Bifunctional degraders of hematopoietic progenitor kinases and their therapeutic uses - Patents.com

Abstract

The present disclosure provides bifunctional compounds as HPK1 degraders via the ubiquitin proteasome pathway, and methods for treating diseases modulated by HPK1. Further embodiments provide methods for treating diseases or disorders associated with increased hematopoietic progenitor kinase 1 (HPK1) activity, increasing T cell activation, treating cancer, inhibiting cancer cell growth or proliferation, treating or preventing Hepatitis B virus (HBV) infection, or treating or preventing human immunodeficiency virus (HIV) infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or any one of the substructures or compounds of Examples 1-303.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 263,875, filed November 10, 2021, which is incorporated herein by reference in its entirety.

[0002] background Technical Field The present invention provides novel bifunctional compounds for the proteolytic degradation of hematopoietic progenitor kinase (HPK1) and methods for treating diseases modulated by HPK1. [Background technology]

[0003] 2. Description of Related Art Immuno-oncology utilizes antibodies that are inhibitors of the immune checkpoint receptors CTLA4, PD-1, and PD-L1. Targeted disruption of these checkpoint pathways releases immune cells from critical regulatory pathways, allowing for a boost of the immune response against cancer cells. Current treatments utilizing these antibodies have been highlighted with significant and durable responses against many different cancers, but are also notable for low overall response rates (<25%). Improvements in these response rates could be benefited from combining checkpoint blockade with other immune activators or cell-based therapies.

[0004] The hematopoietic progenitor kinase 1 (STE20) serine / threonine kinase, a member of the germinal center kinase family, regulates the function of diverse immune populations, including T cells, B cells, and dendritic cells (Hu et al., Gens Dev, 1996; Alzabin et al., J Immunol 2009). In T cells, HPK1 acts as a negative regulator of T cell receptor (TCR) signaling by phosphorylating SLP76 on serine 376, thereby inducing the association of SLP76 with 14-3-3 proteins and resulting in dissociation of the signaling complex (Di Bartolo et al., JEM 2007) (Liou et al., Immunity 2000; Sauer et al., JBC 2001). Further supporting the role of HPK1 as a negative regulator of TCR signaling, murine HPK1-deficient or HPK1 kinase-inactive mutant T cells undergo enhanced ERK1 / 2 activation and effector cytokine secretion upon TCR activation compared to their wild-type counterparts (Shui et al., Nat Immunol 2007; Hernandez et al., Cell Reports 2018).

[0005] Therefore, HPK1 can be targeted for degradation, thereby providing therapeutic opportunities in enhancing anti-tumor immunity and increasing responses to checkpoint receptor blockade. Summary of the Invention [Means for solving the problem]

[0006] Quick Overview As used herein, a bifunctional compound represented by formula (I) [ka] or a pharmaceutically acceptable salt thereof is provided. [In the formula, R 1 teeth, i) halogen, C 1~3 Alkyl, -C(O)N(R11 )2, -CN, -OH, and C 1~3 phenyl optionally substituted with 1 to 3 groups independently selected from alkoxy; ii) 4-6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S (wherein 4-6 membered monocyclic heterocyclyl is not limited to -CN, -OH, halogen, oxo, C 1~3 Alkyl, and C 1~3 optionally substituted with 1 to 3 groups independently selected from alkoxy; iii) -CN, -OH, halogens, C 1~3 Alkyl, and C 1~3 C optionally substituted with 1 to 3 groups independently selected from alkoxy 3~7 Monocyclic or bridged bicyclic cycloalkyl (wherein C 1~3 Alkyl is a group that can be substituted with -OH, halogens, and C 1~3 optionally substituted with 1 to 3 groups independently selected from alkoxy; iv) 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S (wherein the 5-6 membered monocyclic heteroaryl is selected from -CN, -OH, halogen, C 1~3 Alkyl, and C 1~3 optionally substituted with 1 to 3 groups independently selected from alkoxy; v) halogens, C 1~3 Alkyl, -C(O)N(R 11 )2, -CN, -OH, and C 1~3 C optionally substituted with 1 to 3 groups independently selected from alkoxy 1~6 Alkyl and R 2 and R 3 are H, or R 2 and R 3 together form =O, R 4 , R 5 , R 6 , and R10 are each independently H, halogen, or C 1~3 Alkyl, or C 1~3 is an alkoxy, R 7 is H, or -OH, halogen, C 1~3 Alkoxy, and C 3~7 C optionally substituted with 1 to 3 groups independently selected from monocyclic cycloalkyl 1~6 is alkyl, R 8 and R 9 are, independently, i) H, ii) -OH, halogen, C 1~3 Alkyl, and C 1~3 C optionally substituted with 1 to 3 groups independently selected from alkoxy 3~7 monocyclic cycloalkyl, iii) 4- to 7-membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S (wherein the 4- to 6-membered monocyclic heterocyclyl is selected from -OH, halogen, oxo, C 1~3 Alkyl, and C 1~3 optionally substituted with 1 to 3 groups independently selected from alkoxy; iv) a)-CN, b) -OH, c) halogens, d) C 1~3 Alkoxy, e) -OH, halogen, C 1~3 Alkyl, and C 1~3 C optionally substituted with 1 to 3 groups independently selected from alkoxy 3~7 monocyclic cycloalkyl, and f) 5-6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S (wherein the 5-6 membered monocyclic heterocyclyl is not limited to -OH, halogen, oxo, C 1~3 Alkyl, and C 1~3 and optionally substituted with 1 to 3 groups independently selected from alkoxy. C optionally substituted with 1 to 6 groups independently selected from 1~6 Alkyl or

[0007] R 8 and R 9 together with the nitrogen to which they are attached form a 4-10 membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S, wherein the 4-10 membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic heterocyclyl is selected from 1-5 R 12 , where necessary, Each R 11 are, independently, i) H, ii) -CN, -OH, halogens, C 1~3 Alkoxy, and C 3~7 C optionally substituted with 1 to 6 groups independently selected from monocyclic cycloalkyl 1~6 Alkyl, iii) -CN, -OH, halogens, C 1~6 Alkyl, and C 1~6 C optionally substituted with 1 to 6 groups independently selected from alkoxy 3~7 Monocyclic cycloalkyl (where C 1~6 Alkyl is a group consisting of -CN, -OH, halogens, and C 1~3 optionally substituted with 1 to 3 groups independently selected from alkoxy; iv) 4-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S (wherein the 4-6 membered monocyclic heterocyclyl is selected from -CN, -OH, halogen, oxo, C 1~3 Alkyl, and C 1~3 and optionally substituted with 1 to 6 groups independently selected from alkoxy. and Each R 12 are, independently, i)-CN, ii) halogens, iii) -OH, iv) -OH, halogen, C 1~3 Alkoxy, and C 3~7 C optionally substituted with 1 to 3 groups independently selected from monocyclic cycloalkyl 1~6 Alkoxy, v) -OH, halogen, C 1~3 Alkoxy, and C 3~7 C optionally substituted with 1 to 3 groups independently selected from monocyclic cycloalkyl 1~6 Alkyl, vi) -COOH, or vii)-C(O)N(R 13 )2 (where each R 13 are independently H or C 1~6 alkyl) and X is -N(R 11 )- or -O-, where R 11 is R 1 and together with the nitrogen atom to which they are attached, 1 to 3 R b can form an optionally substituted 4- to 12-membered heterocyclyl; L is -L1-L2-L3-L4-L5-L6-, and each L1, L2, L3, L4, L5 and L6 is independently: i) 1 to 3 R b C, substituted as needed 3~12 cycloalkyl, ii) 1 to 3 R b C, substituted as needed 6~12 aryl, iii) 1 to 3 R b 4- to 12-membered heterocyclyl optionally substituted by iv) 1 to 3 R b 5-12 membered heteroaryl optionally substituted with v) direct binding; vi) 1 to 3 R d C, substituted as needed 1~12 Alkylene chain, vii) 1 to 3 Rd C, substituted as needed 2~12 Alkenylene chains, viii) 1 to 3 R d C, substituted as needed 2~12 Alkynylene chains, ix) -C(O)-, -C(O)O-, -O-, -N(R c )-, -S-, -C(S)-, -C(S)-O-, -S(O)2-, -S(O)=N-, -S(O)2NH-, -C(O)-N(R c )-, -C=N-, -OC(O)-N(R c )-, -OC(O)-O-, -(CH2) m -C(O)-, or -NH-(CH2) m -C(O)- (wherein m is 0, 1, 2, or 3) and Each R a are independently halo, -CN, 1 to 3 R d C, substituted as needed 1~3 Alkyl, 1 to 3 R d C, substituted as needed 3~6 Cycloalkyl, or -OR c and Each R b are independently hydrogen, oxo, imino, sulfoximino, halo, nitro, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Aryl, 5- to 12-membered heteroaryl, 4- to 12-membered heterocyclyl, -OR c , -C(O)-R c , -C(O)OR c , -C(O)-N(R c )(R c ), -N(R c )(R c ), -N(R c )C(O)-R c , -N(R c )C(O)OR c , -N(R c)C(O)N(R c )(R c ), -N(R c )S(O)2(R c ), -NR c S(O)2N(R c )(R c ), -N(R c )S(O)2O(R c ), -OC(O)R c , -OC(O)-N(R c )(R c ), -Si(R c )3, -SR c , -S(O)R c , -S(O)(NH)R c , -S(O)2R c or -S(O)N(R c )(R c ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Each of aryl, 5- to 12-membered heteroaryl, and 4- to 12-membered heterocyclyl is selected from 1 to 3 R d and optionally substituted with Each R c are independently hydrogen or C 1~6 is alkyl, Each R d are independently C optionally substituted with halo, oxo, —CN, —OH, or 1 to 3 fluoro; 1~6 Alkyl, or C 3~8 cycloalkyl, or -OC optionally substituted with 1 to 3 fluoro 1~6 is alkyl, W is -C(R g )- or -N-, Y is a direct bond, C 1~4 Alkylene chain, -C(O)-, -C(O)O-, -O-, -N(R g )-, -S- -C(S)-, -C(S)-O-, -OC(O)O-, -C(O)-N(R g)-, or -OC(O)-N(R g )- and The B ring is C 6~12 aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl, each of which is 1 to 3 R j , where necessary, Each R j are independently oxo, imino, sulfoximino, halo, nitro, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Aryl, 5- to 12-membered heteroaryl, 4- to 12-membered heterocyclyl, -OR g , -C(O)-R g , -C(O)OR g , -C(O)-N(R g )(R g ), -N(R g )(R g ), -N(R g )C(O)-R g , -N(R g )C(O)OR g , -N(R g )C(O)N(R g )(R g ), -N(R g )S(O)2(R g ), -NR g S(O)2N(R g )(R g ), -N(R g )S(O)2O(R g ), -OC(O)R g , -OC(O)-N(R g )(R g ), -Si(R g )3, -SR g , -S(O)R g , -S(O)(NH)R g , -S(O)2R g or -S(O)N(R g )(R g ), where C 1~6 Alkyl, C2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Each of aryl, 5- to 12-membered heteroaryl, and 4- to 12-membered heterocyclyl is selected from 1 to 3 R k and optionally substituted with R g is hydrogen or C 1~6 is alkyl, Each R k are independently C optionally substituted with halo, oxo, —CN, —OH, or 1 to 3 fluoro; 1~6 Alkyl, or C 3~8 cycloalkyl, or -OC optionally substituted with 1 to 3 fluoro 1~6 alkyl]. Also herein, a bifunctional compound represented by formula (I) [ka] or a pharmaceutically acceptable salt thereof is provided. [In the formula, R 1 teeth, i) halogen, C 1~3 Alkyl, -C(O)N(R 11 )2, -CN, -OH, and C 1~3 phenyl optionally substituted with 1 to 3 groups independently selected from alkoxy; ii) 4-6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S (wherein 4-6 membered monocyclic heterocyclyl is not limited to -CN, -OH, halogen, oxo, C 1~3 Alkyl, and C 1~3 optionally substituted with 1 to 3 groups independently selected from alkoxy; iii) -CN, -OH, halogens, C 1~3 Alkyl, and C 1~3 C optionally substituted with 1 to 3 groups independently selected from alkoxy 3~7Monocyclic or bridged bicyclic cycloalkyl (wherein C 1~3 Alkyl is a group that can be substituted with -OH, halogens, and C 1~3 optionally substituted with 1 to 3 groups independently selected from alkoxy; iv) 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S (wherein the 5-6 membered monocyclic heteroaryl is selected from -CN, -OH, halogen, C 1~3 Alkyl, and C 1~3 and optionally substituted with 1 to 3 groups independently selected from alkoxy. and R 2 and R 3 are H, or R 2 and R 3 together form =O, R 4 , R 5 , R 6 , and R 10 are each independently H, halogen, or C 1~3 Alkyl, or C 1~3 is an alkoxy, R 7 is H, or -OH, halogen, C 1~3 Alkoxy, and C 3~7 C optionally substituted with 1 to 3 groups independently selected from monocyclic cycloalkyl 1~6 is alkyl, R 8 and R 9 are, independently, i) H, ii) -OH, halogen, C 1~3 Alkyl, and C 1~3 C optionally substituted with 1 to 3 groups independently selected from alkoxy 3~7 monocyclic cycloalkyl, iii) 4- to 7-membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S (wherein the 4- to 6-membered monocyclic heterocyclyl is selected from -OH, halogen, oxo, C 1~3Alkyl, and C 1~3 optionally substituted with 1 to 3 groups independently selected from alkoxy; iv) a)-CN, b) -OH, c) halogens, d) C 1~3 Alkoxy, e) -OH, halogen, C 1~3 Alkyl, and C 1~3 C optionally substituted with 1 to 3 groups independently selected from alkoxy 3~7 monocyclic cycloalkyl, and f) 5-6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S (wherein the 5-6 membered monocyclic heterocyclyl is not limited to -OH, halogen, oxo, C 1~3 Alkyl, and C 1~3 and optionally substituted with 1 to 3 groups independently selected from alkoxy. C optionally substituted with 1 to 6 groups independently selected from 1~6 Alkyl or R 8 and R 9 together with the nitrogen to which they are attached form a 4-10 membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S, wherein the 4-10 membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic heterocyclyl is selected from 1-5 R 12 , where necessary, Each R 11 are, independently, i) H, ii) -CN, -OH, halogens, C 1~3 Alkoxy, and C 3~7 C optionally substituted with 1 to 6 groups independently selected from monocyclic cycloalkyl 1~6 Alkyl, iii) -CN, -OH, halogens, C 1~6 Alkyl, and C1~6 C optionally substituted with 1 to 6 groups independently selected from alkoxy 3~7 Monocyclic cycloalkyl (where C 1~6 Alkyl is a group consisting of -CN, -OH, halogens, and C 1~3 optionally substituted with 1 to 3 groups independently selected from alkoxy; iv) 4-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S (wherein the 4-6 membered monocyclic heterocyclyl is selected from -CN, -OH, halogen, oxo, C 1~3 Alkyl, and C 1~3 and optionally substituted with 1 to 6 groups independently selected from alkoxy. and Each R 12 are, independently, i)-CN, ii) halogens, iii) -OH, iv) -OH, halogen, C 1~3 Alkoxy, and C 3~7 C optionally substituted with 1 to 3 groups independently selected from monocyclic cycloalkyl 1~6 Alkoxy, v) -OH, halogen, C 1~3 Alkoxy, and C 3~7 C optionally substituted with 1 to 3 groups independently selected from monocyclic cycloalkyl 1~6 Alkyl, vi) -COOH, or vii)-C(O)N(R 13 )2 (where each R 13 are independently H or C 1~6 alkyl) and X is -N(R 11 )- or -O-, L is -L1-L2-L3-L4-L5-, and each L1, L2, L3, L4 and L5 is independently: i) 1 to 3 R b C, substituted as needed 3~12 cycloalkyl, ii) 1 to 3 R b C, substituted as needed 6~12 aryl, iii) 1 to 3 R b 4- to 12-membered heterocyclyl optionally substituted by iv) 1 to 3 R b 5-12 membered heteroaryl optionally substituted with v) direct binding; vi) 1 to 3 R d C, substituted as needed 1~12 Alkylene chain, vii) 1 to 3 R d C, substituted as needed 2~12 Alkenylene chains, viii) 1 to 3 R d C, substituted as needed 2~12 Alkynylene chains, ix) -C(O)-, -C(O)O-, -O-, -N(R c )-, -S-, -C(S)-, -C(S)-O-, -S(O)2-, -S(O)=N-, -S(O)2NH-, -C(O)-N(R c )-, -C=N-, -OC(O)-N(R c )-, -OC(O)-O-, -(CH2) m -C(O)-, or -NH-(CH2) m -C(O)- (wherein m is 0, 1, 2, or 3) and Each R a are independently halo, -CN, 1 to 3 R d C, substituted as needed 1~3 Alkyl, 1 to 3 R d C, substituted as needed 3~6 Cycloalkyl, or -OR c and Each R b are independently hydrogen, oxo, imino, sulfoximino, halo, nitro, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Aryl, 5- to 12-membered heteroaryl, 4- to 12-membered heterocyclyl, -OR c , -C(O)-R c , -C(O)OR c , -C(O)-N(R c )(R c ), -N(R c )(R c ), -N(R c )C(O)-R c , -N(R c )C(O)OR c , -N(R c )C(O)N(R c )(R c ), -N(R c )S(O)2(R c ), -NR c S(O)2N(R c )(R c ), -N(R c )S(O)2O(R c ), -OC(O)R c , -OC(O)-N(R c )(R c ), -Si(R c )3, -SR c , -S(O)R c , -S(O)(NH)R c , -S(O)2R c or -S(O)N(R c )(R c ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Each of aryl, 5- to 12-membered heteroaryl, and 4- to 12-membered heterocyclyl is selected from 1 to 3 R d and optionally substituted with Each R c are independently hydrogen or C 1~6 is alkyl, Each R dare independently C optionally substituted with halo, oxo, —CN, —OH, or 1 to 3 fluoro; 1~6 Alkyl, or C 3~8 cycloalkyl, or -OC optionally substituted with 1 to 3 fluoro 1~6 is alkyl, W is -C(R g )- or -N-, Y is a direct bond, C 1~4 Alkylene chain, -C(O)-, -C(O)O-, -O-, -N(R g )-, -S- -C(S)-, -C(S)-O-, -OC(O)O-, -C(O)-N(R g )-, or -OC(O)-N(R g )- and The B ring is C 6~12 aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl, each of which is 1 to 3 R j , where necessary, Each R j are independently oxo, imino, sulfoximino, halo, nitro, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Aryl, 5- to 12-membered heteroaryl, 4- to 12-membered heterocyclyl, -OR g , -C(O)-R g , -C(O)OR g , -C(O)-N(R g )(R g ), -N(R g )(R g ), -N(R g )C(O)-R g , -N(R g )C(O)OR g , -N(R g )C(O)N(R g )(R g ), -N(R g )S(O)2(R g ), -NR gS(O)2N(R g )(R g ), -N(R g )S(O)2O(R g ), -OC(O)R g , -OC(O)-N(R g )(R g ), -Si(R g )3, -SR g , -S(O)R g , -S(O)(NH)R g , -S(O)2R g or -S(O)N(R g )(R g ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Each of aryl, 5- to 12-membered heteroaryl, and 4- to 12-membered heterocyclyl is selected from 1 to 3 R k and optionally substituted with R g is hydrogen or C 1~6 is alkyl, Each R k are independently C optionally substituted with halo, oxo, —CN, —OH, or 1 to 3 fluoro; 1~6 Alkyl, or C 3~8 cycloalkyl, or -OC optionally substituted with 1 to 3 fluoro 1~6 alkyl].

[0008] In some embodiments, R 1 teeth, [ka] isn't it.

[0009] In some embodiments, R 1 but [ka] If [ka] The part is [ka] isn't it.

[0010] In some embodiments, R 2 and R 3 together form =O, and the compound has the structure of formula (Ia) [ka] It has.

[0011] In some embodiments, R 8 and R 9 together with the nitrogen to which they are attached to form piperidinyl, and the compound has the structure of formula (Ib) [ka] It has.

[0012] In some embodiments, X is —NH— and the compound has the structure of Formula (Ic) [ka] It has.

[0013] In other embodiments, X is —O— and the compound has the structure of formula (Id) [ka] It has.

[0014] In a further embodiment, X is —NH— and the compound has the structure of formula (Ie) [ka] It has.

[0015] In a further embodiment, X is —NH— and the compound has the structure of formula (If) [ka] It has.

[0016] In certain other embodiments, R 8 and R 9 are C 1~3 It is alkyl.

[0017] In some embodiments, R 1 is phenyl optionally substituted with halo, pyridinyl optionally substituted with halo, C 3~6 It is a cycloalkyl, or a 4- to 6-membered heterocyclyl.

[0018] In some embodiments, R 1 is 2-fluorophenyl, 3-fluoropyrini-4-yl, cyclopropyl or oxan-4-yl.

[0019] In some embodiments, each L1, L2, L3, L4, and L5 is independently: i) [ka] ii) [ka] iii) [ka] iv) [ka] v) direct binding; vi) C 1~3 an alkylene chain, or vii) -C(O)-, -O-, -C(O)-N(R c )-, -(CH2) m-C(O)- or -NH-(CH2) m -C(O)- (wherein m is 0, 1, 2, or 3) and R b is hydrogen or C 1~3 alkyl, and R c is H or C 1~3 It is alkyl.

[0020] Also provided herein is a pharmaceutical composition comprising a compound of Formula (I), or any one of the substructures or specific compounds of Examples 1-146, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

[0021] Further embodiments provide methods for treating a disease or disorder associated with increased hematopoietic progenitor kinase 1 (HPK1) activity, increasing T cell activation, treating cancer, inhibiting cancer cell growth or proliferation, treating or preventing Hepatitis B virus (HBV) infection, or treating or preventing human immunodeficiency virus (HIV) infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), or any one of the substructures or compounds of Examples 1-303. DETAILED DESCRIPTION OF THE INVENTION

[0022] Detailed Description The specific degradation of HPK1 can be achieved by using heterobifunctional small molecules to recruit HPK1 to ubiquitin ligase, thereby promoting the ubiquitination and proteasomal degradation of HPK1.Therefore, the present specification provides bifunctional compounds, each comprising an HPK1 binder covalently conjugated to a ligase harness moiety (LHM) for targeting ubiquitin ligase via a linker moiety (L).Preferably, the LHM targets cereblon (CRBN) protein, which is a substrate recognition subunit of two ubiquitin-RING E3 ubiquitin ligase complexes that are ubiquitously expressed and biologically important.See, for example, WO2019 / 099926, WO2020 / 023851, and US Patent Application Publication No. 2019 / 0192668.

[0023] One embodiment is a bifunctional compound of formula (I) [ka] or a pharmaceutically acceptable salt thereof. [In the formula, R 1 teeth, i) halogen, C 1~3 Alkyl, -C(O)N(R 11 )2, -CN, -OH, and C 1~3 phenyl optionally substituted with 1 to 3 groups independently selected from alkoxy; ii) 4-6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S (wherein 4-6 membered monocyclic heterocyclyl is selected from -CN, -OH, halogen, oxo, C 1~3 Alkyl, and C 1~3 optionally substituted with 1 to 3 groups independently selected from alkoxy; iii) -CN, -OH, halogens, C 1~3 Alkyl, and C 1~3 C optionally substituted with 1 to 3 groups independently selected from alkoxy 3~7Monocyclic or bridged bicyclic cycloalkyl (wherein C 1~3 Alkyl is a group that can be substituted with -OH, halogens, and C 1~3 optionally substituted with 1 to 3 groups independently selected from alkoxy; iv) 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S (wherein the 5-6 membered monocyclic heteroaryl is selected from -CN, -OH, halogen, C 1~3 Alkyl, and C 1~3 and optionally substituted with 1 to 3 groups independently selected from alkoxy. and R 2 and R 3 are H, or R 2 and R 3 together form =O, R 4 , R 5 , R 6 , and R 10 are each independently H, halogen, or C 1~3 Alkyl, or C 1~3 is an alkoxy, R 7 is H, or -OH, halogen, C 1~3 Alkoxy, and C 3~7 C optionally substituted with 1 to 3 groups independently selected from monocyclic cycloalkyl 1~6 is alkyl, R 8 and R 9 are, independently, i) H, ii) -OH, halogen, C 1~3 Alkyl, and C 1~3 C optionally substituted with 1 to 3 groups independently selected from alkoxy 3~7 monocyclic cycloalkyl, iii) 4- to 7-membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S (wherein the 4- to 6-membered monocyclic heterocyclyl is selected from -OH, halogen, oxo, C 1~3Alkyl, and C 1~3 optionally substituted with 1 to 3 groups independently selected from alkoxy; iv) a)-CN, b) -OH, c) halogens, d) C 1~3 Alkoxy, e) -OH, halogen, C 1~3 Alkyl, and C 1~3 C optionally substituted with 1 to 3 groups independently selected from alkoxy 3~7 monocyclic cycloalkyl, and f) 5-6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S (wherein the 5-6 membered monocyclic heterocyclyl is not limited to -OH, halogen, oxo, C 1~3 Alkyl, and C 1~3 and optionally substituted with 1 to 3 groups independently selected from alkoxy. C optionally substituted with 1 to 6 groups independently selected from 1~6 Alkyl or R 8 and R 9 together with the nitrogen to which they are attached form a 4-10 membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S, wherein the 4-10 membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic heterocyclyl is selected from 1-5 R 12 , where necessary, Each R 11 are, independently, i) H, ii) -CN, -OH, halogens, C 1~3 Alkoxy, and C 3~7 C optionally substituted with 1 to 6 groups independently selected from monocyclic cycloalkyl 1~6 Alkyl, iii) -CN, -OH, halogens, C 1~6 Alkyl, and C1~6 C optionally substituted with 1 to 6 groups independently selected from alkoxy 3~7 Monocyclic cycloalkyl (where C 1~6 Alkyl is a group consisting of -CN, -OH, halogens, and C 1~3 optionally substituted with 1 to 3 groups independently selected from alkoxy; iv) 4-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S (wherein the 4-6 membered monocyclic heterocyclyl is selected from -CN, -OH, halogen, oxo, C 1~3 Alkyl, and C 1~3 and optionally substituted with 1 to 6 groups independently selected from alkoxy. and Each R 12 are, independently, i)-CN, ii) halogens, iii) -OH, iv) -OH, halogen, C 1~3 Alkoxy, and C 3~7 C optionally substituted with 1 to 3 groups independently selected from monocyclic cycloalkyl 1~6 Alkoxy, v) -OH, halogen, C 1~3 Alkoxy, and C 3~7 C optionally substituted with 1 to 3 groups independently selected from monocyclic cycloalkyl 1~6 Alkyl, vi) -COOH, or vii)-C(O)N(R 13 )2 (where each R 13 are independently H or C 1~6 alkyl) and X is -N(R 11 )- or -O-, L is -L1-L2-L3-L4-L5-, and each L1, L2, L3, L4, and L5 is independently: i) 1 to 3 R b C, substituted as needed 3~12cycloalkyl, ii) 1 to 3 R b C, substituted as needed 6~12 aryl, iii) 1 to 3 R b 4- to 12-membered heterocyclyl optionally substituted by iv) 1 to 3 R b 5-12 membered heteroaryl optionally substituted with v) direct binding; vi) 1 to 3 R d C, substituted as needed 1~12 Alkylene chain, vii) 1 to 3 R d C, substituted as needed 2~12 Alkenylene chains, viii) 1 to 3 R d C, substituted as needed 2~12 an alkynylene chain, or ix) -C(O)-, -C(O)O-, -O-, -N(R c )-, -S-, -C(S)-, -C(S)-O-, -S(O)2-, -S(O)=N-, -S(O)2NH-, -C(O)-N(R c )-, -C=N-, -OC(O)-N(R c )-, -OC(O)-O-, -(CH2) m -C(O)-, or -NH-(CH2) m -C(O)- (wherein m is 0, 1, 2, or 3) and Each R a are independently halo, -CN, 1 to 3 R d C, substituted as needed 1~3 Alkyl, 1 to 3 R d C, substituted as needed 3~6 Cycloalkyl, or -OR c and Each R b are independently oxo, imino, sulfoximino, halo, nitro, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Aryl, 5- to 12-membered heteroaryl, 4- to 12-membered heterocyclyl, -OR c , -C(O)-R c , -C(O)OR c , -C(O)-N(R c )(R c ), -N(R c )(R c ), -N(R c )C(O)-R c , -N(R c )C(O)OR c , -N(R c )C(O)N(R c )(R c ), -N(R c )S(O)2(R c ), -NR c S(O)2N(R c )(R c ), -N(R c )S(O)2O(R c ), -OC(O)R c , -OC(O)-N(R c )(R c ), -Si(R c )3, -SR c , -S(O)R c , -S(O)(NH)R c , -S(O)2R c or -S(O)N(R c )(R c ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Each of aryl, 5- to 12-membered heteroaryl, and 4- to 12-membered heterocyclyl is selected from 1 to 3 R d and optionally substituted with Each R c are independently hydrogen or C 1~6 is alkyl, Each R dare independently C optionally substituted with halo, oxo, —CN, —OH, or 1 to 3 fluoro; 1~6 Alkyl, or C 3~8 cycloalkyl, or -OC optionally substituted with 1 to 3 fluoro 1~6 is alkyl, W is -C(R g )- or -N-, Y is a direct bond, C 1~4 Alkylene chain, -C(O)-, -C(O)O-, -O-, -N(R g )-, -S--C(S)-, -C(S)-O-, -OC(O)O-, -C(O)-N(R g )-, or -OC(O)-N(R g )- and The B ring is C 6~12 aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl, each of which is 1 to 3 R j , where necessary, Each R j are independently oxo, imino, sulfoximino, halo, nitro, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Aryl, 5- to 12-membered heteroaryl, 4- to 12-membered heterocyclyl, -OR g , -C(O)-R g , -C(O)OR g , -C(O)-N(R g )(R g ), -N(R g )(R g ), -N(R g )C(O)-R g , -N(R g )C(O)OR g , -N(R g )C(O)N(R g )(R g ), -N(R g )S(O)2(R g ), -NR gS(O)2N(R g )(R g ), -N(R g )S(O)2O(R g ), -OC(O)R g , -OC(O)-N(R g )(R g ), -Si(R g )3, -SR g , -S(O)R g , -S(O)(NH)R g , -S(O)2R g or -S(O)N(R g )(R g ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Each of aryl, 5- to 12-membered heteroaryl, and 4- to 12-membered heterocyclyl is selected from 1 to 3 R k and optionally substituted with R g is hydrogen or C 1~6 is alkyl, Each R k are independently C optionally substituted with halo, oxo, —CN, —OH, or 1 to 3 fluoro; 1~6 Alkyl, or C 3~8 cycloalkyl, or -OC optionally substituted with 1 to 3 fluoro 1~6 alkyl].

[0024] In more specific embodiments, compounds of formula (I) can be represented by one or more of the following substructures, where the variables are as defined herein: [ka]

[0025] In certain embodiments, R 1 teeth, [ka] isn't it.

[0026] In some embodiments, R 1 but [ka] If [ka] teeth, [ka] isn't it.

[0027] In some embodiments, the compound of Formula (I) is not any of the compounds disclosed in PCT / US2021 / 030928. HPK1 binder

[0028] Formula (A) illustrates the HPK1 binder portion of the bifunctional compound of formula (I). [ka] [In the formula, R 1 ~R 9 and X are defined above, and the wavy line illustrates the site of coupling to the linker moiety (L)].

[0029] In some embodiments, X is —NH— and Formula (A) is represented by Formula (A1): [ka]

[0030] In more specific embodiments, R 2 and R 3 forms an oxo, and R 8 and R 9 together with the nitrogen to which they are attached to form a piperidinyl, and the HPK1 binder moiety has the structure of formula (A2). [ka]

[0031] In even more specific embodiments, the compound of formula (A2) can have one of the following diastereomeric structures: [ka]

[0032] In other more specific embodiments, R 8 and R 9 are C 1~3 It is alkyl.

[0033] In yet other more specific embodiments, X is —O—.

[0034] In various embodiments, R 1 is phenyl optionally substituted with halo, pyridinyl optionally substituted with halo, C 3~6 It is a cycloalkyl, or a 4- to 6-membered heterocyclyl.

[0035] In more specific embodiments, R 1 is 2-fluorophenyl, 3-fluoropyrin-4-yl, cyclopropyl or oxan-4-yl.

[0036] In other more specific embodiments, R 1 teeth, [ka] is.

[0037] In other further embodiments, R 1 C optionally substituted with halo or CN 3~6 In more specific embodiments, R 1is cyclobutyl optionally substituted with halo or CN. In even more specific embodiments, R 1 teeth, [ka] is.

[0038] In other embodiments, R 1 is C 1~6 In more specific embodiments, R 1 is isopropyl.

[0039] In still other embodiments, X is —N(R 11 )- and R 11 and R 1 can be taken together with the nitrogen atom to which they are attached to form a 4- to 12-membered heterocyclyl optionally substituted with halo or CN, and the HPK1 binder moiety is represented by formula (A3). [ka]

[0040] In a more specific embodiment, formula (A3) has the following structure: [ka]

[0041] R 2 and R 3 In more specific embodiments of formula (A1), where R 8 and R 9 together with the nitrogen to which they are attached form one of the following heterocycles: [ka] where R j is H or halo.

[0042] In more specific embodiments, the HPK1 binder moiety has one of the following structures: [ka] have [In the formula, R 1 is phenyl optionally substituted with halo, pyridinyl optionally substituted with halo, C 3~6 cycloalkyl, or 4- to 6-membered heterocyclyl; R 4 , R 5 , R 6 and R 7 are independently H or C 1~3 alkyl].

[0043] In more specific embodiments, R 1 is cyclopropyl and R 4 , R 5 , and R 6 is hydrogen and R 7 is cyclopropyl. Ligase harness part (LHM)

[0044] The LHM moiety of the bifunctional compound of formula (I) targets the E3 ligase CRBN, which, when tethered by the bifunctional compound, can induce the ubiquitination of HPK1 and its subsequent degradation by the proteasome.

[0045] The LHM moiety of formula (I) typically comprises a glutarimide or uracil moiety coupled to a ring structure, as represented by formula (B): [ka] wherein W, Y and B are as defined herein.

[0046] In certain embodiments, W is —CH—, Y is a direct bond, and the B ring is [ka] where R j is H or C 1~3 It is alkyl.

[0047] In another embodiment, when W is -CH-, Y is a direct bond and the B ring is [ka] where R j is H, C 1~3 It is alkyl or halo.

[0048] In a more specific embodiment, when W is -CH-, Y is a direct bond and the B ring is [ka] where R j is H, C 1~3 It is alkyl or halo.

[0049] In other embodiments, W is -N-, Y is a direct bond, and the B ring is [ka] where R j is H or C 1~3 It is alkyl.

[0050] In still other embodiments, W is -CH-, Y is -NHC(O)-, and the B ring is [ka] where R j is H or C 1~3 It is alkyl. Linker

[0051] Each bifunctional compound of Formula (I) includes a linker (L), a bivalent moiety that couples the HPK1 binder moiety to the LHM. The structure (e.g., length or rigidity) of the linker moiety can affect the efficiency or selectivity of the degradation process. The linker includes a continuous sequence of covalent bonds between the respective attachment points to the HPK1 binder moiety and the LHM and their respective moieties, including the bonds indicated by the wavy lines in Formulas (A) and (B).

[0052] Typically, the linker moiety comprises multiple bivalent segments (i.e., L1, L2, L3, L4, and L5), which collectively contribute to the overall length and rigidity of the linker in addition to providing respective points of attachment to the HPK1 binder moiety and the LHM. In various embodiments, the linker segments L1, L2, L3, L4, and L5 each independently comprise: i) 1 to 3 R b C, substituted as needed 3~12 cycloalkyl, ii) 1 to 3 R b C, substituted as needed 6~12 aryl, iii) 1 to 3 R b 4- to 12-membered heterocyclyl optionally substituted by iv) 1 to 3 R b 5-12 membered heteroaryl optionally substituted with v) direct binding; vi) 1 to 3 R d C, substituted as needed 1~12 Alkylene chain, vii) 1 to 3 R d C, substituted as needed 2~12 Alkenylene chains, viii) 1 to 3 R d C, substituted as needed 2~12 Alkynylene chains, ix) -C(O)-, -C(O)O-, -O-, -N(R c)-, -S-, -C(S)-, -C(S)-O-, -S(O)2-, -S(O)=N-, -S(O)2NH-, -C(O)-N(R c )-, -C=N-, -OC(O)-N(R c )-, -OC(O)-O-, -(CH2) m -C(O)-, or -NH-(CH2) m -C(O)- (wherein m is 0, 1, 2, or 3) and R d , R c and R d is as defined herein.

[0053] Unless otherwise specified, divalent moieties described herein (e.g., L 1 or L 2 ) are not limited to the orientation in which they are depicted. For example, for a given L 1 For example, -C(O)-NH-, the manner in which it is attached to the rest of the molecule can be in either orientation, i.e., -C(O)-NH- or -NH-C(O)-, as long as the attachment does not violate the valence rules.

[0054] One or more linker segments can be a direct bond. For example, in a linker segment sequence represented by -L2-L3-L4--, if L3 is a direct bond, L2 and L4 are directly bonded to each other, so L3 is effectively eliminated.

[0055] In another embodiment, the linker has one or more rings, which tend to increase the rigidity of the linker. The combination of the chain linkage and ring(s) can be used to adjust the relative orientation of the bifunctional groups or the distance between them.

[0056] In more specific embodiments, each L1, L2, L3, L4 and L5 is independently: i) [ka] ii) [ka] iii) [ka] iv) [ka] v) direct binding; vi) C 1~3 an alkylene chain, or vii) -C(O)-, -O-, -C(O)-N(R c )-, -(CH2) m -C(O)- or -NH-(CH2) m -C(O)- (wherein m is 0, 1, 2, or 3) and R b is H or C 1~3 alkyl, and R c is H or C 1~3 It is alkyl.

[0057] In more specific embodiments, L is attached to the B ring by L, where L is a direct bond, —C(O)—, —N(R c )-(where R c is H or methyl), -O-, -CH2-, or -NH-CH2-C(O)-.

[0058] In further embodiments, when L is attached to the B ring through L1, -L2-L3-L4-L5- has one of the following structures or a stereoisomer thereof: [ka] [ka]

[0059] In other embodiments, the linker can have a particular stereochemical configuration at one or more stereocenters. Thus, in more specific embodiments, L has one of the following structures: [ka] [ka]

[0060] In other more specific embodiments, L is -L1-L2-L3-L4-L5-, and each L1, L2, L3, L4 and L5 is independently: i) [ka] ii) [ka] iii) [ka] iv) [ka] v) [ka] vi) direct binding; vii) 1 to 3 R d C, substituted as needed 1~3 Alkylene chain, viii) 1 to 3 R d C, substituted as needed 2~12 an alkynylene chain, or ix) -S(O)2-, -N(R c )-, -C(O)-, -O-, -C(O)-N(R c )-, -(CH2) m -C(O)- or -NH-(CH2) m -C(O)- (wherein m is 0, 1, 2, or 3) and where each R j are independently H, halo, hydroxy, C 1~3 Alkoxy, CN, C 1~6 alkyl, or haloalkyl; R d is a halo or C 1~3 is alkyl, R c is H or C 1~3 It is alkyl.

[0061] In more specific embodiments, each L1, L2, L3, L4 and L5 is the same or different and independently: i) [ka] [ka] ii) direct binding; iii)-(CH2)-, -CH(CH3)-, -C(CH3)2-, iv) -C≡C-, or v) -S(O)2-, -N(CH3)-, -C(O)-, -O-, -C(O)-N(CH3)-, -(CH2)-C(O)-, or -NH-(CH2) m -C(O)- (wherein m is 0, 1, 2, or 3) is.

