Bifunctional degradation products of hematopoietic precursor kinases and their therapeutic use

Abstract

The present disclosure provides bifunctional compounds as HPK1 degraders via the ubiquitin proteosome pathway and methods for treating diseases modulated by HPK1. The present invention provides novel bifunctional compounds for proteolytically degrading hematopoietic progenitor kinase (HPK1) and methods for treating diseases modulated by HPK1. HPK1 can be targeted for degradation, thereby providing therapeutic opportunities in enhancing anti-tumor immunity and increasing responses to checkpoint receptor blockade.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 63 / 021,045, filed 6 May 2020, which is incorporated herein by reference in its entirety.

[0002] background Technical field This invention provides a novel bifunctional compound for proteolytic degradation of hematopoietic precursor kinase (HPK1), and a method for treating diseases modulated by HPK1. [Background technology]

[0003] Explanation of related technologies Cancer immunology utilizes antibodies that are inhibitors of immune checkpoint receptors CTLA4, PD-1, and PD-L1. Targeted disruption of these checkpoint pathways releases immune cells from critical regulatory pathways, enabling a boost in the immune response against cancer cells. While current therapies utilizing these antibodies have shed light on significant and persistent responses to many different cancers, they have also highlighted low overall response rates (<25%). Improvements in these response rates have been achieved through combinations of checkpoint blockade with other immunoactivators or cell-based therapies.

[0004] STE20 serine / threonine kinase 1, a hematopoietic precursor kinase belonging to 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 association between SLP76 and the 14-3-3 protein and leading to the 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, mouse HPK1-deficient T cells or HPK1 kinase-inactive mutant T cells exhibit enhanced ERK1 / 2 activation and effector cytokine secretion compared to their wild-type counterparts upon TCR activation (Shui et al., Nat Immunol 2007, Hernandez et al., Cell Reports 2018). Therefore, targeting HPK1 degradation can provide therapeutic opportunities in enhancing antitumor immunity and increasing the response to checkpoint receptor blockade. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Hu et al., Gens Dev, 1996, Alzabin et al., J Immunol 2009 [Non-Patent Document 2] Shui et al., Nat Immunol 2007, Hernandez et al., Cell Reports 2018 [Overview of the project] [Means for solving the problem]

[0006] Simple summary In this specification, a bifunctional compound represented by formula (I)

Chemical formula

[0007] In various embodiments, Z is NH and X 1 CH is, R 6 is H, and the compound of formula (I) has the structure of formula (Ia). [ka]

[0008] In a more specific embodiment, the compound of formula (I) has the structure of formula (Ib). [ka]

[0009] Various more specific embodiments, each R 9a , R 9b , R 9c , R 9d , and R 9e These are H, halogen, and C, independently. 1~6 Alkyl, or -C(O)N(R 19 )2, R 19 C 1~6 It is alkyl, R 4 , R 5 and R 10 These are H and R respectively. 7 C 1~6 It is alkyl.

[0010] In various more specific embodiments, R 3 and R 13 These two atoms combine to form O, or X is piperidinyl.

[0011] In a more specific embodiment, the compound of formula (I) has the structure of formula (Ic). [ka] In various more specific embodiments, L is [ka] It is expressed by, in the formula, t is 0, 1, 2, 3, 4, 5, 6, or 7. q is 0, 1, 2, 3, 4, 5, 6, or 7. L 1 These are direct bonds, -C(O)NH-, or -C(O)-. L 2 These are -C(O)NH-, -O-, or -NH-.

[0012] In a more specific embodiment, t is 0 and q is 3, 4, 5, 6, or 7.

[0013] In other, more specific embodiments, q is 0 and t is 1, 3, 5, or 7. In various other more specific embodiments, L is [ka] It is expressed by, in the formula, w is 1, 2, or 3. v is either 1 or 2. p is 1, 2, 3, 4, or 5. Y 1 This is a direct bond, -(CH2) p -, or -O- Y 2 This is a direct bond, -(CH2) p -, -C(O)-, or -C(O)-CH2-, X 3 and X 4 Independently, is N or C(R), and R is either H or C 1~3 It is alkyl, L 4 is either a direct bond, -NH-, -NHC(O)-, or L 4 teeth, [ka] That is the case.

[0014] In other embodiments, L includes a robust ring system, such as an aryl ring (e.g., phenyl), a heteroaryl ring, a bridged ring, a spiro ring, or a mixture thereof.

[0015] In various more specific embodiments, the LHM targets CRBN and has the structure of formula (Id). [ka] [In the formula, W is -C(R g )- or -N-, Z1 is -C(O)--, -C(S)-, -C(NR g )-,-C(R g )2-, -C(R g )2-C(O)-,-C(O)-N(R g )-,-CR g =CR g -, -C(R g )=N-, -C(R g )2-C(S)-, or -C(R g )2-C(R g )2-, q is 0, 1, or 2. R g is hydrogen or C 1~6 It is alkyl, R a C 1~6 alkyl, halo, halo C 1~6 Alkyl, -N(R g )2, CN, nitro, hydroxyl, or -OC 1~4 It is alkyl.

[0016] In other specific embodiments, LHM targets VHL and has the structure of formula (Ie) or (If). [ka] [In the formula, p is either 0 or 1, R j This is 1 to 3 R k It is a 5-6 member heteroaryl that is substituted as needed, Each R k These are independently: halo, oxo, -CN, -OH, C 1~6 Alkyl, C 3~8 Cycloalkyl, or -OC 1~6 It is alkyl, Each R e These are, independently, hydrogen and C 1~6 Alkyl or C 3~8 It is a cycloalkyl, R b is hydrogen or hydroxyl, R c is -C(O)R f And R f C 1~6 Alkyl or C 3~8 [They are cycloalkyl, and each is substituted with a halo or -CN as needed.]

[0017] In other embodiments, the disclosure relates to compounds having the structure of formula (II). [ka] Or provide a pharmaceutically acceptable salt thereof. [In the formula, m is 0, 1, 2, 3, 4, or 5. n is 0, 1, 2, 3, 4, 5, or 6. B is a 4-10 member monocyclic, fused bicyclic, bridging bicyclic, or spirocyclic heterocyclyl ring having 1-3 heteroatoms independently selected from N, O, and S. L is a linker moiety having 2 to 24 continuously covalently bonded atoms of a length selected from the group consisting of C, O, N, and S. LHM is the ligature harness part. R 1 and R 2 One of them is H, -CN, -OH, halogen, or C 1~6It is alkyl, R 1 and R 2 The other is H, halogen, or C 1~6 It is alkyl, and here each C 1~6 The alkyl group is optionally substituted with 1 to 3 groups independently selected from -OH and halogens, or R 1 and R 2 Together with the carbon atoms to which they are bonded, C 3~7 Forming a monocyclic cycloalkyl or a 4-6 member monocyclic heterocycline having one or two heteroatoms independently selected from N, O, and S, where C 3~7 Monocyclic cycloalkyls and 4-6 membered monocyclic heterocyclines each contain one R 11 These are substituted as needed, with -OH, halogen, oxo, and C respectively. 1~3 Alkyl, and C 1~3 It may be substituted as needed with 1 to 3 groups independently selected from the alkoxy, or R 1 and R 2 They come together to form =O, R 11 teeth, i) A 4- to 6-membered monocyclic heterocycline having one or two heteroatoms independently selected from N, O, and S (where a 4- to 6-membered monocyclic heterocycline is -CN, -OH, halogen, oxo, C 1~3 Alkyl, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy), ii)-S(O)2C 1~6 Alkyl, iii)-S(O)2C 3~7 Monocyclic cycloalkyl, iv) -CN, -OH, halogen, C 1~3 Alkoxy, and C 3~7 C is optionally substituted with 1 to 3 groups independently selected from monocyclic cycloalkyl groups. 1~6 Alkyl, or v)-C(O)R 21 And, R 21 teeth, i) H, ii) -CN, -OH, halogen, C 1~3 Alkyl, and C 1~3 C is substituted as needed with 1 to 3 groups independently selected from the alkoxy. 3~7 Monocyclic or cross-linked bicyclic cycloalkyl (where C 1~3 Alkyls are -OH, halogens, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy), iii) A 4- to 6-membered monocyclic heterocycline having one or two heteroatoms independently selected from N, O, and S (where a 4- to 6-membered monocyclic heterocycline is -CN, -OH, halogen, oxo, C 1~3 Alkyl, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy), iv) A 5-6 member monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S (where the 5-6 member monocyclic heteroaryl is -CN, -OH, halogen, C 1~3 Alkyl, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy), v)-NH2, vi)-NH(C 1~6 Alkyl) (Here, C 1~6 Alkyls include -CN, -OH, halogens, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy), vii)-N(C 1~6 Alkyl)2(where each C 1~6 Alkyls may be the same or different, and each C 1~6 Alkyls include -CN, -OH, halogens, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy), viii)-OH, halogen, C 1~3 Alkyl, and C3~7 C is optionally substituted with 1 to 3 groups independently selected from monocyclic cycloalkyl groups. 1~6 Alkoxy, or ix) a)-CN, b)-OH, c) Halogen, d)C 1~3 Alkoxy, e) -CN, -OH, halogen, C 1~3 Alkyl, and C 1~3 C is substituted as needed with 1 to 3 groups independently selected from the alkoxy. 3~7 Monocyclic cycloalkyl, f) A 4- to 6-membered monocyclic heterocycline having one or two heteroatoms independently selected from N, O, and S (where a 4- to 6-membered monocyclic heterocycline is -CN, -OH, halogen, oxo, C 1~3 Alkyl, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy), and g) -OC(O)C which is substituted as needed with one -OH group. 1~6 Alkyl C is replaced as needed with 1 to 3 groups independently selected from 1~6 Alkyl And, R 3 and R 13 These are either H or R 3 and R 13 They come together to form =O, Each R 12 These are independently -OH, halogen, and C 1~3 Alkyl, and C 1~3 Selected from alkoxy, Each R 18 Independently, i)-CN, ii) Halogen, iii) -OH, iv) -OH, halogen, C 1~3 Alkoxy, and C 3~7C is optionally substituted with 1 to 3 groups independently selected from monocyclic cycloalkyl groups. 1~6 Alkoxy, v)-OH, halogen, C 1~3 Alkoxy, and C 3~7 C is optionally substituted with 1 to 3 groups independently selected from monocyclic cycloalkyl groups. 1~6 Alkyl, vi)-COOH, or vii)-C(O)N(R 22 )2(Here, each R 22 H or C 1~6 (It is alkyl.) And, X 1 is N or CR 17 And, R 4 , R 5 , R 6 , R 10 and R 17 These are H, halogen, and C, respectively, independently. 1~3 Alkyl, or C 1~3 It is an alkoxy, R 7 teeth, i) H, ii) -OH, halogen, C 1~3 Alkoxy, and C 3~7 C is optionally substituted with 1 to 3 groups independently selected from monocyclic cycloalkyl groups. 1~6 Alkyl, or iii) -OH, halogen, C 1~3 Alkyl, and C 1~3 C is substituted as needed with 1 to 3 groups independently selected from the alkoxy. 3~7 Monocyclic cycloalkyl And, Z is -O-, -C(R 8 )2-, or -NR 8 -and, Each R 8 H or C 1~3 It is alkyl, R 9a , R 9b , R9c , R 9d , and R 9e Independently, i) H, ii) Halogen, iii) -OH, halogen, C 1~3 Alkyl, and C 3~7 C is optionally substituted with 1 to 3 groups independently selected from monocyclic cycloalkyl groups. 1~6 Alkoxy, iv)-NH2, v)-NH(C 1~6 Alkyl) (Here, C 1~6 Alkyls are -OH, halogens, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy), vi)-N(C 1~6 Alkyl)2(where each C 1~6 Alkyls may be the same or different, and each C 1~6 Alkyls are -OH, halogens, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy), vii)-P(O)(C 1~6 Alkyl)2(where each C 1~6 Alkyls may be the same or different, and each C 1~6 Alkyls are -OH, halogens, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy), viii)-S(O)2C 1~6 Alkyl, ix)-S(O)2N(R 23 )2(Here, each R 23 H or C 1~6 (It is alkyl.) x) a)-OH, b) Halogen, c)C 1~3 Alkoxy, d)C 3~7 Monocyclic cycloalkyl, e) A 5-6 member monocyclic heterocycline having one or two heteroatoms independently selected from N, O, and S (where the 5-6 member monocyclic heterocycline is oxo and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from alkyl groups), as f)-NR 20 C(O)OC 1~3 Alkyl (where R 20 is H or C 1~3 (It is alkyl.) C is replaced as needed with 1 to 3 groups independently selected from 1~6 Alkyl, xi)-OH, halogen, C 1~3 Alkyl, and C 1~3 C is substituted as needed with 1 to 3 groups independently selected from the alkoxy. 3~7 Monocyclic cycloalkyl, xii) A 5-6 member monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S (where the 5-6 member monocyclic heteroaryl is -OH, halogen, C 1~3 Alkyl, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy), xiii) A 4-6 member monocyclic heterocycline having 1-3 heteroatoms independently selected from N, O, and S (where a 4-6 member monocyclic heterocycline is a -OH, halogen, oxo, C 1~3 Alkyl, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy), xiv)-COOH, xv)-C(O)N(R 19 )2, or xvi)-C 1~3 Alkylene-C(O)N(R) 19 )2 And, R 9a , R 9b , R 9c , R 9d , and R 9eOne or more of these are -C(O)N(R 19 )2 or -C 1~3 Alkylene-C(O)N(R) 19 )2, Each R 19 Independently, i) H, ii)-S(O)2C 1~6 Alkyl, iii) -CN, -OH, halogen, C 1~3 Alkoxy, and C 3~7 C is optionally substituted with 1 to 6 groups independently selected from monocyclic cycloalkyl groups. 1~6 Alkyl, iv) -CN, -OH, halogen, C 1~6 Alkyl, and C 1~6 C is substituted as needed with 1 to 6 groups independently selected from the alkoxy. 3~7 Monocyclic cycloalkyl (where C 1~6 Alkyls include -CN, -OH, halogens, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy), or v) A 4-6 member monocyclic heterocycline having 1-3 heteroatoms independently selected from N, O, and S (where a 4-6 member monocyclic heterocycline is -CN, -OH, halogen, oxo, C 1~3 Alkyl, and C 1~3 (Substituted as needed with 1 to 6 groups independently selected from the alkoxy) It is.

