

[0903]

[0904] To a solution of Pd / C (0.50 g, 10% purity) in EtOH (50.0 mL) was added tert-butyl 4-((benzyloxy)methyl)-4-(difluoromethoxy)piperidine-l-carboxylate (1.00 g, 3.69 mmol, 1.00 eq) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (50 Psi.) at 50 °C for 12 hrs. The reaction mixture was filtered and the filtrate was concentrated. (4-(difluoromethoxy)piperidin-4-yl)methanol (630 mg, 3.48 mmol, 94.3% yield) was obtained as yellow oil. ’H NMR (400 MHz, DMSO): d 6.91 (t, J= 76.4 Hz, 1H), 3.49 (s, 2H), 2.85 - 2.77 (m, 4H), 1.74 -1.64 (m, 4H). Step 5: (l-(6-chloropyridazin-4-yl)-4-(difluoromethoxy)piperidin-4-yl)methanol

[0905]

[0906] To a solution of (4-(difluoromethoxy)piperidin-4-yl)methanol (630 mg, 3.48 mmol, 1.00 eq) in DMSO (6.00 mL) was added DIPEA (1.35 g, 10.4 mmol, 1.82 mL, 3.00 eq) and 3,5-dichloropyridazine (518 mg, 3.48 mmol, 1.00 eq) and the reaction mixture was stirred at 100 °C for 1 hr. The mixture was cooled to 25 °C. The reaction mixture was poured into water (10.0 mL) and extracted with DCM (20.0 mL * 2). The organic layer was washed with brine (20.0 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC (column: Phenomenex luna C18 (250 * 70 mm, 10 um); mobile phase: [H2O (0.05% HC1) - ACN]; gradient: 0% - 40% B over 30.0 mins). The residue was concentrated and extracted with DCM (50.0 mL * 2), washed with brine (70.0 mL), dried over Na2SO4, filtered and concentrated. (l-(6-chloropyridazin-4-yl)-4-(difluoromethoxy)piperidin-4-yl)methanol (640 mg, 1.53 mmol, 43.8% yield, 70% purity) was obtained as a brown solid. LCMS: RT = 0.410 min, m / z = 294.2 (M+H)+

[0907] Step 6: (4-(difluoromethoxy)-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperidin-4-yl)methanol

[0908]

[0909] To a solution of (l-(6-chloropyridazin-4-yl)-4-(difluoromethoxy)piperidin-4-yl)methanol (640 mg, 2.18 mmol, 1.00 eq) in dioxane (12.0 mL) and H2O (3.00 mL) was added (2-(methoxymethoxy)phenyl)boronic acid (594 mg, 3.27 mmol, 1.50 eq), K2CC>3 (602 mg, 4.36 mmol, 2.00 eq) and Pd(PPhs)4 (251 mg, 217 pmol, 0.10 eq) and the reaction mixture was stirred at 85 °C for 5 hrs. The mixture was poured into water (20.0 mL) and extracted with DCM (30.0 mL * 2). The combined organic phase was washed with brine (20.0 mL), dried with anhydrous Na2SC>4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / EtOAc = 3 / 1 ~ DCM / MeOH = 5 / 1, DCM / MeOH = 10 / 1, Rf = 0.05, 12) and concentrated in vacuum. (4-(difluoromethoxy)-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperidin-4-yl)methanol (700 mg, 1.50 mmol, 69.0% yield, 85% purity) was obtained as a yellow solid. LCMS: RT = 0.493 min, m / z = 396.3 (M+H)+. ’H NMR (400 MHz, DMSO): d 8.97 (s, 1H), 7.87 - 7.60 (m, 1H), 7.43 - 7.39 (m, 1H), 7.26 - 7.19 (m, 2H), 7.13 - 6.81 (m, 2H), 5.23 - 5.19 (m, 2H), 3.83 - 3.80 (m, 2H), 3.57 - 3.54 (m, 2H), 3.38 - 3.28 (m, 5H), 1.90 - 1.82 (m, 2H), 1.75 - 1.69 (m, 2H). Step 7: 4-(difluoromethoxy)-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperidine-4-carboxylic acid

[0910]

[0911] To a solution of (4-(difluoromethoxy)-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperidin-4-yl)methanol (1.20 g, 3.03 mmol, 1.00 eq) in DCM (24.0 mL) was added DMP (5.15 g, 12.1 mmol, 3.76 mL, 4.00 eq) and the reaction mixture was stirred at 25 °C for 12 hrs. The reaction mixture was added sat. Na2S2O3solution (20.0 mL) and stirred for 1 hr, filtered and concentrated in vacuum. The crude was purified by Prep-HPLC (column: Kromasil Eternity XT 250 * 70 mm * 10 um; mobile phase:

[0912] [H2O (10 mM NH4HCO3) - ACN]; gradient: 0% - 20% B over 20.0 mins), filtered and concentrated in vacuum. The product was dissolved in water and freeze-dried directly. The crude was purified by Prep-HPLC (column: Kromasil Eternity XT 250 * 70 mm * 10 um; mobile phase: [H2O (0.05%NH3H20) -ACN]; gradient: 0% - 20% B over 20.0 mins). The product was dissolved in water and freeze-dried directly. 4-(difluoromethoxy)-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperidine-4-carboxylic acid (515 mg, 1.24 mmol, 40.7% yield, 98.1% purity) was obtained as a yellow solid. LCMS: RT = 0.681 min, m / z = 410.1 (M+H)+. ’HNMR(400 MHz, DMSO): d 8.98 (s, 1H), 7.63 - 7.61 (m, 1H), 7.43 - 7.39 (m, 1H), 7.26 - 7.22 (m, 2H), 7.14 - 6.77 (m, 2H), 5.20 (s, 2H), 3.88 - 3.85 (m, 2H), 3.31 (s, 3H), 3.29 -3.23 (m, 2H), 2.11 -2.03 (m, 2H), 1.90 - 1.86 (m, 2H)

[0913] INTERMEDIATE 32

[0914] l-(6-(2-(METHOXYMETHOXY)PHENYL)PYRIDAZIN-4-YL)-4-METHYLPIPERIDINE-4-CARBOXYLIC ACID

[0915]

[0916] Step 1: methyl 4-methylpiperidine-4-carboxylate hydrochloride

[0917] OMe

[0918] HN^ O

[0919]

[0920] HCI

[0921] A mixture of 1 -(tert-butyl) 4-methyl 4-methylpiperidine-l,4-dicarboxylate (1.00 g, 3.89 mmol, 1.00 eq) in HCl / EtOAc (15.0 mL, 2M) was stirred at 20 °C for 2 hrs. The mixture was concentrated to get methyl 4-methylpiperidine-4-carboxylate hydrochloride (750 mg, crude, HCI) as a light yellow solid. MS: m / z = 158.2 (M+H)+ Step 2: methyl l-(6-chloropyridazin-4-yl)-4-methylpiperidine-4-carboxylate

[0922]

[0923] To a solution of methyl 4-methylpiperidine-4-carboxylate hydrochloride (550 mg, 2.84 mmol, 1.00 eq, HC1) and 3,5-dichloropyridazine (423 mg, 2.84 mmol, 1.00 eq) in IPA (5.00 mL) was added DIEA (1.47 g, 11.4 mmol, 1.98 mL, 4.00 eq) under N2 atmosphere, and the mixture was stirred at 70 °C for 12 hrs. The mixture was diluted with MeOH (5.00 mL) and purified by prep-HPLC (column:

[0924] Kromasil Eternity XT 250*70mm* 10um;mobile phase: [H20(0.05% NH3H2O)-ACN] gradient: 15%-45% B over 20.0 min), concentrated to remove most ACN, then extracted with EtOAc (100 mL * 2), the combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. Methyl l-(6-chloropyridazin-4-yl)-4-methylpiperidine-4-carboxylate (600 mg, 2.19 mmol, 77.0% yield over two steps, 98.3% purity) was obtained as a light yellow solid. LCMS: Rt = 0.843 min, m / z = 270.1 (M+H)+

[0925] Step 3: methyl l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-4-methylpiperidine-4-carboxylate

[0926]

[0927] To a solution of methyl l-(6-chloropyridazin-4-yl)-4-methylpiperidine-4-carboxylate (600 mg, 2.22 mmol, 1.00 eq), (2-(methoxymethoxy)phenyl)boronic acid (810 mg, 4.45 mmol, 2.00 eq) and K2CO3 (922 mg, 6.67 mmol, 3.00 eq) in dioxane (6.00 mL) and H2O (1.50 mL) was added Pd(dppf)C12. CH2C12 (182 mg, 222 pmol, 0.100 eq) under N2 atmosphere, and the mixture was stirred at 100 °C for 2 hrs. The mixture was cooled to 25 °C and poured into H2O (20.0 mL), extracted with EtOAc (20.0 mL * 3), the combined organic layer was washed with brine (30.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 1 to 0 / 1, Petroleum ether / Ethyl acetate = 0 / 1, Rf = 0.2). methyl l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-4-methylpiperidine-4-carboxylate (800 mg, 2.09 mmol, 94.0% yield, 97.1% purity) was obtained as a yellow oil. LCMS: Rt = 0.499 min, m / z = 372.2 (M+H)+Step 4: l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-4-methylpiperidine-4-carboxylic acid

[0928]

[0929] To a solution of methyl l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-4-methylpiperidine-4-carboxylate (800 mg, 2.15 mmol, 1.00 eq) in MeOH (8.00 mL) and H2O (4.00 mL) was added LiOH. H2O (181 mg, 4.31 mmol, 2.00 eq), then the mixture was stirred at 60 °C for 12 hrs. The mixture was cooled to 30 °C and concentrated, adjusted pH to about 7 with 2N HC1 (keep temperature below 25 °C), then concentrated under reduced pressure. The crude was purified by pre-HPLC (column: Kromasil Eternity XT 250*70mm* 10um;mobile phase: [H20(0.05% NH3H2O)-ACN] gradient: 0%-20% B over 20.0 min), concentrated to remove most ACN, then lyophilized. l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-4-methylpiperidine-4-carboxylic acid (0.72 g, 2.00 mmol, 92.9% yield, 99.3% purity) was obtained as an off-white solid. LCMS: Rt = 0.327 min, m / z = 358.2 (M+H)+. ’H NMR (400 MHz, DMSO): d 8.88 (d, J = 3.2 Hz, 1H), 7.61 (dd, J= 1.6, 7.6 Hz, 1H), 7.44 - 7.35 (m, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.17 - 7.07 (m, 2H), 5.20 (s, 2H), 3.72 (br d, J= 13.2 Hz, 2H), 3.32 (s, 3H), 3.13 (brt, J= 10.8 Hz, 2H), 2.06 (br d, J= 13.2 Hz, 2H), 1.29 - 1.15 (m, 2H), 1.01 (s, 3H)

[0930] INTERMEDIATE 33

[0931] l-(6-(2-(ME THOXYMETHOXY)PHENYL)PYRID AZIN-4- YL)-4-PROPYLPIPERIDINE-4-CARBOXYLIC ACID

[0932]

[0933] Step 1: 1 -(tert-butyl) 4-methyl 4-propylpiperidine-l,4-dicarboxylate

[0934] / oMe

[0935] DBoc

[0936]

[0937] O

[0938] To a solution of 1 -(tert-butyl) 4-methyl piperidine- 1,4-dicarboxylate (4.00 g, 16.4 mmol, 1.00 eq) in THF (60.0 mL) was added LDA (2 M, 9.86 mL, 1.20 eq) at -65 °C under N2 and stirred at -65 °C for 1 hr. Then 1-iodopropane (4.19 g, 24.6 mmol, 2.41 mL, 1.50 eq) in THF (20.0 mL) was added dropwise at -65 °C under N2. The mixture was stirred at 25 °C for 12 hrs under N2. The mixture was poured into saturated NH4CI (500 mL) aqueous solution slowly under N2 at 0~10 °C, extracted with EtOAc (200 mL * 2). The combined organics were washed with brine (200 mL), dried over Na2SO4and concentrated. The residue was used for next step without further purification. 1 -(tert-butyl) 4-methyl 4-propylpiperidine- 1,4-dicarboxylate (4.10 g, crude) was obtained as a yellow oil. ’H NMR (400 MHZ, CDC13): 53.80 (d, J= 8.8 Hz, 2H), 3.63 (s, 3H), 2.78 (s, 2H), 2.09 - 1.98 (m, 2H), 1.45 - 1.35 (m, 11H), 1.34 - 1.22 (m, 2H), 1.18 - 1.10 (m, 2H), 0.80 (t, J= 7.2 Hz, 3H)

[0939] Step 2: methyl 4-propylpiperidine-4-carboxylate hydrochloride

[0940] OMe

[0941] NH^ o

[0942]

[0943] HCI

[0944] A solution of 1 -(tert-butyl) 4-methyl 4-propylpiperidine- 1,4-dicarboxylate (4.10 g, 14.3 mmol, 1.00 eq) in HCl / EtOAc (2 M, 100 mL) was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under vacuum at 40 °C. The residue was used for next step without further purification. Methyl 4-propylpiperidine-4-carboxylate hydrochloride (3.10 g, crude, HC1) was obtained as an off-white solid.

[0945] Step 3: methyl l-(6-chloropyridazin-4-yl)-4-propylpiperidine-4-carboxylate

[0946]

[0947] To a solution of methyl 4-propylpiperidine-4-carboxylate hydrochloride (2.98 g, 13.4 mmol, 1.00 eq, HC1) and 3,5-dichloropyridazine (2.40 g, 16.1 mmol, 1.20 eq) in IPA (30.0 mL) was added DIEA (8.69 g, 67.2 mmol, 11.7 mL, 5.00 eq) under N2 atmosphere, and the mixture was stirred at 70 °C for 12 hrs. The mixture was concentrated in vacuum at 40 °C. The residue was purified by flash silica gel chromatography (SiCL: Petroleum ether / Ethyl acetate = 1 / 0 to 0 / 1, Commercial hexanes / Methanol = 1 / 2, Rf = 0.50, 12). Methyl l-(6-chloropyridazin-4-yl)-4-propylpiperidine-4-carboxylate (2.85 g, 9.55 mmol, 71.0% yield, 99.8% purity) was obtained as a brown solid. LCMS: RT = 0.939 min, m / z = 298.1 (M+H)+’HNMR (400 MHz, CDCh): S 8.70 (d, J= 2.8 Hz, 1H), 6.63 (d, J= 2.8 Hz, 1H), 3.73 (s, 3H), 3.73 - 3.66 (m, 2H), 3.14 - 2.99 (m, 2H), 2.28 (d, J= 13.4 Hz, 2H), 1.57 - 1.44 (m, 4H), 1.29 - 1.16 (m, 2H), 0.89 (t, J= 7.2 Hz, 3H)

[0948] Step 4: methyl l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-4-propylpiperidine-4-carboxylate

[0949]

[0950] To a solution of methyl l-(6-chloropyridazin-4-yl)-4-propylpiperidine-4-carboxylate (2.00 g, 6.72 mmol, 1.00 eq), (2-(methoxymethoxy)phenyl)boronic acid (2.44 g, 13.4 mmol, 2.00 eq) and K2CO3 (2.78 g, 20.1 mmol, 3.00 eq) in dioxane (20.0 mL) and H2O (4.00 mL) was added Pd(dppf)C12. CH2C12 (548 mg, 671 pmol, 0.10 eq) at 25 °C under N2 atmosphere, and the mixture was stirred at 100 °C for 12 hrs. The reaction mixture was cooled to 40 °C and diluted with water (200 mL) and extracted with EtOAc (100 mL * 3), and the combined organic layers were washed with brine (200 mL), dried over Na2SO4 and concentrated to obtain crude product under vacuum. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate = 1 / 0 to 0 / 1, Dichloromethane / Methanol = 0 / 1, Rf = 0.30) to give methyl l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-4-propylpiperidine-4-carboxylate (1.46 g, 3.60 mmol, 53.6% yield, 98.5% purity) was obtained as a black brown solid, which was confirmed by LCMS: RT = 1.000 min, m / z = 400.2 (M+H)+ Step 5: l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-4-propylpiperidine-4-carboxylic acid

[0951]

[0952] To a solution of methyl l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-4-propylpiperidine-4-carboxylate (1.00 g, 2.50 mmol, 1.00 eq) in MeOH (10.0 mL) was added a solution of LiOH.H₂O (315 mg, 7.51 mmol, 3.00 eq) in H₂O (5.00 mL). The mixture reaction was stirred at 60 °C for 12 hrs. The mixture was concentrated in vacuum, adjusted pH to about 7 with 2N HC1, concentrated in vacuum. The crude product was purified by reversed-phase HPLC (column: Kromasil Eternity XT

[0953] 250*70mm* 10um;mobile phase: [H20(0.05% NH3H2O)-ACN] gradient: 0%-25% B over 20.0 min), concentrated to removed most ACN and lyophilization. l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-4-propylpiperidine-4-carboxylic acid (0.70 g, 1.80 mmol, 71.8% yield, 99.0% purity) was obtained as a light yellow solid. LCMS: RT = 0.696 min, m / z = 386.2 (M+H)+. ’H NMR (400 MHz, DMSO): <58.89 (d, J=2.8 Hz, 1H), 7.61 (d, J= 1.6, 7.6Hz, 1H), 7.44 - 7.36 (m, 1H), 7.22 (d, J= 8.2 Hz, 1H), 7.18 - 7.07 (m, 2H), 5.20 (s, 2H), 3.80 (d, J= 13.2 Hz, 2H), 3.32 (s, 3H), 3.06 (t, J= 11.4 Hz, 2H), 2.08 (d, J= 12.8 Hz, 2H), 1.38 - 1.17 (m, 6H), 0.80 (t, J= 7.2 Hz, 3H)

[0954] INTERMEDIATE 34

[0955] 4-CYCLOPROPYL-l-(6-(2-(METHOXYMETHOXY)PHENYL)PYRID AZIN-4- YL)PIPERIDINE-4-CARBOXYLIC

[0956] ACID

[0957]

[0958] Step 1: l-(rert-butyl) 4-methyl 4-(l-hydroxyethyl)piperidine-l,4-dicarboxylate

[0959] / -V^OMe

[0960]

[0961] N—7

[0962] „ /

[0963] Boc

[0964] To a solution of l-( / c' / 7-butyl) 4-methyl piperidine- 1,4-dicarboxylate (20.0 g, 82.2 mmol, 1.00 eq) in THF (200 mL) was added drop-wise LDA (2 M, 49.3 mL, 1.20 eq) at -65 °C under N2 and stirred at -65 °C under N2 for 1 hr. Then acetaldehyde (5.43 g, 123 mmol, 6.92 mL, 1.50 eq) in THF (40.0 mL) was added drop-wise at -65 °C under N2. The mixture was warmed to 0 °C slowly and stirred at 0 ~ 25 °C for 2 hrs under N2. The mixture was poured into saturated NH4CI ( 1.00 L) aqueous solution slowly under N2 at 0 ~ 10 °C, extracted with EtOAc (200 mL * 2). The combined organics were washed with brine (500 mL), dried overNa2SO4and concentrated. The crude was used for the next step directly. 1 -(tert-butyl) 4-methyl 4-(l-hydroxyethyl)piperidine- 1,4-dicarboxylate (23.6 g, crude) was obtained as a light yellow oil. 'HNMR: (400 MHz, CDC13) 33.96 (s, 2H), 3.72 (s, 3H), 3.66 - 3.63 (m, 1H), 2.79 - 2.71 (m, 2H), 2.42 (d, J= 7.2Hz, 1H), 2.16 -2.12 (m, 1H), 2.00 - 1.97 (m, 1H), 1.51 - 1.47 (m, 1H), 1.41 (s, 9H), 1.09 (d, J = 6.8 Hz, 3H).

[0965] Step 2: l-(tert-butyl) 4-methyl 4-(l-(((trifluoromethyl)sulfonyl)oxy)ethyl)piperidine-l,4-dicarboxylate

[0966]

[0967] To a solution of 1 -(tert-butyl) 4-methyl 4-(l-hydroxyethyl)piperidine-l,4-dicarboxylate (40.6 g, 141 mmol, 1.00 eq) in DCM (400 mL) was added dropwise Pyridine (44.7 g, 565 mmol, 45.6 mL, 4.00 eq) at 0 °C under N2, and then Tf2O (51.8 g, 184 mmol, 30.3 mL, 1.30 eq) was added dropwise at 0 °C under N2. The resulting mixture was stirred at 25 °C for 12 hrs. The reaction mixture was used to the next step without work-up. 1 -(tert-butyl) 4-methyl 4-(l-(((trifluoromethyl)sulfonyl)oxy)ethyl)piperidine-l,4-dicarboxylate (59.2 g, crude) was obtained as a black brown liquid.

[0968] Step 3: l-(rert-butyl) 4-methyl 4-vinylpiperidine-l,4-dicarboxylate

[0969]

[0970] To a solution of 1 -(tert-butyl) 4-methyl 4-(l-(((trifluoromethyl)sulfonyl)oxy)ethyl)piperidine-l,4-dicarboxylate (59.2 g, 141 mmol, 1.00 eq) in DCM (400 mL) was added DBU (64.5 g, 424 mmol, 63.9 mL, 3.00 eq) at 0 °C. The mixture was stirred at 25 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL. Commercial hexanes / Ethyl acetate = 1 / 0 to 10 / 1; Rf = 0.5, Commercial hexanes / Ethyl acetate = 5:1, KMnCL). Then the eluent was concentrated to give a residue, l-(tert-butyl) 4-methyl 4-vinylpiperidine-1,4-dicarboxylate (2.11 g, 7.83 mmol, 5.54% yield) was obtained as a light yellow oil. ’H NMR: (400 MHz, CDCk) S 5.82 - 5.75 (m, 1H), 5.19 - 5.10 (m, 2H), 3.74 - 3.70 (m, 5H), 3.09 - 3.03 (m, 2H), 2.13 (d, J= 13.6 Hz, 2H), 1.62- 1.56 (m, 2H), 1.44 (s, 9H).

[0971] Step 4: l-(tert-butyl) 4-methyl 4-cyclopropylpiperidine-l,4-dicarboxylate

[0972] / \7. OMe

[0973] _ o

[0974] Boc

[0975]

[0976] u

[0977] Solution 1: l-(tert-butyl) 4-methyl 4-vinylpiperidine-l,4-dicarboxylate, 1.00 eq, 2.11 g, 100%, 2.11 g in DCM, 42.0 mL

[0978] Solution 2: diazomethane, 6.00 eq, 1.9834 g, 0.75 M, 62.667 mL, 4.20%, 47.011 g (in 2-MeTHF) Solution 3: Pd(OAc)2, 0.01 eq, 0.0211 g, 0.01 M, 7.828 mL, 0.17%, 10.339 g (in DCM) The solution 1 was pumped by Pump 1 SI, Pl, 11.313 mL / min to flow reactor 1 FLR1, GL, CSTRs, 5.5 mL, 5 °C; flow reactor 2 FLR2, GL, CSTRs, 5.5 mL, 5 °C The solution 2 was pumped by Pump 2 S2, P2, 16.187 mL / min to flow reactor 1 FLR1, GL, CSTRs, 5.5 mL, 5 °C; flow reactor 2 FLR2, GL, CSTRs, 5.5 mL, 5 °C

[0979] The solution 3 was pumped by Pump 3 S3, P3, 2.024 mL / min to flow reactor 2 FLR2, GL, CSTRs, 5.5 mL, 5 °C

[0980] The residence time of flow reactor 1 was FLR1, 0.2 min

[0981] The residence time of flow reactor 2 was FLR2, 0.186 min

[0982] The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. This crude was used directly in next step without further purification. 1 -(tert-butyl) 4-methyl 4-cyclopropylpiperidine-l,4-dicarboxylate (1.55 g, crude) was obtained as a light yellow oil. ’HNMR: 3 3.96 (s, 2H), 3.70 (s, 3H), 2.78 - 2.72 (m, 2H), 1.99 (d, J= 12 Hz, 2H), 1.44 (s, 9H), 1.33 - 1.27 (m, 2H), 0.96 - 0.89 (m, 1H), 0.40 - 0.30 (m, 4H).

[0983] Step 5: methyl 4-cyclopropylpiperidine-4-carboxylate hydrochloride

[0984] H

[0985]

[0986] CI

[0987] A mixture of 1 -(tert-butyl) 4-methyl 4-cyclopropylpiperidine-l,4-dicarboxylate (1.55 g, 5.47 mmol, 1.00 eq) and HCl / EtOAc (2 M, 50.0 mL) was stirred at 25 °C for 1 hr. The mixture was concentrated under reduced pressure to get a residue. The crude was used for the next step directly. Methyl 4-cyclopropylpiperidine-4-carboxylate hydrochloride (1.20 g, crude, HCI) was obtained as a yellow solid.

[0988] Step 6: methyl l-(6-chloropyridazin-4-yl)-4-cyclopropylpiperidine-4-carboxylate

[0989]

[0990] To a solution of methyl 4-cyclopropylpiperidine-4-carboxylate hydrochloride ( 1.20 g, 5.46 mmol, 1.00 eq, HCI) and 3,5-dichloropyridazine (813 mg, 5.46 mmol, 1.00 eq) in IPA (8.00 mL) was added DIEA (2.82 g, 21.8 mmol, 3.81 mL, 4.00 eq) under N2 atmosphere, and the mixture was stirred at 70 ~ 80 °C for 12 hrs. The reaction mixture was cooled to 25 °C and concentrated under reduced pressure. The residue was purified by column chromatography (SiCL, Commercial hexanes / Ethyl acetate = 10 / 1 to 0 / 1; Rf = 0.1, Commercial hexanes / Ethyl acetate = 1 / 1). Then the eluent was concentrated under reduced pressure to give the product. Methyl l-(6-chloropyridazin-4-yl)-4-cyclopropylpiperidine-4-carboxylate (1.33 g, 4.47 mmol, 81.8% yield, 99.4% purity) was obtained as a yellow solid. C14H18CIN3O2 requires 295.1, found m / z = 296.1 [M+H]+. Step 7: methyl 4-cyclopropyl-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperidine-4-carboxylate

[0991]

[0992] To a solution of methyl l-(6-chloropyridazin-4-yl)-4-cyclopropylpiperidine-4-carboxylate (1.33 g, 4.50 mmol, 1.00 eq), (2-(methoxymethoxy)phenyl)boronic acid (818 mg, 4.50 mmol, 1.00 eq) and K2CO3 (932 mg, 6.75 mmol, 1.50 eq) in dioxane (15.0 mL) and H2O (3.00 mL) was added Pd(dppf)C12. CH2C12 (184 mg, 225 pmol, 0.05 eq) under N2 atmosphere and the mixture was stirred at 110 °C for 12 hrs. The mixture was cooled to 25 °C and concentrated under reduced pressure. The crude was purified by column chromatography (SiC>2, Hexane / Ethyl acetate = 1 / 1 to 0 / 1, Petroleum ether / Ethyl acetate = 0 / 1, Rf = 0.1). Then the eluent was concentrated to get the product. Methyl 4-cyclopropyl-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperidine-4-carboxylate (1.30 g, 3.22 mmol, 71.5% yield, 98.3% purity) was obtained as a brown oil. LCMS C22H27N3O4 requires 397.2, found m / z = 398.2 [M+H]+.

[0993] Step 8: 4-cyclopropyl-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperidine-4-carboxylic acid

[0994]

[0995] To a solution of methyl 4-cyclopropyl-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperidine-4-carboxylate (1.12 g, 2.82 mmol, 1.00 eq) in MeOH (10.0 mL) was added a solution of LiOH. H2O (355 mg, 8.45 mmol, 3.00 eq) in H2O (2.00 mL). The mixture was cooled to 25 °C and adjusted pH to about 7 with IN HC1 (keep temperature below 25 °C), then concentrated under reduced pressure. The crude was purified by pre-HPLC (basic condition: column: Kromasil Eternity XT 250*70mm* lOum; mobile phase: [H20(0.05% NH3H2O)-ACN]; gradient: 0%-30% B over 20.0 min). Then the eluent was freeze-dried to get the product. 4-cyclopropyl-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperidine-4-carboxylic acid (510 mg, 1.30 mmol, 46.0% yield, 97.5% purity) was obtained as a yellow solid. LCMS: Rt = 0.676 min, m / z = 384.2 (M+H)+. ’H NMR (400 MHz, DMSO): d 8.91 (d, J= 2.8 Hz, 1H), 7.62 - 7.60 (m, 1H), 7.42 - 7.38 (m, 1H), 7.22 (d, J= 8.0 Hz, 1H), 7.17 (d, J= 3.2 Hz, 1H), 7.13 - 7.09 (m, 1H), 5.20 (s, 2H), 3.93 (d, J= 13.2 Hz, 2H), 3.32 (s, 3H), 2.95 - 2.89 (m, 2H), 1.99 (d, J= 12.8 Hz, 2H), 1.33 - 1.26 (m, 2H), 0.93 - 0.86 (m, 1H), 0.33 - 0.24 (m, 4H). INTERMEDIATE 35

[0996] 4-ETHYL-l-(6-(2-(METHOXYMETHOXY)PHENYL)PYRIDAZIN-4-YL)PIPERIDINE-4-CARBOXYLIC ACID

[0997]

[0998] Step 1: methyl 4-ethylpiperidine-4-carboxylate hydrochloride

[0999]

[1000] HCI

[1001] A mixture of 1 -(tert-butyl) 4-methyl 4-ethylpiperidine-l,4-dicarboxylate (1.17 g, 4.31 mmol, 1.00 eq) in HCl / dioxane (2 M, 23.4 mL, 10.8 eq) was stirred at 25 °C for 12 hrs. The solvent was removed in vacuum. The crude methyl 4-ethylpiperidine-4-carboxylate hydrochloride (895 mg, 4.31 mmol, 99.9% yield, HCI) as a yellow solid was used into the next step without further purification.

[1002] Step 2: methyl l-(6-chloropyridazin-4-yl)-4-ethylpiperidine-4-carboxylate

[1003]

[1004] To a solution of methyl 4-ethylpiperidine-4-carboxylate hydrochloride (645 mg, 3.11 mmol, 1.00 eq, HCI) and 3,5-dichloropyridazine (462 mg, 3.11 mmol, 1.00 eq) in IPA (5.00 mL) was added DIEA (1.61 g, 12.4 mmol, 2.16 mL, 4.00 eq) under N2 atmosphere, and the mixture was stirred at 70 °C for 5 hrs. The solvent was removed in vacuum. The residue was purified by prep-HPLC (column: Waters Xbridge C18 150*50mm*10um;mobile phase: [H20(0.05%NH3H20)-ACN];gradient:23%-53% B over 12.0 min), the residue was extracted with DCM (50.0 mL * 2), the combined organic layers were dried with Na2SO4, filtered and concentrated under vacuum. Compound methyl l-(6-chloropyridazin-4-yl)-4-ethylpiperidine-4-carboxylate (735 mg, 2.59 mmol, 83.4% yield, 100% purity) was obtained as a light yellow solid. LCMS C13H18CIN3O2 requires 283.1, found m / z = 284.1 [M+H]+.

[1005] Step 3: methyl 4-ethyl-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperidine-4-carboxylate

[1006]

[1007] To a solution of methyl l-(6-chloropyridazin-4-yl)-4-ethylpiperidine-4-carboxylate (735 mg, 2.59 mmol, 1.00 eq), (2-(methoxymethoxy)phenyl)boronic acid (942 mg, 5.18 mmol, 2.00 eq), K2CO3 (1.07 g, 7.77 mmol, 3.00 eq) in dioxane (10.0 mL), H2O (2.00 mL) was added Pd(dppf)C12. CH2C12 (211 mg, 259 pmol, 0.100 eq) under N2 atmosphere, and the mixture was stirred at 100 °C for 12 hrs under N2. The mixture was diluted with water (50.0 mL) and extracted with EtOAc (30.0 mL * 2), and the combined organic layers were washed with brine (20.0 mL), dried over Na2SO4and concentrated under vacuum. The residue was purified by column chromatography (SiCK Petroleum ether / Ethyl acetate = 1 / 1 to 0 / 1, Petroleum ether / Ethyl acetate = 0: 1, Rf = 0.08), concentrated in vacuum. Compound methyl 4-ethyl-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperidine-4-carboxylate (990 mg, 2.48 mmol, 95.68% yield, 96.5% purity) was obtained as a brown oil. LCMS C21H27N3O4 requires 385.2, found m / z = 386.2 [M+H]+.

[1008] Step 4: 4-ethyl-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperidine-4-carboxylic acid

[1009]

[1010] To a mixture of methyl 4-ethyl-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperidine-4-carboxylate (1.18 g, 3.06 mmol, 1.00 eq) in MeOH (5.00 mL) THF (5.00 mL) H2O (1.50 mL) was added LiOH. H2O (385 mg, 9.18 mmol, 3.00 eq) and then stirred at 60 °C for 12 hrs. The solvent was removed in vacuum, the residue was adjusted pH to about 6-7. The residue was purified by prep-HPLC (column: Kromasil Eternity XT 250*70mm* 10um;mobile phase: [H20(0.05% NH3H2O)-ACN] gradient: 0%-20% B over 20.0 min), lyophilized. Compound 4-ethyl-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperidine-4-carboxylic acid (0.88 g, 2.37 mmol, 77.3% yield, 99.9% purity) was obtained as a light yellow solid. LCMS C20H25N3O4 requires 371.2, found m / z = 372.3 [M+H]+.1H NMR (400 MHz, DMSO): d 8.92 (d, J= 2.8 Hz, 1H), 7.62 (dd, J= 1.2, 7.6 Hz, 1H), 7.43 - 7.37 (m, 1H), 7.22 (d, J= 8.4 Hz, 1H), 7.18 (d, J = 2.8 Hz, 1H), 7.11 (t, J= 7.6Hz, 1H), 5.20 (s, 2H), 3.84 (brd, J= 13.2 Hz, 2H), 3.33 (s, 3H), 3.04 (br t, J= 11.2 Hz, 2H), 2.06 (brd, J= 13.2 Hz, 2H), 1.47 (q, J= 7.2 Hz, 2H), 1.38 - 1.27 (m, 2H), 0.78 (t, J = 7.2 Hz, 3H)

[1011] INTERMEDIATE 36

[1012] RAC-(R)-2-(l-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)-4-METHOXYPIPERIDIN-4-YL)ACETALDEHYDE

[1013]

[1014] Step 1: tert-butyl 4-(2-ethoxy-2-oxoethyl)-4-methoxypiperidine-l-carboxylate

[1015]

[1016] To a solution of tert-butyl 4-(2-ethoxy-2-oxoethyl)-4-hydroxypiperidine-l -carboxylate (30.0 g, 104 mmol, 1.00 eq) in DMF (300 mL) was added Ag2O (72.5 g, 313 mmol, 3.00 eq) at 20 ~ 25 °C under N2. Then CH3I (74.0 g, 522 mmol, 32.5 mL, 5.00 eq) was added into the mixture at 0 ~ 10 °C under N2 and stirred at 0 ~ 10 °C under N2 for 16 hrs. The mixture was poured into 20% AcOK solution (1.00 L) under N2 atmosphere, the aqueous phase was extracted with MTBE (800 mL * 2). The combined organic phase was washed with brine (500 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate = 100 / 1 to 10 / 1, Petroleum ether / Ethyl acetate = 2 / 1, Rf= 0.50). The eluent was concentrated under vacuum at 40 °C to get product, tert-butyl 4-(2-ethoxy-2-oxoethyl)-4-methoxypiperidine-l -carboxylate (25.1 g, 83.2 mmol, 79.7% yield) was obtained as a yellow oil. LCMS: RT = 0.140 min, m / z = 202.1 (M-BOC+H)+ 1HNMR (400 MHz, CDCI3): S 4.15 - 4.10 (m, 2H), 3.68 - 3.66 (m, 2H), 3.24 (s, 3H), 3.06 -3.04 (m, 2H), 2.47 - 2.44 (m, 2H), 1.86 - 1.83 (m, 2H), 1.59 - 1.53 (m, 2H), 1.43 (s, 9H), 1.28 - 1.23 (m, 3H)

[1017] Step 2: tert-butyl 4-(2-hydroxyethyl)-4-methoxypiperidine-l-carboxylate

[1018]

[1019] The solution of LAH (2.50 M, 33.3 mL, 1.00 eq) in THF (125 mL) was degassed and purged with N2 for 3 times. Then the solution of tert-butyl 4-(2-ethoxy-2-oxoethyl)-4-methoxypiperidine-l-carboxylate (25.1 g, 83.2 mmol, 1.00 eq) in THF (125 mL) was drop-wise added into the mixture at 0 °C under N2 flow and the reaction mixture was stirred at 0 °C under N2 flow for 2 hrs. The reaction mixture was cool to -10 ~ 0 °C, then dropwise added H2O (3.16 mL) at 0 °C under N2 and stirred for 0.5 hr. The mixture was dropwise added 15% NaOH solution (3.16 mL) and H2O (9.48 mL) and stirred at 15 ~ 25 °C for 15 mins. Then Na2SO4(30.0 g) was added into the mixture and stirred for 15 mins. The mixture was filtered and the cake was washed by THF (100 mL * 2). The filtrate was combined and concentrated tertbutyl 4-(2-hydroxyethyl)-4-methoxypiperidine-l -carboxylate (21.6 g, crude) was obtained as a yellow oil. LCMS: RT = 0.127 min, m / z = 160.2 (M-BOC+H)+’HNMR (400 MHz, CDCh): S 3.74 - 3.69 (m, 4H), 3.17 (s, 3H), 3.09 - 3.04 (m, 2H), 2.65 - 2.63 (m, 1H), 1.83 - 1.70 (m, 4H), 1.44 - 1.42 (m, 2H), 1.41 (s, 9H)

[1020] Step 3: 2-(4-methoxypiperidin-4-yl)ethan-l-ol hydrochloride

[1021]

[1022] A solution of tert-butyl 4-(2-hydroxyethyl)-4-methoxypiperidine-l -carboxylate (21.6 g, 83.2 mmol, 1.00 eq) in HCl / dioxane (2.00 M, 216 mL, 5.19 eq) was stirred at 25 °C for 12 hrs. The reaction mixture was concentrated in vacuum at low temperature. 2-(4-methoxypiperidin-4-yl)ethan-l-ol hydrochloride (20.8 g, crude, HC1) was obtained as a yellow oil. LCMS: RT = 0.110 min, m / z = 160.2 (M+H)+’HNMR: (400 MHz, DMSO-6): d 9.21 - 9.08 (m, 2H), 3.44 - 3.40 (m, 2H), 3.06 (s, 3H), 3.01 -2.98 (m, 2H), 2.87 - 2.78 (m, 2H), 1.85 - 1.82 (m, 2H), 1.74 - 1.61 (m, 4H)

[1023] Step 4: 2-(l-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-4-methoxypiperidin-4-yl)ethan-l-ol

[1024]

[1025] To a solution of 2-(4-methoxypiperidin-4-yl)ethan-l-ol hydrochloride (31.5 g, 70.5 mmol, 1.00 eq), 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (20.7 g, 105 mmol, 1.50 eq, HC1) and CS2CO3 (68.9 g, 211 mmol, 3.00 eq) in DMF (315 mL) was added Xphos Pd G4 (6.07 g, 7.06 mmol, 0.10 eq) at 25 °C under N2. The reaction mixture was stirred at 80 °C for 12 hrs under N2. The reaction mixture was cooled to 25 °C and poured into H2O (1.00 L). The mixture was extracted with EtOAc (600 mL * 3). The combined organic layer was washed with brine (500 mL * 2), dried over Na2SO4and filtered. The combined organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 2 / 1 to 1 / 3, Petroleum ether / Ethyl acetate = 1 / 1, Rf= 0.10). The eluent was concentrated under vacuum at 40 °C to yield 2-(l-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-4-methoxypiperidin-4-yl)ethan-l-ol (11.5 g, 18.0 mmol, 25.5% yield, 82.2% purity) as a yellow oil. LCMS: RT = 0.622 min, m / z = 525.3 (M+H)+

[1026] Step 5: rac-(R)-3-(4-(4-(2-hydroxyethyl)-4-methoxypiperidin-l-yl)phenyl)piperidine-2, 6-dione

[1027]

[1028] A Parr bottle was purged with N2, then added Pd / C (5.75 g, 5.40 mmol, 10% purity, 2.46e-1eq) and Pd(OH)2 (5.75 g, 20.4 mmol, 50% purity, 9.34e-1eq) in the bottle under N2, finally 2-(l-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-4-methoxypiperidin-4-yl)ethan-l-ol (11.5 g, 21.9 mmol, 1.00 eq) in THF (115 mL) and dioxane (115 mL) was added in the bottle. The suspension was degassed and purged with H23 times. The mixture was stirred under H2 (50 psi) at 25 °C for 16 hrs. The mixture was filtered and washed with dioxane (500 mL). The filtrate was concentrated give the residue. The crude product was triturated with MTBE (100 mL) at 25 °C for 30 mins. The suspension was filtered and the filter cake was washed with MTBE (100 mL), dried under vacuum. rac-(R)-3-(4-(4-(2-hydroxyethyl)-4-methoxypiperidin-l-yl)phenyl)piperidine-2, 6-dione (5.20 g, 13.3 mmol, 61.0% yield, 89.1% purity) was obtained as a gray solid.

[1029] LCMS: RT = 0.407 min, m / z = 347.1 (M+H)+

[1030] Step 6: rac-(R)-2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)-4-methoxypiperidin-4-yl)acetaldehyde

[1031]

[1032] To a solution of rac-(R)-3-(4-(4-(2-hydroxyethyl)-4-methoxypiperidin-l-yl)phenyl)piperidine-2, 6-dione (5.20 g, 15.0 mmol, 1.00 eq) in DMSO (52.0 mL) was added IBX (6.30 g, 22.5 mmol, 1.50 eq) at 20 ~ 30 °C under N2. The mixture was stirred at 20 ~ 30 °C for 1 hr under N2. The mixture was cooled to 15 °C and quenched with Na2S2O3(60.0 mL) under pH ~ 5 (with 1 N citric acid aq.). The mixture was extracted by DCM (50.0 mL * 5), the organic layer is washed by water (20.0 mL * 1) and dry by Na2SO4. The residue was purified by prep-HPLC (column: Phenomenex luna Cis (250 * 70 mm, 10 um); mobile phase: [H2O (0.05% HC1) - ACN]; gradient: 1% - 20% B over 27.0 mins). The residue was adjusted to pH = 7 ~ 8 with sat. NaHCOs solution and extracted with DCM (200 mL * 2). The organic layers were washed with water (300 mL), dried over Na2SO4and concentrated. rac-(R)-2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)-4-methoxypiperidin-4-yl)acetaldehyde (1.70 g, 4.84 mmol, 32.2% yield, 98.0% purity) was obtained as a yellow solid. LCMS: RT = 0.413 min, m / z = 345.1 (M+H)+. ’H NMR (400 MHz, DMSO-d6) d 10.77 (s, 1H), 9.75 - 9.74 (m, 1H), 7.05 - 7.02 (m, 2H), 6.09 - 6.88 (m, 2H), 3.73 - 3.69 (m, 1H), 3.35 - 3.34 (m, 1H), 3.33 - 3.32 (m, 1H), 3.18 (s, 3H), 3.00 - 2.93 (m, 2H), 2.64 - 2.59 (m, 3H), 2.49 -2.43 (m, 1H), 2.17 - 2.07 (m, 1H), 2.03 - 1.99 (m, 1H), 1.97 - 1.90 (m, 2H), 1.76 - 1.69 (m, 2H).

[1033] INTERMEDIATE 37

[1034] RAC-(R)-2-(l-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)-4-FLUOROPIPERIDIN-4-YL)ACETALDEHYDE

[1035]

[1036] Step 1: tert-butyl 4-fluoro-4-(2-hydroxyethyl)piperidine-l-carboxylate

[1037] B0C'N^|

[1038]

[1039] A mixture of tert-butyl 4-(2-ethoxy-2-oxoethyl)-4-fluoropiperidine-l -carboxylate (60.0 g, 207 mmol, 1.00 eq) in THF (600 m ) was degassed under vacuum and purged with N2 3 times. The mixture was cooled to -20 ~ 0 °C, then LAH (2.50 M, 82.9 mL, 1.00 eq) was added to the mixture dropwise at -20 ~ 0 °C under N2. The resulting mixture was stirred at -20 ~ 0 °C for 1 hr under N2. The reaction mixture was quenched with water (8.00 mL) at 0 °C under N2. The reaction mixture was added 8.00 mL NaOH (10%) solution dropwise, and diluted with 24.0 mL water at 0 °C under N2. The reaction mixture was filtered to collect the filtrate. The filtrate was dried over Na2SO4, concentrated in vacuo, tert-butyl 4-fluoro-4-(2-hydroxyethyl)piperidine-l -carboxylate (51.2 g, 207 mmol, 99.8% yield) was obtained as yellow oil. MS: m / z = 192.2 (M+H)+. ’H NMR (400 MHz, DMSO-6): S 4.47 (t, J = 4.8 Hz, 1H), 3.75 - 3.72 (d, J = 12.8 Hz, 2H), 3.55 - 3.51 (m, 2H), 2.96 (s, 2H), 1.82 - 1.50 (m, 6H), 1.39 (s, 9H)

[1040] Step 2: 2-(4-fluoropiperidin-4-yl)ethan-l-ol hydrochloride

[1041]

[1042] To a solution of tert-butyl 4-fluoro-4-(2-hydroxyethyl)piperidine-l -carboxylate (51.2 g, 207 mmol, 1.00 eq) in dioxane (50.0 mL) was added HCl / dioxane (2.00 M, 250 mL, 2.42 eq) and the reaction mixture was stirred for 12 hrs at 15 - 25 °C. The reaction mixture was concentrated under reduced pressure. 2-(4-fhioropiperidin-4-yl)ethan-l-ol hydrochloride (35.0 g, 190 mmol, 92.0% yield, HC1) was obtained as a white solid. MS: m / z = 148.2 (M+H)+. ’HNMR: (400 MHz, DMSO-6): S 9.10 (s,2H), 4.72 (s, 1H), 3.56 - 3.52 (m, 2H), 3.18 - 3.15 (m, 2H), 2.95 - 2.93(m, 2H), 2.01 - 1.90 (m, 4H), 1.87 - 1.76 (m, 2H).

[1043] Step 3: 2-(l-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-4-fluoropiperidin-4-yl)ethan-l-ol

[1044]

[1045] Three batches in parallel. To a solution of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (14.5 g, 32.6 mmol, 1.20 eq) and 2-(4-fluoropiperidin-4-yl)ethan-l-ol hydrochloride (5.00 g, 27.2 mmol, 1.00 eq, HC1) in dioxane (50.0 mL) was added CS2CO3 (26.6 g, 81.6 mmol, 3.00 eq and XPhos Pd G3 (1.15 g, 1.36 mmol, 0.05 eq), and the reaction mixture was stirred for 20 hrs at 90 °C under nitrogen atmosphere. The reaction mixture was cooled to 30 °C and diluted with water (450 mL), extracted with ethyl acetate (120 mL * 2). The combined organic phase was washed with brine (100 mL * 2), dried over Na2SO4, concentrated in vacuo. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 1 / 2, Petroleum ether / Ethyl acetate = 1 / 1, Rf = 0.25). 2-(l-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-4-fluoropiperidin-4-yl)ethan-l-ol (12.0 g, 22.8 mmol, 27.9% yield, 97.4% purity) was obtained as brown oil. LCMS: Rt = 0.586 min, m / z = 513.3 (M+H)+. ’H NMR (400 MHz, DMSO-d6): S 7.68 - 7.66 (m, 1H), 7.43 - 7.30 (m, 12H), 6.97 - 6.95 (m, 2H), 6.51 - 6.49 (m, 1H), 5.39 - 5.35 (d, J= 18.4 Hz, 4H), 4.49 (t, J = 4.8 Hz, 1H), 3.60 - 3.50 (m, 4H), 2.99 - 2.92 (m, 2H), 1.86 - 1.70 (m, 6H)

[1046] Step 4: rac-(R)-3-(4-(4-fluoro-4-(2-hydroxyethyl)piperidin-l-yl)phenyl)piperidine-2, 6-dione

[1047]

[1048] To a solution of 2-(l-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-4-fluoropiperidin-4-yl)ethan-l-ol (18.3 g, 35.7 mmol, 1.00 eq) in THF (183 mL) and dioxane (183 mL) was added Pd / C (9.15 g, 8.60 mmol, 10.0% purity, 2.41e-1 eq) and Pd(OH)2(9.15 g, 3.26 mmol, 5.00% purity, 0.09 eq) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi) at 15 - 25 °C for 4 hrs. The reaction mixture was filtered to collect the filtrate. The filtrate was concentrated in vaccuo. rac-(R)-3-(4-(4-fluoro-4-(2-hydroxyethyl)piperidin-l-yl)phenyl)piperidine-2, 6-dione (9.15 g, 25.9 mmol, 72.6% yield, 94.8% purity) was obtained as a gray solid. LCMS: Rt = 0.354 min, m / z = 335.2 (M+H)+. ’H NMR (400 MHz, DMSO-d6): S 10.7 (s, 1H), 7.05 - 7.03 ( m, 2H), 6.92 - 6.90 (m, 2H), 4.48 (t, J= 4.8 Hz, 1H), 3.74 - 3.70 (m, 1H), 3.59 -3.54 (m, 2H), 3.47 - 3.44 (m, 2H), 2.95 - 2.88 (m, 2H), 2.67 - 2.58 (m, 1H), 2.47 - 2.43 (m, 1H), 2.18 - 2.07 (m, 1H), 2.03 - 1.96 (m, 1H), 1.85 - 1.74 (m, 6H).

[1049] Step 5: rac-(R)-2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)-4-fluoropiperidin-4-yl)acetaldehyde

[1050]

[1051] To a mixture of rac-(R)-3-(4-(4-fluoro-4-(2-hydroxyethyl)piperidin-l-yl)phenyl)piperidine-2,6-dione (9.15 g, 27.3 mmol, 1.00 eq) in DMSO (91.0 mL) was added IBX (15.3 g, 54.7 mmol, 2.00 eq) at 15 - 25 °C and the resulting mixture was stirred at 15 - 25 °C for 2 hrs. The mixture was poured into H2O (270 mL), extracted with DCM (100 mL * 3), the combined organic layers were washed with Na2S2O3(80.0 mL), sat. NaHCO3(80.0 mL), brine (80.0 mL), dried with Na2SO4, filtered and concentrated in vacuum. The crude product was triturated with solvent 1 (Petroleum ether / Ethyl acetate = 5 / 1, 12.0 mL) at 15 - 25 °C for 30 mins. rac-(R)-2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)-4-fluoropiperidin-4-yl)acetaldehyde (9.03 g, 25.6 mmol, 93.4% yield, 94.1% purity) was obtained as a yellow solid. MS: m / z = 333.1 (M+H)+. ’H NMR (400 MHz, DMSO-d6): S 10.7 (s, 1H), 9.80 - 9.79 (m, 1H), 7.07 - 7.05 (m, 2H), 6.95 - 6.93 (m, 2H), 3.75 - 3.71 (m, 1H), 3.52 - 3.49 (m, 2H), 3.01 - 2.95 (m, 2H), 2.85 - 2.79 (m, 2H), 2.68 - 2.59 (, 1H), 2.48 - 2.44 (m, 1H), 2.19 - 2.08 (m, 1H), 2.04 - 1.96 (m, 4H), 1.93 - 1.83 (m, 1H).