[0062] In more specific embodiments, L has one of the following structures or a stereoisomer thereof: [ka] [ka] [ka] [ka]

[0063] In a further particular embodiment, L is -L1-L2-L3-L4-L5-L6- and has the following structure: [ka] Composition of the compound of formula (I)

[0064] The synthesis or construction of compounds of formula (I) can be carried out in multiple steps, which typically involve the separate preparation of the HPK1 binder and LHM moiety building blocks, followed by linking the respective building blocks by forming a covalent bond. Generally speaking, one or more linker precursors can be used to prepare either or both building blocks. The linker precursors can be prepared by one or more linker segments (L s ) and has a terminal reactive group for further coupling. Finally, the two building blocks can be coupled (by forming a further linker segment) to give compounds of formula (I).

[0065] The following schemes demonstrate general approaches to preparing the building blocks: Specific examples (Examples 1-303) were synthesized according to the general schemes described herein and characterized according to their respective physicochemical properties. General Scheme Reaction Scheme A [ka] Step 1—Preparation of Compound of Formula (3)

[0066] The compound of formula (3) can be prepared by combining compounds (1) and (2). Compounds (1) and (2) are commercially available or can be prepared by methods known in the art. Compounds (1) and (2) can be mixed in a suitable solvent, such as THF. After stirring at a temperature between 0°C and 100°C for 10 minutes to 24 hours or until the reaction is complete, the reaction is cooled to room temperature. The compound of formula (3) can be obtained by filtration or precipitation. Step 2—Preparation of Compound of Formula (4)

[0067] The compound of formula (4) can be prepared by chlorination of the compound of formula (3) by methods known in the art. The compound of formula (3) can be mixed with POCl3 in a suitable solvent, such as toluene. After stirring at a temperature between 0°C and 100°C for 10 minutes to 24 hours or until the reaction is complete, the reaction is cooled to room temperature. The solvent can then be removed under reduced pressure. To extract the compound of formula (4), an organic solvent, such as ethyl acetate, can be added, followed by washing with water and brine. The organic phase can be concentrated to provide the compound of formula (4). The compound of formula (4) can be purified by any suitable method known in the art, such as chromatography on silica gel, trituration, precipitation, or crystallization. Step 3—Preparation of Compound of Formula (5)

[0068] The compound of formula (5) can be prepared by reduction of the compound of formula (4) by methods known in the art. The compound of formula (4) can be mixed with zinc powder and ammonium chloride in a suitable solvent, such as THF, MeOH, or water, or a mixture of solvents such as THF, MeOH, and water. After stirring at a temperature between 0°C and 100°C for 1 hour to 24 hours or until the reaction is complete, the reaction is cooled to room temperature and filtered through a bed of celite. To extract the compound of formula (5), an organic solvent such as ethyl acetate can be added, followed by washing with water and brine. The organic phase can be concentrated to obtain the compound of formula (5). The compound of formula (5) can be purified by any suitable method known in the art, such as chromatography on silica gel, trituration, precipitation, or crystallization. Step 4—Preparation of Compound of Formula (6)

[0069] The compound of formula (6) can be prepared by cyclization of the compound of formula (5) by methods known in the art. The compound of formula (5) can be mixed with trimethyl orthoformate and formic acid. After stirring at a temperature between 0°C and 100°C for 1 hour to 24 hours or until the reaction is complete, the remaining solvent is removed by distillation. To extract the compound of formula (6), an organic solvent such as dichloromethane can be added, followed by washing with water and brine. The organic phase can be concentrated to obtain the compound of formula (6). The compound of formula (6) can be purified by any suitable method known in the art, such as chromatography on silica gel, trituration, precipitation, crystallization, or washing with an organic solvent such as an ether, including but not limited to methyl t-butyl ether. Step 5—Preparation of Compound of Formula (7)

[0070] The compound of formula (7) can be prepared by fluorination of the compound of formula (6) by methods known in the art. The compound of formula (6) can be mixed with cesium fluoride in a solvent such as DMF. After stirring at a temperature between room temperature and 110°C for 1 hour to 24 hours or until the reaction is complete, the reaction is cooled to between 0°C and room temperature by adding ice water or by adding the reaction mixture to ice water. To extract the compound of formula (7), an organic solvent such as ethyl acetate can be added, followed by washing with water and brine. The organic phase can be concentrated to obtain the compound of formula (7). The compound of formula (7) can be purified by any suitable method known in the art, such as chromatography on silica gel, trituration, precipitation, or crystallization. Step 6—Preparation of Compound of Formula (9)

[0071] Compounds of formula (9) can be prepared by methods known in the art by combining compounds of formula (6) and formula (8) or by combining compounds of formula (7) and formula (8). Compounds of formula (8) are commercially available or can be prepared by methods known in the art. Compounds of formula (8) can be mixed with compounds of either formula (6) or (7) in a suitable solvent, such as NMP or DMA, in the presence of a base, such as sodium hydride. After stirring at a temperature between room temperature and 100°C for 1 hour to 24 hours or until the reaction is complete, the reaction mixture can be added to water and treated with an acid, such as 10% citric acid. Compounds of formula (9) can be obtained by filtration or precipitation. Step 7 - Preparation of Compound of Formula (12)

[0072] The compound of formula (12) can be prepared by combining a compound of formula (10) and a compound of formula (11) by methods known in the art. Compounds of formula (10) and (11) are commercially available or can be prepared by methods known in the art. Compounds of formula (10) and (11) can be mixed in a suitable solvent, such as DMF, in the presence of a base, such as potassium carbonate. After stirring at a temperature between room temperature and 50°C for 1 hour to 24 hours or until the reaction is complete, the reaction is cooled to room temperature. To extract the compound of formula (12), an organic solvent, such as ethyl acetate, can be added, followed by washing with water and brine. The organic phase can be concentrated to obtain the compound of formula (12). The compound of formula (12) can be purified by any suitable method known in the art, such as chromatography on silica gel, trituration, precipitation, or crystallization. Step 8 - Preparation of Compound of Formula (13)

[0073] Compounds of formula (13) can be prepared by reductive amination of compounds of formula (12) by methods known in the art. Compounds of formula (12) and an amine, either commercially available or synthesized by methods known in the art, can be combined with a reducing agent, such as sodium triacetoxyborohydride or sodium cyanoborohydride, in the presence of an acid, such as acetic acid, or a Lewis acid, such as zinc chloride, in a suitable solvent, such as dichloroethane or methanol. After stirring at a temperature between 0°C and room temperature for 1 hour to 24 hours or until the reaction is complete, the reaction can be added to an aqueous solution, such as saturated aqueous sodium bicarbonate. To extract compounds of formula (13), an organic solvent, such as methylene chloride, can be added, followed by washing with water and brine. Compounds of formula (13) can be purified by any suitable method known in the art, such as chromatography on silica gel, trituration, precipitation, or crystallization. Step 9 - Preparation of HPK1 binder building blocks

[0074] The HPK1 binder building block can be prepared by combining a compound of formula (9) and a compound of formula (13) by methods known in the art. Compounds of formula (9) and (13) can be mixed in a suitable solvent, such as a mixture of dimethoxyethane and water or a mixture of DMAc and water, in the presence of a catalyst such as tetrakis(triphenylphosphine)palladium and a base such as cesium carbonate, sodium carbonate, or tribasic potassium phosphate. After stirring at a temperature between 50°C and 150°C for 1 to 24 hours, the reaction is allowed to cool to room temperature. The crude product can be filtered and concentrated under reduced pressure. To extract the compound, an organic solvent such as methylene chloride can be added, followed by washing with water and brine. The organic phase can be concentrated, and the resulting product can be purified by any suitable method known in the art, such as chromatography on silica gel, reverse-phase chromatography, trituration, precipitation, or crystallization. The resulting HPK1 binder building block can be further elaborated chemically, for example, as shown in Reaction Scheme C. Reaction Scheme B1 Pyridine / pyrimidine [ka] Step 1—Preparation of Compound of Formula (16)

[0075] The compound of formula (16) can be prepared by combining compounds of formula (14) (or 14') and (15). Compounds of formula (14) (or 14') and (15) are commercially available or can be prepared by methods known in the art. Compounds of formula (14) (or 14') and (15) can be combined with a suitable base, such as sodium hydride, in a suitable solvent, such as DMA. After stirring at a temperature between 0°C and 100°C for 10 minutes to 24 hours, or until the reaction is complete, the reaction is allowed to cool to room temperature. The compound of formula (16) can be obtained by filtration or precipitation and subsequently purified by any suitable method known in the art, such as chromatography on silica gel, reverse-phase chromatography, trituration, precipitation, or crystallization. Step 2—Preparation of Compound of Formula (18)

[0076] Compounds of formula (18) can be prepared by combining compounds of formula (16) and formula (17) by methods known in the art. Compounds of formula (16) and compound (17) can be mixed in a suitable solvent, such as a mixture of dioxane and water, in the presence of a catalyst, such as Pd(dppf)Cl-DCM, and a base, such as cesium carbonate, sodium carbonate, or potassium phosphate tribasic. After stirring at 100°C for 1-3 hours, the reaction is allowed to cool to room temperature. The crude product can be filtered and concentrated under reduced pressure. To extract the compound, an organic solvent, such as methylene chloride, can be added, followed by washing with water and brine. The organic phase can be concentrated to provide compounds of formula (18), which can be purified by any suitable method known in the art, such as chromatography on silica gel, reverse-phase chromatography, trituration, precipitation, or crystallization. Step 3—Preparation of Compound of Formula (19)

[0077] The compound of formula (19) can be prepared by methods known in the art. The compound of formula (18) can be dissolved in a 1:1 mixture of MeOH and THF, a catalyst such as Pd / C can be added, and the mixture can be stirred under a hydrogen atmosphere for 2 to 24 hours. The reaction can be filtered through Celite and concentrated to provide the compound of formula (19), which can be purified by any suitable method known in the art, such as chromatography on silica gel, reverse-phase chromatography, trituration, precipitation, or crystallization. Step 4—Preparation of Compound of Formula (20)

[0078] The compound of formula (20) can be prepared by methods known in the art. The compound of formula (19) can be dissolved in a suitable solvent, such as DCM, treated with an acid, such as TFA, and stirred at room temperature for 2 to 24 hours. The crude reaction can be concentrated to provide the compound of formula (20) as a salt, which can be purified by any suitable method known in the art, such as chromatography on silica gel, reverse-phase chromatography, trituration, precipitation, or crystallization. Reaction Scheme B2 Aminophenyl [ka] Step 1—Preparation of Compound of Formula (23)

[0079] Compounds of formula (23) can be prepared by combining compounds of formula (21) and (22). Compounds of formula (21) and (22) are commercially available or can be prepared by methods known in the art. Compounds of formula (21) and (22) can be combined with a suitable catalyst, such as XantPhos Pd G3, and a base, such as CsCO3, in a suitable solvent, such as dioxane. After stirring at a temperature of about 100°C for 10 minutes to 24 hours, or until the reaction is complete, the reaction is allowed to cool to room temperature. The reaction can be filtered through Celite and concentrated to provide compounds of formula (23), which can be purified by any suitable method known in the art, such as chromatography on silica gel, reverse-phase chromatography, trituration, precipitation, or crystallization. Step 2—Preparation of Compound of Formula (24)

[0080] Compounds of formula (24) can be prepared by combining compounds of formula (23) and compound (17) by methods known in the art. Compounds of formula (23) and compound (17) can be mixed in a suitable solvent, such as a mixture of dioxane and water, in the presence of a catalyst, such as Pd(dppf)Cl-DCM, and a base, such as cesium carbonate, sodium carbonate, or potassium phosphate tribasic. After stirring at 100°C for 1-3 hours, the reaction is allowed to cool to room temperature. The crude product can be filtered and concentrated under reduced pressure. To extract the compound, an organic solvent, such as methylene chloride, can be added, followed by washing with water and brine. Compounds of formula (24) can be obtained by any suitable method known in the art, such as chromatography on silica gel, reverse-phase chromatography, trituration, precipitation, or crystallization. Step 3—Preparation of Compound of Formula (25)

[0081] The compound of formula (25) can be made by methods known in the art. The compound of formula (24) can be dissolved in a 1:1 mixture of MeOH and THF, a catalyst such as Pd / C can be added, and stirred under a hydrogen atmosphere for 2 to 24 hours. The reaction can be filtered through Celite and concentrated to provide the compound of formula (25), which can be purified by any suitable method known in the art, such as chromatography on silica gel, reverse-phase chromatography, trituration, precipitation, or crystallization. Step 4 - Preparation of Compound of Formula (26)

[0082] Compounds of formula (26) can be made by methods known in the art. Compounds of formula (25) can be dissolved in a suitable solvent, such as DCM, treated with an acid, such as TFA, and stirred at room temperature for 2-24 hours. The crude reaction can be concentrated to provide compounds of formula (26) as salts, which can be purified by any suitable method known in the art, such as chromatography on silica gel, reverse-phase chromatography, trituration, precipitation, or crystallization. Reaction Scheme B3 Phenyl ether [ka] Step 1—Preparation of Compound of Formula (30)

[0083] Compounds of formula (30) can be prepared by combining compounds of formula (28) and (29). Compounds of formula (28) and (29) are commercially available or can be prepared by Mitsunobu coupling methods known in the art. Compounds of formula (28) and (29) can be combined with appropriate reagents, such as DIAD and triphenylphosphine, and a base, such as TEA, in a suitable solvent, such as THF, at 0°C. After stirring at room temperature for 10 minutes to 24 hours, or until the reaction is complete, the reaction is allowed to cool to room temperature. The crude reaction can be purified by any suitable method known in the art, such as chromatography on silica gel, reverse-phase chromatography, trituration, precipitation, or crystallization, to provide compounds of formula (30). Step 2—Preparation of Compound of Formula (31)

[0084] The compound of formula (31) can be prepared by combining the compound of formula (30) and compound (17) by methods known in the art. The compound of formula (30) and compound (17) can be mixed in a suitable solvent, such as a mixture of dioxane and water, in the presence of a catalyst, such as Pd(dppf)Cl-DCM, and a base, such as cesium carbonate, sodium carbonate, or potassium phosphate tribasic. After stirring at 100°C for 1-3 hours, the reaction is allowed to cool to room temperature. The crude product can be filtered and concentrated under reduced pressure. To extract the compound, an organic solvent, such as methylene chloride, can be added, followed by washing with water and brine. The organic phase can be concentrated, and the resulting product can be purified by any suitable method known in the art, such as chromatography on silica gel, reverse-phase chromatography, trituration, precipitation, or crystallization, to obtain the compound of formula (31). Step 3—Preparation of Compound of Formula (32)

[0085] The compound of formula (32) can be made by methods known in the art. The compound of formula (31) can be dissolved in a 1:1 mixture of MeOH and THF, a catalyst such as Pd / C can be added, and stirred under a hydrogen atmosphere for 2 to 24 hours. The reaction can be filtered through Celite and concentrated to provide the compound of formula (32), which can be purified by any suitable method known in the art, such as chromatography on silica gel, reverse-phase chromatography, trituration, precipitation, or crystallization. Step 4—Preparation of Compound of Formula (33)

[0086] Compounds of formula (33) can be made by methods known in the art. Compounds of formula (32) can be dissolved in a suitable solvent, such as DCM, treated with an acid, such as TFA, and stirred at room temperature for 2-24 hours. The crude reaction can be concentrated to provide compounds of formula (33) as salts, which can be purified by any suitable method known in the art, such as chromatography on silica gel, reverse-phase chromatography, trituration, precipitation, or crystallization. Reaction Scheme B4 Dihydrouracil [ka] Step 1—Preparation of Compound of Formula (36)

[0087] Compounds of formula (36) can be prepared by combining compounds of formula (34) and (35), which are commercially available or can be prepared by coupling methods known in the art. Compounds of formula (34) and (35) can be mixed with a suitable base, such as cesium carbonate, in a suitable solvent, such as DMF. After stirring at a temperature of about 90°C for 10 minutes to 24 hours, or until the reaction is complete, the reaction is allowed to cool to room temperature. To extract the compound, an organic solvent, such as methylene chloride, can be added, followed by washing with water and brine. The organic phase can be concentrated, and the resulting product can be purified by any suitable method known in the art, such as chromatography on silica gel, reverse-phase chromatography, trituration, precipitation, or crystallization. Step 2—Preparation of Compound of Formula (37)

[0088] The compound of formula (37) can be made by reduction methods known in the art. The compound of formula (36) can be combined with Fe powder, acetic acid, and water in a suitable solvent, such as EtOH. After stirring at about 50° C. for 2-4 hours, the crude reaction can be filtered to provide the compound of formula (37), which can be purified by any suitable method known in the art, such as chromatography on silica gel, reverse-phase chromatography, trituration, precipitation, or crystallization, to provide the compound of formula (37). Step 3—Preparation of Compound of Formula (38)

[0089] The compound of formula (38) can be obtained by methods known in the art. The compound of formula (37) can be combined with acrylic acid in a suitable solvent, such as dioxane, and stirred at 90° C. for 2 to 4 hours. The crude reaction can be purified by any suitable method known in the art, such as chromatography on silica gel, reverse phase chromatography, trituration, precipitation, or crystallization, to obtain the compound of formula (38). Step 4 - Preparation of Compound of Formula (39)

[0090] The compound of formula (39) can be obtained by methods known in the art. The compound of formula (38) can be combined with urea and acetic acid and stirred at about 90° C. for 12 to 48 hours. To extract the compound, an organic solvent such as methylene chloride can be added, followed by washing with water and brine. The organic phase can be concentrated, and the resulting product can be purified by any suitable method known in the art, such as chromatography on silica gel, reverse-phase chromatography, trituration, precipitation, or crystallization, to obtain the compound of formula (39). Step 5—Preparation of Compound of Formula (40)

[0091] The compound of formula (40) can be prepared by methods known in the art. The compound of formula (39) can be dissolved in an anhydrous solvent such as THF, a catalyst such as Pd / C can be added, and stirred under a hydrogen atmosphere for 2 to 24 hours. The reaction can be filtered through Celite and concentrated to provide the compound of formula (40), which can be purified by any suitable method known in the art, such as chromatography on silica gel, reverse-phase chromatography, trituration, precipitation, or crystallization. Reaction Scheme B5 Amide coupling of the second linker ring [ka] Step 1—Preparation of Compound of Formula (43)

[0092] Compounds of formula (43) can be made by combining compounds of formula (41) and (42) using methods known in the art. Compounds of formula (41) and (42) can be combined with a coupling reagent such as BOP and a base such as DIEA in a suitable solvent such as DMF. After stirring at room temperature for 2-24 hours, compounds of formula (43) can be purified by any suitable method known in the art, such as chromatography on silica gel, reverse-phase chromatography, trituration, precipitation, or crystallization. Step 2 - Preparation of Compound of Formula (44)

[0093] Compounds of formula (44) can be made using methods known in the art. Compounds of formula (43) can be dissolved in a solvent such as DCM and treated with a suitable acid such as TFA. After stirring at room temperature for 2-24 hours, the reaction can be concentrated to provide compounds of formula (44) as salts, which can be purified by any suitable method known in the art, such as chromatography on silica gel, reverse-phase chromatography, trituration, precipitation, or crystallization. Reaction Scheme B6 Reductive amination of the second linker ring [ka] Step 1—Preparation of Compound of Formula (47)

[0094] Compounds of formula (47) can be made by combining compounds of formula (45) and (46) using methods known in the art. Compounds of formula (45) and (46) can be combined with NaCNBH3 and acetic acid in a suitable solvent, such as MeOH. After stirring at room temperature for 2-24 hours, the crude reaction can be diluted with brine and extracted with a solvent, such as DCM. Compounds of formula (47) can be purified by any suitable method known in the art, such as chromatography on silica gel, reverse-phase chromatography, trituration, precipitation, or crystallization. Step 2—Preparation of Compound of Formula (48)

[0095] Compounds of formula (48) can be made using methods known in the art. Compounds of formula (47) can be dissolved in a solvent such as DCM and treated with a suitable acid such as TFA. After stirring at room temperature for 2-24 hours, the reaction can be concentrated to provide compounds of formula (48) as salts, which can be purified by any suitable method known in the art, such as chromatography on silica gel, reverse-phase chromatography, trituration, precipitation, or crystallization. Reaction Scheme B7 Further aminophenyl groups [ka]

[0096] Compounds of formula (55) can be prepared by methods known in the art. For example, compounds of formula (51) can be prepared by coupling compounds of formula (50) and (17) using standard Suzuki-Miyaura conditions in a suitable solvent such as dioxane in the presence of a base such as aqueous potassium carbonate and a catalyst such as Pd(dppf)Cl, typically using thermal heating or microwave irradiation. Compounds of formula (53) can be prepared by coupling compounds of formula (51) and (52) using typical Buchwald-Hartwig amination conditions in a suitable solvent such as dioxane in the presence of a base such as cesium carbonate and a catalyst such as 1,3-bis[2,6-bis(pentan-3-yl)phenyl]-2H-imidazole, 3-chloropyridine, or palladium chloride, typically using thermal heating or microwave irradiation. Compounds of formula (54) can be obtained by subjecting compounds of formula (53) to hydrogenolysis / hydrogenation conditions, such as stirring under 1 atmosphere or greater of hydrogen gas in the presence of a catalyst, such as palladium on carbon, in a suitable solvent, such as a mixture of THF and isopropyl alcohol. Compounds of formula (55) can be made by treating compounds of formula (54) with an acid, such as TFA, in a suitable solvent, such as HFIP. Compounds of formula (55) and their precursors can be isolated and purified by suitable methods known in the art, for example, by partitioning the reaction mixture between an aqueous phase and an organic solvent, followed by isolating the desired product by filtration or concentration of the relevant layer. The crude product can be purified by techniques such as chromatography on silica gel, reverse-phase chromatography, trituration, precipitation, or crystallization. Reaction Scheme B8 More pyridine [ka]

[0097] Compounds of formula (62) can be prepared by methods known in the art. For example, compounds of formula (58) can be prepared by coupling compounds of formulas (56) and (57) using standard Suzuki-Miyaura conditions in a suitable solvent such as dioxane in the presence of a base such as aqueous potassium phosphate and a catalyst such as Pd(dppf)Cl, typically using thermal heating or microwave irradiation. Compounds of formula (59) can be obtained by subjecting compounds of formula (58) to hydrogenolysis / hydrogenation conditions such as stirring under 1 atmosphere or greater of hydrogen gas in a suitable solvent such as THF in the presence of a catalyst such as palladium on carbon and Pd(OH). Compounds of formula (61) can be prepared by heating a mixture of compounds of formulas (59) and (60) in a suitable solvent such as DMSO in the presence of a base such as DIPEA under SNAr conditions. Compounds of formula (62) can be prepared by treating compounds of formula (61) with an acid such as HCl in a suitable solvent such as a DCM / dioxane mixture. Compounds of formula (62) and their precursors can be isolated and purified by suitable methods known in the art, such as partitioning the reaction mixture between an aqueous phase and an organic solvent, followed by isolating the desired product by filtration or concentration of the relevant layer. The crude product can be further purified by techniques such as chromatography on silica gel, reverse-phase chromatography, trituration, precipitation, or crystallization. Reaction Scheme B9 More pyridine [ka]

[0098] Compounds of formula (68) can be prepared by methods known in the art. For example, compounds of formula (65) can be produced by heating a mixture of compounds of formulas (63) and (64) in the presence of a base such as DIPEA in a suitable solvent such as DMSO under SNAr conditions. Compounds of formula (66) can be obtained by coupling compounds of formulas (65) and (17') using standard Suzuki-Miyaura conditions in the presence of a base such as aqueous cesium carbonate and a catalyst such as Pd(dppf)Cl-DCM in a suitable solvent such as dioxane, typically using thermal heating or microwave irradiation. Compounds of formula (67) can be obtained by subjecting compounds of formula (66) to hydrogenolysis / hydrogenation conditions such as stirring under 1 atmosphere or greater of hydrogen gas in a suitable solvent such as a mixture of THF and EtOH in the presence of a catalyst such as palladium on carbon. Compounds of formula (68) can be prepared by treating compounds of formula (67) with an acid such as HCl in a suitable solvent such as a DCM / dioxane mixture. Compounds of formula (68) and their precursors can be isolated and purified by suitable methods known in the art, such as partitioning the reaction mixture between an aqueous phase and an organic solvent, followed by isolating the desired product by filtration or concentration of the relevant layer. The crude product can be further purified by techniques such as chromatography on silica gel, reverse-phase chromatography, trituration, precipitation, or crystallization. Reaction Scheme B10 More pyridine [ka]

[0099] Compounds of formula (72) can be prepared by methods known in the art. For example, compounds of formula (71) can be produced by heating a mixture of compounds of formulas (69) and (70) under SNAr conditions in a suitable solvent, such as DMSO, in the presence of a base, such as DIPEA. Compounds of formula (72) can be prepared by treating compounds of formula (71) with an acid, such as HCl, in a suitable solvent, such as a DCM / dioxane mixture. Compounds of formula (72) and their precursors can be isolated and purified by suitable methods known in the art, such as partitioning the reaction mixture between an aqueous phase and an organic solvent, followed by isolating the desired product by filtration or concentration of the relevant layer. The crude product can be further purified by techniques such as chromatography on silica gel, reverse-phase chromatography, trituration, precipitation, or crystallization. Reaction Scheme B11 More pyridine [ka]

[0100] Compounds of formula (81) can be prepared by methods known in the art. For example, compounds of formula (75) can be obtained by coupling compounds of formulas (73) and (74) using typical Buchwald-Hartwig amination conditions in a suitable solvent such as dioxane in the presence of a base such as sodium tert-butoxide, a ligand such as XantPhos, and a catalyst such as Pd(dba) typically using thermal heating or microwave irradiation. Compounds of formula (76) can be produced by coupling compounds of formulas (75) and (17') using standard Suzuki-Miyaura conditions in a suitable solvent such as a THF / water mixture in the presence of a base such as potassium carbonate and a catalyst such as Pd(PPh) typically using thermal heating or microwave irradiation. Compounds of formula (77) can be obtained by subjecting compounds of formula (76) to hydrogenolysis / hydrogenation conditions, such as stirring under 1 atmosphere or greater of hydrogen gas in the presence of a catalyst, such as palladium on carbon, in a suitable solvent, such as THF. Compounds of formula (78) can be prepared by treating compounds of formula (77) with an acid, such as HCl, in a suitable solvent, such as dioxane. Compounds of formula (80) can be produced by coupling compounds of formula (78) and (79) under standard amide bond-forming conditions, such as BOP, in a suitable solvent, such as DMF, in the presence of a base, such as DIPEA. Compounds of formula (81) can be prepared by treating compounds of formula (80) with an acid, such as TFA, in a suitable solvent, such as HFIP. Compounds of formula (81) and their precursors can be isolated and purified by suitable methods known in the art, for example, by partitioning the reaction mixture between an aqueous phase and an organic solvent, followed by isolating the desired product by filtration or concentration of the relevant layer. The crude product can be further purified by techniques such as chromatography on silica gel, reverse phase chromatography, trituration, precipitation, or crystallization. Reaction Scheme B12 urea [ka]

[0101] Compounds of formula (87) can be prepared by methods known in the art. For example, compounds of formula (83) can be prepared by heating a mixture of compounds of formula (59) and (82) under SNAr conditions in a suitable solvent such as DMSO in the presence of a base such as triethylamine. Compounds of formula (84) can be prepared by treating compounds of formula (83) with an acid such as TFA in a suitable solvent such as DCM. Compounds of formula (86) can be prepared by reacting compounds of formula (84) with compounds of formula (85) in the presence of a catalyst and a base such as pyridine and a solvent such as DCM, typically with heating. Compounds of formula (87) can be prepared by treating compounds of formula (86) with an acid such as TFA in a suitable solvent such as DCM. Compounds of formula (87) and their precursors can be isolated and purified by suitable methods known in the art, for example, by partitioning the reaction mixture between an aqueous phase and an organic solvent, followed by isolating the desired product by filtration or concentration of the relevant layer. The crude product can be further purified by techniques such as chromatography on silica gel, reverse phase chromatography, trituration, precipitation, or crystallization. Reaction Scheme B13 Sulfonamides [ka]

[0102] Compounds of formula (92) can be prepared by methods known in the art. For example, compounds of formula (90) can be prepared by reacting compounds of formula (88) with compounds of formula (89) in the presence of a base such as DIPEA in a suitable solvent such as DCM. Compounds of formula (91) can be prepared by treating compounds of formula (90) with an acid such as TFA in a suitable solvent such as DCM. Compounds of formula (92) can be prepared by heating a mixture of compounds of formula (59) and (91) in the presence of a base such as DIPEA in a suitable solvent such as DMSO under SNAr conditions. Compounds of formula (92) and their precursors can be isolated and purified by suitable methods known in the art, such as partitioning the reaction mixture between an aqueous phase and an organic solvent, followed by isolating the desired product by filtration or concentration of the relevant layer. The crude product can be further purified by techniques such as chromatography on silica gel, reverse-phase chromatography, trituration, precipitation, or crystallization. Reaction Scheme B14 Further phenyldihydrouracils [ka]

[0103] Compounds of formula (99) can be prepared by methods known in the art. For example, compounds of formula (95) can be prepared by coupling compounds of formula (93) and (94) using typical Buchwald-Hartwig amination conditions in a suitable solvent such as dioxane in the presence of a base such as cesium carbonate and a catalyst such as 1,3-bis[2,6-bis(pentan-3-yl)phenyl]-2H-imidazole, 3-chloropyridine, or palladium chloride, typically using thermal heating or microwave irradiation. Compounds of formula (96) can be produced by exposing compounds of formula (95) to reducing conditions such as zinc powder and aqueous ammonium chloride in a suitable solvent such as THF. Compounds of formula (97) can be obtained by treating compounds of formula (96) with acrylic acid in a suitable solvent such as toluene, typically with heating. Compounds of formula (98) can be obtained by treating compounds of formula (97) with urea in refluxing acetic acid. Compounds of formula (99) can be prepared by treating compounds of formula (98) with an acid such as TFA in a suitable solvent such as HFIP. Compounds of formula (99) and their precursors can be isolated and purified by suitable methods known in the art, such as partitioning the reaction mixture between an aqueous phase and an organic solvent, followed by isolating the desired product by filtration or concentration of the relevant layer. The crude product can be further purified by techniques such as chromatography on silica gel, reverse-phase chromatography, trituration, precipitation, or crystallization. Reaction Scheme B15 Further pyridyldihydrouracils [ka]

[0104] Compounds of formula (107) can be prepared by methods known in the art. For example, compounds of formula (101) can be obtained by treating compounds of formula (100) with acrylic acid in a suitable solvent such as toluene, typically with heating. Compounds of formula (102) can be obtained by treating compounds of formula (101) with SOCl in methanol as a solvent. Compounds of formula (103) can be produced by treating compounds of formula (102) with potassium cyanate in a suitable solvent such as an acetic acid / DCM mixture. Compounds of formula (104) can be obtained by treating compounds of formula (103) with a base such as potassium silanolate in a suitable solvent such as THF. Compounds of formula (106) can be prepared using typical Buchwald-Hartwig amination conditions by coupling compounds of formulas (104) and (105) in a suitable solvent such as dioxane in the presence of a base such as cesium carbonate and a catalyst such as 1,3-bis[2,6-bis(pentan-3-yl)phenyl]-2H-imidazole, 3-chloropyridine, or palladium chloride, typically using thermal heating or microwave irradiation. Compounds of formula (107) can be prepared by treating compounds of formula (106) with an acid such as HCl in a suitable solvent such as dioxane. Compounds of formula (107) and their precursors can be isolated and purified by suitable methods known in the art, for example, by partitioning the reaction mixture between an aqueous phase and an organic solvent, followed by isolating the desired product by filtration or concentration of the relevant layer. The crude product can be further purified by techniques such as chromatography on silica gel, reverse-phase chromatography, trituration, precipitation, or crystallization. Reaction Scheme C1 final compound [ka]

[0105] HPK1 binder building blocks prepared according to Reaction Scheme A typically have at least one reactive site, such as an amine or carboxyl moiety, which can be further coupled to the moieties described in Scheme B. In one specific example (structure shown in Reaction Scheme C1), the free piperidine NH group of the HPK1 binder building block (prepared according to Reaction Scheme A) can be coupled with a carboxylic acid prepared according to Reaction Scheme B under conditions known in the art to produce a compound of Formula 49. For example, the amine of the HPK1 binder building block can be combined with a carboxylic acid in a solvent such as DMF, optionally containing an additive such as HOBT, in the presence of a reagent such as BOP, EDCI, or HATU, and sometimes in the presence of a base such as DIPEA. The reaction mixture is typically stirred at room temperature for 15 minutes to 48 hours, and the product is then isolated by a purification method such as flash chromatography or preparative HPLC. In certain cases, the purification method is preceded by an optional workup involving dilution with an organic solvent such as EtOAc or DCM, washing with water or aqueous sodium chloride, sodium bicarbonate or hydrogen chloride, drying over sodium sulfate, filtration and concentration. Reaction Scheme C2 Final Compound, Modular Approach [ka]

[0106] A modular approach to assembling the final compounds is also possible using methods known in the art. For example, the HPK1 binder building block can be coupled with compounds of formula (108) and (109) under standard amide bond forming conditions, such as HATU, in a suitable solvent, such as DMF, in the presence of a base, such as DIPEA, to provide compounds of formula (110) and (111). Compounds of formula (110) can be produced by treating compounds of formula (108) with acid hydrolysis conditions, such as TFA (when Y=t-Bu), in a suitable solvent, such as DCM, or with basic conditions, such as LiOH (when Y=methyl), in a suitable solvent, such as a water / THF mixture. The final compound is prepared by coupling a compound of formula (113) with (115) to give a compound of formula (117), or by coupling a compound of formula (112) with (114) to give a compound of formula (116), under standard amide bond-forming conditions, such as HATU, in a suitable solvent, such as DMF, in the presence of a base, such as DIPEA. Compounds of formula (116) and (117), as well as their precursors, can be isolated and purified by suitable methods known in the art, for example, by partitioning the reaction mixture between an aqueous phase and an organic solvent, followed by isolating the desired product by filtration or concentration of the relevant layer. The crude product can be further purified by techniques such as chromatography on silica gel, reverse-phase chromatography, trituration, precipitation, or crystallization. Reaction Scheme C3 Alkylated Final Compound [ka]

[0107] Compounds of formula (128) and (129) can be prepared using methods known in the art. For example, the HPK1 binder building block can be alkylated with either tert-butyl bromoacetate or tert-butyl 2-bromopropanoate in the presence of a base such as triethylamine and a suitable solvent such as DCM to give compounds of formula (118). Compounds of formula (119) can be produced by treating compounds of formula (118) with an acid such as HCl in a suitable solvent such as a mixture of dioxane and glacial acetic acid. Compounds of formula (122) and (123) can be obtained by first coupling compounds of formula (119) with compounds of formula (120) and (121) under standard amide bond-forming conditions such as BOP in the presence of a base such as DIPEA and a suitable solvent such as DMF, followed by treatment with an acid such as TFA in a suitable solvent such as DCM. Compounds of formula (128) and (129) can be prepared by coupling compounds of formula (123) and (125) or compounds of formula (122) and (124) under standard amide bond-forming conditions, such as BOP, in a suitable solvent, such as DMF, in the presence of a base, such as DIPEA. Alternatively, compounds of formula (119) can be directly converted to compounds of formula (128) and (129) by coupling to compounds of formula (126) or (127) under standard amide bond-forming conditions, such as BOP, in the presence of a base, such as DIPEA, and a suitable solvent, such as DMF. Compounds of formula (128) and (129) and their precursors can be isolated and purified by suitable methods known in the art, for example, by partitioning the reaction mixture between an aqueous phase and an organic solvent, followed by isolating the desired product by filtration or concentration of the relevant layer. The crude product can be further purified by techniques such as chromatography on silica gel, reverse-phase chromatography, trituration, precipitation, or crystallization. Reaction Scheme C4 Urea-containing final compound [ka]

[0108] Compounds of formula (138) and (139) can be prepared using methods known in the art. For example, the HPK1 binder building block can be treated with compounds of formula (130) and (131) in a suitable solvent such as DCM in the presence of a base such as triethylamine, typically with heating. Compounds of formula (134) and (135) can be produced by treating compounds of formula (132) and (133) with an acid such as TFA in a suitable solvent such as DCM. Compounds of formula (138) and (139) can be obtained by coupling compound of formula (134) with (136) and coupling (135) with (137) under standard amide bond forming conditions such as BOP in the presence of a base such as DIPEA and a suitable solvent such as DMF. Compounds of formula (138) and (139) and their precursors can be isolated and purified by suitable methods known in the art, for example, by partitioning the reaction mixture between an aqueous phase and an organic solvent, followed by isolating the desired product by filtration or concentration of the relevant layer. The crude product can be further purified by techniques such as chromatography on silica gel, reverse-phase chromatography, trituration, precipitation, or crystallization. Reaction Scheme C5 Final compounds containing sulfonamides [ka]

[0109] Compounds of formula (148) and (149) can be prepared using methods known in the art. For example, the HPK1 binder building block can be treated with compounds of formula (140) and (141) in the presence of a base such as DIPEA in a suitable solvent such as DMF. Compounds of formula (144) and (145) can be produced by treating compounds of formula (142) and (143) with an acid such as HCl in a suitable solvent such as a DCM / dioxane mixture. Compounds of formula (148) and (149) can be obtained by coupling compound of formula (144) with (146) and coupling (145) with (147) under standard amide bond forming conditions such as BOP in the presence of a base such as DIPEA and a suitable solvent such as DMF. Compounds of formula (148) and (149) and their precursors can be isolated and purified by suitable methods known in the art, for example, by partitioning the reaction mixture between an aqueous phase and an organic solvent, followed by isolation of the desired product by filtration or concentration of the relevant layer. The crude product can be further purified by techniques such as chromatography on silica gel, reverse-phase chromatography, trituration, precipitation, or crystallization. Reaction Scheme AA [ka] Step 1. Amide bond formation between the HPK1 binder moiety and Boc-amino acid

[0110] Barcoded Boc-amino acid stocks in NMP (0.1 M, equivalent weight = 10 μmol) were retrieved from a Hamilton Storage Q20 unit and placed on the deck of a 1.3 m Hamilton Robotics Vantage system. The HPK1 binder moiety was dissolved in NMP (0.1 M) in a 20 mL V-bottom vial and placed in a vial rack on the deck of the 1.3 m Vantage. 100 μL of the Boc-amino acid stock was transferred to the corresponding wells of a 96-deep-well plate, followed by the addition of DIEA (0.2 M, 2 equivalents), DIC (0.1 M, 1 equivalent), and HOBT (0.1 M, 1 equivalent), respectively. The plate was shaken at 600 rpm for 10 minutes for activation. 100 μL of the HPK1 binder stock was transferred to the corresponding wells of the 96-deep-well plate, which was then sealed and shaken at 600 rpm overnight for amide bond formation. Step 2. Deprotection

[0111] The crude material from step 1 was dried under vacuum in a Genevac HT12 instrument with heating at 40° C. for 6 hours, followed by the addition of 500 μL of a 50% TFA / DCM mixture to each well. The plate was shaken at 600 rpm for 60 minutes and then dried under vacuum in a Genevac HT12 instrument with heating at 40° C. overnight. DMF was added to each well (300 μL) and evaporation was repeated for 6 hours to help remove residual TFA from the crude mixture. Step 3. Final amide bond with the LHM moiety

[0112] The crude mixture from the previous step was dissolved in 200 μL of 7% DIEA in NMP and then placed back onto the deck of the 1.3 m Vantage system. The LHM portion was dissolved (0.14 M) in 20% DIEA in NMP in a 20 mL V-bottom vial and placed in a vial rack on the deck of the 1.3 m Vantage system. A mixture of DIC (0.4 M, 1 eq.) and HOBT (0.4 M, 1 eq.) was transferred to the 20 mL V-bottom vial, and the vial rack was then shaken at 600 rpm for 10 minutes for activation. 120 μL of the resulting activated mixture was transferred to the corresponding well, and the plate was then sealed and shaken overnight at 600 rpm for amide bond formation. The crude mixture was then directly subjected to reverse-phase HPLC purification. definition

[0113] The following description sets forth exemplary methods, parameters, etc. However, it should be recognized that such description is not intended as limiting the scope of the present disclosure, but is instead provided as a description of exemplary embodiments.