[0018] In a more specific embodiment, Z is NH and X 1 CH is, R 6 is H, and the compound of formula (II) has the structure of formula (IIa). [ka]

[0019] In a more specific embodiment, the compound of formula (II) has the structure of formula (IIb). [ka]

[0020] Further control methods, each R 9a , R 9b , R 9c , R 9d , and R 9e These are H, halogen, and C, independently. 1~6 Alkyl, or -C(O)N(R 19 )2, R 19 C 1~6 It is alkyl, R 4 , R 5 and R 10 These are H and R respectively. 7 C 1~6 It is alkyl.

[0021] In a further, more specific embodiment, R 3 and R 13 Together, they form =O, R 1 and R 2 These, together with the carbon atoms to which they are bonded, form a 4- to 6-membered monocyclic heterocycline having one or two heteroatoms independently selected from N, O, and S, where the 4- to 6-membered monocyclic heterocycline has one R 11 It is replaced as needed.

[0022] In a preferred embodiment, the compound of formula (II) has the structure of formula (IIc). [ka]

[0023] In further embodiments, L has the following structure: [ka] In the formula, t is 0, 1, 2, 3, 4, 5, 6, or 7, and q is 0, 1, 2, 3, 4, 5, 6, or 7, L 1It is -C(O)NH- and L 2 is -O- or -NH-. In a more specific embodiment, t is 0 and q is 3, 5, or 7.

[0024] In a more specific embodiment, LHM targets VHL and has the structure of formula (If). [ka] [In the formula, p is either 0 or 1, R j This is 1 to 3 R k It is a 5-6 member heteroaryl that is substituted as needed, Each R k These are independently: halo, oxo, -CN, -OH, C 1~6 Alkyl, C 3~8 Cycloalkyl, or -OC 1~6 It is alkyl, Each R e These are, independently, hydrogen and C 1~6 Alkyl or C 3~8 It is a cycloalkyl, R b is hydrogen or hydroxyl, R c is -C(O)R f And here, R f C 1~6 Alkyl or C 3~8 [They are cycloalkyl, and each is substituted with a halo or -CN as needed.]

[0025] In other embodiments, the LHM targets CRBN and has the structure of formula (Id). [ka] [In the formula, W is -C(R g )- or -N-, Z1 is -C(O)--, -C(S)-, -C(NR g )-,-C(Rg )2-, -C(R g )2-C(O)-,-C(O)-N(R g )-,-CR g =CR g -, -C(R g )=N-, -C(R g )2-C(S)-, or -C(R g )2-C(R g )2-, q is 0, 1, or 2. R g is hydrogen or C 1~6 It is alkyl, R a C 1~6 alkyl, halo, halo C 1~6 Alkyl, -N(R g )2, CN, nitro, hydroxyl, or -OC 1~4 It is alkyl.

[0026] Furthermore, this specification provides pharmaceutical compositions comprising a compound of formula (I) or formula (II), or any one of the substructures or specific compounds of Examples 1 to 97, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

[0027] Further embodiments provide methods for treating diseases or disorders associated with increased hematopoietic precursor kinase 1 (HPK1) activity, for increasing T cell activation, for treating cancer, for inhibiting the growth or proliferation of cancer cells, for treating or preventing hepatitis B virus (HBV) infection, or for treating or preventing human immunodeficiency virus (HIV) infection, the method comprising the step of administering to a subject in need thereof a therapeutically effective amount of any one of the compounds of formula (I) or formula (II), the substructures or compounds of Examples 1 to 97. [Modes for carrying out the invention]

[0028] Detailed explanation Specific degradation of HPK1 could be achieved by using heterobifunctional small molecules to recruit HPK1 to a ubiquitin ligase, thereby promoting ubiquitination and proteasome degradation of HPK1. Accordingly, the Specified Bifunctional Compounds are provided, each comprising a ligase harness portion (LHM) for targeting a ubiquitin ligase, conjugated covalently via a linker to an HPK1 binder. Preferably, the LHM targets cereblon (CRBN) or von Hippel-Lindau (VHL) protein, which are substrate-recognizing subunits of two universally expressed, biologically important kaline ring E3 ubiquitin ligase complexes. See, for example, WO2019 / 099926, WO2020 / 023851, and U.S. Patent Application Publication 2019 / 0192668.

[0029] One embodiment is a bifunctional compound of formula (I) [ka] Alternatively, it provides pharmaceutically acceptable salts, isotopic forms, isolated stereoisomers, or mixtures thereof. [In the formula, m is 0, 1, 2, 3, or 4. n is 0, 1, 2, 3, 4, 5, or 6. A is C 3~7 A monocyclic cycloalkyl ring, or a 4-6 member monocyclic heterocyclyl ring having one or two heteroatoms independently selected from N, O, and S, L is a linker moiety having 2 to 24 continuously covalently bonded atoms of a length selected from the group consisting of C, O, N, and S. LHM is the ligature harness part. R 11 teeth, i)-OH, halogen, oxo, C 1~3 Alkyl, and C 1~3 Selected from the group consisting of alkoxys, or ii) A 4- to 6-membered monocyclic heterocycline having one or two heteroatoms independently selected from N, O, and S (where a 4- to 6-membered monocyclic heterocycline is -CN, -OH, halogen, oxo, C 1~3 Alkyl, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy), iii)-S(O)2C 1~6 Alkyl, iv)-S(O)2C 3~7 Monocyclic cycloalkyl, v)-CN, -OH, halogen, C 1~3 Alkoxy, and C 3~7 C is optionally substituted with 1 to 3 groups independently selected from monocyclic cycloalkyl groups. 1~6 Alkyl, or vi)-C(O)R 21 And, Each R 12 These are independently -OH, halogen, and C 1~3 Alkyl, and C 1~3 Selected from alkoxy, R 21 teeth, i) H, ii) -CN, -OH, halogen, C 1~3 Alkyl, and C 1~3 C is substituted as needed with 1 to 3 groups independently selected from the alkoxy. 3~7 Monocyclic or cross-linked bicyclic cycloalkyl (where C 1~3 Alkyls are -OH, halogens, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy), iii) A 4- to 6-membered monocyclic heterocycline having one or two heteroatoms independently selected from N, O, and S (where a 4- to 6-membered monocyclic heterocycline is -CN, -OH, halogen, oxo, C 1~3 Alkyl, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy), iv) A 5-6 member monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S (where the 5-6 member monocyclic heteroaryl is -CN, -OH, halogen, C 1~3 Alkyl, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy), v)-NH2, vi)-NH(C 1~6 Alkyl) (Here, C 1~6 Alkyls include -CN, -OH, halogens, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy), vii)-N(C 1~6 Alkyl)2(where each C 1~6 Alkyls may be the same or different, and each C 1~6 Alkyls include -CN, -OH, halogens, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy), viii)-OH, halogen, C 1~3 Alkyl, and C 3~7 C is optionally substituted with 1 to 3 groups independently selected from monocyclic cycloalkyl groups. 1~6 Alkoxy, or ix) a)-CN, b)-OH, c) Halogen, d)C 1~3 Alkoxy, e) -CN, -OH, halogen, C 1~3 Alkyl, and C 1~3 C is substituted as needed with 1 to 3 groups independently selected from the alkoxy. 3~7 Monocyclic cycloalkyl, f) A 4- to 6-membered monocyclic heterocycline having one or two heteroatoms independently selected from N, O, and S (where a 4- to 6-membered monocyclic heterocycline is -CN, -OH, halogen, oxo, C 1~3 Alkyl, and C 1~3(Substituted as needed with 1 to 3 groups independently selected from the alkoxy), and g) -OC(O)C which is substituted as needed with one -OH group. 1~6 Alkyl C is replaced as needed with 1 to 3 groups independently selected from 1~6 Alkyl And, R 3 and R 13 These are either H or R 3 and R 13 They come together to form =O, X is -NR 15 R 16 And R 15 and R 16 Independently, i) H, ii) -OH, halogen, C 1~3 Alkyl, and C 1~3 C is substituted as needed with 1 to 3 groups independently selected from the alkoxy. 3~7 Monocyclic cycloalkyl, iii) A 4- to 7-membered monocyclic heterocycline having one or two heteroatoms independently selected from N, O, and S (wherein a 4- to 6-membered monocyclic heterocycline, -OH, halogen, oxo, C 1~3 Alkyl, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy), iv)-C(O)C 1~6 Alkyl (where C 1~6 Alkyls include -CN, -OH, halogens, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy), or v) a)-CN, b)-OH, c) Halogen, d)C 1~3 Alkoxy, e)-OH, halogen, C 1~3 Alkyl, and C 1~3C is substituted as needed with 1 to 3 groups independently selected from the alkoxy. 3~7 Monocyclic cycloalkyl, and f) A 5-6 member monocyclic heterocycline having one or two heteroatoms independently selected from N, O, and S (where a 5-6 member monocyclic heterocycline is a -OH, halogen, oxo, C 1~3 Alkyl, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy) C is replaced as needed with 1 to 6 groups independently selected from 1~6 Alkyl is it, or X is a 4-10 member monocyclic, fused bicyclic, bridging bicyclic, or spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S, where the 4-10 member monocyclic, fused bicyclic, bridging bicyclic, or spirocyclic heterocyclyl has 1-5 R 18 It is replaced as needed, Each R 18 Independently, i)-CN, ii) Halogen, iii) -OH, iv) -OH, halogen, C 1~3 Alkoxy, and C 3~7 C is optionally substituted with 1 to 3 groups independently selected from monocyclic cycloalkyl groups. 1~6 Alkoxy, v)-OH, halogen, C 1~3 Alkoxy, and C 3~7 C is optionally substituted with 1 to 3 groups independently selected from monocyclic cycloalkyl groups. 1~6 Alkyl, vi)-COOH, or vii)-C(O)N(R 22 )2(Here, each R 22 H or C 1~6 (It is alkyl.) And, X 1 is N or CR17 And, R 4 , R 5 , R 6 , R 10 and R 17 These are H, halogen, and C, respectively, independently. 1~3 Alkyl, or C 1~3 It is an alkoxy, R 7 teeth, i) H, ii) -OH, halogen, C 1~3 Alkoxy, and C 3~7 C is optionally substituted with 1 to 3 groups independently selected from monocyclic cycloalkyl groups. 1~6 Alkyl, or iii) -OH, halogen, C 1~3 Alkyl, and C 1~3 C is substituted as needed with 1 to 3 groups independently selected from the alkoxy. 3~7 Monocyclic cycloalkyl And, Z is -O-, -C(R 8 )2-, or -NR 8 -and, Each R 8 H or C 1~3 It is alkyl, R 9a , R 9b , R 9c , R 9d , and R 9e Independently, i) H, ii) Halogen, iii) -OH, halogen, C 1~3 Alkyl, and C 3~7 C is optionally substituted with 1 to 3 groups independently selected from monocyclic cycloalkyl groups. 1~6 Alkoxy, iv)-NH2, v)-NH(C 1~6 Alkyl) (Here, C 1~6 Alkyls are -OH, halogens, and C 1~3(Substituted as needed with 1 to 3 groups independently selected from the alkoxy), vi)-N(C 1~6 Alkyl)2(where each C 1~6 Alkyls may be the same or different, and each C 1~6 Alkyls are -OH, halogens, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy), vii)-P(O)(C 1~6 Alkyl)2(where each C 1~6 Alkyls may be the same or different, and each C 1~6 Alkyls are -OH, halogens, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy), viii)-S(O)2C 1~6 Alkyl, ix)-S(O)2N(R 23 )2(Here, each R 23 H or C 1~6 (It is alkyl.) x) a)-OH, b) Halogen, c)C 1~3 Alkoxy, d)C 3~7 Monocyclic cycloalkyl, e) A 5-6 member monocyclic heterocycline having one or two heteroatoms independently selected from N, O, and S (where the 5-6 member monocyclic heterocycline is oxo and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from alkyl groups), as f)-NR 20 C(O)OC 1~3 Alkyl (where R 20 is H or C 1~3 (It is alkyl.) C is replaced as needed with 1 to 3 groups independently selected from 1~6 Alkyl, xi)-OH, halogen, C 1~3 Alkyl, and C1~3 C is substituted as needed with 1 to 3 groups independently selected from the alkoxy. 3~7 Monocyclic cycloalkyl, xii) A 5-6 member monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S (where the 5-6 member monocyclic heteroaryl is -OH, halogen, C 1~3 Alkyl, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy), xiii) A 4-6 member monocyclic heterocycline having 1-3 heteroatoms independently selected from N, O, and S (where a 4-6 member monocyclic heterocycline is a -OH, halogen, oxo, C 1~3 Alkyl, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy), xiv)-COOH, xv)-C(O)N(R 19 )2, or xvi)-C 1~3 Alkylene-C(O)N(R) 19 )2 And, However, R 9a , R 9b , R 9c , R 9d , and R 9e One or more of these are -C(O)N(R 19 )2 or -C 1~3 It is alkylene-C(O)N(R19)2. Each R 19 Independently, i) H, ii)-S(O)2C 1~6 Alkyl, iii) -CN, -OH, halogen, C 1~3 Alkoxy, and C 3~7 C is optionally substituted with 1 to 6 groups independently selected from monocyclic cycloalkyl groups. 1~6 Alkyl, iv) -CN, -OH, halogen, C 1~6 Alkyl, and C1~6 C is substituted as needed with 1 to 6 groups independently selected from the alkoxy. 3~7 Monocyclic cycloalkyl (where C 1~6 Alkyls include -CN, -OH, halogens, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy), or v) A 4-6 member monocyclic heterocycline having 1-3 heteroatoms independently selected from N, O, and S (where a 4-6 member monocyclic heterocycline is -CN, -OH, halogen, oxo, C 1~3 Alkyl, and C 1~3 (Substituted as needed with 1 to 6 groups independently selected from the alkoxy) It is.