[1052] INTERMEDIATE 38

[1053] RAC-(R)-2-(l-(4-(2,6-DIOXOPIPERIDIN-3-YL)-3-FLUOROPHENYL)-4-FLUOROPIPERIDIN-4- YL)ACETALDEHYDE

[1054]

[1055] F

[1056] Step 1: 2-(l-(4-bromo-3-fluorophenyl)-4-fluoropiperidin-4-yl)ethan-l-ol

[1057] HO^ / — \ / =\

[1058] / \NA #Br

[1059] F ' — / \

[1060]

[1061] F

[1062] To a solution of l-bromo-2-fluoro-4-iodobenzene (25.0 g, 83.1 mmol, 1.00 eq) and 2-(4-fluoropiperidin-4-yl)ethan-l-ol hydrochloride (18.3 g, 99.7 mmol, 1.20 eq, HC1) in DMSO (250 mL) was added K2CO3(23.0 g, 166 mmol, 2.00 eq), L-PROLINE (3.83 g, 33.2 mmol, 0.40 eq) and Cui (3.16 g, 16.6 mmol, 0.20 eq) under N2at 25 °C. Then the mixture was heated to 80 °C and stirred at 80 °C for 12 hrs. The mixture was poured into H2O (800 mL), extracted with EtOAc (300 mL * 2), the combined organic layers were washed with brine (800 mL), dried with Na2SC>4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex luna C18 (250 * 70 mm, 10 um); mobile phase: [H2O (0.05% HC1) - ACN]; gradient: 40% - 60% B over 25.0 min) and extracted with EtOAc (50.0 mL * 2), the organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated. 2-(l-(4-bromo-3-fluorophenyl)-4-fluoropiperidin-4-yl)ethan-l-ol (3.60 g, 11.1 mmol, 34.5% yield, 98.9% purity) was obtained as yellow oil. LCMS: RT = 0.528 min, m / z = 320.1 (M+H)+. 'H NMR (400 MHz, DMSO-d6): d 7.42 - 7.38 (m, 1H), 6.96 - 6.92 (m, 2H), 6.73 - 6.37 (m, 1H), 4.48 (s, H), 3.62 - 3.49 (m, 4H), 3.02 - 2.95 (m, 2H), 1.84 - 1.69 (m, 6H).

[1063] Step 2: 2-(l-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3-fluorophenyl)-4-fluoropiperidin-4-yl)ethan-l-ol

[1064] BnO

[1065]

[1066] F

[1067] To a solution of 2-(l-(4-bromo-3-fhrorophenyl)-4-fluoropiperidin-4-yl)ethan-l-ol (3.50 g, 10.9 mmol, 1.00 eq) and 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (5.47 g, 13.1 mmol, 1.20 eq) in dioxane (35.0 mL) and H2O (7.00 mL) was added Pd(PPh3)4(1.26 g, 1.09 mmol, 0.1 eq) and Cs2CO3(8.90 g, 27.3 mmol, 2.50 eq) under N2. The mixture was stirred at 100 °C for 12 hrs under N2. The reaction mixture was cooled to 25 °C and poured into H2O (100 mL), extracted with EtOAc (150 mL * 2). The organic layer was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 50 / 1, Petroleum ether / Ethyl acetate = 3 / 1, Rf= 0.24), then the mixture was concentrated under vacuum. 2-(l-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3-fluorophenyl)-4-fluoropiperidin- 4-yl)ethan-l-ol (5.00 g, 8.91 mmol, 81.5% yield, 94.6% purity) was obtained as a brown oil. LCMS: RT = 0.647 min, m / z = 531.3 (M+H)+. ’HNMR (400 MHz, DMSO-d6): 57.57 (d, J= 4.0 Hz 1H), 7.43 - 7.31 (m, 10H), 6.81 (t,.7= 6,8 Hz 1H), 6.50 (d, J= 6.8 Hz 1H), 6.35 (d, J= 6.8 Hz 4H), 4.45 (t,.7= 6,8 Hz 1H), 3.59 - 3.52 (m, 4H), 3.04 - 2.95 (m, 2H), 1.86 - 1.73 (m, 6H).

[1068] Step 3: rac-(R)-3-(2-fluoro-4-(4-fluoro-4-(2-hydroxyethyl)piperidin-l-yl)phenyl)piperidine-2,6-dione

[1069]

[1070] F

[1071] To a solution of Pd / C (2.50 g, 2.35 mmol, 10.0% purity, 2.49e-1 eq) and Pd(OH)2(2.50 g, 8.90 mmol, 50.0% purity, 9.45e-1 eq) in dioxane (50.0 mL) was added 2-(l-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3-fluorophenyl)-4-fluoropiperidin-4-yl)ethan-l-ol (5.00 g, 9.42 mmol, 1.00 eq) in THF (50.0 mL) under N2 at 25 °C. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (50 Psi) at 25 °C for 12 hrs. The reaction mixture was filtered and the filtrate was concentrated. rac-(R)-3-(2-fluoro-4-(4-fluoro-4-(2-hydroxyethyl)piperidin-l-yl)phenyl)piperidine-2,6-dione (2.80 g, 7.68 mmol, 81.5% yield, 96.7% purity) was obtained as an off-white solid. LCMS: RT = 0.409 min, m / z = 353.2 (M+H)+. ’H NMR (400 MHz, DMSO-d6): 5 10.80 (s, 1H), 7.07 (t, J= 8.4 Hz 1H), 6.77 - 6.73 (m, 1H), 4.92 (t, J = 5.2 Hz 1H), 3.72 (dd, J = 4.8 11.8 Hz 4H), 3.57 - 3.51 (m, 4H), 3.00 - 2.82 (m, 2H), 2.70 - 2.67 (m, 1H), 2.57 - 2.53 (m, 1H), 2.25 - 2.18 (m, 1H), 2.07 - 1.96 (m, 1H), 1.85 -1.69 (m, 6H).

[1072] Step 4: rac-(R)-2-(l-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl)-4-fluoropiperidin-4-yl)acetaldehyde

[1073]

[1074] F

[1075] To a solution of rac-(R)-3-(2-fluoro-4-(4-fluoro-4-(2-hydroxyethyl)piperidin-l-yl)phenyl)piperidine-2, 6-dione (2.80 g, 7.95 mmol, 1.00 eq) in DMSO (28.0 mL) was added IBX (3.34 g, 11.9 mmol, 1.50 eq) at 25 °C and the reaction mixture was stirred at 25 °C for 2 hrs. The mixture was quenched with 10% Na2SOs solution (100 mL). The aqueous phase was extracted with EtOAc (60.0 mL * 2). The combined organic phase was washed with brine (100 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex luna C18 (250 * 70 mm, 10 um); mobile phase: [H2O (0.05% HC1) - ACN]; gradient: 5% - 40% B over 32.0 min) and extracted with EtOAc (100 mL * 2), washed with brine (100 mL). The combined organic layers were dried over Na2SO4 and concentrated. rac-(R)-2-(l-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl)-4-fluoropiperidin-4-yl)acetaldehyde (1.23 g, 3.47 mmol, 43.7% yield, 98.9% purity) was obtained as a yellow solid. LCMS: RT = 0.127 min, m / z = 351.2 (M+H)+. 'HNMR (400 MHz, DMSO-d6): 5 10.81 (s, 1H),9.82 (s, 1H), 7.15 - 7.08 (m, 1H), 6.81 - 6.75 (m, 2H), 3.89 (dd, J= 4.8 11.8 Hz 4H), 3.57 (d, J= 12.8 Hz 1H), 3.06 - 2.99 (m, 2H), 2.82 (dd, J= 1.60 12.8 Hz 2H), 2.71 - 2.68 (m, 1H), 2.56 - 2.53 (m, 1H), 2.28 - 2.12 (m,lH), 2.07 - 1.96 (m, 4H), 1.85 - 1.77 (m, 1H).

[1076] INTERMEDIATE 40

[1077] RAC-(R)-2-(1-(1-(2,6-DIOXOPIPERIDIN-3-YL)-3-METHYL-2-OXO-2,3-DIHYDRO-1H- BENZO[D]IMIDAZOL-4-YL)PIPERIDIN-4-YL)ACETALDEHYDE

[1078]

[1079] Step 1: Synthesis of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine- 2,6-dione

[1080]

[1081] To a stirred solution of 7-bromo-l-methyl-l,3-dihydro-2H-benzo[d]imidazol-2-one (25 g, 110 mmol) in THF (100 mL) was added LiHMDS (1.5 M, 220 mL, 330 mmol) reaction mixture was stirred for 30 min. In another flask 3-bromopiperidine-2, 6-dione (42.3 g, 220 mmol) in THF (80 mL) was taken and above solution was added slowly over a period of 20 minutes. Reaction mixture then stirred at 60°C for 4 h. After completion of the reaction (monitored by TLC and LCMS), reaction mixture cooled down and quenched with aq. NH4Cl solution (500 mL) and extracted with ethyl acetate (3 x 1000 mL).

[1082] Combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get crude product. The crude compound was diluted with IPA:heptane (1:1, 200 mL) and was heated to 50°C for 30 min. Solid obtained was filtered and dried to get title compound as a grey solid (15g, 40%). LCMS: m / z 337.90 [M+H]+; Purity: 87.36 %.

[1083] Step-2: Synthesis of 3-(4-(4-(2-(( / e / 7-butyldimethylsilyl)oxy)ethyl)piperidin-l-yl)-3-methyl-2-oxo- 2, 3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione

[1084]

[1085] To a stirred solution of 3 -(4-bromo-3 -methyl -2 -oxo-2, 3 -dihydro- lH-benzo[d] imidazol-1-yl)piperidine-2, 6-dione (5 g, 14.8 mmol) and 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidine (3.6 g, 14.8 mmol) in Toluene (50 mL) was added LiHMDS solution (50 mL, 73.9 mmol) at RT, Nitrogen gas was purged into reaction mixture for 10 min. Ruphos (690 mg, 1.48 mmol) and RuPhos-Pd-G2 (1.15 g, 1.48 mmol) were added to reaction mixture and stirred at 100°C for 3 h. After completion of the reaction (monitored by TLC and LCMS), Reaction mixture was concentrated under reduced pressure and crude obtained was purified by Flash column chromatography (60-80% EtOAc:heptane) to get title compound as brown solid (2.1 g, 20%). LCMS: m / z 501.20 [M+H]+; Purity: 68.39%

[1086] Step-3: Synthesis of 3-(4-(4-(2-hydroxyethyl)piperidin-l-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo [d] imidazol-l-yl)piperidine-2, 6-dione

[1087]

[1088] To an ice cold stirred solution of 3-(4-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidin-l-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione (2.1 g, 4.19 mmol) in CH3CN (16 mL) and water (4 mb) was added TFA (1.5 mL) and stirred at RT for 3 h. After completion of reaction (monitored by TLC and LCMS), reaction mixture was concentrated and quenched with water (20 mL) and extracted with DCM (2 x 25 mL). Combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get crude product. The crude product was purified by flash column chromatography (3-5% MeOH in DCM) to get the title compound as white solid (700 mg, 44%). LCMS: m / z 387.05[M+H]+; Purity: 99.87%.

[1089] Step-4: Synthesis of the title compound

[1090] To an ice-cold stirred solution of 3-(4-(4-(2-hydroxyethyl)piperidin-l-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione (0.7 g, 1.55 mmol) in DCM (10 mL) were added DMP (1.15 g, 2.72 mmol) and NaHCOs (0.761 g, 9.06 mmol). The reaction mixture was stirred at 15°C for 1 h. After completion of reaction (monitored by TLC and LCMS), the reaction mixture was quenched with water (20 mL) and extracted with 10% MeOH: DCM (2x100 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get the crude product. The crude product was purified by flash column chromatography (5-8% MeOH in DCM) to get the title compound as yellow solid (447 mg, 64%). LCMS: m / z 385.15 [M+H]+; Purity: 99.00% 'HNMR (400 MHz, DMSO-d6): 5 11.08 (s, 1H), 9.72-9.71 (m, 1H), 6.99-6.95 (m, 1H), 6.91-6.85 (m, 2H), 5.36-5.32 (m, 1H), 3.61 (s, 3H), 3.09-3.07 (m, 2H), 2.88-2.84 (m, 1H), 2.73-2.63 (m, 4H), 2.49-2.44 (m, 2H), 1.99-1.96 (m, 2H), 1.77-1.74 (m, 2H), 1.47-1.39 (m, 2H).

[1091] INTERMEDIATE 41

[1092] 3-FLUORO-l-(6-(2-(ME THOXYMETHOXY)PHENYL)PYRID AZIN-4- YL)PIPERIDINE-3-CARBOXYLIC ACID LITHIUM SALT

[1093]

[1094] Step-1: l-(tert-butyl) 3-methyl 3-fluoropiperidine-l,3-dicarboxylate

[1095]

[1096] O

[1097] To a stirred solution 1 -(tert-butyl) 3-methyl piperidine- 1,3 -dicarboxylate (10 g, 41.1 mmol) in THF (0.1 L) was added LiHMDS solution (IM in THF, 61.7 mL, 61.7 mmol) at -78°c. The reaction mixture was stirred at -78°cto RT for 2 h. Then, NFSI (25.9 g, 82.2 mmol) was added at -78°c. The mixture was stirred at RT for 4 h. The reaction mixture was quenched by the addition of saturated NH4Cl solution (0.5 L) and extracted with EtOAc (2 x 0.5 L). The combined organic layer was washed with water (0.5 L), brine solution (0.5 L), dried over anhydrous Na2SO4, filtered concentrated under reduced pressure to get the crude compound. The crude compound was purified by flash column chromatography (10-20% EtOAc in heptane) to get l-(tert-butyl) 3-methyl 3-fluoropiperidine-l,3-dicarboxylate as yellow sticky liquid (4.5 g, 42%). 'HNMR (400 MHz, CDC13): S 4.03-3.92 (m, 1H), 3.87-3.84 (m, 1H), 3.74 (s, 3H), 3.70-3.50 (m, 2H), 3.03- 2.75 (m, 1H), 1.99-1.85 (m, 2H), 1.60- 1.50 (m, 1H), and 1.38 (s, 9H). Step-2: methyl 3-fluoropiperidine-3-carboxylate

[1098]

[1099] O

[1100] To an ice-cold solution of 1 -(tert-butyl) 3-methyl 3-fluoropiperidine-l,3-dicarboxylate 2 (4.5 g, 17.2 mmol) in DCM (45 mL) was added TFA (15 mL). The reaction mixture was stirred at RT for 8 h. After completion of reaction (monitored by TLC and LCMS), the reaction mixture was concentrated under reduced pressure. The crude compound was triturated with Diethyl ether (50 mL) and Pentane (50 mL) and dried to get methyl 3 -fluoropiperidine -3 -carboxylate as an off white solid (3 g, Crude).

[1101] LCMS: m / z 162.30 [M+H]+; Purity: 80%.

[1102] Step-3: methyl l-(6-chloropyridazin-4-yl)-3-fluoropiperidine-3-carboxylate

[1103]

[1104] To a stirred solution of methyl 3 -fluoropiperidine-3 -carboxylate (3 g, 18.6 mmol) in CH3CN (30 mL) was added 3,5-dichloropyridazine (3.05 g, 20.5 mmol) and DIPEA (7.22 mL, 55.8 mmol) at RT under inert atmosphere. The reaction mixture was stirred at 80°cfor 16 h. After completion of reaction (monitored by TLC and LCMS), the reaction mixture was concentrated under reduced pressure to get the crude compound. The crude compound was purified by flash column chromatography (5-10% MeOH in DCM) to get methyl l-(6-chloropyridazin-4-yl)-3 -fluoropiperidine-3 -carboxylate as yellow sticky solid (2.7 g, 57% over two steps).

[1105] LCMS: m / z 274.10 [M+H]+; Purity: 99.47%. Step-4: methyl 3-fluoro-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperidine-3-carboxylate

[1106] N CL N - > N

[1107]

[1108] To a stirred solution methyl l-(6-chloropyridazin-4-yl)-3-fluoropiperidine-3 -carboxylate (2.7 g, 9.86 mmol) and (2-(methoxymethoxy)phenyl)boronic acid (2.15 g, 11.8 mmol) in 1,4-Dioxane (40 mL) was added K3PO4 (3.14 g, 14.8 mmol), and the reaction mixture was purged with nitrogen for 15 minutes. XPhosPdG3(651 mg, 0.77 mmol) was then added to the reaction mixture and stirred at 70°C for 4 h. After completion, the reaction mixture was filtered through celite pad. Filtrate was quenched with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography (80 to 90% EtOAc in heptane) to get methyl 3 -fluoro- 1 -(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperidine-3-carboxylate as brown sticky solid (2 g, 54%). LCMS: m / z 376.50 [M+H]+; Purity: 96.22%.

[1109] Step-5: 3-fluoro-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperidine-3-carboxylic acid (lithium salt)

[1110] To an ice-cold solution of methyl 3 -fluoro- 1 -(6-(2-(methoxymethoxy )phenyl)pyridazin-4-yl)piperidine-3 -carboxylate (2 g, 5.33 mmol) in THF (10 mL) and Water (5 mL) was added LiOH. H2O (0.23 g, 5.33 mmol). The reaction mixture stirred at RT for 4 h. The reaction was concentrated under reduced pressure, diluted with 25% IPA in CHC13 (100 mL) and filtered through a sintered glass funnel. Filtrate was concentrated under reduced pressure. The crude was triturated with Diethyl ether (30 mL) and Pentane (30 mL) to get the title compound as an off white solid (1.51 g, 77%). LCMS: m / z 362.30 [M+H]+; Purity: 97.03%. ’H NMR (400 MHz, DMSO-6): S 8.85 (d, J= 2.8 Hz, 1H), 7.63 (dd, J= 2.0 Hz, 7.6 Hz, 1H), 7.42-7.38 (m, 1H), 7.22 (d, J= 7.9 Hz, 1H), 7.14-7.09 (m, 2H), 5.20 (s, 2H), 4.04-3.98 (m, 2H), 3.50-3.38 (m, 1H), 3.33 (s, 3H), 3.04-2.98 (m, 1H), 2.11-1.94 (m, 1H), 1.86-1.80 (m, 1H), 1.72-1.62 (m, 1H) and 1.58-1.54 (m, 1H).

[1111] INTERMEDIATE 42

[1112] 3-CYCLOBUTOXY-l-(6-(2-(METHOXYMETHOXY)PHENYL)PYRID AZIN-4- YL)PYRROLIDINE-3- CARBOXYLIC ACID LITHIUM SALT

[1113]

[1114] Step-1: methyl 2-cyclobutoxyacrylate

[1115]

[1116] To a stirred solution of methyl 2-methoxyacrylate (5 g, 43.1 mmol) in Benzene (100 mL) were added cyclobutanol (6.45ml, 64.6 mmol), activated powdered 4A MS (4 g) and NaH2PO4(4.13 g, 34.4 mmol). The reaction mixture was degassed thrice with N2gas. Then CuCl2(347 mg, 2.58 mmol) and Bis(benzonitrile)palladium (II) Dichloride (1.65 g, 4.31 mmol) were added, and the reaction mixture was stirred at RT for 16 h. After completion, charcoal (2 g) was added to the reaction mixture and stirred at RT for another 30 min. Then the reaction mixture was filtered through sintered funnel and washed with Diethyl ether (100 mL). Filtrate was diluted with water (50 mL) and organic layer was separated. The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure (below 30°C) to get methyl 2-cyclobutoxyacrylate as colorless liquid (3.7 g, 55%). 1H NMR (400 MHz, CDCl3): 55.33 (d, J= 2.0 Hz, 1H), 4.50 (d, J= 2.0 Hz, 1H), 4.47-4.40 (m, 1H), 3.82 (s, 3H), 2.23-2.13 (m, 4H) and 1.90-1.82 (m, 2H).

[1117] Step-2: methyl l-benzyl-3-cyclobutoxypyrrolidine-3-carboxylate

[1118]

[1119] To a stirred solution of methyl 2-cyclobutoxyacrylate (3.7 g, 23.7 mmol) and N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (11.2 g, 47.4 mmol) in Acetonitrile (50 mL) was added LiF (1.84 g, 71.1 mmol) at RT and the reaction mixture was stirred at 70°C for 16 h. After completion, the reaction mixture was concentrated under reduced pressure to get a crude residue which was purified by flash column chromatography (5% EtOAc in heptane) to get methyl l-benzyl-3-cyclobutoxypyrrolidine-3-carboxylate as pale yellow sticky gum (3 g, 44%). LCMS: m / z 290.00 [M+H]+; Purity: 76%.

[1120] Step-3: methyl 3-cyclobutoxypyrrolidine-3-carboxylate

[1121] HN^\

[1122] ~K ^O

[1123] O II

[1124] o

[1125]

[1126] To a stirred solution of methyl l-benzyl-3 -cyclobutoxypyrrolidine-3 -carboxylate (3 g, 10.4 mmol) in MeOH (30 mL) was added 10% Pd / C (1.5 g, w / w) followed by HCOONH4(3.27 g, 51.8 mmol) at RT and the reaction mixture was stirred at 65°C for 5 h. After completion, the reaction mixture was filtered through celite pad and washed with 30% MeOH in DCM. The filtrate was concentrated under reduced pressure to get methyl 3-cyclobutoxypyrrolidine-3-carboxylate as colorless liquid (1.4 g, 68%). LCMS: m / z 200.18 M+H]+; Purity: 70%.

[1127] Step-4: methyl l-(6-chloropyridazin-4-yl)-3-cyclobutoxypyrrolidine-3-carboxylate

[1128]

[1129] To a stirred solution of methyl 3 -cyclobutoxypyrrolidine -3 -carboxylate (1.9 g, 6.48 mmol) and 3,5-dichloropyridazine (966 mg, 6.48 mmol) in Acetonitrile (20 mL) was added DIPEA (5.65 mL, 32.4 mmol) and the reaction mixture was stirred at 80°C for 16 h. After completion of the reaction (monitored by LCMS and TLC), reaction mixture was concentrated under reduced pressure. The crude was purified by flash column chromatography (3% MeOH in DCM) to get methyl l-(6-chloropyridazin-4-yl)-3-cyclobutoxypyrrolidine-3-carboxylate as white solid (1.1 g, 54%). LCMS: m / z 312.77 [M+H]+; Purity: 99%

[1130] Step-5: methyl 3-cyclobutoxy-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)pyrrolidine-3-carboxylate

[1131] O N'N

[1132] o II

[1133] o

[1134]

[1135] To a stirred solution of methyl l-(6-chloropyridazin-4-yl)-3-cyclobutoxypyrrolidine-3-carboxylate (1 g, 3.21 mmol) and (2-(methoxymethoxy)phenyl)boronic acid (700 mg, 3.85 mmol) in 1,4-Dioxane:water (4: 1, 10 mL) was added K3PO4 (1.02 g, 4.81 mmol) and the reaction mixture was purged with nitrogen gas for 15 minutes. Afterwards, XPhosPdG3(272 mg, 0.32 mmol) was then added to the reaction mixture and stirred at 70°C for 4 h. After completion, the reaction mixture was filtered through celite bed, filtrate was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get crude. The crude was purified by flash column chromatography (80 to 90% EtOAc in Heptane) to get methyl 3 -cyclobutoxy- 1-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)pyrrolidine-3-carboxylate as brown liquid (900 mg, 68%). LCMS: m / z 414.11 [M+H]+; Purity: 99%.

[1136] Step-6: 3-cyclobutoxy-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)pyrrolidine-3-carboxylic acid (Lithium salt)

[1137] O N-NX

[1138] L x ii o

[1139]

[1140] To a stirred solution of methyl 3 -cyclobutoxy- l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)pyrrolidine-3-carboxylate (900 mg, 2.18 mmol) in THF (6 mL) was added solution of LiOH·H2O (110 mg, 2.61 mmol) in water (3 mL) and the resultant reaction mass was stirred at RT for 5 h. After completion of reaction (monitored by TLC and LCMS), reaction mixture was concentrated under reduced pressure, diluted with 25% IPA in CHCl3 (50 mL) and filtered through sintered funnel. Filtrate was concentrated under reduced pressure to get 3 -cyclobutoxy- l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4- yl)pyrrolidine-3 -carboxylic acid (Lithium salt) as an off-white solid (810 mg, 93%). LCMS: m / z 400.37 [M+H]+; Purity: 99.73%. 'HNMR (400 MHz, DMSO-6): S 8.51 (s,1H), 7.64 (dd, J= 1.6 Hz, 7.6 Hz, 1H), 7.41-7.37 (m, 1H), 7.22 (d, J= 8.0 Hz, 1H), 7.12-7.09 (m, 1H), 6.80 (s, 1H), 5.22 (s, 2H), 4.24-4.16 (m, 1H), 3.61 (brs, 1H), 3.40 (brs, 1H), 3.33 (s, 3H), 3.31-3.22 (m, 2H), 2.33-2.25 (m, 1H), 2.13-2.07 (m, 2H), 1.98-1.94 (m, 1H), 1.86-1.78 (m, 1H), 1.76-1.64 (m, 1H), 1.50-1.43 (m, 1H) and 1.37-1.27 (m, 1H).

[1141] EXAMPLES EXAMPLE 1

[1142] N-(l-(2-(l-(4-(2,6-DIOXOPIPERIDIN-3-YL)-3-FLUOROPHENYL)PIPERIDIN-4-YL)ETHYL)PIPERIDIN-4- YL)-1-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-N-ISOBUTYL-4-METHOXYPIPERIDINE-4-

[1143]

[1144] Step 1: Synthesis of l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-N-isobutyl-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide

[1145]

[1146] To a solution of lithio 4-methoxy-l-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}piperidine-4-carboxylate (50.0 mg, 0.13 mmol) and tert-butyl 4-[(2-methylpropyl)amino]piperidine-l -carboxylate (50.69 pL, 50.69 mg, 0.20 mmol) in DCM (1.00 mL) was added N, N-diisopropylethylamine (90.09 pL, 0.53 mmol). Then, bis(2-oxo-l,3-oxazolidin-3-yl)phosphinoyl chloride (100.66 mg, 0.39 mmol) was added and the reaction mixture was stirred at 40 °C overnight. Then, the reaction was quenched with water, extracted with DCM, dried, filtered and concentrated under reduced pressure. The crude material was dissolved in 2.00 mL of THF and 4M HC1 in dioxane (1.00 mL) was added in one portion. The reaction was stirred at RT until complete by LCMS and then concentrated in vacuo to yield the desired product as a solid. LCMS: C26H37N5O3 requires: 467.3, found: m / z = 468.4 [M+H]+.

[1147] Step 2: Synthesis of the title compound

[1148] l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-N-isobutyl-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride (30.0 mg, 0.06 mmol) was dissolved in DMA (1.00 mL) and rac-2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]-3-fluorophenyl}piperidin-4-yl)acetaldehyde (23.74 mg, 0.07 mmol) was added in one portion. N, N-diisopropylethylamine (51.97 pL, 0.04 g, 0.29 mmol) was then added and the mixture was stirred for 30 min. Then, sodium triacetoxyborohydride (25.23 mg, 0.12 mmol) was added. The resulting reaction was stirred at RT until complete by LCMS. Once complete, the solution was injected onto RP-HPLC and purified with a gradient of 5-95% MeCN in H2O to yield the title compound (23.40 mg, 41%) as a white solid. LCMS: C44H58FN7O5 requires 783.4, found: m / z = 784.4 [M+H]+. EXAMPLE 2

[1149] (R)-N-(l-(2-(l-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4-YL)ETHYL)PIPERIDIN-4-YL)-l-(6- (2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXY-N-(2, 2,2- TRIFLUOROETHYL)PIPERIDINE-4-

[1150]

[1151] Step 1: Synthesis of l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-(piperidin-4-yl)-N-(2,2,2-trifluoroethyl)piperidine-4-carboxamide

[1152]

[1153] Lithio 4-methoxy-l-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}piperidine-4-carboxylate (100.00 mg, 0.26 mmol) was dissolved in dry MeCN (4.00 mL). The flask was cooled to 0 °C and a drop of DMF was added. Then, oxalyl chloride (90.4 pL, 133.8 mg, 1.05 mmol) was added dropwise as a 100 pL / mL solution in MeCN. The reaction mixture was stirred at RT until complete by LCMS. Then, the reaction mixture was concentrated to approximately half of the initial volume. The acid chloride concentrated solution was then filtered through a syringe filter directly into an ice cold solution of tertbutyl 4- [(2,2,2-trifluoroethyl)amino]piperidine-l -carboxylate (111.63 mg, 0.39 mmol) and N, N-diisopropylethylamine (138.1 pL, 102.1 mg, 0.79 mmol) in MeCN (0.25 mL). The reaction was slowly warmed to RT and then warmed to 50 °C and stirred until complete by LCMS (4h). Then, the reaction was quenched with water, washed with a saturated solution of K2CO3, extracted with DCM, dried, filtered and concentrated under reduced pressure. The crude material was dissolved in 1.00 mL of DCM and 4M HC1 in dioxane (1.00 mL) was added in one portion. The reaction was stirred at RT until complete by LCMS and then concentrated in vacuo to yield the desired product as a yellow oil. LCMS: C24H30F3N5O3 requires: 493.2, found: m / z = 494.4 [M+H]+.

[1154] Step 2: Synthesis of the title compound

[1155] l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-(piperidin-4-yl)-N-(2,2,2-trifluoroethyl)piperidine-4-carboxamide hydrochloride (14.00 mg, 0.03 mmol) was dissolved in DMA (0.50 mL) and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)acetaldehyde (8.30 mg, 0.03 mmol) was added in one portion. N, N-diisopropylethylamine (23.07 pL, 0.02 g, 0.13 mmol) was then added and the mixture was stirred for 30min. Then, sodium triacetoxyborohydride (11.2 mg, 0.05 mmol) was added. The resulting reaction was stirred at RT until complete by LCMS. Once complete, the solution was injected onto RP-HPLC and purified with a gradient of 5-95% MeCN in H2O to yield the title compound (5.10 mg, 23% yield) as a white solid LCMS: C42H52F3N7O5 requires 791.4, found: m / z = 792.4 [M+H]+. EXAMPLE 3

[1156] N-(l-((R)-2-(l-(4-((R)-2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4-YL)PROPYL)PIPERIDIN-4-YL)- N-ETHYL-1-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4- ME THOXYPIPERIDINE-4-CARBOXAMIDE

[1157]

[1158] Step 1: Synthesis of N-ethyl-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide

[1159]

[1160] To a solution of lithio 4-methoxy-l-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}piperidine-4-carboxylate (1.00 g, 2.63 mmol) and tert-butyl 4-(ethylamino)piperidine-l -carboxylate (0.90 g, 3.95 mmol) in DCM (15.00 mL) was added N, N-diisopropylethylamine (1.84 mL, 1.36 g, 10.5 mmol). Then bis(2-oxo-l,3-oxazolidin-3-yl)phosphinoyl chloride (2.01 g, 7.90 mmol) was added and the reaction mixture was stirred at 40 °C overnight. Then, the reaction was quenched with water, extracted with DCM 3x50 mL, dried, filtered and concentrated under reduced pressure. The crude material was purified via chromatography (MeOH: DCM, gradient) to yield the desired product as an orange foam. The material was dissolved in 10 mL methanol and 4M HC1 in dioxane (10.0 mL) was added in one portion. The reaction was stirred at RT for 1 hour and then concentrated in vacuo to yield the desired product (1.25 g, 99%) as a white solid. LCMS: C24H33N5O3 requires: 439.2, found: m / z = 440.2 [M+H]+

[1161] Step 2: Synthesis of the title compound

[1162] N-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride (30.0 mg, 0.063 mmol) was dissolved in DMA (1.00 mL) and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)propanal (20.7 mg, 0.063 mmol) was added in one portion. N, N-diisopropylethylamine (0.06 mL, 40.73 mg, 0.3151 mmol) was then added followed by sodium triacetoxyborohydride (40.1 mg, 0.189 mmol). The resulting reaction was stirred at RT for 1-2 hrs and monitored via LCMS. Once complete, the reaction was concentrated in vacuo. The residue was dissolved in DMF and purified via RP-HPLC to yield the title compound (10.2 mg, 18.8% yield) as a tan solid. LCMS: C43H57N7O5requires: 751.4, found: m / z = 752.3 [M+H]+ EXAMPLE 4

[1163] N-(l-((RS)-l-(l-(4-((R)-2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4-YL)PROPAN-2- YL)PIPERIDIN-4-YL)-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXY-N-ETHYLPIPERIDINE- 4-CARBOXAMIDE

[1164]

[1165] Step 1: Synthesis of the title compound

[1166] N-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride (30.0 mg, 0.063 mmol) was dissolved in DMA (1.00 mL) and (3R)-3-{4-[4-(2-oxopropyl)piperidin-l-yl]phenyl}piperidine-2, 6-dione (20.7 mg, 0.063 mmol) was added in one portion. N, N-diisopropylethylamine (0.06 mL, 40.7 mg, 0.315 mmol) was then added followed by sodium triacetoxyborohydride (40.1 mg, 0.189 mmol). The resulting reaction was stirred at RT for 1-2 hrs and monitored via LCMS. Once complete, the reaction was concentrated in vacuo. The residue was dissolved in DMF and purified via RP-HPLC to yield the title compound (4.7 mg, 8.1%) as a white solid. LCMS: C43H57N7O5 requires: 751.4, found: m / z = 752.3 [M+H]+

[1167] EXAMPLE 5

[1168] (R)-A-CYCLOBUTYL-A-(l-(2-(l-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4- YL)ETHYL)PIPERIDIN-4-YL)-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXYPIPERIDINE-4- CARBOXAMIDE

[1169]

[1170] Step 1: Synthesis of JV-cyclobutyl-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-JV-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride

[1171]

[1172] The title compound was prepared as described for Example 1 Step 1 using tert-butyl 4-(cyclobutylamino)piperidine- 1 -carboxylate (155 mg, 0.60 mmol) to afford the desired product as a yellow oil. LCMS C33H47N5O6 requires 465.3, found m / z 466.3 [M+H]+.

[1173] Step 2: Synthesis of title compound

[1174] The title compound was prepared as described for Example 2, Step 2, using A'-cyclobutyl- 1 -(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-JV-(piperidin-4-yl)piperidine-4-carboxamide (32.6 mg, 0.07 mmol) to afford the title compound (13.1 mg, 22% yield) as a white solid. LCMS C44H57N7O5 requires 763.4, found m / z = 764.4 [M+H]+.

[1175] EXAMPLE 6

[1176] N-(l-(2-(l-(2-(2,6-DIOXOPIPERIDIN-3-YL)-l,3-DIOXOISOINDOLIN-5-YL)PIPERIDIN-4- YL)ETHYL)PIPERIDIN-4-YL)-1-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXY-N-

[1177]

[1178] Step 1: Synthesis of l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-methyl-N-(piperidin-4-yl)piperidine-4-carboxamide

[1179]

[1180] To a solution of lithio 4-methoxy-l-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}piperidine-4-carboxylate (350.0 mg, 0.92 mmol) and tert-butyl 4-(methylamino)piperidine- 1 -carboxylate (247 pL, 247 mg, 1.15 mmol) in DMA (2.00 mL) was added N, N-diisopropylethylamine (483 pL, 0.36 g, 2.77 mmol). Then, [(dimethylamino) ( { [ 1,2, 3 ]triazolo [4, 5 -b]pyridin-3 -yloxy } )methylidene] dimethylazanium; hexafluoro-lambda5-phosphanuide (526.24 mg, 1.38 mmol) was added and the reaction mixture was stirred at RT until complete by LCMS. Then, the solvent was removed under reduced pressure. The crude product was purified on silica gel with a gradient of EtOAc / Hex 0-100%, then 0-10% MeOH / DCM. Then, the pure material was dissolved in DCM (2.00 mL) and 3N HC1 (1.00 mL) was added to the reaction mixture, and it was stirred at RT until complete by LCMS. Then, the solvent was removed under reduced pressure to yield the desired product. LCMS: C23H31N5O3 requires: 425.2, found: m / z = 426.2 [M+H]+.

[1181] Step 2: Synthesis of the title compound

[1182] The title compound was prepared as described for Example 1, Step 2, using l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-methyl-N-(piperidin-4-yl)piperidine-4-carboxamide and 2-(l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperidin-4-yl)acetaldehyde to afford rac-(R)-N-( 1 -(2-( 1 -(2-(2,6-dioxopiperidin-3 -yl)- 1,3 -dioxoisoindolin-5 -yl)piperidin-4-yl)ethyl)piperidin-4-yl)- 1 -(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-methylpiperidine-4-carboxamide (7.00 mg, 16% yield) as a yellow solid. LCMS: C43H52N8O7 requires 792.4, found: m / z = 793.4 [M+H]+. EXAMPLE 7

[1183] N-(2-(DIMETHYLAMINO)ETHYL)-N-(l-((RS)-8-(4-((R)-2,6-DIOXOPIPERIDIN-3-YL)PHENYL)-l-OXA-8- AZASPIRO[4.5]DECAN- 3- YL)PIPERIDIN-4-YL)-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4- METHOXYPIPERIDINE-4-CARBOXAMIDE

[1184]

[1185] Step 1: Synthesis of N-(2-(dimethylamino)ethyl)-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy- N-(piperidin-4-yl)piperidine-4-carboxamide

[1186] NU — N >

[1187]

[1188] N-(2-(dimethylamino)ethyl)-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide was prepared as described for Example 1, Step 1, using tert-butyl 4-((2-(dimethylamino)ethyl)amino)piperidine-l -carboxylate. LCMS: C26H38N6O3 requires: 482.3, found: m / z = 483.4 [M+H]+.

[1189] Step 2: Synthesis of the title compound

[1190] The title compound was prepared as described for Example 1, Step 2, using N-(2-(dimethylamino)ethyl)-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide and (R)-3-(4-(3-oxo-l-oxa-8-azaspiro[4.5]decan-8-yl)phenyl)piperidine-2, 6-dione to afford N-(2-(dimethylamino)ethyl)-N-(l-((RS)-8-(4-((R)-2,6-dioxopiperidin-3-yl)phenyl)-l-oxa-8-azaspiro[4.5]decan-3-yl)piperidin-4-yl)-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxypiperidine-4-carboxamide (10.20 mg, 24% yield) as a yellow solid. LCMS: C45H60N8O6 requires 780.4, found: m / z = 781.1 [M+H]+. EXAMPLE 8

[1191] N-(l-((S)-8-(4-((R)-2,6-DIOXOPIPERIDIN-3-YL)PHENYL)-l-OXA-8-AZASPIRO[4.5]DECAN-3- YL)PIPERIDIN-4-YL)-N-ETHYL-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXYPIPERIDINE- 4-CARBOXAMIDE

[1192]

[1193] Step 1: Synthesis of the title compound

[1194] N-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride (200 mg, 0.421 mmol) was dissolved in DMA (1.00 mL) and (3S)-3-(4-{3-oxo-l-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)piperidine-2, 6-dione (172 mg, 0.504 mmol) was added in one portion. N, N-diisopropylethylamine (0.37 mL, 271 mg, 2.11 mmol) was then added followed by sodium triacetoxyborohydride (267 mg, 1.26 mmol). The resulting reaction was stirred at RT for 12 h and monitored via LCMS. Once complete, the reaction was concentrated in vacuo. The residue was dissolved in DMF and purified via RP-HPLC. The diastereomers were then separated via chiral SFC purification (RT = 3.16 min, ChiralPak IH, MeOH + 0.1%NH4OH) to yield the product (44.8 mg, 13.9%) as a white solid. LCMS: C43H55N7O6 requires: 765.4, found: m / z = 766.4 [M+H]+

[1195] EXAMPLE 9

[1196] N-(l-((R)-8-(4-((R)-2,6-DIOXOPIPERIDIN-3-YL)PHENYL)-l-OXA-8-AZASPIRO[4.5]DECAN-3- YL)PIPERIDIN-4-YL)-N-ETHYL-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXYPIPERIDINE- 4-CARBOXAMIDE

[1197]

[1198] N-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride (200 mg, 0.421 mmol) was dissolved in DMA (1.00 mL) and (3S)-3-(4-{3-oxo-l-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)piperidine-2, 6-dione (172 mg, 0.504 mmol) was added in one portion. N, N-diisopropylethylamine (0.37 mL, 271 mg, 2.11 mmol) was then added followed by sodium triacetoxyborohydride (267 mg, 1.26 mmol). The resulting reaction was stirred at RT for 12 h and monitored via LCMS. Once complete, the reaction was concentrated in vacuo. The residue was dissolved in DMF and purified via RP-HPLC. The diastereomers were then separated via chiral SFC purification (RT = 2.86 min, ChiralPak IH, MeOH + 0.1%NH4OH) to yield the product (44.9 mg, 13.9%) as a white solid. LCMS: C43H55N7O6 requires: 765.4, found: m / z = 766.4 [M+H]+

[1199] EXAMPLE 10

[1200] N-((lRS,5RS,6SR)-2-(2-(l-(4-((R)-2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4-YL)ETHYL)-2- AZABICYCLO[4.2.0]OCTAN-5-YL)-1-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4- ME THOXY-N- METHYLPIPERIDINE-4-CARBOXAMIDE

[1201]

[1202] Step 1: Synthesis of rac-tert-butyl (lR,5R,6R)-5-(methylamino)-2-azabicyclo [4.2.0] octane-2-carboxylate

[1203]

[1204] To a solution of rac-tert-butyl (lR,6S)-5-oxo-2-azabicyclo[4.2.0]octane-2-carboxylate (50.00 mg, 0.19 mmol) in DMA (0.50 mL) was added methylammonium chloride (52.89 mg, 0.78 mmol) and N, N-diisopropylethylamine (171.02 pL, 0.13 g, 0.98 mmol) and stirred for 30 min. Then, sodium triacetoxyborohydride (83.01 mg, 0.39 mmol) was added and stirred until complete by LCMS. The crude product was used in the next step without further purification. LCMS: C13H24N2O2 requires: 240.2, found: m / z = 241.2 [M+H]+.

[1205] Step 2: Synthesis of rac-N-((lR,5R,6S)-2-azabicyclo [4.2.0] octan-5-yl)-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-methylpiperidine-4-carboxamide

[1206]

[1207] rac-N-((lR,5R,6S)-2-azabicyclo[4.2.0]octan-5-yl)-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-methylpiperidine-4-carboxamide was prepared as described for Example 1, Step 1, using rac-tert-butyl (lR,5R,6R)-5-(methylamino)-2-azabicyclo[4.2.0]octane-2-carboxylate. LCMS: C25H33N5O3 requires: 451.2, found: m / z = 452.4 [M+H]+.

[1208] Step 3: Synthesis of the title compound

[1209] The title compound was prepared as described for Example 1, Step 2, using rac-N-((lR,5R,6S)-2-azabicyclo[4.2.0]octan-5-yl)-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-methylpiperidine-4-carboxamide and (R)-2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)acetaldehyde to affordN-((lRS,5RS,6SR)-2-(2-(l-(4-((R)-2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)ethyl)-2-azabicyclo[4.2.0]octan-5-yl)-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-methylpiperidine-4- carboxamide (13.5 mg, 26% yield) as a white solid. LCMS: C43H55N7O5 requires 749.4, found: m / z = 750.4 [M+H]+.

[1210] EXAMPLE 11

[1211] (R)-N-(1-(2-(1-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4-YL)ETHYL)PIPERIDIN-4-YL)-1-(6- (2-HYDROXYPHENYL)PYRID AZIN-4- YL)-N-ISOBUTYL-4-METHOXYPIPERIDINE-4-CARBOXAMIDE

[1212]

[1213] Step 1: Synthesis of the title compound

[1214] The title compound was prepared as described for Example 1, Step 2, using l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-N-isobutyl-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide and (R)-2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)acetaldehyde to afford (R)-N-(l-(2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-N-isobutyl-4-methoxypiperidine-4-carboxamide (22.4 mg, 44% yield) as white solid. LCMS: C44H59N7O5 requires 765.5, found: m / z = 766.4 [M+H]+.

[1215] EXAMPLE 12

[1216] N-((RS)-8-((l-(4-((R)-2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4-YL)METHYL)-l-OXA-8- AZASPIRO[4.5]DECAN-3-YL)-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXY-N- METHYLPIPERIDINE-4-CARBOXAMIDE

[1217]

[1218] Step 1: Synthesis of rac-(R)-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-methyl-N-(l-oxa-8-azaspir 0 [4.5] decan-3-yl)piperidine-4-carboxamide

[1219]

[1220] rac-(R)- 1 -(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-methyl-N-( 1 -oxa-8-azaspiro[4.5]decan-3-yl)piperidine-4-carboxamide was prepared as described for Example 1, Step 1, using rac -tert-butyl (R)-3-(methylamino)-l-oxa-8-azaspiro[4.5]decane-8-carboxylate. TFA in DCM was used for the cleavage of the Boc protecting group. LCMS: C26H35N5O4 requires: 481.2, found: m / z = 482.4 [M+H]+.

[1221] Step 2: Synthesis of the title compound

[1222] The title compound was prepared as described for Example 1, Step 2, using rac-(R)-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-methyl-N-(l-oxa-8-azaspiro[4.5]decan-3-yl)piperidine-4- carboxamide and (R)-l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbaldehyde to afford N-((RS)-8-((l-(4-((R)-2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)-l-oxa-8-azaspiro[4.5]decan-3-yl)-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-methylpiperidine-4-carboxamide (29.4 mg, 68% yield) as an off-white solid. LCMS: C43H55N7O6 requires 765.4, found: m / z = 766.4 [M+H]+.

[1223] EXAMPLE 13

[1224] RAC-N-BENZYL-N-(l-((R)-8-(4-((S)-2,6-DIOXOPIPERIDIN-3-YL)PHENYL)-l-OXA-8- AZASPIRO[4.5]DECAN- 3- YL)PIPERIDIN-4-YL)-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4- METHOXYPIPERIDINE-4-CARBOXAMIDE

[1225]

[1226] Step 1: Synthesis of N-benzyl-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide

[1227]

[1228] To a solution of lithio 4-methoxy-l-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}piperidine-4-carboxylate (200 mg, 0.527 mmol) and tert-butyl 4-(benzylamino)piperidine-l -carboxylate (192 mg, 0.791 mmol) in DCM (5.00 mL) was added N, N-diisopropylethylamine (0.37 mL, 272 mg, 2.11 mmol). Then bis(2-oxo-l,3-oxazolidin-3-yl)phosphinoyl chloride (402 mg, 1.58 mmol) was added and the reaction mixture was stirred at 40 °C. Then, the reaction was quenched with water, extracted with DCM 3x50 mL, dried, filtered and concentrated under reduced pressure. The crude material was purified via chromatography (MeOH: DCM, gradient) to yield the desired product as an orange foam. The material was dissolved in 1 mL methanol and 4M HC1 in dioxane (1.0 mL) was added in one portion. The reaction was stirred at RT for 1 hour and then concentrated in vacuo to yield the desired product as a white solid. LCMS: C29H35N5O3 requires: 501.2, found: m / z = 502.2 [M+H]+

[1229] Step 2: Synthesis of the title compound

[1230] N-benzyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride (26.0 mg, 0.0483 mmol) was dissolved in DMA (1.00 mL) and (3S)-3-(4-{3-oxo-l-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)piperidine-2, 6-dione (16.5 mg, 0.0483 mmol) was added in one portion. N, N-diisopropylethylamine (31.23 mg, 0.241 mmol) was then added followed by sodium triacetoxyborohydride (30.7 mg, 0.145 mmol). The resulting reaction was stirred at RT overnight and monitored via LCMS. The resulting reaction was stirred at RT for 12 h and monitored via LCMS. Once complete, the reaction was concentrated in vacuo. The residue was dissolved in DMF and purified via RP-HPLC to yield the title compound (14.8 mg, 34.6%) as a white solid. LCMS: C48H57N7O6 requires: 827.4, found: m / z = 828.4 [M+H]+

[1231] EXAMPLE 14

[1232] RAC-N-(l-((R)-8-(4-((S)-2,6-DIOXOPIPERIDIN-3-YL)PHENYL)-l-OXA-8-AZASPIRO[4.5]DECAN-3- YL)PIPERIDIN-4-YL)-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXY-N-(2- METHOXYETHYL)PIPERIDINE-4-CARBOXAMIDE

[1233] &1

[1234] N

[1235]

[1236] Step 1: Synthesis of l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-(2-methoxyethyl)-N- (piperidin-4-yl)piperidine-4-carboxamide

[1237]

[1238] To a solution of lithio 4-methoxy-l-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}piperidine-4-carboxylate (200 mg, 0.527 mmol) and tert-butyl 4- [(2-methoxyethyl)amino]piperidine-l -carboxylate (191 mg, 0.791 mmol) in DCM (5.00 mL) was added N, N-diisopropylethylamine (0.37 mL, 272 mg, 2.11 mmol). Then bis(2-oxo-l,3-oxazolidin-3-yl)phosphinoyl chloride (402 mg, 1.58 mmol) was added and the reaction mixture was stirred at 40 °C. Then, the reaction was quenched with water, extracted with DCM 3x50 mL, dried, filtered and concentrated under reduced pressure. The crude material was purified via chromatography (MeOH: DCM, gradient) to yield the desired product as an orange foam. The material was dissolved in 1 mL methanol and 4M HC1 in dioxane (1.0 mL) was added in one portion. The reaction was stirred at RT for 1 hour and then concentrated in vacuo to yield the desired product as a white solid. LCMS: C25H35N5O4 requires: 469.2, found: m / z = 470.3 [M+H]+

[1239] Step 2: Synthesis of the title compound

[1240] l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxy-N-(2-methoxyethyl)-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride (31.0 mg, 0.0613 mmol) was dissolved in DMA (1.00 mL) and (3S)-3-(4-{3-oxo-l-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)piperidine-2, 6-dione (20.9 mg, 0.0613 mmol) was added in one portion. N, N-diisopropylethylamine (39.6 mg, 0.306 mmol) was then added followed by sodium triacetoxyborohydride (38.9 mg, 0.183 mmol). The resulting reaction was stirred at RT overnight and monitored via LCMS. Once complete, the reaction was concentrated in vacuo. The residue was dissolved in DMF and purified via RP-HPLC to yield the title compound (25.3 mg, 47.3%) as a white solid. LCMS: C44H57N7O7 requires: 795.4, found: m / z = 796.5 [M+H]+

[1241] EXAMPLE 15

[1242] (R)-N-(l-(2-(l-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)-4-FLUOROPIPERIDIN-4-YL)ETHYL)PIPERIDIN- 4- YL)-N-ETHYL-1-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXYPIPERIDINE-4- CARBOXAMIDE

[1243]

[1244] Step 1: Synthesis of the title compound

[1245] N-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride (30.0 mg, 0.063 mmol) was dissolved in DMA (1.00 mL) and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}-4-fluoropiperidin-4-yl)acetaldehyde (20.7 mg, 0.063 mmol) was added in one portion. N, N-diisopropylethylamine (39.6 mg, 0.306 mmol) was then added followed by sodium triacetoxyborohydride (40.1 mg, 0.189 mmol). The resulting reaction was stirred at RT for 1-2 hrs and monitored via LCMS. Once complete, the reaction was concentrated in vacuo. The residue was dissolved in DMF and purified via RP-HPLC to yield the title compound (22.8 mg, 43.1%) as atan solid. LCMS: C42H54FN7O5 requires: 755.4, found: m / z = 756.5 [M+H]+

[1246] EXAMPLE 16

[1247] RAC-(R)-N-(1-((1-(5-(2,6-DIOXOPIPERIDIN-3-YL)PYRIMIDIN-2-YL)PIPERIDIN-4- YL)METHYL)PIPERIDIN-4-YL)-N-ETHYL-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4- METHOXYPIPERIDINE-4-CARBOXAMIDE

[1248]

[1249] Step 1: Synthesis of the title compound

[1250] The title compound was prepared as described for Example 1, Step 2, using N-ethyl-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide and rac-(R)-l-(5-(2,6-dioxopiperidin-3-yl)pyrimidin-2-yl)piperidine-4-carbaldehyde to afford rac-(R)-N-(l-((l-(5-(2,6-dioxopiperidin-3-yl)pyrimidin-2-yl)piperidin-4-yl)methyl)piperidin-4-yl)-N-ethyl-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxypiperidine-4-carboxamide (4.20 mg, 10% yield) as a white solid. LCMS: C39H51N9O5 requires 725.4, found: m / z = 726.4 [M+H]+. EXAMPLE 17

[1251] (R)-N-(l-(2-(l-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4-YL)ETHYL)PIPERIDIN-4-YL)-l-(6- (2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4- ME THOXY-N-(2-METHOXYETHYL)PIPERIDINE-4- CARBOXAMIDE

[1252]

[1253] Step 1: Synthesis of the title compound

[1254] l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxy-N-(2-methoxyethyl)-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride (31.0 mg, 0.061 mmol) was dissolved in DMA (1.00 mL) and 2-(1-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)acetaldehyde (23.1 mg, 0.073 mmol) was added in one portion. N, N-diisopropylethylamine (39.6 mg, 0.31 mmol) was then added followed by sodium triacetoxyborohydride (38.60 mg, 0.18 mmol). The resulting reaction was stirred at RT for 1-2 hrs and monitored via LCMS. Once complete, the reaction was concentrated in vacuo. The residue was dissolved in DMF and purified via RP-HPLC to yield the title compound (28.8 mg, 55.1%) as a yellow solid. LCMS: C43H57N7O6 requires: 767.4, found: m / z = 767.4 [M+H]+

[1255] EXAMPLE 18

[1256] RAC-(R)-N-(l-((l-(3-(2,6-DIOXOPIPERIDIN-3-YL)-4-FLUOROPHENYL)PIPERIDIN-4- YL)METHYL)PIPERIDIN-4-YL)-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXY-N- METHYLPIPERIDINE-4-CARBOXAMIDE

[1257]

[1258] Step 1: Synthesis of the title compound

[1259] The title compound was prepared as described for Example 1, Step 2, using rac-(R)-l-(3-(2,6-dioxopiperidin-3 -yl)-4-fluorophenyl)piperidine-4-carbaldehyde and 1 -(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-methyl-N-(piperidin-4-yl)piperidine-4-carboxamide to afford rac-(R)-N-( 1 -(( 1 -(3-(2,6-dioxopiperidin-3 -yl)-4-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)- 1 -(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-methylpiperidine-4-carboxamide (13.70 mg, 36% yield) as a white solid. LCMS: C40H50FN7O5 requires 727.4, found: m / z = 728.3[M+H]+. EXAMPLE 19

[1260] N-(l-(((lR,4R)-4-(3-((RS)-2,6-DIOXOPIPERIDIN-3-YL)PHENOXY)CYCLOHEXYL)METHYL)PIPERIDIN-4- YL)-1-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXY-N-METHYLPIPERIDINE-4- CARBOXAMIDE

[1261]

[1262] Step 1: Synthesis of the title compound

[1263] The title compound was prepared as described for Example 1, Step 2, using (lR,4r)-4-(3-((RS)-2,6-dioxopiperidin-3-yl)phenoxy)cyclohexane-l-carbaldehyde and l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-methyl-N-(piperidin-4-yl)piperidine-4-carboxamide to afford N-(l-(((lR,4r)-4-(3-((RS)-2,6-dioxopiperidin-3-yl)phenoxy)cyclohexyl)methyl)piperidin-4-yl)-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-methylpiperidine-4-carboxamide (10.70 mg, 29% yield) as a white solid. LCMS: C41H52N6O6 requires 724.4, found: m / z = 725.4[M+H]+.