[0114] A dash ("-") that is not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -C(O)NH2 is attached through the carbon atom. Dashes at the front or end of a chemical group are for convenience. Chemical groups can be represented with one or more dashes or without dashes without losing their usual meaning. A wavy line drawn through a line in a structure indicates the point of attachment of the group. No directionality is given or implied by the order in which chemical groups are written or named unless chemically or structurally required.

[0115] Prefix “C” u~v " indicates that the following group has u to v carbon atoms. For example, "C 1~6 "Alkyl" indicates that the alkyl group has from 1 to 6 carbon atoms.

[0116] Reference herein to a value or parameter preceded by "about" includes (and describes) embodiments that are directed to the value or parameter itself. In certain embodiments, the term "about" includes the stated amount ±10%. In other embodiments, the term "about" includes the stated amount ±5%. In certain other embodiments, the term "about" includes the stated amount ±1%. Also, the term "about X" includes the reference to "X." Additionally, the singular forms "a" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, 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 of skill in the art.

[0117] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain containing no unsaturation. As used herein, alkyl refers to an alkyl group having 1 to 20 carbon atoms (i.e., C 1~20 alkyl), 1 to 12 carbon atoms (i.e., C 1~12 alkyl), 1 to 8 carbon atoms (i.e., C 1~8 alkyl), 1 to 6 carbon atoms (i.e., C 1~6 alkyl), or 1 to 4 carbon atoms (i.e., C 1~4alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by a chemical name or specified by a molecular formula, all positional isomers having that number of carbons can be included. 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).

[0118] An "alkylene" or "alkylene chain" connects the rest of the molecule to the radical group, contains no unsaturation, and has 1 to 20 carbon atoms, or more typically 1 to 12 carbon atoms (C 1~12 alkylene), or 1 to 8 carbon atoms (C 1~8 alkylene), or 1 to 3 carbon atoms (C 1~3 Alkylene refers to an unbranched or branched divalent hydrocarbon chain having an alkylene group (e.g., methylene, ethylene, propylene, n-butylene, etc.). The alkylene chain can be attached to the rest of the molecule and to the radical group through one carbon in the chain or through any two carbons in the chain.

[0119] "Alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C 2~20 alkenyl), or more typically 2 to 12 carbon atoms (i.e., C 2~12 alkenyl), 2 to 8 carbon atoms (i.e., C 2~8 alkenyl), 2 to 6 carbon atoms (i.e., C 2~6 alkenyl), or 2 to 4 carbon atoms (i.e., C 2~4Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0120] "Alkenylene" and "alkenylene chain" refer to an unbranched or branched divalent hydrocarbon chain that connects the rest of the molecule to a radical group, contains at least one double bond, and has 2 to 20 carbon atoms, or more typically 2 to 12 carbon atoms, or 2 to 8 carbon atoms, e.g., ethenylene, propenylene, n-butenylene, and the like. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a double bond or a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons in the chain.

[0121] "Alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C 2~20 alkynyl), or more typically 2 to 12 carbon atoms (i.e., C 2~12 alkynyl), or more typically 2 to 8 carbon atoms (i.e., C 2~8 alkynyl), 2 to 6 carbon atoms (i.e., C 2~6 alkynyl), or 2 to 4 carbon atoms (i.e., C 2~4 The term "alkynyl" refers to an alkyl group having one triple bond and one double bond.

[0122] "Alkynylene" and "alkynylene chain" refer to an unbranched or branched divalent hydrocarbon chain that connects the rest of the molecule to a radical group, contains at least one triple bond, and has 2 to 20 carbon atoms, or more typically 2 to 12 carbon atoms, or 2 to 8 carbon atoms. The 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 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.

[0123] "Alkoxy" refers to the group "alkyl-O-". Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0124] "Haloalkoxy" refers to an alkoxy group, as defined above, in which one or more hydrogen atoms have been replaced by halogen.

[0125] "Alkylthio" refers to the group "alkyl-S-".

[0126] "Amino" is -NR y R y refers to a group, where each R y is 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.

[0127] "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 refers to an aromatic carbocyclic group having 6 to 20 ring carbon atoms (i.e., C 6~20 aryl), 6 to 15 carbon ring atoms (i.e., C 6~15 aryl), or 6 to 10 carbon ring atoms (i.e., C 6~10 aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. However, aryl does not entirely encompass or overlap with heteroaryl, as defined below. When one or more aryl groups are fused to a heteroaryl, the resulting ring system is a heteroaryl. When one or more aryl groups are fused to a heterocyclyl, the resulting ring system is a heterocyclyl.

[0128] "Cyano" refers to the radical -CN.

[0129] "Keto" or "oxo" refers to the group =O.

[0130] "Carbamoyl" is -OC(O)NR y R z The group refers to the "O-carbamoyl" group and the -NR y C(O)OR z "N-carbamoyl" refers to both the N- and N-carbamoyl groups, where R y and R z is independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl, each of which is optionally substituted.

[0131] "Carboxyl" or "carboxylic acid" refers to --C(O)OH.

[0132] "Ester" refers to both -OC(O)R and -C(O)OR, where R is a substituent, each of which can be optionally substituted as defined herein.

[0133] "Cycloalkyl" refers to saturated or partially unsaturated cyclic alkyl groups having a single ring or multiple rings, including fused, bridged, and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond). As used herein, cycloalkyl refers to cyclic alkyl groups having 3 to 15 ring carbon atoms (i.e., C 3~20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3~12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3~10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3~8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3~6Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[2.2.2]octan-1-yl. A cycloalkyl can be attached to the rest of the molecule through a single ring atom (e.g., as a substituent) or through two ring atoms (e.g., as a linker).

[0134] An "ethylene glycol unit" refers to a divalent monomer having the structure -CH2CH2O-, which can be repeated and extended into longer chains. A linker segment can have up to 12 ethylene glycol units, or more typically up to 6 ethylene glycol units.

[0135] A "propylene glycol unit" refers to a divalent monomer having the structure -CH(CH)-CHO-, which can be repeated and extended into longer chains. A linker segment can have up to 12 propylene glycol units, or more typically up to 6 propylene glycol units.

[0136] "Halogen" or "halo" includes fluoro, chloro, bromo, and iodo.

[0137] "Haloalkyl" refers to an unbranched or branched alkyl group as defined above, in which one or more hydrogen atoms are replaced by halogen. For example, if a residue is substituted with more than one halogen, the residue can 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, where the halo groups can be, but are not necessarily, the same halogen. Examples of haloalkyl include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0138] "Heteroalkyl" refers to an alkyl group in which one or more of the carbon atoms (and any attached hydrogen atoms) are each independently replaced with the same or different heteroatoms, such as N, O, S, etc. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon atoms and heteroatoms. For example, one, two, or three carbon atoms may be independently replaced with the same or different heteroatoms. Heteroatom groups include, but are not limited to, -N(R)-, -O-, -S-, -S(O)-, -S(O)-, etc., where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted. Examples of heteroalkyl groups include -OCH, -CHOCH, -SCH, -CHSCH, -NRCH, and -CHNRCH, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which is optionally substituted. As used herein, heteroalkyl contains 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.

[0139] "Heteroaryl" refers to a 5- to 15-membered, or more typically 5- to 12-membered, aromatic group having a single ring, multiple rings, or fused polycyclic rings, with 1 to 3 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl refers to a group having 3 to 12 ring carbon atoms (i.e., C 3~12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C 3~8Heteroaryl) and 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, where the heteroaryl can be attached via any ring of the fused system. Any aromatic ring having a single ring or multiple fused rings and containing at least one heteroatom is considered heteroaryl, regardless of attachment to the rest of the molecule (i.e., via any one of the fused rings). Heteroaryl does not encompass or overlap with aryl (which has no heteroatoms) or heterocyclyl (which has at least one non-aromatic ring). Heteroaryl can be attached to the remainder of the molecule through a single ring atom (e.g., as a substituent) or through two ring atoms (e.g., as a linker).

[0140] "Heterocyclyl" refers to a 3- to 15-membered, or more typically 5- to 12-membered, saturated or unsaturated cyclic alkyl group having 1 to 3 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclyl" includes heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond), bicyclic heterocyclyl groups, bridged heterocyclyl groups, fused heterocyclyl groups, and spiroheterocyclyl groups. A heterocyclyl can be a single ring or multiple rings, where the multiple rings can be fused, bridged, or spiro. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of bonding (i.e., it can be bonded through a carbon atom or a heteroatom). Furthermore, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring can be fused to an aryl or heteroaryl ring, regardless of bonding to the rest of the molecule. As used herein, heterocyclyl has 3 to 15 ring atoms (e.g., 3 to 15-membered heterocyclyl, 3 to 12-membered heterocyclyl, 4 to 10-membered heterocyclyl, 4 to 8-membered heterocyclyl, or 4 to 6-membered heterocyclyl) and has 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur, or oxygen. The 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- to 7-membered sultam, 4- to 7-membered cyclic carbamate, 4- to 7-membered cyclic carbonate, 4- to 7-membered cyclic sulfide, and morpholinyl.As used herein, heterocyclyl can include bridged structures (i.e., "bridged heterocyclyl") in which a 4- to 10-membered cyclic moiety is connected to one or more (e.g., one or two) 4- to 10-membered cyclic moieties (having at least one heteroatom, each heteroatom independently selected from nitrogen, oxygen, and sulfur) at two non-adjacent atoms of the heterocyclyl. As used herein, bridged heterocyclyl includes bicyclic and tricyclic ring systems. Also, as used herein, the term "spiroheterocyclyl" refers to a ring system in which a 3- to 10-membered heterocyclyl has one or more additional rings, wherein the one or more additional rings are 3- to 10-membered cycloalkyl or 3- to 10-membered heterocyclyl, and a single atom of the one or more additional rings is also an atom of the 3- to 10-membered heterocyclyl. Examples of spiroheterocyclyl rings include bicyclic and tricyclic ring systems such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of fused heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 1-oxo-1,2,3,4-tetrahydroisoquinolinyl, 1-oxo-1,2-dihydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be attached via either ring of the fused system. As used herein, a bicyclic heterocyclyl group is a heterocyclyl group that is attached at two points to another cyclic group, where the other cyclic group may itself be a heterocyclic or carbocyclic group. The heteroaryl may be attached to the remainder of the molecule through a single ring atom (e.g., as a substituent) or through two ring atoms (e.g., as a linker).

[0141] "Fused" refers to rings that are connected to adjacent rings and share two adjacent ring atoms that form a covalent bond.

[0142] "Bridged" refers to a ring fusion in which non-adjacent atoms on the ring are linked by a divalent substituent, such as an alkylenyl group, an alkylenyl group containing one or two heteroatoms, or a single heteroatom. Quinuclidinyl and adamantanyl are examples of bridged ring systems.

[0143] "Spiro" refers to a ring substituent that is joined by two bonds at the same carbon atom. Examples of spiro groups include 1,1-diethylcyclopentane, dimethyl-dioxolane, and 4-benzyl-4-methylpiperidine, where the cyclopentane and piperidine are each spiro substituents.

[0144] "Hydroxy" or "hydroxyl" refers to an -OH group. "Hydroxyalkyl" refers to an unbranched or branched alkyl group as defined above in which one or more hydrogen atoms have been replaced by hydroxyl.

[0145] "Nitro" refers to the -NO2 group.

[0146] "Imino" refers to a group containing a C=N double bond, e.g., C=NR y , or =NC(O)R y where R y is selected from the group consisting of hydrogen, alkyl, aryl, cyano, haloalkyl, or heteroaryl, each of which may be optionally substituted. The imino may be a linker segment by being attached to the rest of the molecule at the carbon and nitrogen, respectively.

[0147] "Sulfonyl" refers to the group -S(O)2R, where R is a substituent or defined group.

[0148] "Alkylsulfonyl" refers to the group -S(O)R, where R is a substituent or defined group.

[0149] "Alkylsulfinyl" refers to the group -S(O)R, where R is a substituent or defined group.

[0150] "Thiocyanate" refers to -SCN.

[0151] "Thiol" refers to the group --SR, where R is a substituent or defined group.

[0152] "Thioxo" or "thione" refers to the (=S) or (S) group.

[0153] Certain alternative chemical names in common use can be used. For example, divalent groups, such as divalent "alkyl" groups, divalent "aryl" groups, etc., can also be referred to as "alkylene" or "alkylenyl" groups, "arylene" or "arylenyl" groups, respectively. Also, unless expressly indicated otherwise, when a combination of groups is referred to herein as a single moiety, e.g., arylalkyl, the last-mentioned group contains the atom that connects the moiety to the rest of the molecule.

[0154] The term "optionally" or "optionally" means that the event or circumstance described thereafter may or may not occur, and the description includes cases where said event or circumstance occurs and cases where it does not occur. Also, the term "optionally substituted" refers to any one or more hydrogen atoms adjacent to the specified atom or present in the specified group being replaced or not replaced by a non-hydrogen moiety. "Optionally substituted" can range from 0 to the maximum number of possible substitutions and is independent on each occurrence. When the term "substituted" is used, substitution must occur at a substitutable hydrogen atom of the indicated substituent. Optional substitutions may be the same as or different from (required) substitutions.

[0155] 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," said general term is intended to encompass any term specifically described above, such as (C 1~3 alkyl), (C 4~6 alkyl), -O(C 1~4 alkyl), (C 3~10 cycloalkyl), O-(C 3~10 cycloalkyl), etc. For example, "any aryl" includes both "aryl" and "-O(aryl)," as well as examples of aryls such as phenyl or naphthyl. 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, etc. Similarly, the term "any heteroaryl" includes the terms "heteroaryl" and "O-(heteroaryl)," as well as specific heteroaryls such as pyridine.

[0156] Some compounds of Formula (I) can exist as "stereoisomers" or mixtures of stereoisomers. Stereoisomers refer to compounds made up of the same atoms connected by the same bonds but with different, irreversible three-dimensional structures. The compounds of the present disclosure, or their pharmaceutically acceptable salts, can contain one or more asymmetric centers and thus give rise to enantiomers (two stereoisomers whose molecules are non-superimposable mirror images of one another), diastereomers, and other stereoisomers that can be defined in terms of absolute stereochemistry as (R)- or (S)-. The present disclosure is intended to encompass all such possible isomers, as well as their racemic mixtures (i.e., equal amounts of (R) and (S) enantiomers) and optically pure forms. Optically active (+) and (-), (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as HPLC or SFC using chiral columns.

[0157] The present disclosure also includes "deuterated analogs" of compounds of Formula (I) in which one to n hydrogens bonded to a carbon atom (where n is the number of hydrogens in the molecule) have been replaced by deuterium. Such compounds exhibit increased resistance to metabolism and are therefore useful for extending the half-life of any compound of Formula (I) when administered to mammals, particularly humans. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogens have been replaced by deuterium.

[0158] Deuterium-labeled or substituted therapeutic compounds of the present disclosure can have improved DMPK (drug metabolism and pharmacokinetic) properties with respect to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes, such as deuterium, can confer certain therapeutic advantages, such as increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index, resulting from greater metabolic stability. 18 F-labeled compound can be useful for PET or SPECT research.Isotopically labeled compounds of the present disclosure can generally be prepared by carrying out the procedures disclosed in schemes or in the following examples and preparations, using readily available isotope-labeled reagents instead of non-isotopically labeled reagents.In this context, it is understood that deuterium is considered as a substituent in the compound of formula (I).

[0159] The enrichment of such heavier isotopes, specifically deuterium, can be defined by an isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen," said position is understood to have hydrogen at its natural abundance isotopic composition. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is intended to represent deuterium.

[0160] In many cases, the compounds of the present 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.

[0161] Also provided are pharmaceutically acceptable salts, hydrates, or solvates of the compounds described herein. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials that are useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0162] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and organic acids. In addition, when a compound described herein is 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, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can 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-toluenesulfonic acid, salicylic acid, and the like. Similarly, 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 alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dialkenylamines (i.e., HN(alkenyl)2), trialkenylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl) Included are salts of amines (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl)amines (i.e., N(substituted alkenyl)3, mono-, di-, or tri-cycloalkylamines (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, and the like. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0163] The term "substituted" means that any one or more hydrogen atoms adjacent to the designated atom or present in the designated group have been replaced with one or more substituents other than hydrogen, provided that the replacement does not exceed the normal valence of the designated atom. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof. Polymers or similar indefinite structures arrived at by defining a substituent with an infinite number of additional substituents (e.g., substituted aryl with a substituted alkyl, which is itself substituted with a substituted aryl group, which is further substituted with a substituted heteroalkyl group, etc.) are not intended to be included herein. Unless otherwise noted, the maximum number of consecutive substitutions for compounds described herein is three. For example, the consecutive substitution of a substituted aryl group with two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definition is not intended to include impermissible substitution patterns (e.g., a methyl substituted with five fluorines or a heteroaryl group with two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to those of ordinary skill in the art. When used to modify a chemical group, the term "substituted" may describe other chemical groups defined herein. Unless otherwise specified, when 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. Those skilled in the art will recognize that the substituents and other moieties of the compounds of the general formulas herein should be selected to provide a compound that is sufficiently stable to provide a pharmaceutically useful compound that can be formulated into an acceptably stable pharmaceutical composition. Compounds with such stability are intended to be within the scope of the present invention. It should be understood by those skilled in the art that any combination of the foregoing definitions and substituents should not result in an inoperable species or compound.

[0164] 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, etc. 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.

[0165] A "solvate" is formed by the interaction of a solvent and a compound. Solvates of the salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided. Targeted HPK1 degradation

[0166] Compounds of the present disclosure are demonstrated by cell-based profiling to degrade HPK1.

[0167] The HiBiT HPK1 Jurkat cell line was used in a robust human cell high-throughput format to assess total HPK1 protein levels. The levels of HPK1 remaining after treatment with HPK1 CTM were compared to the D2 achieved at 24 hours when compared to vehicle-treated controls. max The results are reported as (maximum degradation). As further described in the Biological Examples, the results demonstrate that HPK1 CTM can degrade HPK1. These reductions were not the result of cytotoxicity as measured by parallel viability assessments (CTG). See also Tables 1 and 2. Pharmaceutical Compositions and Uses of Bifunctional Compounds of Formula (I)

[0168] The bifunctional compounds of formula (I) have been demonstrated to degrade HPK1 and are therefore useful for treating disease indications or disorders involving HPK1 function, such as signal transduction or scaffolding.

[0169] Various embodiments provide pharmaceutical compositions of a compound of Formula (I), or any one of the substructures or specific compounds of Examples 1-303, and a pharmaceutically acceptable carrier.

[0170] Further embodiments provide methods for treating a disease or disorder associated with increased hematopoietic progenitor kinase 1 (HPK1) activity, increasing T cell activation, treating cancer, inhibiting cancer cell growth or proliferation, treating or preventing Hepatitis B virus (HBV) infection, or treating or preventing human immunodeficiency virus (HIV) infection, said methods comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), any one of the substructures or compounds of Examples 1-303.

[0171] In more specific embodiments, the cancer is selected from the group consisting of bladder cancer, breast cancer, colorectal cancer, gastric cancer, head and neck squamous cell carcinoma, Hodgkin's lymphoma, Merkel cell carcinoma, mesothelioma, melanoma, non-small cell lung cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, small cell lung cancer, transitional cell carcinoma, and urothelial cancer.

[0172] In some embodiments, a compound of Formula (I), or any one of the substructures or specific compounds of Examples 1-303, may be administered with a therapeutically effective amount of one or more additional therapeutic agents, or a pharmaceutically acceptable salt thereof.

[0173] In further embodiments, the one or more additional therapeutic agents are an inducible T-cell costimulatory molecule (ICOS) agonist, a cytotoxic T-lymphocyte antigen 4 (CTLA-4) blocking antibody, a PD1 and / or PD-L1 inhibitor, a cluster of differentiation 47 (CD47) inhibitor, an OX40 agonist, a GITR agonist, a CD27 agonist, a CD28 agonist, a CD40 agonist, a CD137 agonist, a Toll-like receptor 8 (TLR8) agonist, a T-cell immunoglobulin and mucin domain-3 (TIM-3) inhibitor, a lymphocyte-activation gene 3 (LAG-3) inhibitor, a CEACAM1 inhibitor, or a combination thereof. and a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.

[0174] In more specific embodiments, the one or more additional therapeutic agents are rituximab, doxorubicin, gemcitabine, nivolumab, pembrolizumab, pidilizumab, PDR001, TSR-001, atezolizumab, durvalumab, avelumab, pidilizumab, TSR-042, BMS-986016, ruxolitinib, N-(cyanomethyl)-4-[2-(4-morpholinoanilino)pyrimidin-4-yl]benzamide, XL14 7, BKM120, GDC-0941, BAY80-6946, PX-866, CH5132799, XL756, BEZ235, and GDC-0980, wortmannin, LY294002, TGR-1202, AMG-319, GSK2269557, X-339, X-414, RP5090, KAR4141, XL499, OXY111A, IPI-145, IPI-443, GSK2636771, BAY10824391, buparlisib, BYL719, R G7604, MLN1117, WX-037, AEZS-129, PA799, ZSTK474, AS252424, TGX221, TG100115, IC87114, IPI-549, INCB050465, (S)-2-(1-((9H-purin-6-yl)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, (S)-2-(1-((9H-purin-6-yl)amino)ethyl)-6-fluoro-3-phenylquinazolin-4( 3H)-one, (S)-2-(1-((9H-purin-6-yl)amino)ethyl)-3-(2,6-difluorophenyl)quinazolin-4(3H)-one, (S)-4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile, and ipilimumab, or a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.

[0175] In more specific embodiments, the one or more additional therapeutic agents are selected from the group consisting of idelalisib, tirabrutinib, momelotinib, and entospletinib, or a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.

[0176] In further embodiments, the one or more additional therapeutic agents are selected from the group consisting of HBV combination medications, HBV vaccines, HBV DNA polymerase inhibitors, immunomodulatory agents, toll-like receptor (TLR) modulators, interferon alpha receptor ligands, hyaluronidase inhibitors, hepatitis B surface antigen (HBsAg) inhibitors, cytotoxic T lymphocyte-associated protein 4 (ipi4) inhibitors, cyclophilin inhibitors, HBV viral entry inhibitors, antisense oligonucleotides targeting viral mRNA, short interfering RNA (siRNA) and ddRNAi endonuclease modulators, ribonucelotide reductase inhibitors, HBV and / or an E antigen inhibitor, a covalently closed circular DNA (cccDNA) inhibitor, a farnesoid X receptor agonist, an HBV antibody, a CCR2 chemokine antagonist, a thymosin agonist, a cytokine, a nucleoprotein modulator, a retinoic acid-inducible gene 1 stimulator, a NOD2 stimulator, a phosphatidylinositol 3-kinase (PI3K) inhibitor, an indoleamine-2,3-dioxygenase (IDO) pathway inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a recombinant thymosin alpha-1 agonist, a Bruton's tyrosine kinase (BTK) inhibitor, a KDM inhibitor, an HBV replication inhibitor, an arginase inhibitor, and other HBV drugs, or a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.

[0177] In more specific embodiments, the one or more additional therapeutic agents are adefovir (Hepsera®), tenofovir disoproxil fumarate plus emtricitabine (Truvada®), tenofovir disoproxil fumarate (Viread®), entecavir (Baraclude®), lamivudine (Epivir-HBV®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®), Clevudine®, emtricitabine (Emtriva®), pegylated interferon alfa-2b (PEG-Intron®), Multiferon®, interferon alfa 1b (Hapgen®), interferon alfa-2b (Intron®), A®), pegylated interferon alfa-2a (Pegasys®), interferon alfa-n1 (Humoferon®), ribavirin, interferon beta-1a (Avonex®), Bioferon, Ingaron, Inmutag (Inferon), Algeron, Roferon-A, Oligoti de), Zutectra, Shaferon, interferon alpha-2b (Axxo), Alfaferone, interferon alpha-2b, Feron, interferon-alpha 2 (CJ), Bevac, Laferonum, Vipeg, Blauferon-B, Blauferon-A, Intermax alphaAlpha, Realdiron, Lanstion, Pegaferon, PDferon-B, alfainterferon 2b, Kalferon, Pegnano, Feronsure, PegiHep, Optipeg A, Realfa 2B, Reliferon, peginterferon alfa-2b, Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa-2b, Anterferon, Shanferon, MOR-22, interleukin-2 (IL-2), recombinant human interleukin-2 (Shenzhen Neptunus, Layfferon, Ka Shu Ning, Shang Sheng Lei Tai, Intefen, Sinogen, Fukangtai, Alloferon and celmoleukin, or a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.

[0178] In more specific embodiments, the one or more additional therapeutic agents are selected from the group consisting of entecavir, adefovir, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine, and lamivudine, or a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.

[0179] In more specific embodiments, the one or more additional therapeutic agents are selected from the group consisting of tenofovir alafenamide, tenofovir alafenamide fumarate, and tenofovir alafenamide hemifumarate, or a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.

[0180] In further embodiments, the one or more additional therapeutic agents are combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversing agents, compounds targeting the HIV capsid, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nuclear protein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIVand a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.

[0181] In more specific embodiments, the one or more additional therapeutic agents are selected from the group consisting of HIV protease inhibitor compounds, HIV non-nucleoside reverse transcriptase inhibitors, HIV non-nucleoside reverse transcriptase inhibitors, HIV nucleoside reverse transcriptase inhibitors, HIV nucleoside reverse transcriptase inhibitors, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, and other drugs for treating HIV, or pharmaceutically acceptable salts of any of the foregoing, or any combination thereof.

[0182] In more specific embodiments, the one or more additional therapeutic agents are selected from the group consisting of 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, or a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.

[0183] In more specific embodiments, the one or more additional therapeutic agents are selected from the group consisting of 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir, tenofovir alafenamide, tenofovir alafenamide fumarate, or tenofovir alafenamide hemifumarate, or a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.

[0184] In more specific embodiments, the one or more additional therapeutic agents are selected from the group consisting of 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir or a pharmaceutically acceptable salt thereof, tenofovir disoproxil, tenofovir disoproxil hemifumarate or tenofovir disoproxil fumarate, or a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.

[0185] Synthesis procedure Typical LCMS methods Method 1: ACN-Water-0.1%FA-5%B-1.5mL-3 min (90~900)±.lcm Equipment: Shimadzu LCMS-2020 Column: SPD-M20A Solvent A: Water / 0.1% FA Solvent B: ACN / 0.1% FA Flow rate: 1.5000mL / min

[0186] Method 2: ACN-Water-5mM NH4HCO3-10%B-1.5~2.0 min (90~900)±.lcm Equipment: Shimadzu LCMS-2020 Column: HALO Solvent A: Water / 5mM NH4HCO3 Solvent B: Acetonitrile Flow rate: 1.2000mL / min

[0187] Method 3: ACN-Water-0.05%TFA-5%B-1.5~2.0min(90~900).lcm Equipment: Shimadzu LCMS-2020 Column: SPD-M20A Solvent A: Water / 0.05% TFA Solvent B: acetonitrile / 0.05% TFA Flow rate: 1.5000mL / min

[0188] Method 4: LCMS2-036-20-80-95-6-1-25-UV-BCM Instrument: Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific ISQ EC-Mass Spectrometer Column: Kinetex® 2.6 μm XB-C18 (4.6 × 50 mm), 110A, column number 00B-4496-E0, internal column number 036 Solvent A: 0.1% v / v aqueous solution of formic acid Solvent B: 0.1% v / v formic acid in acetonitrile Gradient: [Table 3]

[0189] Method 5: LCMS-019-5-80-80-7-1-25-UV-Rot Instrument: Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQ Plus Column: Kinetex® 2.6 μm XB-C18 (4.6 × 50 mm), 110A, column number OOB-4496-E0, internal column number 019 Solvent A: 0.1% v / v aqueous solution of trifluoroacetic acid Solvent B: 0.1% v / v trifluoroacetic acid in acetonitrile Gradient: [Table 4]

[0190] Typical HPLC purification methods: Method 1: 0-50% Buffer B (ACN + 0.1% TFA) Equipment:DYNAMAX Column: Higgins analytical, C18, 30 x 100 mm column Solvent A: Water + 0.1% TFA (referred to as Buffer A) Solvent B: ACN + 0.1% TFA (referred to as Buffer B) Gradient: 0 to 50% Buffer B (ACN + 0.1% TFA) Flow rate: 40mL / min Duration: 30 minutes

[0191] Method 2:20210423-prep2-60800420-PKU01-087 C18 prep Equipment: Shimadzu Model: CMB-20A, Detector: SPD-M20A IVDD, Pump: LC-20AP, Fraction Collector: FRC-10A Column: Gemini NX-C18, phenomenex: 00G-4454-P0-AX, serial number: H19-002285, 250 × 21.20 mm, 5 μm / 110 Å, equipped with a precolumn: SecurityGuard™ PREP Cartridge Gemini NX-C18, Phenomenex; Catalog Number: AJ0-8370 Solvent A: 0.1% v / v aqueous solution of formic acid Solvent B: 0.1% v / v formic acid in acetonitrile Gradient: [Table 5-1] [Table 5-2]

[0192] Intermediate 1 (3R)-1-((1r,4R)-4-((4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)cyclohexane-1-carbonyl)pyrrolidine-3-carboxylic acid [ka] Step 1: Methyl (3R)-1-[(1r,4r)-4-{[4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl]amino}cyclohexanecarbonyl]pyrrolidine-3-carboxylate: [ka]

[0193] A mixture of (1r,4r)-4-{[4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl]amino}cyclohexane-1-carboxylic acid (300 mg, 0.905 mmol) and HATU (516 mg, 1.357 mmol) in DMF (5 mL) was stirred at room temperature for 0.5 h, then methyl (3R)-pyrrolidine-3-carboxylate (116 mg, 0.905 mmol) and DIEA (702 mg, 5.430 mmol) were added, and the resulting mixture was stirred at room temperature for 1 h. The residue was purified by reverse-phase flash chromatography [ACN and HO mobile phase] to afford 130 mg (32.45%) of the title compound as an orange solid. LCMS: (C 23 H 30 Desired mass of N4O5) = 442.2; Found: m / z = 443.1 [M+H] + . Step 2: (3R)-1-((1r,4R)-4-((4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)cyclohexane-1-carbonyl)pyrrolidine-3-carboxylic acid [ka]

[0194] A mixture of methyl (3R)-1-[(1r,4r)-4-{[4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl]amino}cyclohexanecarbonyl]pyrrolidine-3-carboxylate (80 mg, 0.181 mmol) and HCl (3 mL, 12 M) was stirred at room temperature for 12 hours and then concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography [ACN and HO mobile phase] to give 29 mg (37.44%) of the title compound as a white solid. LCMS: (C 22 H 28 Desired mass of N4O5) = 428.2; Found: m / z = 429.2 [M+H] + .

[0195] Intermediate 2 (3R)-1-((1r,4R)-4-((4-(2,6-dioxopiperidin-3-yl)phenyl)amino)cyclohexane-1-carbonyl)pyrrolidine-3-carboxylic acid [ka] The title compound was synthesized by a method similar to that used for 1-((1R,4r)-4-((4-((RS)-2,6-dioxopiperidin-3-yl)phenyl)amino)cyclohexane-1-carbonyl)piperidine-4-carboxylic acid (Intermediate 31) and by coupling dibromobenzene with methyl (R)-pyrrolidine-3-carboxylate hydrochloride in the first step.

[0196] Intermediate 3 (3R)-1-((1r,4R)-4-((5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)cyclohexane-1-carbonyl)pyrrolidine-3-carboxylic acid [ka] Step 1: tert-butyl (1r,4r)-4-((5-bromopyridin-2-yl)amino)cyclohexane-1-carboxylate [ka]

[0197] To a solution of 5-bromo-fluoropyridine (1.8 g, 10.18 mmol) and tert-butyl (1r,4r)-4-aminocyclohexane-1-carboxylate (507 mg, 2.54 mmol) in anhydrous DMSO (12.7 mL) was added potassium carbonate (1.1 g, 10.18 mmol) and DIPEA (1.8 mL, 10.18 mmol) at room temperature. The reaction mixture was stirred at 130° C. for 2 hours, then the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was used directly in the next step (yellow oil, 612 mg). LCMS: [C 16 H 23 BrN2O2], desired mass = 354.0, observed: m / z = 355.2 [M+H] + . Step 2: tert-Butyl (1r,4r)-4-((2',6'-bis(benzyloxy)-[3,3'-bipyridin]-6-yl)amino)cyclohexane-1-carboxylate [ka]

[0198] To a solution of tert-butyl (1r,4r)-4-((5-bromopyridin-2-yl)amino)cyclohexane-1-carboxylate (674 mg, 1.90 mmol) and 2,6-bis(benzyloxy)pyridin-3-ylboronic acid (639 mg, 1.90 mmol) in 1,4-dioxane (2.38 mL) was added 1N aqueous cesium carbonate solution (4.74 mL, 4.74 mmol). The mixture was degassed with argon gas for 10 minutes, then Pd(dppf)Cl·DCM (314 mg, 0.38 mmol) was added and the vial was sealed. The reaction mixture was stirred under microwave irradiation at 100 °C for 0.5 h. The reaction mixture was then quenched with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by HPLC to give 772 mg (72% yield) of the title compound as a white solid. LCMS: [C 35 H39 N3O4], desired mass = 565.2, observed: m / z = 566.5 [M+H] + . Step 3: tert-Butyl (1r,4r)-4-((5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)cyclohexane-1-carboxylate [ka]

[0199] To a solution of tert-butyl (1r,4r)-4-((2',6'-bis(benzyloxy)-[3,3'-bipyridin]-6-yl)amino)cyclohexane-1-carboxylate (376 mg, 0.66 mmol) in a mixture of THF (3.4 mL) and isopropanol (3.4 mL) was added Pd / C (71 mg, 0.06 mmol). The reaction mixture was stirred at room temperature under H2 gas for 36 hours, then the mixture was diluted with ethyl acetate (30 mL) and filtered through Celite. The filtrate was then concentrated under reduced pressure. The residue was used directly in the next step (yellow oil, 104 mg). LCMS: [C 21 H 29 N3O4], desired mass = 387.2, observed: m / z = 388.2 [M+H] + . Step 4: (1r,4r)-4-((5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)cyclohexane-1-carboxylic acid [ka]

[0200] The title compound was obtained by TFA-mediated deprotection conditions similar to those described for 1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carboxylic acid. The crude product was used directly in the next step (orange oil, 305 mg). LCMS: [C 17 H 21 N3O4], desired mass = 331.1, observed: m / z = 332.4 [M+H]+ . Step 5: tert-Butyl (3R)-1-((1r,4R)-4-((5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)cyclohexane-1-carbonyl)pyrrolidine-3-carboxylate [ka]

[0201] The title compound was synthesized using a method similar to tert-butyl (3R)-1-(1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)pyrrolidine-3-carboxylate using BOP coupling. The crude product was purified by silica gel chromatography using a mobile phase of 0-5% MeOH in DCM to afford 86 mg (54% yield) of the title compound as a pale yellow oil. LCMS: [C 26 H 36 N4O5], desired mass = 484.2, observed: m / z = 485.4 [M+H] + . Step 6: (3R)-1-((1r,4R)-4-((5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)cyclohexane-1-carbonyl)pyrrolidine-3-carboxylic acid [ka]

[0202] The title compound was obtained by TFA-mediated deprotection conditions similar to those described for 1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carboxylic acid. The crude product was used directly in the next step (pale yellow oil, 53 mg). LCMS: [C 22 H 28 N4O5], desired mass = [428.2.1], observed: m / z = [429.3][M+H] + . Intermediate 4 (3R)-1-((1r,4R)-4-((6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)amino)cyclohexane-1-carbonyl)pyrrolidine-3-carboxylic acid [ka] Step 1: Methyl 5-(((1r,4r)-4-(tert-butoxycarbonyl)cyclohexyl)amino)picolinate [ka]

[0203] To a solution of tert-butyl (1r,4r)-4-aminocyclohexane-1-carboxylate (385 mg, 1.9 mmol) and DIPEA (0.68 mL, 0.5 g, 3.87 mmol) in DMSO (2 mL) was added methyl 5-fluoropicolinate (300 mg, 1.9 mmol). The reaction mixture was stirred at 120 °C for 16 h, at which point LCMS indicated that all starting material had been consumed. The reaction mixture was cooled to room temperature, and water was added. The crude mixture was purified by reverse-phase FC (5-50% MeCN / HO + 0.1% TFA) to give the title compound (200 mg, 31% yield). LCMS: [C 18 H 26 N2O4], desired mass = 334.4, observed: m / z = 335.4 [M+H] + . Step 2: 5-(((1r,4r)-4-(tert-butoxycarbonyl)cyclohexyl)amino)picolinic acid: [ka]

[0204] Methyl 5-(((1r,4r)-4-(tert-butoxycarbonyl)cyclohexyl)amino)picolinate (200 mg, 0.6 mmol) was dissolved in THF (5 mL) at rt. To this solution was added 1 M lithium hydroxide solution (3 mL, 3 mmol) and the resulting mixture was stirred vigorously overnight. At this point, LCMS indicated consumption of all starting material, so the reaction mixture was concentrated to dryness to afford the title compound as the lithium salt (80 mg, 41% yield). LCMS: [C 17 H 24 N2O4], desired mass = 320.4, observed: m / z = 321.4 [M+H] + . Step 3: tert-butyl (1r,4r)-4-((6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)amino)cyclohexane-1-carboxylate: [ka]

[0205] To a solution of methyl 5-(((1r,4r)-4-(tert-butoxycarbonyl)cyclohexyl)amino)picolinate (80 mg, 0.25 mmol) in DMF (1 mL) were added HATU (190 mg, 0.49 mmol) and DIPEA (0.22 mL, 0.16 g, 1.25 mmol). Finally, 3-aminopiperidine-2,6-dione (62 mg, 0.37 mmol) was added, and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with DMF and purified by reverse phase FC (5-50% MeCN / HO + 0.1% TFA) to give the title compound (100 mg, 93% yield). LCMS: [C 22 H 30 N4O5], desired mass = 430.5, observed: m / z = 431.5 [M+H] + . Step 4: (1r,4r)-4-((6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)amino)cyclohexane-1-carboxylic acid: [ka]

[0206] tert-Butyl (1r,4r)-4-((6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)amino)cyclohexane-1-carboxylate (100 mg, 0.23 mmol) was treated with 5% TFA in HFIP (1.9 mL, 1.3 mmol). The reaction mixture was stirred for 16 hours and then concentrated to dryness. The resulting product was then used without further purification to give the title compound (80 mg, 92% yield). LCMS: [C 18 H 22 N4O5], desired mass = 374.5, observed: m / z = 375.4 [M+H] + . Step 5: tert-butyl (3R)-1-((1r,4R)-4-((6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)amino)cyclohexane-1-carbonyl)pyrrolidine-3-carboxylate: [ka]

[0207] To a solution of (1r,4r)-4-((6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)amino)cyclohexane-1-carboxylic acid (80 mg, 0.21 mmol), HATU (162 mg, 0.42 mmol) and DIPEA (0.23 mL, 0.17 g, 1.3 mmol) were added. Finally, tert-butyl (R)-pyrrolidine-3-carboxylate (55 mg, 0.32 mmol) was added, and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with DMF and purified by reverse phase FC (5-50% MeCN / HO+0.1% TFA) to give the title compound (110 mg, 97% yield). LCMS: [C 27 H 37 N5O6], desired mass = 527.6, observed: m / z = 528.5 [M+H] + . Step 6: tert-butyl (3R)-1-((1r,4R)-4-((6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)amino)cyclohexane-1-carbonyl)pyrrolidine-3-carboxylate: [ka]

[0208] Prepared by a procedure similar to Step 4 using tert-butyl (3R)-1-((1r,4R)-4-((6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)amino)cyclohexane-1-carbonyl)pyrrolidine-3-carboxylate (110 mg, 0.21 mmol) as starting material. The crude mixture was purified by reverse phase FC (5-50% MeCN / HO) to give the title compound (96 mg, 97% yield). LCMS: [C 23 H 29 N5O6], desired mass = 471.5, observed: m / z = 472.4 [M+H] + . Intermediate 5 (3R)-1-((1r,4R)-4-((6-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)cyclohexane-1-carbonyl)pyrrolidine-3-carboxylic acid [ka] Step 1: tert-butyl (3R)-1-((1r,4R)-4-((6-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)cyclohexane-1-carbonyl)pyrrolidine-3-carboxylate: [ka]