[0030] An alternative embodiment is a compound of formula (II). [ka] Alternatively, it provides pharmaceutically acceptable salts, isotopic forms, isolated stereoisomers, or mixtures thereof. [In the formula, m is 0, 1, 2, 3, 4, or 5. n is 0, 1, 2, 3, 4, 5, or 6. B is a 4-10 member monocyclic, fused bicyclic, bridging bicyclic, or spirocyclic heterocyclyl ring having 1-3 heteroatoms independently selected from N, O, and S. L is a linker moiety having 2 to 24 continuously covalently bonded atoms of a length selected from the group consisting of C, O, N, and S. LHM is the ligature harness part. R 1 and R 2 One of them is H, -CN, -OH, halogen, or C 1~6 It is alkyl, R 1 and R 2 The other is H, halogen, or C 1~6 It is alkyl, and here each C 1~6The alkyl group is optionally substituted with 1 to 3 groups independently selected from -OH and halogens, or R 1 and R 2 Together with the carbon atoms to which they are bonded, C 3~7 Forming a monocyclic cycloalkyl or a 4-6 member monocyclic heterocycline having one or two heteroatoms independently selected from N, O, and S, where C 3~7 Monocyclic cycloalkyls and 4-6 membered monocyclic heterocyclines each contain one R 11 These are substituted as needed, with -OH, halogen, oxo, and C respectively. 1~3 Alkyl, and C 1~3 It may be substituted as needed with 1 to 3 groups independently selected from the alkoxy, or R 1 and R 2 They come together to form =O, R 11 teeth, i) A 4- to 6-membered monocyclic heterocycline having one or two heteroatoms independently selected from N, O, and S (where a 4- to 6-membered monocyclic heterocycline is -CN, -OH, halogen, oxo, C 1~3 Alkyl, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy), ii)-S(O)2C 1~6 Alkyl, iii)-S(O)2C 3~7 Monocyclic cycloalkyl, iv) -CN, -OH, halogen, C 1~3 Alkoxy, and C 3~7 C is optionally substituted with 1 to 3 groups independently selected from monocyclic cycloalkyl groups. 1~6 Alkyl, or v)-C(O)R 21 And, R 21 teeth, i) H, ii) -CN, -OH, halogen, C1~3 Alkyl, and C 1~3 C is substituted as needed with 1 to 3 groups independently selected from the alkoxy. 3~7 Monocyclic or cross-linked bicyclic cycloalkyl (where C 1~3 Alkyls are -OH, halogens, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy), iii) A 4- to 6-membered monocyclic heterocycline having one or two heteroatoms independently selected from N, O, and S (where a 4- to 6-membered monocyclic heterocycline is -CN, -OH, halogen, oxo, C 1~3 Alkyl, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy), iv) A 5-6 member monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S (where the 5-6 member monocyclic heteroaryl is -CN, -OH, halogen, C 1~3 Alkyl, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy), v)-NH2, vi)-NH(C 1~6 Alkyl) (Here, C 1~6 Alkyls include -CN, -OH, halogens, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy), vii)-N(C 1~6 Alkyl)2(where each C 1~6 Alkyls may be the same or different, and each C 1~6 Alkyls include -CN, -OH, halogens, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy), viii)-OH, halogen, C 1~3 Alkyl, and C 3~7 C is optionally substituted with 1 to 3 groups independently selected from monocyclic cycloalkyl groups. 1~6 Alkoxy, or ix) a)-CN, b)-OH, c) Halogen, d)C 1~3 Alkoxy, e) -CN, -OH, halogen, C 1~3 Alkyl, and C 1~3 C is substituted as needed with 1 to 3 groups independently selected from the alkoxy. 3~7 Monocyclic cycloalkyl, f) A 4- to 6-membered monocyclic heterocycline having one or two heteroatoms independently selected from N, O, and S (where a 4- to 6-membered monocyclic heterocycline is -CN, -OH, halogen, oxo, C 1~3 Alkyl, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy), and g) -OC(O)C which is substituted as needed with one -OH group. 1~6 Alkyl C is replaced as needed with 1 to 3 groups independently selected from 1~6 Alkyl And, R 3 and R 13 These are either H or R 3 and R 13 They come together to form =O, Each R 12 These are independently -OH, halogen, and C 1~3 Alkyl, and C 1~3 Selected from alkoxy, Each R 18 Independently, i)-CN, ii) Halogen, iii) -OH, iv) -OH, halogen, C 1~3 Alkoxy, and C 3~7 C is optionally substituted with 1 to 3 groups independently selected from monocyclic cycloalkyl groups. 1~6 Alkoxy, v)-OH, halogen, C 1~3Alkoxy, and C 3~7 C is optionally substituted with 1 to 3 groups independently selected from monocyclic cycloalkyl groups. 1~6 Alkyl, vi)-COOH, or vii)-C(O)N(R 22 )2(Here, each R 22 H or C 1~6 (It is alkyl.) And, X 1 is N or CR 17 And, R 4 , R 5 , R 6 , R 10 and R 17 These are H, halogen, and C, respectively, independently. 1~3 Alkyl, or C 1~3 It is an alkoxy, R 7 teeth, i) H, ii) -OH, halogen, C 1~3 Alkoxy, and C 3~7 C is optionally substituted with 1 to 3 groups independently selected from monocyclic cycloalkyl groups. 1~6 Alkyl, or iii) -OH, halogen, C 1~3 Alkyl, and C 1~3 C is substituted as needed with 1 to 3 groups independently selected from the alkoxy. 3~7 Monocyclic cycloalkyl And, Z is -O-, -C(R 8 )2-, or -NR 8 -and, Each R 8 H or C 1~3 It is alkyl, R 9a , R 9b , R 9c , R 9d , and R 9e Independently, i) H, ii) Halogen, iii) -OH, halogen, C 1~3 Alkyl, and C 3~7 C is optionally substituted with 1 to 3 groups independently selected from monocyclic cycloalkyl groups. 1~6 Alkoxy, iv)-NH2, v)-NH(C 1~6 Alkyl) (Here, C 1~6 Alkyls are -OH, halogens, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy), vi)-N(C 1~6 Alkyl)2(where each C 1~6 Alkyls may be the same or different, and each C 1~6 Alkyls are -OH, halogens, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy), vii)-P(O)(C 1~6 Alkyl)2(where each C 1~6 Alkyls may be the same or different, and each C 1~6 Alkyls are -OH, halogens, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy), viii)-S(O)2C 1~6 Alkyl, ix)-S(O)2N(R 23 )2(Here, each R 23 H or C 1~6 (It is alkyl.) x) a)-OH, b) Halogen, c)C 1~3 Alkoxy, d)C 3~7 Monocyclic cycloalkyl, e) A 5-6 member monocyclic heterocycline having one or two heteroatoms independently selected from N, O, and S (where the 5-6 member monocyclic heterocycline is oxo and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from alkyl groups), as f)-NR 20 C(O)OC 1~3 Alkyl (where R 20 is H or C 1~3 (It is alkyl.) C is replaced as needed with 1 to 3 groups independently selected from 1~6 Alkyl, xi)-OH, halogen, C 1~3 Alkyl, and C 1~3 C is substituted as needed with 1 to 3 groups independently selected from the alkoxy. 3~7 Monocyclic cycloalkyl, xii) A 5-6 member monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S (where the 5-6 member monocyclic heteroaryl is -OH, halogen, C 1~3 Alkyl, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy), xiii) A 4-6 member monocyclic heterocycline having 1-3 heteroatoms independently selected from N, O, and S (where a 4-6 member monocyclic heterocycline is a -OH, halogen, oxo, C 1~3 Alkyl, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy), xiv)-COOH, xv)-C(O)N(R 19 )2, or xvi)-C 1~3 Alkylene-C(O)N(R) 19 )2 And, R 9a , R 9b , R 9c , R 9d , and R 9e One or more of these are -C(O)N(R 19 )2 or -C 1~3 Alkylene-C(O)N(R) 19 )2, Each R 19 Independently, i) H, ii)-S(O)2C 1~6 Alkyl, iii) -CN, -OH, halogen, C 1~3 Alkoxy, and C 3~7 C is optionally substituted with 1 to 6 groups independently selected from monocyclic cycloalkyl groups. 1~6 Alkyl, iv) -CN, -OH, halogen, C 1~6 Alkyl, and C 1~6 C is substituted as needed with 1 to 6 groups independently selected from the alkoxy. 3~7 Monocyclic cycloalkyl (where C 1~6 Alkyls include -CN, -OH, halogens, and C 1~3 (Substituted as needed with 1 to 3 groups independently selected from the alkoxy), or v) A 4-6 member monocyclic heterocycline having 1-3 heteroatoms independently selected from N, O, and S (where a 4-6 member monocyclic heterocycline is -CN, -OH, halogen, oxo, C 1~3 Alkyl, and C 1~3 (Substituted as needed with 1 to 6 groups independently selected from the alkoxy) It is. HPK1 Binder

[0031] The HPK1 binder in the difunctional compounds of formula (I) or (II) generally comprises a 6-azabenzimidazole core (which may be further derivatized to include a cyclobutyl-substituted indoline or 4-azaidinline moiety) and a benzamide moiety. The HPK1 binder provides various sites for coupling to the LHM via a linker (i.e., a linker-LHM moiety). More specifically, in the difunctional compound of formula (I), the HPK1 binder moiety couples to the linker-LHM moiety via the A ring, as shown in the structure represented by formula (A) (the dashed line indicates the coupling site to the linker-LHM moiety). [ka] [In the formula, R 3 , R 4 , R 5 , R 6 , R 7 , R 9a , R 9b , R 9c , R 9d , R 9e , R 10 , R 11 , R 12 and R 13 , X 1 Z, m, and n are defined previously.

[0032] In a more specific embodiment, Z is NH and X 1 CH is, R 6 is H, and the HPK1 binder partial compound has the structure of formula (Aa). [ka]

[0033] In a preferred embodiment, ring A is piperidinyl, and the HPK1 binder portion has the following structure. [ka]

[0034] Various implementation methods, each R 9a , R 9b , R 9c , R 9d , and R 9e These are H, halogen, and C, independently. 1~6 Alkyl, or -C(O)N(R 19 )2, R 19 C 1~6 It is alkyl, R 4 , R 5 and R 10 These are H and R respectively. 7 C 1~6 It is alkyl.

[0035] In other embodiments, R 3 and R13 These two elements combine to form the O symbol.

[0036] In other embodiments, X is piperidinil.

[0037] In yet another embodiment, n is 0 and p is 0.

[0038] In a preferred embodiment, the HPK1 binder portion has the structure of formula (Ac). [ka]

[0039] In a more specific embodiment, the compound of formula (Ac) may have one of the following diastereomer structures. [ka]

[0040] Alternatively, for the bifunctional compound of formula (II), the HPK1 binder moiety couples to the linker-LHM moiety via the B ring, as shown in the structure represented by formula (B) (the dashed line indicates the coupling site to the linker-LHM moiety). [ka] [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9a , R 9b , R 9c , R 9d , R 9e , R 10 , R 12 , R 13 , R 18 , X 1 Z, m, and n are defined previously.

[0041] In a preferred embodiment, Z is NH and X 1 CH is, R 6 It is H, and the HPK1 binder portion has the structure of formula (Ba). [ka]

[0042] In a preferred embodiment, the B ring is piperidinyl, and the HPK1 binder moiety has the structure of formula (Bb). [ka]

[0043] Various further embodiments, each R 9a , R 9b , R 9c , R 9d , and R 9e These are H, halogen, and C, independently. 1~6 Alkyl, or -C(O)N(R 19 )2, R 19 C 1~6 It is alkyl, R 4 , R 5 and R 10 These are H and R respectively. 7 C 1~6 It is alkyl.

[0044] In various further embodiments, R 3 and R 13 Together, they form =O, R 1 and R 2 These, together with the carbon atoms to which they are bonded, form a 4- to 6-membered monocyclic heterocycline having one or two heteroatoms independently selected from N, O, and S, where the 4- to 6-membered monocyclic heterocycline has one R 11 It is replaced as needed in R. 11 This is as defined herein.

[0045] In a preferred embodiment, the HPK1 binder portion has the structure of formula (Bc). [ka] Ligauze harness portion (LHM)

[0046] The LHM of the compound of formula (I) or formula (II) targets the VHL or CRBN of the E3 ligase, which is linked by a bifunctional compound to induce ubiquitination of HPK1 and subsequent degradation by the proteasome.

[0047] Thalidomide derivatives, such as lenalidomide or pomalidomide, can be used to recruit potential substrates to CRBN, a component of the ubiquitin ligase complex.

[0048] One embodiment provides a CRBN-targeting LHM having the following structure (the dashed line indicates the bond attached to the remainder of the compound of formula (I)). [ka] [In the formula, W is -C(R g )- or -N-, Z1 is -C(O)--, -C(S)-, -C(NR g )-,-C(R g )2-, -C(R g )2-C(O)-,-C(O)-N(R g )-,-CR g =CR g -, -C(R g )=N-, -C(R g )2-C(S)-, or -C(R g )2-C(R g )2-, q is 0, 1, or 2. R g is hydrogen or C 1~6 It is alkyl, R a C1~6 alkyl, halo, halo C 1~6 Alkyl, -N(R g )2, CN, nitro, hydroxyl, or -OC 1~4 It is alkyl.

[0049] In a more specific embodiment, the LHM has one of the following structures: [ka]

[0050] In other embodiments, LHM targets VHL and has the structure of formula (Ie) or (If). [ka] [In the formula, p is either 0 or 1, R j This is 1 to 3 R k It is a 5-6 member heteroaryl that is substituted as needed, Each R k These are independently: halo, oxo, -CN, -OH, C 1~6 Alkyl, C 3~8 Cycloalkyl, or -OC 1~6 It is alkyl, Each R e These are, independently, hydrogen and C 1~6 Alkyl or C 3~8 It is a cycloalkyl, R b is hydrogen or hydroxyl, R c is -C(O)R f And R f C 1~6 Alkyl or C 3~8 [They are cycloalkyl, and each is substituted with a halo or -CN as needed.]

[0051] In a more specific embodiment, the LHM has one of the following structures: [ka] Linker

[0052] Each bifunctional compound of formula (I) or formula (II) contains a linker, which is a divalent portion that couples the HPK1 binder moiety to LHM. The structure of the linker moiety (e.g., length or rigidity) can affect the efficiency or selectivity of the degradation process. Typically, the linker moiety comprises multiple segments, which, in addition to providing their respective binding sites to the HPK1 binder moiety and LHM, contribute to the overall length and rigidity of the linker.

[0053] As used herein, the linker portion typically has 2 to 24 continuously covalently bonded atoms of a length selected from the group consisting of C, O, N, and S. In particular, the linker portion includes a continuous sequence of covalent bonds between the respective bonding points to the HPK1 binder portion and LHM, including the bonds shown by the dashed lines in formulas (A), (B), (Id), (Ie), and (If), and their respective substructures.