[1264] EXAMPLE 20

[1265] (R)-A-(l-(2-(l-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4-YL)ETHYL)PIPERIDIN-4-YL)-l-(6- (2-HYDROXYPHENYL)PYRID AZIN-4- M.)- \,4-l)IMi riIOXM’IPI RII)IM -4-( ARBOXAMII)I

[1266]

[1267] Step 1: Synthesis of l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-JV,4-dimethoxy-JV-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride

[1268]

[1269] This compound was prepared as described for Example 1 Step 1, using tert-butyl 4-(methoxyamino)piperidine-l -carboxylate (91.4 mg, 0.40 mmol) to afford the desired compound as a yellow oil. LCMS C23H31N5O4 requires 441.3 found m / z = 442.3 [M+H]+. Step 3: Synthesis of the title compound

[1270] The title compound was prepared as described for the synthesis of Example 2 Step 2, using l-(6-(2-hydroxyphenyl)pyridazin-4-yl)- / V,4-dimethoxy- / V-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride (21.6 mg, 0.05 mmol) to afford the title compound (2.50 mg, 6% yield) as a white solid. LCMS C41H53N7O6 requires 739.4, found m / z =740.4 [M+H]+.

[1271] EXAMPLE 21

[1272] (R)-3-(4-((RS)-3-(8-(l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-ME THOXYPIPERIDINE-4- CARBONYL)-2,8-DIAZASPIRO[4.5]DECAN-2-YL)-l-OXA-8-AZASPIRO[4.5]DECAN-8- YL)PHENYL)PIPERIDINE-2, 6-DIONE

[1273]

[1274] Step 1: Synthesis of (l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxypiperidin-4-yl)(2,8-diazaspiro[4.5]decan-8-yl)methanone

[1275]

[1276] H

[1277] (l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxypiperidin-4-yl)(2,8-diazaspiro[4.5]decan-8-yl)methanone was prepared as described for Example 1, Step 1, tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate. LCMS: C25H33N5O3 requires: 451.2, found: m / z = 452.4 [M+H]+.

[1278] Step 2: Synthesis of the title compound

[1279] The title compound was prepared as described for Example 1, Step 2, using (l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxypiperidin-4-yl)(2,8-diazaspiro[4.5]decan-8-yl)methanone and (R)-3-(4-(3-oxo-l-oxa-8-azaspiro[4.5]decan-8-yl)phenyl)piperidine-2, 6-dione to afford (R)-3-(4-((RS)-3-(8-(l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxypiperidine-4-carbonyl)-2,8-diazaspiro[4.5]decan-2-yl)-l-oxa-8-azaspiro[4.5]decan-8-yl)phenyl)piperidine-2, 6-dione (11.30 mg, 22% yield) as a white solid. LCMS: C44H55N7O6 requires 777.4, found: m / z = 778.4 [M+H]+. EXAMPLE 22

[1280] N-(l-((l-(4-(2,4-DIOXOTETRAHYDROPYRIMIDIN-l(2H)-YL)PHENYL)PIPERIDIN-4- YL)METHYL)PIPERIDIN-4-YL)-N-ETHYL-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4- METHOXYPIPERIDINE-4-CARBOXAMIDE

[1281] \

[1282]

[1283] Step 1: Synthesis of the title compound

[1284] The title compound was prepared as described for Example 1, Step 2, using l-(4-(2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)phenyl)piperidine-4-carbaldehyde and N-ethyl- 1 -(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide to afford N-( 1 -(( 1 -(4-(2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-N-ethyl- 1 -(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxypiperidine-4-carboxamide (11.80 mg, 33% yield) as a white solid. LCMS: C40H52N8O5 requires 724.4, found: m / z = 725.4 [M+H]+.

[1285] EXAMPLE 23

[1286] RAC-(R)-N-(l-(2-(4-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)-l-OXA-4,9-DIAZASPIRO[5.5]UNDECAN-9- YL)ACETYL)PIPERIDIN-4-YL)-N-ETHYL-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4- METHOXYPIPERIDINE-4-CARBOXAMIDE

[1287] \

[1288]

[1289] Step 1: Synthesis of the title compound

[1290] To a solution of N-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide (20.01 mg, 0.05 mmol) and rac-(4-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}-l-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetic acid hydrochloride (25.92 mg, 0.06 mmol) in DMA (0.50 mL), was added N, N-diisopropylethylamine (39.75 pL, 0.03 g, 0.23 mmol) followed by [(dimethylamino)({[l,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro- lambda5-phosphanuide (20.77 mg, 0.05 mmol) and the reaction mixture was stirred at RT until complete by LCMS. Once complete, the solution was injected onto RP-HPLC and purified with a gradient of 5-95% MeCN in H2O to yield the title compound (10.50 mg, 23% yield) as a gray solid. LCMS: C45H58N8O7 requires 822.4, found: m / z = 823.4[M+H]+.

[1291] EXAMPLE 24

[1292] (R)-3-(4-(4-(2-((3ARS,7ASR)-1-(1-(6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL)-4-METHOXYPIPERIDINE-4-CARBONYL)OCTAHYDRO-5H-PYRROLO[3,2-C]PYRIDIN-5-YL)ETHYL)PIPERIDIN-1-YL)PHENYL)PIPERIDINE-2,6-DIONE

[1293]

[1294] Step 1: Synthesis of rac-(1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxypiperidin-4-yl)((3aR,7aS)-octahydro-1H-pyrrolo[3,2-c]pyridin-1-yl)methanone hydrochloride

[1295]

[1296] This compound was prepared as described for Example 1 Step 1 using rac-tert-butyl (3aS,7aR)-octahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate (32.1 mg, 0.08 mmol) to afford the desired product as an orange solid. LCMS C24H31N5O3 requires 437.2, found 438.3 [M+H]+.

[1297] Step 3: Synthesis of title compound

[1298] The title compound was prepared as described for Example 2 Step 2, using rac-(1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxypiperidin-4-yl)((3aR,7aS)-octahydro-1H-pyrrolo[3,2-c]pyridin-1-yl)methanone (35.2 mg, 0.08 mmol) to afford the desired product (36.6 mg, 50% yield) as a bright orange solid. LCMS C42H53N7O5 requires 735.4, found m / z = 736.4 [M+H]+.

[1299] EXAMPLE 25

[1300] (R)-3-(4-((RS)-3-((3ARS,7ASR)-1-(1-(6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL)-4-METHOXYPIPERIDINE-4-CARBONYL)OCTAHYDRO-5H-PYRROLO[3,2-C]PYRIDIN-5-YL)-1-OXA-8-AZASPIRO[4.5]DECAN-8-YL)PHENYL)PIPERIDINE-2,6-DIONE

[1301]

[1302] Step 1: Synthesis of title compound

[1303] The title compound was prepared as described for Example 2 Step 2, using rac-(1-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxypiperidin-4-yl)((3aR,7aS)-octahydro-1H-pyrrolo[3,2-c]pyridin-1-yl)methanone hydrochloride (25.3 mg, 0.06mmol) and (R)-3-(4-(3-oxo-l-oxa-8-azaspiro[4.5]decan-8-yl)phenyl)piperidine-2, 6-dione to afford the title compound (40.9 mg, 80% yield) as a white solid. LCMS C43H53N7O6 requires 763.4 found m / z = 764.4 [M+H]+.

[1304] EXAMPLE 26

[1305] RAC-N-(l-((R)-8-(4-((S)-2,6-DIOXOPIPERIDIN-3-YL)-3-FLUOROPHENYL)-l-OXA-8- AZASPIRO[4.5]DECAN-3-YL)PIPERIDIN-4-YL)-N-ETHYL-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)- 4-METHOXYPIPERIDINE-4-CARBOXAMIDE

[1306]

[1307] Step 1: Synthesis of the title compound

[1308] N-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride (30.0 mg, 0.063 mmol) was dissolved in DMA (1.00 mL) and (3S)-3-(2-fluoro-4-{3-oxo-1-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)piperidine-2,6-dione (22.7 mg, 0.063 mmol) was added in one portion. N, N-diisopropylethylamine (40.7 mg, 0.315 mmol) was then added followed by sodium triacetoxyborohydride (40.1 mg, 0.189 mmol). The resulting reaction was stirred at RT overnight and monitored via LCMS. Once complete, the reaction was concentrated in vacuo. The residue was dissolved in DMF and purified via RP-HPLC to yield the title compound (23.3 mg, 44.1%) as a tan solid. LCMS: C43H54FN7O6 requires: 783.4, found: m / z = 783.4 [M+H]+

[1309] EXAMPLE 27

[1310] RAC-N-(l-((R)-8-(4-((S)-2,6-DIOXOPIPERIDIN-3-YL)-3,5-DIFLUOROPHENYL)-l-OXA-8- AZASPIRO[4.5]DECAN-3-YL)PIPERIDIN-4-YL)-N-ETHYL-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)- 4-METHOXYPIPERIDINE-4-CARBOXAMIDE

[1311]

[1312] Step 1: Synthesis of the title compound

[1313] N-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride (30.0 mg, 0.063 mmol) was dissolved in DMA (1.00 mL) and (3S)-3-(2,6-difluoro-4-{3-oxo-l-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)piperidine-2, 6-dione (23.8 mg, 0.063 mmol) was added in one portion. N, N-diisopropylethylamine (40.7 mg, 0.315 mmol) was then added followed by sodium triacetoxyborohydride (40.1 mg, 0.189 mmol). The resulting reaction was stirred at RT overnight and monitored via LCMS. Once complete, the reaction was concentrated in vacuo. The residue was dissolved in DMF and purified via RP-HPLC to yield the title compound (25.7 mg, 48.1%) as a white solid. LCMS: C43H53F2N7O6 requires: 801.4, found: m / z = 801.5 [M+H]+

[1314] EXAMPLE 28

[1315] RAC-(R)-N-(l-(2-(l-(5-(2,6-DIOXOPIPERIDIN-3-YL)PYRIDIN-2-YL)PIPERIDIN-4-YL)ETHYL)PIPERIDIN- 4- YL)-N-ETHYL-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXYPIPERIDINE-4- CARBOXAMIDE

[1316]

[1317] Step 1: Synthesis of the title compound

[1318] The title compound was prepared as described for Example 1, Step 2, using N-ethyl-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide and rac-(R)-2-( 1 -(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)acetaldehyde to afford rac-(R)-N-(l-(2-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)ethyl)piperidin-4-yl)-N-ethyl-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxypiperidine-4-carboxamide (18.8 mg, 27% yield). LCMS: C41H54N8O5 requires 738.4, found: m / z = 739.4 [M+H]+.

[1319] EXAMPLE 29

[1320] RAC-N-(l-((R)-8-(4-((R)-2,6-DIOXOPIPERIDIN-3-YL)PHENYL)-8-AZASPIRO[4.5]DECAN-2- YL)PIPERIDIN-4-YL)-N-ETHYL-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXYPIPERIDINE- 4-CARBOXAMIDE

[1321]

[1322] Step 1: Synthesis of the title compound

[1323] N-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride (30.0 mg, 0.063 mmol) was dissolved in DMA (1.00 mL) and (3S)-3-(4-{2- oxo-8-azaspiro[4.5]decan-8-yl}phenyl)piperidine-2, 6-dione (21.4 mg, 0.063 mmol) was added in one portion. N, N-diisopropylethylamine (40.7 mg, 0.315 mmol) was then added followed by sodium triacetoxyborohydride (40.1 mg, 0.189 mmol). The resulting reaction was stirred at RT overnight and monitored via LCMS. Once complete, the reaction was concentrated in vacuo. The residue was dissolved in DMF and purified via RP-HPLC to yield the title compound (25.0 mg, 50.4%) as a yellow solid.

[1324] LCMS: C44H57N7O5 requires: 763.4, found: m / z = 764.2 [M+H]+

[1325] EXAMPLE 30

[1326] (R)-N-(l-(2-(l-(4-(2,6-DIOXOPIPERIDIN-3-YL)-3-FLUOROPHENYL)PIPERIDIN-4-YL)ETHYL)PIPERIDIN- 4- YL)-N-ETHYL-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXYPIPERIDINE-4- CARBOXAMIDE

[1327]

[1328] Step 1: Synthesis of the title compound

[1329] N-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride (30.0 mg, 0.063 mmol) was dissolved in DMA (1.00 mL) and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]-3-fluorophenyl}piperidin-4-yl)acetaldehyde (20.9 mg, 0.063 mmol) was added in one portion. N, N-diisopropylethylamine (0.06 mL, 40.7 mg, 0.315 mmol) was then added followed by sodium triacetoxyborohydride (40.1 mg, 0.189 mmol). The resulting reaction was stirred at RT for 1-2 hrs and monitored via LCMS. Once complete, the reaction was concentrated in vacuo. The residue was dissolved in DMF and purified via RP-HPLC to yield the title compound (26.3 mg, 54.3%) as a tan solid.

[1330] LCMS: C42H54FN7O5 requires: 755.4, found: m / z = 756.4 [M+H]+

[1331] EXAMPLE 31

[1332] (R)-N-(l-(2-(l-(4-(2,6-DIOXOPIPERIDIN-3-YL)-3,5-DIFLUOROPHENYL)PIPERIDIN-4- YL)ETHYL)PIPERIDIN-4-YL)-N-ETHYL-l-(6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL)-4- METHOXYPIPERIDINE-4-CARBOXAMIDE

[1333]

[1334] Step 1: Synthesis of the title compound

[1335] N-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride (30.0 mg, 0.063 mmol) was dissolved in DMA (1.00 mL) and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]-3,5-difluorophenyl}piperidin-4-yl)acetaldehyde (22.1 mg, 0.063 mmol) was added in one portion. N, N-diisopropylethylamine (40.7 mg, 0.315 mmol) was then added followed by sodium triacetoxyborohydride (40.1 mg, 0.189 mmol). The resulting reaction was stirred at RT for 1-2 hrs and monitored via LCMS. Once complete, the reaction was concentrated in vacuo. The residue was dissolved in DMF and purified via RP-HPLC to yield the title compound (28.6 mg, 58.6%) as a white solid. LCMS: C42H53F2N7O5 requires: 773.4, found: m / z = 774.6 [M+H]+

[1336] EXAMPLE 32

[1337] RAC-N-(l-((R)-8-(4-((S)-2,6-DIOXOPIPERIDIN-3-YL)PHENYL)-l-OXA-8-AZASPIRO[4.5]DECAN-3- YL)PIPERIDIN-4-YL)-l-(6-(5-FLUORO-2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXY-N- METHYLPIPERIDINE-4-CARBOXAMIDE

[1338]

[1339] Step 1: Synthesis of l-(6-(5-fluoro-2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-methyl-N-(piperidin-4-yl)piperidine-4-carboxamide

[1340]

[1341] dilithium(l+) l-[6-(5-fluoro-2-oxidophenyl)pyridazin-4-yl]-4-methoxypiperidine-4-carboxylate (20.0 mg, 0.055 mmol) and tert-butyl 4-(methylamino)piperidine-l -carboxylate (14.9 mg, 0.069 mmol) were dissolved in 1.0 mL DMA. N, N-diisopropylethylamine (21.6 mg, 0.167 mmol) was added in one portion. [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (31.8 mg, 0.083 mmol) was added in one portion to the reaction mixture and the resulting solution was stirred and monitored by LCMS. Once complete, the reaction is diluted with water and extracted with EtOAc 3 x 5 mL. The organic phase is dried, filtered and concentrated in vacuo. The resulting residue is transferred was taken up in 1 mL DCM and 10% TFA in HFIP (1.0 mL) was added in one portion. The reaction was stirred for 1 h and then concentrated in vacuo to afford the desired product (31 mg, 129%) a brown solid. LCMS: C23H30FN5O3 requires: 443.2, found: m / z = 444.2 [M+H]+

[1342] Step 2: Synthesis of the title compound

[1343] l-[6-(5-fluoro-2-hydroxyphenyl)pyridazin-4-yl]-4-methoxy-N-methyl-N-(piperidin-4-yl)piperidine-4-carboxamide TFA (25.4 mg, 0.053 mmol) was dissolved in DMA (1.00 mL) and (3S)-3-(4-{3-oxo-l-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)piperidine-2, 6-dione (18.1 mg, 0.053 mmol) was added in one portion. N, N-diisopropylethylamine (34.2 mg, 0.265 mmol) was then added followed by sodium triacetoxyborohydride (33.7 mg, 0.159 mmol). The resulting reaction was stirred at RT overnight and monitored via LCMS. Once complete, the reaction was concentrated in vacuo. The residue was dissolved in DMF and purified via RP-HPLC to yield the title compound (10.0 mg, 21.6%) as a yellow solid. LCMS: C42H52FN7O6 requires: 769.4, found: m / z = 770.5 [M+H]+ EXAMPLE 33

[1344] RAC-N-CYCLOPROPYL-N-(l-((R)-8-(4-((S)-2,6-DIOXOPIPERIDIN-3-YL)PHENYL)-l-OXA-8- AZASPIRO[4.5]DECAN-3-YL)PIPERIDIN-4-YL)-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)- METHOXYPIPERIDINE-4-CARBOXAMIDE

[1345]

[1346] Step 1: Synthesis of N-cyclopropyl-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide

[1347]

[1348] To a solution of lithio 4-methoxy-l-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}piperidine-4-carboxylate (2.70 g, 7.1176 mmol) and tert-butyl 4-(cyclopropylamino)piperidine-l -carboxylate (2.57 g, 10.6764 mmol) in DCM (40.00 mL) was added N, N-diisopropylethylamine (4.97 mL, 3.68 g, 28.4705 mmol). Then bis(2-oxo-l,3-oxazolidin-3-yl)phosphinoyl chloride (5.44 g, 21.3529 mmol) was added and the reaction mixture was stirred at 40 °C. Then, the reaction was quenched with water, extracted with DCM 3x50 mL, dried, filtered and concentrated under reduced pressure. The crude material was purified via chromatography (MeOH: DCM, gradient) to yield the desired product as an orange foam. The material was dissolved in 10 mL methanol and 4M HC1 in dioxane (10 mL) was added in one portion. The reaction was stirred at RT for 1 hour and then concentrated in vacuo to yield the desired product (2.86 g, 86%) as a white solid. LCMS: C25H33N5O3 requires: 451.2, found: m / z = 452.3 [M+H]+

[1349] Step 2: Synthesis of the title compound

[1350] N-cyclopropyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride (23.00 mg, 0.0471 mmol) was dissolved in DMA (1.00 mL) and (3S)-3-(4-{3-oxo-l-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)piperidine-2, 6-dione (16.1 mg, 0.047 mmol) was added in one portion. N, N-diisopropylethylamine (30.5 mg, 0.235 mmol) was then added followed by sodium triacetoxyborohydride (29.9 mg, 0.141 mmol). The resulting reaction was stirred at RT overnight and monitored via LCMS. Once complete, the reaction was concentrated in vacuo. The residue was dissolved in DMF and purified via RP-HPLC to yield the title compound (12.6 mg, 33.3%) as a white solid. LCMS: C44H55N7O6 requires: 777.4, found: m / z = 778.4 [M+H]+ EXAMPLE 34

[1351] (R)-N-(l-(2-(l-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4-YL)ETHYL)PIPERIDIN-4-YL)-l-(6- (2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXY-N-PROPYLPIPERIDINE-4-CARBOXAMIDE

[1352]

[1353] Step 1: Synthesis of l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-(piperidin-4-yl)-N-propylpiperidine-4-carboxamide

[1354]

[1355] To a solution of lithio 4-methoxy-l-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}piperidine-4-carboxylate (500 mg, 1.31 mmol) and tert-butyl 4-(propylamino)piperidine-l -carboxylate (479 mg, 1.97 mmol) in DCM (10.00 mL) was added N, N-diisopropylethylamine (0.92 mL, 681 mg, 5.27 mmol). Then bis(2-oxo-l,3-oxazolidin-3-yl)phosphinoyl chloride (1006 mg, 3.95 mmol) was added and the reaction mixture was stirred at 40 °C. Then, the reaction was quenched with water, extracted with DCM 3x50 mL, dried, filtered and concentrated under reduced pressure. The crude material was purified via chromatography (MeOH: DCM, gradient) to yield the desired product as an orange foam. The material was dissolved in 5 mL methanol and 4M HC1 in dioxane (5 mL) was added in one portion. The reaction was stirred at RT for 1 hour and then concentrated in vacuo to yield the desired product (645 mg, 89%) as a white solid. LCMS: C25H35N5O3 requires: 453.2, found: m / z = 454.2 [M+H]+

[1356] Step 2: Synthesis of the title compound

[1357] l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxy-N-(piperidin-4-yl)-N-propylpiperidine-4-carboxamide hydrochloride (250 mg, 0.510 mmol) was dissolved in MeCN (2.50 mL) and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)acetaldehyde (176 mg, 0.561 mmol) was added in one portion. The flask was agitated and then MeOH (0.75 mL) was slowly added until all the solids have dissolved. Sodium triacetoxyborohydride (324 mg, 1.53 mmol) was then added in one portion and the reaction was stirred at RT for 30 mins. After 30 mins, the reaction was dissolved in 10 ml DCM. Sat. NaHCO₃ was then added and the reaction was extracted with DCM 3 x 10 mL. The organic phases were dried, concentrated in vacuo and then purified by SFC chiral separation to yield the title compound (256 mg, 66.7%) as a yellow solid. LCMS: C43H57N7O5 requires: 751.4, found: m / z = 752.4 [M+H]+ EXAMPLE 35

[1358] (R)-N-CYCLOPROPYL-N-(l-(2-(l-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4- YL)ETHYL)PIPERIDIN-4-YL)-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXYPIPERIDINE-4- CARBOXAMIDE

[1359]

[1360] Step 1: Synthesis of the title compound

[1361] N-cyclopropyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride (2.00 g, 4.09 mmol) was dissolved in MeCN (20.00 mL) and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)acetaldehyde (1.42 g, 4.51 mmol) was added in one portion. The flask was agitated and then MeOH (6.00 mL) was slowly added until all the solids have dissolved. Sodium triacetoxyborohydride (2.61 g, 12.3 mmol) was then added in one portion and the reaction was stirred at RT for 30 mins. After 30 mins, the reaction was dissolved in 50 ml DCM. water (30.0 mL) was then added and the layers were separated. The water layer was extracted with DCM 2 x 50 mL and the combined organic fractions were dried, concentrated in vacuo and then purified by SFC chiral separation to yield the title compound (1.67 g, 53.0%) as a white / yellow solid. LCMS: C43H55N7O5 requires: 749.4, found: m / z = 750.3 [M+H]+

[1362] EXAMPLE 36

[1363] (S)-N-(l-(2-(l-(4-(2,6-DIOXOPIPERIDIN-3-YL)PIIENYL)PIPERIDIN-4-YL)ETIIYL)PIPERIDIN-4-YL)-N- ETHYL-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXYPIPERIDINE-4-CARBOXAMIDE

[1364]

[1365] Step 1: Synthesis of the title compound

[1366] N-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride (1.83 g, 3.84 mmol) was dissolved in MeCN (20.00 mL) and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)acetaldehyde (1.33 g, 4.22 mmol) was added in one portion. The flask was agitated and then MeOH (6.00 mL) was slowly added until all the solids have dissolved. Sodium triacetoxyborohydride (2.44 g, 11.5 mmol) was then added in one portion and the reaction was stirred at RT for 30 mins. After 30 mins, the reaction was dissolved in 50 ml DCM. Water (30.0 mL) was then added and the layers were separated. The water layer was extracted with DCM 2 x 50 mL and the combined organic fractions were dried, concentrated in vacuo and then purified by SFC chiral separation to yield the title compound (285 mg, 10.0%) as a white solid. LCMS: C42H55N7O5 requires: 737.4, found: m / z = 738.4 [M+H]+ EXAMPLE 37

[1367] (R)-N-(1-(2-(1-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4-YL)ETHYL)PIPERIDIN-4-YL)-1-(6- (3-FLUORO-2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXYPIPERIDINE-4-CARBOXAMIDE

[1368] o

[1369]

[1370] Step 1: Synthesis of (l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxypiperidin-4-yl)(3,9-diazaspiro[5.5]undecan-3-yl)methanone

[1371]

[1372] 4-cyclopropoxy-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]piperidine-4-carboxylic acid (30.0 mg, 0.084 mmol) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (21.4 mg, 0.084 mmol) were dissolved in 1.0 mb DMA. N, N-diisopropylethylamine (0.04 mb, 32.7 mg, 0.253 mmol) was added in one portion. [(dimethylamino)({[l,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (48.1 mg, 0.126 mmol) was added in one portion to the reaction mixture and the resulting solution was stirred and monitored by LCMS. Once reaction is complete, the reaction is diluted with water and extracted 3x with EtOAc. The organic phase is collected and concentrated in vacuo. The material was dissolved in 1 mb methanol and 4M HC1 in dioxane (1.0 mb) was added in one portion. The reaction was stirred at RT for 1 hour and then concentrated in vacuo to yield the desired product (50.0 mg, 99%) as a white solid. LCMS: C26H35N5O3 requires: 465.2, found: m / z = 466.2 [M+H]+

[1373] Step 2: Synthesis of the title compound

[1374] 2 - [5 -(4- { 3,9-diazaspiro [5.5]undecane-3 -carbonyl } -4-methoxypiperidin- 1 -yl)pyridazin-3 -yl]phenol; trifluoroacetic acid (52.8 mg, 0.091 mmol) was dissolved in DMA (1.00 mb) and l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidine-4-carbaldehyde (27.3 mg, 0.091 mmol) was added in one portion. N, N-diisopropylethylamine (0.08 mb, 58.8 mg, 0.455 mmol) was then added followed by sodium triacetoxyborohydride (57.9 mg, 0.273 mmol). The resulting reaction was stirred at RT for 1-2 h and monitored via LCMS. Once complete, the reaction was concentrated in vacuo. The residue was dissolved in DMF and purified via RP-HPLC to yield the title compound (11.4 mg, 56.6%) as a tan solid. LCMS: C43H55N7O5 requires: 749.4, found: m / z = 750.4 [M+H]+ EXAMPLE 38

[1375] (R)-N-(l-(2-(l-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4-YL)ETHYL)PIPERIDIN-4-YL)-l-(6- (3-FLUORO-2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXYPIPERIDINE-4-CARBOXAMIDE F \ °A _

[1376] Nx

[1377]

[1378] N

[1379] Step 1: Synthesis of l-(6-(3-fluoro-2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide

[1380] F \

[1381] HN\NH

[1382]

[1383] NL N

[1384] dilithium(l+) l-[6-(3-fluoro-2-oxidophenyl)pyridazin-4-yl]-4-methoxypiperidine-4-carboxylate (20.0 mg, 0.055 mmol) and tert-butyl 4-aminopiperidine-l -carboxylate (14.9 mg, 0.069 mmol) were dissolved in 1.0 mL DMA. N, N-diisopropylethylamine (21.6 mg, 0.167 mmol) was added in one portion.

[1385] [(dimethylamino)({[l,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (31.8 mg, 0.083 mmol) was added in one portion to the reaction mixture and the resulting solution was stirred and monitored by LCMS. Once complete, the reaction is diluted with water and extracted with EtOAc 3 x 5 mL. The organic phase is dried, filtered and concentrated in vacuo. The resulting residue is transferred was taken up in 1 mL DCM and 10% TFA in HFIP (1.0 mL) was added in one portion. The reaction was stirred for 1 h and then concentrated in vacuo to afford the desired product (32 mg, 130%) as a yellow solid. LCMS: C22H28FN5O3 requires: 429.2, found: m / z = 430.2 [M+H]+Step 2: Synthesis of the title compound

[1386] l-[6-(3-fluoro-2-hydroxyphenyl)pyridazin-4-yl]-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide (11.9 mg, 0.026 mmol) was dissolved in DMA (1.00 mL) and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)acetaldehyde (9.81 mg, 0.031 mmol) was added in one portion. N, N-diisopropylethylamine (0.02 mL, 16.8 mg, 0.130 mmol) was then added. The solution was stirred for 30 mins before adding sodium triacetoxyborohydride (16.5 mg, 0.078 mmol). The resulting reaction was stirred at RT for 1-2 h and monitored via LCMS. Once complete, the reaction was concentrated in vacuo. The residue was dissolved in DMF and purified via RP-HPLC to yield the title compound (11.4 mg, 56.6%) as a tan solid. LCMS: C41H52FN7O5 requires: 727.3, found: m / z = 727.4 [M+H]+ EXAMPLE 39

[1387] (R)-N-(l-(2-(l-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4-YL)ETHYL)PIPERIDIN-4-YL)-l-(6- (5-FLUORO-2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXY-N-METHYLPIPERIDINE-4-

[1388]

[1389] Step 1: Synthesis of the title compound

[1390] l-[6-(5-fluoro-2-hydroxyphenyl)pyridazin-4-yl]-4-methoxy-N-methyl-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride (25.4 mg, 0.053 mmol) was dissolved in DMA (1.00 mL) and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)acetaldehyde (19.9 mg, 0.063 mmol) was added in one portion. N, N-diisopropylethylamine (0.05 mL, 34.2 mg, 0.265 mmol) was then added followed by sodium triacetoxyborohydride (33.7 mg, 0.159 mmol). The resulting reaction was stirred at RT for 1-2 h and monitored via LCMS. Once complete, the reaction was concentrated in vacuo. The residue was dissolved in DMF and purified via RP-HPLC to yield the title compound (10.6 mg, 23.9%) as awhite solid. LCMS: C₄₁H₅₂FN₇O₅ requires: 741.4, found: m / z = 742.4 [M+H]+

[1391] EXAMPLE 40

[1392] (S)-N-(l-(2-(l-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4-YL)ETHYL)PIPERIDIN-4-YL)-l-(6- (2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4- ME THOXY-N-METHYLPIPERIDINE-4-CARBOXAMIDE

[1393]

[1394] Step 1: Synthesis of the title compound

[1395] l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxy-N-methyl-N-(piperidin-4-yl)piperidine-4-carboxamide; trifluoroacetic acid (81.9 mg, 0.151 mmol) was dissolved in DMA (1.00 mL) and 2-(l-{4-[(3S)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)acetaldehyde (57.2 mg, 0.182 mmol) was added in one portion. N, N-diisopropylethylamine (0.13 mL, 98.1 mg, 0.759 mmol) was then added followed by sodium triacetoxyborohydride (96.5 mg, 0.455 mmol). The resulting reaction was stirred at RT for 1-2 hrs and monitored via LCMS. Once complete, the reaction was concentrated in vacuo. The residue was dissolved in DMF and purified via RP-HPLC to yield the title compound (28.9 mg, 23.9%) as a white solid. LCMS: C41H53N7O5 requires: 723.4, found: m / z = 724.7 [M+H]+ EXAMPLE 41

[1396] RAC-N-(l-((R)-8-(4-((S)-2,6-DIOXOPIPERIDIN-3-YL)PHENYL)-l-OXA-8-AZASPIRO[4.5]DECAN-3- YL)PIPERIDIN-4-YL)-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXYPIPERIDINE-4- CARBOXAMIDE

[1397]

[1398] Step 1: Synthesis of the title compound

[1399] l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide; trifluoroacetic acid (13.0 mg, 0.023 mmol) was dissolved in DMA (1.00 mL) and rac-(3R)-3-(4-{3-oxo-l-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)piperidine-2, 6-dione (9.37 mg, 0.028 mmol) was added in one portion. N, N-diisopropylethylamine (0.02 mL, 15.1 mg, 0.117 mmol) was then added followed by sodium triacetoxyborohydride (14.9 mg, 0.071 mmol). The resulting reaction was stirred at RT for 1-2 hrs and monitored via LCMS. Once complete, the reaction was concentrated in vacuo. The residue was dissolved in DMF and purified via RP-HPLC to yield the title compound (2.9 mg, 15.5%) as a white solid. LCMS: C41H51N7O6 requires: 737.3, found: m / z = 738.4 [M+H]+

[1400] EXAMPLE 42

[1401] RAC-(R)-N-(l-(2-(4-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-l-YL)ETHYL)PIPERIDIN-4-YL)- 1-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXY-N-METHYLPIPERIDINE-4-CARBOXAMIDE

[1402]

[1403] To a solution of 3-[4-(piperidin-4-yl)phenyl]piperidine-2, 6-dione hydrochloride (30.00 mg, 0.10 mmol) in DMF (1.00 mL) and N, N-diisopropylethylamine (50.90 pL, 0.04 g, 0.29 mmol), was added 1-bromo-2 -chloroethane (81.00 pL, 139.32 mg, 0.97 mmol) and the reaction mixture was stirred at 45 °C. Solvent was removed under reduced pressure and the crude product was used in the next step without further purification. LCMS: C18H23CIN2O2 requires 334.8, found: m / z = 335.4 [M+H]+.

[1404] Step 2: Synthesis of the title compound

[1405] To a vial containing l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxy-N-methyl-N-(piperidin-4-yl)piperidine-4-carboxamide; trifluoroacetaldehyde (10.00 mg, 0.02 mmol) and rac-(3R)-3-{4-[l-(2- chloroethyl)piperidin-4-yl]phenyl}piperidine-2, 6-dione (12.79 mg, 0.04 mmol) in DMA (0.50 mL) was added N, N-diisopropylethylamine (16.68 pL, 0.01 g, 0.10 mmol) followed by the addition of potassium iodide (3.20 mg, 0.02 mmol) and stirred at 70 °C until complete by LCMS. Once complete, the solution was injected onto RP-HPLC and purified with a gradient of 5-95% MeCN in H2O to afford the title compound (1.40 mg, 9% yield) as an off-white solid. LCMS: C41H53N7O5 requires 723.4, found: m / z = 724.3 [M+H]+.

[1406] EXAMPLE 43

[1407] RAC-N-(l-((R)-8-(4-((S)-2,6-DIOXOPIPERIDIN-3-YL)PHENYL)-l-OXA-8-AZASPIRO[4.5]DECAN-3- YL)PIPERIDIN-4-YL)-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXY-N- METHYLPIPERIDINE-4-CARBOXAMIDE

[1408]

[1409] Step 1: Synthesis of the title compound

[1410] l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxy-N-methyl-N-(piperidin-4-yl)piperidine-4-carboxamide; trifluoroacetic acid (23.0 mg, 0.043 mmol) was dissolved in DMA (1.00 mL) and rac-(3R)-3-(4-{3-oxo-l-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)piperidine-2, 6-dione (17.5 mg, 0.051 mmol) was added in one portion. N, N-diisopropylethylamine (27.5 mg, 0.213 mmol) was then added followed by sodium triacetoxyborohydride (27.1 mg, 0.128 mmol). The resulting reaction was stirred at RT for 1-2 hrs and monitored via LCMS. Once complete, the reaction was concentrated in vacuo. The residue was dissolved in DMF and purified via RP-HPLC to yield the title compound (5.3 mg, 14.4%) as a tan solid. LCMS: C42H53N7O6 requires: 751.4, found: m / z = 752.5 [M+H]+

[1411] EXAMPLE 44

[1412] RAC-N-(l-((R)-8-(4-((S)-2,6-DIOXOPIPERIDIN-3-YL)PHENYL)-l-OXA-8-AZASPIRO[4.5]DECAN-3- YL)PIPERIDIN-4-YL)-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-CYCLOBUTOXY-N- METHYLPIPERIDINE-4-CARBOXAMIDE

[1413]

[1414] The title compound was prepared according to Example 43 using l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-cyclobutoxy-N-methyl-N-(piperidin-4-yl)piperidine-4-carboxamide. EXAMPLE 45

[1415] RAC-N-(l-((R)-8-(4-((S)-2,6-DIOXOPIPERIDIN-3-YL)PHENYL)-l-OXA-8-AZASPIRO[4.5]DECAN-3- YL)PIPERIDIN-4-YL)-4-ETHOXY-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-N-METHYLPIPERIDINE- 4-CARBOXAMIDE

[1416] Hn °^N^°

[1417] l&1 \

[1418]

[1419] Step 1: Synthesis of the title compound

[1420] 4-ethoxy- 1 -[6-(2-hydroxyphenyl)pyridazin-4-yl] -N-methyl-N-(piperidin-4-yl)piperidine-4-carboxamide; trifluoroacetic acid (13.0 mg, 0.023 mmol) was dissolved in DMA (1.00 mL) and rac-(3R)-3-(4-{3-oxo-l-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)piperidine-2, 6-dione (9.37 mg, 0.028 mmol) was added in one portion. N, N-diisopropylethylamine (0.02 mL, 15.2 mg, 0.117 mmol) was then added followed by sodium triacetoxyborohydride (14.9 mg, 0.071 mmol). The resulting reaction was stirred at RT for 1-2 h and monitored via LCMS. Once complete, the reaction was concentrated in vacuo. The residue was dissolved in DMF and purified via RP-HPLC to yield the title compound (2.2 mg, 10.4%) as a white solid. LCMS: C43H55N7O6 requires: 765.4, found: m / z = 766.4 [M+H]+

[1421] EXAMPLE 46

[1422] RAC-(R)-N-(l-(2-(4-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERAZIN-l-YL)ETHYL)PIPERIDIN-4-YL)- 1-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXY-N-METHYLPIPERIDINE-4-CARBOXAMIDE

[1423]

[1424] Step 1: Synthesis of rac-(R)-3-(4-(4-(2-chloroethyl)piperazin-l-yl)phenyl)piperidine-2, 6-dione

[1425]

[1426] To a solution of 3-[4-(piperazin-l-yl)phenyl]piperidine-2, 6-dione; trifluoroacetic acid (50.00 mg, 0.13 mmol) in DMF (1.00 mL) and N, N-diisopropylethylamine (67.63 pL, 0.05 g, 0.39 mmol), was added l-bromo-2 -chloroethane (107.62 pL, 185.11 mg, 1.29 mmol) and the reaction mixture was stirred at 45 °C. Solvent was removed under reduced pressure and the crude product was used in the next step without further purification. LCMS: C18H23CIN2O2 requires 335.1, found: m / z = 336.2 [M+H]+.

[1427] Step 2: Synthesis of the title compound

[1428] The title compound was prepared as described for Example 42, Step 2, using rac-(R)-3-(4-(4-(2-chloroethyl)piperazin- 1 -yl)phenyl)piperidine-2, 6-dione and 1 -(6-(2-hydroxyphenyl)pyridazin-4-yl)-4- methoxy-N-methyl-N-(piperidin-4-yl)piperidine-4-carboxamide to afford rac-(R)-N-( 1 -(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)ethyl)piperidin-4-yl)-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-methylpiperidine-4-carboxamide (1.00 mg, 5% yield) as a white solid. LCMS: C40H52N8O5 requires 724.4, found: m / z = 725.4 [M+H]+.

[1429] EXAMPLE 47

[1430] (R)-N-(l-((l-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4-YL)METHYL)PIPERIDIN-4-YL)-l-(6- (2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4- ME THOXYPIPERIDINE-4-CARBOXAMIDE

[1431]

[1432] Step 1: Synthesis of the title compound

[1433] l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide; trifluoroacetic acid (13.0 mg, 0.023 mmol) was dissolved in DMA (1.00 mL) and l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidine-4-carbaldehyde (9.37 mg, 0.028 mmol) was added in one portion. N, N-diisopropylethylamine (0.02 mL, 15.2 mg, 0.117 mmol) was then added followed by sodium triacetoxyborohydride (14.9 mg, 0.071 mmol). The resulting reaction was stirred at RT for 1-2 hrs and monitored via LCMS. Once complete, the reaction was concentrated in vacuo. The residue was dissolved in DMF and purified via RP-HPLC to yield the title compound (7.0 mg, 39.5%) as a white solid. LCMS: C39H49N7O5 requires: 695.3, found: m / z = 696.4 [M+H]+

[1434] EXAMPLE 48

[1435] RAC-N-(l-((R)-8-(4-((S)-2,6-DIOXOPIPERIDIN-3-YL)PHENYL)-l-OXA-8-AZASPIRO[4.5]DECAN-3- YL)PIPERIDIN-4-YL)-4-ETHOXY-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-N-METHYLPIPERIDINE-

[1436]

[1437] Step 1: Synthesis of the title compound

[1438] 4-ethoxy- 1 -[6-(2-hydroxyphenyl)pyridazin-4-yl] -N-methyl-N-(piperidin-4-yl)piperidine-4-carboxamide; trifluoroacetic acid (13.3 mg, 0.028 mmol) was dissolved in DMA (1.00 mL) and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)acetaldehyde (10.6 mg, 0.033 mmol) was added in one portion. N, N-diisopropylethylamine (0.02 mL, 18.1 mg, 0.140 mmol) was then added followed by sodium triacetoxyborohydride (17.8 mg, 0.084 mmol). The resulting reaction was stirred at RT for 1-2 h and monitored via LCMS. Once complete, the reaction was concentrated in vacuo. The residue was dissolved in DMF and purified via RP-HPLC to yield the title compound (16.3 mg, 71.0%) as a white solid. LCMS: C42H55N7O5 requires: 737.4, found: m / z = 738.4 [M+H]+

[1439] EXAMPLE 49

[1440] (R)-N-(l-(2-(l-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4-YL)ETHYL)PIPERIDIN-4-YL)-N- ETHYL-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXYPIPERIDINE-4-CARBOXAMIDE

[1441]

[1442] Step 1: Synthesis of the title compound

[1443] N-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride (1.83 g, 3.84 mmol) was dissolved in MeCN (20.0 mL) and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)acetaldehyde (1.33 g, 4.22 mmol) was added in one portion. The flask was agitated and then MeOH (6.00 mL) was slowly added until all the solids have dissolved. Sodium triacetoxyborohydride (2.44 g, 11.5 mmol) was then added in one portion and the reaction was stirred at RT for 30 mins. After 30 mins, the reaction was dissolved in 50 ml DCM. Water (30.0 mL) was then added and the layers were separated. The water layer was extracted with DCM 2 x 50 mL and the combined organic fractions were dried, concentrated in vacuo and then purified by SFC chiral separation to yield the title compound (2.41 g, 84.6%) as a tan solid. LCMS: C42H55N7O5 requires: 737.4, found: m / z = 738.4 [M+H]+

[1444] EXAMPLE 50

[1445] (R)-3-(4-(4-(2-(4-(1-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-ME THOXYPIPERIDINE-4- CARBONYL)PIPERAZIN-l-YL)ETHYL)PIPERIDIN-l-YL)PHENYL)PIPERIDINE-2, 6-DIONE

[1446]

[1447] Step 1: Synthesis of the title compound

[1448] 2- { 5 -[4-methoxy-4-(piperazine- 1 -carbonyl)piperidin- 1 -yl]pyridazin-3 -yl (phenol; trifluoroacetaldehyde (22.3 mg, 0.045 mmol) was dissolved in DMA (0.50 mL) and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)acetaldehyde (18.4 mg, 0.058 mmol) was added in one portion. N, N-diisopropylethylamine (0.04 mL, 29.1 mg, 0.225 mmol) was then added followed by sodium triacetoxyborohydride (28.6 mg, 0.135 mmol). The reaction was stirred at RT for 1-2 hrs and monitored via LCMS. Once complete, the reaction was concentrated in vacuo. The residue was dissolved in ...

Claims

CLAIMS1. A compound having a structure represented by Formula (II):Formula (II)or a stereoisomer, pharmaceutically acceptable salt thereof, wherein:t and q is independently 0 or 1;Z is -N- or -C(R3)-;R1is hydrogen or Ci-6 alkyl optionally substituted with 1 to 3 Ra;R2is hydrogen, halo, hydroxyl, -O-Rc, Ci -6 alkyl optionally substituted with 1 to 3 Ra;R3is hydrogen, -CN, halo (preferably F), -O-Re, Ci-6 alkyl, Ce-i2 aryl, C3-12 cycloalkyl, 5-12 membered heteroaryl, wherein each of C1-6 alkyl, Ce-12 aryl, C3-12 cycloalkyl, and 5-12 membered heteroaryl is optionally substituted with 1 to 3 Rd;R4aand R4bare each independently hydrogen, C1-6 alkyl or C1-6 alkoxy, orR4aand R4btogether may form a C1-3 alkylene chain; orR4aand R3together with the carbons to which they are attached form a C3-12 cycloalkyl or 5-12 membered heterocycle,L comprises up to 8 linker segments represented by -L1-L2-L3-L4-L5-L6-L7-L8-, each Li, L2, L3, L4, L5, Le, L7, or Ls, 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;vii) C1-12 alkenylene chain optionally substituted with 1-3 Rb; orviii) -(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, Ci-s 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(0)0-Rc, -N(RC)C(O)N(RC)( Rc), -N(RC)S(O)2(RC), -NRCS(0)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 Ci-6276alkyl, C2-6 alkenyl, C3-15 cycloalkyl, Ci-s haloalkyl, Ce-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, C1-6 alkoxy, C3-6 cycloalkyl (optionally substituted with 1 or 2 halo, C1-3 alkyl or C1-3 alkoxy), Ce-12 aryl, 4-12 membered heterocyclyl optionally substituted with 1 or 2 C1-3 alkyl), 5-12 membered heteroaryl optionally substituted with 1 or 2 C1-3 alkyl or C1-3 haloalkyl) or C1-6 haloalkyl, wherein C1-6 alkyl is optionally substituted with one or more substituents selected from C1-3 alkoxy, hydroxy, C3-6 cycloalkyl (optionally further substituted with 1 or 2 halo, C1-3 alkoxy or C1-3 alkyl), CN, 5-12 membered heteroaryl (optionally further substituted with 1 or 2 halo or Ci-3 alkyl), Ce-12 aryl and amino;each Rdis independently halo, -CN, -O-Rc, C1-6 alkyl, C 6-12 aryl, C3-6 cycloalkyl or C1-6 haloalkyl, Reis C1-6 alkyl, C3-12 cycloalkyl, Ce-12 aryl, 5-12 membered heteroaryl, each being optionally substituted with C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl or halo;W is -C(R8)- or-N-;Y is direct bond, C1-4 alkylene chain, -C(O)-, -C(O)O-, -O - -N(R8)-, -S--C(S)-, -C(S)-O-, -O-C(O)O-, -C(0)-N(R8)-, or -0-C(0)-N(R8)-;B ring is Ce-12 aryl, 5-12 membered heteroaryl, or 4-12 membered heterocyclyl, each being optionally substituted with 1 to 3 RJ;R8is hydrogen or C1-6 alkyl; andeach RJis independently halo, oxo, -CN, -O-Rc, C1-6 alkyl, or C1-6 haloalkyl.

2. A compound having a structure represented by Formula (I):R1R2Formula (I)or a stereoisomer, pharmaceutically acceptable salt thereof, wherein:t is 0 or 1;R1is hydrogen or C1-6 alkyl optionally substituted with 1 to 3 Ra;R2is hydrogen, halo, hydroxyl, -O-Rc, Ci- 6 alkyl optionally substituted with 1 to 3 Ra;R3is hydrogen, -CN, C1-6 alkyl, Ce-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 Li, L2, L3, L4, L5, LB, L7, or Ls, being independently:i) C3-12 cycloalkyl optionally substituted with 1-3 Rb;ii) Ce-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) Ci-12 alkylene chain optionally substituted with 1-3 Rb; orvn) -(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(0)-, 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, Ci-6 alkyl, C2.6 alkenyl, C3-15 cycloalkyl, Ci-s haloalkyl, Ce-i2aryl, 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 Ci-6alkyl, C2-6 alkenyl, C3-15 cycloalkyl, Ci-s haloalkyl, Ce-i2aryl, 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, C1-6 alkoxy, C3-6 cycloalkyl, Ce-i2aryl, or C1-6 haloalkyl, wherein C1-6 alkyl is optionally substituted with one or more substituents selected from C1-3 alkoxy, hydroxy, C3-6 cycloalkyl, Ce-i2aryl and amino;each Rdis independently halo, -CN, -O-Rc, C1-6 alkyl, C6-i2aryl, or C1-6 haloalkyl,Reis C1-6 alkyl, C3-i2cycloalkyl, Ce-i2aryl, 5-12 membered heteroaryl, each being optionally substituted with C1-6 alkyl, C1-6 haloalkyl or halo;W is -C(R8)- or-N-;Y is direct bond, C1-4 alkylene chain, -C(O)-, -C(O)O-, -O - -N(R8)-, -S--C(S)-, -C(S)-O-, -O-C(O)O-, -C(O)-N(R8)-, or -O-C(O)-N(R8)-;B ring is Ce-i2aryl, 5-12 membered heteroaryl, or 4-12 membered heterocyclyl, each being optionally substituted with 1 to 3 RJ;R8is hydrogen or C1-6 alkyl; andeach RJis independently halo, oxo, -CN, -O-Rc, C1-6 alkyl, or C1-6 haloalkyl.

3. The compound of claim 1 or claim 2, wherein t is 1, q is 1, and the compound has the following structure:Formula (IA).

4. The compound of claim 1 or claim 2, wherein t is 0, q is 1, and the compound has the following structure:Formula (IB).

5. The compound of claim 1 or claim 2, wherein t is 1, q is 1, R4aand R4btogether form a Ci-3 alkylene chain, and the compound has one of the following structures:(wherein v is 1, 2 or 3)(wherein v is 1, 2 or 3) Formula (ID).