[0209] To a solution of (1r,4r)-4-((6-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)cyclohexane-1-carboxylic acid (50 mg, 0.15 mmol) in DMF (1 mL) were added BOP (100 mg, 0.23 mmol) and DIPEA (0.13 mL, 96 mg, 0.74 mmol). Finally, tert-butyl (R)-pyrrolidine-3-carboxylate (39 mg, 0.23 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with DMF and purified by reverse phase FC (5-50% MeCN / HO + 0.1% TFA) to give the title compound (60 mg, 82% yield). LCMS: [C 26 H 36 N4O5], desired mass = 484.6, observed: m / z = 485.6 [M+H] + . Step 2: (3R)-1-((1r,4R)-4-((6-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)cyclohexane-1-carbonyl)pyrrolidine-3-carboxylic acid: [ka]

[0210] tert-Butyl (3R)-1-((1r,4R)-4-((6-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)cyclohexane-1-carbonyl)pyrrolidine-3-carboxylate (60 mg, 0.12 mmol) was treated with 5% TFA in HFIP (1.9 mL, 1.3 mmol). The reaction mixture was stirred for 16 hours and then concentrated to dryness. The resulting product was then used without further purification (unless otherwise noted) to give the title compound (50 mg, 94% yield). LCMS: [C 22 H 28 N4O5], desired mass = 428.5, observed: m / z = 429.3 [M+H] + . Intermediate 6 (3R)-1-[(1r,4r)-4-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}cyclohexanecarbonyl]pyrrolidine-3-carboxylic acid [ka]

[0211] The title compound (1.060 g, 71% yield, yellow solid) was synthesized using a method similar to Intermediate 17, substituting benzyl 2-[(3R)-pyrrolidin-3-yl]acetate hydrochloride for benzyl (3R)-pyrrolidine-3-carboxylate hydrochloride. LCMS: C 25 H 28 N4O7, desired mass = 496.5, observed: m / z = 497.1 [M+H] + . Intermediate 7 (3R)-1-((1r,4R)-4-((5-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)amino)cyclohexane-1-carbonyl)pyrrolidine-3-carboxylic acid [ka] Step 1: (3R)-1-((1r,4R)-4-((5-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)amino)cyclohexane-1-carbonyl)pyrrolidine-3-carboxylic acid [ka]

[0212] Prepared by a procedure similar to Intermediate 5 (Step 1) using (1r,4r)-4-((5-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)amino)cyclohexane-1-carboxylic acid (60 mg, 0.18 mmol) and tert-butyl (R)-pyrrolidine-3-carboxylate (26 mg, 0.18 mmol) as starting materials. The title compound (TFA salt) was isolated as an off-white solid (70 mg, 80% yield). LCMS: [C 26 H 36 N4O5], desired mass = 484.5, observed: m / z = 485.5 [M+H] + . Step 2: (3R)-1-((1r,4R)-4-((5-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)amino)cyclohexane-1-carbonyl)pyrrolidine-3-carboxylic acid [ka]

[0213] Prepared by a procedure similar to Intermediate 5 (Step 2) using tert-butyl (3R)-1-((1r,4R)-4-((5-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)amino)cyclohexane-1-carbonyl)pyrrolidine-3-carboxylate (70 mg, 0.14 mmol) as the starting material. The title compound (TFA salt) was isolated as an off-white solid (50 mg, 84% yield). LCMS: [C 22 H 28 N4O5], desired mass = 428.5, observed: m / z = 429.3 [M+H] + . Intermediate 8 (3R)-1-((1r,4R)-4-(4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclohexane-1-carbonyl)pyrrolidine-3-carboxylic acid [ka] Step 1: Benzyl (3R)-1-[(1r,4r)-4-[4-(2,6-dioxopiperidin-3-yl)phenoxy]cyclohexanecarbonyl]pyrrolidine-3-carboxylate [ka]

[0214] To a solution of (1r,4r)-4-(4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 52) (0.49 g, 1.479 mmol) in DMF (2.5 mL), HATU (0.675 g, 1.775 mmol) and DIPEA (0.5 mL, 2.96 mmol) were added, and the mixture was stirred at room temperature for 0.5 hours. Next, benzyl (3R)-1-(chlorohydrogenio)pyrrolidine-3-carboxylate (0.429 g, 1.775 mmol) and DIPEA (0.5 mL, 2.96 mmol) in DMF (2.5 mL) were added at room temperature. The reaction mixture was stirred overnight at room temperature, then diluted 10-fold with water, and extracted three times with DCM. The combined organic layers were washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography using a mobile phase of DCM and MeOH (0-3% MeOH) to afford 0.362 g (46% yield) of the title compound as an orange solid. LCMS: C 30 H 34 N2O6, desired mass = 518.6, observed: m / z = 519.2 [M+H] + . Step 2: (3R)-1-((1r,4R)-4-(4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclohexane-1-carbonyl)pyrrolidine-3-carboxylic acid [ka]

[0215] To a solution of benzyl (3R)-1-[(1r,4r)-4-[4-(2,6-dioxopiperidin-3-yl)phenoxy]cyclohexanecarbonyl]pyrrolidine-3-carboxylate (0.31 g, 0.598 mmol) in anhydrous DCM (12.0 mL) was added a solution of HBr in AcOH (19.0 mL, 7.77 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. The solvent was concentrated in vacuo. The residue was precipitated with diethyl ether and filtered to give 102 mg (40% yield) of the title compound as a beige solid. LCMS: C 23 H28N2O6, desired mass = 428.5, observed: m / z = 429.0 [M+H] + . Intermediate 9 (1r,4r)-4-((5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)oxy)cyclohexane-1-carboxylic acid [ka]

[0216] Step 1: (1r,4r)-4-[(5-bromopyridin-2-yl)oxy]cyclohexane-1-carboxylate. 5-Bromo-2-fluoropyridine (12.2 g, 69.4 mmol) and (1r,4r)-4-hydroxycyclohexane-1-carboxylic acid (10.0 g, 69.4 mmol) were dissolved in DMA (150.0 mL) and stirred at room temperature. Sodium hydride (5.55 g, 138 mmol, 60.0%) was added, and the reaction mixture was stirred at 100° C. for 10 hours. The product was isolated by flash column chromatography to give the title compound (10.0 g, 48.0% yield). Step 2: (1r,4r)-4-((2',6'-bis(benzoyloxy)-[3,3'-bipyridin]-6-yl)oxy)cyclohexane-1-carboxylic acid

[0217] (1r,4r)-4-[(5-bromopyridin-2-yl)oxy]cyclohexane-1-carboxylate (3.96 g, 13.2 mmol), 2,6-bis(benzyloxy)pyridin-3-ylboronic acid (5.00 g, 12.0 mmol), Pd(dppf)Cl-DCM (877 mg, 1.20 mmol), KCO (2.48 g, 18.0 mmol), and dioxane (50.0 mL) were combined in a sealed vial. The vial was purged with nitrogen gas and stirred at 100 °C for 12 hours. The reaction mixture was poured onto brine, extracted with ethyl acetate, filtered, and then concentrated onto silica. The product was isolated by flash column chromatography to give the title compound (4.00 g, 65.4% yield). Step 3: (1r,4r)-4-((5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)oxy)cyclohexane-1-carboxylic acid

[0218] (1r,4r)-4-((2',6'-bis(benzoyloxy)-[3,3'-bipyridin]-6-yl)oxy)cyclohexane-1-carboxylic acid (4.00 g, 7.83 mmol) was dissolved in THF (60.0 mL). Pd / C (500 mg, 10.0% purity) was added and the reaction mixture was stirred under a hydrogen atmosphere for 12 hours. After filtration and concentration, the crude residue was triturated with ethyl acetate (15.0 mL) to give the title compound (2.60 g, 79.9% yield). LCMS: C 17 H 20 Desired mass of N2O5 = 332.36, Found: m / z = 333.1 [M+H] + . Intermediate 10 (R)-1-((1r,4R)-4-((5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)oxy)cyclohexane-1-carbonyl)pyrrolidine-3-carboxylic acid [ka] Step 1: Benzyl (3R)-1-[(1r,4r)-4-{[5-(2,4-dioxo-1,3-diazinan-1-yl)pyridin-2-yl]oxy}cyclohexanecarbonyl]pyrrolidine-3-carboxylate [ka]

[0219] To a solution of (1r,4r)-4-((5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)oxy)cyclohexane-1-carboxylic acid (Intermediate 53) (0.29 g, 0.87 mmol) in anhydrous DMF (8.0 mL) were added HATU (0.31 g, 1.31 mmol) and DIPEA (0.23 mL, 1.31 mmol) at 25° C. and stirred at 25° C. for 0.5 h. Then, a solution of benzyl (3R)-pyrrolidine-3-carboxylate hydrochloride (0.25 g, 1.04 mmol) in anhydrous DMF (8.0 mL) was added and the reaction mixture was stirred at 25° C. for 16 h. The solvent was evaporated to dryness and the residue was purified by silica gel chromatography using a mobile phase of DCM and IPA to give 0.182 g (40% yield) of the title compound. LCMS: C 28 H 32 N4O6, desired mass = 520.2, observed: m / z = 521.1 [M+H] + . Step 2: (R)-1-((1r,4R)-4-((5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)oxy)cyclohexane-1-carbonyl)pyrrolidine-3-carboxylic acid [ka]

[0220] To a solution of benzyl (3R)-1-[(1r,4r)-4-{[5-(2,4-dioxo-1,3-diazinan-1-yl)pyridin-2-yl]oxy}cyclohexanecarbonyl]pyrrolidine-3-carboxylate (0.15 g, 0.288 mmol) in anhydrous THF (38.5 mL) was added Pd / C (0.015 g, 0.015 mmol) at 25° C. The reaction mixture was stirred under H (1 atm) at 25° C. overnight. The mixture was filtered through a celite cake and evaporated to dryness to give 86 mg (70% yield) of the title compound as an off-white solid. LCMS: C 21 H 26 N4O6, desired mass = 430.2, observed: m / z = 431.2 [M+H] + . Intermediate 11 (3R)-1-(1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)pyrrolidine-3-carboxylic acid [ka] Step 1: tert-Butyl 1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carboxylate [ka]

[0221] To a solution of 3-(6-fluoropyridin-3-yl)piperidine-2,6-dione (200 mg, 0.96 mmol) and tert-butyl piperidine-4-carboxylate (267 mg, 1.44 mmol) in DMSO (0.6 mL) was added DIPEA (0.5 mL, 2.88 mmol) at room temperature. The reaction mixture was stirred at 120 °C for 16 hours, then diluted with ethyl acetate (10 mL) and washed with water (3 × 5 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mobile phase of 0-5% MeOH in DCM to afford 232 mg (65% yield) of the title compound as an orange solid. LCMS: [C 20 H27 N3O4], desired mass = 373.2, observed: m / z = 374.1 [M+H] + . Step 2: 1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carboxylic acid [ka]

[0222] To a solution of tert-butyl 1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carboxylate (196 mg, 0.52 mmol) in HFIP (5.2 mL) was added TFA (0.26 mL, 3.37 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours, then concentrated under reduced pressure, and then resuspended and reconcentrated in diethyl ether (3 x 5 mL). The residue (yellow oil, 388 mg) was used directly in the next step. LCMS: [C 16 H 19 N3O4], desired mass = 317.1, observed: m / z = 318.1 [M+H] + . Step 3: tert-Butyl (3R)-1-(1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)pyrrolidine-3-carboxylate [ka]

[0223] To a solution of 1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carboxylic acid (266 mg, 1.53 mmol) in anhydrous DMF (10.2 mL) was added BOP (678 mg, 1.53 mmol) and stirred at room temperature for 10 minutes, followed by the addition of DIPEA (0.89 mL, 5.09 mmol). The reaction mixture was stirred at room temperature for 16 hours, then the reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mobile phase of 0-5% MeOH in DCM to afford 272 mg (48% yield) of the title compound as an off-white solid. LCMS: [C 25 H 34 N4O5], desired mass = 470.2, observed: m / z = 471.4 [M+H] + . Step 4: (3R)-1-(1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)pyrrolidine-3-carboxylic acid [ka]

[0224] The title compound was produced by TFA deprotection of tert-butyl (3R)-1-(1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)pyrrolidine-3-carboxylate, similar to the method used in Step 2. The crude product was used directly in the next step (off-white solid, 305 mg). LCMS: [C 21 H 26 N4O5], desired mass = 414.1, observed: m / z = 415.3 [M+H] + . Intermediate 12 (1r,4r)-4-(4-((5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)piperidine-1-carbonyl)cyclohexane-1-carboxylic acid [ka] Step 1: tert-Butyl 4-((5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)piperidine-1-carboxylate [ka]

[0225] To a solution of 3-(6-fluoro-3-pyridyl)-2,6-piperidinedione (250 mg, 1.20 mmol) in DMSO, tert-butyl 4-aminopiperidine-1-carboxylate (289 mg, 1.44 mmol) and N,N-diisopropylethylamine (0.85 mL, 4.87 mmol) were added. The reaction mixture was stirred at 120 °C for 108 h and then worked up with water (50 mL) and EtOAc (3 × 50 mL). The combined organic layers were dried over Na SO and concentrated. The crude was purified by silica gel column chromatography (DCM / MeOH, 0-20%) to give the title compound (white solid, 49 mg, 0.126 mmol, 11% yield). LCMS: [C 20 H 28 N4O4], desired mass = 388.2, observed: m / z = 389.3 [M+H] + . Step 2: 3-[6-(4-piperidylamino)-3-pyridyl]-2,6-piperidinedione [ka]

[0226] A solution of tert-butyl 4-((5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)piperidine-1-carboxylate (49 mg, 0.126 mmol) in 4N HCl (0.8 mL, 3.2 mmol) in dioxane was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness and co-evaporated with ether three times to give the title compound (white solid, 38 mg), which was used directly in the next step. LCMS: [C 15 H20 N4O2], desired mass = 288.1, observed: m / z = 288.8 [M+H] + . Step 3: Methyl (1r,4r)-4-(4-((5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)piperidine-1-carbonyl)cyclohexane-1-carboxylate [ka]

[0227] The title compound was synthesized using a method similar to Intermediate 11 using BOP coupling. A white powder (46 mg, 0.1008 mmol, 76% yield) was obtained as the free base. LCMS: [C 24 H 32 N4O5], desired mass = 456.5, observed: m / z = 457.4 [M+H] + . Step 4: (1r,4r)-4-(4-((5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)piperidine-1-carbonyl)cyclohexane-1-carboxylic acid [ka]

[0228] A solution of methyl (1r,4r)-4-(4-((5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)piperidine-1-carbonyl)cyclohexane-1-carboxylate (46 mg, 0.1008 mmol) in TFA (1.0 mL) and HO (0.5 mL) was stirred at 70° C. for 6.5 hours. The reaction mixture was concentrated to give the title compound (viscous oil, 69 mg), which was used directly in the next step. LCMS: [C 23 H 30 N4O5], desired mass = 442.2, observed: m / z = 443.4 [M+H] + . Intermediate 13 3-(6-(piperidin-4-yloxy)pyridin-3-yl)piperidine-2,6-dione [ka] Step 1: tert-Butyl 4-[(5-bromopyridin-2-yl)oxy]piperidine-1-carboxylate

[0229] 5-Bromo-2-fluoropyridine (0.58 mL, 1.00 g, 5.68 mmol) and tert-butyl 4-hydroxypiperidine-1-carboxylate (1.14 g, 5.68 mmol) were dissolved in NMP (5.00 mL) and stirred at room temperature. Sodium hydride (0.27 g, 11.36 mmol) was added, and the reaction mixture was heated at 60° C. for 2 hours. The product was isolated by flash column chromatography to give the title compound (0.75 g, 37.0% yield). Step 2: tert-Butyl 4-{[2',6'-bis(benzyloxy)-[3,3'-bipyridin]-6-yl]oxy}piperidine-1-carboxylate

[0230] tert-Butyl 4-[(5-bromopyridin-2-yl)oxy]piperidine-1-carboxylate (750.00 mg, 2.10 mmol), Pd(dppf)Cl-DCM (342.8 mg, 0.42 mmol), cesium carbonate 1N solution (5.25 mL, 5.25 mmol), 2,6-bis(benzyloxy)pyridin-3-ylboronic acid (703.6 mg, 2.10 mmol), and dioxane (5.00 mL) were combined in a sealed vial. The vial was purged with nitrogen gas and stirred at 100 °C for 60 minutes. The reaction mixture was poured onto brine, extracted with ethyl acetate, filtered, and then concentrated onto silica. The product was isolated by flash column chromatography to give the title compound (1.05 g, 88% yield). Step 3: 3-(6-(piperidin-4-yloxy)pyridin-3-yl)piperidine-2,6-dione

[0231] tert-Butyl 4-{[2',6'-bis(benzyloxy)-[3,3'-bipyridin]-6-yl]oxy}piperidine-1-carboxylate (1.05 g, mmol) was dissolved in MeOH (20.00 mL). 10% palladium on carbon (0.20 g, 0.18 mmol) was added, and the reaction mixture was stirred under a hydrogen balloon for 12 hours. The reaction mixture was filtered through Celite and concentrated. This material was dissolved in DCM (10.00 mL), treated with 4 M HCl in dioxane (3.0 mL), and stirred at room temperature overnight. The reaction mixture was concentrated to give the title compound as an off-white crystalline solid as the HCl salt (0.425 g, 84% yield). LCMS: C 15 H 19 Desired mass of N3O3: 289.3, Measured: m / z = 290.2 [M+H] + . Intermediate 14 (1s,4s)-4-(4-{[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl]amino}piperidine-1-carbonyl)cyclohexane-1-carboxylic acid [ka]

[0232] The title compound 16 was synthesized using a method similar to that of intermediate 12, using (1r,4r)-4-(methoxycarbonyl)-cyclohexane-1-carboxylic acid instead of (1s,4s)-4-(methoxycarbonyl)cyclohexane-1-carboxylic acid. The final step was carried out as follows: To a solution of tert-butyl (1s,4s)-4-(4-{[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl]amino}piperidine-1-carbonyl)cyclohexane-1-carboxylate (157 mg, 0.32 mmol) in acetic acid (2.50 mL) was added 4 M HCl in dioxane (1.26 mL, 5.04 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 2 hours, and then the solvent was evaporated to dryness under reduced pressure. The crude compound was triturated with EtO (2 x 15 mL), heptane (30 mL), and dried under reduced pressure. The residue was then dissolved in water (10 mL), frozen, and freeze-dried overnight. The residue was purified by preparative HPLC (Method 20210423-prep2-60800420-PKU01-087 C18 prep) to afford 105 mg (75%) of the title compound as a white solid. LCMS: C 23 H 30 N4O5, desired mass = 442.5, observed: m / z = 443.3 [M+H] + . Intermediate 15 (1r,4r)-4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-carbonyl)cyclohexane-1-carboxylic acid [ka] Step 1: (1r,4r)-4-[(benzyloxy)carbonyl]cyclohexane-1-carboxylic acid [ka]

[0233] To a mixture of (1r,4r)-cyclohexane-1,4-dicarboxylic acid (10 g, 58.079 mmol) and K2CO3 (24.0 g, 174.2 mmol) in DMF (50 mL) was added BnBr (9.93 g, 58.0 mmol) at room temperature. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere overnight. The resulting mixture was allowed to cool to room temperature. The mixture was poured into ice water. The solid was collected by filtration. The solid was washed with HO / MeOH (1 / 1) to give 8 g (crude) of the title compound as a white solid. Step 2: tert-Butyl 4-[(1r,4r)-4-[(benzyloxy)carbonyl]cyclohexanecarbonyl]piperazine-1-carboxylate [ka]

[0234] To a mixture of (1r,4r)-4-[(benzyloxy)carbonyl]cyclohexane-1-carboxylic acid (5 g, 19.084 mmol) and tert-butyl piperazine-1-carboxylate (3.54 g, 19.084 mmol) in DMF (10 mL) was added TEA (11.56 g, 114.5 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 15 minutes. To the previous mixture was added T3P (12.13 g, 38.168 mmol) at 0° C. The resulting mixture was stirred at room temperature overnight. The resulting mixture was purified by reverse-phase flash chromatography in [CH3CN and HO] to afford 1.5 g (16.63%) of the title compound as a white solid. LCMS: (C 24 H 34 Desired mass of N2O5) = 431.3; Found: m / z = 431.2 [M+H] + . Step 3: Benzyl (1r,4r)-4-(piperazine-1-carbonyl)cyclohexane-1-carboxylate [ka]

[0235] A mixture of tert-butyl 4-[(1r,4r)-4-[(benzyloxy)carbonyl]cyclohexanecarbonyl]piperazine-1-carboxylate (2 g, 4.646 mmol) in HCl / dioxane (20 mL, 4N) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to give 1.5 g (crude) of the title compound as a white solid. LCMS: (C 19 H 26 Desired mass of N2O3 = 330.2; Found: m / z = 331.4 [M+H] + . Step 4: Benzyl (1r,4r)-4-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazine-1-carbonyl]cyclohexane-1-carboxylate [ka]

[0236] To a mixture of benzyl (1r,4r)-4-(piperazine-1-carbonyl)cyclohexane-1-carboxylate (1.5 g, 4.540 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (1.25 g, 4.540 mmol) in DMSO (10 mL) was added DIEA (1.76 g, 13.619 mmol, 3 equiv.) at room temperature. The resulting mixture was stirred at 80 °C overnight. The resulting mixture was purified by reverse-phase flash chromatography [CH CN and HO] to afford 600 mg (21.47%) of the title compound as a yellow solid. LCMS: (C 32 H 34 Desired mass of N4O7) = 586.2; Found: m / z = 587.4 [M+H] + . Step 5: (1r,4r)-4-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazine-1-carbonyl]cyclohexane-1-carboxylic acid [ka]

[0237] To a mixture of benzyl (1r,4r)-4-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazine-1-carbonyl]cyclohexane-1-carboxylate (600 mg, 1.023 mmol) in THF (10 mL) was added Pd / C (300 mg) at room temperature. The resulting mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours.

[0238] The solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography with [CHCN and H2O] to give 392.8 mg (75.90%) of the title compound as a yellow solid. LCMS (Method 1): (C 25 H 28 Desired mass of N4O7) = 496.2; Found: m / z = 497.1 [M+H] + . Intermediate 16 (3S)-1-(1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)pyrrolidine-3-carboxylic acid [ka] Step 1: tert-Butyl (3S)-1-(1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)pyrrolidine-3-carboxylate [ka]

[0239] Prepared by a procedure similar to Intermediate 5 (Step 1) using 1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carboxylic acid (60 mg, 0.19 mmol) and tert-butyl (S)-pyrrolidine-3-carboxylate (32 mg, 0.19 mmol) as starting materials. The title compound (TFA salt) was isolated as an off-white solid (80 mg, 90% yield). LCMS: [C25 H 34 N4O5], desired mass = 470.6, observed: m / z = 471.5 [M+H] + . Step 2: (3S)-1-(1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)pyrrolidine-3-carboxylic acid: [ka]

[0240] Prepared by a procedure similar to Intermediate 5 (Step 2) using tert-butyl (3S)-1-(1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)pyrrolidine-3-carboxylate (80 mg, 0.17 mmol) as the starting material. The title compound (TFA salt) was isolated as an off-white solid (68 mg, 96% yield). LCMS: [C 21 H 26 N4O5], desired mass = 414.5, observed: m / z = 415.4 [M+H] + . Intermediate 17 2-((3R)-1-((1r,4R)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)cyclohexane-1-carbonyl)pyrrolidin-3-yl)acetic acid [ka] Step 1: (1r,4r)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)cyclohexane-1-carboxylic acid [ka]

[0241] To a solution of (1r,4r)-4-aminocyclohexane-1-carboxylic acid (0.74 g, 5.17 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (0.740 g, 5.17 mmol) in anhydrous DMSO (25.0 mL) were added 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (1.43 g, 5.17 mmol) and potassium fluoride (1.20 g, 20.67 mmol) at 25° C. The reaction mixture was stirred at 120° C. for 24 hours, then the mixture was poured into 250 mL of HO and extracted with EtOAc (5×50 mL). The combined organic extracts were further washed with 50 mL of brine, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by silica gel chromatography using a mobile phase of DCM and MeOH to give 1500 mg (73% yield) of the title compound as a yellow solid. LCMS: C 20 H 21 N3O6, desired mass = 399.1, observed: m / z = 400.4 [M+H] + . Step 2: tert-Butyl (3R)-3-[2-(benzyloxy)-2-oxoethyl]pyrrolidine-1-carboxylate [ka]

[0242] To a solution of 2-[(3R)-1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl]acetic acid (500 mg, 2.18 mmol) in anhydrous DMF (10 mL) was added CsCO (852 mg, 2.62 mmol). The reaction mixture was placed in an ice bath and stirred at 0 °C for 1 h, then benzyl bromide (410 mg, 2.4 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 12 h, then the mixture was poured into 150 mL of brine and extracted with EtOAc (5 × 50 mL). The combined organic layers were washed with 50 mL of brine, dried over MgSO, and concentrated under reduced pressure to afford 695 mg (100% yield) of the title compound as a yellow oil, which was used directly in the next step. Step 3: Benzyl 2-[(3R)-pyrrolidin-3-yl]acetate hydrochloride [ka]

[0243] To a solution of tert-butyl (3R)-3-[2-(benzyloxy)-2-oxoethyl]pyrrolidine-1-carboxylate (695 mg, 2.18 mmol) in anhydrous DCM (30 mL) was added 2 M HCl (6.51 g, 17.4 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 12 h, and then the solvent was evaporated to dryness under reduced pressure. The crude compound was washed with EtO (2 × 10 mL) and dried in vacuo to afford 550 mg (99% yield) of the title compound as a white amorphous solid, which was used directly in the next step. LCMS: C 13 H 17 NO2, desired mass = 219.1, observed: m / z = 220.5 [M+H] + . Step 4: Benzyl 2-((3R)-1-((1r,4R)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)cyclohexane-1-carbonyl)pyrrolidin-3-yl)acetate [ka]

[0244] To a solution of benzyl 2-[(3R)-pyrrolidin-3-yl]acetate hydrochloride (550 mg, 2.15 mmol) in anhydrous DMF (50 mL) was added (1r,4r)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)cyclohexane-1-carboxylic acid (859 mg, 2.15 mmol), HATU (1.23 g, 0.47 mmol), and DIPEA (834 mg, 6.45 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 48 h, then the mixture was poured into 800 mL of brine, followed by extraction with DCM (4×50 mL). The organic extract was dried over MgSO and evaporated under reduced pressure. The residue was purified by silica gel chromatography using a mobile phase of hexane and EtOAc to give 1959 mg (82% yield) of the title compound as a yellow solid. LCMS:C 33 H 36 N4O7, desired mass = 600.3, observed: m / z = 601.8 [M+H] + . Step 5: 2-[(3R)-1-[(1r,4r)-4-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}cyclohexanecarbonyl]pyrrolidin-3-yl]acetic acid [ka]

[0245] To a solution of benzyl 2-((3R)-1-((1r,4R)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)cyclohexane-1-carbonyl)pyrrolidin-3-yl)acetate (1.06 g, 1.76 mmol) in anhydrous THF (25 mL) was added 10% wt Pd(OH) / C (25 mg, 0.176 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 12 h, followed by the addition of a second amount of 10% wt Pd(OH) / C (25 mg, 0.176 mmol) at 25° C. The reaction mixture was stirred at 25° C. for an additional 12 h, then filtered through Celite and evaporated to dryness. The residue was purified by precipitation from a THF / Et2O mixture to give 524 mg (58% yield) of the title compound as a yellow solid. LCMS: C 26 H 30 N4O7, desired mass = 510.2, observed: m / z = 511.2 [M+H] + . Intermediate 18 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carboxylic acid [ka]

[0246] 2-(2,6-Dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (2.0 g, 5.2 mmol) and tert-butyl piperidine-4-carboxylate (1.34 g, 7.24 mmol) were dissolved in DMSO (5.00 mL) and N,N-diisopropylethylamine (1.00 mL, 0.74 g, 5.74 mmol), and the reaction mixture was irradiated at 125° C. for 3 hours. The reaction mixture was poured onto brine and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness. The resulting material was dissolved in DCM (50 mL), treated with TFA (20.0 mL), and stirred for 12 hours. The product was isolated by reverse-phase flash column eluting with DCM and MeOH to give 1.45 g of the title compound as an off-white solid. Intermediate 19 4-{4-[4-(2,6-dioxopiperidin-3-yl)phenyl]piperazine-1-carbonyl}benzoic acid [ka] Step 1: tert-Butyl 4-[4-(4-bromophenyl)piperazine-1-carbonyl]benzoate [ka]

[0247] To a mixture of 4-(tert-butoxycarbonyl)benzoic acid (1 g, 4.478 mmol) in DMF (8 mL) was added HATU (1.28 g, 3.358 mmol) in several portions at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. To the previous mixture were added 1-(4-bromophenyl)piperazine (540 mg, 2.239 mmol) and DIEA (0.87 g, 6.717 mmol). The resulting mixture was stirred at room temperature overnight. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography [PE and EA] to give 1 g (90.24%) of the title compound as a white solid. LCMS: (C 22 H 25 Desired mass of BrN2O3) = 444.1; Found: m / z = 445.2 [M+H] + . Step 2: tert-Butyl 4-(4-{4-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}piperazine-1-carbonyl)benzoate [ka]

[0248] To a mixture of tert-butyl 4-[4-(4-bromophenyl)piperazine-1-carbonyl]benzoate (960 mg, 2.156 mmol) in THF (10 mL), 2,6-bis(benzyloxy)pyridin-3-ylboronic acid (1083 mg, 3.234 mmol), KCO (595 mg, 4.312 mmol) in HO (2 mL), and Pd(PPh) (249 mg, 0.216 mmol) were added at room temperature. The reaction mixture was irradiated with microwave radiation at 110 °C for 40 minutes. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography [PE and EA] to afford 1 g (67.20%) of the title compound as a white solid. LCMS: (C 41 H 41 Desired mass of N3O5) = 655.3; Found: m / z = 656.4 [M+H] + . Step 3: tert-Butyl 4-{4-[4-(2,6-dioxopiperidin-3-yl)phenyl]piperidine-1-carbonyl}benzoate [ka]

[0249] A procedure similar to that of Step 5 of Intermediate 15 was followed using tert-butyl 4-(4-{4-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}piperazine-1-carbonyl)benzoate (600 mg, 0.915 mmol), EtOH (6 mL), THF (6 mL), and Pd / C (449 mg). The residue was purified by silica gel column chromatography [PE and EA] to afford 450 mg (82.56%) of the title compound as a white solid. LCMS: (C 27 H 31 Desired mass of N3O5) = 477.2; Found: m / z = 478.2 [M+H] + . Step 4: 4-{4-[4-(2,6-dioxopiperidin-3-yl)phenyl]piperazine-1-carbonyl}benzoic acid [ka]

[0250] A procedure similar to that of Step 3 of Intermediate 15 was followed using tert-butyl 4-{4-[4-(2,6-dioxopiperidin-3-yl)phenyl]piperidine-1-carbonyl}benzoate (450 mg, 0.944 mmol) and HCl / dioxane (15 mL, 4 M). The residue was purified by silica gel column chromatography [ACN and HO] to afford 46.5 mg (12.91%) of the title compound as a green solid. LCMS (Method 2): (C 23 H 23 Desired mass of N3O5) = 421.2; Found: m / z = 422.1 [M+H] + . Intermediate 20 4-(4-[2-(2,6-dioxopiperidin-3-yl)]-1,3-dioxoisoindol-5-yl]piperazine-1-carbonyl)benzoic acid [ka] Step 1: 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione [ka]

[0251] A procedure similar to that of Step 4 of Intermediate 15 was followed using 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (1 g, 3.620 mmol), piperazine (0.47 g, 5.430 mmol), ACN (10 mL), and DIEA (1.4 g, 10.861 mmol). The crude residue was purified by reverse-phase flash chromatography using a mobile phase of [CHCN and HO] to afford 250 mg (16.94%) of the title compound as a yellow solid. LCMS: (C 17 H 18 Desired mass of N4O4 = 342.1; Found: m / z = 343.1 [M+H] + . Step 2: tert-Butyl 4-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazine-1-carbonyl]benzoate [ka]

[0252] To a mixture of 4-(tert-butoxycarbonyl)benzoic acid (324.58 mg, 1.460 mmol) in DCM (10 mL) and DMF (0.1 mL) was added oxalyl chloride (0.12 mL, 0.980 mmol) at 0° C. under N. The resulting mixture was stirred at 0° C. for 1 h under N. The acid chloride solution was added to a mixture of 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione (500 mg, 1.460 mmol) and NaCO (464 mg, 4.381 mmol) in NMP (8 mL) at 0° C. The resulting mixture was stirred at room temperature under N for 2 h. The resulting mixture was quenched with water and purified by reverse-phase flash chromatography, mobile phase [CHCN and H2O] to afford 550 mg (66.83%) of the title compound as a yellow solid. LCMS: (C 29 H 30 Desired mass of N4O7) = 546.2; Found: m / z = 547.2 [M+H] + . Step 3: 4-(4-[2-[2,6-dioxopiperidin-3-yl]-1,3-dioxoisoindol-5-yl]piperazine-1-carbonyl)benzoic acid [ka]

[0253] A procedure similar to that of Step 3 of Intermediate 15 was followed using tert-butyl 4-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazine-1-carbonyl]benzoate (530 mg, 0.970 mmol) and HCl / 1,4-dioxane (35 mL, 4 M). The residue was purified by reverse-phase flash chromatography using a mobile phase of [CHCN and HO] to afford 227 mg (47.64%) of the title compound as a yellow solid. LCMS (Method 3): (C 25 H 22 Desired mass of N4O7) = 490.2; Found: m / z = 491.2 [M+H] + . Intermediate 21 4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-carbonyl)benzoic acid [ka] Step 1: 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione [ka]

[0254] To a mixture of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (1 g, 3.620 mmol) and piperazine (0.47 g, 5.430 mmol) in ACN (10 mL) was added DIEA (1.4 g, 10.861 mmol). The resulting mixture was stirred at 80 °C overnight. The resulting mixture was purified by reverse-phase flash chromatography [CHCN and HO mobile phase] to afford 250 mg (16.94%) of the title compound as a yellow solid. LCMS: (C 17 H 18 Desired mass of N4O4 = 342.1; Found: m / z = 343.1 [M+H] + . Step 2: tert-butyl 4-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazine-1-carbonyl]benzoate: [ka]

[0255] To a mixture of 4-(tert-butoxycarbonyl)benzoic acid (324.58 mg, 1.460 mmol) in DCM (10 mL) was added DMF (0.1 mL) and oxalyl chloride (0.73 mL, 1.460 mmol, 2 mol / L) at 0° C. under N. The resulting mixture was stirred at 0° C. for 1 h under N. To a mixture of 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione (500 mg, 1.460 mmol, 1 equiv.) in NMP (8 mL) was added NaCO (464 mg, 4.381 mmol, 3 equiv.) and the previous mixture at 0° C. under N. The resulting mixture was stirred at room temperature under N for 2 h, then washed with water and concentrated in vacuo. The residue was purified by reverse-phase flash chromatography [CHCN and H2O mobile phase] to give 550 mg (66.83%) of the title compound as a yellow solid. LCMS: (C 29 H 30 Desired mass of N4O7) = 546.2; Found: m / z = 547.2 [M+H] + . Step 3: 4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-carbonyl)benzoic acid [ka]

[0256] A mixture of tert-butyl 4-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazine-1-carbonyl]benzoate (530 mg, 0.970 mmol, 1 equiv.) in HCl / 1,4-dioxane (35 mL, 4 M) was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography [CHCN and HO mobile phase] to afford 227 mg (47.64%) of the title compound as a yellow solid. LCMS: (C 25 H 22 Desired mass of N4O7) = 490.2; Found: m / z = 491.2 [M+H] + . Intermediate 22 4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}carbamoyl)benzoic acid [ka] Step 1: Benzyl 4-{4-[(tert-butoxy)carbonyl]benzamido}piperidine-1-carboxylate [ka]

[0257] To a solution of 4-[(tert-butoxy)carbonyl]benzoic acid (484 mg, 2.07 mmol) and HATU (870 mg, 2.17 mmol) in anhydrous DMF (20.7 mL) was added DIPEA (0.401 g, 3.10 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 0.5 h, and then benzyl 4-aminopiperidine-1-carboxylate (613 mg, 2.49 mmol) in DMF (20.7 mL) was added, and the reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was evaporated, dissolved in EtOAc, and washed sequentially with 5% aqueous citric acid, saturated NaHCO solution, and brine. The organic layer was dried over NaSO and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using a mobile phase of EtOAc to give 685 mg (75% yield) of the title compound. LCMS: C 25 H 30 N2O5, desired mass = 438.2, observed: m / z = 439.5 [M+H] + . Step 2: tert-Butyl 4-[(piperidin-4-yl)carbamoyl]benzoate [ka]

[0258] To a solution of benzyl 4-{4-[(tert-butoxy)carbonyl]benzamido}piperidine-1-carboxylate (680 mg, 1.55 mmol) in EtOH (38.8 mL) was added Pd(OH) / C 10% wt (221 mg, 0.16 mmol), and the reaction mixture was stirred under H (1 atm) at 25 °C for 24 h. The reaction mixture was filtered through a pad of Celite, washed with MeOH, and concentrated under reduced pressure to give 550 mg (99% yield) of the title compound. LCMS: C 17 H 24 N2O3, desired mass = 304.2, observed: m / z = 305.4 [M+H] + . Step 3: tert-Butyl 4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}carbamoyl)benzoate [ka]

[0259] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (357 mg, 1.29 mmol) in DMSO (2.58 mL) was added tert-butyl 4-[(piperidin-4-yl)carbamoyl]benzoate (0.555 g, 1.55 mmol) and DIPEA (670 mg, 5.17 mmol) at 25° C. The reaction mixture was stirred at 90° C. for 24 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography using a mobile phase of hexane and EtOAc to give 450 mg (58% yield) of the title compound. LCMS: C 30 H 32 N4O7, desired mass = 560.2, observed: m / z = 561.6 [M+H] + . Step 4: 4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}carbamoyl)benzoic acid [ka]

[0260] tert-Butyl 4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}carbamoyl)benzoate (463 mg, 0.77 mmol) was suspended in HFIP (12.8 g, 75.99 mmol) and heated in a microwave reactor at 150° C. for 2 h. The HFIP was then evaporated under reduced pressure and the solid residue was triturated with EtO to give 216 mg (54% yield) of the title compound. LCMS: C 26 H 24 N4O7, desired mass = 504.2, observed: m / z = 505.2 [M+H] + . Intermediate 23 6-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazine-1-carbonyl}pyridine-3-carboxylic acid [ka]

[0261] The title compound (60 mg, 43% yield) was synthesized using a method similar to intermediate 22, substituting 4-[(tert-butoxy)carbonyl]benzoic acid for 5-[(tert-butoxy)carbonyl]pyridine-2-carboxylic acid and benzyl 4-aminopiperidine-1-carboxylate for benzyl 1-piperazinecarboxylate. LCMS: C 24 H 21 N5O7, desired mass = 491.1, observed: m / z = 492.3 [M+H] + . Intermediate 24 (1r,4r)-4-(6-(2,6-dioxopiperidin-3-yl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carbaldehyde [ka] Step 1: -Butyl 6-(2,6-bis(benzyloxy)pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0262] To a 40 mL vial was added tert-butyl 6-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylate (1000.00 mg, 3.20 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1470.31 mg, 3.52 mmol), potassium phosphate tribasic (2.04 g, 9.61 mmol), Pd(dppf)Cl₂·DCM (0.26 g, 0.32 mmol), dioxane (7.00 mL), and water (2.50 mL). The reaction mixture was degassed with nitrogen for 15 minutes and then stirred at 90 °C for 16 hours. The reaction mixture was then diluted with water and EtOAc and then filtered through Celite. The product was extracted with EtOAc (3 times), dried over MgSO₄, and then concentrated. The resulting residue was purified by FC (80 g silica, 0-25% EtOAc / hexane) to give the title compound as a colorless oil (1.48 g, 88% yield). LCMS: [C 33 H 34 N2O4], desired mass = 522.3, observed: m / z = 523.3 [M+H] + . Step 2: tert-Butyl 6-(2,6-dioxopiperidin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0263] To a 40 mL vial was added tert-butyl 6-[2,6-bis(benzyloxy)pyridin-3-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (1480.00 mg, 2.83 mmol), Pd / C (700.00 mg), THF (10.00 mL), and EtOH (10.00 mL). The reaction mixture was sparged with hydrogen for 5 minutes, and then the reaction mixture was stirred under a hydrogen atmosphere (balloon) for 16 hours. The reaction mixture was filtered through Celite and then concentrated. The resulting residue was purified by FC (40 g silica, 0-10% MeOH / DCM) to give the title compound as a white solid (852 mg, 87% yield). LCMS: [C 19 H 24 N2O4], desired mass = 344.2, observed: m / z = 345.2 [M+H] + . Step 3: 3-(1,2,3,4-tetrahydroisoquinolin-6-yl)piperidine-2,6-dione