[0054] In some embodiments, the linker portion has the following chain-like structure: [ka] During the ceremony, t is 0, 1, 2, 3, 4, 5, 6, or 7. q is 0, 1, 2, 3, 4, 5, 6, or 7. L 1 These are direct bonds, -C(O)NH-, or -C(O)-. L 2 These are -C(O)NH-, -O-, or -NH-.

[0055] In a more specific embodiment, t is 0 and q is 3, 4, 5, 6, or 7.

[0056] In other, more specific embodiments, q is 0 and t is 1, 3, 5, or 7.

[0057] In a further, more specific embodiment, the linker has one of the following structures: [ka]

[0058] When used herein, the divalent portion * These typically indicate the binding sites to the remainder of the compound, such as the HPK1 binder portion and LHM, or to other linker segments. * And the dashed line is understood to be interchangeable.

[0059] The length of the linker can be determined by the total number of atoms forming the continuously connected bonds. For example, using the linker portion described above, the total number of atoms is the number of atoms directly bonded to the HPK1 binder portion (e.g., L 1 From atoms that form continuous covalent bonds (e.g., C, N, or O), to atoms that directly bond to the linker portion (e.g., L) 2 This is the number of atoms up to the C, O, or N of the ring. Atoms that do not participate in the continuous covalent bond (e.g., H or O when connected by a double bond) are excluded from the count of the total number of atoms. For linker moieties containing one or more ring structures, the total number of atoms is the number counted along only the single sequence of linearly connected atoms, not around the ring. For example, a divalent 1,6-cyclohexyl ring moiety is counted as 4 atoms, not 6.

[0060] Unless otherwise specified, the divalent portion described herein (for example, L) is provided that the valence is satisfied. 1 or L 2 It should be understood that these are not limited to the direction in which they are represented. For example, given L 1For example, with respect to -C(O)-NH-, the way it is attached to the rest of the molecule can be in either direction, namely -C(O)-NH- or -NH-C(O)-, as long as it does not violate the rules of valence.

[0061] One or more linker segments can be directly linked. For example, in a sequence of linker segments represented by -L2-L3-L4--, if L3 is directly linked, then L2 and L4 are directly linked to each other, and L3 effectively disappears.

[0062] In another embodiment, the linker portion has one or more rings that tend to increase the rigidity of the linker. The combination of chain bonds and rings(s) can be used to adjust the relative orientation of the difunctional groups or the distance between those groups.

[0063] In a more specific embodiment, the linker portion has the following structure: [ka] During the ceremony, p is either 1 or 2. q is 0, 1, 2, or 3. X 2 is CH or N, L 3 teeth, i)-(CH2) q -, ii)-(CH2) q -C(O)NH-, or iii) [ka] That is the case.

[0064] In yet another embodiment, the linker portion has the following structure: [ka] During the ceremony, w is 1, 2, or 3. v is either 1 or 2. p is 1, 2, 3, 4, or 5. Y 1 This is a direct bond, -(CH2) p -, or -O- Y 2 This is a direct bond, -(CH2) p -, -C(O)-, or -C(O)-CH2-, X 3 and X 4 Independently, is N or C(R), and R is either H or C 1~3 It is alkyl, L 4 is either a direct bond, -NH-, -NHC(O)-, or L 4 teeth, [ka] That is the case.

[0065] In a more specific embodiment, the linker portion has the following structure. [ka] [ka] [ka] [ka]

[0066] In other embodiments, the linker portion includes a strong ring system, such as an aryl ring (e.g., phenyl), a heteroaryl ring, a bridged ring, a spiro ring, or a mixture thereof.

[0067] In a more specific embodiment, the linker portion has one of the following structures. [ka] [ka] Composition of compounds of formulas (I) and (II)

[0068] The synthesis or construction of the compound of formula (I) or formula (II) can be carried out in several steps, which typically involve separately preparing the HPK1 binder and LHM moiety construction blocks, and then linking each construction block by covalent bond formation. Generally speaking, one or more linker precursors (L x The linker precursor can be used to prepare either or both construction blocks. s ) contains and has terminal reaction groups for further coupling. Finally, the two types of construction blocks are coupled (L s By forming segments, compounds of formula (I) or formula (II) can be obtained.

[0069] The following scheme demonstrates a general method for preparing construction blocks. Specific examples (Examples 1-97) were synthesized and characterized by their respective physiological and chemical properties according to the general scheme described herein. A. General scheme for preparing HPK1 binder construction blocks

[0070] The HPK1 binder building block can be prepared using a method similar to reaction scheme A shown below. For the compound of formula (I), R 1 and R 2 These, together with the carbon atoms to which they are bonded, form an A ring, and in the compound of formula (II), X is a B ring. Reaction scheme A [ka] Step 1 - Preparation of compound (3)

[0071] 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 after cooling the reactants to room temperature until the reaction is complete, the compound of formula (3) can be obtained by filtration or precipitation. Step 2 - Preparation of compound (4)

[0072] 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 after cooling the reactants to room temperature until the reaction is complete, 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 obtain the compound of formula (4). The compound of formula (4) can be purified by any suitable method known in the art, such as chromatography, polishing, precipitation, or crystallization on silica gel. Step 3 - Preparation of compound (5)

[0073] 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 solvent mixture consisting of THF, MeOH, and water. After stirring at a temperature between 0°C and 100°C for 1 to 24 hours, or until the reaction is complete, the reactants are cooled to room temperature and filtered through a Celite bed. 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, polishing, precipitation, or crystallization on silica gel. Step 4 - Preparation of compound (6)

[0074] 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 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, polishing, precipitation, crystallization, or washing with organic solvents such as ether, including but not limited to methyl t-butyl ether. Step 5 - Preparation of compound (7)

[0075] 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 to 24 hours, or by adding ice water or by adding the reaction mixture to ice water until the reaction is complete, the reactants are cooled to between 0°C and room temperature. 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, polishing, precipitation, or crystallization on silica gel. Step 6 - Preparation of compound (9)

[0076] The compound of formula (9) can be prepared by combining the compound of formula (6) and the compound of formula (8), or by combining the compound of formula (7) and the compound of formula (8), by methods known in the art. The compound of formula (8) is commercially available or can be prepared by methods known in the art. The compound of formula (8) can be mixed with either the compound of 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 to 24 hours, or until the reaction is complete, the reactants can be added to water and treated with an acid such as 10% citric acid. The compound of formula (7) can be obtained by filtration or precipitation. Step 7 - Preparation of compound (12)

[0077] The compound of formula (12) can be prepared by combining the compounds of formula (10) and (11) by methods known in the art. The compounds of formula (10) and (11) are commercially available or can be prepared by methods known in the art. The 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 to 24 hours, or after cooling the reactants to room temperature until the reaction is complete, the compound of formula (12) can be extracted by adding an organic solvent such as ethyl acetate, 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, polishing, precipitation, or crystallization in silica gel. Step 8 - Preparation of compound (13)

[0078] The compound of formula (13) can be prepared by reductive amination of the compound of formula (12) by methods known in the art. The compound of formula (12) and the amine, which are commercially available or synthesized by methods known in the art, can be mixed 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 to 24 hours, or until the reaction is complete, the reactants can be added to an aqueous solution such as a saturated sodium bicarbonate solution. To extract the compound of (13), an organic solvent such as methylene chloride can be added, followed by washing with water and brine. The organic phase can be concentrated to obtain the compound of formula (13). The compound of formula (13) can be purified by any suitable method known in the art, such as chromatography on silica gel, polishing, precipitation, or crystallization. Step 9 - Preparation of HPK1 Binder Construction Blocks

[0079] The HPK1 binder building block can be prepared by combining the compound of formula (9) and the compound of formula (13) by methods known in the art. The 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 mixture is cooled to room temperature. The crude product can be filtered and concentrated under reduced pressure. To extract the compounds, 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, polishing, precipitation, or crystallization. The resulting HPK1 binder building block is used as an intermediate to be further coupled to the linker portion.

[0080] The HPK1 binder construction blocks prepared according to reaction scheme A have at least one reactive site, typically an amine or carboxyl moiety, which can be further coupled to the remainder of the molecule of formula (I) or (II) by the formation of a covalent bond. In the specific HPK1 binder construction blocks shown below, the -NH- moiety of spiro[indole-piperidinyl] in intermediate 1 and the carboxylic acid of intermediate 2 (structure shown below) represent their respective reactive sites. [ka] These intermediates are described in more detail below. Intermediate 1: 4-Fluoro-N-isopropyl-5-((3-isopropyl-6-(2-oxo-1-((1s,3s)-3-(piperidine-1-yl)cyclobutyl)spiro[indoline-3,4'-piperidine]-6-yl)-3H-imidazo[4,5-c]pyridine-4-yl)amino)-2-methylbenzamide

[0081] Step 1: Synthesis of tert-butyl 2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4'-piperidine]-1'-carboxylate. In a 100 mL short-neck round-bottom flask equipped with a reflux condenser, tert-butyl 6-bromo-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate (1) (0.99 g, 2.6 mmol), bis(pinacolate)boron (0.86 g, 3.4 mmol), potassium acetate (0.76 g, 7.8 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex dichloromethane adduct (0.21 g, 0.26 mmol) were added to dioxane (10 mL). The mixture was degassed by bubbling with N2 for 5 minutes, then stirred at 80°C for 16 hours. The mixture was then cooled to RT, quenched with water, and extracted with toluene. The combined organic layers were washed with water and brine, dried over Na2SO4, concentrated, and purified by flash chromatography (0-100% toluene / hexane) to obtain the title compound product.

[0082] Step 2: Synthesis of tert-butyl 2-oxo-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4'-piperidine]-1'-carboxylate. In a 100 mL short-neck round-bottom flask equipped with a reflux condenser, tert-butyl 2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4'-piperidine]-1'-carboxylate (2) (0.81 g, 1.9 mmol), potassium carbonate (0.65 g, 4.7 mmol, 325 mesh), and 3-bromocyclobutanone (0.21 mL, 2.53 mmol) were added in DMF (10 mL). The mixture was stirred at 50°C for 1 hour, then cooled to RT, filtered, and potassium carbonate was removed. The filtrate was diluted with RINKAN, quenched with water, and extracted with RINKAN. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and purified by flash chromatography (0-100% RINKAN / hexane) to obtain the title compound.

[0083] Step 3: Synthesis of tert-butyl 2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indole-3,4'-piperidine]-1'-carboxylate. To a stirred solution of tert-butyl 2-oxo-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indole-3,4'-piperidine]-1'-carboxylate (2.60 g, 5.24 mmol), acetic acid (0.60 mL, 10.5 mmol), and piperidine (1.55 mL, 15.7 mmol) in DCM (29 mL), STAB (3.33 g, 15.7 mmol) was added in three equal parts over 10 minutes. After stirring for 3 hours, the reaction mixture was diluted with sodium bicarbonate aqueous solution (100 mL), and the organic layer was separated. The aqueous layer was extracted with DCM (2 × 75 mL), and the combined organic layers were washed with brine (2 × 100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (2.9 g, 96%).

[0084] Step 4: Synthesis of 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridine-4-yl)amino)-4-fluoro-2-methylbenzoic acid. In a 250 mL single-neck round-bottom flask equipped with a reflux condenser, 5-amino-4-fluoro-2-methylbenzoic acid (2.0 g, 11 mmol) was added to DMF (40 mL). NaH (60%, 1.6 g, 39 mmol) was added, and the resulting mixture was stirred at RT for 15 minutes, followed by the addition of 6-bromo-4-fluoro-3-isopropyl-imidazo[4,5-c]pyridine (7) (2.0 g, 7.8 mmol). The mixture was stirred at 60°C for 16 hours, then cooled to RT, quenched with water, and then 10% citric acid was added to adjust the pH to approximately 5. The precipitate was filtered, washed with water, and dried to obtain the title compound.

[0085] Step 5: Synthesis of 5-({6-bromo-3-isopropylimidazo[4,5-c]pyridine-4-yl}amino)-4-fluoro-N-isopropyl-2-methylbenzamide. HATU (1.91 g, 5.03 mmol) was added in a single dose to a solution of 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridine-4-yl)amino)-4-fluoro-2-methylbenzoic acid (1.0 g, 2.5 mmol), isopropylamine (0.43 mL, 5.0 mmol), and DIPEA (2.58 mL, 14.8 mmol) in DMF (16 mL). The reaction mixture was stirred at RT for 16 hours, then cooled to 0°C and quenched by adding water (30 mL). The mixture was stirred at RT for 20 minutes, and the solid was filtered. The solid was rinsed with water and dried under reduced pressure overnight to obtain the title compound (0.95 g, 86%).

[0086] Step 6: Synthesis of tert-butyl 6-(4-{[2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl]amino}-3-isopropylimidazo[4,5-c]pyridine-6-yl)-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]spiro[indole-3,4'-piperidine]-1'-carboxylate. In a microwave vial equipped with a stirring rod, 5-({6-bromo-3-isopropylimidazo[4,5-c]pyridine-4-yl}amino)-4-fluoro-N-isopropyl-2-methylbenzamide (500 mg, 1.12 mmol), tert-butyl 2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indole-3,4'-piperidine]-1'-carboxylate (694 mg, 1.23 mmol), sodium carbonate (438 mg, 4.13 mmol), and tetrakis(triphenylphosphine)palladium (0) (91 mg, 0.08 mmol) were combined in a mixture of 1,2-dimethoxyethane (12 mL) and water (4.1 mL). Next, the reaction mixture was heated in a microwave at 125°C for 50 minutes with stirring. After cooling to rt, the reaction mixture was concentrated on silica gel and purified according to chromatography B to obtain the title compound (650 mg, 72%).

[0087] Step 7: Synthesis of 4-fluoro-N-isopropyl-5-((3-isopropyl-6-(2-oxo-1-((1s,3s)-3-(piperidine-1-yl)cyclobutyl)spiro[indoline-3,4'-piperidine]-6-yl)-3H-imidazo[4,5-c]pyridine-4-yl)amino)-2-methylbenzamide. To a solution of tert-butyl 6-(4-{[2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl]amino}-3-isopropylimidazo[4,5-c]pyridine-6-yl)-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]spiro[indole-3,4'-piperidine]-1'-carboxylate (900 mg, 1.12 mmol) in DCM (9 mL), HCl (4N in dioxane, 4.5 mL) was added. After stirring the mixture for 3 hours, the solvent was removed under reduced pressure. The crude residue was purified according to chromatography C to obtain the title compound (750 mg, 90%).