6. The compound of claim 1 or claim 2, wherein t is 0, q is 1, and R4aand R3together form a methylene chain, and the compound has the following structure:

7. The compound of claim 1 or claim 2, wherein t is 0, and q is 0, and the compound has the following structure:Formula (IF).2798. The compound of any one of claims 1-7, wherein each Li, L2, L3, L4, L5, Ls, L7, or Ls is independently:280ii) direct bond;iii) Ci.6 alkylene chain optionally substituted with 1-3 Rb; oriv) -C(O)-, -O- -(CH2)m-C(0)-N(Rc)-, -(CH2)m-C(O)- -(CH2)m-N(Rc)-, -C(0)-N(Rc)-(CH2)m- or -NH-(CH2)m-C(0)-, -(CH2)m-S(O)2NH- m being 0, 1, 2 or 3; wherein,n is 0, 1, or 2;Rbis halo, -O-Rc, -CN, C1-6 alkyl, or C1-6 haloalkyl; andRcis hydrogen, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, phenyl, or C1-6 haloalkyl, wherein C1-6 alkyl is optionally substituted with C1-3 alkoxy, hydroxy, C3-6 cycloalkyl, phenyl and amino.

9. The compound of any one of claims 1-7, wherein each Li, L2, L3, L4, L5, Ls, L7, or Ls is independently:i) a bivalent ring moiety selected from the group consisting of:ii) direct bond;iii) C1-6 alkylene chain optionally substituted with 1-3 Rb;iv) C1-6 alkenylene chain optionally substituted with 1-3 Rb; orv) -C(O)-, -O- -(CH2)m-C(O)-N(Rc)-, -(CH2)m-C(O)-, -(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, C1-6 alkyl, or C1-6 haloalkyl; andwherein Rcis hydrogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-6 cycloalkyl (optionally substituted with 1 or 2 halo, C1-3 alkyl or C1-3 alkoxy), 4-12 membered heterocyclyl (optionally substituted with 1 or 2 C1-3 alkyl), or 5-12 membered heteroaryl (optionally substituted with 1 or 2 C1-3 alkyl or C1-3 haloalkyl), wherein C1-6 alkyl is optionally substituted with 1 or 2 substituents selected from281the group consisting of C1-3 alkoxy, CN, 5-12 member heteroaryl (optionally further substituted with 1 or 2 halo or C1-3 alkyl), hydroxy, C3-6 cycloalkyl (optionally further substituted with 1 or 2 halo, C1-3 alkoxy or C1-3 alkyl), phenyl and amino.

10. The compound of any one of claims 1-9, wherein,Y is direct bond,-C(O)-N(R8)- (wherein R8is hydrogen or C1-6 alkyl), or -NH-; and2, RJis halo, -CN, -O-Rc, C1-6 alkyl, or C1-6 haloalkyl.

11. The compound of any one of claims 1-10, wherein R1is hydrogen and R2is hydrogen.

12. The compound of any one of claims 1-10, wherein R1is hydrogen and R2is halo or C1-3 alkyl.

13. The compound of any one of claims 1-3 and 8-12, wherein R1is hydrogen, L&, L7 and Ls are direct bonds, and the compound has the following structure: / — \Formula (IAA)wherein,R2is hydrogen, halo or C1-3 alkyl;R3is halo, C3-6 cycloalkyl, Ce-12 aryl, -O-Re(wherein Reis C3-6 cycloalkyl or C1-6 alkyl optionally substituted with one or more Ci.salkoxy or halo), C1-6 alkyl optionally substituted with Ci.salkoxy, Ce-12 aryl, halo, or 5-12 membered heteroaryl optionally substituted with 1 or 2 C1-6 alkyl or C1-6 haloalkyl;Li is -C(O)- or -C(O)-N(RC)-, wherein Rcis hydrogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-6 cycloalkyl (optionally substituted with 1 or 2 halo, C1-3 alkyl or C1-3 alkoxy), 4-12 membered heterocyclyl (optionally substituted with 1 or 2 C1-3 alkyl), or 5-12 membered heteroaryl (optionally substituted with 1 or 2 C1-3 alkyl or C1-3 haloalkyl), wherein C1-6 alkyl is optionally substituted with 1 or 2 substituents selected from the group consisting of C1-3 alkoxy, CN, 5-12 member heteroaryl (optionally further substituted with 1 or 2 halo or C1-3 alkyl), hydroxy, C3-6 cycloalkyl (optionally further substituted with 1 or 2 halo, C1-3 alkoxy or C1-3 alkyl), phenyl and amino;282L3is direct bond, -CH2-C(O)-, -(CH2)2-O-, or C1.4 alkylene chain optionally substituted with C1.3 alkyl or C2.4 alkylene chain optionally substituted with C1.3 alkyl;n is 0, 1 or 2, Rbis halo, C1-3 alkyl, or C’ualkoxy:L5 is direct bond or -O-Y is direct bond, or -C(0)-N(Me)-; andW is CH or N.

14. The compound of any one of claims 1, 2, 3, 8, and 10-12, wherein R1is hydrogen, L&, L7 and Ls are direct bonds, and the compound has the structure represented by Formula (IAA):Formula (IAA)wherein,R2is hydrogen, halo or C1-3 alkyl;R3is -O-Re(wherein Reis C3-6 cycloalkyl or C1-6 alkyl), C1-6 alkyl optionally substituted with Ci-salkoxy, 5-12 membered heteroaryl optionally substituted with 1 or 2 C1-6 alkyl, or C1-6 haloalkyl;Li is -C(O)- or -C(O)-N(RC)-, wherein Rcis hydrogen, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, or Ci.6 haloalkyl, wherein C1-6 alkyl is optionally substituted with 1 or 2 C1-3 alkoxy, hydroxy, C3-6 cycloalkyl (optionally substituted with C1-3 alkoxy), phenyl or amino;L3 is direct bond, -CH2-C(0)- or C1-2 alkylene chain optionally substituted with C1-3 alkyl;n is 0, 1 or 2, Rbis halo or C1-3 alkyl;L5 is direct bond or -O- Owherein p is 0, 1, or 2, RJis halo;Y is direct bond, or -C(0)-N(Me)-; andW is CH or N.

15. The compound of claim 14, wherein Y is direct bond, W is CH, and the compound has the following structure:Formula (IAA1).

16. The compound of claim 14 or claim 15, wherein,-L2-L3-L4- has the following structures:

17. The compound of any one of claims 14-16, whereinR2is hydrogen, F, Cl or methyl;R3is -O-Re(wherein Reis methyl, ethyl, propyl, cyclopropyl or cyclobutyl), -CH₂OCH₃, thiazol-4yl, thiazol-5yl, 1 -methyl- lH-pyrazol-5yl, 1 -ethyl- lH-pyrazol-5yl, l,3-dimethyl-lH-pyrazol-5-yl, 1,4-dimethyl- lH-pyrazol-5 -yl;Li is C(O), or -C(O)-N(RC)-, wherein Rcis hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, -OCH3, -CH2CF3, -CH2CH2-N(CH3)2, -CH2CH2-OCH3, -CFb-cyclopropyl. benzyl, or l,3-dihydroxypropan-2yl; andOwherein p is 0, 1, or 2, RJis F.

18. The compound of claim 14 or claim 15, whereinL3 is a direct bond, and-L2-L3-L4- has the following structures:28519. The compound of any one of claims 14, 15 or 18, whereinR2is hydrogen;R3is -O-Re(wherein Reis methyl, ethyl, propyl, cyclopropyl or cyclobutyl), thiazol-4yl, thiazol-5yl, 1 -methyl- lH-pyrazol-5yl, 1 -ethyl- lH-pyrazol-5yl, l,3-dimethyl-lH-pyrazol-5-yl, 1,4-dimethyl-lH-pyrazol-5-yl, l-(oxan-4-yl)-lH-pyrazol-5-yl, l-methyl-3-(trifluoromethyl)-lH-pyrazol-5-yl, or 2-methyl-2H-indazol-3-yl;Li is C(O), or -C(O)-N(RC)-, wherein Rcis hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, -CH2CF3, -CH2CH2-N(CH3)2, -CH2CH2-OCH3, or benzyl; and, wherein p is 0, 1, or 2, R is halo.

20. The compound of any one of claims 1-3, 8, 10-12 and 14-18, wherein R3is pyrazol-5yl (optionally substituted with 1 or 2 methyl, trifluoromethyl, oxan-4-yl), thiazolyl, or indazolyl (optionally substituted with 1 or 2 methyl), -CH₂OCH₃, or O-cyclobutyl.

21. The compound of claim 14 having the structure of Formula (IAA2) or Formula (IAA3):Formula (IAA2)286Formula (IAA3)wherein,R3is -O-Re(wherein Reis C3-6 cycloalkyl or C1-6 alkyl), C1-6 alkyl optionally substituted with Ci-salkoxy, or 5-12 membered heteroaryl optionally substituted with 1 or 2 Ci-6 alkyl or Ci-6 haloalkyl;Li is C(O), or -C(O)-N(RC)-, wherein Rcis hydrogen, Ci-6 alkyl, Ci-6 alkoxy, C3-6 cycloalkyl, or Ci.6 haloalkyl, wherein C1-6 alkyl is optionally substituted with 1 or 2 C1-3 alkoxy, hydroxy, C3-6 cycloalkyl, phenyl or amino;287p is 0, 1, or 2; andRJis halo.

22. The compound of claim 21, wherein Rcis Ci-6 alkoxy, C3-6 cycloalkyl, Ci-6 haloalkyl, or Ci-6 alkyl substituted with 1 or 2 C1.3 alkoxy, hydroxy, C3-6 cycloalkyl, phenyl or amino.

23. The compound of claim 21 or claim 22, wherein R3is ORe, and Reis methyl, ethyl, or cyclopropyl.

24. The compound of claim 21 or claim 22, wherein R3is pyrazol-5yl (optionally substituted with 1 or 2 methyl, trifluoromethyl, oxan-4-yl), thiazolyl, or indazolyl (optionally substituted with 1 or 2 methyl), -CH₂OCH₃, or O-cyclobutyl.

25. The compound of claim 14, wherein R1is hydrogen, R2is hydrogen, L6, L7and L8are direct bonds, and W is N, the compound has the following structure:Formula (IAA4)wherein,Reis Ci-6 alkyl;Li is-C(O)-N(Rc)-, wherein Rcis hydrogen, or Ci-6 alkyl;28826. The compound of claim 14, wherein R1is hydrogen, R2is hydrogen, L6, L7 and L8 are direct bonds, the compound has the following structure:Formula (IAA5)wherein,Reis Ci-6 alkyl;Li is-C(O)-N(Rc)-, wherein Rcis hydrogen, or Ci-6 alkyl;27. The compound of any one of claims 1, 2, 3, and 8-13, wherein R1is hydrogen, L&, L? and Ls are direct bonds, and the compound has the structure represented by Formula (IAA1):Formula (IAA1)wherein,R2is hydrogen, halo or C1.3 alkyl;R3is halo, C3-6 cycloalkyl, Ce-i2 aryl, Ci-6 haloalkyl, C1-6 alkyl optionally substituted with C1-3 alkoxy, or -O-Re(wherein Reis C3-6 cycloalkyl or Ci-6 alkyl optionally substituted with one or more Ci.3alkoxy or halo)Li is -C(O)- or -C(O)-N(RC)-, wherein Rcis hydrogen, Ci-6 alkyl, Ci-6 alkoxy, C3-6 cycloalkyl (optionally substituted with 1 or 2 halo, C1.3 alkyl or C1.3 alkoxy), 4-12 membered heterocyclyl optionally substituted with 1 or 2 C1.3 alkyl), 5-12 membered heteroaryl optionally substituted with 1 or 2 C1.3 alkyl or C1.3 haloalkyl), phenyl, or Ci-6 haloalkyl, wherein Ci-6 alkyl is optionally substituted with 1 or 2 C1.3 alkoxy, CN, 5-12 member heteroaryl (optionally further substituted with 1 or 2 halo or C1.3 alkyl), or C3-6 cycloalkyl (optionally further substituted with 1 or 2 halo, C1.3 alkoxy or C1.3 alkyl);L3 is direct bond, -CH2-C(0)-, -(CH₂)-O-, C1-4 alkylene chain optionally substituted with C1-3 alkyl or C2-4 alkylene chain optionally substituted with C1-3 alkyl;289n is 0, 1 or 2, Rbis halo, C1-3 alkyl or Ci-salkoxy;L5 is direct bond or -O-wherein p is 0, 1, or 2, R is halo.

28. The compound of claim 27, wherein,R2is hydrogen, F, Cl or methyl;R3is F, cyclopropyl, phenyl, benzyl, C1.3 haloalkyl, Ci-6 alkyl (optionally substituted 1 or 2 C1.3 alkoxy), or -O-Re(wherein Reis cyclopropyl, cyclobutyl, or Ci.6 alkyl optionally substituted with one or more Ci.salkoxy or halo);Li is -C(O)-N(RC)-, wherein Rcis Ci-6 alkyl, Ci-6 alkoxy, cyclopropyl (optionally substituted with methyl or methoxy), cyclobutyl (optionally substituted with 1 or 2 methyl or F), azetidinyl (optionally substituted with 1 or 2 methyl), pyrazolyl (optionally substituted with difluoromethyl), phenyl, or Ci-6 haloalkyl, wherein Ci-6 alkyl is optionally substituted with 1 or 2 C1.3 alkoxy, CN, oxazolyl, thiazolyl (optionally substituted with methyl), pyrazinyl, pyrimidinyl, 1 -methyl- 1,2, 3 -triazolyl, pyrazolyl (optionally substituted with 1 or 2 C1.3 alkyl), oxadiazolyl (optionally substituted with methyl), cyclopropyl (optionally substituted with C1.3 alkoxy), cyclobutyl, or 3, 3 -difluorocyclobutyl);29029. The compound of claim 27, wherein,R2is hydrogen or F;R3is Ci-6 alkyl (optionally substituted 1 or 2 C1-3 alkoxy), or -O-Re(wherein Reis C1-6 alkyl optionally substituted with one or more C1-3 alkoxy or halo);Li is -C(O)-; and30. The compound of any one of claims 2, 4 or 8, having the following structure:Formula (IB 1)wherein,Reis C1-6 alkyl;Li is-C(O)-N(Rc)-, wherein Rcis hydrogen, or Ci-6 alkyl;31. The compound of any one of claims 1-2, 4 and 8-12, wherein R1is hydrogen, L6, L7and L8are direct bonds, and the compound has the following structure:291Formula (IB2)wherein,R2is hydrogen or halo;R3is hydrogen, halo, Ce-i2 aryl, Ci-6 alkyl optionally substituted with C’ualkoxy. or -O-Re(wherein Reis C3-6 cycloalkyl, or Ci-6 alkyl optionally substituted with one or more Ci ^alkoxy or halo);R4ais hydrogen, Ci-6 alkyl or Ci-6 alkoxy;Li is -C(O)-, -C(O)-N(RC)- or -CH2-C(0)-N(RC)-, wherein Rcis hydrogen, Ci-6 haloalkyl, C3-6 cycloalkyl (optionally substituted with 1 or 2 halo, C1.3 alkyl or C1.3 alkoxy), or Ci-6 alkyl (optionally substituted with 1 or 2 C1.3 alkoxy or 5-12 membered heteroaryl (optionally further substituted with 1 or 2 halo or C 1.3 alkyl));L3 is direct bond, C1.4 alkylene chain optionally substituted with C1-3 alkyl or C2-4 alkylene chain optionally substituted with C1-3 alkyl;Nn is 0, 1 or 2, Rbis halo, C1-3 alkyl, or hydroxy;L5 is direct bond or -O-Nwherein p is 0, 1, or 2, R is halo.

32. The compound of claim 31, wherein,R2is hydrogen or F;R3is F, Ci-3 alkyl, phenyl, or -O-Re(wherein Reis cyclopropyl or C1.3 alkyl);R4ais hydrogen, or methoxy;Li is -C(O)- or -C(O)-N(RC)-, wherein Rcis hydrogen, Ci-6 alkyl, C1.3 alkyl (optionally substituted with methoxy, oxazolyl, thiazolyl, pyrazinyl, pyrimidinyl, 1 -methyl- 1,2, 3 -triazolyl, pyrazolyl (optionally substituted with 1 or 2 C1.3 alkyl), oxadiazolyl (optionally substituted with methyl), or cyclopropyl (optionally substituted with 1 or 2 F, methyl, or methoxy);29233. The compound of any one of claims 1, 2, 5 and 8-12, wherein the compound has one of the following structures:wherein,R2is hydrogen or halo;R3is hydrogen or C1-3 alkyl;Li is-C(O)-N(Rc)-, wherein Rcis hydrogen, C1-6 haloalkyl, C1-6 alkoxy, C3-6 cycloalkyl or C1-6 alkyl optionally substituted with C3-6 cycloalkyl, 5-7 member heteroaryl (preferably thiazolyl), or C1-6 alkoxy;29334. The compound of any one of claims 1, 2, 5, and 8-12, wherein the compound has the following structure:wherein,R2is hydrogen or halo;R3is hydrogen or C1.3 alkyl;35. The compound of any one of claims 1, 2, 6 and 8-12, wherein the compound has the following structure:Formula (IE1)wherein,R2is hydrogen or halo;Li is-C(O)-N(Rc)-, wherein Rcis hydrogen or C1-6 alkyl;; and29436. The compound of any one of claims 1, 2 and 7-11, wherein the compound has the following structure:wherein,R2is hydrogen or halo;R3is hydrogen, Ci-6 alkyl, or -ORe(wherein R3is Ci-6 alkyl);Li is-C(O)-N(Rc)-, wherein Rcis hydrogen or Ci-6 alkyl;37. A compound selected from the group consisting of Examples 1-263.

38. A pharmaceutical composition comprising the compound of any one of claims 1-37, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

39. The pharmaceutical composition of claim 38, further comprising one or more additional therapeutic agents, or a pharmaceutically acceptable salt thereof.

40. A compound of any one of claims 1-37, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 38 or claim 39, for use in therapy.

41. Use of compound of any one of claims 1-37, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 38 or claim 39, for treating SMARCA2 -mediated diseases.

42. The use according to claim 41 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,295ependymoma, 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.296EXAMPLE 76N-{1-[(3RS)-8-{4-[(3R)-2,6-DIOXOPIPERIDIN-3-YL]PHENYL}-1-OXA-8-AZASPIRO[4.5]DECAN-3- YL]PIPERIDIN-4-YL}-1-[6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL]-N-METHYL-4-(2-METHYL-2H- INDAZOL-3-YL)PIPERIDINE-4-CARBOXAMIDEStep 1: l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-methyl-4-(2-methylindazol-3-yl)-N-(piperidin-4-yl)piperidine-4-carboxamidel-[6-(2-hydroxyphenyl)pyridazin-4-ylJ-N-methyl-4-(2-methylindazol-3-yl)-N-(piperidin-4-yl)piperidine-4-carboxamide was prepared as described for Example 32, Step 1, using l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-4-(2-methyl-2H-indazol-3-yl)piperidine-4-carboxylic acid. LCMS: C30H35N7O2 requires: 525.3, found: m / z = 526.4 [M+H]+.Step 2: Synthesis of the title compoundThe title compound was prepared as described for Example 1, Step 2, using l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-methyl-4-(2-methylindazol-3-yl)-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride and (3R)-3-(4-{3-oxo-l-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)piperidine-2, 6-dione to afford N-{l-[(3RS)-8-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}-l-oxa-8-azaspiro[4.5]decan-3-yl]piperidin-4-yl}-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N -methyl -4-(2-methylindazol-3-yl)piperidine-4-carboxamide (12.5 mg, 51.6%). LCMS: C49H57N9O5 requires 851.4, found: m / z = 852.4 [M+H]+.EXAMPLE 77A AND 77B(7?)-JV-(1-(2-(1-(4-((7?)-2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4-YL)ETHYL)PIPERIDIN-4-YL)- 1-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-3-METHOXY-JV-METHYLPYRROLIDI E-3-CARBOXAMIDE AND (A)-N-(1-(2-(1-(4-((R)-2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4-YL)ETHYL)PIPERIDIN-4- YL)-1-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-3-METHOXY-N-METHYLPYRROLIDINE-3-159(R5)-A-(l-(2-(l-(4-((R)-2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-3-methoxy-JV-methylpyrrolidine-3-carboxamide (Example 55) was subjected to two stages of SFC chromatography (Chiralpak IH, EtOH + 60ACN + 0.1% Nf LOI I followed by Whelk-01 ( / ?. / ?). EtOH + 60ACN + 0.1% NH4OH) to afford Example 77A (second peak in second SFC stage, RT = 2.47 min, 36.7 mg, 28% yield) and Example 77B (second peak in second SFC stage, RT = 3.28 min, 33 6 mg, 26% yield) as white solids. Example 77A LCMS C40H51N7O5 requires: 709.4, found: m / z = 710.4 [M+H]+. Example 77B LCMS C40H51N7O5 requires: 709.4, found: m / z = 710.4 [M+H]+. Assignment of absolute stereochemistry for both compounds is arbitrary. Two additional isomers were also isolated following a similar process.EXAMPLE 78(R)-3-(4-(4-(2-(9-((7? X)-1-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-3-METHOXYP YRROLIDINE-3- CARBONYL)-3,9-DIAZASPIRO[5.5]UNDECAN-3-YL)ETHYL)PIPERIDIN-1-YL)PHENYL)PIPERIDINE-2,6-Step 1: rac-( / ?)-(l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-3-methoxypyrrolidin-3-yl)(3,9-diazaspir 0 [5.5] undecan -3-yl)methanone hydrochlorideThe title compound was prepared as described for Example 1, Step 1 using rac-(R)-3 -methoxy- 1-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)pyrrolidine-3-carboxylic acid (Intermediate 5) and tert-160butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate to afford the product as a yellow oil. LCMS C25H33N5O3 requires 451.3, found m / z = 452.3 [M+H]+.Step 2: Synthesis of title compoundThe title compound was prepared as described for Example 1, Step 2, using rac-( / ?)-( l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-3-methoxypyrrolidin-3-yl)(3,9-diazaspiro[5.5]undecan-3-yl)methanone hydrochloride to afford the title compound (24.9 mgs, 24% yield) as a white solid. LCMS: C43H55N7O5 requires: 749.4, found: m / z = 750.4 [M+H]+.EXAMPLE 79R4C-(7?)-3-(2-FLUORO-4-(4-(2-(2-((X)-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-3- METHOXYPYRROLIDINE-3-CARBONYL)-2,7-DIAZASPIRO[3.5]NONAN-7-YL)ETHYL)PIPERIDIN-l- YL)PHENYL)PIPERIDINE-2, 6-DIONEStep 1: Synthesis of rac-(7?)-(l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-3-methoxypyrrolidin-3-yl)(2,7-diazaspiro [3.5] nonan-2-yl)methanone (TFA salt)The title compound was prepared as described for Example 1, Step 1, using rac-(R)-3 -methoxy- 1-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)pyrrolidine-3-carboxylic acid (Intermediate 5) and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate. TFA in DCM was used for the cleavage of the BOC protecting group. The product was afforded as yellow oil. LCMS C23H29N5O3 requires 423.2, found m / z = 424.

2. [M+H]+.Step 2: Synthesis of title compoundThe title compound was prepared as described for Example 1, Step 2, using rac-( / ?)-( l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-3-methoxypyrrolidin-3-yl)(2,7-diazaspiro[3.5]nonan-2-yl)methanone 2,2,2-trifluoroacetate to afford the title compound (22.3 mg, 18% yield) as a white solid. LCMS:C41H50FN7O5 requires: 739.4, found: m / z = 740.4 [M+H]+EXAMPLE 80A(7?)-Af-(l-(2-(l-(4-((7?)-2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4-YL)ETHYL)PIPERIDIN-4-YL)- 3-ETHOXY-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-W-METHYLPYRROLIDINE-3-CARBOXAMIDEStep 1: Synthesis of rac-( / ?)-3-ethoxy-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-X-methyl-X- (piperidin-4-yl)pyrrolidine-3-carboxamide (TFA salt)The title compound was prepared as described for Example 2, Step 2 using rac-( / ?)-3-cthoxy- 1 -(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)pyrrolidine-3-carboxylic acid (Intermediate 26) and tert-butyl 4-(methylamino)piperidine- 1 -carboxylate. TFA in DCM was used for cleavage of the BOC protecting group. The desired product was afforded as a yellow oil. LCMS C23H31N5O3 requires 425.2, found m / z =426.2 [M+H]+.Step 2: Synthesis of the title compoundThe title compound was synthesized as prepared for Example 1, Step 2, using rac-( / ?)-3-cthoxy-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-jV-methyl-jV-(piperidin-4-yl)pyrrolidine-3-carboxamide 2,2,2-trifluoroacetate. After RP-HPLC, this compound was subjected to 2 stages of chiral SFC purification (Whelk-01 (R, R), EtOH + 60ACN + 0.1% NH4OH followed by Chiralpak IBN, EtOH + 60ACN + 0.1% NH4OH). The peak was collected and concentrated to afford the title compound as a white solid (Peak 1 after second SFC stage, RT = 7.33 min, 26.4 mg, 38% yield). Assignment of absolute stereochemistry is arbitrary. LCMS C41H53N7O5 requires 723.4, found m / z = 724.4 [M+H]+.EXAMPLE 80B(S)-N-(1-(2-(1-(4-((R)-2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4-YL)ETHYL)PIPERIDIN-4-YL)-3- ETHOXY-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-N-METHYLPYRROLIDINE-3-CARBOXAMIDEStep 1: Synthesis of the title compoundThe title compound was synthesized as prepared for Example 1, Step 2, using rac-( / ?)-3-cthoxy-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-JV-methyl-jV-(piperidin-4-yl)pyrrolidine-3-carboxamide 2,2,2-162trifluoroacetate. After RP-HPLC, this compound was subjected to 2 stages of chiral SFC purification (Whelk-01 (R, R), EtOH + 60ACN + 0.1% NH4OH followed by Chiralpak IBN, EtOH + 60ACN + 0.1% NH4OH). The peak was collected and concentrated to afford the title compound as a white solid (Peak 2 after second SFC stage, RT = 7.55 min, 22.1 mg, 31.6% yield). Assignment of absolute stereochemistry is arbitrary. LCMS C41H53N7O5 requires 723.4, found m / z = 724.4 [M+H]+.EXAMPLE 81( / ?)-V-(l-(2-( l-(4-((tS’)-2,6-DIOXOPIPERIDIN-3-YL)-3-FLUOROPHENYL)PIPERIDIN-4- YL)ETHYL)PIPERIDIN-4-YL)-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-3-METHOXY-W- METHYLPYRROLIDINE-3-CARBOXAMIDEStep 1: Synthesis of title compoundThe title compound was prepared as described for Example 1, Step 2, using rac-( / ?)-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-3-methoxy-A-methyl-A-(piperidin-4-yl)pyrrolidine-3-carboxamide hydrochloride (Example 55, Step 1) and rac-(R)-2-(l-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl)piperidin-4-yl)acetaldehyde. After RP-HPLC, this compound was subjected to 2 stages of chiral SFC purification (Chiralpak IH, EtOH + 60ACN + 0.1% NH4OH followed by Whelk-Ol (R, R), EtOH + 60ACN + 0.1% NH4OH). The peak was collected and concentrated to afford the title compound as a white solid (Peak 2 after second SFC stage, RT = 7.52 min, 21.4 mg, 11% yield). Assignment of absolute stereochemistry is arbitrary. LCMS C40H50FN7O5 requires, 727.4, found m / z = 728.4 [M+H]+.EXAMPLE 82l-(2-(l-(4-((5)-2,6-DIOXOPIPERIDIN-3-YL)-3,5-DIFLUOROPHENYL)PIPERIDIN-4- YL)ETHYL)PIPERIDIN-4-YL)-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-3-METHOXY-W- METHYLPYRROLIDINE-3-CARBOXAMIDEF Step 1: Synthesis of title compoundThe title compound was prepared as described for Example 2, Step 2, using rac-( / ?)-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-3-methoxy-A-methyl-A-(piperidin-4-yl)pyrrolidine-3-carboxamide hydrochloride (Example 55, Step 1) and rac-(R)-2-(l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidin-4-yl)acetaldehyde. After RP-HPLC, this compound was subjected to 2 stages of chiral SFC purification (Chiralpak IH, EtOH + 60ACN + 0.1% NH4OH followed by Whelk-Ol (R, R), EtOH + 60ACN + 0.1% NH4OH). The peak was collected and concentrated to afford the title compound163as a white solid (Peak 2 after second SFC stage, RT = 7.69 min, 27.4 mg, 11% yield). Assignment of absolute stereochemistry is arbitrary. LCMS C4oFL9F2N705 requires 745.4, found m / z = 746.4 [M+H]+.EXAMPLE 83RAC-(R)-N-(l-(2-(l-(4-((S)-2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4-YL)ETHYL)PIPERIDIN-4- YL)-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-3-ISOPROPOXY-N-METHYLPYRROLIDINE-3- CARBOXAMIDEy— NH. NN &i y=oNVi 'Step 1: Synthesis of methyl 2-isopropoxyacrylateTo a stirred solution of methyl 2-methoxyacrylate (13 g, 111 mmol) in PrOH (150 mL) was added CuCl2(903 mg, 6.7 mmol), NaH2PC>4 (9.40 g, 78 mmol) and Bis(benzonitrile)palladium (II) dichloride (4.29 g, 11.1 mmol) and the reaction mixture was stirred at RT for 48 h. After completion of reaction (monitored by TLC), charcoal (10 g) was added to the reaction mixture and the solution was stirred at RT for another 30 min. The reaction mixture was then filtered through a fritted funnel and washed with diethyl ether (250 mL). The filtrate was diluted with water (200 mL) and the organic layer was separated. The aqueous layer was further extracted with diethyl ether (2 x 250 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure (below 30°C) to get the desired compound as colorless liquid (6.5 g, 40%). ’H NMR (400 MHz, CDCfi-t / e): <55.41 (d, J = 2.0 Hz, 1H), 4.61 (d, J= 2.0 Hz, 1H), 4.32-4.26 (m, 1H), 3.82 (s, 3H), 1.35-1.32 (m, 6H).Step 2: Synthesis of methyl l-benzyl-3-isopropoxypyrrolidine-3-carboxylateTo a stirred solution of methyl 2-isopropoxyacrylate (2.5 g, 17 mmol) and N-benzyl-l-methoxy-N-((trimethylsilyl)methyl)methanamine (16.46 g, 68 mmol) in acetonitrile (30 mL) was added LiF (1.35 g, 52 mmol) at RT and the resulting reaction mixture was stirred at 70°C for 16 h. After completion of reaction (monitored by TLC and LCMS), reaction mixture was concentrated under reduced pressure to get a crude residue which was purified by flash column chromatography (5% EtOAc in heptane) to get the desired compound as pale yellow sticky gum (1.5 g, 31%).Step 3: Synthesis of methyl l-benzyl-3-isopropoxypyrrolidine-3-carboxylateTo a stirred solution of methyl l-benzyl-3-isopropoxypyrrolidine-3-carboxylate (750 mg, 2.7 mmol) in EtOH (10 mL) was added 10% Pd / C (375 mg) and HOONH4 (852 mg, 13 mmol) at RT under inert atmosphere and the resulting mixture was stirred at 70°C for 2 h. After completion of the reaction (monitored by TLC and LCMS), the reaction mixture was filtered through a celite bed and washed with EtOH (50 mL). The filtrate was concentrated under reduced pressure to get the desired compound as colorless viscous liquid (430 mg, 84%).164Step 4: Synthesis of methyl 3-isopropoxy-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)pyrrolidine-3-carboxylateTo a stirred solution of methyl 3 -isopropoxypyrrolidine-3 -carboxylate 6 (400 mg, 2.1 mmol) and 5-chloro-3-(2-(methoxymethoxy)phenyl)pyridazine 7 (535 mg, 2.1 mmol) in DMA (10 mL) was added DIPEA (1.14 mL, 6.4 mmol) and the reaction mixture was stirred at 100°C for 8 h. After completion of reaction (monitored by LCMS), the reaction mixture was diluted with cold water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (3% MeOH in DCM) to get desired compound as yellow gummy solid (430 mg, 50%).Step 5: Synthesis of 3-isopropoxy-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)pyrrolidine-3-carboxylic acidTo a stirred solution of methyl 3 -isopropoxy- l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)pyrrolidine-3-carboxylate (430 mg, 1.07 mmol) in THE (5 mL) was added a solution of LiOH·H2O (45 mg, 1.07 mmol) in water (2.5 mL) and the resulting solution was stirred at RT for 16 h. After completion of reaction (monitored by TLC), the mixture was concentrated under reduced pressure, diluted with 25% IPA in CHCL (50 mL) and filtered through a fritted funnel. The filtrate was concentrated under reduced pressure to get the desired compound as a grey solid (400 mg, 96%). ’H NMR (400 MHz, DMSO-t / e): <5 8.51 (d, J= 2.8 Hz, 1H), 7.64 (dd, J= 1.6 Hz, 7.6 Hz, 1H), 7.41-7.36 (m, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.12-7.08 (m, 1H), 6.79 (d, J= 2.8 Hz, 1H), 5.21 (s, 2H), 3.92-3.83 (m, 1H), 3.68 (brs, 1H), 3.41-3.37 (m, 3H), 3.33 (s, 3H), 2.32-2.25 (m, 1H), 1.99-1.93 (m, 1H), 1.07 (d, J= 6.0 Hz, 3H) and 0.98 (d, J= 6.0 Hz, 3H).Step 6: Synthesis of 3-isopropoxy-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)pyrrolidine-3-carboxylic acidTo an ice-cold stirred solution of 3 -isopropoxy- 1 -(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)pyrrolidine-3 -carboxylic acid Lithium salt (200 mg, 0.51 mmol) and tert-butyl 4-(methylamino)-l-piperidinecarboxylate (165 mg, 0.77 mmol) in DMF (3 mL) was added DIPEA (0.45 mL, 2.5 mmol) under inert atmosphere followed by HATU (215 mg, 0.56 mmol) and the reaction mixture was stirred at RT for 2 h. After completion of the reaction (monitored by TLC and LCMS), the reaction mixture was diluted with water (20 mL) and extracted with 5% MeOH in DCM (2 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (eluent 2% MeOH in DCM) to get the desired compound as a green sticky solid (200 mg, 67%).Step 7: Synthesis of l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-3-isopropoxy-N-methyl-N-(piperidin-4-yl) pyrrolidine-3-carboxamideTo an ice-cold stirred solution of tert-butyl 4-(3 -isopropoxy- 1-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-N-methylpyrrolidine-3-carboxamido) piperidine- 1 -carboxylate (200 mg, 0.34 mmol) in DCM (5 mL) was added TFA (1 mL) under inert atmosphere and the reaction mixture was stirred at RT for 3 h. After completion of reaction (monitored by TLC and LCMS), the165reaction mixture was concentrated under reduced pressure. The crude residue was triturated with diethyl ether (10 mL) and Pentane (10 mL) to get the desired compound as an off-white solid (140 mg, 92%). Step 8: Synthesis of N-(l-(2-(l-(4-((R)-2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-3-isopropoxy-N-methylpyrrolidine-3-carboxamideTo an ice-cold stirred solution of l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-3-isopropoxy-N-methyl-N-(piperidin-4-yl)pyrrolidine-3-carboxamide (140 mg, 0.31 mmol) and (R)-2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)acetaldehyde (100 mg, 0.31 mmol) in MeOH (1.5 mL) and ACN (4.5 mL) was added DIPEA (205 mg, 1.5 mmol) and the reaction mixture was stirred at RT for 30 min. Reaction mixture was then cooled to 0°C, and sodium triacetoxyborohydride (202 mg, 0.95 mmol) was added and the resulting mixture was stirred at RT for another 2 h. After completion of reaction (monitored by TLC & LCMS), the mixture was quenched with water (20 mL) and extracted with 10% MeOH in DCM (2x30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by RP-HPLC purification using Column: Atlantis T3 C-18 (19x250) mm, 5p) Mobile phase: A: - 0.1% FA in Water B: - 100% ACN and Flow rate: 20 ml / min., to get the title compound as an off white solid (30 mg, 12%). ’H NMR (400 MHz, DMSO-t / e): <514.79 (brs, 1H), 10.76 (s, 1H), 8.66 (s, 1H), 8.10-8.08 (m, 1H), 7.35-7.27 (m, 2H), 7.04-7.01 (m, 2H), 6.94-6.87 (m, 4H), 4.35-4.28 (m, 1H), 3.98-3.87 (m, 2H), 3.83-3.78 (m, 1H), 3.77-3.72 (m, 1H), 3.69-3.63 (m, 2H), 3.57-3.51 (m, 2H), 3.12 (brs, 4H), 2.75 (s, 1H), 2.67-2.58 (m, 4H), 2.44-2.42 (m, 4H), 2.24 (brs, 1H), 2.11-2.07 (m, 1H), 2.03-1.99 (m, 1H), 1.87-1.65 (m, 5H), 1.58 (brs, 2H), 1.46 (brs, 3H), 1.29-1.21 (m, 2H) and 1.12-1.03 (m, 6H).EXAMPLE 84(X)-A-(l-((l-(2-((7iS)-2,6-DIOXOPIPERIDIN-3-YL)-l-OXO-l,2-DIHYDROISOQUINOLIN-6-YL)PIPERIDIN- 4- YL)METHYL)PIPERIDIN-4-YL)-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-3-METHOXY-A- METHYLPYRROLIDINE-3-CARBOXAMIDEStep 1: Synthesis of (iS)-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-3-methoxy-A-methyl-A-(piperidin-4-yl)pyrrolidine-3-carboxamide hydrochlorideThe title compound was prepared as described for Example 1, Step 1, using (. S)-3-mcthoxy- 1 -(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)pyrrolidine-3-carboxylic acid (Intermediate 25-1) and tertbutyl 4-(methylamino)piperidine- 1 -carboxylate to afford the title compound as a yellow oil. LCMS C22H29N5O3 requires 411.2, found m / z = 412.2 [M+H]+.Step 2: Synthesis of the title compoundThe title compound was prepared as described for Example 2, Step 2, using (. S')-l-(6-(2-hydroxyphcnyl)pyridazin-4-yl)-3-mcthoxy-A-mcthyl-A-(pipcridin-4-yl)pyrrolidinc-3-carboxamidc hydrochloride (Example 84, Step 1) and rac-(A)-l-(2-(2,6-dioxopiperidin-3-yl)-l-oxo-l,2-dihydroisoquinolin-6-yl)piperidine-4-carbaldehyde (WO2021168197 Al) to afford the title compound (4.6 mgs, 49% yield) as a white solid. LCMS C42H50N8O6 requires: 762.4, found: m / z = 763.4 [M+H]+.EXAMPLE 85(5)-N-(l-(2-(l-(4-((7iS)-2,6-DIOXOPIPERIDIN-3-YL)PHENYL)-4-HYDROXYPIPERIDIN-4- YL)ETHYL)PIPERIDIN-4-YL)-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-3-METHOXY-A- METHYLPYRROLIDINE-3-CARBOXAMIDEStep 1: Synthesis of title compoundThe title compound was prepared as described for Example 1, Step 2, using (. S)-l-(6-(2-hydroxyphcnyl)pyridazin-4-yl)-3-mcthoxy-A-mcthyl-A-(pipcridin-4-yl)pyrrolidinc-3-carboxamidc hydrochloride (Example 84, Step 1) and rac-(A)-2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)-4-hydroxypiperidin-4-yl)acetaldehyde to afford the title compound (8.5 mg, 57% yield) as a white solid. LCMS C4OH5IN706 requires: 725.4, found: m / z = 726.3 [M+H]+.EXAMPLE 86(X)-A-(l-((l-(4-((7?)-2,6-DIOXOPIPERIDIN-3-YL)-3-FLUOROPHENYL)PIPERIDIN-4- YL)METHYL)PIPERIDIN-4-YL)-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-3-METHOXY-A- METHYLPYRROLIDINE-3-CARBOXAMIDE167Step 1: Synthesis of the title compoundThe title compound was prepared as described for Example 1, Step 2 using (. S')-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-3-methoxy- / V-methyl- / V-(piperidin-4-yl)pyrrolidine-3-carboxamide hydrochloride (Example 84, Step 1) and ( / ?)-l-(4-(2.6-dioxopipcridin-3-yl)-3-fluorophcnyl)pipcridinc-4-carbaldehyde to afford the title compounds (3.8 mgs, 42% yield) as a white solid. LCMS C39H48FN7O5 requires: 713.4, found: m / z = 714.4 [M+H]+.EXAMPLE 87(. S’)-V-( l-(2-(l-(5-((7iS)-2,6-DIOXOPIPERIDIN-3-YL)PYRIDIN-2-YL)PIPERIDIN-4-YL)ETHYL)PIPERIDIN- 4- YL)-1-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-3-METHOXY-A-METHYLPYRROLIDINE-3- CARBOXAMIDEHOStep 1: Synthesis of the title compoundThe title compound was prepared as described for Example 1, Step 2, using (. S')-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-3-methoxy- / V-methyl- / V-(piperidin-4-yl)pyrrolidine-3-carboxamide hydrochloride (Example 84, Step 1) and rac-(J?)-2-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)acetaldehyde to afford the title compound (6.9 mgs, 57% yield) as a white solid. LCMS: C39H50N8O5 requires: 710.4, found: m / z = 711.3 [M+H]+.EXAMPLE 88(5)-A-(l-(7-(4-((7iS)-2,6-DIOXOPIPERIDIN-3-YL)PHENYL)-7-AZASPIRO[3.5]NONAN-2-YL)PIPERIDIN-4- YL)-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-3-METHOXY-A-METHYLPYRROLIDINE-3- CARBOXAMIDEStep 1: Synthesis of the title compoundThe title compound was prepared as described for the synthesis of Example 1, Step 2, using ( S')- 1 -(6-(2-hydroxyphenyl)pyridazin-4-yl)-3-methoxy- / V-methyl- / V-(piperidin-4-yl)pyrrolidine-3-carboxamide hydrochloride (Example 84, Step 1) and rac-(J?)-3-(4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)phenyl)piperidine-2, 6-dione to afford the title compound (5.5 mgs, 52% yield) as a white solid. LCMS: C41H51N7O5 requires: 721.4, found: m / z = 722.3 [M+H]+.168EXAMPLE 89(R)-N-(2,2-DIFLUOROETHYL)-N-(l-(2-(l-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4- YL)ETHYL)PIPERIDIN-4-YL)-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXYPIPERIDINE-4- CARBOXAMIDEFStep 1: Synthesis of N-(2,2-difluoroethyl)-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N- (piperidin-4-yl)piperidine-4-carboxamideLithio 4-methoxy-l-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}piperidine-4-carboxylate (300.00 mg, 0.79 mmol) was dissolved in dry acetonitrile (12.00 mL). The flask was cooled to 0 °C and a drop of DMF was added. Then, oxalyl chloride (271.28 pL, 3.16 mmol) was added dropwise as a solution in 2 mL of acetonitrile. The reaction mixture was stirred at room temperature until complete by LCMS. Then, the reaction mixture was concentrated to approximately half of the initial volume. The acid chloride concentrated solution was then filtered through a syringe filter directly into an ice cold solution of tertbutyl 4- [(2,2-difluoroethyl)amino]piperidine-l -carboxylate (313.55 mg, 1.19 mmol) andN, N-diisopropylethylamine (414.38 pL, 306.64 mg, 2.37 mmol) in acetonitrile (0.25mL). The reaction was slowly warmed to room temperature and then warmed to 50 °C and stirred until complete by LCMS. Then, the reaction was quenched with water, washed with a saturated solution of K2CO3, extracted with DCM, dried, filtered and concentrated under reduced pressure. The crude product was purified on silica gel with a gradient of EtOAc / Hex 0-100%, then 0-10% EtOAc / MeOH to afford the pure product as a yellow oil (195 mg, 40%). The pure material was dissolved in 2.00 mL of DCM and 4M HC1 in Dioxane (1.00 mL) was added in one portion. The reaction was stirred at room temperature until complete by LCMS and then concentrated in vacuo to yield the desired product as a yellow foam. LCMS:C24H31F2N5O3 requires 475.2, found: m / z = 476.2 [M+H]+.Step 2: Synthesis of the title compoundThe title compound was prepared as described for Example 1, Step 2, using N-(2,2-difluoroethyl)-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide and (R)-2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)acetaldehyde to afford the title compound (22 mg, 41%). ’H NMR (700 MHz, DMSO) 5 10.78 (s, 1H), 8.94 (d, J= 2.8 Hz, 1H), 8.12 - 8.10 (m, 1H), 7.56 (d, J= 2.9 Hz, 1H), 7.33 (t, J= 7.6 Hz, 1H), 7.02 (d, J= 8.4 Hz, 2H), 6.92 (d, J= 7.8 Hz, 2H), 6.88 (d, J= 8.5 Hz, 2H), 6.14 (tt, J= 57.3, 4.5 Hz, 1H), 4.67 - 4.60 (m, 1H), 3.94 (d, J= 13.8 Hz, 2H), 3.71 (dd, J= 11.4, 5.2 Hz, 1H), 3.64 (d, J= 12.1 Hz, 2H), 3.59 (td, J= 13.7, 4.0 Hz, 2H), 3.47 - 1693.32 (m, 3H), 3.23 (s, 3H), 2.99 (d, J= 11.1 Hz, 2H), 2.67 - 2.58 (m, 3H), 2.45 (dt, J= 17.1, 4.4 Hz, 1H), 2.36 (t, J= 7.1 Hz, 2H), 2.12 (dd, J= 12.0, 3.9 Hz, 1H), 2.06 - 1.92 (m, 7H), 1.76 (dd, J= 24.3, 11.5 Hz, 4H), 1.59 (d, J= 11.9 Hz, 2H), 1.40 (t, J= 6.6 Hz, 3H), 1.28 - 1.19 (m, 2H). LCMS: C42H53F2N7O5requires 773.4, found: m / z = 774.3 [M+H]+.EXAMPLE 90(R)-N-(l-(2-(l-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4-YL)ETHYL)PIPERIDIN-4-YL)-N- ETHYL-l-(6-(5- FLUORO- 2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXYPIPERIDINE-4- CARBOXAMIDEOStep 1: Synthesis of N-ethyl-l-(6-(5-fluoro-2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N- (piperidin-4-yl)piperidine-4-carboxamideTo a solution of lithium l-(6-(5-fluoro-2-(methoxymethoxy)phenyl)pyridazin-4-yl)-4-methoxypiperidine-4-carboxylate (1.00 g, 2.52 mmol) and tert-butyl 4-(ethylamino)piperidine-l-carboxylate (0.90 g, 3.95 mmol) in DCM (15.00 mL) was added N, N-diisopropylethylamine (1.84 mL, 1.36 g, 10.5 mmol). Then bis(2-oxo-l,3-oxazolidin-3-yl)phosphinoyl chloride (2.01 g, 7.90 mmol) was added and the reaction mixture was stirred at 40°C overnight. Once complete, the reaction was quenched with water, extracted with DCM (3x50 mL), dried with Na2SC>4, filtered and concentrated under reduced pressure. The crude material was purified via chromatography (MeOH: DCM, gradient) to yield the desired product as an orange foam. The obtained material was dissolved in 10 mL methanol and 4M HC1 in Dioxane (10.0 mL) was added in one portion. The reaction was stirred at RT for 1 hour and then concentrated in vacuo to yield the desired product (1.22 g, 98%) as a white solid. LCMS: C24H32N5O3F requires: 457.2, found: m / z = 457.3 [M+H]+Step 2: Synthesis of the title compoundN-ethyl-l-[6-(5-fluoro-2-hydroxyphenyl)pyridazin-4-yl]-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride (300.00 mg, 0.6073 mmol) was dissolved in MeCN (4.50 mL) and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)acetaldehyde (210.01 mg, 0.6680 mmol) was added in one portion. The flask was agitated and then MeOH (1.30 mL) was slowly added until all the solids have dissolved. Sodium triacetoxyborohydride (386.12 mg, 1.8218 mmol) was then added in one portion and the reaction was stirred at RT for 30 mins. After 30 mins, the reaction mixture was dissolved in DCM (10 mL) and water (20 mL) was added. The organic phase was separated and the aqueous layer was170further extracted with DCM (2 x 10 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by RP-FC to yield the title compound (275 mg, 59.5%) as a white solid. LCMS: C42H54FN7O5 requires: 755.4, found: m / z = 756.3 [M+H]+EXAMPLE 91(R)-N-(1-(2-(1-(4-(2,6-DIOXOPIPERIDIN-3-YL)PIIENYL)PIPERIDIN-4-YL)ETIIYL)PIPERIDIN-4-YL)-1-(6- (2-HYDROXYPHENYL)PYRID AZIN-4- YL)-N-ISOPROPOXY-4-METHOXYPIPERIDINE-4-CARBOXAMIDEStep 1: Synthesis of l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-N-isopropoxy-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamideThe title compound was prepared as described for Example 89, Step 1, using tert-butyl 4-(isopropoxyamino)piperidine-l -carboxylate to afford the desired product as a white solid. LCMS:C25H35N5O4 requires 469.3, found: m / z = 470.2 [M+H]+.Step 2: Synthesis of the title compoundThe title compound was prepared as described for Example 1, Step 2, using l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-N-isopropoxy-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide and (R)-2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)acetaldehyde to afford the title compound (2.1 mg, 6%). LCMS: C43H57N7O6 requires 767.4, found: m / z = 768.4 [M+H]+.EXAMPLE 92RAC-(lR,5S,8S)-N-(l-(2-(l-(4-((R)-2,6-DIOXOPIPERIDIN-3-YL)-3-FLUOROPHENYL)PIPERIDIN-4-YL)ETHYL)PIPERIDIN-4-YL)-3-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-N-(THIAZOL- 5- YLMETHYL)- 3-AZABICYCLO[3.2.1]OCTANE-8-CARBOXAMIDE171Step 1: Synthesis of (lR,5S,8s)-3-(6-(2-hydroxyphenyl)pyridazin-4-yl)-N-(piperidin-4-yl)-N-(thiazol- 5-ylmethyl)-3-azabicyclo [3.2.1] octane-8-carboxamideTo a solution of (lR,5S,8S)-3-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-3-azabicyclo[3.2.1]octane-8-carboxylic acid (45.00 mg, 0.12 mmol) and tert-butyl 4-[(l,3-thiazol-5-ylmethyl)amino]piperidine-l -carboxylate (43.48 mg, 0.15 mmol) in DCM (1.00 mL) was added N, N-diisopropylethylamine (85.10 pL, 0.06 g, 0.49 mmol). Then, bis(2-oxo-l,3-oxazolidin-3-yl)phosphinoyl chloride (93.03 mg, 0.37 mmol) was added and the reaction mixture was stirred at 40 °C until complete by LCMS. Then, the reaction mixture was filtered and the solvent removed under reduced pressure. The crude product was purified on silica gel with a gradient of EtOAc / Hex 0-100%, then 0-10% EtOAc / MeOH to afford the pure product as a yellow oil (77 mg, 99%). The pure material was dissolved in 1.5 mL of DCM and 4M HC1 in Dioxane (1.00 mL) was added in one portion. The reaction was stirred at room temperature until complete by LCMS and then concentrated in vacuo to yield the desired product as a yellow foam. LCMS: C27H32N6O2S requires 504.2, found: m / z = 505.2 [M+H]+.Step 2: Synthesis of the title compoundThe title compound was prepared as described for Example 1, Step 2, using (lR,5S,8s)-3-(6-(2-hydroxyphenyl)pyridazin-4-yl)-N-(piperidin-4-yl)-N-(thiazol-5-ylmethyl)-3-azabicyclo[3.2.1]octane-8-carboxamide and rac-(R)-2-(l-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl)piperidin-4-yl)acetaldehyde to afford the title compound (9.2 mg, 49%). LCMS: C45H53EN8O4 requires 820.4, found: m / z = 821.4 [M+H]+.EXAMPLE 93RAC-(R)-N-(l-(2-(l-(4-(2,6-DIOXOPIPERIDIN-3-YL)-3-FLUOROPHENYL)PIPERIDIN-4- YL)ETHYL)PIPERIDIN-4-YL)-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXY-N-(2, 2,2- TRIFLUOROETHYL)PIPERIDINE-4-CARBOXAMIDEFStep 2: Synthesis of the title compoundThe title compound was prepared as described for Example 1, Step 2, using l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-(piperidin-4-yl)-N-(2,2,2-trifluoroethyl)piperidine-4-carboxamide and rac-(R)-2-(l-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl)piperidin-4-yl)acetaldehyde to172afford the title compound (12.4 mg, 76%). LCMS: C42H51F4N7O5 requires 809.4, found: m / z = 810.3 [M+H]+.EXAMPLE 94RAC-(1R,5S,8S)-N-(1-(2-(1-(4-((R)-2,6-DIOXOPIPERIDIN-3-YL)-3,5-DIFLUOROPHENYL)PIPERIDIN-4- YL)ETHYL)PIPERIDIN-4-YL)-N-((l-HYDROXYCYCLOPROPYL)METHYL)-3-(6-(2- HYDROXYPHENYL)PYRID AZIN-4- YL)-3-AZABICYCLO[3.2.1]OCTANE-8-CARBOXAMIDEHO F 0Step 1: Synthesis of tert-butyl 4-(((l-methoxycyclopropyl)methyl)amino)piperidine-l-carboxylateTo a vial containing tert-butyl 4-oxopiperidine-l -carboxylate (500.00 mg, 2.51 mmol) dissolved in 1,2-dichloroethane (2.00 mL) was added 1-(1 -methoxy cyclopropyl)methanamine hydrochloride (414.38 mg, 3.01 mmol), N, N -diisopropylethylamine (876.60 pL, 0.65 g, 5.02 mmol) and the reaction was allowed to stir at room temperature. After 30 minutes, sodium triacetoxyborohydride (797.77 mg, 3.76 mmol) was added in one portion and the reaction was allowed to stir at room temperature overnight. The reaction mixture was dissolved with CH2CI2, quenched with a saturated solution of NaHCO3. extracted with CH2Q2, dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The crude product was purified on silica gel with a gradient of MeOH / CFLCfi 0-20% to afford the title compound (331 mg, 46%) as a colorless oil. LCMS: C15H28N2O3 requires 284.2, found: m / z = 285.2 [M+H]+.Step 2: Synthesis of (lR,5S,8s)-N-((l-hydroxycyclopropyl)methyl)-3-(6-(2-hydroxyphenyl)pyridazin-4-yl)-N-(piperidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxamideThe title compound was prepared as described for Example 6, Step 1, using tert-butyl 4-(((l-methoxycyclopropyl)methyl)amino)piperidine-l -carboxylate to afford the desired product as a beige foam. TFA in CFECLwas used for the cleavage of the BOC protecting group. LCMS: C27H35N5O3 requires 477.3, found: m / z = 478.2 [M+H]+.173Step 3: Synthesis of the title compoundThe title compound was prepared as described for Example 1, Step 2, using (lR,5S,8s)-N-((l-hydroxycyclopropyl)methyl)-3-(6-(2-hydroxyphenyl)pyridazin-4-yl)-N-(piperidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxamide and rac-(R)-2-(l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidin-4-yl)acetaldehyde to afford the title compound (10.3 mg, 62%). LCMS:C45H57N7O5 requires 775.4, found: m / z = 776.4 [M+H]+.EXAMPLE 95N-(l-(2-(l-(4-((R)-2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4-YL)ETHYL)PIPERIDIN-4-YL)-l-(6- (2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXY-N-((R)-l-METHOXYPROP AN-2- YL)PIPERIDINE-4- CARBOXAMIDEStep 1: Synthesis of tert-butyl (R)-4-((l-methoxypropan-2-yl)amino)piperidine-l-carboxylateThe title compound was prepared as described for Example 94, Step 1, using (2R)-1-methoxypropan-2-amine hydrochloride (367.71 pL, 268.43 mg, 3.01 mmol) to afford the desired product as a colorless oil. LCMS: C14H28N2O3 requires 272.2, found: m / z = 273.2 [M+H]+.Step 2: Synthesis of (R)-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-(l-methoxypropan-2-yl)-N-(piperidin-4-yl)piperidine-4-carboxamideThe title compound was prepared as described for Example 89, Step 1, using tert-butyl (R)-4-((l-methoxypropan-2-yl)amino)piperidine-l -carboxylate to afford the desired product as a brown oil. LCMS: C26H37N5O4 requires 483.3, found: m / z = 484.2 [M+H]+.Step 3: Synthesis of the title compoundThe title compound was prepared as described for Example 1, Step 2, using (R)-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-(l-methoxypropan-2-yl)-N-(piperidin-4-yl)piperidine-4-carboxamide and (R)-2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)acetaldehyde to afford the title compound (20.9 mg, 27%). LCMS: C44H59N7O6 requires 781.5, found: m / z = 782.4 [M+H]+.174EXAMPLE 96(R)-N-(2-CYANOETHYL)-N-(l-(2-(l-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4- YL)ETHYL)PIPERIDIN-4-YL)-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXYPIPERIDINE-4- CARBOXAMIDEStep 1: Synthesis of N-(2-cyanoethyl)-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N- (piperidin-4-yl)piperidine-4-carboxamideTo a solution of lithio 4-methoxy-l-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}piperidine-4-carboxylate (367.00 mg, 0.9675 mmol) and tert-butyl 4-[(2-cyanoethyl)amino]piperidine-l -carboxylate (367.66 mg, 1.4512 mmol) in DCM (5.00 mL) was added N, N-diisopropylethylamine (0.68 mL, 500.17 mg, 3.8699 mmol). Then bis(2-oxo-l,3-oxazolidin-3-yl)phosphinoyl chloride (738.84 mg, 2.9024 mmol) was added and the reaction mixture was stirred at 40 °C overnight. Once complete, the reaction was quenched with water (5 mL), extracted with DCM (3 x 10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified via chromatography (MeOH: DCM gradient) to yield the desired product. The obtained material was dissolved in 10 mL methanol and 4M HC1 in Dioxane (10.0 mL) was added in one portion. The reaction was stirred at RT for 1 hour and then concentrated in vacuo to yield the desired product (1.22 g) as a white solid. LCMS: C32H44N6O6 requires 464.2, found m / z = 465.2 [M+H]+Step 2: Synthesis of the title compoundN-(2-cyanoethyl)-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride (30.00 mg, 0.0607 mmol) was dissolved in MeCN (0.45 mL) and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)acetaldehyde (21.00 mg, 0.0668 mmol) was added in one portion. The flask was agitated and then MeOH (0.13 mL) was slowly added until all the solids have dissolved. Sodium triacetoxyborohydride (38.61 mg, 0.1822 mmol) was then added in one portion and the reaction was stirred at RT for 30 mins. After 30 mins, the reaction was checked by LCMS and the reaction mixture was dissolved in DCM and water was added. The reaction was extracted 3x with DCM and concentrated in vacuo. The residue was then purified by RP-FC to yield the title compound (9.4 mg, 17.6%) as a white solid. LCMS: C43H54N8O5 requires: 762.4, found: m / z = 763.4 [M+H]+175EXAMPLE 97(R)-N-(CYANOMETHYL)-N-(l-(2-(l-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4- YL)ETHYL)PIPERIDIN-4-YL)-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXYPIPERIDINE-4-HO NNStep 1: Synthesis of the title compoundN-(cyanomethyl)-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride (20.00 mg, 0.0411 mmol) was dissolved in MeCN (0.45 mL) and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)acetaldehyde (14.20 mg, 0.0452 mmol) was added in one portion. The flask was agitated and then MeOH (0.13 mL) was slowly added until all the solids have dissolved. Sodium triacetoxyborohydride (26.11 mg, 0.1232 mmol) was then added in one portion and the reaction was stirred at RT for 30 mins. After 30 mins, the reaction was checked by LCMS and the reaction mixture was dissolved in DCM and water was added. The reaction was extracted 3x with DCM and concentrated in vacuo. The residue was then purified via RP-FC to afford the title compound (4.1 mg, 10.27%) as the formate salt. LCMS: C42H52N8O5 requires: 748.4, found: m / z = 749.3 [M+H]+EXAMPLE 98(lRS,5SR,8SR)-N-(l-(2-(l-(4-((RS)-2,6-DIOXOPIPERIDIN-3-YL)-3,5-DIFLUOROPHENYL)PIPERIDIN-4- YL)ETHYL)PIPERIDIN-4-YL)-3-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-N-((R)-2- METHOXYPROPYL)-3-AZABICYCLO[3.2.1]OCTANE-8-CARBOXAMIDEStep 1: Synthesis of tert-butyl (R)-4-((2-methoxypropyl)amino)piperidine-l-carboxylateThe title compound was prepared as described for Example 94, Step 1, using tert-butyl 4-oxopiperidine- 1 -carboxylate (500.01 mg, 2.51 mmol) to afford the desired product as a colorless oil. LCMS: CI4H28N2O3 requires 272.2, found: m / z = 273.2 [M+H]+.176Step 2: Synthesis of (lRS,5SR,8SR)-3-(6-(2-hydroxyphenyl)pyridazin-4-yl)-N-((R)-2-methoxypropyl)-N-(piperidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxamideThe title compound was prepared as described for Example 6, Step 1, using tert-butyl (R)-4-((2-methoxypropyl)amino)piperidine-l -carboxylate to afford the desired product as a yellow foam. TFA in CIFCT was used for the cleavage of the BOC protecting group. LCMS: C27H37N5O3 requires 479.3, found: m / z = 480.2 [M+H]+.Step 3: Synthesis of the title compoundThe title compound was prepared as described for Example 1, Step 2, using (lRS,5SR,8SR)-3-(6-(2-hydroxyphenyl)pyridazin-4-yl)-N-((R)-2-methoxypropyl)-N-(piperidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxamide and rac-(R)-2-(l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidin-4-yl)acetaldehyde to afford the title compound (8.3 mg, 47%). LCMS:C45H57F2N7O5 requires 813.4, found: m / z = 814.5 [M+H]+.EXAMPLE 99RAC-(R)-N-(l-(2-(l-(l-(2,6-DIOXOPIPERIDIN-3-YL)-3-METHYL-2-OXO-2,3-DIHYDRO-lH- BENZO[D]IMIDAZOL-4-YL)PIPERIDIN-4-YL)ETHYL)PIPERIDIN-4-YL)-N-ETHYL-l-(6-(2- HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXYPIPERIDINE-4-CARBOXAMIDEStep 1: Synthesis of the title compoundThe title compound was prepared as described for Example 1, Step 2, using N-ethyl-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide and rac-(R)-2-( 1 -(l-(2, 6-dioxopiperidin-3-yl)-3-methyl-2 -oxo-2, 3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-4-yl)acetaldehyde to afford the title compound (10.1 mg, 28%). LCMS: C44H57N9O6 requires 807.4, found: m / z = 808.4 [M+H]+.177EXAMPLE 100(lRS&,5SR&,8RS&)-N-{l-[2-(l-{l-[(3RS)-2,6-DIOXOPIPERIDIN-3-YL]-3-METHYL-2-OXO-2,3- DIHYDRO-1 H-l,3-BENZODIAZOI^4-YL}PIPERIDIN-4-YL)ETHYL]PIPERIDIN-4-YL}-3-[6-(2- HYDROXYPHENYL)PYRID AZIN-4- YL]-N-(PROP AN-2- YLOXY)-3-AZABICYCLO[3.2.1]OCTANE-8- CARBOXAMIDEStep 1: tert-butyl 4-[N-isopropoxy(lR,5S,8S)-3-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-3-azabicyclo[3.2.1]octane-8-amido]piperidine-l-carboxylateTo a solution of (lR,5S,8S)-3-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-3-azabicyclo[3.2.1]octane-8-carboxylic acid (45.01 mg, 0.1218 mmol) in DMA (1.00 mL) was added tertbutyl 4-(isopropoxyamino)piperidine-l -carboxylate (37.77 mg, 0.1462 mmol) and N, N-diisopropylethylamine (106.11 pL, 0.08 g, 0.6092 mmol). [(dimethylamino)({[l,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (55.59 mg, 0.1462 mmol) was added and the reaction was stirred at rt overnight. Added more HATU (55 mg) and continued stirring at 45°C overnight. Purified directly by RP-HPLC to yield tert-butyl 4-[N-isopropoxy(lR,5S,8S)-3-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-3-azabicyclo[3.2.1]octane-8-amido]piperidine-l-carboxylate (0.0304 g, 34.47%). LCMS: C33H47N5O6 requires: 609.4, found: m / z = 610.2 [M+H]+.Step 2: (lR,5S,8S)-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-isopropoxy-N-(piperidin-4-yl)-3-azabicyclo [3.2.1] octane-8-carboxamide(lR,5S,8S)-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-isopropoxy-N-(piperidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxamide was prepared as described for Example 107 step 2. LCMS: C26H35N5O3 requires: 465.3, found: m / z = 466.2 [M+H]+.178Step: 3 Synthesis of the title compoundThe title compound was synthesized as described for Example 153 step 5, using (lR,5S,8S)-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-isopropoxy-N-(piperidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxamide hydrochloride and rac-2-(l-{l-[(3R)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-l,3-benzodiazol-4-yl}piperidin-4-yl)acetaldehyde to yield (lRS&,5SR&,8RS&)-N-{l-[2-(l-{l-[(3RS)-2,6-dioxopiperidin-3 -yl] -3 -methyl-2-oxo- 1,3 -benzodiazol-4-yl }piperidin-4-yl)ethyl]piperidin-4-yl} -3 - [6 -(2 -hydroxyphenyl)pyridazin-4-yl]-N-isopropoxy-3-azabicyclo[3.