[0264] To a 40 mL vial was added tert-butyl 6-[(3RS)-2,6-dioxopiperidin-3-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (852.00 mg, 2.47 mmol) and DCM (2.00 mL). To the reaction mixture was added 4 M hydrogen chloride in dioxane (6.18 mL, 0.90 g, 24.74 mmol) dropwise. After 1 hour, the reaction mixture was concentrated to give the title compound as a white solid (707 mg, quantitative yield). LCMS: [C 14 H 16 Desired mass of N2O2 = 244.1, Found: m / z = 245.0 [M+H] + . Step 4: 3-(2-((1r,4r)-4-(hydroxymethyl)cyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)piperidine-2,6-dione

[0265] To a 1-dram vial was added 3-(1,2,3,4-tetrahydroisoquinolin-6-yl)piperidine-2,6-dione hydrochloride (10.00 mg, 0.04 mmol), (1r,4r)-4-(hydroxymethyl)cyclohexane-1-carboxylic acid (5.63 mg, 0.04 mmol), N,N-diisopropylethylamine (0.06 mL, 0.05 g, 0.36 mmol), and DMF (0.25 mL). To the reaction mixture was added [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda 5-phosphanide (13.54 mg, 0.04 mmol) in DMF (0.25 mL). After 3 h, the reaction mixture was quenched with NaHCO (aq). The product was extracted with 10% MeOH / DCM (3 times), dried over MgSO4, and then concentrated. The resulting residue was used in the next step without further purification. LCMS: [C 22 H 28 Desired mass of N2O4 = 384.2, Found: m / z = 385.3 [M+H] + . Step 5: (1r,4r)-4-(6-(2,6-dioxopiperidin-3-yl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carbaldehyde

[0266] To a 1-dram vial was added (3RS)-3-{2-[(1r,4r)-4-(hydroxymethyl)cyclohexanecarbonyl]-3,4-dihydro-1H-isoquinolin-6-yl}piperidine-2,6-dione (13.70 mg, 0.04 mmol), IBX polystyrene (1.2 mmol / g, 0.09 g, 3 equiv.), DMSO (0.10 mL), and DCM (0.50 mL). The reaction mixture was stirred for 16 hours. The reaction mixture was filtered and concentrated with DCM. The resulting residue was used in the subsequent step without further purification. LCMS: [C 22 H 26 Desired mass of N2O4 = 382.2, Found: m / z = 383.3 [M+H] + . Intermediate 25 (3R)-1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidine-3-carboxylic acid [ka]

[0267] 3-(6-Fluoropyridin-3-yl)piperidine-2,6-dione (100.00 mg, 0.48 mmol), (3R)-pyrrolidine-3-carboxylic acid (110.60 mg, 0.96 mmol), N,N-diisopropylethylamine (0.34 mL, 248.32 mg, 1.92 mmol), and DMSO (1.00 mL) were combined in a microwave vial and irradiated at 140° C. for 2 hours. The product was isolated by reverse-phase flash column chromatography to give the title compound (42 mg, 29% yield). Intermediate 26 1-((1r,4r)-4-(6-(2,6-dioxopiperidin-3-yl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carbonyl)piperidine-4-carboxylic acid [ka] Step 1: (1r,4r)-4-(6-(2,6-dioxopiperidin-3-yl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid [ka]

[0268] To a suspension of methyl (1r,4r)-4-(6-(2,6-dioxopiperidin-3-yl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylate (180 mg, 0.44 mmol) in water (1.8 mL) was added TFA (3.6 mL, 47.0 mmol) at room temperature. The reaction mixture was stirred at 70° C. for 6.5 hours, then it was concentrated under high vacuum. The residue was used directly in the next step (yellow oil, 173 mg). LCMS: [C22 H 26 N2O5], desired mass = 398.4, observed: m / z = 399.1 [M+H] + . Step 2: tert-Butyl 1-((1r,4r)-4-(6-(2,6-dioxopiperidin-3-yl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carbonyl)piperidine-4-carboxylate [ka]

[0269] The title compound was synthesized using a method similar to tert-butyl (3R)-1-(1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)pyrrolidine-3-carboxylate using BOP coupling. The crude product was used directly in the next step (pale yellow oil, 96 mg). LCMS: [C 32 H 43 N3O6], desired mass = 565.3, observed: m / z = 566.7 [M+H] + . Step 3: 1-((1r,4r)-4-(6-(2,6-dioxopiperidin-3-yl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carbonyl)piperidine-4-carboxylic acid [ka]

[0270] The title compound was synthesized by TFA-mediated deprotection conditions similar to those described for 1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carboxylic acid. The crude product was used directly in the next step (light yellow oil, 126 mg). LCMS: [C 28 H 35 N3O6], desired mass = 509.2, observed: m / z = 510.4 [M+H] + . Intermediate 27 (1r,4r)-4-(6-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid [ka] Step 1: 3-((2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)propanoic acid

[0271] To a 20 mL vial was added tert-butyl 6-amino-3,4-dihydro-1H-isoquinoline-2-carboxylate (1000.00 mg, 4.03 mmol), acrylic acid (0.28 mL, 290.20 mg, 4.03 mmol), and toluene (7.00 mL). The reaction mixture was stirred at 80° C. for 16 hours and then concentrated. The resulting crude product was used in the subsequent step without further purification. LCMS: [C 17 H 24 N2O4], desired mass = 320.2, observed: m / z = 321.2 [M+H] + . Step 2: 1-(1,2,3,4-tetrahydroisoquinolin-6-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0272] To a 40 mL vial was added 3-{[2-(tert-butoxycarbonyl)-3,4-dihydro-1H-isoquinolin-6-yl]amino}propanoic acid (1291.17 mg, 4.03 mmol), urea (0.48 g, 8.06 mmol), and acetic acid (2.00 mL). The reaction mixture was stirred at 120° C. for 16 h. To the crude reaction mixture was added TFA (1 mL). The reaction mixture was stirred for 1 h and then purified by reverse-phase FC (415 g of C18 silica, 0-20% MeCN / water) to give the title compound as an off-white solid (126 mg, 10% yield). LCMS: [C 13 H 15 Desired mass of N3O2 = 245.1, Found: m / z = 246.1 [M+H] + . Step 3: Synthesis of methyl (1r,4r)-4-(6-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylate

[0273] To a 1-dram vial was added 1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1,3-diazinan-2,4-dione; trifluoroacetic acid (25.00 mg, 0.07 mmol); (1r,4r)-4-(methoxycarbonyl)cyclohexane-1-carboxylic acid (14.25 mg, 0.08 mmol); N,N-diisopropylethylamine (0.12 mL, 0.09 g, 0.70 mmol); and DMF (0.3 mL). To the reaction mixture was added [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluorolambda 5-phosphanide (29.10 mg, 0.08 mmol) in DMF (0.3 mL). The reaction mixture was stirred for 1 h and then quenched with NaHCO3 (aq). The product was extracted with DCM, dried over MgSO4, and then concentrated. The resulting residue was purified by reverse-phase chromatography (4 g silica, 0-10% MeOH / DCM). m / z=359.2 An impurity co-elutes with the product. The product was further purified by reverse-phase FC (30 g C18 silica, 0-60% MeCN / water + 0.1% TFA) to give the title compound as a white solid (16 mg, 57% yield). LCMS [C 22 H 27 N3O5], desired mass = 413.2, observed: m / z = 414.3 [M+H] + . Step 4: Synthesis of (1r,4r)-4-(6-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid

[0274] To a 2-dram vial was added methyl (1r,4r)-4-[6-(2,4-dioxo-1,3-diazinan-1-yl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]cyclohexane-1-carboxylate (16.00 mg, 0.04 mmol), water (0.20 mL), and TFA (0.20 mL). The reaction mixture was stirred at 70° C. for 1 hour and then at 80° C. for an additional 2 hours. The reaction mixture was concentrated and used without further purification. LCMS [C 21 H 25 N3O5], desired mass = 399.2, observed: m / z = 400.3 [M+H] + . Intermediate 28 (1r,4r)-4-(7-(2,6-dioxopiperidin-3-yl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid [ka] Step 1: 3-(1,2,3,4-tetrahydroisoquinolin-7-yl)piperidine-2,6-dione

[0275] The title compound was prepared using a procedure similar to Intermediate 24, using tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate as the starting material. LCMS: [C 14 H 16 N2O2], desired mass = 244.1, observed: m / z = 245.3 [M+H] + . Step 2: (1r,4r)-4-(7-(2,6-dioxopiperidin-3-yl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid

[0276] The title compound was prepared using a procedure similar to Intermediate 27 using 3-(1,2,3,4-tetrahydroisoquinolin-7-yl)piperidine-2,6-dione as the starting material. Intermediate 29 (1r,4r)-4-(6-(2,6-dioxopiperidin-3-yl)-1,2,3,4-tetrahydroquinoline-1-carbonyl)cyclohexane-1-carboxylic acid [ka] Step 1: 3-(1,2,3,4-tetrahydroquinolin-6-yl)piperidine-2,6-dione

[0277] The title compound was prepared using a procedure similar to Intermediate 24, using tert-butyl 6-bromo-3,4-dihydroquinoline-1(2H)-carboxylate as the starting material. LCMS: [C 14 H 16 N2O2], desired mass = 244.1, observed: m / z = 245.4 [M+H] + . Step 2: (1R,4r)-4-(6-((RS)-2,6-dioxopiperidin-3-yl)-1,2,3,4-tetrahydroquinoline-1-carbonyl)cyclohexane-1-carboxylic acid

[0278] The title compound was prepared using a procedure similar to Intermediate 27 using (RS)-3-(1,2,3,4-tetrahydroquinolin-6-yl)piperidine-2,6-dione as the starting material. Intermediate 30 1-((1r,4r)-4-((4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)cyclohexane-1-carbonyl)piperidine-4-carboxylic acid [ka] Step 1: tert-butyl 1-((1r,4r)-4-((4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)cyclohexane-1-carbonyl)piperidine-4-carboxylate [ka]

[0279] Prepared by a procedure similar to Intermediate 5 (Step 1) using (1r,4r)-4-((4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)cyclohexane-1-carboxylic acid (75 mg, 0.226 mmol) and tert-butyl piperidine-4-carboxylate (63 mg, 0.34 mmol) as starting materials. The title compound (TFA salt) was isolated as an off-white solid (100 mg, 89% yield). LCMS: [C 27 H 38 N4O5], desired mass = 499.6, observed: m / z = 471.5 [M+H] + . Step 2: 1-((1r,4r)-4-((4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)cyclohexane-1-carbonyl)piperidine-4-carboxylic acid [ka]

[0280] Prepared by a procedure similar to Intermediate 5 (Step 2) using tert-butyl 1-((1r,4r)-4-((4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)cyclohexane-1-carbonyl)piperidine-4-carboxylate (100 mg, 0.2 mmol) as the starting material. The title compound (TFA salt) was isolated as an off-white solid (64 mg, 72% yield). LCMS: [C 23 H 30 N4O5], desired mass = 442.5, observed: m / z = 443.4 [M+H] + . Intermediate 31 1-((1R,4r)-4-((4-((RS)-2,6-dioxopiperidin-3-yl)phenyl)amino)cyclohexane-1-carbonyl)piperidine-4-carboxylic acid [ka] Step 1: (1r,4r)-4-[(4-bromophenyl)amino]cyclohexane-1-carboxylic acid [ka]

[0281] To a mixture of methyl (1r,4r)-4-aminocyclohexane-1-carboxylate hydrochloride (5 g, 25.817 mmol) in toluene (30 mL) was added dibromobenzene (12.18 g, 51.631 mmol), Pd(dba) (2.36 g, 2.577 mmol), BINAP (3.22 g, 5.171 mmol), and t-BuONa (4.96 g, 51.610 mmol). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure, and the residue was diluted with water (100 mL). The aqueous layer was washed with EtOAc. The aqueous layer was acidified to pH 4 with HCl (3 M) and extracted with EtOAc. The organic mixture was concentrated under reduced pressure to give 1.3 g (crude) of the title compound as a brown solid. LCMS: (C 13 H 16 Desired mass of BrNO2) = 297.0; Found: m / z = 297.8 [M+H] + . Step 2: tert-butyl 1-[(1r,4r)-4-[(4-bromophenyl)amino]cyclohexanecarbonyl]piperidine-4-carboxylate: [ka]

[0282] To a mixture of (1r,4r)-4-[(4-bromophenyl)amino]cyclohexane-1-carboxylic acid (1.3 g, 4.360 mmol) in DMF (15 mL) was added tert-butyl piperidine-4-carboxylate (0.81 g, 4.360 mmol) and TEA (2.65 g, 26.160 mmol). The resulting mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. To the previous mixture was added T3P (2.77 g, 8.720 mmol) at 0° C. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 1.24 g (crude) of the title compound as a brown solid. The residue was used directly in the next step. LCMS: (C 23 H 33 Desired mass of BrN2O3) = 464.2; Found: m / z = 465.2 [M+H] + . Step 3: tert-Butyl 1-[(1r,4r)-4-({4-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}amino)cyclohexanecarbonyl]piperidine-4-carboxylate [ka]

[0283] To a mixture of tert-butyl 1-[(1r,4r)-4-[(4-bromophenyl)amino]cyclohexanecarbonyl]piperidine-4-carboxylate (1 g, 2.149 mmol) in HO (2 mL) and dioxane (10 mL) was added 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.90 g, 2.149 mmol), Pd(dppf)Cl.CHCl (0.35 g, 0.430 mmol), and KCO (0.89 g, 6.447 mmol). The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography [PE and EA mobile phases] to give 420 mg (26.03%) of the title compound as a yellow solid. LCMS: (C 42 H 49 Desired mass of N3O5) = 675.4; Found: m / z = 676.2 [M+H] + Step 4: tert-butyl 1-[(1r,4r)-4-{[4-(2,6-dioxopiperidin-3-yl)phenyl]amino}cyclohexanecarbonyl]piperidine-4-carboxylate: [ka]

[0284] To a mixture of tert-butyl 1-[(1r,4r)-4-({4-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}amino)cyclohexanecarbonyl]piperidine-4-carboxylate (200 mg, 0.296 mmol) in THF (20 mL) was added Pd / C (400 mg). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours. The resulting mixture was filtered, and the filter cake was washed with THF. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography [PE and EA mobile phase] to afford 100 mg (64.51%) of the title compound as a white solid. LCMS: (C 28 H 39Desired mass of N3O5) = 497.3; Found: m / z = 498.3 [M+H] + . Step 5: 1-((1R,4r)-4-((4-((RS)-2,6-dioxopiperidin-3-yl)phenyl)amino)cyclohexane-1-carbonyl)piperidine-4-carboxylic acid [ka]

[0285] A procedure similar to that of Intermediate 21 (Step 3) was used with tert-butyl 1-[(1r,4r)-4-{[4-(2,6-dioxopiperidin-3-yl)phenyl]amino}cyclohexanecarbonyl]piperidine-4-carboxylate (120 mg, 0.241 mmol) and HCl in 1,4-dioxane (10 mL, 4 M). The residue was purified by reverse-phase flash chromatography [ACN and HO mobile phase] to afford 93 mg (84.73%) of the title compound as a white solid. LCMS: (C 24 H 31 Desired mass of N3O5) = 441.2; Found: m / z = 442.2 [M+H] + . Intermediate 32 1-[(1r,4r)-4-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}cyclohexanecarbonyl]piperidine-4-carboxylic acid [ka]

[0286] The title compound (289 mg, 81% yield, yellow solid) was synthesized using a method similar to Intermediate 17, substituting benzyl 2-[(3R)-pyrrolidin-3-yl]acetate hydrochloride for tert-butyl piperidine-4-carboxylate hydrochloride. LCMS: C 30 H 38 N4O7, desired mass = 566.7, observed: m / z = 567.8 [M+H]+ . Intermediate 33 1-((1r,4r)-4-((5-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)amino)cyclohexane-1-carbonyl)piperidine-4-carboxylic acid [ka] Step 1: tert-butyl 1-((1r,4r)-4-((4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)cyclohexane-1-carbonyl)piperidine-4-carboxylate: [ka]

[0287] Prepared by a procedure similar to Intermediate 5 (Step 1) using (1r,4r)-4-((4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)cyclohexane-1-carboxylic acid (60 mg, 0.18 mmol) and tert-butyl piperidine-4-carboxylate (44 mg, 0.24 mmol) as starting materials. The title compound (TFA salt) was isolated as an off-white solid (80 mg, 889% yield). LCMS: [C 27 H 38 N4O5], desired mass = 498.6, observed: m / z = 499.7 [M+H] + . Step 2: 1-((1r,4r)-4-((5-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)amino)cyclohexane-1-carbonyl)piperidine-4-carboxylic acid: [ka]

[0288] Prepared by a procedure similar to Intermediate 5 (Step 2) using tert-butyl 1-((1r,4r)-4-((4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)cyclohexane-1-carbonyl)piperidine-4-carboxylate (80 mg, 0.16 mmol) as the starting material. The title compound (TFA salt) was isolated as an off-white solid (60 mg, 85% yield). LCMS: [C 23 H 30 N4O5], desired mass = 442.5, observed: m / z = 443.4 [M+H] + . Intermediate 34 1-((1r,4r)-4-(4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclohexane-1-carbonyl)piperidine-4-carboxylic acid [ka] Step 1: tert-Butyl 1-[(1r,4r)-4-[4-(2,6-dioxopiperidin-3-yl)phenoxy]cyclohexanecarbonyl]piperidine-4-carboxylate [ka]

[0289] To a solution of (1r,4r)-4-(4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 52) (0.504 g, 1.48 mmol) in DMF (2.5 mL) were added HATU (0.675 g, 1.78 mmol) and N,N-diisopropylethylamine (0.5 mL, 2.96 mmol). The reaction mixture was stirred at room temperature for 0.5 hours, followed by the addition of 4-piperidinecarboxylic acid t-butyl ester hydrochloride salt (0.328 g, 1.48 mmol) and DIPEA (0.5 mL, 2.96 mmol) in DMF (2.5 mL) at room temperature. The reaction mixture was stirred overnight at room temperature, then diluted 10-fold with water and extracted three times with DCM. The combined organic layers were washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography using a mobile phase of hexane and EtOAc to give 0.62 g (75% yield) of the title compound as a yellow solid. LCMS:C 28 H 38 N2O6, desired mass = 498.6, observed: m / z = 499.2 [M+H] + . Step 2: 1-[(1r,4r)-4-[4-(2,6-dioxopiperidin-3-yl)phenoxy]cyclohexanecarbonyl]piperidine-4-carboxylic acid [ka]

[0290] To a solution of tert-butyl 1-[(1r,4r)-4-[4-(2,6-dioxopiperidin-3-yl)phenoxy]cyclohexanecarbonyl]piperidine-4-carboxylate (0.57 g, 1.14 mmol) in anhydrous DCM (11.4 mL) was added 4 M HCl in dioxane (11.4 mL, 45.7 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, and then the solvent was removed in vacuo. The residue was purified by preparative HPLC to give 0.13 g (26% yield) of the title compound as a white powder. LCMS: C 24 H 30N2O6, desired mass = 442.512, observed: m / z = 442.98 [M+H] + . Intermediate 35 (1r,4r)-4-((5-(2,6-dioxopiperidin-3-yl)-2H-indazol-2-yl)methyl)cyclohexane-1-carboxylic acid [ka] Step 1: 5-(2,6-bis(benzyloxy)pyridin-3-yl)-1H-indazole

[0291] To a 100 mL flask was added 5-bromo-1H-indazole (2.00 g, 10.2 mmol, 1.00 equiv.), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4.45 g, 10.6 mmol, 1.05 equiv.), dioxane (20.0 mL), HO (4.00 mL), KCO (2.81 g, 20.3 mmol, 2.00 equiv.), and Pd(dppf)Cl.CHCl (829 mg, 1.02 mmol, 0.10 equiv.). The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was then concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 3 / 1, petroleum ether / ethyl acetate = 2 / 1, R f =0.55) to give the title compound as a yellow solid (3.10 g, 74%). LCMS: [C 26 H 21 N3O2], desired mass = 407.2, observed: m / z = 408.1 [M+H] + . Step 2: Methyl (1r,4r)-4-((5-(2,6-bis(benzyloxy)pyridin-3-yl)-2H-indazol-2-yl)methyl)cyclohexane-1-carboxylate

[0292] To a 100 mL flask was added methyl (1r,4r)-4-(((methylsulfonyl)oxy)methyl)cyclohexane-1-carboxylate (3.10 g, 7.49 mmol, 1.00 equiv), K2CO3 (3.10 g, 22.4 mmol, 3.00 equiv), and DMF (30.0 mL). To the reaction mixture was added 5-(2,6-bis(benzyloxy)pyridin-3-yl)-1H-indazole (3.75 g, 15.0 mmol, 2.00 equiv). The reaction mixture was stirred at 70 °C for 16 h and then filtered. The resulting filtrate was purified by preparative HPLC (column: YMC Triart C18 250 x 80 mm x 7 um; mobile phase: [water (NH4HCO3)-ACN]; B%: 75% to 95%, 22 min) to give the title compound (1.20 g, 28%). LCMS: [C 35 H 35 N3O4], desired mass = 561.3, observed: m / z = 562.2 [M+H] + . Step 3: (1r,4r)-4-((5-(2,6-bis(benzyloxy)pyridin-3-yl)-2H-indazol-2-yl)methyl)cyclohexane-1-carboxylic acid

[0293] To a 100 mL flask was added (1r,4r)-4-((5-(2,6-bis(benzyloxy)pyridin-3-yl)-2H-indazol-2-yl)methyl)cyclohexane-1-carboxylate (1.20 g, 2.12 mmol, 99.3% purity, 1.00 equiv.), THF (12.0 mL), MeOH (12.0 mL), HO (12.0 mL), and LiOH.HO (178 mg, 4.24 mmol, 2.00 equiv.). The reaction mixture was stirred at 25 °C for 16 h and then concentrated. The resulting residue was dissolved in water (20 mL), and the pH was adjusted to 2-3 with 1.0 N HCl (5.00 mL). The resulting precipitate was filtered and washed with water (3 × 10 mL). The filter cake was dried under reduced pressure to give the title compound as a white solid (0.90 g, 78%). LCMS: [C 34 H 33 N3O4], desired mass = 547.3, observed: m / z = 548.2 [M+H] + . Step 4: (1r,4r)-4-((5-(2,6-dioxopiperidin-3-yl)-2H-indazol-2-yl)methyl)cyclohexane-1-carboxylic acid

[0294] To a 100 mL flask was added (1r,4r)-4-((5-(2,6-bis(benzyloxy)pyridin-3-yl)-2H-indazol-2-yl)methyl)cyclohexane-1-carboxylic acid (0.90 g, 1.63 mmol, 1.00 equiv), Pd / C (225 mg, 10.0% purity), Pd(OH) (225 mg, 20.0% purity), EtOH (22.5 mL), and THF (22.5 mL). The reaction mixture was stirred under a H atmosphere (15 psi) for 4 hours. The reaction mixture was filtered through Celite, and the resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: YMC Triart C18 250 x 50 mm x 7 um; mobile phase: [water (HCl)-ACN]; B%: 22% to 52%, 10 min) to give the title compound as a red-brown solid (0.37 g, 59%). LCMS: [C 20 H 23 N3O4], desired mass = 369.2, observed: m / z = 370.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.8 (s, 1H), 8.31 (s, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.51 (s, 1H), 7.11 - 7.09 (m, 1H), 4.26 (d, J = 7.2 Hz, 2H), 3.93 - 3.89 (m, 1H), 2.72 - 2.55 (m, 1H), 2.53 - 2.52 (m, 1H), 2.40 - 2.30 (m, 1H), 2.13 - 2.08 (m, 2H), 1.89 - 1.87 (m, 3H), 1.56 - 1.54 (m, 2H), 1.27 - 1.23 (m, 2H), 1.07 - 1.06 (m, 2H). Intermediate 36 (1r,4r)-4-((5-(2,6-dioxopiperidin-3-yl)-1H-indazol-1-yl)methyl)cyclohexane-1-carboxylic acid [ka]

[0295] The title compound was prepared using a procedure similar to Intermediate 35 using methyl (1r,4r)-4-((5-(2,6-bis(benzyloxy)pyridin-3-yl)-1H-indazol-1-yl)methyl)cyclohexane-1-carboxylate. LCMS: [C 20 H 23 N3O4], desired mass = 369.2, observed: m / z = 370.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.57 (s, 1H), 7.23 (d, J = 8.4 Hz, 1H), 4.23 (d, J = 7.2 Hz, 2H), 3.97 - 3.93 (m, 1H), 2.69 - 2.54 (m, 1H), 2.53 - 2.52 (m, 1H), 2.40 - 2.30 (m, 1H), 2.06 - 2.04 (m, 2H), 1.85 - 1.82 (m, 3H), 1.54 - 1.52 (m, 2H), 1.21 - 1.15 (m, 2H), 1.06 - 1.03 (m, 2H). Intermediate 37 (3S)-1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidine-3-carboxylic acid [ka]

[0296] 3-(6-Fluoropyridin-3-yl)piperidine-2,6-dione (100.00 mg, 0.48 mmol), (3S)-1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidine-3-carboxylic acid (110.60 mg, 0.96 mmol), N,N-diisopropylethylamine (0.34 mL, 248.32 mg, 1.92 mmol), and DMSO (1.00 mL) were combined in a microwave vial and irradiated at 140° C. for 2 hours. The product was isolated by reverse-phase flash column chromatography to give the title compound (57 mg, 31% yield). Intermediate 38 1-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)piperidine-4-carboxylic acid [ka] Step 1: tert-butyl 1-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)piperidine-4-carboxylate [ka]

[0297] The title compound was synthesized using a method similar to Intermediate 11 using BOP coupling. A white powder (112 mg, 0.231 mmol) was obtained as the free base. LCMS: [C 27 H 37 N3O5], desired mass = 483.2, observed: m / z = 485.5 [M+H] + . Step 2: 1-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)piperidine-4-carboxylic acid [ka]

[0298] The title compound was synthesized using a method similar to Intermediate 11 using TFA. LCMS: [C 23 H 29 N3O5], desired mass = 427.2, observed: m / z = 429.2 [M+H] + . Intermediate 39 1-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbonyl)piperidine-4-carboxylic acid [ka] Step 1: tert-butyl 1-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbonyl)piperidine-4-carboxylate: [ka]

[0299] Prepared by a procedure similar to Intermediate 5 (Step 1) using 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carboxylic acid (80 mg, 0.25 mmol) and tert-butyl piperidine-4-carboxylate (47 mg, 0.25 mmol) as starting materials. The title compound (TFA salt) was isolated as an off-white solid (90 mg, 74% yield). LCMS: [C 26 H 36 N4O5], desired mass = 484.6, observed: m / z = 485.5 [M+H] + . Step 2: 1-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbonyl)piperidine-4-carboxylic acid: [ka]

[0300] Prepared by a procedure similar to Intermediate 5 (Step 2) using 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carboxylic acid (90 mg, 0.16 mmol) as the starting material. The title compound (TFA salt) was isolated as an off-white solid (60 mg, 75% yield). LCMS: [C 22 H 28 N4O5], desired mass = 428.5, observed: m / z = 429.4 [M+H] + . Intermediate 40 1-(1-{5-[2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidine-4-carbonyl)piperidine-4-carboxylic acid [ka] Step 1: tert-Butyl 1-{1-[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl]piperidine-4-carbonyl}piperidine-4-carboxylate [ka]

[0301] To a mixture of 1-[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl]piperidine-4-carboxylic acid (70 mg, 0.221 mmol, 1 equiv.) in DMF (4 mL) was added tert-butyl piperidine-4-carboxylate (40 mg, 0.221 mmol) at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. To the previous mixture were added DIEA (142 mg, 1.105 mmol) and BOP (126 mg, 0.287 mmol). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was purified by reverse-phase flash chromatography in [CHCN and HO] to afford 75 mg (66.66%) of the title compound as a light brown solid. LCMS: (C 26 H 36 Desired mass of N4O5) = 484.3; Found: m / z = 485.2 [M+H] + . Step 2: 1-(1-{5-[2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidine-4-carbonyl)piperidine-4-carboxylic acid [ka]

[0302] A procedure similar to that of Step 3 of Intermediate 15 was followed using tert-butyl 1-{1-[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl]piperidine-4-carbonyl}piperidine-4-carboxylate (75 mg, 0.155 mmol) and HCl / dioxane (3 mL, 4 M). The residue was purified by reverse-phase flash chromatography in [CHCN and HO] to afford 53.8 mg (75.37%) of the title compound as a pale yellow solid. LCMS (Method 4): (C 22 H 28 Desired mass of N4O5) = 428.2; Found: m / z = 429.2 [M+H] + . Intermediate 41 1-(1-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carboxylic acid [ka] Step 1: tert-butyl 1-(1-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carboxylate: [ka]

[0303] Prepared by a procedure similar to Intermediate 5 (Step 1) using 1-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)piperidine-4-carboxylic acid (150 mg, 0.47 mmol) and tert-butyl piperidine-4-carboxylate (87 mg, 0.47 mmol) as starting materials. The title compound (TFA salt) was isolated as an off-white solid (100 mg, 44% yield). LCMS: [C 25 H 35 N5O5], desired mass = 485.6, observed: m / z = 486.3 [M+H] + . Step 2: 1-(1-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carboxylic acid: [ka]

[0304] Prepared by a procedure similar to Intermediate 5 (Step 2) using tert-butyl 1-(1-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carboxylate (100 mg, 0.21 mmol) as the starting material. The title compound (TFA salt) was isolated as an off-white solid (54 mg, 61% yield). LCMS: [C 21 H 27 N5O5], desired mass = 429.4, observed: m / z = 430.3 [M+H] + . Intermediate 42 1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidine-4-carboxylic acid [ka] Step 1: tert-butyl 1-(6-chloropyridin-3-yl)piperidine-4-carboxylate: [ka]

[0305] To a mixture of 5-bromo-2-chloropyridine (40 g, 207.857 mmol) and tert-butyl piperidine-4-carboxylate (50.06 g, 270.214 mmol) in dioxane (30 mL) was added XantPhos (24.05 g, 41.571 mmol), Pd(dba) (19.03 g, 20.786 mmol), and t-BuONa (59.93 g, 623.571 mmol) under a nitrogen atmosphere at 0° C. The resulting mixture was stirred at 100° C. under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography [PE and EA mobile phase] to afford 14.7 g (21.54%) of the title compound as a yellow solid. LCMS: (C 15 H 21 Desired mass of ClN2O2) = 296.1; Found: m / z = 297.1 [M+H] + . Step 2: tert-Butyl 1-[2',6'-bis(benzyloxy)-[2,3'-bipyridin]-5-yl]piperidine-4-carboxylate [ka]

[0306] To a mixture of tert-butyl 1-(6-chloropyridin-3-yl)piperidine-4-carboxylate (14.5 g, 48.854 mmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (50.97 g, 122.135 mmol) in THF (30 mL) and HO (10 mL) was added Pd(PPh) (5.65 g, 4.885 mmol) and KCO (13.50 g, 97.708 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 110 °C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography [PE and EA mobile phase] to afford 3.4 g (11.35%) of the title compound as a yellow solid. LCMS:(C 34 H 37 Desired mass of N3O4) = 551.3; Found: m / z = 552.2 [M+H] + . Step 3: tert-Butyl 1-[6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl]piperidine-4-carboxylate [ka]

[0307] To a mixture of tert-butyl 1-[2',6'-bis(benzyloxy)-[2,3'-bipyridin]-5-yl]piperidine-4-carboxylate (3.2 g, 5.800 mmol) in THF (10 mL) was added Pd / C (6.4 g). The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with THF. The filtrate was concentrated under reduced pressure to give 860 mg (crude) of the title compound as a crude white solid. LCMS: (C 20 H 27 Desired mass of N3O4) = 373.2; Found: m / z = 374.2 [M+H] + . Step 4: 1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidine-4-carboxylic acid [ka]

[0308] A procedure similar to that of Intermediate 21 (Step 3) was used with tert-butyl 1-[6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl]piperidine-4-carboxylate (860 mg, 2.303 mmol) and HCl / 1,4-dioxane (5 mL, 4 M). The residue was purified by reverse-phase flash chromatography [ACN and HO mobile phase] to afford 496 mg (63.60%) of the title compound as a brown solid. LCMS: (C 16 H 19 Desired mass of N3O4) = 317.1; Found: m / z = 317.9 [M+H] + . Intermediate 43 1-(1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidine-4-carbonyl)piperidine-4-carboxylic acid [ka] Step 1: tert-butyl 1-(1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidine-4-carbonyl)piperidine-4-carboxylate: [ka]

[0309] Prepared by a procedure similar to Intermediate 5 (Step 1) using 1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidine-4-carboxylic acid (120 mg, 0.38 mmol) and tert-butyl piperidine-4-carboxylate (70 mg, 0.38 mmol) as starting materials. The title compound (TFA salt) was isolated as an off-white solid (80 mg, 44% yield). LCMS: [C 26 H 36 N4O5], desired mass = 484.5, observed: m / z = 485.3 [M+H]+ . Step 2: 1-(1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidine-4-carbonyl)piperidine-4-carboxylic acid: [ka]

[0310] Prepared by a procedure similar to Intermediate 5 (Step 2) using tert-butyl 1-(1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidine-4-carbonyl)piperidine-4-carboxylate (85 mg, 0.18 mmol) as the starting material. The title compound (TFA salt) was isolated as an off-white solid (60 mg, 80% yield). LCMS: [C 22 H 28 N4O5], desired mass = 428.5, observed: m / z = 429.3 [M+H] + . Intermediate 44 1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)piperidine-4-carboxylic acid [ka]

[0311] BOP-mediated coupling of 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carboxylic acid (10 mg, 0.03 mmol, Intermediate 18) and tert-butyl piperidine-4-carboxylate (4.9 mg, 0.03 mmol) using conditions similar to those used for tert-butyl (3R)-1-(1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)pyrrolidine-3-carboxylate (Intermediate 11, Step 3) was carried out, followed by concentration and treatment with HCl (4N in dioxane, 1 mL) overnight, then concentration and purification by reverse-phase column chromatography (mobile phase of ACN and HO) to afford the title compound as an off-white solid (11 mg, 78% yield). Intermediate 45 1-(1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidine-4-carbonyl)piperidine-4-carboxylic acid [ka] Step 1: Synthesis of tert-butyl 1-(1-(5-(2,6-dioxopiperidin-3-yl)pyrimidin-2-yl)piperidine-4-carbonyl)piperidine-4-carboxylate: [ka]

[0312] Prepared by a procedure similar to Intermediate 5 (Step 1) using 1-(5-(2,6-dioxopiperidin-3-yl)pyrimidin-2-yl)piperidine-4-carboxylic acid (150 mg, 0.41 mmol) and tert-butyl piperidine-4-carboxylate (131 mg, 0.71 mmol) as starting materials. The title compound (TFA salt) was isolated as an off-white solid (160 mg, 70% yield). LCMS: [C 25 H 35 N5O5], desired mass = 484.5, observed: m / z = 485.3 [M+H] + . Step 2: 1-(1-(5-(2,6-dioxo-112-piperidin-3-yl)pyrimidin-2-yl)piperidine-4-carbonyl)piperidine-4-carboxylic acid: [ka]

[0313] Prepared by a procedure similar to Intermediate 5 (Step 2) using tert-butyl 1-(1-(5-(2,6-dioxopiperidin-3-yl)pyrimidin-2-yl)piperidine-4-carbonyl)piperidine-4-carboxylate (160 mg, 0.33 mmol) as the starting material. The title compound (TFA salt) was isolated as an off-white solid (140 mg, 79% yield). LCMS: [C 21 H 27 N5O5], desired mass = 429.4, observed: m / z = 430.2 [M+H] + . Intermediate 46 1-(2-(1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)acetyl)piperidine-4-carboxylic acid [ka] Step 1: tert-Butyl 1-(2-(1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)acetyl)piperidine-4-carboxylate [ka]

[0314] The title compound was synthesized using a method similar to Intermediate 11 using BOP coupling. A white solid (320 mg, 0.642 mmol) was obtained as the free base. LCMS: [C 27 H 38 N4O5], exact mass = 498.2, found: m / z = 498.5 [M+H] + . Step 2: 1-(2-(1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)acetyl)piperidine-4-carboxylic acid [ka]

[0315] The title compound was synthesized using a method similar to Intermediate 11 using TFA. A white solid (250 mg, 0.564 mmol) was obtained as the free base. LCMS: [C 23 H 30 N4O5], desired mass = 442.2, observed: m / z = 443.3 [M+H] + . Intermediate 47 1-(2-(4-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperazin-1-yl)acetyl)piperidine-4-carboxylic acid [ka] Step 1: tert-butyl 2-(4-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperazin-1-yl)acetate: [ka]

[0316] To a solution of tert-butyl 2-(piperazin-1-yl)acetate (285 mg, 1.44 mmol) and DIPEA (0.67 mL, 0.5 g, 3.84 mmol) in DMSO (1 mL) was added 3-(6-fluoropyridin-3-yl)piperidine-2,6-dione (200 mg, 0.96 mmol). The reaction mixture was stirred at 120 °C for 16 h, at which point LCMS indicated that the starting material had been consumed. The reaction mixture was cooled to room temperature, and water was added. The crude mixture was purified by reverse-phase FC (5-50% MeCN / HO + 0.1% TFA) to give the title compound (TFA salt) as an off-white solid (330 mg, 88% yield). LCMS: [C 20H 28 N4O4], desired mass = 388.5, observed: m / z = 389.2 [M+H] + . Step 2: 2-(4-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperazin-1-yl)acetic acid [ka]

[0317] Prepared by a procedure similar to Intermediate 5 (Step 2) using tert-butyl 2-(4-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperazin-1-yl)acetate (330 mg, 0.85 mmol) as the starting material. The title compound (TFA salt) was isolated as an off-white solid (260 mg, 92% yield). LCMS: [C 16 H 20 N4O4], desired mass = 332.4, observed: m / z = 333.2 [M+H] + . Step 3: tert-butyl 1-(2-(4-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperazin-1-yl)acetyl)piperidine-4-carboxylate: [ka]

[0318] Prepared by a procedure similar to Intermediate 5 (Step 1) using 2-(4-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperazin-1-yl)acetic acid (300 mg, 0.9 mmol) and tert-butyl piperidine-4-carboxylate (334 mg, 1.8 mmol) as starting materials. The title compound (TFA salt) was isolated as an off-white solid (80 mg, 17% yield). LCMS: [C 26 H 37 N5O5], desired mass = 499.6, observed: m / z = 500.3 [M+H] + . Step 4: 1-(2-(4-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperazin-1-yl)acetyl)piperidine-4-carboxylic acid [ka]