[0088] Intermediate 2: (3R)-1-[(1s,3s)-3-[1'-acetyl-6-(4-{[2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl]amino}-3-isopropylimidazo[4,5-c]pyridine-6-yl)-2-oxospiro[indole-3,4'-piperidine]-1-yl]cyclobutyl]piperidine-3-carboxylic acid

[0089] Step 1: Synthesis of tert-butyl 2-oxo-1-[(1s,3s)-3-[(3R)-3-(ethoxycarbonyl)piperidine-1-yl]cyclobutyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indole-3,4'-piperidine]-1'-carboxylate. The reaction was carried out according to general procedure D, using tert-butyl 2-oxo-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indole-3,4'-piperidine]-1'-carboxylate (1.5 g, 3.0 mmol) and ethyl (3R)-piperidine-3-carboxylate hydrochloride (761 mg, 3.93 mmol, 1.3 equivalents), with the addition of TEA (0.42 mL, 3.02 mmol, 1 equivalent) to obtain the title compound (1.9 g, 3.0 mmol, 99%).

[0090] Step 2: Synthesis of tert-butyl 6-(4-{[2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl]amino}-3-isopropylimidazo[4,5-c]pyridine-6-yl)-2-oxo-1-[(1s,3s)-3-[(3R)-3-(ethoxycarbonyl)piperidine-1-yl]cyclobutyl]spiro[indole-3,4'-piperidine]-1'-carboxylate. In a microwave vial equipped with a stirring rod, a mixture of 1,2-dimethoxyethane (12 mL) and water (4.1 mL) is prepared, containing 5-({6-bromo-3-isopropylimidazo[4,5-c]pyridine-4-yl}amino)-4-fluoro-N-isopropyl-2-methylbenzamide (500 mg, 1.12 mmol, 1 equivalent), tert-butyl 2-oxo-1-[(1s,3s)-3-[(3R)-3-(ethoxycarbonyl)pipette The reaction mixture was packed with lysine-1-yl]cyclobutyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indole-3,4'-piperidine]-1'-carboxylate (782 mg, 1.1 equivalents, 1.23 mmol), sodium carbonate (438 mg, 4.13 mmol, 3.7 equivalents), and tetrakis(triphenylphosphine)palladium (91 mg, 0.08 mmol, 0.07 equivalents). The reaction mixture was heated by microwave at 125°C for 25 minutes. The reaction product was filtered through Celite, and the filter cake was rinsed with a 1:1 mixture of DCM and methanol. The filtrate was concentrated and purified by chromatography B to obtain the title product (0.9 g, 1.0 mmol, 92%).

[0091] Step 3: Synthesis of ethyl(3R)-1-[(1s,3s)-3-[6-(4-{[2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl]amino}-3-isopropylimidazo[4,5-c]pyridine-6-yl)-2-oxospiro[indole-3,4'-piperidine]-1-yl]cyclobutyl]piperidine-3-carboxylate. The reaction was carried out according to general procedure B using tert-butyl 6-(4-{[2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl]amino}-3-isopropylimidazo[4,5-c]pyridine-6-yl)-2-oxo-1-[(1s,3s)-3-[(3R)-3-(ethoxycarbonyl)piperidine-1-yl]cyclobutyl]spiro[indole-3,4'-piperidine]-1'-carboxylate (1.8 g, 2.1 mmol) to obtain the title compound (1.9 g, quantitative).

[0092] Step 4: Synthesis of ethyl(3R)-1-[(1s,3s)-3-[1'-acetyl-6-(4-{[2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl]amino}-3-isopropylimidazo[4,5-c]pyridine-6-yl)-2-oxospiro[indole-3,4'-piperidine]-1-yl]cyclobutyl]piperidine-3-carboxylate. The ethyl(3R)-1-[(1s,3s)-3-[6-(4-{[2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl]amino}-3-isopropylimidazo[4,5-c]pyridine-6-yl)-2-oxospiro[indole-3,4'-piperidine]-1-yl]cyclobutyl]piperidine-3-carboxylate (1.90 g, 2.44 mmol, 1 equivalent), HATU (1.95 g, 5.12 mmol, 2.1 equivalents), and acetic acid (0.35 mL, 6.1 mmol) were added to a solution of dimethylformamide (28.7 mL, 0.85 M) by slowly adding DIPEA (2.76 mL, 15.9 mmol, 6.5 equivalents). The reaction mixture was stirred at RT for 1 hour. The reaction mixture was quenched with water (30 mL), the solid precipitate was removed by filtration, and the mixture was dried overnight under vacuum in a nitrogen stream to obtain the title compound (0.9 g, 1.10 mmol, 45%).

[0093] Step 5: (3R)-1-[(1s,3s)-3-[1'-acetyl-6-(4-{[2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl]amino}-3-isopropylimidazo[4,5-c]pyridine-6-yl)-2-oxospiro[indole-3,4'-piperidine]-1-yl]cyclobutyl]piperidine-3-carboxylic acid. The reaction was carried out according to general procedure C using ethyl(R)-1-((1s,3S)-3-(1'-acetyl-6-(4-((2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridine-6-yl)-2-oxospiro[indoline-3,4'-piperidine]-1-yl)cyclobutyl)piperidine-3-carboxylate (900 mg, 1.10 mmol) to obtain the title compound (790 mg, 1.0 mmol, 91%). General scheme for preparing B.LHM construction blocks

[0094] First, an LHM targeting CRBN can be coupled to a linker precursor, and the resulting construct can be further coupled to an HPK1 binder construct (e.g., intermediate 1 or intermediate 2). In certain embodiments, LHM-linker construction blocks targeting CRBN can generally be prepared according to reaction scheme B1. Reaction scheme B1 [ka]

[0095] In reaction scheme B1, the functionalized thalidomide is first coupled to a linker precursor. The linker precursor (amino ester) contains "linker A" (representing one or more linker segments), as well as two terminal reactive groups: an amine in ester form and a protected carboxylic acid. Step 1 describes further details of the initial coupling step using an exemplary amino ester linker precursor.

[0096] Step 1: A mixture of 2-(2,6-dioxopiperidine-3-yl)-4-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (0.26 mmol), amino ester (0.26 mmol), ethylbis(propan-2-yl)amine (0.52 mmol), and DMF (1 mL) was stirred overnight at 90°C. The mixture was cooled and purified by HPLC (5-95% MeCN and 0.1% TFA in H2O) to obtain the tert-butyl ester intermediate.

[0097] Subsequently, the tert-butyl ester intermediate undergoes hydrolysis (see Step 2) to yield a CRBN-targeting LHM construction block having a carboxylic acid group at its terminus, "linker A," which can then react and couple with another part, such as an HPK1 binder construction block or another linker segment.

[0098] Step 2: A mixture of tert-butyl 4-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]aminobutanoate (0.10 mmol), CH2Cl2 (1 mL), and TFA (1 mL) was stirred at rt for 2 hours. The mixture was concentrated to obtain the carboxylic acid product.

[0099] Below are further examples of LHM constructs targeting CRBN that can be prepared according to reaction scheme B1. More detailed explanations can be found in WO2020038415, WO2019207538, and WO2018089736, and their references are incorporated by reference in their entirety.

[0100] Intermediate 3: 3-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)ethoxy)propanoic acid. [ka]

[0101] Product of Step 1: tert-butyl 3-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindorin-4-yl]amino]ethoxy]propanoate (1.8g, 52%). LCMS;C 22 H 27 Required value for N3O7: 445, measured value: m / z = 468 [M + Na] + .

[0102] Product of Step 2: 3-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindoline-4-yl]amino]ethoxy]propanoic acid (526 mg, 32%). LCMS;C 18 H 19 Required value for N3O7: 389, Measured value: m / z = 390 [M+H] + .

[0103] Intermediate 4: 3-(2-(2-((2-((2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)amino)ethoxy)ethoxy)ethoxy)propanoic acid. [ka]

[0104] Product of Step 1: tert-butyl3-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxoisoindoline-5-yl]amino]ethoxy]ethoxy]ethoxy]propanoate.

[0105] Product of Step 2: 3-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindoline-5-yl]amino]ethoxy]ethoxy]ethoxy]propanoic acid. Intermediate 5: 6-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)amino)hexanoic acid [ka] Step 1: tert-butyl6-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisindole-5-yl]aminohexanoate

[0106] In 3 ml of NMP, a mixture of 2-(2,6-dioxopiperidine-3-yl)-5-fluoroisoindole-1,3-dione (250 mg, 0.91 mmol) and tert-butyl 6-aminohexanoate hydrochloride (203 mg, 0.91 mmol) was mixed with N,N-diisopropylethylamine (0.6 mL), which was heated overnight at 85°C. The crude reaction mixture was purified by silica gel chromatography using butyl / hexane (0-100%) to obtain tert-butyl 6-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl]amino}hexanoate (111 mg, 28%). LCMS:C 23 H 29 N3O6, Required value: 443.5, Measured value: m / z = 444.4 [M+H] + . Step 2: 6-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)amino)hexanoic acid

[0107] To a DCM solution of tert-butyl 6-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl]amino}hexanoate (111 mg, 0.25 mmol), TFA (0.5 mL) was added. The reaction mixture was stirred at room temperature for 30 minutes, and then the reaction mixture was concentrated to obtain 6-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexanoic acid (78 mg, 78%). 1H NMR (500 MHz, DMSO-d6) δ 12.00 (s, 1H), 11.06 (s, 1H), 7.57 (d, J = 8.3 Hz, 1H), 7.11 (s, 1H), 6.95 (d, J = 2.1 Hz, 1H), 6.85 (dd, J = 8.4, 2.1 Hz, 1H), 5.04 (dd, J = 12.7, 5.4 Hz, 1H), 3.16 (q, J = 6.4 Hz, 2H), 2.23 (t, J = 7.4 Hz, 2H), 2.03 - 1.97 (m, 1H), 1.56 (dq, J = 14.8, 7.2 Hz, 4H), 1.39 (q, J = 7.9 Hz, 2H).LCMS:C 19 H 21 N3O6, Required value: 387.4, Measured value: m / z = 388.4 [M+H] + . Intermediate 6: 8-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl]amino}octanoic acid

[0108] Intermediate 6 can be prepared in the same manner as intermediate 5, except that hexanoic acid is replaced with octanoic acid.

[0109] Reaction scheme B2 illustrates an alternative method for preparing an LHM construction block targeting CRBN, which is constructed using a ring-containing linker precursor. The linker precursor typically contains an aldehyde reactive group, which can be further coupled to another construction block by reductive amination (see, for example, general reaction G). Reaction scheme B2 [ka] Step 1: 2-(2,6-dioxopiperidine-3-yl)-5-fluoroisoindoline-1,3-dione

[0110] A mixture of 5-fluoro-1,3-dihydro-2-benzofuran-1,3-dione (5.0 g, 30.10 mmol), 3-aminopiperidine-2,6-dione hydrochloride (6.9 g, 42.14 mmol), and NaOAc (4.2 g, 51.17 mmol) in HOAc (50 mL) was stirred at 120°C for 5 hours and then concentrated under vacuum. The residue was washed with water, and the solid was collected by filtration. The crude product was washed twice with water, then twice with ethyl acetate, and dried under oven conditions to obtain 2-(2,6-dioxopiperidine-3-yl)-5-fluoroisoindorin-1,3-dione (7.7 g, 92%) as a light brown solid. 1 H NMR (300 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.03 - 8.00 (m, 1H), 7.87 - 7.85 (m, 1H), 7.75 - 7.70 (m, 1H), 5.19 - 5.15 (m, 1H), 2.94 - 2.86 (m, 1H), 2.63 - 2.48 (m, 2H), 2.12 - 2.06 (m, 1H). Step 2: Amine substitution with aryl fluoride

[0111] To a 10 mL solution of 2-(2,6-dioxopiperidine-3-yl)-5-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (1.0 g, 3.62 mmol) in NMP (3.60 mmol), amine (3.60 mmol) and DIPEA (1.4 g, 10.83 mmol) were added. The resulting solution was stirred at 80°C for 16 hours. The reaction mixture was cooled to room temperature and purified by reverse-phase flash chromatography to obtain the corresponding final product. Step 3: Oxidation of alcohol to aldehyde

[0112] Dess-Martin periodinane (2.12 mmol) was added to a mixture of alcohols (1.06 mmol) in CH2Cl2 (10 mL). The mixture was stirred at room temperature for 1 hour. The mixture was purified by column chromatography to obtain the desired aldehyde.

[0113] It should be understood that using 4-fluoro-1,3-dihydro-2-benzofuran-1,3-dione as a starting material provided an alternative position for linking the linker to thalidomide.