2. l]octane-8-carboxamide (0.0064 g, 55.76%). LCMS: C46H59N9O6 requires: 833.5, found: m / z = 834.3 [M+H]+EXAMPLE 101(R)-N-(1-(2-(1-(4-(2,6-DIOXOPIPERIDIN-3-YL)-3,5-DIFLUOROPHENYL)PIPERIDIN-4- YL)ETHYL)PIPERIDIN-4-YL)-N-ETHYL-l-(6-(5-FLUORO-2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4- METHOXYPIPERIDINE-4-CARBOXAMIDEFStep 1: Synthesis of the title compoundN-ethyl-l-[6-(5-fluoro-2-hydroxyphenyl)pyridazin-4-yl]-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride (13.00 mg, 0.0263 mmol) was dissolved in DMA (1.00 mL) and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]-3,5-difluorophenyl}piperidin-4-yl)acetaldehyde (8.75 mg, 0.0263 mmol) was added in one portion. N, N-diisopropylethylamine (0.02 mL, 17.01 mg, 0.1316 mmol) was then added followed by sodium triacetoxyborohydride (16.73 mg, 0.0789 mmol). The resulting reaction was stirred at RT for 1-2 hrs and monitored via LCMS. Once complete, the reaction was concentrated in purified by RP-FC to afford the title compound (11.7 mg, 53.1%) as a formate salt. LCMS: C42H52F3N7O5 requires: 791.4, found: m / z = 792.3 [M+H]+EXAMPLE 102(R)-N-(1-(2-(1-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4-YL)ETHYL)PIPERIDIN-4-YL)-1-(6- (2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXY-N-(OXAZOI^4-YLMETHYL)PIPERIDINE-4- CARBOXAMIDE179Step 1: Synthesis of l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-(oxazol-4-ylmethyl)-N- (piperidin-4-yl)piperidine-4-carboxamideThe title compound was prepared as described for Example 92, Step 1, using tert-butyl 4-((oxazol-4-ylmethyl)amino)piperidine-l-carboxylateto afford the desired product as a yellow foam. LCMS: C26H32N6O4 requires 492.3, found: m / z = 493.2 [M+H]+.Step 2: Synthesis of the title compoundThe title compound was prepared as described for Example 1, Step 2, using l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-(oxazol-4-ylmethyl)-N-(piperidin-4-yl)piperidine-4-carboxamide and (R)-2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)acetaldehyde to afford the title compound (35.8 mg, 81%). LCMS: C44H54N8O6 requires 790.4, found: m / z = 791.3 [M+H]+.EXAMPLE 103(R)-N-(l-(2-(l-(4-(2,6-DIOXOPIPERIDIN-3-YL)-3-FLUOROPHENYL)PIPERIDIN-4-YL)ETHYL)PIPERIDIN- 4- YL)-l-(6-(5-FLUORO-2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXY-N-PROPYLPIPERIDINE-4-Step 1: Synthesis of l-(6-(5-fluoro-2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-(piperidin-4-yl)- N-propylpiperidine-4-carboxamideTo a solution of lithio l-{6-[5-fluoro-2-(methoxymethoxy)phenyl]pyridazin-4-yl}-4-methoxypiperidine-4-carboxylate (300.00 mg, 0.7550 mmol) and tert-butyl 4-(propylamino)piperidine-l-carboxylate (274.49 mg, 1.1326 mmol) in DCM (4.00 mL) was added N, N-diisopropylethylamine (390.35 mg, 3.0202 mmol). Then bis(2-oxo-l,3-oxazolidin-3-yl)phosphinoyl chloride (576.61 mg, 2.2651 mmol) was added and the reaction mixture was stirred at 40 C. Once complete, the reaction was quenched with water (5 mL), extracted with DCM (3 x 10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified via chromatography (MeOH: DCM gradient) to yield the desired product. The obtained material was dissolved in 1 mL methanol and 4M HC1 in Dioxane (1.0 mL) was added in one portion. The reaction was stirred at RT for 1 hour and then concentrated in vacuo to yield180the desired product (292 mg, 62.1%) as an orange solid. LCMS: C25H34FN5O3 requires 471.2, found m / z = 472.5 [M+H]+Step 2: Synthesis of the title compoundl-[6-(5-fluoro-2-hydroxyphenyl)pyridazin-4-yl]-4-methoxy-N-(piperidin-4-yl)-N-propylpiperidine-4-carboxamide hydrochloride (11.00 mg, 0.0217 mmol) was dissolved in DMA (1.00 mL) and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]-3-fluorophenyl}piperidin-4-yl)acetaldehyde (7.20 mg, 0.0217 mmol) was added in one portion. N, N-diisopropylethylamine (0.02 mL, 13.99 mg, 0.1083 mmol) was then added followed by sodium triacetoxyborohydride (13.77 mg, 0.0650 mmol). The resulting reaction was stirred at RT for 1-2 hrs and monitored via LCMS. Once complete, the reaction was concentrated in vacuo and purified by RP-FC to yield the title compound (13.1 mg, 71.1 %) as a formate salt. LCMS: C43H55F2N7O5 requires: 787.4, found: m / z = 788.3 [M+H]+EXAMPLE 104(lRS&,5SR&,8RS&)-N-(2,2-DIFLUOROETHYL)-N-{l-[2-(l-{l-[(3RS)-2,6-DIOXOPIPERIDIN-3-YL]-3-METHYL-2-OXO-2,3-DIHYDRO-lH-l,3-BENZODIAZOL-4-YL}PIPERIDIN-4-YL)ETHYL]PIPERIDIN-4-YL}- 3- [6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL]-3-AZABICYCLO[3.2.1]OCTANE-8-CARBOXAMIDEFStep 1: tert-butyl 4-[N-(2,2-difluoroethyl)(lR,5S,8S)-3-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-3-azabicyclo[3.2.1]octane-8-amido]piperidine-l-carboxylateTo a solution of (lR,5S,8S)-3-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-3-azabicyclo[3.2.1]octane-8-carboxylic acid (45.01 mg, 0.1218 mmol) in DMA (1.00 mL) was added tertbutyl 4-[(2,2-difluoroethyl)amino]piperidine-1-carboxylate (48.31 mg, 0.1828 mmol) and N, N-diisopropylethylamine (63.67 pL, 0.05 g, 0.3655 mmol). [(dimethylamino)({[l,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (55.59 mg, 0.1462 mmol) was added. Stirred at rt for 2h, then added more N, N-diisopropylethylamine (63.67 pL. 0.05 g, 0.3655 mmol) and HATU (55 mg) and stirred overnight. Added more HATU (55 mg) and continued stirring at 40°C overnight, then added more HATU (50 mg) and then more amine (48 mg) and stirred at 40°C. Purified directly by RP-HPLC to yield tert-butyl 4-[N-(2,2-difluoroethyl)(lR,5S,8S)-3-{6-[2-181(methoxymethoxy)phenyl]pyridazin-4-yl } -3 -azabicyclo [3.2.1 ] octane-8-amido]piperidine- 1 -carboxylate (0.0386 g, 43.41%). LCMS: C32H43F2N5O5 requires: 615.3, found: m / z = 616.2 [M+H]+Step 2: (lR,5S,8S)-N-(2,2-difluoroethyl)-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(piperidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxamide(lR,5S,8S)-N-(2,2-difluoroethyl)-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(piperidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxamide was prepared as described for Example 107 step 2. LCMS: C25H31F2N5O2 requires: 471.2, found: m / z = 472.2 [M+H]+Step: 3 Synthesis of the title compoundThe title compound was synthesized as described for Example 153 step 5, using (1R,5S,8S)-N-(2,2-difluoroethyl)-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(piperidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxamide hydrochloride and rac-2-(l-{l-[(3R)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-l,3-benzodiazol-4-yl}piperidin-4-yl)acetaldehyde to yield (lRS&,5SR&,8RS&)-N-(2,2-difluoroethyl)-N-{1-[2-(1-{1-[(3RS)-2,6-dioxopiperidin-3-yl] -3 -methyl-2-oxo- 1,3 -benzodiazol-4-yl }piperidin-4-yl)ethyl]piperidin-4-yl}-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-3-azabicyclo[3.2.1]octane-8-carboxamide (0.0074 g, 52.90%). LCMS: C45H55F2N9O5 requires: 839.4, found: m / z = 840.3 [M+H]+EXAMPLE 105(R)-N-(l-(2-(l-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4-YL)ETHYL)PIPERIDIN-4-YL)-l-(6- (5- FLUORO-2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXY-N-PROPYLPIPERIDINE-4- CARBOXAMIDEStep 1: Synthesis of the title compoundl-[6-(5-fluoro-2-hydroxyphenyl)pyridazin-4-yl]-4-methoxy-N-(piperidin-4-yl)-N-propylpiperidine-4-carboxamide hydrochloride (30.00 mg, 0.0607 mmol) was dissolved in MeCN (0.45 mL) and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)acetaldehyde (21.00 mg, 0.0668 mmol) was added in one portion. The flask was agitated and then MeOH (0.13 mL) was slowly added until all the solids have dissolved. Sodium triacetoxyborohydride (38.61 mg, 0.1822 mmol) was then182added in one portion and the reaction was stirred at RT for 30 mins. After 30 mins, the reaction was checked by LCMS and the reaction mixture was dissolved in DCM and water was added. The reaction was extracted 3x with DCM and concentrated in vacuo. The residue was then purified by RP-FC to yield the title compound (29.2 mg, 57.57%) as a formate salt. LCMS: C43H56FN7O5 requires: 769.4, found: m / z = 770.3 [M+H]+EXAMPLE 106(lRS,5SR,8RS)-N-(2,2-DIFLUOROETHYL)-N-{l-[2-(l-{4-[(3R)-2,6-DIOXOPIPERIDIN-3- YL]PHENYL}PIPERIDIN-4-YL)ETHYL]PIPERIDIN-4-YL}-3-[6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL]-3- AZABICYCLO[3.2.1]OCTANE-8-CARBOXAMIDECombined (lR,5S,8S)-N-(2,2-difluoroethyl)-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(piperidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxamide hydrochloride (7.90 mg, 0.0156 mmol) and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)acetaldehyde (5.13 mg, 0.0163 mmol) in DMA (0.40 mL) and then added sodium triacetoxyborohydride (5.93 mg, 0.0280 mmol) and stirred for Ih. Purified by RP-HPLC to yield (lRS,5SR,8RS)-N-(2,2-difluoroethyl)-N-{l-[2-(l-{4-[(3R)-2,6-dioxopiperidin-3 -yl]phenyl }piperidin-4-yl)ethyl]piperidin-4-yl } -3 -[6-(2-hydroxyphenyl)pyridazin-4-yl] -3-azabicyclo[3.2.1]octane-8-carboxamide (0.0065 g, 50.97%). LCMS: C43H53F2N7O4 requires: 769.4, found: m / z = 770.3 [M+H]+EXAMPLE 1074-(DIFLUOROMETHOXY)-N-{l-[2-(l-{4-[(3R)-2,6-DIOXOPIPERIDIN-3-YL]PHENYL}PIPERIDIN-4- YL)ETHYL]PIPERIDIN-4-YL}-N-ETHYL-1-[6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL]PIPERIDINE-4- CARBOXAMIDEF183Step 1: tert-butyl 4-[N-ethyl-4-(difluoromethoxy)-l-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}piperidine-4-amido]piperidine-l-carboxylateTo a solution of 4-(difluoromethoxy)-l-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}piperidine-4-carboxylic acid (38.00 mg, 0.0928 mmol) in DMA (0.50 mL) was added tert-butyl 4-(ethylamino)piperidine-l -carboxylate (42.39 mg, 0.1856 mmol) and N, N-diisopropylethylamine (56.59 pL, 0.04 g, 0.3249 mmol). Then, bis(2-oxo-l,3-oxazolidin-3-yl)phosphinoyl chloride (47.26 mg, 0.1856 mmol) was added and the reaction was stirred at rt for 3d. More amine (1 eq, 21 pL) and BOP-CI (1 eq, 24 mg) were added and the reaction was stirred overnight, then it was purified directly by RP-HPLC (0.1% TFA in water / ACN) to yield tert-butyl 4-[N-ethyl-4-(difluoromethoxy)-l-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}piperidine-4-amido]piperidine-l-carboxylate (0.028 g, 48.68%). LCMS: C31H43F2N5O6 requires: 619.3, found: m / z = 620.3 [M+H]+Step 2: 4-(difluoromethoxy)-N-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(piperidin-4-yl)piperidine-4-carboxamideTert-butyl 4-[N-ethyl-4-(difluoromethoxy)-l-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}piperidine-4-amido]piperidine-l-carboxylate (28.00 mg, 0.0452 mmol) was dissolved in 1 M HC1 in dioxane (2.00 mL) and methanol (0.40 mL). After Ih, the reaction was concentrated under reduced pressure and the residue was lyophilized from 1: 1 ACN / water to yield tert-butyl 4-[N-ethyl-4-(difluoromethoxy)- 1 - {6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}piperidine-4-amido]piperidine- 1 -carboxylate (28.00 mg, 0.0452 mmol). LCMS: C24H31F2N5O3 requires: 475.2, found: m / z = 476.2 [M+H]+Step 3: Synthesis of the title compoundCombined 4-(difluoromethoxy)-N-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride (12.00 mg, 0.0234 mmol) and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)acetaldehyde (8.11 mg, 0.0258 mmol) in DMA (0.30 mL) and then added N, N-diisopropylethylamine (12.28 pL, 0.01 g, 0.0703 mmol) and sodium triacetoxyborohydride (7.45 mg, 0.0352 mmol) and stirred for 2h. The reaction was purified directly by RP-HPLC to yield 4-(difhioromethoxy)-N-{ l-[2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)ethyl]piperidin-4-yl}-N-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]piperidine-4-carboxamide (0.0086 g, 44.75%). LCMS: C42H53F2N7O5requires: 773.4, found: m / z = 774.3 [M+H]+184EXAMPLE 108(lRS&,5SR&,8RS&)-N-{l-[2-(l-{4-[(3RS)-2,6-DIOXOPIPERIDIN-3-YL]-3,5- DIFLUOROPHENYL}PIPERIDIN-4- YL)E THYL] PI PE R ID I N-4- YL} -3- [6-(2-HYDROXYPHENYL)PYRIDAZIN- 4-YL]-N-(PROPAN-2-YL)-3-AZABICYCLO[3.2.1]OCTANE-8-CARBOXAMIDEStep 1: tert-butyl 4-[N-isopropyl(lR,5S,8S)-3-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-3-azabicyclo[3.2.1]octane-8-amido]piperidine-l-carboxylateTo a solution of (lR,5S,8S)-3-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-3-azabicyclo[3.2.1]octane-8-carboxylic acid (45.00 mg, 0.1218 mmol) in DMA (1.00 mL) was added tertbutyl 4-(isopropylamino)piperidine-l -carboxylate (44.28 mg, 0.1827 mmol) and N, N-diisopropylethylamine (63.65 pL, 0.05 g, 0.3654 mmol). [(dimethylamino)({[l,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (55.58 mg, 0.1462 mmol) was added. Stirred at rt for 2h, then added more N, N-diisopropylethylamine (63.65 pL, 0.05 g, 0.3654 mmol) and HATU (55 mg) and stirred overnight. Added more HATU (55 mg) and continued stirring at 40°C overnight. Added more HATU, then added more amine (133 mg) and heated to 40°C. Purified directly by RP-HPLC to yield tert-butyl 4-[N-isopropyl(lR,5S,8S)-3-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl } -3 -azabicyclo [3.2.1] octane-8-amido]piperidine- 1 -carboxylate (0.023 g, 26.68%). LCMS: C33H47N5O5 requires: 593.4, found: m / z = 594.2 [M+H]+.Step 2: (lR,5S,8S)-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-isopropyl-N-(piperidin-4-yl)-3-azabicyclo [3.2.1] octane-8-carboxamide(lR,5S,8S)-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-isopropyl-N-(piperidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxamide was prepared as described for Example 107 step 2. LCMS: C26H35N5O2 requires: 449.3, found: m / z = 450.2 [M+H]+.Step: 3 Synthesis of the title compoundThe title compound was synthesized as described for Example 153 step 5, using (lR,5S,8S)-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-isopropyl-N-(piperidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxamide hydrochloride and rac-2-( 1 - {4- [(3R)-2,6-dioxopiperidin-3 -yl] -3,5 -difluorophenyl }piperidin-4-yl)acetaldehyde to yield (lRS&,5SR&,8RS&)-N-{l-[2-(l-{4-[(3RS)-2,6-dioxopiperidin-3-yl]-3,5-difluorophenyl}piperidin-4-yl)ethyl]piperidin-4-yl}-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-isopropyl-1853-azabicyclo[3.2.1]octane-8-carboxamide (0.0041 g, 37.04%). LCMS: C44H55F2N7O4 requires: 783.4, found: m / z = 784.3 [M+H]+EXAMPLE 109RAC-N-{l-[2-(l-{4-[(3R)-2,6-DIOXOPIPERIDIN-3-YL]-3-FLUOROPHENYL}PIPERIDIN-4- YL)ETHYL]PIPERIDIN-4-YL}-4-ETHOXY-N-ETHYL-1-[6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL] PIPERIDINE- 4- CARBOXAMIDEStep 1: tert-butyl 4-(N-ethyl-4-ethoxy-l-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}piperidine-4-amido)piperidine-l-carboxylateTert-butyl 4-(N-ethyl-4-ethoxy-l-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}piperidine-4-amido)piperidine-l -carboxylate was prepared as described for EXAMPLE 107 step 1, using 4-ethoxy-l-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}piperidine-4-carboxylic acid to yield tert-butyl 4-(N-ethyl-4-ethoxy- 1 - {6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}piperidine-4-amido)piperidine- 1 -carboxylate (0.053 g, 34.35%). LCMS: C32H47N5O6 requires: 597.4, found: m / z = 598.4 [M+H]+.Step 2: 4-ethoxy-N-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(piperidin-4-yl)piperidine-4-carboxamide4-ethoxy-N-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(piperidin-4-yl)piperidine-4-carboxamide was prepared as described for Example 107 step 2. LCMS: C25H35N5O3 requires: 453.3, found: m / z = 454.4 [M+H]+.Step 3: Synthesis of the title compoundCombined 4-ethoxy-N-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride (5.00 mg, 0.0102 mmol) and rac-2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]-3-fluorophenyl}piperidin-4-yl)acetaldehyde (3.73 mg, 0.0112 mmol) in DMA (0.30 mL) and then added sodium triacetoxyborohydride (3.24 mg, 0.0153 mmol) and stirred for 2h, then186purified directly by HTP to yield rac-N-{l-[2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]-3-fluorophenyl}piperidin-4-yl)ethyl]piperidin-4-yl}-4-ethoxy-N-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]piperidine-4-carboxamide (0.0046 g, 54.59%). LCMS: C43H56FN7O5 requires: 769.4, found: m / z = 770.3 [M+H]+EXAMPLE 110RAC-4-(DIFLUOROMETHOXY)-N-{l-[2-(l-{4-[(3R)-2,6-DIOXOPIPERIDIN-3-YL]-3- FLUOROPHENYL}PIPERIDIN-4-YL)ETHYL]PIPERIDIN-4-YL}-N-ETHYL-l-[6-(2- HYDROXYPHENYL)PYRID AZIN-4- YL|PIPERIDINE-4-CARBOXAMIDEThe title compound was synthesized as described for Example 107 step 3, using rac-2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]-3-fluorophenyl}piperidin-4-yl)acetaldehyde to yield rac-4-(difluoromethoxy)-N-{1-[2-(1-{4-[(3R)-2,6-dioxopiperidin-3-yl]-3-fluorophenyl}piperidin-4-yl)ethyl]piperidin-4-yl}-N-ethyl-1-[6-(2-hydroxyphenyl)pyridazin-4-yl]piperidine-4-carboxamide (0.0026 g, 47.81%). LCMS: C42H52F3N7O5 requires: 791.4, found: m / z = 792.3 [M+H]+EXAMPLE 111RAC-N-{l-[2-(l-{4-[(3R)-2,6-DIOXOPIPERIDIN-3-YL]PHENYL}-4-METHOXYPIPERIDIN-4- YL)ETHYL]PIPERIDIN-4- YL}-N-ETHYL-l-[6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL]-4- METHOXYPIPERIDINE-4-CARBOXAMIDEThe title compound was synthesized as described for Example 107 step 3, using rac-2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}-4-methoxypiperidin-4-yl)acetaldehyde to yield rac-N-{ l-[2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}-4-methoxypiperidin-4-yl)ethyl]piperidin-4-yl}-N-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxypiperidine-4-carboxamide (0.0113 g, 39.49%). LCMS:C43H57N7O6 requires: 767.4, found: m / z = 768.2 [M+H]+187EXAMPLE 112RAC-N-{l-[2-(l-{4-[(3R)-2,6-DIOXOPIPERIDIN-3-YL]-3-FLUOROPHENYL}-4-FLUOROPIPERIDIN-4- YL)ETHYL]PIPERIDIN-4- YL}-N-ETHYL-1-[6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL]-4-The title compound was synthesized as described for Example 107 step 3, using rac-2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl] -3 -fluorophenyl }-4-fluoropiperidin-4-yl)acetaldehyde to yield rac-N-{ l-[2-( 1 - {4- [(3R)-2,6-dioxopiperidin-3 -yl] -3 -fluorophenyl } -4-fluoropiperidin-4-yl)ethyl]piperidin-4-yl } -N-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxypiperidine-4-carboxamide (0.0063 g, 24.38%). LCMS: C42H53F2N7O5 requires: 773.4, found: m / z = 774.4 [M+H]+EXAMPLE 113(lRS&,5SR&,8RS&)-N-{l-[2-(l-{l-[(3RS)-2,6-DIOXOPIPERIDIN-3-YL]-3-METHYL-2-OXO-2,3- DIHYDRO-1 H-l,3-BENZODIAZOI^4-YL}PIPERIDIN-4-YL)ETHYL]PIPERIDIN-4-YL}-3-[6-(2- HYDROXYPHENYL)PYRID AZIN-4- YL]-N-(2- ME THYLPROPYL)-3-AZABICYCLO[3.2.1]OCTANE-8- CARBOXAMIDEStep 1: tert-butyl 4-[N-(2-methylpropyl)(lR,5S,8S)-3-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-3-azabicyclo[3.2.1]octane-8-amido]piperidine-l-carboxylateTo a solution of (lR,5S,8S)-3-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-3-azabicyclo[3.2.1]octane-8-carboxylic acid (45.00 mg, 0.1218 mmol) in DMA (1.00 mL) was added tertbutyl 4-[(2-methylpropyl)amino]piperidine-l-carboxylate (34.35 mg, 0.1340 mmol) and N, N-diisopropylethylamine (106.09 pL, 0.08 g, 0.6091 mmol). [(dimethylamino)({[l,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (55.58 mg, 0.1462 mmol) was added. Stirred at rt for 2h, then added more HATU (55 mg) and stirred overnight. Purified188directly by RP-HPLC to yield tert-butyl 4-[N-(2-methylpropyl)(lR,5S,8S)-3-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl } -3 -azabicyclo [3.2.1 ] octane-8-amido]piperidine- 1 -carboxylate (0.0496 g, 56.41%). LCMS: C34H49N5O5 requires: 607.4, found: m / z = 608.4 [M+H]+.Step 2: (lR,5S,8S)-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(2-methylpropyl)-N-(piperidin-4-yl)-3-azabicyclo [3.2.1] octane-8-carboxamide(lR,5S,8S)-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(2-methylpropyl)-N-(piperidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxamide was prepared as described for Example 107 step 2. LCMS: C27H37N5O2 requires: 463.3, found: m / z = 464.2 [M+H]+.Step: 3 Synthesis of the title compoundThe title compound was synthesized as described for Example 153 step 5, using (lR,5S,8S)-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(2-methylpropyl)-N-(piperidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxamide hydrochloride and rac-2-(l-{l-[(3R)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-l,3-benzodiazol-4-yl}piperidin-4-yl)acetaldehyde to yield (lRS&,5SR&,8RS&)-N-{l-[2-(l-{l-[(3RS)-2,6-dioxopiperidin-3 -yl] -3 -methyl-2-oxo- 1,3 -benzodiazol-4-yl }piperidin-4-yl)ethyl]piperidin-4-yl} -3 - [6 -(2 -hydroxyphenyl)pyridazin-4-yl]-N-(2-methylpropyl)-3-azabicyclo[3.