[0319] Prepared by a procedure similar to Intermediate 5 (Step 2) using tert-butyl 1-(2-(4-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperazin-1-yl)acetyl)piperidine-4-carboxylate (80 mg, 0.16 mmol) as the starting material. The title compound (TFA salt) was isolated as an off-white solid (65 mg, 91% yield). LCMS: C 22 H 29 Desired mass of N5O5: 443.5, measured m / z = 444.3 [M+H] + . Intermediate 48 1-(4-{5-[2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidine-1-carbonyl)piperidine-4-carboxylic acid [ka] Step 1: 5-[2,6-bis(benzyloxy)pyridin-3-yl]-1',2',3',6'-tetrahydro-2,4'-bipyridine [ka]

[0320] A procedure similar to that of Step 3 of Intermediate 15 was followed using tert-butyl 5-[2,6-bis(benzyloxy)pyridin-3-yl]-3',6'-dihydro-2'H-[2,4'-bipyridine]-1'-carboxylate (500 mg, 0.910 mmol) and HCl / dioxane (10 mL, 4 M). The reaction mixture was concentrated to give 400 mg (crude) of the title compound as a pale yellow solid. LCMS: (C 29 H 27Desired mass of N3O2) = 449.2; Found: m / z = 450.2 [M+H] + . Step 2: tert-Butyl 1-{5-[2,6-bis(benzyloxy)pyridin-3-yl]-3',6'-dihydro-2'H-[2,4'-bipyridine]-1'-carbonyl}piperidine-4-carboxylate [ka]

[0321] To a mixture of tert-butyl piperidine-4-carboxylate hydrochloride (222 mg, 1.001 mmol) and DIEA (389 mg, 3.003 mmol) in DCM (20 mL) was added triphosgene (149 mg, 0.500 mmol). The reaction mixture was stirred at 0° C. under a nitrogen atmosphere for 15 minutes, followed by the dropwise addition of 5-[2,6-bis(benzyloxy)pyridin-3-yl]-1′,2′,3′,6′-tetrahydro-2,4′-bipyridine (450 mg, 1.001 mmol) at 0° C. The resulting mixture was stirred overnight at 50° C. under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mobile phase of [PE and EA] to afford 220 mg (29.93%) of the title compound as a yellow oil. LCMS: (C 40 H 44 Desired mass of N4O5) = 660.3; Found: m / z = 661.3 [M+H] + . Step 3: tert-Butyl 1-{4-[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl]piperidine-1-carbonyl}piperidine-4-carboxylate [ka]

[0322] A procedure similar to that of Step 5 of Intermediate 15 was followed using tert-butyl 1-{5-[2,6-bis(benzyloxy)pyridin-3-yl]-3',6'-dihydro-2'H-[2,4'-bipyridine]-1'-carbonyl}piperidine-4-carboxylate (220 mg, 0.333 mmol) and Pd / C (330 mg) in EtOH (20 mL). This gave 100 mg (crude) of the title compound as a white solid. LCMS: (C 26 H 36 Desired mass of N4O5) = 484.3; Found: m / z = 485.2 [M+H] + . Step 4: 1-(4-{5-[2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidine-1-carbonyl)piperidine-4-carboxylic acid [ka]

[0323] A procedure similar to that of Step 3 of Intermediate 15 was followed using tert-butyl 1-{4-[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl]piperidine-1-carbonyl}piperidine-4-carboxylate (90 mg, 0.186 mmol) in HCl / dioxane (10 mL, 4 M). The residue was purified by reverse-phase flash chromatography [ACN and HO] to afford 31.4 mg (37.68%) of the title compound as a brown solid. LCMS (Method 5): (C 22 H 28 Desired mass of N4O5) = 428.2; Found: m / z = 429.3 [M+H] + . Intermediate 49 2-(1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)acetaldehyde [ka] Step 1: 3-(6-(4-(2-hydroxyethyl)piperidin-1-yl)pyridin-3-yl)piperidine-2,6-dione

[0324] To a 40 mL vial was added 3-(6-fluoropyridin-3-yl)piperidine-2,6-dione (1500.00 mg, 7.20 mmol), 4-piperidineethanol (977.44 mg, 7.57 mmol), N,N-diisopropylethylamine (5.03 mL, 3.72 g, 28.82 mmol), and DMSO (10.00 mL). The mixture was stirred at 130 °C for 16 h. The reaction mixture was concentrated, and the resulting residue was purified by reverse-phase column chromatography (415 g of C18 silica, 5-50% MeCN / HO + 0.1% TFA) to give the title compound as an amorphous solid (2.10 g, 92%). LCMS: [C 17 H 23 N3O3], desired mass = 317.2, found: 318.2 [M+H] + . Step 2: 2-(1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)acetaldehyde

[0325] To a 40 mL vial was added 3-{6-[4-(2-hydroxyethyl)piperidin-1-yl]pyridin-3-yl}piperidine-2,6-dione; trifluoroacetic acid (1600.00 mg, 3.71 mmol); and DCM (30.00 mL). The reaction mixture was cooled to 0 °C, and then 1,1-bis(acetyloxy)-3-oxo-1 lambda 5,2-benzoiodoxol-1-yl acetate (1.73 g, 4.08 mmol) was added in one portion. After 10 min, the ice bath was removed, and the reaction mixture was stirred for 1 h while warming to RT. 3 mL of TEA was added to the reaction mixture, and the crude reaction mixture was adsorbed onto silica and then purified by column chromatography (80 g silica, 20–100% EtOAc + 1% TEA / DCM) to afford the title compound as a white solid (278 mg, 47%). LCMS:[C 17 H 21 N3O3], desired mass = 315.2, observed: m / z = 316.2 [M+H] + . Intermediate 50 2-(1-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidine-4-carbonyl)piperidin-4-yl)acetic acid [ka] Step 1: Benzyl 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidine-4-carboxylate

[0326] BOP-mediated coupling of (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycine (175 mg, 0.39 mmol) and benzyl piperidine-4-carboxylate (86 mg, 0.39 mmol) using conditions similar to those used for tert-butyl (3R)-1-(1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)pyrrolidine-3-carboxylate (Intermediate 11, Step 3) afforded the title compound as an off-white solid (212 mg, 96% yield). Step 2: 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidine-4-carboxylic acid

[0327] Benzyl 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidine-4-carboxylate (200 mg, 0.38 mmol) was diluted in a 1:1 mixture of EtOAc and EtOH (2 mL each). Pd / C (15 mg) was added, and the reaction mixture was stirred under a hydrogen atmosphere for 5 hours. The reaction mixture was purged with N gas for 5 minutes and then filtered through a Celite pad, washing with EtOAc, DCM, and MeOH. The filtrate was concentrated in vacuo, and the residue was purified by reverse-phase column chromatography (ACN and water mobile phase) to afford the title compound as a yellow solid (120 mg, 72% yield). Step 3: 2-(1-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidine-4-carbonyl)piperidin-4-yl)acetic acid

[0328] BOP-mediated coupling of 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidine-4-carboxylic acid (44 mg, 0.10 mmol) and tert-butyl 2-(piperidin-4-yl)acetate (21.8 mg, 0.11 mmol) using conditions similar to those used for tert-butyl (3R)-1-(1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)pyrrolidine-3-carboxylate (Intermediate 11, Step 3) was carried out, followed by concentration and treatment with HCl (4N in dioxane, 1 mL) overnight, then concentration and purification by reverse-phase column chromatography (mobile phase of ACN and HO) to afford the title compound as an off-white solid (25 mg, 44% yield). Intermediate 51 3-(6-((R)-3-methylpiperazin-1-yl)pyridin-3-yl)piperidine-2,6-dione [ka]

[0329] To a 20 mL microwave vial were added 3-(6-fluoropyridin-3-yl)piperidine-2,6-dione (500.0 mg, 2.40 mmol), tert-butyl (2R)-2-methylpiperazine-1-carboxylate (577.2 mg, 2.88 mmol), N,N-diisopropylethylamine (1.68 mL, 1.24 g, 9.61 mmol), and DMSO (5.00 mL). The reaction mixture was stirred at 180° C. for 6 hours and then concentrated. The crude material was dissolved in DCM (10.0 mL), treated with 4 M HCl in dioxane (3.0 mL), and stirred at room temperature for 4 hours. The crude mixture was purified by reverse-phase flash column chromatography to afford the title compound (131.0 mg, 19% yield) as a white solid. Intermediate 52 (1r,4r)-4-(4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclohexane-1-carboxylic acid [ka] Step 1: Benzyl (1s,4s)-4-hydroxycyclohexane-1-carboxylate

[0330] To a solution of cis-4-hydroxycyclohexanecarboxylic acid (2.0 g, 13.9 mmol) in anhydrous DMF (23.1 mL) was added K2CO3 (3.8 g, 27.6 mmol) at room temperature. Benzyl chloride (2.1 mL, 18.2 mmol) was then added dropwise at 55 °C. The reaction mixture was stirred at 55 °C for 12 h, and then water (150 mL) was poured into the reaction mixture, which was extracted with DCM (4 x 150 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (100 mL) and brine, then dried over Na2SO4, and the solvent was evaporated in vacuo. 3.14 g (97% yield) of the title compound was obtained as a white powder and used directly in the next step. LCMS: C 14 H 18 O3, desired mass = 234.3, observed: m / z = 235.7 [M+H] + . Step 2: Benzyl (1r,4r)-4-(4-bromophenoxy)cyclohexane-1-carboxylate [ka]

[0331] To a solution of 4-bromophenol (7.45 g, 42.2 mmol) in anhydrous THF (63.0 mL) was added benzyl (1s,4s)-4-hydroxycyclohexane-1-carboxylate (11.9 g, 50.6 mmol), triethylamine (7.06 mL, 50.6 mmol), and triphenylphosphine (22.1 g, 84.4 mmol) at room temperature. Next, diisopropyl azodicarboxylate (16.6 mL, 84.4 mmol) was added slowly at 0 °C under an argon atmosphere, and the reaction mixture was stirred at room temperature overnight. The solvent was then removed under reduced pressure. The residue was purified by silica gel chromatography using a hexane / DCM (100-30% hexane) mobile phase to afford 6.94 g (42% yield) of the title compound as a yellow oil. Step 3: Benzyl (1r,4r)-4-{4-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxy}cyclohexane-1-carboxylate [ka]

[0332] To a solution of 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.69 g, 3.85 mmol) in degassed anhydrous DMF (11.0 mL), benzyl (1r,4r)-4-(4-bromophenoxy)cyclohexane-1-carboxylate (1.50 g, 3.85 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.154 g, 0.193 mmol), and potassium carbonate (1.60 g, 11.6 mmol) were added at room temperature. The reaction mixture was stirred at 85 °C overnight, then the mixture was diluted 10-fold with water and extracted three times with DCM. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography using a mobile phase of hexane / DCM (0-70% DCM) to give 1.53 g (66% yield) of the title compound as a brown oil. LCMS: C 39 H 37 NO5, desired mass = 599.73, observed: m / z = 600.20 [M+H] + . Step 4: (1r,4r)-4-(4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclohexane-1-carboxylic acid [ka]

[0333] To a solution of benzyl (1r,4r)-4-{4-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxy}cyclohexane-1-carboxylate (0.511 g, 0.852 mmol) in degassed tetrahydrofuran (50.1 mL) was added palladium on carbon (0.154 g, 1.45 mmol) with a water content of 60-65% under H2 (1 atm) at room temperature. The reaction mixture was stirred overnight under H2 (1 atm) at room temperature, and then the mixture was filtered. The filtrate was concentrated under reduced pressure to give 0.253 g (87% yield) of the title compound as a white solid. LCMS: C 18 H 21 NO5, desired mass = 331.37, observed: m / z = 332.05 [M+H]+ . Intermediate 53 (1r,4r)-4-((5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)oxy)cyclohexane-1-carboxylic acid [ka] Step 1: Benzyl (1r,4r)-4-hydroxycyclohexane-1-carboxylate [ka]

[0334] To a solution of trans-4-hydroxycyclohexanecarboxylic acid (7.9 g, 54.79 mmol) in anhydrous DMF (55 mL) was added K2CO3 (15.08 g, 109.15 mmol) at 25 °C, and the reaction mixture was heated to 55 °C. Then, benzyl chloride (8.25 mL, 71.73 mmol) was added dropwise to the mixture, and the reaction mixture was stirred at 55 °C for 16 h. The reaction mixture was quenched with water (150 mL) and extracted with DCM (4 × 100 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (100 mL) and brine (150 mL), dried over Na2SO4, and evaporated to dryness to give 12.7 g (99% yield) of the title compound. Step 2: Benzyl (1r,4r)-4-[(5-nitropyridin-2-yl)oxy]cyclohexane-1-carboxylate [ka]

[0335] To a solution of 2-fluoro-5-nitropyridine (2.86 g, 28.38 mmol) in anhydrous DMF (59.0 mL) in a pressure vessel at 25° C., benzyl (1r,4r)-4-hydroxycyclohexane-1-carboxylate (6.65 g, 28.38 mmol) was added, and the reaction mixture was stirred at 90° C. overnight. An additional amount of 2-fluoro-5-nitropyridine (1.43 g, 14.19 mmol) was added, and the reaction mixture was stirred at 90° C. overnight. The reaction mixture was then evaporated to dryness, and the residue was purified by silica gel chromatography using a mobile phase of hexane and EtOAc to afford 3.24 g (32% yield) of the title compound. Step 3: Benzyl (1r,4r)-4-[(5-aminopyridin-2-yl)oxy]cyclohexane-1-carboxylate [ka]

[0336] To a solution of benzyl (1r,4r)-4-[(5-nitropyridin-2-yl)oxy]cyclohexane-1-carboxylate (3.93 g, 11.2 mmol) in a mixture of EtOH (16.8 mL), acetic acid (16.4 mL), and water (8.42 mL), Fe powder (0.94 g, 16.84 mmol) was added at 25 °C, and the reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The remaining aqueous solution was neutralized with NaHCO to pH = 7 and extracted with EtOAc (4 x 100 mL). The combined organic extracts were evaporated to dryness under reduced pressure to give 3.44 g (94% yield) of the title compound. LCMS: C 19 H 22 N2O3, desired mass = 326.2, observed: m / z = 327.8 [M+H + ]. Step 4: 3-[(6-{[(1r,4r)-4-[(benzyloxy)carbonyl]cyclohexyl]oxy}pyridin-3-yl)amino]propanoic acid [ka]

[0337] To a solution of benzyl (1r,4r)-4-[(5-aminopyridin-2-yl)oxy]cyclohexane-1-carboxylate (3.94 g, 12.07 mmol) in anhydrous dioxane (40 mL) was added acrylic acid (0.9 mL, 12.07 mmol) at 25° C., and the reaction mixture was stirred at 90° C. for 16 hours. Next, an additional amount of acrylic acid (0.45 mL, 6.03 mmol) was added, and the reaction mixture was stirred at 90° C. for 48 hours. Additional acrylic acid (0.22 mL, 3.01 mmol) was added, and the reaction mixture was stirred at 90° C. for 16 hours, achieving complete consumption of the starting material. The reaction mixture was evaporated to dryness under reduced pressure to give 4.8 g (60% yield) of the title compound, which was used directly in the next step. LCMS: C 22 H 26 N2O5, desired mass = 398.2, observed: m / z = 399.1 [M+H] + . Step 5: Benzyl (1r,4r)-4-{[5-(2,4-dioxo-1,3-diazinan-1-yl)pyridin-2-yl]oxy}cyclohexane-1-carboxylate [ka]

[0338] To a solution of 3-[(6-{[(1r,4r)-4-[(benzyloxy)carbonyl]cyclohexyl]oxy}pyridin-3-yl)amino]propanoic acid (4.8 g, 12.05 mmol) in acetic acid (48.0 mL) was added urea (1.45 g, 24.09 mmol) at 25° C., and the reaction mixture was stirred at 90° C. for 72 hours. The reaction mixture was then concentrated to dryness under reduced pressure, and the residue was purified by silica gel chromatography using a mobile phase of DCM and MeOH, then hexane and EtOAc, and finally DCM and IPA to give 1.12 g (22% yield) of the title compound. LCMS: C 23 H 25 N3O5, desired mass = 423.2, observed: m / z = 424.5 [M+H] + . Step 6: (1r,4r)-4-((5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)oxy)cyclohexane-1-carboxylic acid [ka]

[0339] To a solution of benzyl (1r,4r)-4-{[5-(2,4-dioxo-1,3-diazinan-1-yl)pyridin-2-yl]oxy}cyclohexane-1-carboxylate (1.12 g, 0.273 mmol) in anhydrous THF (38.5 mL) was added Pd / C (0.05 g, 0.043 mmol) at 25° C. The reaction mixture was stirred under H (1 atm) at 25° C. overnight. The mixture was filtered through a celite cake and evaporated to dryness to give 0.8 g (89% yield) of the title compound as an off-white solid. LCMS: C 23 H 25 N3O5, desired mass = 333.1, observed: m / z = 334.2 [M+H] + . Intermediate 54 1-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)-4-methylpiperidine-4-carboxylic acid [ka] Step 1: tert-butyl 1-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)-4-methylpiperidine-4-carboxylate: [ka]

[0340] Prepared by a procedure similar to Intermediate 5 (Step 1) using 1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carboxylic acid (40 mg, 0.13 mmol) and tert-butyl 4-methylpiperidine-4-carboxylate (25 mg, 0.13 mmol) as starting materials. The title compound (TFA salt) was isolated as an off-white solid (50 mg, 79% yield). LCMS: [C 28 H 39 N3O5], desired mass = 497.6, observed: m / z = 498.4 [M+H] + . Step 2: 1-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)-4-methylpiperidine-4-carboxylic acid: [ka]

[0341] Prepared by a procedure similar to Intermediate 5 (Step 2) using tert-butyl 1-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)-4-methylpiperidine-4-carboxylate (50 mg, 0.10 mmol) as the starting material. The title compound (TFA salt) was isolated as an off-white solid (45 mg, 100% yield). LCMS: [C 24 H 31 N3O5], desired mass = 441.5, observed: m / z = 442.3 [M+H] + . Intermediate 55 1-(1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)-4-methylpiperidine-4-carboxylic acid [ka] Step 1: tert-Butyl 1-[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl]piperidine-4-carboxylate [ka]

[0342] To a solution of 3-(6-fluoropyridin-3-yl)piperidine-2,6-dione (1.0 g, 4.80 mmol) in N-methyl-2-pyrrolidone (9.6 mL) was added tert-butyl piperidine-4-carboxylate (2.403 g, 12.97 mmol) and DIPEA (2.48 g, 19.22 mmol) at 25 °C. The reaction mixture was stirred at 120 °C for 72 hours, then poured into 100 mL of water and extracted with DCM (4 × 60 mL). The combined organic layers were washed with water (100 mL), dried under NaSO, and evaporated under reduced pressure. The crude compound was purified by silica gel column chromatography using a mobile phase of DCM and MeOH to give 2.45 g (56% yield) of the title compound. LCMS: C 20 H 27 N3O4, desired mass = 373.2, observed: m / z = 374.5 [M+H] + . Step 2: 1-[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl]piperidine-4-carboxylic acid hydrochloride [ka]

[0343] To a solution of 1-[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl]piperidine-4-carboxylate (0.678 g, 1.815 mmol) dissolved in anhydrous DCM (7.26 mL) was added 4 M HCl in dioxane (7.26 mL, 29.05 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 24 h and then evaporated to dryness under reduced pressure. The residue was triturated with EtO to give 559 mg (86% yield) of the title compound. LCMS: C 20 H 27 N3O4, desired mass = 317.1, observed: m / z = 318.23 [M+H] + . Step 3: tert-Butyl 1-{1-[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl]piperidine-4-carbonyl}-4-methylpiperidine-4-carboxylate [ka]

[0344] To a solution of 1-[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl]piperidine-4-carboxylic acid hydrochloride (0.989 g, 2.77 mmol) in anhydrous DMF (5.53 mL) was added HATU (0.989 g, 2.77 mmol) and DIPEA (2.41 mL, 13.84 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 24 hours and then quenched with water. The resulting solid was filtered off, dried under reduced pressure, and purified by silica gel column chromatography using a mobile phase of DCM and MeOH to give 0.33 g (67% yield) of the title compound. LCMS: C 27 H 38 N4O5, desired mass = 498.3, observed: m / z = 499.7 [M+H] + . Step 4: 1-(1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)-4-methylpiperidine-4-carboxylic acid [ka]

[0345] To a solution of 1-{1-[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl]piperidine-4-carbonyl}-4-methylpiperidine-4-carboxylate (0.330 g, 0.66 mmol) in anhydrous DCM (2.6 mL) was added 4 M HCl in dioxane (2.6 mL, 10.56 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 24 hours and then evaporated to dryness under reduced pressure. The residue was triturated with EtO to give 281 mg (90% yield) of the title compound (HCl salt). LCMS: C 23 H 30N4O5, desired mass = 442.2, observed: m / z = 443.2 [M+H] + . Intermediate 56 1-(1-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)piperidine-4-carbonyl)-4-methylpiperidine-4-carboxylic acid [ka] Step 1: Synthesis of tert-butyl 1-(1-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)piperidine-4-carbonyl)-4-methylpiperidine-4-carboxylate: [ka]

[0346] Prepared by a procedure similar to Intermediate 5 (Step 1) using 1-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)piperidine-4-carboxylic acid (30 mg, 0.094 mmol) and tert-butyl 4-methylpiperidine-4-carboxylate (28 mg, 0.14 mmol) as starting materials. The title compound (TFA salt) was isolated as an off-white solid (35 mg, 74% yield). LCMS: [C 26 H 37 N5O5], desired mass = 499.6, observed: m / z = 500.4 [M+H] + . Step 2: 1-(1-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)piperidine-4-carbonyl)-4-methylpiperidine-4-carboxylic acid: [ka]

[0347] Prepared by a procedure similar to Intermediate 5 (Step 2) using tert-butyl 1-(1-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)piperidine-4-carbonyl)-4-methylpiperidine-4-carboxylate (35 mg, 0.07 mmol) as the starting material. The title compound (TFA salt) was isolated as an off-white solid (30 mg, 100% yield). LCMS: [C 22 H 29 N5O5], desired mass = 443.5, observed: m / z = 444.3 [M+H] + . Intermediate 57 1-(1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidine-4-carbonyl)-4-methylpiperidine-4-carboxylic acid [ka] Step 1: Synthesis of tert-butyl 1-(1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidine-4-carbonyl)-4-methylpiperidine-4-carboxylate: [ka]

[0348] Prepared by a procedure similar to that of Intermediate 5 (Step 1) using 1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidine-4-carboxylic acid (40 mg, 0.13 mmol) and tert-butyl 4-methylpiperidine-4-carboxylate (25 mg, 0.13 mmol) as starting materials. The title compound (TFA salt) was isolated as an off-white solid (50 mg, 79% yield). LCMS: [C 27 H 38 N4O5], desired mass = 498.6, observed: m / z = 499.4 [M+H] + . Step 2: 1-(1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidine-4-carbonyl)-4-methylpiperidine-4-carboxylic acid: [ka]

[0349] Prepared by a procedure similar to Intermediate 5 (Step 2) using tert-butyl 1-(1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidine-4-carbonyl)-4-methylpiperidine-4-carboxylate (50 mg, 0.10 mmol) as the starting material. The title compound (TFA salt) was isolated as an off-white solid (42 mg, 95% yield). LCMS: [C 23 H 30 N4O5], desired mass = 442.5, observed: m / z = 443.3 [M+H] + . Intermediate 58 Methyl 1-{1-[(tert-butoxy)carbonyl]piperidine-4-carbonyl}-4-methylpiperidine-4-carboxylate [ka] Step 1: Methyl 1-{1-[(tert-butoxy)carbonyl]piperidine-4-carbonyl}-4-methylpiperidine-4-carboxylate [ka]

[0350] To a solution of 1-[(tert-butoxy)carbonyl]piperidine-4-carboxylic acid (592 mg, 2.58 mmol) in anhydrous DMF (52 mL) were added HATU (1472 mg, 3.87 mmol) and DIPEA (1.80 mL, 10.33 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 20 minutes. Methyl 4-methylpiperidine-4-carboxylate hydrochloride (500 mg, 2.58 mmol) was then added at 25° C. The reaction mixture was stirred at 25° C. for 16 hours and then poured into 450 mL of brine and extracted with EtOAc (4×50 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mobile phase of DCM and MeOH to afford 828 mg (83% yield) of the title compound as a yellow solid. Step 2: 1-{1-[(tert-butoxy)carbonyl]piperidine-4-carbonyl}-4-methylpiperidine-4-carboxylic acid [ka]

[0351] To a solution of methyl 1-{1-[(tert-butoxy)carbonyl]piperidine-4-carbonyl}-4-methylpiperidine-4-carboxylate (828 mg, 2.14 mmol) in THF (5 mL) and water (1 mL) was added lithium hydroxide monohydrate (138 mg, 3.21 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 16 hours, and then the THF was evaporated under reduced pressure. Aqueous KHSO4 was then added to the aqueous layer until a pH of 2 was reached. The precipitated crystalline solid was filtered, washed with water, and then dried under reduced pressure to give 736 mg (97% yield) of the title compound as a white solid. Step 3: 4-Methyl-1-(piperidine-4-carbonyl)piperidine-4-carboxylic acid [ka]

[0352] To 1-{1-[(tert-butoxy)carbonyl]piperidine-4-carbonyl}-4-methylpiperidine-4-carboxylic acid (499 mg, 1.41 mmol) was added HFIP (3.06 mL, 29.07 mmol) at 25° C. The reaction mixture was stirred at 150° C. in a microwave reactor for 2 hours, and then the mixture was concentrated under reduced pressure. The residue was triturated with EtO (3×15 mL) to afford 564 mg (90% yield) of the title compound as a cream-white solid. Step 4: 1-{1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidine-4-carbonyl}-4-methylpiperidine-4-carboxylic acid [ka]

[0353] To a solution of 4-methyl-1-(piperidine-4-carbonyl)piperidine-4-carboxylic acid (565 mg, 1.27 mmol) in anhydrous DMSO (2.8 mL) was added 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (233 mg, 0.84 mmol) and potassium fluoride (196 mg, 3.37 mmol) at 25 °C. The reaction mixture was stirred at 120 °C for 16 hours, then poured into 50 mL of water and extracted with EtOAc (5 × 30 mL). The combined organic extracts were dried over Na SO and evaporated under reduced pressure. The residue was purified by silica gel chromatography using a mobile phase of DCM and MeOH to give 136 mg (32% yield) of the title compound as a yellow solid. LCMS: C 26 H 30 N4O7, desired mass = 510.6, observed: m / z = 511.2 [M+H] + . Intermediate 59 4-(4-{2-[2,6-dioxopiperidin-3-yl]-1,3-dioxoisoindol-5-yl}piperazine-1-carbonyl)-2-methylbenzoic acid [ka] Step 1: Benzyl 4-(4-bromo-3-methylbenzoyl)piperazine-1-carboxylate [ka]

[0354] A procedure similar to that of Step 1 of Intermediate 19 was followed using 4-bromo-3-methylbenzoic acid (3 g, 13.951 mmol), DCM (15 mL), HATU (7.96 g, 20.926 mmol), benzyl piperazine-1-carboxylate (3.07 g, 13.937 mmol), and DIEA (5.41 g, 41.852 mmol). The residue was purified by silica gel chromatography using a mobile phase of [PE and EA] to afford 5 g (81.59%) of the title compound as a colorless oil. LCMS: (C 20 H 21 Desired mass of BrN2O3) = 416.1; Found: m / z = 417.1 [M+H] + . Step 2: Benzyl 4-[4-(methoxycarbonyl)-3-methylbenzoyl]piperazine-1-carboxylate: [ka]

[0355] To a mixture of benzyl 4-(4-bromo-3-methylbenzoyl)piperazine-1-carboxylate (2.5 g, 5.991 mmol) in MeOH (10 mL) was added TEA (1.82 g, 17.973 mmol) and Pd(dppf)Cl (0.88 g, 1.198 mmol). The resulting mixture was stirred at 100° C. under a carbon monoxide atmosphere (1 atm) for 5 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mobile phase of [PE and EA] to afford 900 mg (34.10%) of the title compound as a dark red solid. LCMS: (C 22 H 24Desired mass of N2O5) = 396.2; Found: m / z = 397.0 [M+H] + . Step 3: Methyl 2-methyl-4-(piperazine-1-carbonyl)benzoate [ka]

[0356] A procedure similar to that of Step 5 of Intermediate 15 was followed using benzyl 4-[4-(methoxycarbonyl)-3-methylbenzoyl]piperazine-1-carboxylate (900 mg, 2.270 mmol) in MeOH (10 mL) and Pd / C (900 mg) was added. The residue was purified by silica gel chromatography using a mobile phase of [CHCl and MeOH] to afford 560 mg (86.52%) of the title compound as a brown oil. LCMS: (C 14 H 18 Desired mass of N2O3) = 262.1; Found: m / z = 263.0 [M+H] + . Step 4: 2-Methyl-4-(piperazine-1-carbonyl)benzoic acid [ka]

[0357] To a mixture of methyl 2-methyl-4-(piperazine-1-carbonyl)benzoate (500 mg, 1.906 mmol) in THF (2 mL) and HO (2 mL) was added LiOH (456 mg, 19.060 mmol). The resulting mixture was stirred at room temperature for 1 h. The mixture was acidified to pH 2 with aqueous HCl (2 M). The resulting mixture was concentrated under reduced pressure to give 400 mg (crude) of the title compound as a brown solid. The residue was used directly in the next step. LCMS: (C 13 H 16 Desired mass of N2O3) = 248.1; Found: m / z = 249.1 [M+H] + . Step 5: 4-(4-{2-[2,6-dioxopiperidin-3-yl]-1,3-dioxoisoindol-5-yl}piperazine-1-carbonyl)-2-methylbenzoic acid [ka]

[0358] A procedure similar to that of Step 4 of Intermediate 15 was followed using 2-methyl-4-(piperazine-1-carbonyl)benzoic acid (400 mg, 1.611 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (222 mg, 0.806 mmol), DMSO (5 mL), and DIEA (312.33 mg, 2.417 mmol). The mixture was purified by reverse-phase flash chromatography [ACN and HO] to afford 111.5 mg (26.75%) of the title compound as a yellow solid. LCMS (Method 6): (C 26 H 24 Desired mass of N4O7) = 504.2; Found: m / z = 505.1 [M+H] + . Intermediate 60 4-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazine-1-carbonyl}-3-methylbenzoic acid [ka] Step 1: Benzyl 4-[4-(methoxycarbonyl)-2-methylbenzoyl]piperazine-1-carboxylate [ka]

[0359] The title compound was synthesized using a method similar to Step 1 for Intermediate 58, using 1-[(tert-butoxy)carbonyl]piperidine-4-carboxylic acid in place of 4-(methoxycarbonyl)-2-methylbenzoic acid and methyl 4-methylpiperidine-4-carboxylate hydrochloride in place of benzyl 1-piperazinecarboxylate to afford 500 mg (98% yield) of the title compound as a dark red oil. LCMS: C 22 H 24 N2O5, desired mass = 396.4, observed: m / z = 397.4 [M+H] + . Step 2: 4-{4-[(benzyloxy)carbonyl]piperazine-1-carbonyl}-3-methylbenzoic acid [ka]

[0360] The title compound was synthesized using a method similar to Step 2 for Intermediate 58, using methyl 1-{1-[(tert-butoxy)carbonyl]piperidine-4-carbonyl}-4-methylpiperidine-4-carboxylate instead of benzyl 4-[4-(methoxycarbonyl)-2-methylbenzoyl]piperazine-1-carboxylate to afford 417 mg (87% yield) of the title compound as a cream-white solid. LCMS: C 21 H 22 N2O5, desired mass = 382.4, observed: m / z = 383.2 [M+H] + . Step 3: 3-Methyl-4-(piperazine-1-carbonyl)benzoic acid [ka]

[0361] To a solution of 4-{4-[(benzyloxy)carbonyl]piperazine-1-carbonyl}-3-methylbenzoic acid (414 mg, 1.08 mmol) in anhydrous THF (54 mL) was added 10% wt Pd / C (62 mg) at 25° C. The reaction mixture was stirred at 25° C. for 16 h, followed by the addition of a second portion of 10% wt Pd / C (206 mg) at 25° C. The reaction mixture was stirred at 25° C. for an additional 72 h, followed by the addition of a third portion of 10% wt Pd / C (206 mg) at 25° C. The reaction mixture was stirred at 25° C. for 16 h, then filtered through a Celite pad and evaporated to dryness under reduced pressure. The residue was triturated with EtO (3×15 mL) to give 230 mg (86% yield) of the title compound as a white solid. LCMS: C 13 H 16 N2O3, desired mass = 248.3, observed: m / z = 249.4 [M+H] + . Step 4: Benzyl 3-methyl-4-(piperazine-1-carbonyl)benzoate [ka]

[0362] To a solution of 3-methyl-4-(piperazine-1-carbonyl)benzoic acid (200 mg, 0.81 mmol) in anhydrous toluene (20.0 mL) was added anhydrous benzyl alcohol (0.83 mL, 8.05 mmol) and TsOH monohydrate (169 mg, 0.89 mmol) at 25° C. The reaction mixture was stirred at 140° C. for 16 hours and then evaporated under reduced pressure. The residue was triturated with EtO (3×15 mL) and diisopropyl ether (2×15 mL), then saturated aqueous NaHCO (10 mL) was added to the residue, and the mixture was extracted with DCM (5×50 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 169 mg (62% yield) of the title compound as a brown oil. LCMS: C 20 H 22 N2O3, desired mass = 338.4, observed: m / z = 339.5 [M+H] + . Step 5: Benzyl 4-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazine-1-carbonyl}-3-methylbenzoate [ka]

[0363] To a solution of benzyl 3-methyl-4-(piperazine-1-carbonyl)benzoate (169 mg, 0.50 mmol) in anhydrous DMSO (1.4 mL) was added 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (115 mg, 0.42 mmol) and DIPEA (0.29 mL, 1.67 mmol) at 25° C. The reaction mixture was stirred at 100° C. for 72 hours and then concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mobile phase of hexane and EtOAc to afford 121 mg (49% yield) of the title compound as a yellow solid. LCMS: C 33 H 30 N4O7, desired mass = 594.6, observed: m / z = 595.2 [M+H] + . Step 6: 4-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazine-1-carbonyl}-3-methylbenzoic acid [ka]

[0364] To a solution of benzyl 4-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazine-1-carbonyl}-3-methylbenzoate (120 mg, 0.20 mmol) in anhydrous THF (15 mL) was added 10% wt Pd / C (30 mg) at 25° C. The reaction mixture was stirred at 25° C. for 16 hours, followed by the addition of a second amount of 10% wt Pd / C (30 mg) at 25° C. The reaction mixture was stirred at 25° C. for an additional 48 hours, followed by the addition of a third amount of 10% wt Pd / C (12 mg) at 25° C. The reaction mixture was stirred at 25° C. for 96 hours, then filtered through a Celite pad and evaporated to dryness. The residue was purified by silica gel chromatography using a mobile phase of DCM and MeOH to give 62 mg (61% yield) of the title compound as a yellow solid. LCMS:C 26 H 24 N4O7, desired mass = 504.5, observed: m / z = 505.2 [M+H] + . Intermediate 61 (3R)-1-((1r,4R)-4-((5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)(methyl)amino)cyclohexane-1-carbonyl)pyrrolidine-3-carboxylic acid [ka]

[0365] Benzyl (3R)-pyrrolidine-3-carboxylate hydrochloride was synthesized using Method for Intermediate 62: Steps 5-6. Step 1: Methyl (1r,4r)-4-{[(tert-butoxy)carbonyl](methyl)amino}cyclohexane-1-carboxylate [ka]

[0366] To a solution of methyl trans-4-(N-Boc-amino)cyclohexanecarboxylate (17.0 g, 66.1 mmol) in anhydrous DMF (146.8 mL) was added sodium hydride (1.902 g, 79.27 mmol, 1.2 equiv.) at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes, then methyl iodide (6.17 mL, 99.1 mmol) was added at 0° C., and the mixture was stirred at room temperature overnight. The reaction mixture was then evaporated to dryness and quenched with saturated aqueous NH4Cl. The aqueous phase was extracted with Et2O, and the organic fraction was evaporated to dryness. 17.8 g (99% yield) of the title compound was obtained as a clear oil and used directly in the next step. LCMS: C 14 H 25 NO4, desired mass = 271.36, observed: m / z = 272.10 [M+H] + . Step 2: Methyl (1r,4r)-4-(methylamino)cyclohexane-1-carboxylate hydrochloride [ka]

[0367] To a solution of methyl (1r,4r)-4-{[(tert-butoxy)carbonyl](methyl)amino}cyclohexane-1-carboxylate (17.8 g, 65.6 mmol) in DCM (262.4 mL, 0.25 M) was added 4 M HCl in 1,4-dioxane (262.4 mL, 1050 mmol) dropwise at 0° C. The reaction mixture was allowed to reach room temperature overnight, and the mixture was concentrated and re-evaporated with DCM three times. 13.62 g (quantitative yield) of the title compound was obtained as a white powder and used directly in the next step. LCMS: CH 18 ClNO2, desired mass = 207.70, observed: m / z = none [M+H] + . Step 3: Methyl (1r,4r)-4-[(5-bromopyridin-2-yl)(methyl)amino]cyclohexane-1-carboxylate [ka]

[0368] To a solution of 5-bromo-2-fluoropyridine (5.43 g, 30.8 mmol) in anhydrous DMSO (30.85 mL) was added methyl (1r,4r)-4-(methylamino)cyclohexane-1-carboxylate hydrochloride (3.23 g, 15.4 mmol) and cesium carbonate (20.1 g, 61.7 mmol) at room temperature. The reaction mixture was stirred at 130 °C overnight, and then the mixture was concentrated. The residue was suspended in DCM, the formed solid was filtered, and the resulting filtrate was concentrated. The residue was purified by silica gel chromatography using a mobile phase of hexane and ethyl acetate (0-10%) to give 1.53 g (30% yield) of the title compound as a yellow oil. LCMS: C 14 H 19 BrN2O2, desired mass = 327.22, found: m / z = 327.25 [M+H] + . Step 4: Methyl (1r,4r)-4-{[2',6'-bis(benzyloxy)-[3,3'-bipyridin]-6-yl](methyl)amino}cyclohexane-1-carboxylate [ka]

[0369] To a solution of methyl (1r,4r)-4-[(5-bromopyridin-2-yl)(methyl)amino]cyclohexane-1-carboxylate (1.53 g, 4.68 mmol) in degassed dimethylformamide (13.37 mL) was added 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.95 g, 4.68 mmol), 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (0.171 g, 0.234 mmol), and potassium carbonate (1.94 g, 14.0 mmol) at room temperature. The reaction mixture was stirred at 85 °C overnight, and then the mixture was evaporated in vacuo. The residue was purified by silica gel chromatography using a mobile phase of hexane and ethyl acetate (0-30%) to give 1.49 g (59% yield) of the title compound as a brown oil. LCMS: C 33 H 35 N3O4, desired mass = 537.66, observed: m / z = 538.70 [M+H] + . Step 5: (1r,4r)-4-{[2',6'-bis(benzyloxy)-[3,3'-bipyridin]-6-yl](methyl)amino}cyclohexane-1-carboxylic acid [ka]

[0370] To a solution of methyl (1r,4r)-4-{[2',6'-bis(benzyloxy)-[3,3'-bipyridin]-6-yl](methyl)amino}cyclohexane-1-carboxylate (1.44 g, 2.68 mmol) in a mixture of THF (4.32 mL) and water (1.42 mL) was added lithium hydroxide monohydrate (0.225 g, 5.36 mmol) at room temperature. The reaction mixture was stirred at room temperature for 8 hours, and then the THF was evaporated. To the remaining aqueous layer, KHSO4 (0.729 g, 5.36 mmol) was added to adjust the pH to 4-5. The solid formed was filtered, dissolved in DCM, and dried over Na2SO4. 1.26 g (90% yield) of the title compound was obtained as a yellow solid and used directly in the next step. LCMS: C33 H 34 N2O4, desired mass = 522.65, observed: m / z = 523.70 [M+H] + . Step 6: (1r,4r)-4-{[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl](methyl)amino}cyclohexane-1-carboxylic acid [ka]