[0114] Further examples of CRBN-targeted LHM constructor blocks that can be prepared according to reaction scheme B2 are described below. Intermediate 7: (3S)-1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pyrrolidine-3-carbaldehyde [ka] Step 2: 2-(2,6-dioxopiperidine-3-yl)-5-((S)-3-(hydroxymethyl)pyrrolidine-1-yl)isoindoline-1,3-dione

[0115] Following step 1 of scheme B2, 2-(2,6-dioxopiperidine-3-yl)-5-fluoroisoindorin-1,3-dione was reacted with (S)-pyrrolidine-3-ylmethanol to obtain 2-(2,6-dioxopiperidine-3-yl)-5-((S)-3-(hydroxymethyl)pyrrolidine-1-yl)isoindorin-1,3-dione (643.1 mg, 33%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.64 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 2.1 Hz, 1H), 6.80 (dd, J = 8.4, 2.1 Hz, 1H), 5.06 (dd, J = 12.9, 5.4 Hz, 1H), 4.78 (t, J = 5.4 Hz, 1H), 3.59 - 3.41 (m, 5H), 3.22 - 3.17 (m, 1H), 2.95 - 2.83 (m, 1H), 2.67 - 2.44 (m, 3H), 2.12 - 1.88 (m, 2H), 1.87 - 1.76 (m, 1H).(C 18 H19 MS(ESI) calculated value for N3O5 [M+H] + , 358.1; measured value 358.1. Step 3: (3S)-1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pyrrolidine-3-carbaldehyde

[0116] In a 5 mL volume of DCM, a mixture of 2-(2,6-dioxopiperidine-3-yl)-5-[(3S)-3-(hydroxymethyl)pyrrolidine-1-yl]isoindole-1,3-dione (258 mg, 0.72 mmol) is added, along with 1,1-bis(acetyloxy)-3-oxo-1λ 5 2-benzoiodaoxol-1-yl acetate (0.61 g, 1.44 mmol) was added. After 90 minutes, silica gel was added and the mixture was concentrated to dryness. The resulting powder was transferred to a loading cartridge, and the mixture was purified by flash chromatography using a 24 g column and eluted with 0-100% ethyl acetate / hexane to obtain (3S)-1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl]pyrrolidine-3-carbaldehyde (198 mg, 77%). LCMS C 18 H 17 Required value for N3O5: 355, Measured value: m / z = 356 [M + H] + . Intermediate 8: (3S)-1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)pyrrolidine-3-carbaldehyde [ka]

[0117] Intermediate 8 can be prepared in the same manner as intermediate 7, except that 2-(2,6-dioxopiperidine-3-yl)-5-fluoroisoindoline-1,3-dione is replaced with 2-(2,6-dioxopiperidine-3-yl)-4-fluoroisoindoline-1,3-dione prepared from 4-fluoro-1,3-dihydro-2-benzofuran-1,3-dione. Intermediate 9: 3-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl]piperazine-1-yl}propanoic acid [ka] Step 1: tert-butyl3-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl)propanoate

[0118] In 10 ml of NMP, tert-butyl 3-(piperazin-1-yl)propanoate (400.00 mg, 1.87 mmol) and 2-(2,6-dioxopiperidine-3-yl)-5-fluoroisoindole-1,3-dione (516 mg, 1.87 mmol) were added, to which N,N-diisopropylethylamine (0.65 mL, 0.48 g, 3.73 mmol) was added, followed by heating at 85-90°C for 16 hours. The resulting reaction mixture was then cooled to rt and separated into HCl / water. Next, the organic layer was washed with brine, dried, and concentrated. Purification using 10-100% HCl / hexane by silica gel column chromatography yielded 823 mg of the title compound. LCMS: C24H30N4O6, required value: 470.5, measured value: m / z = 471.8 [M+H] + . Step 2: 3-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl]piperazine-1-yl}propanoic acid

[0119] 820.00 mg, 1.74 mmol of tert-butyl 3-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl]piperazin-1-yl}propanoate was dissolved in trifluoroacetic acid (9.94 g, 87.14 mmol), and after 1 hour, the TFA was evaporated. The product was freeze-dried to obtain 3-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl]piperazin-1-yl}propanoic acid (722 mg, 100% yield). LCMS:C 20 H 22 N4O6, Required value: 414.4, Measured value: m / z = 415.4 [M+H] + . Intermediate 10: 3-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl]piperazine-1-yl}acetic acid

[0120] Intermediate 10 was prepared in the same manner as intermediate 9, except that tert-butyl 3-(piperazin-1-yl)propanoate was replaced with tert-butyl 3-(piperazin-1-yl)acetate. Intermediate 11: 2-(2-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)-2,7-diazaspiro[3.5]nonane-7-yl)acetic acid [ka] Step 1: Benzyl 2-{2-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisindole-5-yl]-2,7-diazaspiro[3.5]nonane-7-yl}acetate

[0121] In 2 mL of NMP, a mixture of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (70.00 mg, 0.25 mmol) and benzyl 2-{2,7-diazaspiro[3.5]nonan-7-yl}acetate (69.53 mg, 0.25 mmol) was added with N,N-diisopropylethylamine (0.13 mL) and heated at 85 °C overnight. The crude mixture was purified by column chromatography eluting with EtOAc / hexane (10 - 100%) to give benzyl 2-{2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-2,7-diazaspiro[3.5]nonan-7-yl}acetate (68 mg, 51%). LCMS C 29 H 30 Required value for C + . Step 2: 2-(2-(2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)acetic acid

[0122] To a solution of benzyl 2-{2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-2,7-diazaspiro[3.5]nonan-7-yl}acetate (68 mg, 0.13 mmol) in EtOH (5 mL) and DCM (2 mL) was added palladium on carbon (6 mg, 0.06 mmol). The reaction mixture was sparged with hydrogen and maintained under 1 atm of hydrogen using a balloon and stirred at room temperature for 48 h. The reaction mixture was filtered through a Celite pad and concentrated to give benzyl 2-{2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-2,7-diazaspiro[3.5]nonan-7-yl}acetate (56 mg, 99%). LCMS C 22 H 24 Required value for C + . Intermediate 12: 1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperidine-4-carbaldehyde [ka] Step 2: 2-(2,6-dioxopiperidine-3-yl)-5-(4-(hydroxymethyl)piperidine-1-yl)isoindorin-1,3-dione

[0123] Following step 1 of scheme B2, 2-(2,6-dioxopiperidine-3-yl)-5-fluoroisoindorin-1,3-dione was reacted with piperidine-4-ylmethanol to obtain 2-(2,6-dioxopiperidine-3-yl)-5-(4-(hydroxymethyl)piperidine-1-yl)isoindorin-1,3-dione (939 mg, 70%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 11.09 (s, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 2.4 Hz, 1H), 7.23 (dd, J = 8.4, 2.4 Hz, 1H), 5.07 (dd, J = 12.6, 5.4 Hz, 1H), 4.51 (t, J = 5.1 Hz, 1H), 4.07 (d, J = 13.2 Hz, 2H), 3.27 (t, J = 5.7 Hz, 2H), 2.99 - 2.80 (m, 3H), 2.62 - 2.55 (m, 2H), 2.17 - 1.95 (m, 1H), 1.76 - 1.67 (m, 3H), 1.24 - 1.12 (m, 2H).(C 19 H 21 MS(ESI) calculated value for N3O5 [M+H] + 372.1; measured value 372.2. Step 3: 1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperidine-4-carbaldehyde

[0124] According to Scheme B2, 2-(2,6-dioxopiperidin-3-yl)-5-(4-(hydroxymethyl)piperidin-1-yl)isoindoline-1,3-dione was oxidized to obtain 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbaldehyde. LCMS C 19 H 19 Required value of N3O5: 369, measured value: m / z = 370 [M+H] + .

[0125] LHM building blocks targeting VHL can generally be prepared according to Reaction Scheme B3, where first the LHM is coupled with a linker precursor containing "Linker A" (representing one or more linker segments) and two terminal reactive groups. One of the reactive groups is a carboxylic acid or its reactive equivalent, and the other reactive group X can be, for example, a carboxylic acid, hydroxyl or aldehyde group. The resulting LHM building block has a reactive moiety (X) and can be further coupled to another moiety. Reaction Scheme B3 [Chemical formula]

[0126] Further examples of LHM building blocks targeting VHL that can be prepared according to Reaction Scheme B3 are described below. Intermediate 13: 5-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-5-oxopentanoic acid [Chemical formula]

[0127] To a solution of glutaric acid (135 mg, 1.0 mmol) in THF (10 mL) and methanol (5 mL), HATU (0.39 g, 1.0 mmol) and N,N-diisopropylethylamine (0.33 mL, 1.9 mmol) were added, and the reaction mixture was stirred for 5 minutes. Then (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazole-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide (0.40 g, 0.93 mmol) was added. The reaction mixture was stirred for 16 hours, followed by quenching with 4N HCl (0.25 mL) in dioxane. The crude mixture was then concentrated on silica gel and purified by reverse-phase chromatography. LCMS C 27 H 36 Required value for N4O6S: 544, Measured value: m / z = 567.5 [M + Na] + .

[0128] 1 H NMR (500 MHz, DMSO-d6) δ 12.01 (s, 1H), 9.00 (s, 1H), 8.58 (d, J = 6.4 Hz, 1H), 7.91 (d, J = 9.3 Hz, 1H), 7.43 (p, J = 7.8, 6.7 Hz, 4H), 5.14 (d, J = 3.7 Hz, 1H), 4.55 (d, J = 9.2 Hz, 1H), 4.53 - 4.43 (m, 2H), 4.37 (s, 1H), 4.23 (dd, J = 16.0, 5.2 Hz, 1H), 3.78 - 3.52 (m, 2H), 2.46 (s, 3H), 2.28 (dt, J = 15.7, 7.7 Hz, 1H), 2.25 - 2.15 (m, 3H), 2.05 (t, J = 10.6 Hz, 1H), 1.98 - 1.83 (m, 1H), 1.72 (h, J = 6.4 Hz, 2H), 0.95 (s, 9H). Intermediate 14: 6-{[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}hexanoic acid

[0129] Intermediate 14 can be prepared in the same manner as intermediate 13, except that glutaric acid is replaced with hexanoic acid and (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazole-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide is replaced with (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}pyrrolidine-2-carboxamide. Intermediate 15: 10-{[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}decanoic acid

[0130] Intermediate 15 can be prepared in the same manner as intermediate 13, except that glutaric acid is replaced with decanoic acid, and (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazole-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide is replaced with (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}pyrrolidine-2-carboxamide. Reaction scheme B4 demonstrates another method for creating LHM construction blocks that target VHL via various binding sites to LHM. Reaction scheme B4 [ka]

[0131] Reaction scheme B4 begins by coupling a linker precursor to a VHL-targeting LHM, namely (2S,4R)-1-[(2S)-2-[(1-fluorocyclopropyl)formamide]-3,3-dimethylbutanoyl]-4-hydroxy-N-{[2-hydroxy-4-(4-methyl-1,3-thiazole-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide. The VHL-targeting LHM is prepared according to the following steps. [ka] Step 1: 2-Hydroxy-4-(4-methyl-1,3-thiazole-5-yl)benzonitrile

[0132] A solution of 4-bromo-2-hydroxybenzonitrile (25.0 g, 126 mmol), 4-methylthiazole (25.0 g, 253 mmol, 2.0 equivalents), and anhydrous KOAc (24.78 g, 252.5 mmol) in DMF (210.42 mL, 0.6 M) was foamed with argon on an ultrasonic bath for 10 minutes. Then, Pd(OAc)2 (0.567 g, 2.52 mmol) was added. The resulting mixture was stirred at 110°C under argon for 5 hours, with additional amounts of Pd(OAc)2 (0.283 g, 1.26 mmol) added every hour until the total volume of Pd(OAc)2 (1.417 g, 6.31 mmol) was reached in three steps. The reaction mixture was cooled to rt, filtered through Celite, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried on anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH) to obtain 2-hydroxy-4-(4-methyl-1,3-thiazole-5-yl)benzonitrile (17.6 g, 65%) as a yellow solid. LCMS:C 11 Required value for H8N2OS: 216.3, Measured value: m / z = 217.5 [M+H] +

[0133] 1 H NMR (300 MHz, DMSO-d6) δ 11.36 (s, 1H), 9.08 (s, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.14 (d, J = 1.6 Hz, 1H), 7.08 (dd, J = 8.0, 1.7 Hz, 1H), 2.50 (s, 3H). Step 2: 2-(aminomethyl)-5-(4-methyl-1,3-thiazole-5-yl)phenol

[0134] To a 1M LAH solution in THF (203.9 mL, 203.9 mmol), a solution of 2-hydroxy-4-(4-methyl-1,3-thiazole-5-yl)benzonitrile (17.64 g, 81.57 mmol) in THF (203.92 mL, 0.4 M) was slowly added at -10°C under argon. After the addition was complete, the reaction mixture was slowly reduced to rt over 5 hours. The reaction product was quenched by the addition of Na2SO4·10H2O and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH) to obtain 2-(aminomethyl)-5-(4-methyl-1,3-thiazole-5-yl)phenol (9.18 g, 52%) as an amber-colored oil. LCMS:C 11 H 12 Required value for N2OS: 220.3, Measured value: m / z = 221.5 [M+H] +

[0135] 1 H NMR (300 MHz, DMSO-d6) δ 8.96 (s, 1H), 7.23 - 7.15 (m, 1H), 6.87 - 6.81 (m, 2H), 3.88 (s, 2H), 2.45 (s, 3H). Step 3: Methyl(2S,4R)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-carboxylate

[0136] To a solution of methyl(2S)-2-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylbutanoic acid (41.0 g, 0.177 mol) and DIPEA (46.3 mL, 0.266 mol) in anhydrous THF (1770 mL, 0.1 M), HATU (70.8 g, 0.186 mol) was added as a solid in several portions at 10°C, and an activated ester was formed within 30 minutes. In a separate reactor, a solution of (2S,4R)-4-hydroxypyrrolidine-2-carboxylate hydrochloride (48.0 g, 1.266 mol) and DIPEA (46.3 mL, 0.266 mol, 1.5 equivalents) was prepared and cooled to -45°C under an inert atmosphere. The activated ester solution was added dropwise over 0.5 hours at -45 to -40°C, and the RM was slowly warmed overnight to RT. Water (approximately 500 mL) was added all at once to quench the reaction, and the volatiles were concentrated under vacuum. The oily residue was extracted with toluene (3 × 400 mL), washed with saturated NaHCO3 aqueous solution (250 mL), 10% KHSO4 aqueous solution (250 mL), and brine (300 mL), dried over MgSO4, filtered, and evaporated to obtain the crude product, which was purified by FC. Concentration of the corresponding fraction yielded methyl(2S,4R)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-carboxylate as a pale yellow oil (64 g, 99%). LCMS:C 17 H 30 Required value for N2O6: 358.4, Measured value: m / z = 359.3 [M + H] +

[0137] 1 H NMR (300 MHz, DMSO-d6) δ 6.54 (d, J = 9.3 Hz, 1H), 5.23 (d, J = 3.8 Hz, 1H), 4.42 - 4.29 (m, 2H), 4.16 (d, J = 9.4 Hz, 1H), 3.71 - 3.61 (m, 2H), 2.11 (dd, J = 12.2, 9.2 Hz, 1H), 1.95 - 1.85 (m, 1H), 1.38 (s, 10H), 0.94 (s, 9H). Step 4: (2S,4R)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-carboxylic acid

[0138] To a solution of methyl(2S,4R)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-carboxylate (63.5 g, 0.177 mol) in THF (220 mL, 0.8 M), LiOH·H2O (14.9 g, 0.355 mol) was added all at once as an aqueous solution (86 mL, 0.2 M) under RT. The RM was stirred under RT for 3 hours and monitored by TLC / UPLC. After the reaction was complete, 10% KHSO4 aqueous solution was added until the pH was approximately 3. The THF was concentrated under reduced pressure, and the residue was extracted with RINKAN (3 × 400 mL). The combined organic fraction was washed with 10% KHSO4 aqueous solution (200 mL) and brine (300 mL), dried over MgSO4, filtered, and evaporated to dryness. The viscous, pale yellow oily residue was sonicated with anhydrous THF (300 ml) to obtain an off-white precipitate, which was filtered and dried in vacuum at 50°C to obtain 69.6 g of (2S,4R)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-carboxylic acid (69.6 g, containing approximately 15 wt% THF). LCMS:C 16 H 28 Required value for N2O6: 344.4, Measured value: m / z = 345.2 [M + H] +