2. l]octane-8-carboxamide (0.0101 g, 54.73%). LCMS: C47H61N9O5 requires: 831.5, found: m / z = 832.4 [M+H]+EXAMPLE 114N-((RS)-l-((SR)-8-(4-((R)-2,6-DIOXOPIPERIDIN-3-YL)PHENYL)-l-OXA-8-AZASPIRO[4.5]DECAN-3-YL)- 3, 3-DIFLUOROPIPERIDIN-4-YL)-N-ETHYL-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4- METHOXYPIPERIDINE-4-CARBOXAMIDEStep 1: Synthesis of rac-(R)-N-(3,3-difluoropiperidin-4-yl)-N-ethyl-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxypiperidine-4-carboxamideThe title compound was prepared as described for Example 89, Step 1, using tert-butyl 4-(ethylamino)-3,3-difluoropiperidine-l-carboxylate to afford the desired product as a yellow solid. LCMS: C24H31F2N5O3 requires 475.2, found: m / z = 476.4 [M+H]+.Step 2: Synthesis of the title compoundThe title compound was prepared as described for Example 1, Step 2, using rac-(R)-N-(3,3-difluoropiperidin-4-yl)-N-ethyl-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxypiperidine-4-carboxamide and (R)-3-(4-(3-oxo-l-oxa-8-azaspiro[4.5]decan-8-yl)phenyl)piperidine-2, 6-dione to afford the title compound (7.2 mg, 20%). LCMS: C43H53F2N7O6 requires 801.4, found: m / z = 802.4 [M+H]+.EXAMPLE 115RAC-N-(1-(((1R,4R)-4-(4-((R)-2,6-DIOXOPIPERIDIN-3- YL)PHENOXY)CYCLOHEXYL)METHYL)PIPERIDIN-4-YL)-N-ETHYIM-(6-(2- HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXYPIPERIDINE-4-CARBOXAMIDEStep 1: Synthesis of the title compoundThe title compound was prepared as described for Example 1, Step 2, using N-ethyl-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide and rac-(lR,4r)-4-(4-((R)-2,6-dioxopiperidin-3-yl)phenoxy)cyclohexane-l-carbaldehyde (synthesized as described in WO2024254532 Al 2024-12-12) to afford the title compound (6.5 mg, 18%). LCMS: C42H54N6O6 requires 738.4, found: m / z = 739.4 [M+H]+.EXAMPLE 116( / ?)-A-(2,2-l)II I.l ()ROI IIIM.)-A-(l-(2-(l-(4-(2,6-l)IOXOPIPI RII)IX-3-M.)PHI XY I.)PIPI RII)IX-4- YL)ETHYL)PIPERIDIN-4-YL)-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4- (METHOXYMETHYL)PIPERIDINE-4-CARBOXAMIDE190Step 1: Synthesis of JV-(2,2-difluoroethyl)-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(methoxymethyl)-JV-(piperidin-4-yl)piperidine-4-carboxamide hydrochlorideThe title compound was prepared as described for Example 2, Step 1 using l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-4-(methoxymethyl)piperidine-4-carboxylic acid (Intermediate 13) and tert-butyl 4-((2,2-difluoroethyl)amino)piperidine-l -carboxylate to afford the title compound as a yellow oil. LCMS C25H33F2N5O3 requires: 489.3, found m / z = 490.3 [M+H]+.Step 2: Synthesis of the title compoundThe title compound was prepared as described for Example 1, Step 2, using A'-(2.2-difluorocthyl)-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-(methoxymethyl)-JV-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride (Example 116, Step 1) and ( / ?)-2-(l-(4-(2.6-dioxopipcridin-3-yl)phcnyl)pipcridin-4-yl)acetaldehyde to afford the title compound (33.5 mgs, 78% yield) as a white solid. LCMS:C43H55F2N7O5 requires: 787.4, found: m / z = 788.3 [M+H]+.EXAMPLE 117(lRS&,5SR&,8RS&)-N-{l-[2-(l-{l-[(3RS)-2,6-DIOXOPIPERIDIN-3-YL]-3-METHYL-2-OXO-2,3- DIHYDRO-1 H-l,3-BENZODIAZOI^4-YL}PIPERIDIN-4-YL)ETHYL]PIPERIDIN-4-YL}-3-[6-(2- HYDROXYPHENYL)PYRID AZIN-4- YL]-N-(3, 3, 3-TRIFLUOROPROPYL)-3-AZABICYCLO[3.2.1]OCTANE-8- CARBOXAMIDEStep 1: tert-butyl 4-[N-(3,3,3-trifluoropropyl)(lR,5S,8S)-3-{6-[2- (methoxymethoxy)phenyl]pyridazin-4-yl}-3-azabicyclo[3.2.1]octane-8-amido]piperidine-l-carboxylateF3C191To a solution of (lR,5S,8S)-3-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-3-azabicyclo[3.2.1]octane-8-carboxylic acid (45.01 mg, 0.1218 mmol) in DMA (1.00 mb) was added tertbutyl 4-[(3,3,3-trifluoropropyl)amino]piperidine-l-carboxylate (39.72 mg, 0.1340 mmol) and N, N-diisopropylethylamine (63.67 pL, 0.05 g, 0.3655 mmol). [(dimethylamino)({[l,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (55.59 mg, 0.1462 mmol) was added. Stirred at rt for 2h, then added more N, N-diisopropylethylamine (63.67 pL, 0.05 g, 0.3655 mmol) and HATU (55 mg) and stirred overnight. Added more HATU (55 mg) and continued stirring at rt for 3 h, then at 40°C overnight. Purified directly by RP-HPLC to yield tert-butyl 4-[N-(3,3,3-trifhioropropyl)(lR,5S,8S)-3-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-3-azabicyclo[3.2.1]octane-8-amido]piperidine-l -carboxylate (0.049 g, 52.79%). LCMS: C33H44F3N5O5 requires: 647.3, found: m / z = 648.2 [M+H]+.Step 2: (lR,5S,8S)-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(piperidin-4-yl)-N-(3,3,3-trifluoropropyl)-3-azabicyclo [3.2.1] octane-8-carboxamide(lR,5S,8S)-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(piperidin-4-yl)-N-(3,3,3-trifluoropropyl)-3-azabicyclo[3.2.1]octane-8-carboxamide was prepared as described for Example 107 step 2. LCMS: C26H32F3N5O2 requires: 503.3, found: m / z = 504.2 [M+H]+Step: 3 Synthesis of the title compoundThe title compound was synthesized as described for Example 153 step 5, using (lR,5S,8S)-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(piperidin-4-yl)-N-(3,3,3-trifluoropropyl)-3-azabicyclo[3.2.1]octane-8-carboxamide hydrochloride and rac-2-(l-{l-[(3R)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-l,3-benzodiazol-4-yl}piperidin-4-yl)acetaldehyde to yield (lRS&,5SR&,8RS&)-N-{l-[2-( 1 - { 1 - [(3RS)-2,6-dioxopiperidin-3-yl] -3 -methyl -2 -oxo- 1,3 -benzodiazol-4-yl }piperidin-4-yl)ethyl]piperidin-4-yl}-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(3,3,3-trifluoropropyl)-3-azabicyclo[3.2.1]octane-8-carboxamide (0.0104 g, 61.18%). LCMS: C46H56F3N9O5 requires: 871.4, found: m / z = 872.3 [M+H]+192EXAMPLE 118(lRS&,5SR&,8RS&)-N-{l-[2-(l-{4-[(3RS)-2,6-DIOXOPIPERIDIN-3-YL]-3,5- DIFLUOROPHENYL}PIPERIDIN-4- YL)E THYL] PI PE R ID I N-4- YL} -3- [6-(2-HYDROXYPHENYL)PYRIDAZIN- 4-YL]-N-(3,3,3-TRIFLUOROPROPYL)-3-AZABICYCLO[3.2.1]OCTANE-8-CARBOXAMIDEOThe title compound was synthesized as described for Example 153 step 5, using (lR,5S,8S)-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(piperidin-4-yl)-N-(3,3,3-trifluoropropyl)-3-azabicyclo[3.2.1]octane-8-carboxamide hydrochloride and rac-2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]-3,5-difluorophenyl}piperidin-4-yl)acetaldehyde to yield (lRS&,5SR&,8RS&)-N-{ l-[2-(l-{4-[(3RS)-2,6-dioxopiperidin-3 -yl] -3,5 -difluorophenyl}piperidin-4-yl)ethyl]piperidin-4-yl } -3- [6-(2-hydroxyphenyl)pyridazin-4-yl] -N-(3,3, 3 -trifluoropropyl) -3 -azabicyclo [3.2.1] octane -8 -carboxamide (0.0103 g, 62.92%). LCMS: C44H52F5N7O4 requires: 837.4, found: m / z = 838.3 [M+H]+EXAMPLE 119(X)-A-CYCLOPROPYL-A-(l-(2-(l-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4- YL)ETHYL)PIPERIDIN-4-YL)-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4- (METHOXYMETHYL)PIPERIDINE-4-CARBOXAMIDEThe title compound was synthesized as described for Example 59.EXAMPLE 120(lRS,5SR,8RS)-N-{l-[2-(l-{4-[(3R)-2,6-DIOXOPIPERIDIN-3-YL]-3-FLUOROPHENYL}PIPERIDIN-4- YL)ETHYL]PIPERIDIN-4-YL}-3-[6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL]-N-(3, 3,3- TRIFLUOROPROPYL)-3-AZABICYCLO[3.2.1]OCTANE-8-CARBOXAMIDE193The title compound was synthesized as described for Example 153 step 5, using (lR,5S,8S)-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(piperidin-4-yl)-N-(3,3,3-trifluoropropyl)-3-azabicyclo[3.2.1]octane-8-carboxamide hydrochloride and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]-3-fluorophenyl}piperidin-4-yl)acetaldehyde to yield (lRS,5SR,8RS)-N-{l-[2-(l-{4-[(3R)-2,6-dioxopiperidin-3 -yl] -3 -fluorophenyl}piperidin-4-yl)ethyl]piperidin-4-yl }-3-[6-(2-hydroxyphenyl)pyridazin-4-yl] -N-(3,3, 3 -trifluoropropyl) -3 -azabicyclo [3.2.1] octane -8 -carboxamide (0.0105 g, 65.41%). LCMS: C44H53F4N7O4 requires: 819.4, found: m / z = 820.2 [M+H]+EXAMPLE 121RAC-N-(CYCLOPROPYLMETHYL)-N-{l-[2-(l-{5-[(3R)-2,6-DIOXOPIPERIDIN-3-YL]PYRIDIN-2- YL}PIPERIDIN-4- YL)ETHYL]PIPERIDIN-4-YL}-1-[6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL]-4- (METHOXYMETHYL)PIPERIDINE-4-CARBOXAMIDEStep 1: Synthesis of benzyl 4-[(cyclopropylmethyl)amino]piperidine-l-carboxylateTo a mixture of benzyl 4-oxopiperidine- 1 -carboxylate (500 mg, 2.14 mmol) and 1-cyclopropylmethanamine (152 mg, 2.14 mmol) in DCM (5.00 mL) was added sodium triacetoxyborohydride (1.36 g, 6.43 mmol). After 2 hours, water was added. The mixture was extracted twice with DCM. The combined organic layers were concentrated. The crude residue was purified by flash chromatography on a 40g column eluted with 0 to 20% MeOH / DCM to provide benzyl 4-[(cyclopropyhnethyl)amino]piperidine-l -carboxylate (0.617 g, 100%). LCMS: C17H24N2O2 requires: 288.2, found: m / z = 289.2 [M+H]+.Step 2: Synthesis of tert-butyl 4-({l-[(benzyloxy)carbonyl]piperidin-4-yl}(cyclopropylmethyl)carbamoyl)-4-(methoxymethyl)piperidine-l-carboxylateTo a vial with l-(tert-butoxycarbonyl)-4-(methoxymethyl)piperidine-4-carboxylic acid (250 mg, 0.915 mmol) in DCM (3.00 mL) was added benzyl 4-[(cyclopropylmethyl)amino]piperidine-l-carboxylate (340 mg, 1.18 mmol) and N, N-diisopropylethylamine (0.64 mL, 0.47 g, 3.66 mmol) followed by bis(2-oxo-l,3-oxazolidin-3-yl)phosphinoyl chloride (699 mg, 2.74 mmol). The mixture was194heated at 40°C for 90 minutes then overnight at room temp. The mixture was diluted with water and extracted 3X DCM. The combined organic layers were dried overNa2SO4and concentrated. The crude residue was purified by flash chromatography on a 24 g column eluted with gradient elution to 70% EtOAc / heptane to provide tert-butyl 4-({l-[(benzyloxy)carbonyl]piperidin-4-yl}(cyclopropylmethyl)carbamoyl)-4-(methoxymethyl)piperidine-l -carboxylate (0.243 g, 49%). LCMS: C30H45N3O6 requires: 543.3, found: m / z = 566.4 [M+Na]+.Step 3: Synthesis of benzyl 4-[N-(cyclopropylmethyl)-4-(methoxymethyl)piperidine-4-amido]piperidine-l-carboxylatetert-butyl 4-({l-[(benzyloxy)carbonyl]piperidin-4-yl}(cyclopropylmethyl)carbamoyl)-4-(methoxymethyl)piperidine-l -carboxylate (243 mg, 0.447 mmol) was stirred in MeOH (2.00 m ) and 4M hydrogen chloride in dioxane solution (2.00 m, 0.29 g, 8.00 mmol) for 40 minutes then was concentrated to provide benzyl 4-[N-(cyclopropylmethyl)-4-(methoxymethyl)piperidine-4-amido]piperidine-l -carboxylate (0.198 g, 100%). ECMS: C25H37N3O4 requires: 443.3, found: m / z = 444.2 [M+H]+.Step 4: Synthesis of benzyl 4-[N-(cyclopropylmethyl)-l-(6-chloropyridazin-4-yl)-4-(methoxymethyl)piperidine-4-amido]piperidine-l-carboxylateA mixture of benzyl 4-[N-(cyclopropylmethyl)-4-(methoxymethyl)piperidine-4-amido]piperidine-l -carboxylate (198 mg, 0.447 mmol), 3,5-dichloropyridazine (76.2 mg, 0.512 mmol) and N, N-diisopropylethylamine (0.45 mb, 0.33 g, 2.56 mmol) in DMSO (1.50 mb) was heated in a 100°C heating block for 30 minutes. 13mb water was added. The mixture was extracted 3X ethyl acetate. The combined organic layers were dried overNa2SO4and concentrated. The crude residue was purified by flash chromatography on a 24g column eluted with gradient elution with 0 to 10% MeOH / EtOAc to provide benzyl 4-[N-(cyclopropylmethyl)-l-(6-chloropyridazin-4-yl)-4-(methoxymethyl)piperidine-4-amido]piperidine-l-carboxylate (0.185 g, 74%). ECMS: C29H38CIN5O4 requires: 555.3, found: m / z = 556.2 [M+H]+.195Step 5: Synthesis of benzyl 4-[N-(cyclopropylmethyl)-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4- (methoxymethyl)piperidine-4-amido]piperidine-l-carboxylateTo a vial with benzyl 4-[N-(cyclopropylmethyl)-l-(6-chloropyridazin-4-yl)-4-(methoxymethyl)piperidine-4-amido]piperidine-l-carboxylate (183 mg, 0.329 mmol), 2-hydroxyphenylboronic acid (59.0 mg, 0.428 mmol), and potassium carbonate (136 mg, 0.987 mmol) was added dioxane (4.50 mL) and water (1.00 mL). A vacuum was pulled until the mixture bubbled then the headspace was backfilled with argon for 5 cycles. tetrakis(triphenylphosphine)palladium(0) (38.0 mg, 0.0329 mmol) was added. A vacuum was pulled until the mixture bubbled then the headspace was backfilled with argon for 5 cycles. The mixture was heated in a 100°C heating block overnight. Water was added and the mixture was extracted 3X EtOAc. The combined organic layers were dried over Na2SO4and concentrated. The crude residue was purified by flash chromatography on a 24g column eluted with 0 to 100% EtOAc / heptane to provide benzyl 4-[N-(cyclopropylmethyl)-l-[6-(2-hydroxyphenyl)pyridazin-4-yl] -4-(methoxymethyl)piperidine-4-amido]piperidine- 1 -carboxylate (0.147 g, 73%). LCMS: C35H43N5O5 requires: 613.3, found: m / z = 556.2 [M+H]+.Step 6: Synthesis of N-(cyclopropylmethyl)-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-(methoxymethyl)-N-(piperidin-4-yl)piperidine-4-carboxamideTo a mixture of benzyl 4-[N-(cyclopropylmethyl)-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-(methoxymethyl)piperidine-4-amido]piperidine-l -carboxylate (147 mg, 0.240 mmol) in THF (2.00 mL) and EtOH (2.00 mL) was added 10% Pd / C (15.00 mg). The mixture was stirred under a balloon of H2 overnight. The mixture was diluted with THF and filtered through a pad of celite then concentrated to provide N-(cyclopropylmethyl)-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-(methoxymethyl)-N-(piperidin-4-yl)piperidine-4-carboxamide (0.115 g, 100%). LCMS: C27H37N5O3 requires: 479.3, found: m / z = 480.4 [M+H]+.Step 7: Synthesis of the title compoundTo a vial with N-(cyclopropylmethyl)-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-(methoxymethyl)-N-(piperidin-4-yl)piperidine-4-carboxamide (36.0 mg, 0.0751 mmol) and rac-2-(l-{5- 196[(3R)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)acetaldehyde (23.7 mg, 0.0751 mmol) in DMA (1.00 mL) was added sodium triacetoxyborohydride (19.1 mg, 0.0901 mmol). After 1 hour, the mixture was filtered with a syringe fdter then purified by reverse phase HPLC to provide the title compound (0.0039 g, 6%). LCMS: C44H58N8O5 requires: 778.5, found: m / z = 779.3 [M+H]+.EXAMPLE 122RAC-N-(CYCLOPROPYLMETHYL)-N-{1-[2-(1-{4-[(3R)-2,6-DIOXOPIPERIDIN-3-YL]-3- FLUOROPHENYL}PIPERIDIN-4-YL)ETHYL]PIPERIDIN-4-YL}-l-[6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL]-4-(METHOXYMETHYL)PIPERIDINE-4-CARBOXAMIDEThe title compound was prepared as described for Example 121, Step 7, using rac-2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]-3-fluorophenyl}piperidin-4-yl)acetaldehyde (24.3 mg, 0.0730 mmol) to afford the title compound (7.4 mg, 12% yield). LCMS: C45H58FN7O5 requires 795.5, found m / z = 796.3 [M+H]+.EXAMPLE 123RAC-N-CYCLOPROPYL-N-{l-[2-(l-{4-[(3R)-2,6-DIOXOPIPERIDIN-3-YL]PHENYL}PIPERIDIN-4- YL)ETHYL] PIPERIDIN-4- YL}- 1- [6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL] -4- (METHOXYMETHYL)PIPERIDINE-4-CARBOXAMIDEStep 1: Synthesis of benzyl 4-(cyclopropylamino)piperidine-l-carboxylateThe title compound was prepared as described for Example 121 Step 1 using aminocyclopropane (269 mg, 4.72 mmol) to afford benzyl 4-(cyclopropylamino)piperidine-l -carboxylate (1.12 g, 95%). LCMS: C16H22N2O2 requires 274.2, found m / z = 275.2 [M+H]+.197Step 2: Synthesis of tert-butyl 4-({l-[(benzyloxy)carbonyl]piperidin-4-yl}(cyclopropyl)carbamoyl)- 4-(methoxymethyl)piperidine-l-carboxylateOThe title compound was prepared as described for Example 121 Step 2 using benzyl 4-(cyclopropylamino)piperidine-l -carboxylate (1.21 g, 4.41 mmol) to afford tert-butyl 4-({l-[(benzyloxy)carbonyl]piperidin-4-yl}(cyclopropyl)carbamoyl)-4-(methoxymethyl)piperidine-l-carboxylate (0.899 g, 52%). LCMS: C29H43N3O6 requires 529.3, found m / z = 552.4 [M+Na]+.Step 3: Synthesis of benzyl 4-[N-cyclopropyl-4-(methoxymethyl)piperidine-4-amido]piperidine-l-carboxylateThe title compound was prepared as described for Example 121 Step 3 using tert-butyl 4-({ 1-[(benzyloxy)carbonyl]piperidin-4-yl}(cyclopropyl)carbamoyl)-4-(methoxymethyl)piperidine-l-carboxylate (899 mg, 1.70 mmol) to afford benzyl 4-[N-cyclopropyl-4-(methoxymethyl)piperidine-4-amido]piperidine-l -carboxylate (0.729 g, 100%). LCMS: C24H35N3O4 requires 429.3, found m / z = 430.4 [M+H]+.Step 4: Synthesis of benzyl 4-[N-cyclopropyl-l-(6-chloropyridazin-4-yl)-4- (methoxymethyl)piperidine-4-amido]piperidine-l-carboxylateOThe title compound was prepared as described for Example 121 Step 4 using benzyl 4-[N-cyclopropyl-4-(methoxymethyl)piperidine-4-amido]piperidine-l-carboxylate (729 mg, 1.70 mmol) to afford benzyl 4-[N-cyclopropyl- 1 -(6-chloropyridazin-4-yl)-4-(methoxymethyl)piperidine-4-amido]piperidine-l -carboxylate (0.760 g, 82%). LCMS: C28H36CIN5O4 requires 541.3, found m / z = 542.4 [M+H]+.198Step 5: Synthesis of benzyl 4-{N-cyclopropyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4- (methoxymethyl)piperidine-4-amido}piperidine-l-carboxylateThe title compound was prepared as described for Example 121 Step 5 using benzyl 4-[N-cyclopropyl- 1 -(6-chloropyridazin-4-yl)-4-(methoxymethyl)piperidine-4-amido]piperidine- 1 -carboxylate (749 mg, 1.38 mmol) to afford benzyl 4-{N-cyclopropyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-(methoxymethyl)piperidine-4-amido}piperidine-l-carboxylate (0.580 g, 70%). LCMS: C34H41N5O5 requires 599.3, found m / z = 600.4 [M+H]+.Step 6: Synthesis of N-cyclopropyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-(methoxymethyl)-N- (piperidin-4-yl)piperidine-4-carboxamideThe title compound was prepared as described for Example 121 Step 6 using benzyl 4-{N-cyclopropyl- 1 -[6-(2-hydroxyphenyl)pyridazin-4-yl] -4-(methoxymethyl)piperidine-4-amido}piperidine- 1 -carboxylate (561 mg, 0.935 mmol) to afford N-cyclopropyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-(methoxymethyl)-N-(piperidin-4-yl)piperidine-4-carboxamide (0.435 g, 100%). LCMS: C26H35N5O3 requires 465.3, found m / z = 466.4 [M+H]+.Step 7: Synthesis of the title compoundTo a vial with N-cyclopropyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-(methoxymethyl)-N-(piperidin-4-yl)piperidine-4-carboxamide (82 mg, 0.176 mmol) and rac-2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)acetaldehyde (55.4 mg, 0.176 mmol) in acetonitrile (1.50 mL) and MeOH (0.50 mL) was added sodium triacetoxyborohydride (112 mg, 0.528 mmol). After 30 minutes, water was added and the mixture was extracted 3X DCM. The combined organic layers were concentrated then purified by prep TLC eluted with 10% MeOH / DCM to provide rac-N-cyclopropyl-N-{ 1 -[2-( 1 -{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)ethyl]piperidin-4-yl} - 1 - [6-(2-hydroxyphenyl)pyridazin-4-yl]-4-(methoxymethyl)piperidine-4-carboxamide (0.0644 g, 48%). 'HNMR (500 MHz, DMSO) 5 14.66 (s, 1H), 10.77 (s, 1H), 8.88 (d, J= 3.0 Hz, 1H), 8.10 (dd, J= 8.4, 1.7 Hz, 1H), 7.48 (d, J= 2.9 Hz, 1H), 7.33 (ddd, J= 8.5, 7.1, 1.5 Hz, 1H), 7.06 - 7.00 (m, 2H), 6.96 - 6.82 (m, 4H), 3.99 - 3.82 (m, 3H), 3.72 (dd, J= 11.0, 4.9 Hz, 1H), 3.64 (d, J= 12.2 Hz, 2H), 3.49 (s, 2H), 3.26 (s, 3H), 3.15 (t, J= 11.6 Hz, 2H), 2.96 (s, 2H), 2.63 (ddd, J= 12.4, 9.1, 6.7 Hz, 3H), 2.45 - 2.21 (m, 6H), 2.22 -1.96 (m, 5H), 1.94 - 1.83 (m, 1H), 1.81 - 1.61 (m, 4H), 1.55 (d, J= 11.4 Hz, 2H), 1.47- 1.30 (m, 3H),1991.30 - 1.16 (m, 2H), 0.81 - 0.73 (m, 2H), 0.55 - 0.42 (m, 2H). LCMS: C44H57N7O5requires: 763.4, found: m / z = 764.4 [M+H]+EXAMPLE 124N-{l-[2-(l-{4-[(3R)-2,6-DIOXOPIPERIDIN-3-YL]PHENYL}PIPERIDIN-4-YL)ETHYL]PIPERIDIN-4-YL}-l- [6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL]-4-(METHOXYMETHYL)-N-(2-METHYLPROPYL)PIPERIDINE- 4-CARBOXAMIDE!absHO / FNNStep 1: Synthesis of benzyl 4-[(2-methylpropyl)amino]piperidine-l-carboxylateHNThe title compound was prepared as described for Example 121 Step 1 using isobutylamine (157 mg, 2.14 mmol) to afford benzyl 4-[(2-methylpropyl)amino]piperidine-l -carboxylate (0.479 g, 77%). LCMS: C17H26N2O2requires: 290.2, found: m / z = 291.2 [M+H]+Step 2: Synthesis of tert-butyl 4-({l-[(benzyloxy)carbonyl]piperidin-4-yl}(2-methylpropyl)carbamoyl)-4-(methoxymethyl)piperidine-l-carboxylateThe title compound was prepared as described for Example 121 Step 2 using benzyl 4-[(2-methylpropyl)amino]piperidine- 1 -carboxylate (479 mg, 1.65 mmol) to afford tert-butyl 4-({l-[(benzyloxy)carbonyl]piperidin-4-yl}(2-methylpropyl)carbamoyl)-4-(methoxymethyl)piperidine-l-carboxylate (0.505 g, 72%). LCMS: C30H49N3O6requires: 545.4, found: m / z = 568.4 [M+Na]+Step 3: Synthesis of benzyl 4-[N-(2-methylpropyl)-4-(methoxymethyl)piperidine-4-amido]piperidine-l-carboxylate0\5 N200The title compound was prepared as described for Example 121 Step 3 using tert-butyl 4-({l-[(benzyloxy)carbonyl]piperidin-4-yl}(2-methylpropyl)carbamoyl)-4-(methoxymethyl)piperidine-l-carboxylate (505.00 mg, 0.9254 mmol) to afford benzyl 4-[N-(2-methylpropyl)-4-(methoxymethyl)piperidine-4-amido]piperidine-l-carboxylate (0.412 g, 100%). LCMS: C25H39N3O4 requires: 445.3, found: m / z = 446.4 [M+H]+Step 4: Synthesis of benzyl 4-[N-(2-methylpropyl)-l-(6-chloropyridazin-4-yl)-4-(methoxymethyl)piperidine-4-amido]piperidine-l-carboxylateThe title compound was prepared as described for Example 121 Step 4 using benzyl 4-[N-(2-methylpropyl)-4-(methoxymethyl)piperidine-4-amido]piperidine-l-carboxylate (412 mg, 0.926 mmol) to afford benzyl 4-[N-(2 -methylpropyl)- 1 -(6-chloropyridazin-4-yl)-4-(methoxymethyl)piperidine-4-amido]piperidine-l -carboxylate (0.277 g, 54%). LCMS: C29H40ClN5O4requires: 557.3, found: m / z = 558.4 [M+H]+Step 5: Synthesis of benzyl 4-[N-(2-methylpropyl)-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-(methoxymethyl)piperidine-4-amido]piperidine-l-carboxylateThe title compound was prepared as described for Example 121 Step 5 using benzyl 4-[N-(2-methylpropyl)- 1 -(6-chloropyridazin-4-yl)-4-(methoxymethyl)piperidine-4-amido]piperidine- 1 -carboxylate (267 mg, 0.478 mmol) to afford benzyl 4-[N-(2-methylpropyl)-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-(methoxymethyl)piperidine-4-amido]piperidine-l-carboxylate (0.243 g, 82%). LCMS: C35H45N5O5 requires: 615.3, found: m / z = 616.4 [M+H]+Step 6: Synthesis of l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-(methoxymethyl)-N-(2-methylpropyl)-N-(piperidin-4-yl)piperidine-4-carboxamideThe title compound was prepared as described for Example 121 Step 6 using benzyl 4-[N-(2-methylpropyl)-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-(methoxymethyl)piperidine-4-amido]piperidine-2011-carboxylate (243 mg, 0.395 mmol) to afford l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-(methoxymethyl)-N-(2-methylpropyl)-N-(piperidin-4-yl)piperidine-4-carboxamide (0.190 g, 100%). LCMS: C27H39N5O3 requires: 481.3, found: m / z = 482.3 [M+H]+Step 7: Synthesis of the title compoundThe title compound was prepared as described for Example 123 Step 7 using l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-(methoxymethyl)-N-(2-methylpropyl)-N-(piperidin-4-yl)piperidine-4-carboxamide (66.0 mg, 0.137 mmol) and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)acetaldehyde (43.1 mg, 0.137 mmol) to afford N-{l-[2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)ethyl]piperidin-4-yl}-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-(methoxymethyl)-N-(2-methylpropyl)piperidine-4-carboxamide (0.0112 g, 9%). 'H NMR (500 MHz, DMSO) 5 14.64 (s, 1H), 10.78 (s, 1H), 9.02 (s, 1H), 8.88 (d, J= 2.9 Hz, 1H), 8.19 - 7.97 (m, 1H), 7.47 (d, J= 2.9 Hz, 1H), 7.34 (td, J= 7.6, 1.6 Hz, 1H), 7.14 - 6.96 (m, 2H), 6.96 - 6.79 (m, 4H), 4.20 (s, 1H), 3.87 (d, J= 13.9 Hz, 2H), 3.80 - 3.63 (m, 3H), 3.63 - 3.45 (m, 4H), 3.28 - 3.02 (m, 8H), 3.00 - 2.80 (m, 2H), 2.72 - 2.56 (m, 3H), 2.49 - 2.41 (m, 1H), 2.27 (d, J= 13.8 Hz, 2H), 2.19 - 1.89 (m, 5H), 1.88 - 1.67 (m, 7H), 1.62 (s, 2H), 1.48 (s, 1H), 1.39 - 1.15 (m, 2H), 0.81 (d, J= 6.7 Hz, 6H). LCMS: C45H61N7O5 requires: 779.5, found: m / z = 780.3 [M+H]+EXAMPLE 125RAC-(lR,5S,8S)-N-(CYCLOPROPYLMETHYL)-N-(l-(2-(l-(4-((R)-2,6-DIOXOPIPERIDIN-3-YL)-3,5-DIFLUOROPHENYL)PIPERIDIN-4-YL)ETHYL)PIPERIDIN-4-YL)-3-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-3-AZABICYCLO[3.2.1]OCTANE-8-CARBOXAMIDEy— NHN &2 y=°NNStep 1: Synthesis of the title compoundN-(cyclopropylmethyl)-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(piperidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxamide hydrochloride (8.00 mg, 0.0150 mmol) and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]-3,5-difluorophenyl}piperidin-4-yl)acetaldehyde (5.18 mg, 0.0165 mmol) were added to a vial and DMA (0.50 mb) was added. Sodium triacetoxyborohydride (9.52 mg, 0.0449 mmol) was then added the reaction was stirred at RT for 30 mins and checked by LCMS. Once complete, the reaction was directly purified by RP-FC to afford the title compound (2.5 mg, 19.5%) as a formate salt. LCMS: C45H55F2N7O4 requires: 795.4, found: m / z = 796.3 [M+H]+202EXAMPLE 126RAC-N-(2,2-DIMETHYLPROPYL)-N-{l-[2-(l-{4-[(3R)-2,6-DIOXOPIPERIDIN-3-YL]-3- FLUOROPHENYL}PIPERIDIN-4-YL)ETHYL]PIPERIDIN-4-YL}-1-[6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL]-4-(METHOXYMETHYL)PIPERIDINE-4-CARBOXAMIDEStep 1: Synthesis of benzyl 4-[(2,2-dimethylpropyl)amino]piperidine-l-carboxylateOThe title compound was prepared as described for Example 121 Step 1 using neopentylamine (187 mg, 2.14 mmol) to afford benzyl 4-[(2,2-dimethylpropyl)amino]piperidine-l -carboxylate (0.652 g, 100%). LCMS: C18H28N2O2requires: 304.2, found: m / z = 305.2 [M+H]+Step 2: Synthesis of tert-butyl 4-({l-[(benzyloxy)carbonyl]piperidin-4-yl}(2,2-dimethylpropyl)carbamoyl)-4-(methoxymethyl)piperidine-l-carboxylateThe title compound was prepared as described for Example 121 Step 2 using benzyl 4-[(2,2-dimethylpropyl)amino]piperidine-l -carboxylate (652 mg, 2.14 mmol) to afford tert-butyl 4-({l-[(benzyloxy)carbonyl]piperidin-4-yl}(2,2-dimethylpropyl)carbamoyl)-4-(methoxymethyl)piperidine-l-carboxylate (0.510 g, 55%). LCMS: C31H49N3O6 requires: 559.4, found: m / z = 582.4 [M+Na]+Step 3: Synthesis of benzyl 4-[N-(2,2-dimethylpropyl)-4-(methoxymethyl)piperidine-4-amido]piperidine-l-carboxylate203The title compound was prepared as described for Example 121 Step 3 using tert-butyl 4-({ 1-[(benzyloxy)carbonyl]piperidin-4-yl}(2,2-dimethylpropyl)carbamoyl)-4-(methoxymethyl)piperidine-l-carboxylate (510 mg, 0.911 mmol) to afford benzyl 4-[N-(2,2-dimethylpropyl)-4-(methoxymethyl)piperidine-4-amido]piperidine-l-carboxylate (0.419 g, 100%). LCMS: C26H41N3O4 requires: 459.3, found: m / z = 460.4 [M+H]+Step 4: Synthesis of benzyl 4-[N-(2,2-dimethylpropyl)-l-(6-chloropyridazin-4-yl)-4-(methoxymethyl)piperidine-4-amido]piperidine-l-carboxylateThe title compound was prepared as described for Example 121 Step 4 using benzyl 4-[N-(2,2-dimethylpropyl)-4-(methoxymethyl)piperidine-4-amido]piperidine-l-carboxylate (419 mg, 0.911 mmol) to afford benzyl 4-[N-(2,2-dimethylpropyl)- 1 -(6-chloropyridazin-4-yl)-4-(methoxymethyl)piperidine-4-amido]piperidine-l -carboxylate (0.141 g, 15%). LCMS: C30H42CIN5O4 requires: 571.3, found: m / z = 572.4 [M+H]+Step 5: Synthesis of 4-[N-(2,2-dimethylpropyl)-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-(methoxymethyl)piperidine-4-amido]piperidine-l-carboxylateThe title compound was prepared as described for Example 121 Step 5 using benzyl 4-[N-(2,2-dimethylpropyl)- 1 -(6-chloropyridazin-4-yl)-4-(methoxymethyl)piperidine-4-amido]piperidine- 1 -carboxylate (141 mg, 0.246 mmol) to afford 4-[N-(2,2-dimethylpropyl)-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-(methoxymethyl)piperidine-4-amido]piperidine-l-carboxylate (0.111 g, 72%). LCMS:C36H47N5O5 requires: 629.4, found: m / z = 630.4 [M+H]+204Step 6: Synthesis of N-(2,2-dimethylpropyl)-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4- (methoxymethyl)-N-(piperidin-4-yl)piperidine-4-carboxamideThe title compound was prepared as described for Example 121 Step 6 using benzyl 4-[N-(2,2-dimethylpropyl)- 1 - [6-(2-hydroxyphenyl)pyridazin-4-yl] -4-(methoxymethyl)piperidine-4-amido]piperidine-l -carboxylate (110 mg, 0.175 mmol) to afford N-(2,2-dimethylpropyl)-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-(methoxymethyl)-N-(piperidin-4-yl)piperidine-4-carboxamide (0.087 g, 100%). LCMS: C28H41N5O3requires: 495.3, found: m / z = 496.4 [M+H]+Step 7: Synthesis of the title compoundThe title compound was prepared as described for Example 123 Step 7 using N-(2,2-dimethylpropyl)-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-(methoxymethyl)-N-(piperidin-4-yl)piperidine-4-carboxamide (33.0 mg, 0.0666 mmol) and rac-2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]-3-fluorophenyl}piperidin-4-yl)acetaldehyde (22.1 mg, 0.0666 mmol) to provide rac-N-(2,2-dimethylpropyl)-N-{l-[2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]-3-fluorophenyl}piperidin-4-yl)ethyl]piperidin-4-yl } - 1 -[6-(2-hydroxyphenyl)pyridazin-4-yl] -4-(methoxymethyl)piperidine-4-carboxamide (0.0088 g, 16%). 'HNMR (500 MHz, DMSO) 5 14.67 (s, 1H), 10.80 (s, 1H), 8.89 (d, J = 2.8 Hz, 1H), 8.16- 8.05 (m, 1H), 7.48 (d, J=2.9Hz, 1H), 7.33 (td, J= 7.7, 1.6 Hz, 1H), 7.07 (t, J= 8.7 Hz, 1H), 6.99 - 6.89 (m, 2H), 6.77 - 6.63 (m, 2H), 3.88 (dd, J= 12.4, 4.9 Hz, 1H), 3.85 - 3.76 (m, 2H), 3.70 (d, J= 12.4 Hz, 2H), 3.54 (s, 2H), 3.45 (t, J= 10.4 Hz, 2H), 3.25 (s, 3H), 3.18 - 2.79 (m, 3H), 2.76 -2.60 (m, 3H), 2.45 - 2.07 (m, 6H), 2.07 - 1.90 (m, 2H), 1.90 - 1.66 (m, 6H), 1.59 - 1.48 (m, 2H), 1.48 -1.32 (m, 3H), 1.32- 1.14 (m, 5H), 0.83 (s, 9H). LCMS: C46H62FN7O5requires: 811.5, found: m / z = 812.4 [M+H]+EXAMPLE 127N-[(2R)-BUTAN-2-YL]-N-{l-[2-(l-{4-[(3R)-2,6-DIOXOPIPERIDIN-3-YL]PHENYL}PIPERIDIN-4- YL)ETHYL] PIPERIDIN-4- YL}- 1- [6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL] -4- (METHOXYMETHYL)PIPERIDINE-4-CARBOXAMIDE205Step 1: Synthesis of benzyl 4-[(2R)-butan-2-ylamino]piperidine-l-carboxylateThe title compound was prepared as described for Example 121 Step 1 using (R)-2-butanamine (157 mg, 2.14 mmol) to afford benzyl 4-[(2R)-butan-2-ylamino]piperidine-l-carboxylate (0.616 g, 99%). LCMS: C17H26N2O2requires: 290.2, found: m / z = 291.2 [M+H]+Step 2: Synthesis of tert-butyl 4-({l-[(benzyloxy)carbonyl]piperidin-4-yl}[(2R)-butan-2-yl]carbamoyl)-4-(methoxymethyl)piperidine-l-carboxylateThe title compound was prepared as described for Example 121 Step 2 using benzyl 4-[(2R)-butan-2-ylamino]piperidine- 1 -carboxylate (500 mg, 1.72 mmol) to afford tert-butyl 4-({l-[(benzyloxy)carbonyl]piperidin-4-yl}[(2R)-butan-2-yl]carbamoyl)-4-(methoxymethyl)piperidine-l-carboxylate (0.546 g, 58%). LCMS: C30H47N3O6 requires: 545.4, found: m / z = 568.4 [M+Na]+Step 3: Synthesis of benzyl 4-{N-[(2R)-butan-2-yl]-4-(methoxymethyl)piperidine-4-amido}piperidine-l-carboxylateThe title compound was prepared as described for Example 121 Step 3 using tert-butyl 4-({ 1-[(benzyloxy)carbonyl]piperidin-4-yl}[(2R)-butan-2-yl]carbamoyl)-4-(methoxymethyl)piperidine-l-carboxylate (546 mg, 1.00 mmol) to afford benzyl 4-{N-[(2R)-butan-2-yl]-4-(methoxymethyl)piperidine-4-amido}piperidine-l-carboxylate (0.445 g, 100%). LCMS: C25H39N3O4 requires: 445.3, found: m / z = 446.4 [M+H]+206Step 4: Synthesis of benzyl 4-{N-[(2R)-butan-2-yl]-l-(6-chloropyridazin-4-yl)-4-(methoxymethyl)piperidine-4-amido}piperidine-l-carboxylateThe title compound was prepared as described for Example 121 Step 4 using benzyl 4-{N-[(2R)-butan-2-yl]-4-(methoxymethyl)piperidine-4-amido}piperidine-l-carboxylate (445 mg, 1.00 mmol) to afford benzyl 4-{N-[(2R)-butan-2-yl]-l-(6-chloropyridazin-4-yl)-4-(methoxymethyl)piperidine-4-amido}piperidine-l-carboxylate (0.120 g, 21%). LCMS: C29H40ClN5O4requires: 557.3, found: m / z = 558.4 [M+H]+Step 5: Synthesis of benzyl 4-{N-[(2R)-butan-2-yl]-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-(methoxymethyl)piperidine-4-amido}piperidine-l-carboxylateThe title compound was prepared as described for Example 121 Step 5 using benzyl 4-{N-[(2R)-butan-2-yl]-l-(6-chloropyridazin-4-yl)-4-(methoxymethyl)piperidine-4-amido}piperidine-l-carboxylate (118 mg, 0.211 mmol) to afford benzyl 4-{N-[(2R)-butan-2-yl]-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-(methoxymethyl)piperidine-4-amido}piperidine-l-carboxylate (0.096 g, 74%). LCMS: C35H45N5O5 requires: 615.3, found: m / z = 616.4 [M+H]+Step 6: Synthesis of N-[(2R)-butan-2-yl]-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-(methoxymethyl)-N-(piperidin-4-yl)piperidine-4-carboxamideThe title compound was prepared as described for Example 121 Step 6 using benzyl 4-{N-[(2R)-butan-2-yl] - 1 - [6-(2-hydroxyphenyl)pyridazin-4-yl] -4-(methoxymethyl)piperidine-4-amido (piperidine- 1 -carboxylate (96.0 mg, 0.156 mmol) to afford N-[(2R)-butan-2-yl]-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-2074-(methoxymethyl)-N-(piperidin-4-yl)piperidine-4-carboxamide (0.075 g, 100%). LCMS: C27H39N5O3 requires: 481.3, found: m / z = 482.4 [M+H]+Step 7: Synthesis of the title compoundThe title compound was prepared as described for Example 123 Step 7 using N-[(2R)-butan-2-yl]-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-(methoxymethyl)-N-(piperidin-4-yl)piperidine-4-carboxamide (45.0 mg, 0.0934 mmol) and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)acetaldehyde (29.4 mg, 0.0934 mmol) to afford N-[(2R)-butan-2-yl]-N-{l-[2-(l-{4-[(3R)-2,6-dioxopiperidin-3 -yl]phenyl }piperidin-4-yl)ethyl]piperidin-4-yl } - 1 -[6-(2-hydroxyphenyl)pyridazin-4-yl] -4-(methoxymethyl)piperidine-4-carboxamide (0.0184 g, 24%). 'HNMR (500 MHz, DMSO) 5 14.69 (s, 1H), 10.79 (s, 1H), 8.88 (d, J= 3.0 Hz, 1H), 8.21 - 8.01 (m, 1H), 7.48 (d, J = 3.3 Hz, 1H), 7.33 (td, J = 7.6, 1.6 Hz, 1H), 7.03 (d, J= 8.2 Hz, 2H), 6.97 - 6.82 (m, 4H), 4.08 - 3.79 (m, 3H), 3.72 (dd, J= 11.0, 4.9 Hz, 1H), 3.64 (d, J= 11.9 Hz, 2H), 3.50 (s, 2H), 3.26 (s, 3H), 2.98 (d, J= 11.4 Hz, 3H), 2.87 - 2.68 (m, 1H), 2.68 -2.56 (m, 3H), 2.48 - 2.41 (m, 1H), 2.41 - 2.31 (m, 2H), 2.31 - 2.06 (m, 4H), 2.07 - 1.90 (m, 2H), 1.87- 1.63 (m, 7H), 1.63 - 1.49 (m, 2H), 1.48 - 1.33 (m, 4H), 1.31 - 1.10 (m, 6H), 0.98 - 0.89 (m, 1H), 0.78 (t, J= 7.5 Hz, 2H). LCMS: C45H61N7O5requires: 779.5, found: m / z = 780.2 [M+H]+EXAMPLE 128(R)-N-(l-(2-(l-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4-YL)ETHYL)PIPERIDIN-4-YL)-l-(6- (2-HYDROXYPHENYL)PYRID AZIN-4- YL)-N-ISOPROPOXY-4-(METHOXYMETHYL)PIPERIDINE-4- CARBOXAMIDEStep 1: Synthesis of benzyl 4-((l-(tert-butoxycarbonyl)piperidin-4-yl)(isopropoxy)carbamoyl)-4- (methoxymethyl)piperidine-l-carboxylateTo a solution of l-[(benzyloxy)carbonyl]-4-(methoxymethyl)piperidine-4-carboxylic acid (400.00 mg, 1.30 mmol) and tert-butyl 4-(isopropoxyamino)piperidine- 1 -carboxylate (420.31 mg, 1.63 mmol) in CH2CI2 (3.00 mL) was added N, N-diisopropylethylamine (909.25 pL, 0.67 g, 5.21 mmol). Then, bis(2-oxo-l,3-oxazolidin-3-yl)phosphinoyl chloride (993.90 mg, 3.90 mmol) was added and the reaction mixture was stirred at 40 °C until complete by LCMS. Then, the reaction was filtered and the solvent removed under reduced pressure. The crude product was purified on silica gel with a gradient of EtOAc / Hex 0-100% to afford the desired product as a colorless oil. LCMS: C29H45N3O7 requires 547.3, found: m / z = 448.2 [M-BOC]+.208Step 2: Synthesis of tert-butyl 4-(N-isopropoxy-4-(methoxymethyl)piperidine-4-carboxamido)piperidine-l-carboxylateA I T \ / — \ °HN. J N— ( N—N' OTo a round bottom flask containing palladium (194.31 mg, 0.18 mmol) and EtOH (1.50 mL) was added benzyl 4-{[l-(tert-butoxycarbonyl)piperidin-4-yl](isopropoxy)carbamoyl}-4-(methoxymethyl)piperidine-l -carboxylate (200.00 mg, 0.36 mmol) dissolved in THF (1.5mL). The flask was fitted with a three-way adapter and a hydrogen balloon. The atmosphere was changed to hydrogen, and the reaction was stirred until complete by LCMS. Then, the crude product was filtered through a plug of celite, and the solvent was removed under reduced pressure to afford the desired product as a dark brown oil (130 mg, 86%). LCMS: C21H39N3O5 requires 413.3, found: m / z = 414.4 [M+H]+.Step 3: Synthesis of tert-butyl 4-(N-isopropoxy-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-4-(methoxymethyl)piperidine-4-carboxamido)piperidine-l-carboxylateA mixture of tert-butyl 4-[N-isopropoxy-4-(methoxymethyl)piperidine-4-amido]piperidine-l-carboxylate (130.00 mg, 0.31 mmol), 5-chloro-3-[2-(methoxymethoxy)phenyl]pyridazine (78.80 mg, 0.31 mmol) and N, N-diisopropylethylamine (274.51 pL, 0.20 g, 1.57 mmol) was dissolved in DMSO (1.20 mL). Then, the flask was heated to 100 °C and allowed to react until complete by LCMS. Then, it was quenched with water, extracted with ethyl acetate, washed with brine, dried over Na2SO4, filtered and the solvent removed under reduced pressure. The crude oil was purified via flash chromatography in silica with a gradient of 0-20% McOH / CFLCL to afford the desired product as a yellow oil. LCMS: C33H49N5O7 requires 627.4, found: m / z = 628.4 [M+H]+.Step 4: Synthesis of l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-N-isopropoxy-4-(methoxymethyl)-N- (piperidin-4-yl)piperidine-4-carboxamidetert-butyl 4-(N-isopropoxy- 1 -(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-4-(methoxymethyl)piperidine-4-carboxamido)piperidine-l -carboxylate was dissolved in 2.00 mL of THF and 4M HC1 in Dioxane (1.00 mL) was added in one portion. The reaction was stirred at room209temperature until completed by LCMS and then concentrated in vacuo to yield the desired product as a yellow solid. LCMS: C26H37N5O4 requires: 483.3, found: m / z = 484.4 [M+H]+.Step 5: Synthesis of the title compoundThe title compound was prepared as described for Example 1, Step 2, using l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-N-isopropoxy-4-(methoxymethyl)-N-(piperidin-4-yl)piperidine-4-carboxamide and (R)-2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)acetaldehyde to afford the title compound (7.2 mg, 18%). LCMS: C44H59N7O6 requires 781.5, found: m / z = 782.4 [M+H]+.EXAMPLE 129N-{l-[2-(l-{4-[(3R)-2,6-DIOXOPIPERIDIN-3-YL]PHENYL}PIPERIDIN-4-YL)ETHYL]PIPERIDIN-4-YL}-l- [6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL]-N,4-DIMETHYLPIPERIDINE-4-CARBOXAMIDEStep 1: tert-butyl 4-(N-methyl-l-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-4-methylpiperidine-4-amido)piperidine-l-carboxylateTo a solution of l-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-4-methylpiperidine-4-carboxylic acid (50.00 mg, 0.1399 mmol) in DMA (0.30 mL) was added tert-butyl 4-(methylamino)piperidine-l -carboxylate (44.97 mg, 0.2098 mmol) and N, N-diisopropylethylamine (73.10 pL, 0.05 g, 0.4197 mmol). [(dimethylamino)({[l,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafhroro-lambda5-phosphanuide (63.83 mg, 0.1679 mmol) was added and the reaction was stirred at rt for 2 days. More amine (255mg, 2 eq), DIPEA (0.276 mL, 2 eq) and HATU (226 mg, 2 eq) were added and after stirring overnight, the reaction was partitioned between DCM and water, washed DCM layer with sat NH4C1 and passed through a phase separator. The solvent was removed by rotovap to yield crude tert-butyl 4-(N-methyl-l-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-4-methylpiperidine-4-amido)piperidine-l -carboxylate. LCMS: C30H43N5O5 requires: 553.4, found: m / z = 554.4 [M+H]+.Step 2: l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N,4-dimethyl-N-(piperidin-4-yl)piperidine-4-carboxamide210l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N,4-dimethyl-N-(piperidin-4-yl)piperidine-4-carboxamide was prepared as described for Example 107 step 2. LCMS: C23H31N5O2 requires: 409.2, found: m / z = 410.2 [M+H]+.Step 3: Synthesis of the title compoundThe title compound was synthesized as described for Example 107 step 3, using 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)acetaldehyde to yield N-{l-[2-(l-{4-[(3R)-2,6-dioxopiperidin-3 -yl]phenyl }piperidin-4-yl)ethyl]piperidin-4-yl } - 1 -[6-(2-hydroxyphenyl)pyridazin-4-yl] -N,4-dimethylpiperidine-4-carboxamide (0.0064 g, 20.42%). LCMS: C41H53N7O4 requires: 707.4, found: m / z = 708.4 [M+H]+EXAMPLE 130N-{l-[2-(l-{4-[(3R)-2,6-DIOXOPIPERIDIN-3-YL]PHENYL}PIPERIDIN-4-YL)ETHYL]PIPERIDIN-4-YL}-l- [6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL]-N-METHYL-4-PROPYLPIPERIDINE-4-CARBOXAMIDEO HStep 1: tert-butyl 4-(N-methyl-l-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-4-propylpiperidine-4-amido)piperidine-l-carboxylateTert-butyl 4-(N-methyl-l-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-4-propylpiperidine-4-amido)piperidine- 1 -carboxylate was synthesized as described for Example 129, step 1 using l-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-4-propylpiperidine-4-carboxylic acid to yield tert-butyl 4-(N-methyl- 1 - { 6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl } -4-propylpiperidine-4-amido)piperidine- 1 -carboxylate (quantitative yield). LCMS: C30H43N5O5 requires: 581.4, found: m / z = 582.4 [M+H]+.Step 2: l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-methyl-N-(piperidin-4-yl)-4-propylpiperidine-4-carboxamide211l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-methyl-N-(piperidin-4-yl)-4-propylpiperidine-4-carboxamide was prepared as described for Example 107 step 2. LCMS: C25H35N5O2 requires: 437.3, found: m / z = 438.2 [M+H]+.Step 3: Synthesis of the title compoundThe title compound was synthesized as described for Example 107 step 3, using l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-methyl-N-(piperidin-4-yl)-4-propylpiperidine-4-carboxamide hydrochloride and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)acetaldehyde to yield N-{l-[2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)ethyl]piperidin-4-yl}-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-methyl-4-propylpiperidine-4-carboxamide (0.0076 g, 21.28%). LCMS: C43H57N7O4 requires: 735.4, found: m / z = 736.4 [M+H]+EXAMPLE 131(7iS)-A-(l-(2-(l-(4-((7?)-2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4-YL)ETHYL)PIPERIDIN-4-YL)- l-(6-(5-FLUORO-2-HYDROXYPHENYL)PYRID AZIN-4- YL)-3-METHOXY-A-METHYLPYRROLIDINE-3-Step 1: Synthesis of rac-(7?)-l-(6-(5-fluoro-2-hydroxyphenyl)pyridazin-4-yl)-3-methoxy-JV-methyl- JV-(piperidin-4-yl)pyrrolidine-3-carboxamide hydrochlorideThe title compound was prepared as described for the synthesis of Example 1, Step 1, using rac-(R)-l-(6-(5-fluoro-2-(methoxymethoxy)phenyl)pyridazin-4-yl)-3-methoxypyrrolidine-3-carboxylic acid (Intermediate 27) and tert-butyl 4-(methylamino)piperidine-l -carboxylate to afford the title compound as a yellow oil. LCMS C22H28FN5O3 requires 429.2, found m / z = 430.2 [M+H]+.Step 2: Synthesis of the title compoundThe title compound was prepared as described for the synthesis of Example 2, Step 2, using rac-(R)-l-(6-(5-fluoro-2-hydroxyphenyl)pyridazin-4-yl)-3-methoxy- / V-methyl- / V-(piperidin-4-yl)pyrrolidine-3 -carboxamide hydrochloride, to afford the title compound (18.3 mgs, 40% yield) as a white solid.LCMS: C40H50FN7O5 requires: 727.4, found: m / z = 728.4 [M+H]+.212EXAMPLE 132N-{l-[2-(l-{4-[(3R)-2,6-DIOXOPIPERIDIN-3-YL]PHENYL}PIPERIDIN-4-YL)ETHYL]PIPERIDIN-4-YL}-N- ETHYL-1- [6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL] -4-METHYLPIPERIDINE-4-CARBOXAMIDEStep 1: benzyl 4-{[l-(tert-butoxycarbonyl)piperidin-4-yl](ethyl)carbamoyl}-4-methylpiperidine-l-carboxylateTo a solution of l-[(benzyloxy)carbonyl]-4-methylpiperidine-4-carboxylic acid (222.00 mg, 0.8005 mmol) in DMA (2.00 mL) was added tert-butyl 4-(ethylamino)piperidine-l -carboxylate (219.34 mg, 0.9606 mmol) and N, N-diisopropylethylamine (327.68 pL, 0.24 g, 1.8812 mmol). Added bis(2-oxo-l,3-oxazolidin-3-yl)phosphinoyl chloride (244.54 mg, 0.9606 mmol) at rt and then placed the reaction in a 40°C heating block. After Ih, the reaction was purified directly by RP-HPLC to yield benzyl 4-{ [1 -(tert-butoxycarbonyl)piperidin-4-yl](ethyl)carbamoyl}-4-methylpiperidine-l -carboxylate (0.074 g, 18.96%). LCMS: CjylLiNsOs requires: 487.3, found: m / z = 510.2 [M+Na]+.Step 2: tert-butyl 4-(N-ethyl-4-methylpiperidine-4-amido)piperidine-l-carboxylateBenzyl 4- { [ 1 -(tert-butoxycarbony 1 )pipe ridi n-4-y 1 ] (ethyl)carbamoyl } -4-methylpiperidine- 1 -carboxylate (74.00 mg, 0.1518 mmol) was dissolved in ethanol (2.00 mL) and purged with nitrogen. Pd / C was added and the reaction was stirred under a hydrogen atmosphere (balloon). After a few hours, the reaction was filtered and concentrated down to an oil to yield tert-butyl 4-(N-ethyl-4-methylpiperidine-4-amido)piperidine-l -carboxylate (0.053 g, 98.80%). LCMS: C19H35N3O3 requires: 353.3, found: m / z = 354.2 [M+H]+Step 3: tert-butyl 4-[N-ethyl-l-(6-chloropyridazin-4-yl)-4-methylpiperidine-4-amido]piperidine-l-carboxylateTert-butyl 4-(N-ethyl-4-methylpiperidine-4-amido)piperidine-l-carboxylate (54.58 mg, 0.1544 mmol), 3,5-dichloropyridazine (23.00 mg, 0.1544 mmol) and N-methylmorpholine (37.34 pL, 0.03 g, 0.3397 mmol) were dissolved in DMSO (0.30 mL) and stirred in an 80°C heating block for 30 min. After213cooling, the reaction was diluted with 3 mL water and the product extracted with EtOAc (3 x 2 mL). The combined organic layers were dried with a phase separator and concentrated by rotary evaporation to yield tert-butyl 4-[N-ethyl-l-(6-chloropyridazin-4-yl)-4-methylpiperidine-4-amido]piperidine-l-carboxylate (0.0487 g, 67.69%). LCMS: C23H36CIN5O3 requires: 465.3, found: m / z = 466.2 [M+H]+. Step 4: tert-butyl 4-{N-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methylpiperidine-4-amido}piperidine-l-carboxylateTert-butyl 4-[N-ethyl-l-(6-chloropyridazin-4-yl)-4-methylpiperidine-4-amido]piperidine-l-carboxylate (48.70 mg, 0.1045 mmol) was dissolved in 1,4-dioxane (2.00 mL) and water (0.30 mL) along with 2-hydroxyphenylboronic acid (28.83 mg, 0.2090 mmol) and potassium carbonate (43.33 mg, 0.3135 mmol) and Pd(dppf)C12 (7.65 mg, 0.0105 mmol). The reaction was sealed under nitrogen and stirred in a 90°C heating block. After 90min, added more catalyst (15 mg) and continued heating for 60min, then left at rt overnight. Added more boronic acid (15 mg, leq), K-carb (14 mg, 1 eq) and catalyst (7.7 mg, 0.1 eq). Heated for another 90 min. Purified by RP-HPLC to yield tert-butyl 4-{N-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methylpiperidine-4-amido}piperidine-l-carboxylate (0.041 g, 74.92%). LCMS: C29H41N5O4 requires: 523.3, found: m / z = 524.3 [M+H]+.Step 5: N-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methyl-N-(piperidin-4-yl)piperidine-4-carboxamideN-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methyl-N-(piperidin-4-yl)piperidine-4-carboxamide was prepared as described for Example 107 step 2. LCMS: C24H33N5O2 requires: 423.3, found: m / z = 424.2 [M+H]+.Step 6: Synthesis of the title compoundThe title compound was synthesized as described for Example 109 step 3, using N-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methyl-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)acetaldehyde to yield N-{ l-[2-(l-{4-[(3R)-2,6-dioxopiperidin-3 -yl]phenyl }piperidin-4-yl)ethyl]piperidin-4-yl } -N-ethyl- 1 - [6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methylpiperidine-4-carboxamide (0.011 g, 43.03%). LCMS:C42H55N7O4 requires: 721.4, found: m / z = 722.3 [M+H]+214EXAMPLE 1334-CYCLOPROPYL-N-{l-[2-(l-{4-[(3R)-2,6-DIOXOPIPERIDIN-3-YL]PHENYL}PIPERIDIN-4- YL)ETHYL]PIPERIDIN-4-YL}-1-[6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL]-N-METHYLPIPERIDINE-4- CARBOXAMIDEJ?"C> HStep 1: tert-butyl 4-(N-methyl-4-cyclopropyl-l-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}piperidine-4-amido)piperidine-l-carboxylateTert-butyl 4-(N-methyl-4-cyclopropyl-l-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}piperidine-4-amido)piperidine-l-carboxylate was synthesized as described for Example 129 step 1, using 4-cyclopropyl-l-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}piperidine-4-carboxylic acid and tert-butyl 4-(methylamino)piperidine-l -carboxylate to yield tert-butyl 4-(N-methyl-4-cyclopropyl-l-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}piperidine-4-amido)piperidine-l-carboxylate (0.086 g, 111.53%). LCMS: C32H45N5O5 requires: 579.3, found: m / z = 580.4 [M+H]+.Step 2: 4-cyclopropyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-methyl-N-(piperidin-4-yl)piperidine-4-carboxamide4-cyclopropyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-methyl-N-(piperidin-4-yl)piperidine-4-carboxamide was prepared as described for Example 107 step 2. LCMS: C25H33N5O2 requires: 435.3, found: m / z = 436.2 [M+H]+.Step 3: Synthesis of the title compoundThe title compound was synthesized as described for Example 109 step 3, using 4-cyclopropyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-methyl-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)acetaldehyde to yield 4-cyclopropyl-N-{l-[2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)ethyl]piperidin-4-yl}-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-methylpiperidine-4-carboxamide (0.014 g, 60.52%). LCMS: C43H55N7O4 requires: 733.4, found: m / z = 734.2 [M+H]+215EXAMPLE 134RAC-N-{l-[2-(l-{4-[(3R)-2,6-DIOXOPIPERIDIN-3-YL]PHENYL}-4-FLUOROPIPERIDIN-4- YL)ETHYL]PIPERIDIN-4-YL}-4-ETHYL-1-[6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL]-N- METHYLPIPERIDINE-4-CARBOXAMIDEStep 1: tert-butyl 4-(N-methyl-4-ethyl-l-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}piperidine-4-amido)piperidine-l-carboxylateTert-butyl 4-(N-methyl-4-ethyl-l-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}piperidine-4-amido)piperidine- 1 -carboxylate was synthesized as described for Example 129 step 1, using 4-ethyl-l-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}piperidine-4-carboxylic acid and tert-butyl 4-(methylamino)piperidine-l -carboxylate to yield tert-butyl 4-(N-methyl-4-ethyl-l-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}piperidine-4-amido)piperidine-l-carboxylate (quantitative yield). LCMS: C31H45N5O5 requires: 567.3, found: m / z = 568.4 [M+H]+.Step 2: 4-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-methyl-N-(piperidin-4-yl)piperidine-4-carboxamide4-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-methyl-N-(piperidin-4-yl)piperidine-4-carboxamide was prepared as described for Example 107 step 2. LCMS: C24H33N5O2 requires: 423.3, found: m / z = 424.2 [M+H]+.Step 3: Synthesis of the title compoundCombined 4-ethyl- 1 -[6-(2-hydroxyphenyl)pyridazin-4-yl] -N-methyl-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride (15.50 mg, 0.0337 mmol) and rac-2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}-4-fluoropiperidin-4-yl)acetaldehyde (12.32 mg, 0.0371 mmol) in DMA (0.30 mL) and then added sodium triacetoxyborohydride (10.71 mg, 0.0505 mmol) and stirred for 2h, then purified directly by HTP to yield rac-N-{ l-[2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}-4-fhioropiperidin-4-yl)ethyl]piperidin-4-yl}-4-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-216methylpiperidine-4-carboxamide (0.0034 g, 12.52%). LCMS: C42H54FN7O4 requires: 739.4, found: m / z = 740.3 [M+H]+EXAMPLE 135RAC-N-{l-[2-(l-{4-[(3R)-2,6-DIOXOPIPERIDIN-3-YL]-3-FLUOROPHENYL}PIPERIDIN-4- YL)ETHYL]PIPERIDIN-4- YL}-1-[6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL]-N,4-DIMETHYLPIPERIDINE- 4-CARBOXAMIDEO HThe title compound was synthesized as described for Example 109 step 3, using l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N,4-dimethyl-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride and rac-2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]-3-fluorophenyl}piperidin-4-yl)acetaldehyde to yield rac-N-{l-[2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]-3-fluorophenyl}piperidin-4-yl)ethyl]piperidin-4-yl}-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N,4-dimethylpiperidine-4-carboxamide (0.0068 g, 25.67%). LCMS: C41H52FN7O4 requires: 725.4, found: m / z = 726.3 [M+H]+EXAMPLE 136RAC-N-{1-[2-(1-{4-[(3R)-2,6-DIOXOPIPERIDIN-3-YL]-3-FLUOROPHENYL}PIPERIDIN-4- YL)ETHYL]PIPERIDIN-4-YL}-4-ETHYL-l-[6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL]-N- METHYLPIPERIDINE-4-CARBOXAMIDEO HThe title compound was synthesized as described for Example 109 step 3, using 4-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-methyl-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride and rac-2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]-3-fluorophenyl}piperidin-4-yl)acetaldehyde to yield rac-N-{ 1-[2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]-3-fluorophenyl}piperidin-4-yl)ethyl]piperidin-4-yl}-4-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-methylpiperidine-4-carboxamide (0.0046 g, 17.37%). LCMS:C42H54FN7O4 requires: 739.4, found: m / z = 740.3 [M+H]+217EXAMPLE 137RAC-N-{l-[2-(l-{4-[(3R)-2,6-DIOXOPIPERIDIN-3-YL]-3-FLUOROPHENYL}PIPERIDIN-4- YL)ETHYL] PIPERIDIN-4- YL}- 1- [6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL] -N-METHYL-4- PROPYLPIPERIDINE-4-CARBOXAMIDEThe title compound was synthesized as described for Example 109 step 3, using l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-methyl-N-(piperidin-4-yl)-4-propylpiperidine-4-carboxamide hydrochloride and rac-2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]-3-fluorophenyl}piperidin-4-yl)acetaldehyde to yield rac-N-{ l-[2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]-3-fluorophenyl}piperidin-4-yl)ethyl]piperidin-4-yl}-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-methyl-4-propylpiperidine-4-carboxamide (0.0053 g, 19.63%). LCMS: C43H56FN7O4 requires: 753.4, found: m / z = 754.3 [M+H]+EXAMPLE 138RAC-N-{l-[2-(l-{4-[(3R)-2,6-DIOXOPIPERIDIN-3-YL]-3,5-DIFLUOROPHENYL}PIPERIDIN-4- YL)ETHYL]PIPERIDIN-4-YL}-4-ETHYL-l-[6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL]-N- METHYLPIPERIDINE-4-CARBOXAMIDEThe title compound was synthesized as described for Example 109 step 3, using 4-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-methyl-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride and rac-2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]-3,5-difluorophenyl}piperidin-4-yl)acetaldehyde to yield rac-N-{l-[2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]-3,5-difluorophenyl}piperidin-4-yl)ethyl]piperidin-4-yl}-4-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-methylpiperidine-4-carboxamide (0.0042 g, 15.50%). LCMS: C42H53F2N7O4 requires: 757.4, found: m / z = 758.6 [M+H]+EXAMPLE 139RAC-N-{l-[2-(l-{4-[(3R)-2,6-DIOXOPIPERIDIN-3-YL]-3-FLUOROPHENYL}PIPERIDIN-4- YL)ETHYL]PIPERIDIN-4-YL}-1-[6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL]-N-(2-METHOXYETHYL)-4- METHYLPIPERIDINE-4-CARBOXAMIDE218Step 1: benzyl 4-{[l-(tert-butoxycarbonyl)pipendin-4-yl](2-methoxyethyl)carbamoyl}-4-methylpiperidine-l-carboxylateBenzyl 4- { [ 1 -(tert-butoxycarbony 1 )pi peridi n-4-y 1 ] (2-methoxyethyl)carbamoyl } -4-methylpiperidine-1 -carboxylate was synthesized as described for Example 132 step 1 using 1-[(benzyloxy)carbonyl]-4-methylpiperidine-4-carboxylic acid and / c77-biityl 4-[(2-methoxyethyl)amino]piperidine-l -carboxylate to yield benzyl 4-{[l-(tert-butoxycarbonyl)piperidin-4-yl](2-methoxyethyl)carbamoyl}-4-methylpiperidine-l-carboxylate (0.138 g, 18.76%). LCMS:C28H43N3O6 requires: 517.3, found: m / z = 540.4 [M+Na]+.Step 2: tert-butyl 4-[N-(2-methoxyethyl)-4-methylpiperidine-4-amido]piperidine-l-carboxylateTert-butyl 4-[N-(2-methoxyethyl)-4-methylpiperidine-4-amido]piperidine-l-carboxylate was synthesized as described for Example 132 step 2 (quantitative yield). LCMS: C20H37N3O4 requires: 383.3, found: m / z = 384.2 [M+H]+.Step 3: tert-butyl 4-[N-(2-methoxyethyl)-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methylpiperidine-4-amido]piperidine-l-carboxylateTert-butyl 4-[N-(2-methoxyethyl)-4-methylpiperidine-4-amido]piperidine-l-carboxylate (93.55 mg, 0.2439 mmol), 2-(5-chloropyridazin-3-yl)phenol (42.00 mg, 0.2033 mmol) and N, N-diisopropylethylamine (141.62 pL, 0.11 g, 0.8130 mmol) were dissolved in DMSO (1.00 mL) and stirred in an 100°C heating block. After 3h, the reaction was cooled and directly purified by RP-HPLC to yield tert-butyl 4-[N-(2-methoxyethyl)- 1 -[6-(2-hydroxyphenyl)pyridazin-4-yl] -4-methylpiperidine-4-amido]piperidine-l -carboxylate (0.108 g, 95.96%). LCMS: C30H43N5O5 requires: 553.3, found: m / z = 554.4 [M+H]+.219Step 4: l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(2-methoxyethyl)-4-methyl-N-(piperidin-4-yl)piperidine-4-carboxamidel-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(2-methoxyethyl)-4-methyl-N-(piperidin-4-yl)piperidine-4-carboxamide was prepared as described for Example 107 step 2. LCMS: C25H35N5O3 requires: 453.3, found: m / z = 454.2 [M+H]+.Step 5: Synthesis of the title compoundCombined 1 -[6-(2-hydroxyphenyl)pyridazin-4-yl] -N-(2-methoxyethyl)-4-methyl-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride (15.00 mg, 0.0306 mmol) and rac-2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]-3-fluorophenyl}piperidin-4-yl)acetaldehyde (11.19 mg, 0.0337 mmol) in DMA (0.30 mL) and then added sodium triacetoxyborohydride (9.73 mg, 0.0459 mmol) and stirred for 2h, then purified directly by RP-HPLC to yield rac-N-{l-[2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]-3-fluorophenyl}piperidin-4-yl)ethyl]piperidin-4-yl}-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(2-methoxyethyl)-4-methylpiperidine-4-carboxamide (0.0079 g, 33.05%). LCMS: C43H56FN7O5 requires: 769.4, found: m / z = 770.4 [M+H]+EXAMPLE 140N-CYCLOPROPYL-N-{l-[2-(l-{4-[(3R)-2,6-DIOXOPIPERIDIN-3-YL]PHENYL}PIPERIDIN-4- YL)ETHYL]PIPERIDIN-4-YL}-1-[6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL]-4-METHYLPIPERIDINE-4- CARBOXAMIDEStep 1: benzyl 4-{[l-(ter / -butoxycarbonyl)piperidin-4-yl](cyclopropyl)carbamoyl}-4-methylpiperidine-l-carboxylatebenzyl 4-{ [ 1 -(tert-butoxycarbony 1 )piperidin-4-y 1 ] (cyclopropyl)carbamoyl} -4-methylpiperidine- 1 -carboxylate was synthesized as described for Example 132 step 1, using l-[(benzyloxy)carbonyl]-4-methylpiperidine-4-carboxylic acid and / c77-biityl 4-(cyclopropylamino)piperidine-l -carboxylate to yield benzyl 4-{ [ 1 -(tert-butoxycarbony 1 )piperidin-4-y 1 ] (cyclopropyl)carbamoyl} -4-methylpiperidine- 1 -carboxylate (0.126 g, 18.02%). LCMS: C28H41N3O5 requires: 499.3, found: m / z = 522.4 [M+Na]+.220Step 2: tert-butyl 4-(N-cyclopropyl-4-methylpiperidine-4-amido)piperidine-l-carboxylateTert-butyl 4-(N-cyclopropyl-4-methylpiperidine-4-amido)piperidine- 1 -carboxylate was synthesized as described for Example 132 step 2 (quantitative yield). LCMS: C20H35N3O3 requires: 365.3, found: m / z = 366.4 [M+H]+.Step 3: tert-butyl 4-{N-cyclopropyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methylpiperidine-4-amido}piperidine-l-carboxylatetert-butyl 4-{N-cyclopropyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methylpiperidine-4-amido}piperidine-l -carboxylate was synthesized as described for Example 139 step 3, using tert-butyl 4-(N-cyclopropyl-4-methylpiperidine-4-amido)piperidine-l-carboxylate to yield tert-butyl 4-{N-cyclopropyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methylpiperidine-4-amido}piperidine-l-carboxylate (0.111 g, 101.94%). LCMS: C30H41N5O4 requires: 535.3, found: m / z = 536.4 [M+H]+.Step 4: N-cyclopropyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methyl-N-(piperidin-4-yl)piperidine-4-carboxamideN-cyclopropyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methyl-N-(piperidin-4-yl)piperidine-4-carboxamide was prepared as described for Example 107 step 2. LCMS: C25H33N5O2 requires: 435.3, found: m / z = 436.4 [M+H]+.Step 5: Synthesis of the title compoundThe title compound was synthesized as described for Example 109 step 3, using N-cyclopropyl-1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methyl-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)acetaldehyde to yield N-cyclopropyl-N-{l-[2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)ethyl]piperidin-4-yl}-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methylpiperidine-4-carboxamide (0.014 g, 59.99%). LCMS: C43H55N7O4 requires: 733.4, found: m / z = 734.3 [M+H]+221EXAMPLE 141RAC-N-CYCLOPROPYL-N-{l-[2-(l-{4-[(3R)-2,6-DIOXOPIPERIDIN-3-YL]PHENYL}-4- FLUOROPIPERIDIN-4- YL)ETHYL] PIPERIDIN-4- YL}- 1- [6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL] -4- METHYLPIPERIDINE-4-CARBOXAMIDEO HThe title compound was synthesized as described for Example 109 step 3, using N-cyclopropyl-1-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methyl-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride and rac-2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}-4-fluoropiperidin-4-yl)acetaldehyde to yield rac-N-cyclopropyl-N-{ l-[2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}-4-fluoropiperidin-4-yl)ethyl]piperidin-4-yl}-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methylpiperidine-4-carboxamide (0.0091 g, 35.49%). LCMS: C43H54FN7O4 requires: 751.4, found: m / z = 752.3 [M+H]+EXAMPLE 142N-{1-[2-(1-{4-[(3R)-2,6-DIOXOPIPERIDIN-3-YL]PHENYL}PIPERIDIN-4-YL)ETHYL]PIPERIDIN-4-YL}-1- [6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL]-N-(2-METHOXYETHYL)-4-METHYLPIPERIDINE-4- CARBOXAMIDEThe title compound was synthesized as described for Example 109 step 3, using l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(2-methoxyethyl)-4-methyl-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)acetaldehyde to yield N-{ l-[2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)ethyl]piperidin-4-yl}-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(2-methoxyethyl)-4-methylpiperidine-4-carboxamide (0.0039 g, 15.36%). LCMS: C43H57N7O5 requires: 751.4, found: m / z = 752.3 [M+H]+EXAMPLE 143RAC-(lR,5S,8S)-N-(CYCLOPROPYLMETHYL)-N-(l-(2-(l-(4-((R)-2,6-DIOXOPIPERIDIN-3-YL)-3- FLUOROPHENYL)PIPERIDIN-4-YL)ETHYL)PIPERIDIN-4-YL)-3-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-3-AZABICYCLO[3.2.1]OCTANE-8-CARBOXAMIDE222Step 1: Synthesis of the title compoundN-(cyclopropylmethyl)-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(piperidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxamide hydrochloride (8.00 mg, 0.0150 mmol) and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]-3-fluorophenyl}piperidin-4-yl)acetaldehyde (5.18 mg, 0.0165 mmol) were added to a vial and DMA (0.50 mL) was added. Sodium triacetoxyborohydride (9.52 mg, 0.0449 mmol) was then added the reaction was stirred at RT for 30 mins and checked by LCMS. Once complete, the reaction was directly purified by RP-FC to afford the title compound (9.1 mg, 72.3%) as a formate salt. LCMS:C45H56FN7O4 requires: 777.4, found: m / z = 778.3 [M+H]+EXAMPLE 144( / ?. S’)-A-(l-(2-( l-(4-(( / ?)-2,6-l)IOXOPIPI RII)IX-3-M.)PIII XY I.)PIPI RII)IX-4-M.)i riIM.)PIPI RII)IX-4-M.)- 3-FLUORO-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)- / V-METHYLPYRROLIDINE-3-CARBOXAMIDEStep 1: Synthesis of rac-(R)-3-fluoro-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-JV-methyl-JV-(piperidin- 4-yl)pyrrolidine-3-carboxamide hydrochlorideThe title compound was prepared as described for the synthesis of Example 1, Step 1, using rac-(R)-3-fluoro-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)pyrrolidine-3-carboxylic acid (Intermediate 28) and / c' / 7-butyl 4-(methylamino)piperidine-l -carboxylate to afford the title compound as a yellow oil. LCMS C21H26FN5O2 requires 399.2, found m / z = 400.2 [M+H]+.Step 2: Synthesis of the title compoundThe title compound was prepared as described for the synthesis of Example 2, Step 2 using rac-( / ?)-3-fliioro-l-(6-(2-hydroxyphcnyl)pyridazin-4-yl)- '-mcthyl- '-(pipcridin-4-yl)pyrrolidinc-3-carboxamide hydrochloride to afford the title compound (36.1 mgs, 42% yield) as a white solid. LCMS: C39H48FN7O4 requires: 697.4, found: m / z = 698.3 [M+H]+.EXAMPLE 145(3RS)-N-{l-[2-(l-{4-[(3R)-2,6-DIOXOPIPERIDIN-3-YL]PHENYL}PIPERIDIN-4-YL)ETHYL]PIPERIDIN-4- YL}-l-[6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL]-N,3-DIMETHYLPYRROLIDINE-3-CARBOXAMIDE223Step 1: rac-methyl (3R)-l-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-3-methylpyrrolidine-3-carboxylaterac-methyl (3R)-3-methylpyrrolidine-3-carboxylate (158.66 pL, 169.77 mg, 1.1857 mmol), 5-chloro-3-[2-(methoxymethoxy)phenyl]pyridazine (270.20 mg, 1.0779 mmol) andN, N-diisopropylethylamine (413.05 pL, 0.31 g, 2.3713 mmol) were dissolved in DMSO (2.00 mL) and stirred in an 80°C heating block overnight. Added more DIPEA (0.2 mL) and amine (53 pL) and heated to 100°C. Purified by RP-HPLC to yield rac-methyl (3R)-l-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-3-methylpyrrolidine-3-carboxylate (0.404 g, 79.51%). LCMS: C19H23N3O4 requires: 357.2, found: m / z = 358.2 [M+H]+.Step 2: rac-(3R)-l-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-3-methylpyrrolidine-3-carboxylic acidrac-methyl (3 R)- 1 - { 6- [2-(methoxymethoxy)phenyl] pyridazin-4-yl } -3 -methylpyrrolidine -3 -carboxylate (404.00 mg, 1.1304 mmol) was dissolved in THF (5.00 mL), then lithium hydroxide monohydrate (5.71 mL, 47.90 mg, 1.1417 mmol) was added and the reaction was stirred at rt. After Ih, added another 3 mg of Li OH and stirred overnight. THF was removed by rotovap and the remaining solution was lyophilized from 1: 1 ACN / water to give the Li salt. Quant yield. LCMS: C18H21N3O4 requires: 343.2, found: m / z = 344.2 [M+H]+.Step 3: rac-tert-butyl 4-[N-methyl(3R)-l-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-3-methylpyrrolidine-3-amido]piperidine-l-carboxylateRac-tert-butyl 4-[N-methyl(3R)-l-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-3-methylpyrrolidine-3-amido]piperidine-l -carboxylate was prepared as described for Example 107 step 1, using rac-(3R)- 1 - { 6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl } -3 -methylpyrrolidine-3 -carboxylic acid and tert-butyl 4-(methylamino)piperidine- 1 -carboxylate to yield rac-tert-butyl 4-[N-methyl(3R)-l-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-3-methylpyrrolidine-3-amido]piperidine-l-carboxylate (0.0737 g, 58.62%). LCMS: C29H41N5O5 requires: 539.3, found: m / z = 540.4 [M+H]+.224Step 4: rac-(3R)-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N,3-dimethyl-N-(piperidin-4-yl)pyrrolidine- 3-carboxamiderac-(3R)-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N,3-dimethyl-N-(piperidin-4-yl)pyrrolidine-3-carboxamide was prepared as described for Example 107 step 2. LCMS: C22H29N5O2 requires: 395.2, found: m / z = 396.2 [M+H]+.Step 5: Synthesis of the title compoundThe title compound was synthesized as described for Example 109 step 3, using rac-(3R)-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N,3-dimethyl-N-(piperidin-4-yl)pyrrolidine-3-carboxamide hydrochloride and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)acetaldehyde to yield (3RS)-N-{l-[2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)ethyl]piperidin-4-yl}-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N,3-dimethylpyrrolidine-3-carboxamide (0.0097 g, 54.54%). LCMS: C40H51N7O4 requires: 693.4, found: m / z = 694.4 [M+H]+EXAMPLE 146(1RS&,5SR&,8RS&)-N-{1-[2-(1-{4-[(3RS)-2,6-DIOXOPIPERIDIN-3-YL]-3,5- DIFLUOROPHENYL}PIPERIDIN-4- YL)E THYL] PI PE R ID I N-4- YL} -3- [6-(2-HYDROXYPHENYL)PYRIDAZIN- 4-YL]-N-(3-METHOXYPROPYL)-3-AZABICYCLO[3.2.1]OCTANE-8-CARBOXAMIDEOStep 1: tert-butyl 4-[N-(3-methoxypropyl)(lR,5S,8S)-3-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-3-azabicyclo[3.2.1]octane-8-amido]piperidine-l-carboxylateOTo a solution of (lR,5S,8S)-3-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-3-azabicyclo[3.2.1]octane-8-carboxylic acid (45.01 mg, 0.1218 mmol) in DMA (1.00 mL) was added tert-butyl 4-[(3-methoxypropyl)amino]piperidine-l-carboxylate (36.51 mg, 0.1340 mmol) and N, N-diisopropylethylamine (63.67 pL, 0.05 g, 0.3655 mmol). [(dimethylamino)({[l,2,3]triazolo[4,5-b]pyridin- 2253-yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (55.59 mg, 0.1462 mmol) was added. Stirred at rt for 2h, then added more HATU (55 mg) and stirred overnight. Purified directly by RP-HPLC to yield tert-butyl 4-[N-(3-methoxypropyl)(lR,5S,8S)-3-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl } -3 -azabicyclo [3.2.1 ] octane-8-amido]piperidine- 1 -carboxylate (0.068 g, 75.64%). LCMS: C34H49N5O6 requires: 623.4, found: m / z = 624.4 [M+H]+.Step 2: (lR,5S,8S)-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(3-methoxypropyl)-N-(piperidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxamideTert-butyl 4-[N-(3 -methoxypropyl)( lR,5S,8S)-3- { 6- [2-(methoxymethoxy)phenyl]pyridazin-4-yl}-3-azabicyclo[3.2.1]octane-8-amido]piperidine-l-carboxylate (68.00 mg, 0.1090 mmol) was dissolved in TFA (4.00 mb). After 90 min the reaction was concentrated down to an oil, then lyophilized from 1:1 water / ACN. Tris TFA salt based on a quantitative yield. LCMS: C27H37N5O3 requires: 479.3, found: m / z = 480.2 [M+H]+.Step: 3 Synthesis of the title compoundCombined ( 1 R,5 S, 8 S)-3 -[6-(2-hydroxyphenyl)pyridazin-4-yl] -N-(3 -methoxypropyl)-N -(piperidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxamide; tris(trifluoroacetic acid) (15.10 mg, 0.0184 mmol) and rac-2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]-3,5-difluorophenyl}piperidin-4-yl)acetaldehyde (6.76 mg, 0.0193 mmol) in DMA (0.40 mL) with N, N-diisopropylethylamine (9.63 pL, 0.01 g, 0.0551 mmol) and then added sodium triacetoxyborohydride (7.01 mg, 0.0331 mmol) and stirred for Ih. Purified the reaction directly by RP-HPLC to yield (lRS&,5SR&,8RS&)-N-{l-[2-(l-{4-[(3RS)-2,6-dioxopiperidin-3 -yl] -3,5 -difluorophenyl}piperidin-4-yl)ethyl]piperidin-4-yl } -3 - [6 -(2 -hydroxyphenyl)pyridazin-4-yl]-N-(3-methoxypropyl)-3-azabicyclo[3.