[0371] To a solution of (1r,4r)-4-{[2',6'-bis(benzyloxy)-[3,3'-bipyridin]-6-yl](methyl)amino}cyclohexane-1-carboxylic acid (2.8 g, 5.347 mmol) in a mixture of degassed tetrahydrofuran (140.72 mL) and isopropanol (140.72 mL) was added palladium on carbon (60-65% water content) (0.29 g, 2.72 mmol) at room temperature. The reaction mixture was stirred at room temperature under H2 (1 atm) for 24 h, followed by the addition of an additional amount of palladium on carbon (60-65% water content) (0.29 g, 2.72 mmol) and a mixture of degassed tetrahydrofuran (70.36 mL) and isopropanol (70.36 mL) at room temperature. The reaction mixture was stirred under H2 (1 atm) at room temperature for an additional 24 h, then the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC method 1 to give 179.8 mg (21% yield) of the title compound as a grey solid. LCMS: C 18 H 23 N3O4, desired mass = 345.40, observed: m / z = 346.25 [M+H] + . Step 7: Benzyl (3R)-1-[(1r,4r)-4-{[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl](methyl)amino}cyclohexanecarbonyl]pyrrolidine-3-carboxylate [ka]

[0372] To a solution of (1r,4r)-4-{[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl](methyl)amino}cyclohexane-1-carboxylic acid (0.12 g, 0.35 mmol) in anhydrous DMF (1.2 mL, 0.3 M) was added HATU (0.16 g, 0.42 mmol) and DIPEA (0.24 mL, 1.39 mmol) at 25 °C and stirred at 25 °C for 0.5 h. Next, a solution of benzyl (3R)-pyrrolidine-3-carboxylate hydrochloride (0.1 g, 0.42 mmol) in anhydrous DMF (1.2 mL, 0.3 M) was added, and the reaction mixture was stirred at 25 °C for 16 h. The solvent was evaporated to dryness, and the residue was purified by silica gel chromatography using a mobile phase of DCM and MeOH to give 0.075 g (39% yield) of the title compound. LCMS: C 30 H 36 N4O5, desired mass = 532.3, observed: m / z = 533.5 [M+H] + . Step 8: (3R)-1-((1r,4R)-4-((5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)(methyl)amino)cyclohexane-1-carbonyl)pyrrolidine-3-carboxylic acid [ka]

[0373] Benzyl (3R)-1-[(1r,4r)-4-{[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl](methyl)amino}cyclohexanecarbonyl]pyrrolidine-3-carboxylate (0.075 g, 0.14 mmol) was dissolved in a solution of HBr in AcOH (10.30 mL, 4.22 mmol) at 25° C. and stirred at 25° C. for 16 h. The reaction mixture was then concentrated, triturated with EtO, and lyophilized to give 0.061 g (77% yield) of the title compound as an orange solid. LCMS: C 23 H 30 N4O5, desired mass = 442.5, observed: m / z = 443.3 [M+H] + . Intermediate 62 (3R)-1-((1r,4R)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)(methyl)amino)cyclohexane-1-carbonyl)pyrrolidine-3-carboxylic acid [ka] Step 1: Methyl (1r,4r)-4-{[(tert-butoxy)carbonyl](methyl)amino}cyclohexane-1-carboxylate [ka]

[0374] To a solution of methyl trans-4-(N-Boc-amino)cyclohexanecarboxylate (3.0 g, 11.66 mmol) in anhydrous DMF (20.0 mL) was added sodium hydride (536 mg, 14.0 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, and then methyl iodide (1.09 mL, 17.50 mmol) was added at 0 °C. The reaction mixture was stirred at 25 °C for 16 h, and then the resulting mixture was coevaporated with toluene (3 × 100 mL) and quenched with saturated aqueous NH Cl. The aqueous phase was extracted with Et O (3 × 50 mL), and the organic fraction was concentrated to dryness to afford 3.276 g (99% yield) of the title compound as a clear oil, which was used directly in the next step. Step 2: (1r,4r)-4-{[(tert-butoxy)carbonyl](methyl)amino}cyclohexane-1-carboxylic acid [ka]

[0375] To a solution of methyl (1r,4r)-4-{[(tert-butoxy)carbonyl](methyl)amino}cyclohexane-1-carboxylate (3.276 g, 12.07 mmol) in THF (25 mL) and water (5 mL) was added lithium hydroxide monohydrate (1.037 g, 24.15 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 16 h, and then the THF was evaporated under reduced pressure. Aqueous KHSO was then added to the aqueous layer until a pH of 2 was reached, followed by extraction with EtOAc (4 × 25 mL). The combined organic extracts were dried over NaSO and evaporated under reduced pressure to give 2.510 g (81% yield) of the title compound as a white solid, which was used directly in the next step. Step 3: (1r,4r)-4-(methylamino)cyclohexane-1-carboxylic acid hydrochloride [ka]

[0376] To a solution of (1r,4r)-4-{[(tert-butoxy)carbonyl](methyl)amino}cyclohexane-1-carboxylic acid (2.510 g, 9.75 mmol) in anhydrous DCM (130.0 mL) was added 2 M HCl in EtO (39.0 mL, 78.03 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 16 h, and then the solvent was evaporated to dryness under reduced pressure to give 1.740 g (92% yield) of the title compound as a white solid, which was used directly in the next step. Step 4: (1r,4r)-4-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl](methyl)amino}cyclohexane-1-carboxylic acid [ka]

[0377] To a solution of (1r,4r)-4-(methylamino)cyclohexane-1-carboxylic acid hydrochloride (1.737 g, 9.00 mmol) in anhydrous DMSO (50.0 mL) were added 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (2.485 g, 9.0 mmol) and KF (2.090 g, 35.98 mmol) at 25 °C. The reaction mixture was stirred at 120 °C for 16 h, then poured into 1000 mL of brine and extracted with EtOAc (5 × 100 mL). The combined organic extracts were dried over Na SO and evaporated under reduced pressure. The residue was purified by silica gel chromatography using a mobile phase of DCM and MeOH, followed by MeCN and HO to afford 768 mg (21% yield) of the title compound as a yellow solid. LCMS: C 21 H 23 N3O6, desired mass = 413.4, observed: m / z = 414.3 [M+H] + . Step 5: 3-Benzyl 1-tert-butyl (3R)-pyrrolidine-1,3-dicarboxylate [ka]

[0378] To a solution of (3R)-1-[(tert-butoxy)carbonyl]pyrrolidine-3-carboxylic acid (5.00 g, 23.23 mmol) in anhydrous DMF (258 mL) was added CsCO (9.08 g, 27.87 mmol). The reaction mixture was placed in an ice bath and stirred at 0 °C for 1 h. Benzyl bromide (3.04 mL, 25.55 mmol) was then added dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 12 h, and then the mixture was poured into 1800 mL of brine and extracted with EtOAc (5 × 150 mL). The combined organic layers were dried over MgSO and concentrated under reduced pressure to give 6.228 g (88% yield) of the title compound as a yellow solid, which was used directly in the next step. Step 6: Benzyl (3R)-pyrrolidine-3-carboxylate hydrochloride [ka]

[0379] To a solution of 3-benzyl 1-tert-butyl(3R)-pyrrolidine-1,3-dicarboxylate (6.228 g, 20.39 mmol) in anhydrous DCM (255.0 mL) was added 2 M HCl in EtO (81.58 mL, 163.16 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 16 h, and then the solvent was evaporated to dryness under reduced pressure to give 4.929 g (100% yield) of the title compound as a yellow oil, which was used directly in the next step. Step 7: Benzyl (3R)-1-[(1r,4r)-4-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl](methyl)amino}cyclohexanecarbonyl]pyrrolidine-3-carboxylate [ka]

[0380] To a solution of (1r,4r)-4-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl](methyl)amino}cyclohexane-1-carboxylic acid (450 mg, 1.09 mmol) in anhydrous DMF (22.0 mL) were added HATU (621 mg, 1.63 mmol) and DIPEA (0.76 mL, 4.35 mmol). The reaction mixture was stirred at 25° C. for 20 minutes. Benzyl (3R)-pyrrolidine-3-carboxylate hydrochloride (263 mg, 1.09 mmol) was then added at 25° C. The reaction mixture was stirred at 25° C. for 16 hours, and then the mixture was poured into 250 mL of brine and extracted with EtOAc (4×40 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mobile phase of DCM and MeOH to give 379 mg (58% yield) of the title compound as a yellow solid. LCMS:C 33 H 36N4O7, desired mass = 600.7, observed: m / z = 599.8 [MH + ]. Step 8: (3R)-1-((1r,4R)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)(methyl)amino)cyclohexane-1-carbonyl)pyrrolidine-3-carboxylic acid [ka]

[0381] To a solution of benzyl (3R)-1-[(1r,4r)-4-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl](methyl)amino}cyclohexanecarbonyl]pyrrolidine-3-carboxylate (379 mg, 0.63 mmol) in anhydrous THF (7.9 mL) was added 10% wt Pd / C (38 mg) at 25° C. The reaction mixture was stirred at 25° C. for 16 hours, followed by the addition of a second amount of 10% wt Pd / C (38 mg) at 25° C. The reaction mixture was stirred at 25° C. for an additional 16 hours, then filtered through a Celite pad and evaporated to dryness. The residue was purified by silica gel chromatography using a mobile phase of DCM and MeOH to afford 180 mg (56% yield) of the title compound as a yellow solid. LCMS: C 26 H 30 N4O7, desired mass = 510.6, observed: m / z = 510.8 [M+H] + . Intermediate 63 1-((1r,4r)-4-((5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)(methyl)amino)cyclohexane-1-carbonyl)piperidine-4-carboxylic acid [ka]

[0382] (1r,4r)-4-{[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl](methyl)amino}cyclohexane-1-carboxylic acid was synthesized according to the procedure for intermediate 61: steps 1-6. Step 1: tert-Butyl 1-[(1r,4r)-4-{[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl](methyl)amino}cyclohexanecarbonyl]piperidine-4-carboxylate [ka]

[0383] To a solution of (1r,4r)-4-{[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl](methyl)amino}cyclohexane-1-carboxylic acid (0.15 g, 0.43 mmol) in anhydrous DMF (1.5 mL, 0.3 M) was added HATU (0.2 g, 0.52 mmol) and DIPEA (0.3 mL, 1.74 mmol) at 25° C. and stirred at 25° C. for 0.5 h. Next, tert-butyl piperidine-4-carboxylate (0.12 g, 0.52 mmol) was added, and the reaction mixture was stirred at 25° C. for 16 h. The solvent was evaporated to dryness, and the residue was purified by silica gel chromatography using a mobile phase of hexane and EtOAc to give 0.08 g (34% yield) of the title compound. LCMS: C 28 H 40 N4O5, desired mass = 512.3, observed: m / z = 513.6 [M+H + ]. Step 2: 1-[(1r,4r)-4-{[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl](methyl)amino}cyclohexanecarbonyl]piperidine-4-carboxylic acid trifluoroacetate [ka]

[0384] To a solution of tert-butyl 1-[(1r,4r)-4-{[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl](methyl)amino}cyclohexanecarbonyl]piperidine-4-carboxylate (0.084 g, 0.16 mmol) in DCM (3.12 mL, 0.05 M) was added trifluoroacetic acid (0.36 mL, 4.69 mmol) dropwise at 25° C., and the reaction mixture was stirred at 25° C. for 1 hour. The mixture was concentrated under reduced pressure, and the residue was triturated with EtO to give 0.053 g (55% yield) of the title compound as an off-white solid. LCMS: C 23 H 30 N4O5, desired mass = 442.5, observed: m / z = 443.3 [M+H] + . Intermediate 64 1-((1r,4r)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)(methyl)amino)cyclohexane-1-carbonyl)piperidine-4-carboxylic acid [ka]

[0385] Following a procedure similar to intermediate 15 (steps 4 and 5), using (1r,4r)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)(methyl)amino)cyclohexane-1-carboxylic acid and benzyl piperidine-4-carboxylate as coupling partners, the title compound was obtained as an off-white solid (52 mg, 39% yield over two steps). Intermediate 65 3-(4-(methyl(piperidin-4-yl)amino)phenyl)piperidine-2,6-dione [ka]

[0386] Using a procedure similar to the preparation of Intermediate 31 (Steps 1, 3, and 4) using 1,4-dibromobenzene and tert-butyl 4-(methylamino)piperidine-1-carboxylate as starting materials in Step 1, followed by a procedure similar to Step 2 of Intermediate 12, the title compound was obtained as an off-white solid (84 mg). LCMS: [C 17 H 23 N3O2], desired mass = 301.2, observed: m / z = 302.3 [M+H] + . Intermediate 66 3-(4-(methyl(piperidin-4-yl)amino)phenyl)piperidine-2,6-dione [ka]

[0387] A procedure similar to that for Intermediate 12 (Steps 1 and 2) was followed, using tert-butyl 4-(methylamino)piperidine-1-carboxylate and 3-(6-fluoro-3-pyridyl)-2,6-piperidinedione as starting materials in Step 1. The title compound was obtained as the HCl salt (off-white solid, 327 mg, 23% yield). LCMS: [C 16 H 22 N4O2], desired mass = 302.2, observed: m / z = 303.1 [M+H] + . Intermediate 67 4-(4-((5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)(methyl)amino)piperidine-1-carbonyl)benzoic acid [ka]

[0388] A procedure similar to that for preparing Intermediate 1 (Step 1) was carried out using 4-(tert-butoxycarbonyl)benzoic acid and 3-(4-(methyl(piperidin-4-yl)amino)phenyl)piperidine-2,6-dione as starting materials, followed by tert-butyl ester deprotection using a procedure similar to that in Step 2 of Intermediate 68. The title compound was obtained as an off-white solid (48 mg, 72% yield). LCMS: [C 24 H 26 N4O5], desired mass = 450.2, observed: m / z = 451.4 [M+H] + . Intermediate 68 4-((1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)(methyl)carbamoyl)benzoic acid [ka] Step 1: tert-Butyl 4-({1-[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl]piperidin-4-yl}(methyl)carbamoyl)benzoate [ka]

[0389] A procedure similar to Step 1 of Intermediate 1 was followed using 4-(tert-butoxycarbonyl)benzoic acid (837 mg, 3.770 mmol), DMF (8 mL), HATU (1075 mg, 2.828 mmol), 3-{6-[4-(methylamino)piperidin-1-yl]pyridin-3-yl}piperidine-2,6-dione (570 mg, 1.885 mmol) and DIEA (730 mg, 5.655 mmol). The residue was purified by reverse-phase flash chromatography [ACN and HO mobile phase] to afford 440 mg (41.47%) of the title compound as an orange solid. LCMS: (C 28 H 34 Desired mass of N4O5) = 506.3; Found: m / z = 507.2 [M+H] + . Step 2: 4-((1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)(methyl)carbamoyl)benzoic acid [ka]

[0390] A mixture of tert-butyl 4-({1-[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl]piperidin-4-yl}(methyl)carbamoyl)benzoate (100 mg, 0.197 mmol) and HCl (10 mL, 12 M) was stirred at room temperature for 2 hours, and then the mixture was concentrated. The residue was purified by reverse-phase flash chromatography [ACN and HO mobile phase] to afford 41.9 mg (46.46%) of the title compound as a white solid. LCMS: (C 24 H 26 Desired mass of N4O5) = 450.2; Found: m / z = 451.1 [M+H] + . Intermediate 69 1-((1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-4-yl)methyl)piperidine-4-carboxylic acid [ka] Step 1: 1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidine-4-carbaldehyde [ka]

[0391] 3-(4-(4-(hydroxymethyl)piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (prepared using a procedure similar to Step 3 of Intermediate 70, followed by a procedure similar to Step 5 of Intermediate 15, using 4-benzyloxymethyl-piperidine and 1-[2,6-bis(benzyloxy)pyridin-3-yl]-4-bromo-3-methyl-1,3-benzodiazol-2-one as starting materials) (49.7 mg, 0.13 mmol) was dissolved in DMSO (1 mL) and then treated with polystyrene-supported 2-iodoxybenzoic acid (330 mg of 1.2 mmol / g, 0.39 mmol). The reaction mixture was stirred for 16 h, then filtered and washed with DCM. The DCM was removed under reduced pressure and the title compound was used in the next step as a DMSO solution. LCMS: desired mass for (C19H22N4O4) = 370.2; found: m / z = 371.1 [M+H] + . Step 2: 1-((1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-4-yl)methyl)piperidine-4-carboxylic acid

[0392] 1-(1-(2,6-Dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidine-4-carbaldehyde (DMSO solution from above) was diluted in 1,2-dichloroethane (0.41 mL), then tert-butyl piperidine-4-carboxylate (43 mg, 0.26 mmol) and sodium triacetoxyborohydride (33 mg, 0.16 mmol) were added. The reaction mixture was stirred for 1 h, then saturated sodium bicarbonate solution was added (20 mL). The aqueous layer was extracted with DCM (3 × 10 mL), and the combined organic layers were washed with saturated sodium chloride solution (2 × 5 mL), dried over sodium sulfate, and purified by reverse-phase chromatography (mobile phase: ACN and water). After lyophilization of the desired fractions, DCM (1 mL) was added to the residue, followed by HCl (1 mL of a 4N solution in dioxane). The reaction mixture was stirred overnight and then concentrated under reduced pressure to give the title compound as the HCl salt (off-white solid, 42 mg, 76% yield). LCMS: (C 25 H 33 Desired mass of N5O5 = 483.3; Found: m / z = 484.4 [M+H] + . Intermediate 70 (3S)-1-[(1r,4r)-4-({1-[(3RS)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-1,3-benzodiazol-4-yl}amino)cyclohexanecarbonyl]pyrrolidine-3-carboxylic acid [ka] Step 1: 2,6-Bis(benzyloxy)-N-(3-bromo-2-nitrophenyl)pyridin-3-amine [ka]

[0393] To a mixture of 2,6-bis(benzyloxy)pyridin-3-amine (3.48 g, 11.364 mmol) in THF (10 mL) was added t-BuOK (2.55 g, 22.728 mmol) and 1-bromo-3-fluoro-2-nitrobenzene (2.5 g, 11.364 mmol). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mobile phase of [PE and EA] to afford 2 g (24.33%) of the title compound as a red oil. LCMS: (C 25 H 20 Desired mass of BrN3O2) = 505.1; Found: m / z = 506.2. [M+H] + . Step 2: N-1-[2,6-bis(benzyloxy)pyridin-3-yl]-3-bromobenzene-1,2-diamine [ka]

[0394] To a mixture of 2,6-bis(benzyloxy)-N-(3-bromo-2-nitrophenyl)pyridin-3-amine (14 g, 27.649 mmol) in IPA (700 mL) was added Fe (7.72 g, 138.245 mmol) and saturated aqueous NH4Cl (100 mL). The resulting mixture was stirred at 80°C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mobile phase of [PE and EA] to afford 11 g (58.46%) of the title compound as a brown oil. LCMS: (C 25 H 22 Desired mass of BrN3O2) = 475.1; Found: m / z = 476.0 [M+H] + . Step 3: 1-[2,6-bis(benzyloxy)pyridin-3-yl]-4-bromo-3H-1,3-benzodiazol-2-one [ka]

[0395] To a mixture of N-1-[2,6-bis(benzyloxy)pyridin-3-yl]-3-bromobenzene-1,2-diamine (700 mg, 1.469 mmol) in DCM (6 mL) was added DIEA (228 mg, 1.763 mmol) and triphosgene (262 mg, 0.881 mmol) at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mobile phase of [PE and EA] to afford 590 mg (71.93%) of the title compound as a pink solid. LCMS: (C 26 H 20 Desired mass of BrN3O3) = 501.1; Found: m / z = 502.1 [M+H] + . Step 4: 1-[2,6-bis(benzyloxy)pyridin-3-yl]-4-bromo-3-methyl-1,3-benzodiazol-2-one [ka]

[0396] To a mixture of NaH (56 mg, 2.348 mmol) in THF (10 mL) was added 1-[2,6-bis(benzyloxy)pyridin-3-yl]-4-bromo-3H-1,3-benzodiazol-2-one (590 mg, 1.174 mmol) under a nitrogen atmosphere at 0° C. The resulting mixture was stirred at room temperature for 30 minutes. To the previous mixture was added MeI (500 mg, 3.522 mmol) at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was quenched with water at 0° C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mobile phase of [PE and EA] to give 580 mg (83.20%) of the title compound as a yellow solid. LCMS: (C 27 H 22 Desired mass of BrN3O3) = 515.1; Found: m / z = 516.1 [M+H] + . Step 5: Methyl (1r,4r)-4-({1-[2,6-bis(benzyloxy)pyridin-3-yl]-3-methyl-2-oxo-1,3-benzodiazol-4-yl}amino)cyclohexane-1-carboxylate [ka]

[0397] To a mixture of 1-[2,6-bis(benzyloxy)pyridin-3-yl]-4-bromo-3-methyl-1,3-benzodiazol-2-one (5 g, 9.683 mmol) in toluene (30 mL) was added methyl (1r,4r)-4-aminocyclohexane-1-carboxylate hydrochloride (2.25 g, 11.620 mmol), RuPhos palladacycle 3rd generation (0.81 g, 0.968 mmol), and CsCO (9.46 g, 29.049 mmol). The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mobile phase of [PE and EA] to afford 4 g (62.73%) of the title compound as a white solid. LCMS: (C 35 H 36 Desired mass of N4O5) = 592.3; Found: m / z = 593.4 [M+H] + . Step 6: (1r,4r)-4-({1-[2,6-bis(benzyloxy)pyridin-3-yl]-3-methyl-2-oxo-1,3-benzodiazol-4-yl}amino)cyclohexane-1-carboxylic acid [ka]

[0398] Following a procedure similar to that of Step 4 of Intermediate 59, 3.2 g (crude) of the title compound was obtained as a white solid using methyl (1r,4r)-4-({1-[2,6-bis(benzyloxy)pyridin-3-yl]-3-methyl-2-oxo-1,3-benzodiazol-4-yl}amino)cyclohexane-1-carboxylate (4 g, 6.749 mmol), water (10 mL), THF (10 mL), MeOH (10 mL), and LiOH (1.62 g, 67.490 mmol). The residue was used directly in the next step. LCMS: (C 34 H 34 Desired mass of N4O5) = 578.3; Found: m / z = 579.3 [M+H] + . Step 7: tert-Butyl (3S)-1-[(1r,4r)-4-({1-[2,6-bis(benzyloxy)pyridin-3-yl]-3-methyl-2-oxo-1,3-benzodiazol-4-yl}amino)cyclohexanecarbonyl]pyrrolidine-3-carboxylate [ka]

[0399] A procedure similar to that of Step 1 of Intermediate 19 was followed using (1r,4r)-4-({1-[2,6-bis(benzyloxy)pyridin-3-yl]-3-methyl-2-oxo-1,3-benzodiazol-4-yl}amino)cyclohexane-1-carboxylic acid (3 g, 5.184 mmol), HATU (2.96 g, 7.776 mmol), DMF (6 mL), tert-butyl (3S)-pyrrolidine-3-carboxylate (0.89 g, 5.184 mmol), and DIEA (2.01 g, 15.552 mmol). The residue was purified by reverse-phase flash chromatography in [CHCN and HO] to afford 2.5 g (62.59%) of the title compound as a white solid. LCMS: (C 43 H 49 Desired mass of N5O6) = 731.4; Found: m / z = 732.4 [M+H] + . Step 8: tert-Butyl (3S)-1-[(1r,4r)-4-{[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-4-yl]amino}cyclohexanecarbonyl]pyrrolidine-3-carboxylate [ka]

[0400] Following a procedure similar to that of Step 5 of Intermediate 15, 260 mg (crude) of the title compound was obtained as a white solid using tert-butyl (3S)-1-[(1r,4r)-4-({1-[2,6-bis(benzyloxy)pyridin-3-yl]-3-methyl-2-oxo-1,3-benzodiazol-4-yl}amino)cyclohexanecarbonyl]pyrrolidine-3-carboxylate (0.5 g, 0.683 mmol), THF (25 mL), and Pd / C (1.6 g). The residue was used directly in the next step. LCMS: (C 29 H 39 Desired mass of N5O6) = 553.3; Found: m / z = 554.2 [M+H] + . Step 9: (3S)-1-[(1r,4r)-4-({1-[(3RS)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-1,3-benzodiazol-4-yl}amino)cyclohexanecarbonyl]pyrrolidine-3-carboxylic acid [ka]

[0401] To a mixture of tert-butyl (3S)-1-[(1r,4r)-4-{[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-4-yl]amino}cyclohexanecarbonyl]pyrrolidine-3-carboxylate (300 mg, 0.542 mmol) in DCM (6 mL) was added TFA (2 mL) at 0° C. The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under vacuum. The residue was triturated with acetonitrile. The precipitated solid was collected by filtration and washed with acetonitrile to give 252.9 mg (92.02%) of the title compound as a white solid. LCMS (Method 7): (C 25 H 31 Desired mass of N5O6) = 497.2; Found: m / z = 498.2 [M+H] + . Intermediate 71 (3R)-1-[(1r,4r)-4-({1-[(3RS)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-1,3-benzodiazol-4-yl}amino)cyclohexanecarbonyl]pyrrolidine-3-carboxylic acid [ka] Step 1: tert-Butyl (3R)-1-[(1r,4r)-4-({1-[2,6-bis(benzyloxy)pyridin-3-yl]-3-methyl-2-oxo-1,3-benzodiazol-4-yl}amino)cyclohexanecarbonyl]pyrrolidine-3-carboxylate [ka]

[0402] A procedure similar to that of Step 1 of Intermediate 19 was followed using (1r,4r)-4-({1-[2,6-bis(benzyloxy)pyridin-3-yl]-3-methyl-2-oxo-1,3-benzodiazol-4-yl}amino)cyclohexane-1-carboxylic acid (2 g, 3.456 mmol), DMF (10 mL), HATU (1.97 g, 5.184 mmol), tert-butyl (3R)-pyrrolidine-3-carboxylate (0.71 g, 4.147 mmol), and DIEA (1.34 g, 10.368 mmol). The residue was purified by silica gel chromatography using a mobile phase of [PE and EA] to afford 1.4 g (52.58%) of the title compound as a white solid. LCMS: (C 43 H 49 Desired mass of N5O6) = 731.4; Found: m / z = 732.3 [M+H] + . Step 2: tert-Butyl (3R)-1-[(1r,4r)-4-{[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-4-yl]amino}cyclohexanecarbonyl]pyrrolidine-3-carboxylate [ka]

[0403] Following a procedure similar to that of Step 5 of Intermediate 15, using tert-butyl (3R)-1-[(1r,4r)-4-({1-[2,6-bis(benzyloxy)pyridin-3-yl]-3-methyl-2-oxo-1,3-benzodiazol-4-yl}amino)cyclohexanecarbonyl]pyrrolidine-3-carboxylate (1 g, 1.366 mmol) in THF (20 mL), and Pd / C (2 g), 500 mg (crude) of the title compound was obtained as a white solid. The residue was used directly in the next step. LCMS: (C 29 H 39 Desired mass of N5O6) = 553.3; Found: m / z = 554.3 [M+H] + . Step 3: (3R)-1-[(1r,4r)-4-({1-[(3RS)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-1,3-benzodiazol-4-yl}amino)cyclohexanecarbonyl]pyrrolidine-3-carboxylic acid [ka]

[0404] A procedure similar to that of Step 9 of Intermediate 70 was followed using tert-butyl (3R)-1-[(1r,4r)-4-{[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-4-yl]amino}cyclohexanecarbonyl]pyrrolidine-3-carboxylate (500 mg, 0.903 mmol), DCM (15 mL), and TFA (3 mL). The residue was purified by reverse-phase flash chromatography in [CHCN and HO] to afford 300.9 mg (65.96%) of the title compound as an off-white solid. LCMS (Method 8): (C 25 H 31 Desired mass of N5O6) = 497.2; Found: m / z = 498.2 [M+H] + . Intermediate 72 5-(4-{2-[2,6-dioxopiperidin-3-yl]-1,3-dioxoisoindol-5-yl}piperazine-1-carbonyl)-1-methylpyrazole-3-carboxylic acid [ka] Step 1: 5-Bromo-2-methylpyrazole-3-carboxylic acid: [ka]

[0405] To a mixture of 3,5-dibromo-1-methylpyrazole (3 g, 12.505 mmol) in THF (30 mL), n-BuLi (6.5 mL, 16.236 mmol, 2.5 mol / L) in n-hexane was added dropwise at −70° C. The resulting mixture was stirred at −70° C. for 30 minutes under a nitrogen atmosphere. Dry ice (5.50 g, 124.973 mmol) was added to the above mixture at −70° C. The resulting mixture was stirred at −65° C. for an additional 1 hour. The reaction mixture was quenched at −65° C. by the addition of aqueous HCl (6 M). The resulting mixture was concentrated under reduced pressure. The aqueous layer was extracted with CHCl and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mobile phase of [PE and EA] to give 680 mg (23.87%) of the title compound as a yellow solid. LCMS: desired mass for (C5H5BrN2O2) = 204.0; found: m / z = 205.2 [M+H] + . Step 2: tert-butyl 4-(5-bromo-2-methylpyrazole-3-carbonyl)piperazine-1-carboxylate: [ka]

[0406] A procedure similar to that of Step 2 of Intermediate 20 was followed using 5-bromo-2-methylpyrazole-3-carboxylic acid (650 mg, 3.171 mmol), DCM (8 mL), DMF (0.1 mL), oxalyl chloride (2.4 mL, 4.756 mmol, 2 mol / L), tert-butyl piperazine-1-carboxylate (1181 mg, 6.341 mmol), and TEA (962 mg, 9.512 mmol, 3 equiv). The residue was purified by silica gel chromatography using a mobile phase of [PE and EA] to afford 0.9 g (68.45%) of the title compound as a white solid. LCMS: (C 14 H 21 Desired mass of BrNO) = 372.1; Found: m / z = 373.1 [M+H] + . Step 3: tert-Butyl 4-[5-(ethoxycarbonyl)-2-methylpyrazole-3-carbonyl]piperazine-1-carboxylate [ka]

[0407] To a solution of tert-butyl 4-(5-bromo-2-methylpyrazole-3-carbonyl)piperazine-1-carboxylate (350 mg, 0.938 mmol) in EtOH (8 mL) was added potassium acetate (184 mg, 1.876 mmol) and Pd(dppf)Cl (137 mg, 0.188 mmol) in a pressure tank. The mixture was purged with nitrogen for 10 minutes and then pressurized with CO to 30 atm at 140° C. overnight. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mobile phase of [PE and EA] to afford 270 mg (70.72%) of the title compound as a white solid. LCMS: (C 17 H 26 Desired mass of N4O5) = 366.2; Found: m / z = 367.1 [M+H] + . Step 4: Ethyl 1-methyl-5-(piperazine-1-carbonyl)pyrazole-3-carboxylate [ka]

[0408] Following a procedure similar to that of Step 3 of Intermediate 15, using tert-butyl 4-[5-(ethoxycarbonyl)-2-methylpyrazole-3-carbonyl]piperazine-1-carboxylate (200 mg, 0.546 mmol) and HCl / dioxane (3 mL, 4 M), 150 mg (crude) of the title compound was obtained as a white solid. The residue was used directly in the next step. LCMS: (C 12 H 18 Desired mass of N4O3) = 266.1; Found: m / z = 267.1 [M+H] + . Step 5: 1-Methyl-5-(piperazine-1-carbonyl)pyrazole-3-carboxylic acid [ka]

[0409] Following a procedure similar to that of Step 4 of Intermediate 59, using ethyl 1-methyl-5-(piperazine-1-carbonyl)pyrazole-3-carboxylate (250 mg, 0.939 mmol), THF (3 mL), HO (3 mL), MeOH (3 mL), and LiOH (225 mg, 9.390 mmol), 420 mg (crude) of the title compound was obtained as a white solid. The residue was used directly in the next step. LCMS: (C 10 H 14 Desired mass of N4O3) = 238.1; Found: m / z = 239.3 [M+H] + . Step 6: 5-(4-{2-[2,6-dioxopiperidin-3-yl]-1,3-dioxoisoindol-5-yl}piperazine-1-carbonyl)-1-methylpyrazole-3-carboxylic acid [ka]

[0410] A procedure similar to that of Step 4 of Intermediate 15 was followed using 1-methyl-5-(piperazine-1-carbonyl)pyrazole-3-carboxylic acid (400 mg, 1.679 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (557 mg, 2.015 mmol), DMSO (5 mL), and DIEA (1302 mg, 10.074 mmol). The resulting mixture was purified by reverse-phase flash chromatography [CHCN and HO] to afford 114.3 mg (13.16%) of the title compound as an off-white solid. LCMS (Method 9): (C 23 H 22 Desired mass of N6O7) = 494.2; Found: m / z = 495.2 [M+H] + . Intermediate 73 3-(6-fluoropyridin-3-yl)piperidine-2,6-dione [ka] Step 1: 2,6-Bis(benzyloxy)-6'-fluoro-3,3'-bipyridine [ka]

[0411] To a mixture of 2,6-bis(benzyloxy)-3-bromopyridine (250 g, 675 mmol, 1.00 equiv.), (6-fluoropyridin-3-yl)boronic acid (104 g, 742 mmol, 1.10 equiv.) in dioxane (1.50 L), KPO (429 g, 2.03 mol, 3.00 equiv.) and Pd(dppf)Cl.DCM (27.6 g, 33.7 mmol, 0.05 equiv.) in HO (500 mL) were added at 25 °C under N, and the mixture was then stirred at 90 °C for 16 h under N. Water (2.00 L) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2.00 L × 3). The combined organic phase was washed with brine (3.00 L), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel to give the title compound (400 g, 1.02 mol, 75.9% yield) as a white solid. Step 2: 3-(6-fluoropyridin-3-yl)piperidine-2,6-dione [ka]

[0412] A mixture of 2,6-bis(benzyloxy)-6'-fluoro-3,3'-bipyridine (150 g, 388 mmol, 1.00 equiv.), Pd / C (30.0 g, 10% purity), and Pd(OH) (30.0 g, 42.7 mmol) in THF (500 mL) was degassed and purged with N three times, then the mixture was stirred under H (50 psi) at 25 °C for 16 h. The mixture was filtered through Celite, and the filtrate was concentrated in vacuo. The residue was triturated with MTBE (300 mL) at 25 °C for 1 h to give the title compound (105 g, 498 mmol, 64.2% yield) as a white solid. LCMS: C 10 H9FN2O2, desired mass = 208.1, observed: m / z = 209.1 [M+H] + . Intermediate 74 1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carboxylic acid [ka] Step 1: 2,6-Bis(benzyloxy)-3-(4-bromophenyl)pyridine [ka]

[0413] To a 20 mL microwave reaction vial was added 4-bromoiodobenzene (800.00 mg, 2.83 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (944.05 mg, 2.26 mmol), 1 M aqueous potassium carbonate (8.48 mL, 8.48 mmol), Pd(dppf)Cl (0.23 g, 0.28 mmol), and dioxane (8.00 mL). The reaction mixture was purged with nitrogen for 5 minutes and then stirred at 115 °C in a microwave reactor for 25 minutes. The reaction mixture was filtered through a thin layer of Celite. The filtrate was diluted with water and EtOAc. The organic layer was dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel chromatography eluting with 0-100% EtOAc / hexanes to give 400 mg (47% yield) of the title compound as a white solid. LCMS: [C 25 H 20 BrNO2], desired mass = 445.1, observed: m / z = 446.3 [M+H] + . Step 2: tert-Butyl 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidine-4-carboxylate [ka]

[0414] To a solution of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (400.00 mg, 0.90 mmol) and tert-butyl piperidine-4-carboxylate (182.63 mg, 0.99 mmol) in 1,4-dioxane (5 mL), cesium carbonate (875.97 mg, 2.69 mmol) and 1,3-bis[2,6-bis(pentan-3-yl)phenyl]-2H-imidazole; 3-chloropyridine; and palladium chloride (35.56 mg, 0.04 mmol) were added at room temperature. The reaction mixture was purged with nitrogen and stirred at 100° C. overnight. The reaction mixture was then quenched with water (20 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc / heptane to give the title compound as a white solid (375 mg, 77%). LCMS: [C 35 H 38 N2O4], desired mass = 550.3, observed: m / z = 551.4 [M+H] + . Step 3: tert-Butyl 1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carboxylate [ka]

[0415] To a solution of tert-butyl 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidine-4-carboxylate (375 mg, 0.68 mmol) in a mixture of THF (3 mL) and isopropanol (3 mL) was added Pd / C (74 mg, 0.06 mmol). The reaction mixture was stirred under H gas at room temperature for 36 hours, then the mixture was diluted with ethyl acetate (30 mL) and filtered through Celite. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc / heptane to give the title compound as a white solid (248 mg, 98%). LCMS: (C 21 H 28Desired mass of N2O4) = 372.2, Found: m / z = 373.4 [M+H] + . Step 4: 1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carboxylic acid [ka]

[0416] A mixture of tert-butyl 1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carboxylate (780 mg, 2.02 mmol) in HFIP (20 mL) was treated with TFA (1.55 mL, 20 mmol) and stirred at room temperature overnight. The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography (CHCN and HO as mobile phase) to give the title compound as a white solid (760 mg, 84%). LCMS: (C 17 H 20 Desired mass of N2O4) = 316.1; Found: m / z = 317.4 [M+H] + . Intermediate 75 1-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)piperidine-4-carboxylic acid [ka] Step 1: tert-Butyl 1-(5-nitropyridin-2-yl)piperidine-4-carboxylate [ka]

[0417] A mixture of 2-fluoro-5-nitropyridine (1000.00 mg, 7.04 mmol), tert-butyl piperidine-4-carboxylate (1434.27 mg, 7.74 mmol), and N,N-diisopropylethylamine (2.46 mL, 14.08 mmol) in DMSO was stirred at 100° C. overnight. The reaction mixture was cooled to room temperature and diluted with water and EtOAc. The organic layer was separated, dried over sodium sulfate, and then concentrated in vacuo. The resulting residue was purified by silica gel chromatography eluting with 0-100% EtOAc / hexane to afford the title compound as a white solid (1700 mg, 78% yield). LCMS: [C 15 H 21 N3O4], desired mass = 307.2, observed: m / z = 308.3 [M+H] + . Step 2: tert-Butyl 1-(5-aminopyridin-2-yl)piperidine-4-carboxylate [ka]

[0418] A mixture of tert-butyl 1-(4-nitrophenyl)piperidine-4-carboxylate (1000.00 mg, 3.25 mmol), iron powder (908 mg, 16 mmol), and 1M aqueous ammonium chloride (16 mL, 16 mmol) in EtOH (5 mL) was heated at 50° C. for 30 minutes. The reaction mixture was cooled to room temperature and diluted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by flash chromatography using 0-60% ethyl acetate / hexane as the mobile phase to give the title compound (650 mg, 72%) as a white solid. LCMS: [C 15 H 23 N3O2], desired mass = 277.2, observed: m / z = 278.5 [M+H] + . Step 3: 3-({6-[4-(tert-butoxycarbonyl)piperidin-1-yl]pyridin-3-yl}amino)propanoic acid [ka]

[0419] To a solution of tert-butyl 1-(5-aminopyridin-2-yl)piperidine-4-carboxylate (420.00 mg, 1.51 mmol) in toluene (1.51 mL) was added acrylic acid (0.05 mL, 0.75 mmol). The reaction mixture was heated to 100° C. for 3 hours, and then a second portion of acrylic acid (0.05 mL, 0.75 mmol) was added. Heating at 100° C. was continued for 16 hours, at which point LCMS analysis indicated a mixture of mono- and bis-substituted products. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was purified by C18 reverse-phase chromatography (eluting with CHCN and water) to afford the title compound (290 mg, 55%) as a brown oil. LCMS: [C 18 H 27 Desired mass of N3O4 = 349.2, Found: m / z = 350.4 [M+H] + . Step 4: tert-Butyl 1-[5-(2,4-dioxo-1,3-diazinan-1-yl)pyridin-2-yl]piperidine-4-carboxylate [ka]

[0420] To a solution of 3-({6-[4-(tert-butoxycarbonyl)piperidin-1-yl]pyridin-3-yl}amino)propanoic acid (100.00 mg, 0.29 mmol) in toluene (1.51 mL) and acetic acid (0.16 mL, 2.86 mmol) was added urea (86 mg, 1.43 mmol). The resulting suspension was heated to reflux for 3 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was purified by C18 reverse phase chromatography (eluting with CHCN and water) to give the title compound as a brown oil (50 mg, 47%). LCMS: [C 19 H 26 Desired mass of N4O4 = 374.2, Found: m / z = 375.4 [M+H] + . Step 5: 1-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)piperidine-4-carboxylic acid [ka]

[0421] A mixture of tert-butyl 1-[5-(2,4-dioxo-1,3-diazinan-1-yl)pyridin-2-yl]piperidine-4-carboxylate (50 mg, 0.133 mmol) in HFIP (2 mL) was treated with TFA (0.1 mL, 1.33 mmol) and stirred at room temperature overnight. The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography (eluted with CHCN and HO) to give the title compound as a white solid (40 mg, 94%). LCMS: [C 15 H 18 Desired mass of [NO4] = 318.1; Found: m / z = 319.4 [M+H] + . Intermediate 76 1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidine-4-carboxylic acid [ka] Step 1: 2,6-Bis(benzyloxy)-3-(4-chloro-3-fluorophenyl)pyridine [ka]

[0422] 1-Chloro-2-fluoro-4-iodobenzene (0.29 mL, 0.50 g, 2.3873 mmol), 2,6-bis(benzyloxy)pyridin-3-ylboronic acid (1.00 g, 2.3873 mmol), cesium carbonate 1N aqueous solution (4.77 mL, 4.7746 mmol), Pd(dppf)Cl-DCM (0.39 g, 0.4775 mmol), and dioxane (10.00 mL) were combined in a sealed vial and stirred at 70° C. for 3 hours. The reaction mixture was concentrated onto silica and purified by flash column chromatography to give the title compound (0.912 g, 86% yield). Step 2: tert-Butyl 1-{4-[2,6-bis(benzyloxy)pyridin-3-yl]-2-fluorophenyl}piperidine-4-carboxylate [ka]

[0423] 2,6-Bis(benzyloxy)-3-(4-chloro-3-fluorophenyl)pyridine (0.58 mL, 1.00 g, 4.7746 mmol), tert-butyl piperidine-4-carboxylate (0.88 g, 4.7746 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.44 g, 0.4775 mmol), xantphos (0.28 g, 0.4775 mmol), potassium tert-butoxide (1.07 g, 9.5493 ​​mmol), and toluene (5.00 mL) were combined in a sealed vial and stirred at 70° C. for 4 hours. The reaction mixture was purified by flash column chromatography to provide the title compound (0.234 g, 8% yield). Step 3: tert-Butyl 1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidine-4-carboxylate [ka]

[0424] tert-Butyl 1-{4-[2,6-bis(benzyloxy)pyridin-3-yl]-2-fluorophenyl}piperidine-4-carboxylate (0.25 g, 1.768 mmol) was dissolved in isopropanol (5.00 mL) and THF (5.00 mL). 10% palladium on carbon (0.19 g, 0.1768 mmol) was added, and the reaction mixture was stirred under a hydrogen balloon for 12 hours. The reaction mixture was filtered through Celite and concentrated to give the title compound (0.170 g, 98% yield). Step 4: 1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidine-4-carboxylic acid [ka]

[0425] tert-Butyl 1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidine-4-carboxylate (0.170 g, 0.435 mmol) was dissolved in DCM (2.0 mL). 4 M HCl in dioxane (2.0 mL) was added and the reaction mixture was stirred at room temperature for 4 hours. The crude reaction mixture was evaporated onto silica gel and purified by reverse-phase flash column chromatography eluting with acetonitrile / water to give the title compound (0.134 g, 93% yield). LCMS: C 17 H 19 FN2O4, desired mass = 334.3, observed: m / z = 335.4 [M+H] + . Intermediate 77 1-(1-(5-(2,6-dioxopiperidin-3-yl)-3-methylpyridin-2-yl)piperidine-4-carbonyl)-4-methylpiperidine-4-carboxylic acid [ka] Step 1: tert-Butyl 1-(5-bromo-3-methylpyridin-2-yl)piperidine-4-carboxylate [ka]

[0426] To a solution of tert-butyl piperidine-4-carboxylate hydrochloride (4.00 g, 18.04 mmol) in anhydrous DMSO (36.0 mL) were added 5-bromo-2-fluoro-3-methylpyridine (6.856 g, 36.08 mmol) and CsCO (23.511 g, 72.16 mmol) at 25 °C. The reaction mixture was stirred at 130 °C for 24 h, then poured into 400 mL of brine and extracted with EtOAc (4 × 400 mL). The combined organic extracts were dried over NaSO and evaporated under reduced pressure. The residue was purified by silica gel chromatography using a mobile phase of hexane and EtOAc to give the title compound (5.082 g, 79% yield) as a yellow solid. LCMS: C 16 H 23 BrN2O2, desired mass = 355.3, found: m / z = 357.0 [M+H + ]. Step 2: tert-Butyl 1-[2',6'-bis(benzyloxy)-5-methyl-[3,3'-bipyridin]-6-yl]piperidine-4-carboxylate [ka]

[0427] To ...