[0139] 1H NMR (300 MHz, DMSO-d6) δ 12.43 (s, 1H), 6.49 (d, J = 9.4 Hz, 1H), 5.18 (d, J = 3.7 Hz, 1H), 4.33 (bs, 1H), 4.26 (t, J = 8.4 Hz, 1H), 4.16 (d, J = 9.4 Hz, 1H), 3.69-3.52 (m, 2H),2.18 - 2.02 (m, 1H), 1.89 (ddd, J = 13.2, 9.1, 4.6 Hz, 1H), 1.38 (s, 9H), 0.94 (s, 9H). Step 5: tert-butyl N-[(2S)-1-[(2S,4R)-4-hydroxy-2-({[2-hydroxy-4-(4-methyl-1,3-thiazole-5-yl)phenyl]methyl}carbamoyl)pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate

[0140] To a solution of (2S,4R)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-carboxylic acid (14.352 g, 41.67 mmol) in DMF (138.9 mL, 0.3 M), which had been cooled under argon using an ice bath, DIPEA (10.89 mL, 62.5 mmol) and HATU (16.64 g, 43.8 mmol) were added. The resulting mixture was allowed to rise to room temperature over 0.5 hours, and then slowly added dropwise at -40°C under argon to a solution of 2-(aminomethyl)-5-(4-methyl-1,3-thiazole-5-yl)phenol (9.180 g, 41.7 mmol) and DIPEA (7.26 mL, 42.7 mmol) in DMF (83.3 mL, 0.5 M). After addition, the reaction mixture was placed in a cooling bath and slowly brought to room temperature over 5 hours. The reaction mixture was quenched by adding 5 mL of water and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (DCM / MeOH) to obtain (2S,4R)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-carboxylic acid (13.4 g, 58%) as a yellowish solid. LCMS:C 27 H 38 Required value for N4O6S: 546.7, Measured value: m / z = 547.9 [M+H] + .

[0141] After purification by flash chromatography, the double acylation byproduct 2-({[(2S,4R)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-yl]formamide}methyl)-5-(4-methyl-1,3-thiazole-5-yl)phenyl(2S)-1-(2-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylbutanoyl)pyrrolidine-2-carboxylate) was also obtained. The acyl group can be cleaved according to step 5a.

[0142] 1H NMR (300 MHz, Chloroform-d) δ 9.28 (br s, 1H), 8.70 (s, 1H), 8.11 (t, J = 6.6 Hz, 1H), 7.13 (d, J = 7.8 Hz, 1H), 6.98 (d, J = 1.8 Hz, 1H), 6.88 (dd, J = 7.7, 1.8 Hz, 1H), 5.19 (d, J = 8.9 Hz, 1H), 4.77 (t, J = 7.9 Hz, 1H), 4.51 (dd, J = 15.0, 6.9 Hz, 2H), 4.12 (td, J = 20.4, 8.4 Hz, 3H), 3.57 (dd, J = 11.4, 3.6 Hz, 1H), 2.85 (br s, 2H), 2.53 (m, 4H), 2.11 (dd, J = 13.5, 8.1 Hz, 1H), 1.56 - 1.43 (m, 2H), 1.41 (s, 9H), 0.84 (s, 9H). Step 5a: tert-butyl N-[(2S)-1-[(2S,4R)-4-hydroxy-2-({[2-hydroxy-4-(4-methyl-1,3-thiazole-5-yl)phenyl]methyl}carbamoyl)pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate

[0143] 2-({[(2S,4R)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-yl]formamide}methyl)-5-(4-methyl-1,3-thiazole-5-yl)phenyl(2S)-1-(2-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylbutanoyl)pyrrolidine-2-carboxylate (3.0 g, 3.5 mmol) was dissolved in MeOH (70 mL, 0.05 M) and K2CO3 (0.48 g, 3.5 mmol) was added. The reaction mixture was stirred at rt for 12 hours. The reaction mixture was concentrated, the residue was diluted with water, neutralized with KHSO4, extracted with DCM (3 times), and the resulting organic layer was dried under Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel flash chromatography (5% DCM / MeOH) to obtain tert-butyl N-[(2S)-1-[(2S,4R)-4-hydroxy-2-({[2-hydroxy-4-(4-methyl-1,3-thiazole-5-yl)phenyl]methyl}carbamoyl)pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate (2.14 g, 99%) as a yellowish solid. LCMS:C 27 H 38 Required value for N4O6S: 546.7, Measured value: m / z = 547.2 [M+H] +

[0144] 1H NMR (300 MHz, Chloroform-d) δ 9.29 (s, 1H), 8.80 (s, 1H), 8.19 (s, 1H), 7.14 (d, J = 7.8 Hz, 1H), 6.98 (d, J = 1.8 Hz, 1H), 6.87 (dd, J = 7.7, 1.8 Hz, 1H), 5.14 (d, J = 8.9 Hz, 1H), 4.81 (t, J = 7.9 Hz, 1H), 4.56 (q, J = 7.8 Hz, 2H), 4.12 (td, J = 13.6, 12.6, 4.7 Hz, 3H), 3.56 (dd, J = 11.4, 3.5 Hz, 1H), 2.56 (s, 4H), 2.19 - 2.05 (m, 1H), 0.83 (s, 10H). Step 6: (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-{[2-hydroxy-4-(4-methyl-1,3-thiazole-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide

[0145] To a solution of tert-butyl N-[(2S)-1-[(2S,4R)-4-hydroxy-2-({[2-hydroxy-4-(4-methyl-1,3-thiazole-5-yl)phenyl]methyl}carbamoyl)pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate (5.27 g, 9.64 mmol) in DCM (48.2 mL, 0.2 M), which had been cooled in an ice bath, 2 M HCl (38.56 mL, 77.12 mmol) in Et2O was added. The reaction mixture was stirred at room temperature for 2 hours. The solid was polished on an ultrasonic bath, filtered, washed with DCM on the filter, and dried under vacuum to obtain (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-{[2-hydroxy-4-(4-methyl-1,3-thiazole-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide (5.05 g, 99%) as a white solid. LCMS:C 22 H 30 Required value for N4O4S: 446.6, Measured value: m / z = 447.7 [M+H] +

[0146] 1 H NMR (300 MHz, D2O) δ 9.50 (d, J = 1.0 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.04 - 6.89 (m, 2H), 4.58 (dd, J = 9.9, 7.6 Hz, 1H), 4.52 (s, 1H), 4.44 - 4.23 (m, 2H), 4.08 (s, 1H), 3.80 (d, J = 11.9 Hz, 1H), 3.68 (dd, J = 11.9, 3.4 Hz, 1H), 3.46 (q, J = 7.1 Hz, 1H), 2.45 (s, 3H), 2.28 (dd, J = 13.9, 7.7 Hz, 1H), 2.01 (ddd, J = 14.0, 9.9, 4.2 Hz, 1H), 1.08 (t, J = 7.1 Hz, 2H), 0.98 (s, 9H). Step 7: (2S,4R)-1-[(2S)-2-[(1-fluorocyclopropyl)formamide]-3,3-dimethylbutanoyl]-4-hydroxy-N-{[2-hydroxy-4-(4-methyl-1,3-thiazole-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide

[0147] To a solution of 1-fluorocyclopropane-1-carboxylic acid (1.337 g, 12.85 mmol) cooled in an ice bath and dissolved in DMF (128 mL, 0.1 M), HATU (5.129 g, 13.49 mmol) and DIPEA (3.36 mL, 19.3 mmol) were added. The resulting mixture was brought to room temperature over 0.5 hours, and then (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-{[2-hydroxy-4-(4-methyl-1,3-thiazole-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide (5.05 g, quantitative yield) (6.674 g, 12.85 mmol) and DIPEA (7.83 mL, 45.0 mmol) were added dropwise at -40°C to a solution of DMF (42 mL, 0.3 M). After the addition, the reaction mixture was placed in a cooling bath and slowly brought to room temperature over 16 hours. Next, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried on anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH) to obtain (2S,4R)-1-[(2S)-2-[(1-fluorocyclopropyl)formamide]-3,3-dimethylbutanoyl]-4-hydroxy-N-{[2-hydroxy-4-(4-methyl-1,3-thiazole-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide (5.05 g, 74%) as a yellow solid. LCMS:C 26 H 33 Required value for N4O5SF: 532.6, Measured value: m / z = 533.8 [M+H] +

[0148] 1H NMR (300 MHz, Chloroform-d) δ 9.29 (s, 1H), 8.70 (s, 1H), 8.09 (dd, J = 7.5, 5.5 Hz, 1H), 7.13 (d, J = 7.8 Hz, 1H), 7.01 (dd, J = 8.5, 3.7 Hz, 1H), 6.98 (d, J = 1.8 Hz, 1H), 6.88 (dd, J = 7.7, 1.8 Hz, 1H), 4.73 (t, J = 7.9 Hz, 1H), 4.53 (br s, 1H), 4.51 - 4.40 (m, 2H), 4.18 (dd, J = 14.6, 5.4 Hz, 1H), 3.99 (d, J = 11.3 Hz, 1H), 3.63 (dd, J = 11.2, 3.7 Hz, 1H), 2.53 (s, 3H), 2.47 (ddd, J = 12.9, 7.9, 4.6 Hz, 1H), 2.15 - 2.01 (m, 1H), 1.36 - 1.22 (m, 4H), 0.91 (s, 9H).

[0149] Below are further examples of LHM constructors targeting VHL that can be prepared according to reaction scheme B4. Intermediate 16: 10-[2-({[(2S,4R)-1-[(2S)-2-[(1-fluorocyclopropyl)formamide]-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-yl]formamide}methyl)-5-(4-methyl-1,3-thiazole-5-yl)phenoxy]decanoic acid [ka] Step 1: tert-butyl 10-bromodecanoate

[0150] To a solution of 10-bromodecanoic acid (CAS: 50530-12-6, 10.0 g, 39.8 mmol, 1.0 equivalent) in anhydrous dichloromethane (0.25 M), tert-butyl alcohol (18.9 mL, 199 mmol, 5.0 equivalents) was added, followed by the addition of DMAP (0.96 g, 4.0 mmol, 0.1 equivalents) under nitrogen at 0°C. After 5 minutes, dicyclohexylcarbodiimide (9.04 g, 44 mmol, 1.1 equivalents) was added to the solution at 0°C. The reaction mixture was heated to room temperature and stirred for 20 hours. The volatile matter was concentrated, and the crude residue was directly loaded onto silica (5-10% ethyl hexane). The title compound, contaminated with DCC as an impurity, was isolated (9.0 g). Further purification was carried out by FC (eluent: 10-50% DCM in hexane) to obtain 5.8 g of tert-butyl 10-bromodecanoate as a colorless oil (yield 47%).

[0151] 1 H NMR (300 MHz, Chloroform-d) δ 3.42 (t, J = 6.9 Hz, 2H), 2.22 (t, J = 7.5 Hz, 2H), 1.87 (p, J = 6.9 Hz, 2H), 1.68 - 1.51 (m, 2H), 1.46 (s, 9H), 1.45 - 1.37 (m, 2H), 1.31 (s, 8H). Step 2: tert-butyl10-[2-({[(2S,4R)-1-[(2S)-2-[(1-fluorocyclopropyl)formamide]-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-yl]formamide}methyl)-5-(4-methyl-1,3-thiazole-5-yl)phenoxy]decanoate

[0152] (2S,4R)-1-[(2S)-2-[(1-fluorocyclopropyl)formamide]-3,3-dimethylbutanoyl]-4-hydroxy-N-{[2-hydroxy-4-(4-methyl-1,3-thiazole-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide (0.8 g, 1.5 mmol, 1.0 equivalent) was dissolved in anhydrous DMF (15 mL, 0.1 M) to which Cs2CO3 (0.734 g, 2.25 mmol, 1.5 equivalents) and tert-butyl 10-bromodecanoate (0.646 g, 2.10 mmol, 1.4 equivalents) were added. The reaction mixture was purged with argon, sealed, and stirred at 25°C for 16 hours. The solid was filtered, washed with ELISA (5 mL), and discarded. The resulting filtrate was diluted with water (60 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. This crude product was purified by flash chromatography (hexane / ethyl acetate) to obtain 0.99 g of the title compound as a white solid (yield 87%). ESI(+)[M+H] + =782.4

[0153] 1H NMR (300 MHz, Chloroform-d) δ 8.70 (s, 1H), 7.34 (d, J = 7.7 Hz, 1H), 7.25 (t, J = 5.9 Hz, 1H), 7.05 (dd, J = 8.7, 3.6 Hz, 1H), 6.96 (dd, J = 7.6, 1.6 Hz, 1H), 6.89 (d, J = 1.6 Hz, 1H), 4.76 (t, J = 7.7 Hz, 1H), 4.61 - 4.49 (m, 3H), 4.44 (dd, J = 14.8, 5.4 Hz, 1H), 4.09 - 3.97 (m, 3H), 3.64 (dd, J = 11.3, 3.9 Hz, 1H), 2.65 - 2.56 (m, 1H), 2.55 (s, 3H), 2.22 (t, J = 7.5 Hz, 2H), 2.15 (d, J = 2.6 Hz, 1H), 1.87 (p, J = 6.6 Hz, 2H), 1.59 (t, J = 7.1 Hz, 2H), 1.52 (m, 2H), 1.46 (s, 9H), 1.43 - 1.32 (m, 10H), 0.96 (s, 9H). Step 3: 10-[2-({[(2S,4R)-1-[(2S)-2-[(1-fluorocyclopropyl)formamide]-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-yl]formamide}methyl)-5-(4-methyl-1,3-thiazole-5-yl)phenoxy]decanoic acid