2. l]octane-8-carboxamide (0.0082 g, 50.38%). LCMS: C45H57F2N7O5 requires: 813.4, found: m / z = 814.4 [M+H]+EXAMPLE 147N-{l-[2-(l-{4-[(3R)-2,6-DIOXOPIPERIDIN-3-YL]-3-FLUOROPHENYL}PIPERIDIN-4- YL)ETHYL]PIPERIDIN-4-YL}-l-[6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL]-N-(2-ME THOXYETHYL)-4- METHYLPIPERIDINE-4-CARBOXAMIDE4.8mg of Example 139 was subjected to SFC chiral separation. Peak 2 is Example 147.226Name Yield(mg) Purity(%) Column Used Ex 139 pk 1 2.1 96.4 Whelk-01(R, R) Ex. 139 pk 2 2.1 97.6 Whelk-01(R, R)LCMS: C43H56FN7O5 requires: 769.4, found: m / z = 770.3 [M+H]+EXAMPLE 148(R)-N-CYCLOPROPYL-N-(l-(2-(l-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4- YL)ETHYL)PIPERIDIN-4-YL)-1-(6-(5-FLUORO-2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4- (METHOXYMETHYL)PIPERIDINE-4-CARBOXAMIDEStep 1: Synthesis of tert-butyl 4-(l-(6-chloropyridazin-4-yl)-N-cyclopropyl-4- (methoxymethyl)piperidine-4-carboxamido)piperidine-l-carboxylateBoctert-butyl 4-[N-cyclopropyl-4-(methoxymethyl)piperidine-4-amido]piperidine- 1 -carboxylate (220.00 mg, 0.5562 mmol) and 3,5-dichloropyridazine (82.86 mg, 0.5562 mmol) were dissolved in 3 mL DMSO under argon atmosphere. N, N -diisopropylethylamine (0.48 mL, 359.43 mg, 2.7810 mmol) was then added and the resulting solution was stirred at 100 °C overnight. The reaction was monitored via LCMS. Once complete, the reaction was concentrated to remove excess DIPEA and then quenched with H2O and extracted with EtOAc. The organic phases were combined, dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified on silica gel (EtOAc / hexanes gradient) to afford the desired product (188 mg, 66.5%) as a pink solid.Step 2: Synthesis of N-cyclopropyl-l-(6-(5-fluoro-2-hydroxyphenyl)pyridazin-4-yl)-4- (methoxymethyl)-N-(piperidin-4-yl)piperidine-4-carboxamideA flask was charged with tert-butyl 4-[N-cyclopropyl-l-(6-chloropyridazin-4-yl)-4-(methoxymethyl)piperidine-4-amido]piperidine-l -carboxylate (188.00 mg, 0.3700 mmol), potassium carbonate (153.42 mg, 1.1101 mmol), and 4-fluoro-2-hydroxyphenylboronic acid (57.70 mg, 0.3700227mmol). 1,4-Dioxane (3.75 mL) and Water (1.25 mL) were sequentially added to the flask. The resulting solution was degassed with an Argon balloon for 5 minutes and then tetrakis(triphenylphosphine)palladium(0) (42.76 mg, 0.0370 mmol) was added in one portion. The flask was sealed, and the resulting mixture was stirred at 100 °C for 18 h. Upon completion, the flask was diluted in DCM and sat. NH4C1 was added. The mixture was extracted 3x with DCM and the organic phases were dried over sodium sulfate, concentrated in vacuo and purified on silica gel to afford the BOC-protected product as a yellow solid. The obtained material was then dissolved in MeOH (1.0 mL) and 4M HC1 in dioxane (1.0 mL) was added in one portion. The resulting solution was stirred at RT for 1 hour and monitored via LCMS. Once complete, the reaction was concentrated in vacuo to afford the desired product (75 mg, 45.1%) as a tan solid. LCMS: C26H34FN5O3 requires: 483.2, found: m / z = 484.2 [M+H]+Step 3: Synthesis of the title compoundN-cyclopropyl-l-[6-(5-fluoro-2-hydroxyphenyl)pyridazin-4-yl]-4-(methoxymethyl)-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride (20.00 mg, 0.0385 mmol) was dissolved in MeCN (0.45 mL) and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)acetaldehyde (13.30 mg, 0.0423 mmol) was added in one portion. The flask was agitated and then MeOH (0.13 mL) was slowly added until all the solids have dissolved. Sodium triacetoxyborohydride (24.45 mg, 0.1154 mmol) was then added in one portion and the reaction was stirred at RT for 30 mins. After 30 mins, the reaction was checked by LCMS and the reaction mixture was dissolved in DCM and water was added. The reaction was extracted 3x with DCM and concentrated in vacuo. The residue was then purified by RP-FC to yield the title compound (29.2 mg, 57.57%) as a formate salt. LCMS: C44H56FN7O5 requires: 781.4, found: m / z = 782.3 [M+H]+EXAMPLE 149((R)-N-(l-(2-(l-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4-YL)ETHYL)PIPERIDIN-4-YL)-N- ETHYL-l-(6-(5-FLUORO-2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-(METHOXYMETHYL)PIPERIDINE-4- CARBOXAMIDEStep 1: Synthesis of tert-butyl 4-(l-(6-chloropyridazin-4-yl)-N-ethyl-4-(methoxymethyl)piperidine-4-carboxamido)piperidine-l-carboxylatetert-butyl 4-[N-ethyl-4-(methoxymethyl)piperidine-4-amido]piperidine-l-carboxylate (260.00 mg, 0.6779 mmol) and 3,5-dichloropyridazine (100.99 mg, 0.6779 mmol) were dissolved in 0.5M DMSO under argon atmosphere. N, N-diisopropylethylamine (0.59 mL, 438.09 mg, 3.3895 mmol) was then added228and the resulting solution was stirred at 100 °C overnight. The reaction was monitored via LCMS. Once complete, the reaction was concentrated to remove excess DIPEA and then quenched with H2O and extracted with EtOAc. The organic phases were combined, dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified on silica gel (EtOAc / hexanes gradient) to afford the desired product (217 mg, 64.5%) as an orange solid.Step 2: Synthesis of N-ethyl-l-(6-(5-fluoro-2-hydroxyphenyl)pyridazin-4-yl)-4-(methoxymethyl)-N-(piperidin-4-yl)piperidine-4-carboxamideA flask was charged with tert-butyl 4-[N-ethyl-l-(6-chloropyridazin-4-yl)-4-(methoxymethyl)piperidine-4-amido]piperidine-l -carboxylate (110.00 mg, 0.2218 mmol), potassium carbonate (91.94 mg, 0.6653 mmol), and 4-fhroro-2-hydroxyphenylboronic acid (34.58 mg, 0.2218 mmol). 1,4-Dioxane (2.50 mb) and Water (1.00 mL) were sequentially added to the flask. The resulting solution was degassed with an Argon balloon for 5 mins and then tetrakis(triphenylphosphine)palladium(0) (25.63 mg, 0.0222 mmol) was added in one portion. The flask was sealed, and the resulting mixture was stirred at 100 °C for 18 h. Upon completion, the flask was diluted in DCM and sat. NH4C1 was added. The mixture was extracted 3x with DCM and the organic phases were dried over sodium sulfate, concentrated in vacuo and purified on silica gel to afford the BOC-protected product as a yellow solid. The obtained material was then dissolved in MeOH (1.0 mL) and 4M HC1 in dioxane (1.0 mL) was added in one portion. The resulting solution was stirred at RT for 1 hour and monitored via LCMS. Once complete, the reaction was concentrated in vacuo to afford the desired product (66 mg) as atan solid. LCMS: C25H34FN5O3 requires: 471.2, found: m / z = 472.3 [M+H]+Step 3: Synthesis of the title compoundN-ethyl-l-[6-(5-fluoro-2-hydroxyphenyl)pyridazin-4-yl]-4-(methoxymethyl)-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride (20.00 mg, 0.0394 mmol) was dissolved in MeCN (0.45 mL) and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)acetaldehyde (13.61 mg, 0.0433 mmol) was added in one portion. The flask was agitated and then MeOH (0.13 mL) was slowly added until all the solids have dissolved. Sodium triacetoxyborohydride (25.03 mg, 0.1181 mmol) was then added in one portion and the reaction was stirred at RT for 30 mins. After 30 mins, the reaction was checked by LCMS and the reaction mixture was dissolved in DCM and water was added. The reaction was extracted 3x with DCM and concentrated in vacuo. The residue was then purified by RP-LC to yield the title compound (9.5 mg, 29.5%) as a formate salt. LCMS: C43H56FN7O5 requires: 769.4, found: m / z = 770.3 [M+H]+229EXAMPLE 150(lRS,5SR,8RS)-N-{l-[2-(l-{4-[(3R)-2,6-DIOXOPIPERIDIN-3-YL]-3-FLUOROPHENYL}PIPERIDIN-4- YL)ETHYL]PIPERIDIN-4-YL}-3-[6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL]-N-(3-METHOXYPROPYL)-3- AZABICYCLO[3.2.1]OCTANE-8-CARBOXAMIDECombined ( 1 R,5 S, 8 S)-3 -[6-(2-hydroxyphenyl)pyridazin-4-yl] -N-(3 -methoxypropyl)-N -(piperidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxamide; tris(trifluoroacetic acid) (15.10 mg, 0.0184 mmol) and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]-3-fluorophenyl}piperidin-4-yl)acetaldehyde (6.41 mg, 0.0193 mmol) in DMA (0.40 mL) with N, N-diisopropylethylamine (9.63 pL, 0.01 g, 0.0551 mmol) and then added sodium triacetoxyborohydride (7.01 mg, 0.0331 mmol) and stirred for Ih. Purified the reaction directly by RP-HPLC (lRS,5SR,8RS)-N-{l-[2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]-3-fluorophenyl}piperidin-4-yl)ethyl]piperidin-4-yl}-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(3-methoxypropyl)-3-azabicyclo[3.2.1]octane-8-carboxamide (0.0086 g, 53.41%). LCMS: C45H58FN7O5 requires: 795.4, found: m / z = 796.3 [M+H]+EXAMPLE 151(R)-N-(l-(2-(l-(5-(2,6-DIOXOPIPERIDIN-3-YL)PYRIDIN-2-YL)PIPERIDIN-4-YL)ETHYL)PIPERIDIN-4-YL)- N-ETHYL-1-(6-(5-FLUORO-2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-(METHOXYMETHYL)PIPERIDINE- 4-CARBOXAMIDEStep 1: Synthesis of the title compoundN-ethyl-l-[6-(5-fluoro-2-hydroxyphenyl)pyridazin-4-yl]-4-(methoxymethyl)-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride (10.00 mg, 0.0192 mmol) was dissolved in DMA (1.00 mL) and rac-2-(l-{5-[(3R)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)acetaldehyde (6.39 mg, 0.0192 mmol) was added in one portion. N, N-diisopropylethylamine (12.43 mg, 0.0961 mmol) was then added followed by sodium triacetoxyborohydride (12.23 mg, 0.0577 mmol). The resulting reaction was stirred at RT for 1 hour and monitored via LCMS. Once complete, the reaction was concentrated in vacuo and purified via RP-FC to afford the title compound (2.3 mg, 14.3%) as a formate salt. LCMS: C42H55FN8O5 requires: 770.4, found: m / z = 771.4 [M+H]+230EXAMPLE 152(R)-A-(1-(2-(1-(4-((R)-2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4-YL)ETHYL)PIPERIDIN-4-YL)- 3-FLUORO-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-A-METHYLPYRROLIDINE-3-CARBOXAMIDEStep 1: Synthesis of the title compound(RS)-N-( 1 -(2-( 1 -(4-(( / ?)-2.6-dioxopi peridi n-3 -yl)phenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-3 -fluoro- l-(6-(2-hydroxyphenyl)pyridazin-4-yl)- / V-methylpyrrolidine-3 -carboxamide (Example 144, 36.1 mgs, 0.052 mmol) was subjected to SFC chromatography (first-eluting isomer, RT = 3.32 min, ChiralPak IH, EtOH + 60ACN + 0.1%NH4OH) to afford the title compound (15.1 mgs, 42% yield) as a white solid. LCMS: C39H48FN7O4requires: 697.4, found: m / z = 698.3 [M+H]+.EXAMPLE 153(lR,5S,8R)-N-{l-[2-(l-{4-[(3R)-2,6-DIOXOPIPERIDIN-3-YL]PHENYL}PIPERIDIN-4- YL)ETHYL]PIPERIDIN-4- YL}-N-ETHYL-3-[6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL]-3- AZABICYCLO[3.2.1]OCTANE-8-CARBOXAMIDEStep 1: methyl (lR,5S,8S)-3- {6- [2-(meth oxymeth oxy)phenyl]pyridazin-4-yl}-3-azabicyclo[3.2.1]octane-8-carboxylateMethyl (lR,5S,8R)-3-azabicyclo[3.2.1]octane-8-carboxylate hydrochloride (492.29 mg, 2.3935 mmol), 5-chloro-3-[2-(methoxymethoxy)phenyl]pyridazine (400.00 mg, 1.5957 mmol) andN, N-diisopropylethylamine (833.83 pL, 0.62 g, 4.7870 mmol) were dissolved in DMSO (5.00 mL) and stirred in an 80°C heating block overnight. Added more DIPEA (0.2 mL) and amine (53 pL) and heated to 100°C and then purified by RP-HPLC to yield methyl (lR,5S,8S)-3-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-3-azabicyclo[3.2.1]octane-8-carboxylate (0.482 g, 60.72%). LCMS: C21H25N3O4 requires: 383.2, found: m / z = 384.2 [M+H]+.231Step 2: (lR,5S,8S)-3- {6- [2-(meth oxymeth oxy)phenyl]pyridazin-4-yl}-3-azabicyclo [3.2.1] octane-8-carboxylic acidmethyl (lR,5S,8S)-3-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-3-azabicyclo[3.2.1]octane-8-carboxylate (482.00 mg, 1.2570 mmol) was dissolved in THF (6.00 mL) and 0.2 M lithium hydroxide monohydrate (6.29 mL, 52.74 mg, 1.2570 mmol). After an hour more 0.2 M lithium hydroxide monohydrate (6.29 mL, 52.74 mg, 1.2570 mmol) was added. After another hour, the THF was removed and the solution was frozen and lyo'd. Quant yield. LCMS: C20H23N3O4 requires: 369.2, found: m / z = 370.2 [M+H]+.Step 3: tert-butyl 4-[N-ethyl(lR,5S,8S)-3-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-3-azabicyclo[3.2.1]octane-8-amido]piperidine-l-carboxylateTo a solution of (lR,5S,8S)-3-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-3-azabicyclo[3.2.1]octane-8-carboxylic acid (150.50 mg, 0.4074 mmol) in DMA (1.00 mL) was added tert-butyl 4-(ethylamino)piperidine- 1 -carboxylate (139.53 mg, 0.6111 mmol) andN, N-diisopropylethylamine (212.89 pL, 0.16 g, 1.2222 mmol). [(dimethylamino)({[l,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (185.89 mg, 0.4889 mmol) was added and the reaction was stirred at rt for 2h. Purified directly by RP-HPLC to yield tert-butyl 4-[N-ethyl( 1 R,5 S, 8 S)-3 - { 6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl } -3 -azabicyclo[3.2.1]octane-8-amido]piperidine-l-carboxylate (0.127 g, 44.93%). LCMS: C32H45N5O5 requires: 579.3, found: m / z = 580.4 [M+H]+.Step 4: (lR,5S,8S)-N-ethyl-3- [6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(piperidin-4-yl)-3-azabicyclo [3.2.1] octane-8-carboxamide(lR,5S,8S)-N-ethyl-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(piperidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxamide was prepared as described for Example 107 step 2. LCMS: C25H33N5O2 requires: 435.3, found: m / z = 436.2 [M+H]+.232Step 5: Synthesis of the title compoundCombined (lR,5S,8S)-N-ethyl-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(piperidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxamide hydrochloride (12.00 mg, 0.0254 mmol) and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)acetaldehyde (8.79 mg, 0.0280 mmol) in DMA (0.30 mL) and then added N, N-diisopropylethylamine (13.32 pL, 0.01 g, 0.0763 mmol) and sodium triacetoxyborohydride (8.08 mg, 0.0381 mmol) and stirred for 2h, then purified directly by RP-HPLC to yield (lR,5S,8R)-N-{l-[2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)ethyl]piperidin-4-yl}-N-ethyl-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-3-azabicyclo[3.2.1]octane-8-carboxamide (0.014 g, 70.18%). LCMS: C43H55N7O4requires: 733.4, found: m / z = 734.2 [M+H]+EXAMPLE 154(1R,5S,8R)-N- {1- [2-(l-{4- [(3RS)-2,6-DIOXOPIPERIDIN-3-YL] -3-FLUOROPHENYL}PIPERIDIN-4- YL)ETHYL]PIPERIDIN-4- YL}-N-ETHYL-3-[6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL]-3- AZABICYCLO[3.2.1]OCTANE-8-CARBOXAMIDEThe title compound was synthesized as described for Example 153 step 5, using rac-2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]-3-fluorophenyl}piperidin-4-yl)acetaldehyde to yield (lR,5S,8R)-N-{ l-[2-(l-{4-[(3RS)-2,6-dioxopiperidin-3-yl]-3-fluorophenyl}piperidin-4-yl)ethyl]piperidin-4-yl}-N-ethyl-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-3-azabicyclo[3.2.1]octane-8-carboxamide (0.0146 g, 70.96%). LCMS: C43H54FN7O4 requires: 751.4, found: m / z = 752.2 [M+H]+EXAMPLE 155(. S’)-A-(l-(2-( l-(4-(( / ?)-2,6-l)IOXOPIPI RII)IX-3-M.)-3-I I.l ()ROPIII XM.)PIPI RII)IX-4- YL)ETHYL)PIPERIDIN-4-YL)-3-FLUORO-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-A- METHYLPYRROLIDINE-3-CARBOXAMIDEStep 1: Synthesis of the title compoundThe title compound was prepared as described for the synthesis of Example 1, Step 2, using rac-(R)-3-fluoro-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-A-methyl-A-(piperidin-4-yl)pyrrolidine-3-carboxamide hydrochloride (Example 144, Step 1). After RP-HPLC, the compound was subjected to two stages of SFC purification (Whelk-Ol (R, R), EtOH + 60ACN + 0.1%NH4OH followed by Chiralpak IBN, EtOH + 60ACN + 0.1% NH4OH) to afford the title compound (Peak 1 after Stage 2 SFC, RT = 3.92233min, 11.6 mgs, 10% yield) as a white solid. Assignment of absolute stereochemistry is arbitrary. LCMS C39H47F2N7O4 requires 715.4, found m / z = 716.4 [M+H]+.EXAMPLE 156(lR,5S,8R)-N-{l-[2-(l-{4-[(3R)-2,6-DIOXOPIPERIDIN-3-YL]PHENYL}PIPERIDIN-4- YL)ETHYL] PIPERIDIN-4- YL}-3- [6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL] -N- ME THYL-3- AZABICYCLO[3.2.1]OCTANE-8-CARBOXAMIDEStep 1: tert-butyl 4-[N-methyl(lR,5S,8S)-3-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-3-azabicyclo[3.2.1]octane-8-amido]piperidine-l-carboxylateTert-butyl 4- [N-methyl( 1 R,5 S, 8 S)-3 - { 6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl } -3 -azabicyclo[3.2.1]octane-8-amido]piperidine-l-carboxylate was synthesized as described for Example 153 step 3, using (lR,5S,8S)-3-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-3-azabicyclo[3.

2. l]octane-8-carboxylic acid and tert-butyl 4-(methylamino)piperidine- 1 -carboxylate to yield tert-butyl 4-[N-methyl(lR,5S,8S)-3-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-3-azabicyclo[3.2.1]octane-8-amido]piperidine-l -carboxylate (0.0509 g, 55.40%). LCMS: C31H43N5O5 requires: 565.3, found: m / z = 566.4 [M+H]+.Step 2: (lR,5S,8S)-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-methyl-N-(piperidin-4-yl)-3-azabicyclo [3.2.1] octane-8-carboxamide(lR,5S,8S)-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-methyl-N-(piperidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxamide was prepared as described for Example 107 step 2. LCMS: C24H31N5O2 requires: 421.2, found: m / z = 422.2 [M+H]+.Step 3: Synthesis of the title compoundThe title compound was synthesized as described for Example 153 step 5, using (lR,5S,8S)-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-methyl-N-(piperidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxamide hydrochloride and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)acetaldehyde to yield234(lR,5S,8R)-N-{l-[2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)ethyl]piperidin-4-yl}-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-methyl-3-azabicyclo[3.

2. l]octane-8-carboxamide (0.0064 g, 38.27%). LCMS: C42H53N7O4requires: 719.4, found: m / z = 720.2 [M+H]+EXAMPLE 157(R)-W-(1-(2-(1-(4-((R)-2,6-DIOXOPIPERIDIN-3-YL)-3-FLUOROPHENYL)PIPERIDIN-4- YL)ETHYL)PIPERIDIN-4-YL)-3-FLUORO-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YI.)-V- METHYLPYRROLIDINE-3-CARBOXAMIDEThe title compound was prepared as described for the synthesis of Example 1, Step 2, using rac-(R)-3-fluoro-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-JV-methyl-jV-(piperidin-4-yl)pyrrolidine-3-carboxamide hydrochloride (Example 144, Step 1). After RP-HPLC, the compound was subjected to two stages of SFC purification (Whelk-Ol (R, R), EtOH + 60ACN + 0.1%NH4OH followed by Chiralpak IBN, EtOH + 60ACN + 0.1% NH4OH) to afford the title compound (Peak 1 after Stage 2 SFC, RT = 3.99 min, 10.8 mgs, 9% yield) as a white solid. Assignment of absolute stereochemistry is arbitrary. LCMS C39H47F2N7O4 requires 715.4, found m / z = 716.4 [M+H]+.EXAMPLE 158(1R,5S,8R)-N- {1- [2-(l-{4- [(3RS)-2,6-DIOXOPIPERIDIN-3-YL] -3-FLUOROPHENYL}PIPERIDIN-4- YL)ETHYL] PIPERIDIN-4- YL}-3- [6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL] -N- ME THYL-3- AZABICYCLO[3.2.1]OCTANE-8-CARBOXAMIDEThe title compound was synthesized as described for Example 153 step 5, using (lR,5S,8S)-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-methyl-N-(piperidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxamide hydrochloride and rac-2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]-3-fluorophenyl}piperidin-4-yl)acetaldehyde to yield (lR,5S,8R)-N-{l-[2-(l-{4-[(3RS)-2,6-dioxopiperidin-3-yl]-3-fhiorophenyl}piperidin-4-yl)ethyl]piperidin-4-yl}-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-methyl-3-azabicyclo[3.2.1]octane-8-carboxamide (0.0118 g, 67.70%). LCMS: C42H52FN7O4 requires: 737.4, found: m / z = 738.2 [M+H]+235EXAMPLE 159(X)-A-(l-(2-(l-(4-((X)-2,6-DIOXOPIPERIDIN-3-YL)-3,5-DIFLUOROPHENYL)PIPERIDIN-4- YL)ETHYL)PIPERIDIN-4-YL)-3-FLUORO-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- M.)-A- METHYLPYRROLIDINE-3-CARBOXAMIDEStep 1: Synthesis of the title compoundThe title compound was prepared as described for the synthesis of Example 1, Step 2, using rac-( / ?)-3-fliioro-l-(6-(2-hydroxyphcnyl)pyridazin-4-yl)-A'-mcthyl-A'-(pipcridin-4-yl)pyrrolidinc-3-carboxamide hydrochloride (Example 144, Step 1) and rac-(R)-2-(l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidin-4-yl)acetaldehyde. After RP-HPLC, the compound was subjected to two stages of SFC purification (Chiralpak IH, EtOH + 60ACN + 0.1% NH4OH followed by Chiralpak IBN, EtOH + 60ACN + 0.1% NH4OH) to afford the title compound (Peak 1 after Stage 2 SFC, RT = 2.98 min, 10.9 mgs, 9% yield) as a white solid. Assignment of absolute stereochemistry is arbitrary. LCMS C39H46F3N7O4 requires 733.4, found m / z = 734.4 [M+H]+.EXAMPLE 160(7?)-A-(l-(2-(l-(4-((X)-2,6-DIOXOPIPERIDIN-3-YL)-3,5-DIFLUOROPHENYL)PIPERIDIN-4- YL)ETHYL)PIPERIDIN-4-YL)-3-FLUORO-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- M.)-A- METHYLPYRROLIDINE-3-CARBOXAMIDEStep 1: Synthesis of the title compoundThe title compound was prepared as described for the synthesis of Example 1, Step 2, using rac-( / ?)-3-fliioro-l-(6-(2-hydroxyphcnyl)pyridazin-4-yl)-A'-mcthyl-A'-(pipcridin-4-yl)pyrrolidinc-3-carboxamide hydrochloride (Example 144, Step 1) and rac-(R)-2-(l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidin-4-yl)acetaldehyde. After RP-HPLC, the compound was subjected to SFC purification (Chiralpak IH, EtOH + 60ACN + 0.1% NH4OH to afford the title compound (third peak after SFC, RT = 6.37 min, 11.5 mgs, 9% yield) as a white solid. Assignment of absolute stereochemistry is arbitrary. LCMS C39H46F3N7O4 requires 733.4, found m / z = 734.4 [M+H]+.236EXAMPLE 161( / . S')-A-(A( I. OPROPM.-A-(1-(2-(1-(4-(( / )-2,6-I)IOXOPIPI RII)IX-3-M.)PIII XY I.)PIPI RII)IX-4- YL)ETHYL)PIPERIDIN-4-YL)-3-FLUORO-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)PYRROLIDINE-3- CARBOXAMIDEStep 1: Synthesis of rac-( / ?)-A cyclopropyl-3-fluoro-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-A (piperidin-4-yl)pyrrolidine-3-carboxamide hydrochlorideThe title compound was prepared as described for the synthesis of Example 1, Step 1, using rac-(J?)-3-fluoro-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)pyrrolidine-3-carboxylic acid (Intermediate 28) and / c / 7-butyl 4-(cyclopropylamino)piperidine-l -carboxylate to afford the title compound as a yellow oil. LCMS C23H28FN5O2 requires 425.2, found m / z = 426.2 [M+H]+.Step 2: Synthesis of the title compoundThe title compound was prepared as described for the synthesis of Example 2, Step 2, using Synthesis of rac-( / ?)- '-cyclopropyl-3-fliioro- l-(6-(2-hydroxyphcnyl)pyridazin-4-yl)-A'-(pipcridin-4-yl)pyrrolidinc-3-carboxamide hydrochloride (Example 161, Step 1) to afford the title compound (6.5 mgs, 7% yield), as a white solid. LCMS: C41H50FN7O4 requires: 723.4, found: m / z = 724.4 [M+H]+.EXAMPLE 162(1R,5S,8R)-N- {1- [2-(l-{4- [(3RS)-2,6-DIOXOPIPERIDIN-3-YL] -3-FLUOROPHENYL}PIPERIDIN-4- YL)ETHYL]PIPERIDIN-4-YL}-3-[6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL]-N-(2-METHOXYETHYL)-3- AZABICYCLO[3.2.1]OCTANE-8-CARBOXAMIDEStep 1: tert-butyl 4-[N-(2-methoxyethyl)(lR,5S,8S)-3-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-3-azabicyclo[3.2.1]octane-8-amido]piperidine-l-carboxylatetert-butyl 4-[N-(2-methoxyethyl)( lR,5S,8S)-3- { 6- [2-(methoxymethoxy)phenyl]pyridazin-4-yl } -3-azabicyclo[3.2.1]octane-8-amido]piperidine-l-carboxylate was synthesized as described for Example 153 step 3, using (lR,5S,8S)-3-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-3-azabicyclo[3.2.1]octane-8-carboxylic acid and tert-butyl 4-[(2-methoxyethyl)amino]piperidine-l-carboxylate to yield tert-butyl 4-[N-(2-methoxyethyl)(lR,5S,8S)-3-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl } -3 -azabicyclo [3.2.1 ] octane-8-amido]piperidine- 1 -carboxylate (0.0253 g, 32.28%). LCMS: C33H47N5O6 requires: 609.4, found: m / z = 610.2 [M+H]+.Step 2: (lR,5S,8S)-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(2-methoxyethyl)-N-(piperidin-4-yl)-3-azabicyclo [3.2.1] octane-8-carboxamide( 1 R,5 S,8 S)-3 -[6-(2-hydroxyphenyl)pyridazin-4-yl] -N-(2-methoxyethyl)-N -(piperidin-4-yl)-3 -azabicyclo[3.2.1]octane-8-carboxamide was prepared as described for Example 107 step 2. LCMS: C26H35N5O3 requires: 465.3, found: m / z = 466.2 [M+H]+.Step 3: Synthesis of the title compoundThe title compound was synthesized as described for Example 153 step 5, using (lR,5S,8S)-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(2-methoxyethyl)-N-(piperidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxamide hydrochloride and rac-2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]-3-fluorophenyl}piperidin-4-yl)acetaldehyde to yield (lR,5S,8R)-N-{l-[2-(l-{4-[(3RS)-2,6-dioxopiperidin-3-yl]-3-fhrorophenyl}piperidin-4-yl)ethyl]piperidin-4-yl}-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(2-methoxyethyl)-3-azabicyclo[3.2.1]octane-8-carboxamide (0.0055 g, 36.50%). LCMS: C44H56FN7O5 requires: 781.4, found: m / z = 782.2 [M+H]+238EXAMPLE 163(lR,5S,6S)-N-{l-[2-(l-{l-[(3RS)-2,6-DIOXOPIPERIDIN-3-YL]-3-METHYL-2-OXO-2,3-DIHYDRO-lH-l,3- BENZODIAZOL-4-YL}PIPERIDIN-4-YL)ETHYL]PIPERIDIN-4-YL}-N-ETHYL-3-[6-(2- HYDROXYPHENYL)PYRID AZIN-4- YL] -3- AZABIC YCLO [3.1.1] HEPTANE-6-C A R BOX A M I D EStep 1: methyl 3-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-3-azabicyclo[3.1.1]heptane-6-carboxylateMethyl 3-azabicyclo[3.1.1]heptane-6-carboxylate hydrochloride (481.67 mg, 2.5132 mmol), 5-chloro-3-[2-(methoxymethoxy)phenyl]pyridazine (420.00 mg, 1.6754 mmol) andN, N-diisopropylethylamine (875.52 pL, 0.65 g, 5.0263 mmol) were dissolved in DMSO (5.00 mL) and stirred in an 80°C heating block overnight. Added more DIPEA (0.2 mL) and amine (53 pL) and heated to 100°C. Purified by RP-HPLC to yield methyl 3-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-3-azabicyclo[3.1.1]heptane-6-carboxylate (0.589 g, 72.72%). C20H23N3O4 requires: 369.2, found: m / z = 370.2 [M+H]+.Step 2: 3-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-3-azabicyclo[3.1.1]heptane-6-carboxylic acidDissolved methyl 3 - { 6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl } -3 -azabicyclo [3.1.1 ]heptane-6-carboxylate (589.00 mg, 1.5944 mmol) in THF (8.00 mL) and added 0.2 M LiOH (8.77 mL, 73.59 mg, 1.7538 mmol). Added more LiOH 0.2 M LiOH (8.77 mL, 73.59 mg, 1.7538 mmol). After another hour, the THF was removed and the solution was frozen and lyophilized (quantitative yield). LCMS:C19H21N3O4 requires: 355.2, found: m / z = 356.2 [M+H]+.239Step 3: tert-butyl 4-((lR,5S,6s)-N-ethyl-3-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamido)piperidine-l-carboxylateTo a solution of 3-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-3-azabicyclo[3.1.1]heptane-6-carboxylic acid (201.00 mg, 0.5656 mmol) in DMA (1.00 mL) was added tert-butyl 4-(ethylamino)piperidine-l -carboxylate (193.71 mg, 0.8484 mmol) and N, N-diisopropylethylamine (295.55 pL, 0.22 g, 1.6967 mmol). [(dimethylamino)({[l,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (258.06 mg, 0.6787 mmol) was added and the reaction was stirred at rt for 2h. Purified directly by RP-HPLC followed by chiral SFC separation to yield the later eluting peak tert-butyl 4-((lR,5S,6s)-N-ethyl-3-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamido)piperidine-l-carboxylate (0.052 g, 13.53%). LCMS: C31H43N5O5 requires: 565.3, found: m / z = 566.4 [M+H]+. The later eluting peak was carried forward to the next step and stereochemistry was assigned arbitrarily. Step 4: (lR,5S,6s)-N-ethyl-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(piperidin-4-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide(lR,5S,6s)-N-ethyl-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(piperidin-4-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide was prepared as described for Example 107 step 2. LCMS: C24H31N5O2 requires: 421.2, found: m / z = 422.2 [M+H]+.Step 5: Synthesis of the title compoundThe title compound was synthesized as described for Example 153 step 5, using (lR,5S,6s)-N-ethyl-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(piperidin-4-yl)-3-azabicyclo[3.