Claims

1. A compound having a structure represented by formula (I) 【Chemical 885】 or a pharmaceutically acceptable salt thereof [In the formula, R １ teeth, i) halogen, C １～３ Alkyl, —C(O)N(R １１ ) ２ , -CN, -OH, and C １～３ phenyl optionally substituted with 1 to 3 groups independently selected from alkoxy; ii) a 4- to 6-membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein said 4- to 6-membered monocyclic heterocyclyl is selected from -CN, -OH, halogen, oxo, C １～３ Alkyl, and C １～３ optionally substituted with 1 to 3 groups independently selected from alkoxy; iii) —CN, —OH, halogen, C １～３ Alkyl, and C １～３ C optionally substituted with 1 to 3 groups independently selected from alkoxy ３～７ Monocyclic or bridged bicyclic cycloalkyl (wherein the C １～３ Alkyl is substituted with —OH, halogen, and C １～３ optionally substituted with 1 to 3 groups independently selected from alkoxy; iv) 5-6 membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, wherein said 5-6 membered monocyclic heteroaryl is selected from -CN, -OH, halogen, C １～３ Alkyl, and C １～３ optionally substituted with 1 to 3 groups independently selected from alkoxy; v) halogen, C １～３ Alkyl, —C(O)N(R １１ ) ２ , -CN, -OH, and C １～３ C optionally substituted with 1 to 3 groups independently selected from alkoxy １～６ Alkyl and R ２ and R ３ are each H, or R ２ and R ３ together form =O, R ４ , R ５ , R ６ , and R １０ are each independently H, halogen, or C １～３ Alkyl, or C １～３ is an alkoxy, R ７ is H, or -OH, halogen, C １～３ Alkoxy, and C ３～７ C optionally substituted with 1 to 3 groups independently selected from monocyclic cycloalkyl １～６ is alkyl, R ８ and R ９ are, independently, i) H, ii) —OH, halogen, C １～３ Alkyl, and C １～３ C optionally substituted with 1 to 3 groups independently selected from alkoxy ３～７ monocyclic cycloalkyl, iii) 4-7 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 4-6 membered monocyclic heterocyclyl is selected from -OH, halogen, oxo, C １～３ Alkyl, and C １～３ optionally substituted with 1 to 3 groups independently selected from alkoxy; iv) a) -CN, b) —OH, c) halogens, d) C １～３ Alkoxy, e) —OH, halogen, C １～３ Alkyl, and C １～３ C optionally substituted with 1 to 3 groups independently selected from alkoxy ３～７ monocyclic cycloalkyl, and f) a 5- to 6-membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein said 5- to 6-membered monocyclic heterocyclyl is selected from -OH, halogen, oxo, C １～３ Alkyl, and C １～３ and optionally substituted with 1 to 3 groups independently selected from alkoxy. C optionally substituted with 1 to 6 groups independently selected from １～６ Alkyl or R ８ and R ９ together with the nitrogen to which they are attached form a 4-10 membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S, wherein said 4-10 membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic heterocyclyl is selected from 1-5 R １２ , where necessary, Each R １１ are, independently, i) H, ii) —CN, —OH, halogen, C １～３ Alkoxy, and C ３～７ C optionally substituted with 1 to 6 groups independently selected from monocyclic cycloalkyl １～６ Alkyl, iii) —CN, —OH, halogen, C １～６ Alkyl, and C １～６ C optionally substituted with 1 to 6 groups independently selected from alkoxy ３～７ Monocyclic cycloalkyl (wherein the C １～６ Alkyl includes -CN, -OH, halogen, and C １～３ optionally substituted with 1 to 3 groups independently selected from alkoxy; iv) 4-6 membered monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S, wherein said 4-6 membered monocyclic heterocyclyl is selected from -CN, -OH, halogen, oxo, C １～３ Alkyl, and C １～３ and optionally substituted with 1 to 6 groups independently selected from alkoxy. and Each R １２ are, independently, i) -CN, ii) halogens, iii) —OH, iv) —OH, halogen, C １～３ Alkoxy, and C ３～７ C optionally substituted with 1 to 3 groups independently selected from monocyclic cycloalkyl １～６ Alkoxy, v) —OH, halogen, C １～３ Alkoxy, and C ３～７ C optionally substituted with 1 to 3 groups independently selected from monocyclic cycloalkyl １～６ Alkyl, vi) —COOH, or vii) -C(O)N(R １３ ) ２ (where, each R １３ are independently H or C １～６ alkyl) and X is -N(R １１ )- or -O-, where R １１ is R １ and together with the nitrogen atom to which they are attached, 1 to 3 R ｂ can form an optionally substituted 4- to 12-membered heterocyclyl with L is -L １ -L ２ -L ３ -L ４ -L ５ -L ６ - and each L １ , L ２ , L ３ , L ４ , L ５ and L ６ are, independently, i) 1 to 3 R ｂ C optionally substituted with ３～１２ cycloalkyl, ii) 1 to 3 R ｂ C optionally substituted with ６～１２ aryl, iii) 1 to 3 R ｂ 4- to 12-membered heterocyclyl optionally substituted by iv) 1 to 3 R ｂ 5-12 membered heteroaryl optionally substituted with v) direct binding; vi) 1 to 3 R ｄ C optionally substituted with １～１２ Alkylene chains, vii) 1 to 3 R ｄ C optionally substituted with ２～１２ Alkenylene chains, viii) 1 to 3 R ｄ C optionally substituted with ２～１２ Alkynylene chains, ix) -C(O)-, -C(O)O-, -O-, -N(R ｃ )-, -S-, -C(S)-, -C(S)-O-, -S(O) ２ -, -S(O)=N-, -S(O) ２ NH-, -C(O)-N(R ｃ )-, -C=N-, -O-C(O)-N(R ｃ )-, -O-C(O)-O-, -(CH ２ ) ｍ -C(O)-, or -NH-(CH ２ ) ｍ -C(O)- (where m is 0, 1, 2 or 3) and Each R ａ are independently halo, —CN, 1 to 3 R ｄ C optionally substituted with １～３ alkyl, 1 to 3 R ｄ C optionally substituted with ３～６ cycloalkyl, or —OR ｃ and Each R ｂ are independently hydrogen, oxo, imino, sulfoximino, halo, nitro, —CN, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～１５ Cycloalkyl, C １～８ Haloalkyl, C ６～１２ Aryl, 5- to 12-membered heteroaryl, 4- to 12-membered heterocyclyl, —O—R ｃ , —C(O)—R ｃ , -C(O)O-R ｃ , -C(O)-N(R ｃ ) (R ｃ ), -N(R ｃ ) (R ｃ ), -N(R ｃ ) C(O)-R ｃ , -N(R ｃ ) C(O)O-R ｃ , -N(R ｃ )C(O)N(R ｃ ) (R ｃ ), -N(R ｃ ) S (O) ２ (R ｃ ), -NR ｃ S (O) ２ N (R ｃ ) (R ｃ ), -N(R ｃ ) S (O) ２ O (R ｃ ), -OC(O)R ｃ , -OC(O)-N(R ｃ ) (R ｃ ), -Si(R ｃ ) ３ , -S-R ｃ , -S(O)R ｃ , -S(O)(NH)R ｃ , -S(O) ２ R ｃ or -S(O) ２ N (R ｃ ) (R ｃ ), where C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～１５ Cycloalkyl, C １～８ Haloalkyl, C ６～１２ Each of the aryl, 5- to 12-membered heteroaryl, and 4- to 12-membered heterocyclyl is selected from 1 to 3 R ｄ and optionally substituted with Each R ｃ are independently hydrogen or C １～６ is alkyl, Each R ｄ are independently C optionally substituted with halo, oxo, —CN, —OH, 1 to 3 fluoro １～６ Alkyl, or C ３～８ cycloalkyl, or —O—C optionally substituted with 1 to 3 fluoro １～６ is alkyl, W is -C(R ｇ )- or -N-; Y is a direct bond, C １～４ Alkylene chain, —C(O)—, —C(O)O—, —O—, —N(R ｇ )-, -S- -C(S)-, -C(S)-O-, -O-C(O)O-, -C(O)-N(R ｇ )-, or -O-C(O)-N(R ｇ ) - and The B ring is C ６～１２ aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl, each of which is 1 to 3 R ｊ , where necessary, Each R ｊ are independently hydrogen, oxo, imino, sulfoximino, halo, nitro, —CN, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～１５ Cycloalkyl, C １～８ Haloalkyl, C ６～１２ Aryl, 5- to 12-membered heteroaryl, 4- to 12-membered heterocyclyl, —O—R ｇ , —C(O)—R ｇ , -C(O)O-R ｇ , -C(O)-N(R ｇ ) (R ｇ ), -N(R ｇ ) (R ｇ ), -N(R ｇ ) C(O)-R ｇ , -N(R ｇ ) C(O)O-R ｇ , -N(R ｇ )C(O)N(R ｇ ) (R ｇ ), -N(R ｇ ) S (O) ２ (R ｇ ), -NR ｇ S (O) ２ N (R ｇ ) (R ｇ ), -N(R ｇ ) S (O) ２ O (R ｇ ), -OC(O)R ｇ , -OC(O)-N(R ｇ ) (R ｇ ), -Si(R ｇ ) ３ , -S-R ｇ , -S(O)R ｇ , -S(O)(NH)R ｇ , -S(O) ２ R ｇ or -S(O) ２ N (R ｇ ) (R ｇ ), where C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～１５ Cycloalkyl, C １～８ Haloalkyl, C ６～１２ Each of the aryl, 5- to 12-membered heteroaryl, and 4- to 12-membered heterocyclyl is selected from 1 to 3 R ｋ and optionally substituted with R ｇ is hydrogen or C １～６ is alkyl, Each R ｋ are independently C optionally substituted with halo, oxo, —CN, —OH, 1 to 3 fluoro １～６ Alkyl, or C ３～８ cycloalkyl, or —O—C optionally substituted with 1 to 3 fluoro １～６ alkyl].

2. A compound of formula (I) according to claim 1 【Chemical 886】 or a pharmaceutically acceptable salt thereof [In the formula, R １ teeth, i) halogen, C １～３ Alkyl, —C(O)N(R １１ ) ２ , -CN, -OH, and C １～３ phenyl optionally substituted with 1 to 3 groups independently selected from alkoxy; ii) a 4- to 6-membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein said 4- to 6-membered monocyclic heterocyclyl is selected from -CN, -OH, halogen, oxo, C １～３ Alkyl, and C １～３ optionally substituted with 1 to 3 groups independently selected from alkoxy; iii) —CN, —OH, halogen, C １～３ Alkyl, and C １～３ C optionally substituted with 1 to 3 groups independently selected from alkoxy ３～７ Monocyclic or bridged bicyclic cycloalkyl (wherein the C １～３ Alkyl is substituted with —OH, halogen, and C １～３ optionally substituted with 1 to 3 groups independently selected from alkoxy; iv) 5-6 membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, wherein said 5-6 membered monocyclic heteroaryl is selected from -CN, -OH, halogen, C １～３ Alkyl, and C １～３ and optionally substituted with 1 to 3 groups independently selected from alkoxy. and R ２ and R ３ are each H, or R ２ and R ３ together form =O, R ４ , R ５ , R ６ , and R １０ are each independently H, halogen, or C １～３ Alkyl, or C １～３ is an alkoxy, R ７ is H, or -OH, halogen, C １～３ Alkoxy, and C ３～７ C optionally substituted with 1 to 3 groups independently selected from monocyclic cycloalkyl １～６ is alkyl, R ８ and R ９ are, independently, i) H, ii) —OH, halogen, C １～３ Alkyl, and C １～３ C optionally substituted with 1 to 3 groups independently selected from alkoxy ３～７ monocyclic cycloalkyl, iii) 4-7 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the 4-6 membered monocyclic heterocyclyl is selected from -OH, halogen, oxo, C １～３ Alkyl, and C １～３ optionally substituted with 1 to 3 groups independently selected from alkoxy; iv) a) -CN, b) —OH, c) halogens, d) C １～３ Alkoxy, e) —OH, halogen, C １～３ Alkyl, and C １～３ C optionally substituted with 1 to 3 groups independently selected from alkoxy ３～７ monocyclic cycloalkyl, and f) a 5- to 6-membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein said 5- to 6-membered monocyclic heterocyclyl is selected from -OH, halogen, oxo, C １～３ Alkyl, and C １～３ and optionally substituted with 1 to 3 groups independently selected from alkoxy. C optionally substituted with 1 to 6 groups independently selected from １～６ Alkyl or R ８ and R ９ together with the nitrogen to which they are attached form a 4-10 membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S, wherein said 4-10 membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic heterocyclyl is selected from 1-5 R １２ , where necessary, Each R １１ are, independently, i) H, ii) —CN, —OH, halogen, C １～３ Alkoxy, and C ３～７ C optionally substituted with 1 to 6 groups independently selected from monocyclic cycloalkyl １～６ Alkyl, iii) —CN, —OH, halogen, C １～６ Alkyl, and C １～６ C optionally substituted with 1 to 6 groups independently selected from alkoxy ３～７ Monocyclic cycloalkyl (wherein the C １～６ Alkyl includes -CN, -OH, halogen, and C １～３ optionally substituted with 1 to 3 groups independently selected from alkoxy; iv) 4-6 membered monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S, wherein said 4-6 membered monocyclic heterocyclyl is selected from -CN, -OH, halogen, oxo, C １～３ Alkyl, and C １～３ and optionally substituted with 1 to 6 groups independently selected from alkoxy. and Each R １２ are, independently, i) -CN, ii) halogens, iii) —OH, iv) —OH, halogen, C １～３ Alkoxy, and C ３～７ C optionally substituted with 1 to 3 groups independently selected from monocyclic cycloalkyl １～６ Alkoxy, v) —OH, halogen, C １～３ Alkoxy, and C ３～７ C optionally substituted with 1 to 3 groups independently selected from monocyclic cycloalkyl １～６ Alkyl, vi) —COOH, or vii) -C(O)N(R １３ ) ２ (where, each R １３ are independently H or C １～６ alkyl) and X is -N(R １１ )- or -O-; L is -L １ -L ２ -L ３ -L ４ -L ５ - and each L １ , L ２ , L ３ , L ４ and L ５ are, independently, i) 1 to 3 R ｂ C optionally substituted with ３～１２ cycloalkyl, ii) 1 to 3 R ｂ C optionally substituted with ６～１２ aryl, iii) 1 to 3 R ｂ 4- to 12-membered heterocyclyl optionally substituted by iv) 1 to 3 R ｂ 5-12 membered heteroaryl optionally substituted with v) direct binding; vi) 1 to 3 R ｄ C optionally substituted with １～１２ Alkylene chains, vii) 1 to 3 R ｄ C optionally substituted with ２～１２ Alkenylene chains, viii) 1 to 3 R ｄ C optionally substituted with ２～１２ an alkynylene chain, or ix) -C(O)-, -C(O)O-, -O-, -N(R ｃ )-, -S-, -C(S)-, -C(S)-O-, -S(O) ２ -, -S(O)=N-, -S(O) ２ NH-, -C(O)-N(R ｃ )-, -C=N-, -O-C(O)-N(R ｃ )-, -O-C(O)-O-, -(CH ２ ) ｍ -C(O)-, or -NH-(CH ２ ) ｍ -C(O)- (where m is 0, 1, 2 or 3) and Each R ａ are independently halo, —CN, 1 to 3 R ｄ C optionally substituted with １～３ alkyl, 1 to 3 R ｄ C optionally substituted with ３～６ cycloalkyl, or —OR ｃ and Each R ｂ are independently oxo, imino, sulfoximino, halo, nitro, —CN, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～１５ Cycloalkyl, C １～８ Haloalkyl, C ６～１２ Aryl, 5- to 12-membered heteroaryl, 4- to 12-membered heterocyclyl, —O—R ｃ , —C(O)—R ｃ , -C(O)O-R ｃ , -C(O)-N(R ｃ ) (R ｃ ), -N(R ｃ ) (R ｃ ), -N(R ｃ ) C(O)-R ｃ , -N(R ｃ ) C(O)O-R ｃ , -N(R ｃ )C(O)N(R ｃ ) (R ｃ ), -N(R ｃ ) S (O) ２ (R ｃ ), -NR ｃ S (O) ２ N (R ｃ ) (R ｃ ), -N(R ｃ ) S (O) ２ O (R ｃ ), -OC(O)R ｃ , -OC(O)-N(R ｃ ) (R ｃ ), -Si(R ｃ ) ３ , -S-R ｃ , -S(O)R ｃ , -S(O)(NH)R ｃ , -S(O) ２ R ｃ or -S(O) ２ N (R ｃ ) (R ｃ ), where C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～１５ Cycloalkyl, C １～８ Haloalkyl, C ６～１２ Each of the aryl, 5- to 12-membered heteroaryl, and 4- to 12-membered heterocyclyl is selected from 1 to 3 R ｄ and optionally substituted with Each R ｃ are independently hydrogen or C １～６ is alkyl, Each R ｄ are independently C optionally substituted with halo, oxo, —CN, —OH, 1 to 3 fluoro １～６ Alkyl, or C ３～８ cycloalkyl, or —O—C optionally substituted with 1 to 3 fluoro １～６ is alkyl, W is -C(R ｇ )- or -N-; Y is a direct bond, C １～４ Alkylene chain, —C(O)—, —C(O)O—, —O—, —N(R ｇ )-, -S- -C(S)-, -C(S)-O-, -O-C(O)O-, -C(O)-N(R ｇ )-, or -O-C(O)-N(R ｇ ) - and The B ring is C ６～１２ aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl, each of which is 1 to 3 R ｊ , where necessary, Each R ｊ are independently oxo, imino, sulfoximino, halo, nitro, —CN, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～１５ Cycloalkyl, C １～８ Haloalkyl, C ６～１２ Aryl, 5- to 12-membered heteroaryl, 4- to 12-membered heterocyclyl, —O—R ｇ , —C(O)—R ｇ , -C(O)O-R ｇ , -C(O)-N(R ｇ ) (R ｇ ), -N(R ｇ ) (R ｇ ), -N(R ｇ ) C(O)-R ｇ , -N(R ｇ ) C(O)O-R ｇ , -N(R ｇ )C(O)N(R ｇ ) (R ｇ ), -N(R ｇ ) S (O) ２ (R ｇ ), -NR ｇ S (O) ２ N (R ｇ ) (R ｇ ), -N(R ｇ ) S (O) ２ O (R ｇ ), -OC(O)R ｇ , -OC(O)-N(R ｇ ) (R ｇ ), -Si(R ｇ ) ３ , -S-R ｇ , -S(O)R ｇ , -S(O)(NH)R ｇ , -S(O) ２ R ｇ or -S(O) ２ N (R ｇ ) (R ｇ ), where C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～１５ Cycloalkyl, C １～８ Haloalkyl, C ６～１２ Each of the aryl, 5- to 12-membered heteroaryl, and 4- to 12-membered heterocyclyl is selected from 1 to 3 R ｋ and optionally substituted with R ｇ is hydrogen or C １～６ is alkyl, Each R ｋ are independently C optionally substituted with halo, oxo, —CN, —OH, 1 to 3 fluoro １～６ Alkyl, or C ３～８ cycloalkyl, or —O—C optionally substituted with 1 to 3 fluoro １～６ alkyl].

3. R １ but, 【Chemical 887】 3. The compound of claim 1 or claim 2, which is not:

4. R １ but, 【Chemical 888】 If 【Chemical 889】 teeth, 【Chemical 890】 3. The compound of claim 1 or claim 2, which is not:

5. R ２ and R ３ taken together to form =0, and said compound has the structure of formula (Ia) 【Chemistry 891】 The compound according to any one of claims 1 to 4, having the formula:

6. R ８ and R ９ together with the nitrogen to which they are attached to form piperidinyl, and said compound has the structure of formula (Ib) 【Chemical 892】 6. The compound of claim 5 having the formula:

7. R ８ and R ９ However, each １～３ The compound of claim 5, wherein the compound is alkyl.

8. The compound of claim 5, wherein X is -NH-.

9. The compound of claim 5, wherein X is —O—.

10. R １ is phenyl optionally substituted with halo, pyridinyl optionally substituted with halo, C ３～６ The compound of claim 5, which is cycloalkyl or 4- to 6-membered heterocyclyl.

11. R １ The compound of claim 10, wherein is 2-fluorophenyl, 3-fluoropyrin-4-yl, cyclopropyl, or oxan-4-yl.

12. R １ But C １～６ Alkyl, 【Chemical 893】 or C optionally substituted with halo or CN ３～６ The compound of any one of claims 1 to 9, which is cycloalkyl.

13. R １ isopropyl, or 【Chemical 894】 13. The compound of claim 12, wherein:

14. X is -N(R １１ )- and R １１ and R １ can be taken together with the nitrogen atom to which they are attached to form a 4- to 12-membered heterocyclyl optionally substituted with halo or CN.

15. -X-R １ but, 【Chemical 895】 15. The compound of claim 14, wherein:

16. R ２ and R ３ forms an oxo group, and R ８ and R ９ together with the nitrogen to which they are attached to form one of the following heterocycles: 【Chemical 896】 where R ｊ The compound of any one of claims 1 to 4, wherein is H or halo.

17. R １ is phenyl optionally substituted with halo, pyridinyl optionally substituted with halo, C ３～６ cycloalkyl, or 4- to 6-membered heterocyclyl, and R ４ , R ５ , R ６ and R ７ are independently H or C １～３ 17. The compound of claim 16, wherein the compound is alkyl.

18. R １ is cyclopropyl, and R ４ , R ５ , and R ６ is hydrogen, and R ７ 18. The compound of claim 17, wherein is cyclopropyl.

19. L is -L 1 -L 2 -L 3 -L 4 -L 5 -, and each L １ , L ２ , L ３ , L ４ and L ５ But independently, i) 【Chemical 897】 ii) 【Chemical 898】 iii) 【Chemical 899】 iv) 【Chemical 900】 v) direct binding; vi) C １～３ an alkylene chain, or vii) -C(O)-, -O-, -C(O)-N(R ｃ ) -, -(CH ２ ) ｍ -C(O)- or -NH-(CH ２ ) ｍ -C(O)- (where m is 0, 1, 2 or 3) and R ｂ is C １～３ alkyl, and R ｃ is H or C １～３ is alkyl, The compound according to any one of claims 2 to 4.

20. L is L １ is attached to the B ring by L １ is a direct bond, —C(O)—, —N(R ｃ ) - (where R ｃ is H or methyl), —O—, —CH ２ -, or -NH-CH ２ The compound of claim 19, which is -C(O)-.

21. -L ２ -L ３ -L ４ -L ５ - but the following structure 【Chemical 901】 【Chemical 902】 21. The compound of claim 20, having one of:

22. -L ２ -L ３ -L ４ -L ５ - but the following structure 【Chemical 903】 【Chemical 904】 【Chemical 905】 21. The compound of claim 20, having one of:

23. L is the following structure: 【Chemical 906】 【Chemical 907】 【Chemical 908】 20. The compound of claim 19, having one of:

24. L is -L １ -L ２ -L ３ -L ４ -L ５ - and each L １ , L ２ , L ３ , L ４ and L ５ But independently, i) 【Chem.909】 ii) 【Chemical 910】 iii) 【Chemical 911】 iv) 【Chemical 912】 v) 【Chemical Formula 913】 vi) direct binding; vii) 1 to 3 R ｄ C optionally substituted with １～３ Alkylene chain, viii) 1 to 3 R ｄ C optionally substituted with ２～１２ an alkynylene chain, or ix) -S(O) ２ -, -N(R ｃ )-, -C(O)-, -O-, -C(O)-N(R ｃ ) -, -(CH ２ ) ｍ -C(O)- or -NH-(CH ２ ) ｍ -C(O)- (where m is 0, 1, 2 or 3) and Here, each R ｊ are independently H, halo, hydroxy, C １～３ Alkoxy, CN, C １～６ alkyl, or haloalkyl; R ｄ But halo or C １～３ is alkyl, R ｃ is H or C １～３ is alkyl, The compound according to any one of claims 1 to 4.

25. Each L １ , L ２ , L ３ , L ４ and L ５ are the same or different and independently, i) 【Chemical 914】 【Chemical 915】 ii) direct binding; iii)-(CH ２ )-、-CH(CH ３ )-、-C(CH ３ ) ２ -、 iv) -C≡C-, or v) -S(O) ２ -, -N(CH ３ )-, -C(O)-, -O-, -C(O)-N(CH ３ ) -, -(CH ２ )-C(O)-, or -NH-(CH ２ ) ｍ -C(O)- (where m is 0, 1, 2 or 3) 25. The compound of claim 24, wherein:

26. L is the following structure: 【Chemical Formula 916】 【Chemical Formula 917】 【Chemical Formula 918】 【Chemical Formula 919】 25. The compound of claim 24, having one of:

27. L is -L １ -L ２ -L ３ -L ４ -L ５ -L ６ - and has the following structure 【Chemical 920】 The compound according to any one of claims 1 to 4, having the formula:

28. W is —CH—; Y is a direct bond; The B ring is 【Chemical 921】 where R ｊ is H or C １～３ is alkyl, The compound according to any one of claims 1 to 4.

29. W is —N—; Y is a direct bond; The B ring is 【Chemical Formula 922】 where R ｊ is H or C １～３ is alkyl, The compound according to any one of claims 1 to 4.

30. W is —CH—; Y is —NHC(O)—, The B ring is 【Chemical 923】 where R ｊ is H or C １～３ is alkyl, The compound according to any one of claims 1 to 4.

31. W is —CH—, Y is a direct bond, and ring B is 【Chemical 924】 where R ｊ is H, C １～３ alkyl or halo; The compound according to claims 1 to 4.

32. The B ring is 【Chemical 925】 32. The compound of claim 31 , wherein:

33. 2. The compound of claim 1, selected from the group consisting of compounds of Examples 1 to 303.

34. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

35. 35. The pharmaceutical composition of claim 34, further comprising one or more additional therapeutic agents, or pharmaceutically acceptable salts thereof.

36. 10. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, for use in therapy.

37. 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating a disease or disorder associated with increased hematopoietic progenitor kinase 1 (HPK1) activity in a subject in need thereof.

38. 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, for use in a method of increasing T cell activation in a subject in need thereof.

39. 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer in a subject in need thereof.

40. 40. The compound of claim 39, wherein the cancer is selected from the group consisting of bladder cancer, breast cancer, colorectal cancer, gastric cancer, head and neck squamous cell carcinoma, Hodgkin's lymphoma, Merkel cell carcinoma, mesothelioma, melanoma, non-small cell lung cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, small cell lung cancer, transitional cell carcinoma, and urothelial cancer.

41. 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, for use in a method of inhibiting the growth or proliferation of cancer cells in a subject in need thereof.

42. 42. The compound of any one of claims 36 to 41, wherein the use further comprises administering a therapeutically effective amount of one or more additional therapeutic agents, or pharmaceutically acceptable salts thereof.

43. the one or more additional therapeutic agents are selected from the group consisting of an inducible T-cell costimulatory molecule (ICOS) agonist, a cytotoxic T-lymphocyte antigen 4 (CTLA-4) blocking antibody, a PD1 and / or PD-L1 inhibitor, a cluster of differentiation 47 (CD47) inhibitor, an OX40 agonist, a GITR agonist, a CD27 agonist, a CD28 agonist, a CD40 agonist, a CD137 agonist, a Toll-like receptor 8 (TLR8) agonist, a T-cell immunoglobulin and mucin domain-3 (TIM-3) inhibitor, a lymphocyte activation gene 3 (LAG-3) inhibitor, a CEACAM1 inhibitor, an Ig and ITIM inhibitor, a vasoconstrictor ...

43. The compound of claim 42, wherein the compound is selected from the group consisting of a T-cell immunoreceptor having a V-domain (TIGIT) inhibitor, a V-domain immunoglobulin (Ig)-containing suppressor of T-cell activation (VISTA) inhibitor, an anti-killer IgG-like receptor (KIR) inhibitor, a STING agonist, a C-X-C chemokine receptor type 4 (CXCR-4) inhibitor, a B7-H3 inhibitor, a CD73 inhibitor, an inhibitory RNA, an IL2 / 15 / 17 fusion protein, an MKNK1 / 2 inhibitor, a JAK inhibitor, and a PI3K inhibitor, or a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.

44. the one or more additional therapeutic agents are selected from the group consisting of rituximab, doxorubicin, gemcitabine, nivolumab, pembrolizumab, pidilizumab, PDR001, TSR-001, atezolizumab, durvalumab, avelumab, pidilizumab, TSR-042, BMS-986016, ruxolitinib, N-(cyanomethyl)-4-[2-(4-morpholinoanilino)pyrimidin-4-yl]benzamide, XL147, BKM120, GDC-0941, BAY8 0-6946, PX-866, CH5132799, XL756, BEZ235, and GDC-0980, wortmannin, LY294002, TGR-1202, AMG-319, GSK2269557, X-339, X-414, RP5090, KAR4141, XL499, OXY111A, IPI-145, IPI-443, GSK2636771, BAY10824391, buparlisib, BYL719, RG7604, MLN1117, WX-0 37, AEZS-129, PA799, ZSTK474, AS252424, TGX221, TG100115, IC87114, IPI-549, INCB050465, (S)-2-(1-((9H-purin-6-yl)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, (S)-2-(1-((9H-purin-6-yl)amino)ethyl)-6-fluoro-3-phenylquinazolin-4(3H)-one, (S)-2-(1- 44. The compound of claim 43, selected from the group consisting of ((9H-purin-6-yl)amino)ethyl)-3-(2,6-difluorophenyl)quinazolin-4(3H)-one, (S)-4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile, and ipilimumab, or a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.

45. 44. The compound of claim 43, wherein the one or more additional therapeutic agents are selected from the group consisting of idelalisib, tirabrutinib, momelotinib, and entospletinib, or a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.

46. 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or preventing hepatitis B virus (HBV) infection in a subject in need thereof.

47. 47. The compound of claim 46, wherein the use further comprises administering a therapeutically effective amount of one or more additional therapeutic agents, or pharmaceutically acceptable salts thereof.

48. the one or more additional therapeutic agents are selected from the group consisting of HBV combination drugs, HBV vaccines, HBV DNA polymerase inhibitors, immunomodulatory agents, Toll-like receptor (TLR) modulators, interferon alpha receptor ligands, hyaluronidase inhibitors, hepatitis b surface antigen (HBsAg) inhibitors, cytotoxic T lymphocyte-associated protein 4 (ipi4) inhibitors, cyclophilin inhibitors, HBV viral entry inhibitors, antisense oligonucleotides targeting viral mRNA, short interfering RNA (siRNA) and ddRNAi endonuclease modulators, ribonucleotide reductase inhibitors, HBV 48. The compound of claim 47, selected from the group consisting of an E antigen inhibitor, a covalently closed circular DNA (cccDNA) inhibitor, a farnesoid X receptor agonist, an HBV antibody, a CCR2 chemokine antagonist, a thymosin agonist, a cytokine, a nuclear protein modulator, a retinoic acid-inducible gene 1 stimulator, a NOD2 stimulator, a phosphatidylinositol 3-kinase (PI3K) inhibitor, an indoleamine-2,3-dioxygenase (IDO) pathway inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a recombinant thymosin alpha-1 agonist, a Bruton's tyrosine kinase (BTK) inhibitor, a KDM inhibitor, an HBV replication inhibitor, an arginase inhibitor, and other HBV drugs, or a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.

49. The one or more additional therapeutic agents are adefovir (Hepsera®), tenofovir disoproxil fumarate plus emtricitabine (Truvada®), tenofovir disoproxil fumarate (Viread®), entecavir (Baraclude®), lamivudine (Epivir-HBV®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®), Clevudine®, emtricitabine (Emtriva®), pegylated interferon alfa-2b (PEG-Intron®), Multiferon®, interferon alfa 1b (Hapgen®), interferon alfa-2b (Intron®) A (registered trademark)), pegylated interferon alfa-2a (Pegasys (registered trademark)), interferon alfa-n1 (Humoferon (registered trademark)), ribavirin, interferon beta-1a (Avonex (registered trademark)), Bioferon, Ingalon, Inmutag (Inferon), Argelon, Roferon-A, Oligotide, Ztectra, Chaferon, interferon alfa-2b (Axxo), Alphaferon, interferon alfa-2b, Feron, interferon-alpha 2 (CJ), Bevac, Raferonam, Bipe Blauferon-B, Blauferon-A, Intermax Alpha, Realgyron, Lancetion, Pegaferon, PDferon-B, Alpha Interferon 2b, Calferon, PegNano, Feronsure, Pegihep, Optipeg A, Real Alpha 2B, Reliferon, Peginterferon Alpha-2b, Reaferon-EC, Prokiferon, Uniferon, Uriflon, Interferon Alpha-2b, Interferon, Shanferon, MOR-22, Interleukin-2 (IL-2), Recombinant Human Interleukin-2 (ShenzhenNeptunus), Liferon, Ka Shu Ning, Shan Sheng Lei Tai, Intefen, Sinogen, Fucantai, Alloferon and Celmoleukin, or a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.

50. 49. The compound of any one of claims 47-48, wherein the one or more additional therapeutic agents are selected from the group consisting of entecavir, adefovir, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine, and lamivudine, or a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.

51. 49. The compound of any one of claims 47-48, wherein the one or more additional therapeutic agents are selected from the group consisting of tenofovir alafenamide, tenofovir alafenamide fumarate, and tenofovir alafenamide hemifumarate, or a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.

52. 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating or preventing human immunodeficiency virus (HIV) infection in a subject in need thereof.

53. 53. The compound of claim 52, wherein the use further comprises administering a therapeutically effective amount of one or more additional therapeutic agents, or pharmaceutically acceptable salts thereof.

54. the one or more additional therapeutic agents are selected from the group consisting of combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latent infection reactivators, compounds targeting the HIV capsid, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nuclear protein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3-binding nonintegrin 1 inhibitors, HIV 54. The compound of claim 53, selected from the group consisting of a GAG protein inhibitor, an HIV POL protein inhibitor, a complement factor H modulator, a ubiquitin ligase inhibitor, a deoxycytidine kinase inhibitor, a cyclin-dependent kinase inhibitor, a proprotein convertase PC9 stimulator, an ATP-dependent RNA helicase DDX3X inhibitor, a reverse transcriptase priming complex inhibitor, a G6PD and NADH-oxidase inhibitor, a pharmacokinetic enhancer, an HIV gene therapy, and an HIV vaccine, or a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.

55. 55. The compound of any one of claims 53-54, wherein the one or more additional therapeutic agents are selected from the group consisting of HIV protease inhibitor compounds, HIV non-nucleoside reverse transcriptase inhibitors, HIV non-nucleotide reverse transcriptase inhibitors, HIV nucleoside reverse transcriptase inhibitors, HIV nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, and other drugs for treating HIV, or a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.

56. 55. The compound of any one of claims 53-54, wherein the one or more additional therapeutic agents are selected from the group consisting of 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, or a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.

57. 55. The compound of any one of claims 53-54, wherein the one or more additional therapeutic agents are selected from the group consisting of 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir, tenofovir alafenamide, tenofovir alafenamide fumarate, or tenofovir alafenamide hemifumarate, or a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.

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