1. l]heptane-6-carboxamide hydrochloride and rac-2-(l-{l-[(3R)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-l,3-benzodiazol-4-yl}piperidin-4-yl)acetaldehyde to yield (lR,5S,6s)-N-{l-[2-(l-{l-[(3RS)-2,6-dioxopiperidin-3 -yl] -3 -methyl-2-oxo- 1,3 -benzodiazol-4-yl }piperidin-4-yl)ethyl]piperidin-4-yl } -N-ethyl-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-3-azabicyclo[3.

1. l]heptane-6-carboxamide (0.0041 g, 65.87%). LCMS: C44H55N9O5 requires: 789.4, found: m / z = 790.2 [M+H]+240EXAMPLE 164RAC-(3R)-3-(2,6-DIFLUORO-4-(4-(2-(4-(3-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-3, 8- DIAZABICYCLO[3.2.1]OCTANE-8-CARBONYL)PIPERIDIN-l-YL)ETHYL)PIPERIDIN-l- YL)PHENYL)PIPERIDINE-2, 6-DIONEStep 1: Synthesis of 3-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-3,8-diazabicyclo [3.2.1] octanetert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400.00 mg, 1.8842 mmol) and 5-chloro-3-[2-(methoxymethoxy)phenyl]pyridazine (472.33 mg, 1.8842 mmol) were dissolved in 6 mL DMSO under argon atmosphere. N, N-diisopropylethylamine (1.65 mL, 1217.63 mg, 9.4209 mmol) was then added and the resulting solution was stirred at 100 °C overnight. The reaction was monitored via LCMS. Once complete, the reaction was concentrated to remove excess DIPEA and then quenched with H2O and extracted with DCM. The organic phases were combined, dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified on silica gel (MeOH: DCM gradient) to afford the desired BOC-protected product (267 mg) as a yellow foam. The product was then dissolved in 2 mL MeOH and 4M HC1 in dioxane (2 mL) was added in one portion. The reaction was monitored via LCMS and once complete, the mixture was concentrated in vacuo to afford the desired compound (220 mg, 35.5%) as a red oil.Step 2: Synthesis of (3-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(piperidin-4-yl)methanone2-(5-{3,8-diazabicyclo[3.2.1]octan-3-yl}pyridazin-3-yl)phenol (220.00 mg, 0.7792 mmol) was dissolved in DMA (2.00 mL) and l-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (178.65 mg, 0.7792 mmol) and N, N-diisopropylethylamine (0.41 mL, 302.12 mg, 2.3375 mmol) were added241sequentially. [(dimethylamino)({[l,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda5-phosphanuide (444.41 mg, 1.1688 mmol) was then added and the reaction was stirred at RT and monitored via LCMS. Once complete, the reaction was diluted with water and extracted with EtOAc 3x. The organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified on silica gel to afford the desired product (172 mg) as an orange oil. The material was then dissolved in 2.0 mL MeOH and 4M HC1 in dioxane (2.0 mL) was added in one portion. The resulting solution was stirred at RT for 1 hour and monitored via LCMS. Once complete, the reaction was concentrated in vacuo to afford the desired product (240 mg) as a brown solid.Step 3: Synthesis of the title compound2-{5-[8-(piperidine-4-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyridazin-3-yl}phenol (8.00 mg, 0.0203 mmol) was dissolved in DMA (1.00 mL) and rac-2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]-3,5-difluorophenyl}piperidin-4-yl)acetaldehyde (6.11 mg, 0.0203 mmol) was added in one portion. N, N-diisopropylethylamine (0.02 mL, 13.14 mg, 0.1017 mmol) was then added followed by sodium triacetoxyborohydride (12.93 mg, 0.0610 mmol). The resulting reaction was stirred at RT for 1 hour and monitored via LCMS. Once complete, the reaction was concentrated in vacuo and purified via RP-LC to afford the title compound (2.3 mg, 14.3%) as a trifluoroacetate salt. LCMS: C40H47F2N7O4 requires: 727.4, found: m / z = 728.1 [M+H]+EXAMPLE 165(R)-N-(l-(2-(l-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4-YL)ETHYL)PIPERIDIN-4-YL)-N- ETHYL-4-FLUORO-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)PIPERIDINE-4-CARBOXAMIDEStep 1: Synthesis of benzyl 4-(N-ethyl-4-fluoropiperidine-4-carboxamido)piperidine-l-carboxylateThe title compound was prepared as described for Example 92, Step 1, using l-(tert-butoxycarbonyl)-4-fluoropiperidine-4-carboxylic acid and benzyl 4-(ethylamino)piperidine-l -carboxylate to afford the desired product as a colorless oil. LCMS: C21H30FN3O3 requires 391.2, found: m / z = 392.2 [M+H]+.242Step 2: Synthesis of benzyl 4-(N-ethyl-4-fluoro-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)piperidine-4-carboxamido)piperidine-l-carboxylateThe title compound was prepared as described for Example 128, Step 3, using 5-chloro-3-(2-(methoxymethoxy)phenyl)pyridazine and benzyl 4-(N-ethyl-4-fluoropiperidine-4-carboxamido)piperidine- 1 -carboxylate to afford the desired product as a yellow foam. LCMS:C31H36FN5O4 requires 561.3, found: m / z = 562.2 [M+H]+.Step 3: Synthesis of N-ethyl-4-fluoro-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-N-(piperidin-4-yl)piperidine-4-carboxamideTo a round bottom flask containing palladium (301.21 mg, 0.28 mmol) and EtOH (4.00 mL) was added benzyl 4-{N-ethyl-4-fluoro-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]piperidine-4-amido}piperidine-1-carboxylate (310.00 mg, 0.57 mmol) dissolved in THF (4.00 mL). The flask was fitted with a three-way adapter and a hydrogen balloon. The atmosphere was changed to hydrogen, and the reaction was stirred at room temperature until complete by LCMS. Then, the crude product was filtered through a plug of celite, and the solvent was removed under reduced pressure to afford the desired product as a yellow oil (206 mg, 85%). LCMS: C23H30FN5O2 requires 427.2, found: m / z = 428.2 [M+H]+.Step 4: Synthesis of the title compoundThe title compound was prepared as described for Example 1, Step 2, using N-ethyl-4-fluoro-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-N-(piperidin-4-yl)piperidine-4-carboxamide and (R)-2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)acetaldehyde to afford the title compound (19.7 mg, 53%). LCMS: C41H52FN7O4requires 725.4, found: m / z = 726.4 [M+H]+.243EXAMPLE 166RAC-(lR,5S,8S)-N-(l-(2-(l-(l-((R)-2,6-DIOXOPIPERIDIN-3-YL)-3-METHYL-2-OXO-2,3-DIHYDRO-lH- BENZO[D]IMIDAZOL-4-YL)PIPERIDIN-4-YL)ETHYL)PIPERIDIN-4-YL)-3-(6-(2- HYDROXYPHENYL)PYRID AZIN-4- YL)-N-(2, 2,2- TRIFLUOROETHYL)-3-AZABICYCLO[3.2.1]OCTANE-8- CARBOXAMIDEStep 1: Synthesis of (lR,5S,8s)-3-(6-(2-hydroxyphenyl)pyridazin-4-yl)-N-(piperidin-4-yl)-N-(2,2,2-trifluoroethyl)-3-azabicyclo [3.2.1] octane-8-carboxamideThe title compound was prepared as described for Example 89, Step 1, using tert-butyl (R)-4- (sec-butylamino)piperidine-l -carboxylate to afford the desired product as a dark yellow solid. LCMS: C25H30F3N5O2 requires 489.2, found: m / z = 490.2 [M+H]+.Step 3: Synthesis of the title compoundThe title compound was prepared as described for Example 1, Step 2, using (lR,5S,8s)-3-(6-(2-hydroxyphenyl)pyridazin-4-yl)-N-(piperidin-4-yl)-N-(2,2,2-trifluoroethyl)-3-azabicyclo[3.2.1]octane-8-carboxamide and rac-(R)-2-(l-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-4-yl)acetaldehyde to afford the title compound (7.4 mg, 28%). LCMS: C45H54F3N9O5 requires 857.4, found: m / z = 858.3 [M+H]+.244EXAMPLE 167A(3RS)-3-CYCLOBUTOXY-N-{l-[2-(l-{4-[(3R)-2,6-DIOXOPIPERIDIN-3-YL]PHENYL}PIPERIDIN-4- YL)ETHYL]PIPERIDIN-4- YL}-l-[6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL]-N-METHYLPYRROLIDINE-3- CARBOXAMIDEStep-1: Synthesis of tert-butyl 4-(3-cyclobutoxy-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-N-methylpyrrolidine-3-carboxamido)piperidine-l-carboxylateTo an ice-cold stirred solution of 3 -cyclobutoxy- l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)pyrrolidine-3 -carboxylic acid (250 mg, 0.626 mmol) in DMF (2 mL) was added DIPEA (0.32 mL, 1.88 mmol) under inert atmosphere. Then tert-butyl 4-(methylamino)piperidine-l -carboxylate 2 (201 mg, 0.939 mmol) and HATU (262 mg, 0.688 mmol) were added to the reaction mixture. The resulting reaction mixture was stirred at RT for 6 h. After completion of reaction (monitored by TLC and LCMS), the reaction mixture was quenched with ice cold water (30 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. The crude obtained was purified by flash column chromatography (5-8% MeOH: DCM) to get tert-butyl 4-(3-cyclobutoxy-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-N-methylpyrrolidine-3-carboxamido)piperidine-l -carboxylate (220 mg, 59%) as yellow solid. LCMS: m / z 596.31 [M+H]+; Purity: 97%.Step-2: Synthesis of 3-cyclobutoxy-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-N-methyl-N-(piperidin-4-yl)pyrrolidine-3-carboxamideTo an ice-cold stirred solution of tert-butyl 4-(3 -cyclobutoxy- 1-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl) -N -methylpyrrolidine -3 -carboxamido)piperidine - 1 -carboxylate (180 mg, 0.302 mmol) in DCM (4 mL) was added TFA (1 mL) and the reaction was stirred at room temperature for 6 h. After completion of reaction (monitored by TLC and LCMS), the reaction mixture245was concentrated under reduced pressure to get crude. The crude compound was triturated with Diethyl ether: Pentane (1:1, 10 mL) to get 3-cyclobutoxy-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-N-methyl-N-(piperidin-4-yl)pyrrolidine-3-carboxamide as an off-white solid (130 mg, crude). LCMS: m / z 452.33 [M+H]+; Purity: 99%.Step-3: Synthesis of the title compoundTo an ice-cold stirred solution of 3-cyclobutoxy-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-N-methyl-N-(piperidin-4-yl)pyrrolidine-3-carboxamide (130 mg, 0.288 mmol) in ACN: MeOH (4 mL, 3:1) were added (R)-2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)acetaldehyde 5 (72.4 mg, 0.230 mmol) and DIPEA (0.24 mL, 1.44 mmol) and the reaction mixture was stirred for 30 min. Afterwards, STAB (183 mg, 0.864 mmol) was added to the reaction mixture at 0°C and gradually warmed to RT for 2 h. After completion, the reaction was quenched with water (10 mL) and extracted with 10% MeOH in DCM (2 x 20 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by RP-HPLC purification using Column: X Select fluorophenyl (250 X 19), 5pm Mobile Phase A: 0.1% Pormic Acid in Water Mobile Phase B: Acetonitrile with flow rate 18 mL / min to get 3-cyclobutoxy-N-(l-(2-(l-(4-((R)-2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-N-methylpyrrolidine-3-carboxamide as an off white solid (59 mg, 26% over 2 steps). LCMS: m / z 750.59 [M+H]+; Purity: 98.57 %. ’HNMR(400 MHz, DMSO-d6): 5 14.76 (brs, 1H), 10.76 (s, 1H), 8.64 (s, 1H), 8.09 (d, J= 7.4 Hz, 1H), 7.34 (t, J= 8 Hz, 1H), 7.25 (brs, 1H), ), 7.02 (d, J= 8.6 Hz, 2H), 6.94-6.86 (m, 4H), 4.37-4.22 (m, 1H), 3.92-3.79 (m, 3H), 3.73-3.62 (m, 4H), 3.56-3.51 (m, 1H), 3.07-2.76 (m, 5H), 2.63-2.58 (m, 3H), 2.45-2.42 (m, 4H), 2.16-1.80 (m, 9H), 1.75-1.72 (m, 3H), 1.64-1.50 (m, 3H), 1.40 (brs, 4H) and 1.29-1.19 (m, 2H).EXAMPLE 167B(S)-3-CYCLOBUTOXY-N-(l-(2-(l-(4-((R)-2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4-YL)ETHYL)PIPERIDIN-4-YL)-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-N-METHYLPYRROLIDINE-3- CARBOXAMIDEStep 1: SFC separation of title compoundThe racemic compound was separated using SFC conditions (Stage 1 column: IBN, Stage 2 column: IH, EtOH + 60% CAN + 0.1% NH4OH). Peak 1 was collected to yield the title compound (15.5 mg) as a white solid.246EXAMPLE 168(lR,5S,8R)-N-{l-[2-(l-{4-[(3R)-2,6-DIOXOPIPERIDIN-3-YL]PHENYL}PIPERIDIN-4- YL)ETHYL]PIPERIDIN-4-YL}-3-[6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL]-N-(2-METHOXYETHYL)-3- AZABICYCLO[3.2.1]OCTANE-8-CARBOXAMIDEOHNNabs tNHOThe title compound was synthesized as described for Example 153 step 5, using (lR,5S,8S)-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(2-methoxyethyl)-N-(piperidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxamide hydrochloride and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)acetaldehyde to yield (lR,5S,8R)-N-{ l-[2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)ethyl]piperidin-4-yl}-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(2-methoxyethyl)-3-azabicyclo[3.2.1]octane-8-carboxamide (0.0054 g, 39.43%). LCMS: C44H57N7O5 requires: 763.4, found: m / z = 764.4 [M+H]+EXAMPLE 169(lR,5S,8R)-N-{l-[2-(l-{4-[(3R)-2,6-DIOXOPIPERIDIN-3-YL]-3-FLUOROPHENYL}PIPERIDIN-4- YL)ETHYL]PIPERIDIN-4-YL}-3-[6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL]-N-(2-METHOXYETHYL)-3- AZABICYCLO[3.2.1]OCTANE-8-CARBOXAMIDEOHNNCombined (lR,5S,8S)-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(2-methoxyethyl)-N-(piperidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxamide hydrochloride (19.00 mg, 0.0378 mmol) and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]-3-fluorophenyl}piperidin-4-yl)acetaldehyde (13.21 mg, 0.0397 mmol) in ACN (0.40 mL) and methanol (0.20 mL) and then added sodium triacetoxyborohydride (12.03 mg, 0.0568 mmol) and stirred for 2h. Concentrated down to an oil, then redissolved in DCM and purified directly by MPLC (DCM / methanol) to yield (lR,5S,8R)-N-{l-[2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]-3-fhiorophenyl}piperidin-4-yl)ethyl]piperidin-4-yl}-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(2-methoxyethyl)-3-azabicyclo[3.2.1]octane-8-carboxamide (0.0078 g, 23.46%). LCMS: C44H56FN7O5 requires: 781.4, found: m / z = 782.2 [M+H]+247EXAMPLE 170(lR,5S,8R)-N-{l-[2-(l-{4-[(3S)-2,6-DIOXOPIPERIDIN-3-YL]-3-FLUOROPHENYL}PIPERIDIN-4- YL)ETHYL]PIPERIDIN-4-YL}-3-[6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL]-N-(2-METHOXYETHYL)-3- AZABICYCLO[3.2.1]OCTANE-8-CARBOXAMIDECombined (lR,5S,8S)-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(2-methoxyethyl)-N-(piperidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxamide hydrochloride (10.60 mg, 0.0211 mmol) and 2-(l-{4-[(3S)-2,6-dioxopiperidin-3-yl]-3-fluorophenyl}piperidin-4-yl)acetaldehyde (7.72 mg, 0.0232 mmol) in ACN (0.40 mL) and then added sodium triacetoxyborohydride (6.71 mg, 0.0317 mmol) and stirred for 2h. Concentrated down to an oil, then dissolved in DCM and purified by MPLC (DCM / methanol) to yield (lR,5S,8R)-N-{l-[2-(l-{4-[(3S)-2,6-dioxopiperidin-3-yl]-3-fluorophenyl}piperidin-4-yl)ethyl]piperidin-4-yl}-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(2-methoxyethyl)-3-azabicyclo[3.2.1]octane-8-carboxamide (0.0058 g, 30.39%). LCMS: C44H56FN7O5 requires: 781.4, found: m / z = 782.4 [M+H]+EXAMPLE 171(lR,5S,8R)-N-{l-[2-(l-{4-[(3R)-2,6-DIOXOPIPERIDIN-3-YL]PHENYL}PIPERIDIN-4- YL)ETHYL]PIPERIDIN-4-YL}-3-[6-(2-HYDROXYPHENYL)PYRID AZIN-4- YLJ-N-PROPYL- 3- AZABICYCLO[3.2.1]OCTANE-8-CARBOXAMIDEStep 1: tert-butyl 4-[N-propyl(lR,5S,8S)-3-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-3-azabicyclo[3.2.1]octane-8-amido]piperidine-l-carboxylatetert-butyl 4-[N-propyl(lR,5S,8S)-3-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-3-azabicyclo[3.2.1]octane-8-amido]piperidine-l-carboxylate was synthesized as described for Example 153 step 3, using (lR,5S,8S)-3-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-3-azabicyclo[3.

2. l]octane-8-248carboxylic acid and tert-butyl 4-(propylamino)piperidine- 1 -carboxylate to yield tert-butyl 4-[N-propyl(lR,5S,8S)-3-{6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl}-3-azabicyclo[3.2.1]octane-8-amido]piperidine-l -carboxylate (0.045 g, 47.54%). LCMS: C33H47N5O5 requires: 593.4, found: m / z = 594.2 [M+H]+.Step 2: (lR,5S,8S)-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(piperidin-4-yl)-N-propyl-3-azabicyclo [3.2.1] octane-8-carboxamide(lR,5S,8S)-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(piperidin-4-yl)-N-propyl-3-azabicyclo[3.2.1]octane-8-carboxamide was prepared as described for Example 107 step 2. LCMS: C26H35N5O2 requires: 449.3, found: m / z = 450.2 [M+H]+.Step 3: Synthesis of the title compoundCombined (lR,5S,8S)-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-(piperidin-4-yl)-N-propyl-3-azabicyclo[3.2.1]octane-8-carboxamide hydrochloride (16.60 mg, 0.0342 mmol) and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)acetaldehyde (11.27 mg, 0.0359 mmol) in ACN (0.40 mL) and methanol (0.20 mL) and then added sodium triacetoxyborohydride (13.03 mg, 0.0615 mmol) and stirred for 2h. Concentrated down to an oil, then dissolved in DCM and purified on MPLC (DCM / methanol) to yield (lR,5S,8R)-N-{l-[2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)ethyl]piperidin-4-yl}-3-[6-(2-hydroxyphenyl)pyridazin-4-yl]-N-propyl-3-azabicyclo[3.2.1]octane-8-carboxamide (0.0149 g, 56.52%). LCMS: C44H57N7O4 requires: 747.4, found: m / z = 748.4 [M+H]+EXAMPLE 172N-(l-(2-(l-(4-((R)-2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4-YL)ETHYL)PIPERIDIN-4-YL)-3- FLUORO-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-N-METHYLPIPERIDINE-3-CARBOXAMIDE249Step-1: tert-butyl 4-(3-fluoro-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-N-methylpiperidine- 3-carboxamido)piperidine-l-carboxylateTo an ice cold stirred solution of 3-fhioro-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperidine -3 -carboxylic acid Lithium salt (300 mg, 0.83 mmol) and tert-butyl 4-(methylamino)piperidine-l -carboxylate (267 mg, 1.25 mmol) in DMF (5 mL) was added DIPEA (0.5 ml, 2.49 mmol) followed by HATU (347 mg, 0.91 mmol) under inert atmosphere and reaction mixture was stirred at RT for 3 h. After completion, the reaction mixture was quenched with water (20 mL) and extracted with DCM (2 x 30 mL). The combined organic layer was washed with ice-cold water (3 x 20 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get the crude. The crude product was purified by flash column chromatography (-8% MeOH in DCM) to get tertbutyl 4-(3-fluoro-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-N-methylpiperidine-3-carboxamido)piperidine- 1 -carboxylate as a yellow sticky solid (250 mg, 55 %). LCMS: m / z 558.43 [M+H]+; Purity: 92%.Step-2: 3-fluoro-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-N-methyl-N-(piperidin-4-yl)piperidine-3-carboxamide HC1 saltOHTo an ice-cold stirred solution of tert-butyl 4-(3 -fluoro- 1-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-N-methylpiperidine-3-carboxamido)piperidine-l-carboxylate (230 mg, 0.41 mmol) in DCM (6 mL) was added 4 N HC1 in Dioxane (2 mL) and the reaction mixture was stirred at RT for 5 h. After completion, the reaction mixture was concentrated under reduced pressure and triturated with Diethyl ether (30 mL) to get 3-fluoro-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-N-methyl-N-(piperidin-4-yl)piperidine-3-carboxamide HC1 salt as an off white solid (170 mg, crude).LCMS: m / z 414.28 [M+H]+; Purity: 95%.Step-3: Synthesis of the title compoundTo an ice cold stirred solution 3-fluoro-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-N-methyl-N-(piperidin-4-yl)piperidine-3-carboxamide HC1 salt (170 mg, 0.41 mmol) and (R)-2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)acetaldehyde (103 mg, 0.33 mmol) in CHsCbhMeOH (3:1, 8 mL) was added DIPEA (0.35 mL, 2.06 mmol) and the reaction mixture was stirred at RT for 30 min before adding STAB (261 mg, 1.23 mmol) at 0°C. The reaction mixture was stirred at RT for another 3 h. After completion (monitored by TLC and LCMS), the reaction mixture was concentrated, quenched250with water (20 mL) and extracted with 10% MeOH: DCM (2x30 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get the crude. The crude product was purified by RP-HPLC purification Column: X-Bridge C8250 x 19,5 pm, Mobile phase: A- 5mM Ammonium Acetate in Water B: -ACN with flow rate 18 ml / min to get N-(l-(2-(l-(4-((R)-2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-3-fluoro-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-N-methylpiperidine-3-carboxamide as an off white solid (74 mg, 25% over 2 steps). LCMS: m / z 712.63 M+H]+; Purity: 99.61%. 1H NMR (400 MHz, DMSO-d6): 5 14.58 (brs, 1H), 10.76 (s, 1H), 8.97 (s, 1H), 8.15-8.13 (m, 1H), 7.60 (s, 1H), 7.34-7.30 (m, 1H), 7.02 (d, J= 8.0 Hz, 2H), 6.93-6.86 (m, 4H), 4.63-4.57 (m, 1H), 4.28-3.92 (m, 2H), 3.80-3.71 (m, 2H), 3.70-3.61 (m, 2H), 3.26-3.20 (m, 1H), 2.95-2.89 (m, 4H), 2.65-2.56 (m, 3H), 2.46-2.42 (m, 2H), 2.25-2.16 (m, 3H), 2.12-1.91 (m, 4H), 1.81-1.63 (m, 7H), 1.54-1.39 (m, 5H) and 1.23-1.19 (m, 2H).EXAMPLE 173N-(1-(2-(1-(4-((R)-2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4-YL)ETHYL)PIPERIDIN-4-YL)-N- ETHYL- 3- FLUORO-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)PIPERIDINE-3-CARBOXAMIDEStep-1: tert-butyl 4-(N-ethyl-3-fluoro-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperidine-3-carboxamido)piperidine-l-carboxylateTo an ice cold stirred solution of 3 -fluoro- l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperidine-3 -carboxylic acid lithium salt (300 mg, 0.83 mmol) and tert-butyl 4-(ethylamino)piperidine- 1-carboxylate (152 mg, 0.66 mmol) in DMF (5 mL) was added DIPEA (0.5 ml, 2.49 mmol) followed by HATU (347 mg, 0.91 mmol) under inert atmosphere and stirred at RT for 16 h. After completion, the reaction mixture was concentrated, quenched with water (20 mL) and extracted with EtOAc (2 x 20 mL). The organic layer was washed thoroughly with chilled brine solution (2 x 40 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get crude. Crude product was purified by flash column chromatography (silica gel, 12 g SNAP) using eluents 5-8% MeOH in DCM to get tert-butyl 4-(N-ethyl-3-fluoro-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperidine-3-carboxamido)piperidine-l-carboxylate as yellow sticky solid (235 mg, 50 %). LCMS: m / z 572.15 [M+H]+; Purity: 91%.251Step-2: N-ethyl-3-fluoro-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-N-(piperidin-4-yl)piperidine-3-carboxamideOHTo an ice-cold stirred solution of tert-butyl 4-(N-ethyl-3-fluoro-l-(6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperidine-3-carboxamido)piperidine-l -carboxylate (210 mg, 0.38 mmol) in DCM (5 mL) was added 4 N HC1 in 1,4 Dioxane (2.5 mL) and the reaction mixture was stirred at RT for 5 h. After completion of reaction (monitored by TLC and LCMS), the reaction mixture was concentrated under reduced pressure and triturated with diethyl ether (10 mL) to get N-ethyl-3-fluoro- 1 -(6-(2-hydroxyphenyl)pyridazin-4-yl)-N-(piperidin-4-yl)piperidine-3-carboxamide as white solid (175 mg, crude). LCMS: m / z 428.05 M+H]+; Purity: 93%.Step-3: Synthesis of the title compoundTo an ice cold stirred solution N-ethyl-3-fluoro-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-N-(piperidin-4-yl)piperidine-3-carboxamide 4 (155 mg, 0.33 mmol) and (R)-2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)acetaldehyde 5 (83 mg, 0.26 mmol) in CH3CN: MeOH (3:1, 8 mL) was added DIPEA (0.28 mL, 1.65 mmol) and reaction mixture was stirred at RT for 30 min before adding STAB (210 mg, 0.99 mmol) at 0°C. Reaction mixture was stirred at RT for another 3 h. After completion (monitored by TLC and LCMS), the reaction mixture was concentrated, quenched with water (20 mL) and extracted with 10% MeOH: DCM (2 x 30 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get the crude. The crude product was purified by RP-HPLC purification Column: X SELECT FLOURO PHENYL (250 X 19), 5pm Mobile phase: 5mM Ammonium Formate in Water B: -ACN with flow rate 18 ml / min to get N-(l-(2-(l-(4-((R)-2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-N-ethyl-3-fluoro-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)piperidine-3-carboxamide as an off white solid (80 mg, 30% over two steps). LCMS: m / z 726.62 M+H]+; Purity: 97.38%. 1HNMR (400 MHz, DMSO-d6): 5 14.57 (brs, 1H), 10.76, (s, 1H), 8.99-8.97 (m, 1H), 8.14 (d, J= 8.0Hz, 1H), 7.60 (d, J = 2.6Hz, 1H), 7.32 (t, J= 7.6 Hz, 1H), 7.02 (d, J= 8.4 Hz, 2H), 6.93-6.85 (m, 4H), 4.66-4.55 (m, 1H), 4.29-4.26 (m, 1H), 3.92 (m, 1H), 3.81-3.60 (m, 4H), 3.28-3.20 (m, 2H), 2.94-2.88 (m, 2H), 2.64-2.56 (m, 3H), 2.44-2.43 (m, 1H), 2.25-1.97 (m, 6H), 1.90 (s, 1H), 1.79-1.56 (m, 10H), 1.39-1.34 (m, 3H), 1.23-1.19 (m, 2H) and 1.12-1.05 (m, 3H)252EXAMPLE 174(R)-3-CYCLOBUTOXY-N-(l-(2-(l-(4-((R)-2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4- YL)ETHYL)PIPERIDIN-4-YL)-1-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-N-METHYLPYRROLIDINE-3- CARBOXAMIDEStep 1: SFC separation of title compoundThe racemic compound of Example 167A was separated using SFC conditions (Stage 1 column: IBN, Stage 2 column: IH, EtOH + 60% CAN + 0.1% NH4OH). Peak 2 was collected to yield the title compound (15.8 mg) as a white solid.EXAMPLE 175RAC-N-(l-((R)-l-(l-(4-((S)-2,6-DIOXOPIPERIDIN-3-YL)PIIENYL)PIPERIDIN-4-YL)PROPAN-2- YL)PIPERIDIN-4-YL)-N-ETIIYL-l-(6-(2-HYDROXYPIIENYL)PYRID AZIN-4- YL)-4-METHOXYPIPERIDINE- 4-CARBOXAMIDEStep 1: Synthesis of the title compoundN-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride (30.00 mg, 0.0630 mmol) was dissolved in DMA (1.00 mL) and (3R)-3-{4-[4-(2-oxopropyl)piperidin-l-yl]phenyl}piperidine-2, 6-dione (20.70 mg, 0.0630 mmol) was added in one portion. N, N-diisopropylethylamine (0.06 mL, 40.73 mg, 0.3151 mmol) was then added followed by sodium triacetoxyborohydride (40.07 mg, 0.1891 mmol). The resulting reaction was stirred at RT for 1-2 hrs and monitored via LCMS. Once complete, the reaction was concentrated in vacuo and purified via RP-FC to afford the title compound (4.7 mg, 8.1%) as a formate salt. LCMS: C43H57N7O5 requires: 751.4, found: m / z = 752.3 [M+H]+253EXAMPLE 176RAC-N- [l-(6- {4- [(3R)-2,6-DIOXOPIPERIDIN-3- YL]PHENYL}-6-AZASPIRO[3.4] OCTAN-2-YL)PIPERIDIN- 4- YL]-N-ETHYL-l-[6-(2-HYDROXYPHENYL)PYRID AZIN-4- YLJ-4-METHOXYPIPERIDINE-4-Combined N-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride (10.10 mg, 0.0212 mmol) and 3-(4-{2-oxo-6-azaspiro[3.4]octan-6-yl}phenyl)piperidine-2, 6-dione (7.29 mg, 0.0233 mmol) in DMA (0.30 m ) and then added N, N-diisopropylethylamine (3.71 pL, 0.00 g, 0.0212 mmol) and sodium triacetoxyborohydride (6.75 mg, 0.0318 mmol) and stirred for 3d, then purified directly by RP-HPLC to yield rac-N-[l-(6-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}-6-azaspiro[3.4]octan-2-yl)piperidin-4-yl]-N-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxypiperidine-4-carboxamide (0.0084 g, 49.11%). LCMS: C42H53N7O5 requires: 735.4, found: m / z = 736.3 [M+H]+.EXAMPLE 177(R)-N-(1-((1-(4-(2,6-DIOXOPIPERIDIN-3-YL)PIIENYL)PIPERIDIN-4-YL)METHYL)PIPERIDIN-4-YL)-N- ETHYL-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXYPIPERIDINE-4-CARBOXAMIDEStep 1: Synthesis of the title compoundN-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride (30.00 mg, 0.0630 mmol) was dissolved in DMA (1.00 m ) and l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidine-4-carbaldehyde (18.93 mg, 0.0630 mmol) was added in one portion. N, N-diisopropylethylamine (40.73 mg, 0.3151 mmol) was then added followed by sodium triacetoxyborohydride (40.07 mg, 0.1891 mmol). The resulting reaction was stirred at RT for 1-2 hrs and monitored via LCMS. Once complete, the reaction was concentrated in vacuo and purified via RP-FC to afford the title compound (25.3 mg, 50.3%) as a formate salt. LCMS: C41H53N7O5 requires: 723.4, found: m / z = 724.4 [M+H]+254EXAMPLE 178N-((R)-SEC-BUTYL)-N-(l-(2-(l-(4-((R)-2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4- YL)ETHYL)PIPERIDIN-4-YL)-l-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXYPIPERIDINE-4- CARBOXAMIDEStep 1: Synthesis of tert-butyl (R)-4-(sec-butylamino)piperidine-l-carboxylateThe title compound was prepared as described for Example 94, Step 1, using (R)-butan-2-amine to afford the desired product as a colorless oil. ’H NMR (700 MHz, DMSO) 53.81 (s, 2H), 2.89 - 2.69 (m, 2H), 2.66 - 2.55 (m, 2H), 1.75 - 1.67 (m, 2H), 1.38 (s, 9H), 1.35 (ddd, J= 13.1, 7.5, 5.4 Hz, 1H), 1.20 (dp, J= 14.3, 7.3 Hz, 1H), 1.12 - 0.98 (m, 2H), 0.92 (d, J= 6.2 Hz, 3H), 0.82 (t, J= 7.4 Hz, 3H). LCMS: CI4H28N2O2requires 256.2, found: m / z = 257.2 [M+H]+.Step 2: Synthesis of (R)-N-(sec-butyl)-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamideThe title compound was prepared as described for Example 89, Step 1, using tert-butyl (R)-4-(sec-butylamino)piperidine-l -carboxylate to afford the desired product as a light brown solid. LCMS: CMH37N5O3 requires 467.3, found: m / z = 468.4 [M+H]+.Step 3: Synthesis of the title compoundThe title compound was prepared as described for Example 1, Step 2, using (R)-N-(sec-butyl)-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide and (R)-2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)acetaldehyde to afford the title compound (5 mg, 28%). LCMS: C44H59N7O5 requires 765.5, found: m / z = 766.3 [M+H]+.255EXAMPLE 179RAC-(R)-N-(l-(2-(l-(4-(2,6-DIOXOPIPERIDIN-3-YL)PHENYL)-4-FLUOROPIPERIDIN-4- YL)ETHYL)PIPERIDIN-4-YL)-N-ETHYL-1-(6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL)-4- METHOXYPIPERIDINE-4-CARBOXAMIDEStep 1: Synthesis of the title compoundN-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride (30.00 mg, 0.0630 mmol) was dissolved in DMA (1.00 mL) and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}-4-fluoropiperidin-4-yl)acetaldehyde (20.70 mg, 0.0630 mmol) was added in one portion followed by sodium triacetoxyborohydride (40.07 mg, 0.1891 mmol). The resulting reaction was stirred at RT for 1-2 hrs and monitored via LCMS. Once complete, the reaction was concentrated in vacuo and purified via RP-FC to afford the title compound (22.8 mg, 43.1%) as a formate salt. LCMS: C42H54FN7O5 requires: 755.4, found: m / z = 756.3 [M+H]+EXAMPLE 180(R)-3-(4-((RS)-3-(8-(1-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4-ME THOXYPIPERIDINE-4- CARBONYL)-2,8-DIAZASPIRO[4.5]DECAN-2-YL)-l-OXA-8-AZASPIRO[4.5]DECAN-8- YL)PHENYL)PIPERIDINE-2, 6-DIONEStep 1: Synthesis of (l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxypiperidin-4-yl)(2,8-diazaspiro [4.5] decan-8-yl)methanoneThe title compound was prepared as described for Example 92, Step 1, using tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate to afford the desired product as a yellow solid. LCMS: C25H33N5O3 requires 451.3, found: m / z = 452.4 [M+H]+.256Step 2: Synthesis of the title compoundThe title compound was prepared as described for Example 1, Step 2, using (l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxypiperidin-4-yl)(2,8-diazaspiro[4.5]decan-8-yl)methanone and (R)-3-(4-(3-oxo-l-oxa-8-azaspiro[4.5]decan-8-yl)phenyl)piperidine-2, 6-dione to afford the title compound (11.3 mg, 22%). LCMS: C44H55N7O6 requires 777.4, found: m / z = 778.4 [M+H]+.EXAMPLE 181N-((lRS,3RS,5SR)-8-(2-(l-(4-((R)-2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4-YL)ETHYL)-8- AZABICYCLO[3.2.1]OCTAN-3-YL)-N-ETHYlM-(6-(2-HYDROXYPHENYL)PYRID AZIN-4- YL)-4- METHOXYPIPERIDINE-4-CARBOXAMIDEStep 1: Synthesis of N-((lR,3r,5S)-8-azabicyclo [3.2.1] octan-3-yl)-N-ethyl-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxypiperidine-4-carboxamideThe title compound was prepared as described for Example 92, Step 1, using tert-butyl (lR,3r,5S)-3-(ethylamino)-8-azabicyclo[3.2.1]octane-8-carboxylate to afford the desired product as a grey solid. LCMS: C26H35N5O3 requires 465.3, found: m / z = 466.4 [M+H]+.Step 2: Synthesis of the title compoundThe title compound was prepared as described for Example 1, Step 2, using N-((lR,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)-N-ethyl-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxypiperidine-4-carboxamide and (R)-2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)acetaldehyde to afford the title compound (8.3 mg, 16%). LCMS: C44H57N7O5 requires 763.4, found: m / z = 764.4 [M+H]+.EXAMPLE 182RAC-N-(1-(((1R,4R)-4-(3-((R)-2,6-DIOXOPIPERIDIN-3- YL)PHENOXY)CYCLOHEXYL)METHYL)PIPERIDIN-4-YL)-N-ETHYIM-(6-(2- HYDROXYPHENYL)PYRID AZIN-4- YL)-4-METHOXYPIPERIDINE-4-CARBOXAMIDEStep 2: Synthesis of the title compoundThe title compound was prepared as described for Example 1, Step 2, using N-ethyl-l-(6-(2-hydroxyphenyl)pyridazin-4-yl)-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide and rac-(lR,4r)-2574-(3-((R)-2,6-dioxopiperidin-3-yl)phenoxy)cyclohexane-l-carbaldehyde to afford the title compound (9 mg, 24%). LCMS: C42H54N6O6 requires 738.4, found: m / z = 739.3 [M+H]+.EXAMPLE 183RAC-N-(l-((R)-2-(l-(4-((R)-2,6-DIOXOPIPERIDIN-3-YL)PHENYL)PIPERIDIN-4-YL)PROPYL)PIPERIDIN- 4-YL)-N-ETHYL-1-(6-(2-HYDROXYPHENYL)PYRIDAZIN-4-YL)-4-METHOXYPIPERIDINE-4-Step 1: Synthesis of the title compoundN-ethyl-l-[6-(2-hydroxyphenyl)pyridazin-4-yl]-4-methoxy-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride (30.00 mg, 0.0630 mmol) was dissolved in DMA (1.00 mL) and 2-(l-{4-[(3R)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)propanal (20.70 mg, 0.0630 mmol) was added in one portion. N, N-diisopropylethylamine (0.06 mL, 40.73 mg, 0.3151 mmol) was then added followed by sodium triacetoxyborohydride (40.07 mg, 0.1891 mmol). The resulting reaction was stirred at RT for 1-2 hrs and monitored via LCMS. Once complete, the reaction was concentrated in vacuo and purified via RP-FC to afford the title compound (10.2 mg, 18.8%) as a formate salt. LCMS: C43H57N7O5 requires:751.4, found: m / z = 752.3 [M+H]+EXAMPLES 184-263The following additional compounds were prepared according to the synthetic schemes described258260261262263264265266BIOLOGICAL EXAMPLE SMARCA2 CELLULAR DEGRADATION ASSAYWestern Blot Analysis for SMARCA2 DegradationFrozen cell pellets were thawed on ice and resuspended in RIPA lysis buffer (Millipore, Cat. No. 20-188) supplemented with 0.2% SDS (Fisher Scientific, Cat. No. 24730020), 200 mM P-glycerophosphate (Alfa Aesar, Cat. No. J62121), 500 mM NaF (Rigaku, Cat. No. 1008046), protease inhibitor (1 tablet per 10 mL, Sigma, Cat. No. 11836170001), 250 U / µL benzonase (Millipore, Cat. No.71206), 200 mM sodium orthovanadate (FivePhoton, Cat. No. ActVO-4), and 100 mM PMSF (Sigma, Cat. No.10837091001). 50 µL lysis buffer was used to lyse each pellet containing 5x 10E5 - lx 10E6 live cells extracted from tumors. Lysates were centrifuged for 10 mins at 20,817 x g and lysate supernatants were saved for further analysis. Protein levels were determined by the BCA Assay performed according to manufacturer’s protocol (EMD Millipore, Cat. No. 71285-3). Samples were evaluated by Western blot analysis on the Jess Platform (ProteinSimple). Lysates were diluted with complete lysis buffer (as described above) and 5 µg of total proteins were loaded onto each capillary. Samples were prepared using the ProteinSimple EZ Standard Pack 1 (Cat. No. PS-ST01EZ-8; containing tubes with powdered (5X) Fluorescent Master Mix, DTT, and biotinylated ladder) and run using the ProteinSimple 25-Capillary Cartridge kit (Cat. No. SM-W004; containing 25-capillary cartridge Wash reagent, and 10X Sample Buffer reagent), the ProteinSimple Anti-Rabbit HRP Detection Module for Jess (Cat. No. DM-001; containing Antibody Diluent, anti-rabbit secondary antibody, Luminol-S, Peroxide, and Streptavidin-HRP), and the ProteinSimple Anti-Mouse NIR Detection Module for Jess (Cat. No. DM-009; containing Antibody Diluent, anti-mouse NIR secondary antibody, and Streptavidin-NIR) as the following describes. The DTT was reconstituted with 40 µL water to make a 400 mM solution, 20 µL of the DTT solution plus 20 µL of 10X Sample Buffer were added to reconstitute the 5X Fluorescent Master Mix, and 20 µL of H2O was used to reconstitute the biotinylated ladder. For each sample, lysate (4 µL) was combined with 5X Fluorescent Master Mix (1 µL) and heated at 95°C for 5 minutes. Samples were cooled and stored on ice. Primary antibody solution was made using anti-SMARCA2 antibody (Abeam, Cat. No. 240648, 1:10) and anti-beta- Actin antibody (Cell Signaling Technology, Cat. No. 3700S, 1:25) in antibody diluent. The 25-capillary cartridges were prepared per standard ProteinSimple protocol with each sample in a column. For the biotinylated ladder in column 1, the following were added: 5 pL of ladder sample in Row A, 10270pL of antibody diluent in Rows B and C, 10 pL of Streptavidin-NIR in Row D, and 15 pL ofa 50:50 Luminol-s / Peroxide solution in Row E. For each test sample (columns 2-25), the following were added per column: 5 pL of sample in Row A, 10 pL of antibody diluent in Row B, 10 pL of primary antibody solution in Row C, 10 pL of secondary antibody in Row D, and 15 pL of a 50:50 Luminol-S / Peroxide solution in Row E. 500 µL wash buffer was added to the wash buffer wells in the cartridge and cartridge was spun at 1000 x g for 5 minutes prior to loading into the Jess. Samples were run using the Chemiluminescence and Fluorescence immunoassays in the ProteinSimple Compass for SimpleWestem program (version 5.0.0). After running, SMARCA2, actin, and background curves were identified in the Compass software; note that in the Compass software, the electropherograms are also visualized as bands for comparison with standard Western blot outputs. The electropherogram area reading for each sample curve was normalized to that of the corresponding actin curve per column following background (capillary background) subtraction using the following equation:[SMARCA2 Area ValueSample Normalized Value = — - - —P - Actin Area ValueFollowing normalization, the percentage of SMARCA2 remaining per sample relative to the vehicle control was calculated as follows:[Example # / Treated Sample Normalized Value% remaining = xlOOMean (Vehicle Sample Normalized ValueTable 2 demonstrates the biological activities of certain representative compounds of Formula (I).Table 2Biological DataDC50 (nM) Dmax (%) SMARCA2 SMARCA4 Calu-6 SMARCA2 Calu-6 SMARCA4 Calu-6 Example #Calu-6 C-3E9) C-5A6) C-3E9) [%] C-5A6) [%] 1 6.4 10000 87.06 35.88 2 1.97 10000 90.45 44.52 3 15.6 10000 71.44 15.94 2.18 10000 93.42 46.55 5 18.03 1000 69.06 25.04 6 13.22 10000 72.5 48.87 7 48.06 10000 67.17 24.25 8 2.95 10000 86.36 37.03 9 7.17 10000 79.63 23.38 10 18.69 10000 73.39 46.1 11 5.82 10000 86.92 39.412 18.62 10000 74.34 49.26 13 203.1 10000 60.85 6.11 14 21.78 10000 69.81 13.11 15 6.64 10000 84.34 29.48 16 12.08 10000 79.58 40.97 17 5.72 10000 78.64 25.98 18 24.57 10000 66.09 51.9819 121.07 10000 63.24 32.01271DC50 (nM) Dmax (%) SMARCA2 SMARCA4 Calu-6 SMARCA2 Calu-6 SMARCA4 Calu-6 Example #Calu-6 C-3E9) C-5A6) C-3E9) [%] C-5A6) [%] 20 5.35 10000 83.19 35 21 7.35 41.3 82.68 61.8 22 10000 10000 39.85 17.92 23 51.45 10000 73.4 42.21 24 13.72 10000 69.92 39.77 25 37.75 10000 67.18 40.67 26 3.56 10000 86.39 36.85 27 1.84 63.61 92.93 59.09 28 5.69 10000 84.2 27.29 29 11.99 10000 70.42 13.51 30 2.27 10000 91.16 44.44 31 1.18 94.39 92.77 53.73 32 35.7 10000 72.42 35.4 33 12.98 10000 75.21 18.32 34 2.98 10000 87.82 38.22 35 5.6 10000 80.97 27.3 36 16.56 10000 72.45 24.3 37 3.72 27.59 86.33 64.22 38 10000 10000 27.2 21.1 39 10.64 541.1 76.12 35.7 40 144.15 10000 55.27 22.99 41 180.98 10000 52.96 30.87 42 24.63 10000 58.75 17.94 43 33.18 10000 71.65 29.85 45 44.5 10000 67.08 32.17 46 143.96 10000 55.03 15.45 47 50.69 10000 56.25 37.82 48 8.14 10000 77.68 38.7 49 2.55 10000 90.47 33.56 50 22.42 10000 61.65 17.46 51 10000 10000 50.38 22.14 52 4.42 174.83 87.76 54.51 53 26.93 10000 65.34 21.27 54 10000 10000 42.00 21.00 55 14.93 10000 72.46 23.08 56 10.97 10000 79.73 40.37 57 12 10000 81 26 58 3.4 10000 89.13 31.88 59 5.82 10000 85.68 23.29 60 1.63 10000 90.35 48.5 61 1.57 71.11 89.53 55.44 62 1.51 44.8 89.82 52.2 64 1.81 41.7 88.55 58.87 63 2.19 61.81 84.72 51.3865 4.24 10000 83.65 37.86272DC50 (nM) Dmax (%) SMARCA2 SMARCA4 Calu-6 SMARCA2 Calu-6 SMARCA4 Calu-6 Example #Calu-6 C-3E9) C-5A6) C-3E9) [%] C-5A6) [%] 66 7.04 10000 81.81 33.06 67 4.06 10000 83.67 28.66 68 6.05 10000 80.45 27.43 69 5.42 10000 82.63 29.99 70 6.87 10000 81.39 28.3 71 4.65 10000 82.87 33.65 72 4.82 10000 82.98 32.88 73 2.98 10000 84.92 35.89 74 17.37 10000 69.54 13.8 75 5.25 10000 85.73 33.58 76 9.08 10000 81.82 24.16 77A 4.83 1000 86.66 30.14 77B 19.4 1000 79.94 26.15 78 32.8 1000 69.34 43.62 79 34.7 1000 67.01 43.34 80A 7.14 1000 81.31 27.51 80B 63.2 1000 72.81 24.11 81 2.55 1000 94.37 41.45 82 2.07 1000 94.92 43.74 83 19.1 1000 69.87 46.1 84 8.55 1000 79.35 29.21 85 14.9 1000 78.99 15.01 86 18.2 1000 65.45 35.49 87 5.59 1000 88.43 23.14 88 11.3 1000 81.32 33.19 89 4.81 1000 92.15 37.98 90 2.77 1000 89.33 28.96 91 4.35 1000 86.50 36.18 92 4.55 1000 89.69 21.9 93 2.08 1000 93.98 43.19 94 5.62 1000 89.44 23.5 95 2.26 1000 89.17 40.77 96 3.15 1000 88.39 35.42 97 4.9 1000 86.15 33.51 98 10.2 1000 85.36 8.51 99 0.22 4.48 97.89 86.57 100 8.78 1000 85.43 21.43 101 0.77 43.4 95.72 60.66 102 5.34 1000 83.27 37.55 103 3.24 1000 90.68 40.75 104 0.23 19.9 98.71 75.21 105 3.28 1000 89.59 44.72 106 2.76 1000 93.31 29.86 107 5.08 1000 86.52 22.64108 8.12 1000 83.17 7.19273DC50 (nM) Dmax (%) SMARCA2 SMARCA4 Calu-6 SMARCA2 Calu-6 SMARCA4 Calu-6 Example #Calu-6 C-3E9) C-5A6) C-3E9) [%] C-5A6) [%] 109 1.12 39.6 95.44 61.94 110 5.42 1000 91.74 46.21 111 4.1 1000 88.4 35.88 112 2.65 99.7 96.1 56.27 113 2.34 1000 94.01 32.76 114 17.4 10000 79.9 31.29 115 18.2 10000 77.39 38.63 116 1.17 1000 95.2 48.18 117 0.8 107 97.55 55.77 118 7.04 1000 90.74 22.21 119 4.88 1000 87.76 21.95 120 7.06 1000 90.52 23.11 121 3.42 1000 88.82 45.94 122 2.1 1000 93.15 48.34 123 1.81 1000 92.49 33.94 124 1.36 108 95.37 52.87 125 3.54 1000 89.56 14.78 126 2.71 142 95.31 57.57 127 5.21 1000 82.02 35.91 128 2.41 111 92.23 53.09 129 3.84 1000 87.14 39.57 130 7.5 1000 82.14 35.36 131 11.7 1000 71.18 24.33 132 1.38 161 93.22 51.61 133 3.6 237 88.45 51.62 134 22 1000 78.39 48.21 135 6.19 1000 87.54 49.51 136 7.39 135 88.35 60.64 137 6.75 1000 85.41 46.3 138 3.94 53.2 92.1 67.81 139 7.3 1000 84.03 19.03 140 1.73 1000 93.1 35.38 141 3.3 1000 94.65 39.71 142 9.72 1000 82.64 22.87 143 7.01 1000 89.76 18.45 144 11.4 1000 76.67 10.91 145 28.4 1000 63.39 22.82 146 6.34 1000 88.1 23.42 147 3.87 1000 87.72 25.14 148 1.81 1000 91.91 35.99 149 1.51 1000 93.65 37.67 150 7.15 1000 86.89 24.54 151 3.31 113 90.35 53.04 152 10.1 1000 86.67 23.65153 0.98 25.3 96.96 72.69274DC50 (nM) Dmax (%) SMARCA2 SMARCA4 Calu-6 SMARCA2 Calu-6 SMARCA4 Calu-6 Example #Calu-6 C-3E9) C-5A6) C-3E9) [%] C-5A6) [%] 154 0.9 25.9 97.57 77.06 155 26.1 1000 87.46 39.17 156 4.8 90.6 93.68 46.94 157 3.3 1000 92.81 49.64 158 1.72 81.3 96.27 63.57 159 2.4 351 96.09 53.12 160 15.1 1000 73.21 45.29 161 2.68 1000 92.38 45.54 162 6.37 1000 90.22 17.75 163 23 1000 70.29 2.13 164 18.3 1000 71.95 35.07 165 16.1 1000 78.45 28.37 166 0.3 28.3 98.27 74.19 167A 2.67 1000 87.71 25.39 167B 6.04 1000 84.17 12.12 168 7.58 1000 88.58 15.04 169 5.85 1000 85.81 15.13 170 23 1000 84.53 15.1 171 5.12 1000 91.49 20.15 172 19.7 1000 77.96 19.62 173 19.2 1000 69.23 11.86 174 1000 1000 49.13 19.37 175 2.18 10000 93.42 46.52 176 4.17 10000 86.45 52.04 177 6.32 10000 82.46 44.28 178 6.22 1000 86.51 39.52 179 5.11 1000 90.38 38.38 180 7.35 41.3 82.68 61.8 181 14.8 10000 68.53 26.03 182 15.6 10000 81.32 45.53183 15.7 10000 71.44 15.91The various embodiments described above can be combined to provide further embodiments. All of the U. S. patents, U. S. patent application publications, U. S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and / or listed in the Application Data Sheet are incorporated herein by reference, in their entirety. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, applications and publications to provide yet further embodiments.These and other changes can be made to the embodiments in light of the above -detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.275

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