[0154] To a solution of tert-butyl 10-[2-({[(2S,4R)-1-[(2S)-2-[(1-fluorocyclopropyl)formamide]-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-yl]formamide}methyl)-5-(4-methyl-1,3-thiazole-5-yl)phenoxy]decanoate (0.993 g, 1.31 mmol, 1.0 equivalent) in anhydrous DCM (6.5 mL, 0.2 M), TFA (2.00 mL, 26.17 mmol, 20 equivalents) was added. The reaction mixture was stirred at 25°C for 3 hours. The reaction mixture was evaporated under vacuum, and the resulting oily substance was treated with aqueous ammonia solution (20%, 5 mL). After stirring for 1 hour, an oily substance was formed. The supernatant was decanted. The oily substance was dried under vacuum and purified using reverse-phase flash chromatography (20%-60% acetonitrile / 0.1% formic acid aqueous solution) to obtain 0.703 g of the title compound as a white solid (yield 77%). LC-MS (254 nm): RT = 3.037 min, 100% purity, ESI (+) [M+H] + =703.2

[0155] 1H NMR (300 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.99 (s, 1H), 8.51 (t, J = 5.9 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.31 (dd, J = 9.3, 2.9 Hz, 1H), 7.01 (d, J = 1.7 Hz, 1H), 6.96 (dd, J = 7.7, 1.6 Hz, 1H), 5.19 (s, 1H), 4.66 - 4.57 (m, 1H), 4.53 (t, J = 8.2 Hz, 1H), 4.36 (s, 1H), 4.25 (qd, J = 16.7, 5.9 Hz, 2H), 4.05 (t, J = 6.3 Hz, 2H), 3.73 - 3.56 (m, 2H), 2.47 (s, 3H), 2.19 (t, J = 7.3 Hz, 2H), 2.15 - 2.09 (m, 1H), 1.93 (ddd, J = 13.0, 8.9, 4.5 Hz, 1H), 1.76 (p, J = 6.4 Hz, 2H), 1.57 - 1.38 (m, 6H), 1.38 - 1.15 (m, 12H), 0.97 (s, 9H). Intermediate 17: 3-{2-[2-({[(2S,4R)-1-[(2S)-2-[(1-fluorocyclopropyl)formamide]-3-methylbutanoyl]-4-hydroxypyrrolidine-2-yl]formamide}methyl)-5-(4-methyl-1,3-thiazole-5-yl)phenoxy]ethoxy}propanoic acid [ka] Step 1: tert-butyl 3-(2-bromoethoxy)propanoate

[0156] A solution of tert-butyl 3-(2-hydroxyethoxy)propanoate (3.0 g, 16 mmol, 1 equivalent) and carbon tetrabromide (7.8 g, 24 mmol, 1.5 equivalents) in dichloromethane (15 mL) was prepared in a 50 mL flask and cooled to 0°C. Triphenylphosphine (6.2 g, 24 mmol, 1.5 equivalents) was added in several portions over 30 minutes via a powder funnel with vigorous stirring. Upon addition of phosphine, the colorless solution turned light brown, and the mixture was stirred for a further 2 hours at room temperature. The mixture was concentrated and rapidly added to hexane (50 mL) with stirring. The white precipitate was filtered, the remaining solution was concentrated, and the resulting residue was purified by FC (elution with DCM / MeOH-9 / 1 yielded 4.1 g of the title compound (yield 62%)).

[0157] Step 2: tert-butyl3-{2-[2-({[(2S,4R)-1-[(2S)-2-[(1-fluorocyclopropyl)formamide]-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-yl]formamide}methyl)-5-(4-methyl-1,3-thiazole-5-yl)phenoxy]ethoxy}propanoate

[0158] (2S,4R)-1-[(2S)-2-[(1-fluorocyclopropyl)formamide]-3,3-dimethylbutanoyl]-4-hydroxy-N-{[2-hydroxy-4-(4-methyl-1,3-thiazole-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide (1.5 g, 2.82 mmol, 1.0 equivalent) was dissolved in DMF (18.77 mL, 0.15 M), to which Cs2CO3 (1.376 g, 4.22 mmol, 1.5 equivalents) and tert-butyl 3-(2-bromoethoxy)propanoate (2.18 g, 3.94 mmol, 1.4 equivalents) were added. The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, extracted with ethyl acetate (3 times), the organic layer was dried over Na2SO4, concentrated, and the resulting residue was purified by elution with DCM / MeOH-9 / 1 by FC to obtain 1.8 g of the title compound as a pale yellow oily substance (quantitative yield). UPLC (12 min, 254 nm): RT=6.25 min, 100% purity, ESI[M]+ H + ]+=705.6 Step 3: 3-{2-[2-({[(2S,4R)-1-[(2S)-2-[(1-fluorocyclopropyl)formamide]-3-methylbutanoyl]-4-hydroxypyrrolidine-2-yl]formamide}methyl)-5-(4-methyl-1,3-thiazole-5-yl)phenoxy]ethoxy}propanoic acid

[0159] To a solution of tert-butyl 3-{2-[2-({[(2S,4R)-1-[(2S)-2-[(1-fluorocyclopropyl)formamide]-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-yl]formamide}methyl)-5-(4-methyl-1,3-thiazole-5-yl)phenoxy]ethoxy}propanoate (1.8 g, 2.64 mmol, 1 equivalent) in DCM (17.6 mL, 0.15 M), TFA (13.2 mL, 0.2 M) was added dropwise at 0°C. The reaction mixture was stirred at RT for 1 hour. The reaction mixture was concentrated, and the residue was diluted with 50 mL of NH4OH aqueous solution (to pH=11), placed in an ultrasonic bath for 0.5 hours, and then stirred for exactly 1 hour. The resulting slurry was concentrated and purified twice by RF. First, 0.3 g of the title compound was obtained by elution with ACN / H2O, and then 1 g of the title compound was obtained by elution with ACN / H2O (0.1% formic acid).

[0160] After neutralization with NH4OH, the product began to form an ammonium salt, which was released along with formic acid during the second purification. The total amount was combined to obtain 1.3 g of the title compound (76% yield). LC-MS (254 nm): RT=2.29 min, 99% purity, ESI(+)[M+H] + = 649.1.

[0161] 1H NMR (300 MHz, Chloroform-d) δ 8.70 (s, 1H), 7.37 (d, J = 7.8 Hz, 2H), 7.09 - 7.03 (m, 1H), 6.99 (dd, J = 7.7, 1.6 Hz, 1H), 6.91 (d, J = 1.6 Hz, 1H), 4.76 (t, J = 8.1 Hz, 1H), 4.64 - 4.51 (m, 3H), 4.41 (dd, J = 14.3, 5.2 Hz, 1H), 4.20 (t, J = 4.2 Hz, 2H), 4.03 (d, J = 11.3 Hz, 1H), 3.89 (td, J = 8.6, 7.8, 4.4 Hz, 4H), 3.77 (dd, J = 11.3, 3.7 Hz, 1H), 2.66 (ddd, J = 19.7, 14.9, 5.1 Hz, 2H), 2.54 (s, 3H), 2.33 - 2.14 (m, 2H), 1.41 - 1.23 (m, 4H), 1.03 (s, 9H).

[0162] Intermediate 18: 1-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide)methyl)-5-(4-methylthiazole-5-yl)phenoxy)ethoxy}ethoxy)ethoxy]propanoic acid

[0163] Intermediate 18 was prepared in a similar manner to intermediate 17, by using tert-butyl 3-(2-hydroxyethoxy)propanoate instead of tert-butyl 3-{2-[2-(2-bromoethoxy)ethoxy]ethoxy}propanoate in step 1, to obtain the title compound as a white solid. LCMS (254 nm): RT = 2.27 min, 96.35% purity, ESI [M+H] + = 736.88.

[0164] 1H NMR (300 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.51 (t, J = 6.0 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.31 (dd, J = 9.2, 2.9 Hz, 1H), 7.04 (d, J = 1.7 Hz, 1H), 6.97 (dd, J = 7.7, 1.6 Hz, 1H), 5.19 (s, 1H), 4.60 (d, J = 9.1 Hz, 1H), 4.51 (t, J = 8.2 Hz, 1H), 4.35 (s, 1H), 4.28 (d, J = 6.1Hz, 1H), 4.25 - 4.14 (m, 3H), 3.79 (dd, J = 5.8, 3.4 Hz, 2H), 3.66 - 3.46 (m, 12H), 2.46 (s, 3H), 2.42 (t, J = 6.3 Hz, 2H), 2.10 (dd, J = 13.0, 8.0 Hz, 1H), 1.92 (ddd, J = 13.1, 9.0, 4.4 Hz, 1H), 1.49 - 1.28 (m, 2H), 1.21 (tq, J = 8.4, 4.6, 3.8 Hz, 2H), 0.96 (s, 9H). General scheme for coupling C.HPK1 binder and LHM construction blocks

[0165] The following general methods A to F illustrate the formation of bonds to obtain compounds of formula (I) or formula (II) and their respective substructures by coupling the construction blocks. General Procedure A: Connecting the SNAR to the harness [ka]

[0166] Substituted anilines were prepared as follows: 1 equivalent of aryl fluoride was added to a 0.4 M solution of primary or secondary amine (1 equivalent) and DIPEA (4.0 equivalents). The reaction mixture was stirred at 120°C for 4 hours. At this point, LC-MS indicated the loss of starting material. The reaction mixture was cooled to rt, and water (half the volume of NMP) was added. This crude mixture was directly injected onto a reverse-phase ISCO and purified by chromatography C to obtain the desired product.

[0167] General procedure B: Deprotection of BOC (and t-butyl ester hydrolysis) [ka] Tert-butylcarbamate was deprotected according to a general procedure to yield primary and secondary amines, and tert-butyl ester was deprotected according to a general procedure to yield carboxylic acids. To a stirred solution of tert-butylcarbamate (or tert-butyl ester) substrate (1 equivalent) in DCM (0.23 M), HCl (4N in dioxane, 18 equivalents) was added dropwise. 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. General procedure C: Saponification of esters [ka]

[0168] The saponification reactions of methyl and ethyl esters were carried out according to the following general procedure. One equivalent of the ester starting material was dissolved in rt of THF (0.25 M). To this solution, lithium hydroxide (aqueous solution, 0.55 M, 1.1 equivalents) was added, and the resulting mixture was vigorously stirred overnight. At this point, LC-MS showed the loss of the starting material, and the reactants were concentrated to dryness to obtain the lithium salt product. General Procedure D: Reductive Amination [ka]

[0169] To a solution of aldehyde (1 equivalent) and amine (1 equivalent) in DCM (0.25 M), STAB (3 equivalents) was added, and the reaction mixture was stirred at rt for 30 minutes to 24 hours until LC-MS showed conversion to the desired product. The reaction mixture was quenched by the addition of saturated sodium bicarbonate. The reaction mixture was extracted with DCM (twice), the combined organic matter was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. General Procedure E: Alkylation of Amines [ka]

[0170] Potassium carbonate (2 equivalents) was added to a stirred amine solution in DMF (0.2 M), followed by the dropwise addition of alkyl bromide (1.1 equivalents in 0.57 M DMF solution). The reaction mixture was stirred overnight in RT. The reaction mixture was diluted in DCM, the organic phase was washed with water (twice) and brine (once), dried over sodium sulfate, filtered, and concentrated under vacuum. The crude residue was purified by chromatography B to obtain the desired product. General Procedure F: Coupling of BOP amides [ka]

[0171] Amine (1 equivalent) and DIPEA (5 equivalents) were added to a DMF solution of acid (0.1 M). Finally, BOP (1.3 equivalents) was added, and the reaction mixture was stirred at rt for 16 hours. The reaction mixture was diluted with DMF, filtered using a syringe filter, and further purified by RP-HPLC to obtain the desired product. definition

[0172] The following description outlines exemplary methods, parameters, etc. However, it should be noted that such description is not intended to limit the scope of this disclosure and is instead provided as a description of exemplary embodiments.

[0173] A dash ("-") that is not present between two letters or symbols is used to indicate the bonding point of a substituent. For example, -C(O)NH2 is bonded via a carbon atom. Dashes at the beginning or end of a chemical group are for convenience only. Chemical groups can be illustrated with or without dashes, with or without, without losing their usual meaning. A wavy line drawn through a single line within a structure indicates the bonding point of a group. Unless chemically or structurally required, the order in which chemical groups are written or named neither indicates nor implies direction.

[0174] Prefix “C” u~v " indicates that the following group has u to v carbon atoms. For example, "C 1~6 The term "alkyl" indicates that an alkyl group has 1 to 6 carbon atoms.

[0175] References to values ​​or parameters marked "approximately" in this specification include (and are described) embodiments relating to the value or parameter itself. In certain embodiments, the term "approximately" includes the indicated amount ± 10%. In other embodiments, the term "approximately" includes the indicated amount ± 5%. In certain other embodiments, the term "approximately" includes the indicated amount ± 1%. Also, the term "approximately X" includes the description of "X". Furthermore, the singular forms "a" and "the" include references to the plural unless otherwise explicitly stated by the context. Thus, for example, a reference to "the compound" includes multiple such compounds, and a reference to "the assay" includes references to one or more assays and their equivalents known to those skilled in the art.

[0176] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain that does not contain unsaturated atoms. As used herein, alkyl refers to a chain with 1 to 20 carbon atoms (i.e., C 1~20 Alkyl), 1 to 12 carbon atoms (i.e., C 1~12 Alkyl), 1 to 8 carbon atoms (i.e., C1~8 Alkyl), 1 to 6 carbon atoms (i.e., C 1~6 Alkyl) or 1 to 4 carbon atoms (i.e., C 1~4 Alkyl compounds include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbon atoms is named by its chemical name or identified by its molecular formula, any positional isomer having that number of carbon atoms may be included. For example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0177] An alkylene or alkylene chain is a molecule in which the rest of the molecule is linked to a radical group, does not contain unsaturated atoms, 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 1-3 carbon atoms (C 1~3 This refers to unbranched or branched divalent hydrocarbon chains containing alkylenes, such as methylene, ethylene, propylene, and n-butylene. Alkylene chains can be bonded to the rest of the molecule and radical groups via one carbon in the chain or via any two carbons in the chain.

[0178] "Alkenyl" contains at least one carbon-carbon double bond and 2 to 20 carbon atoms (i.e., C 2~20 Alkenyls), or more typically 2 to 12 carbon atoms (i.e., C 2~12 Alkenyl), 2 to 8 carbon atoms (i.e., C 2~8(alkenyl), 2 to 6 carbon atoms (i.e., C 2~6 (alkenyl), or 2 to 4 carbon atoms (i.e., C 2~4 (alkenyl) refers to an alkyl group having. Examples of alkenyl groups include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0179] "Alkenylene" and "alkenylene chain" link the rest of the molecule to a radical group and contain at least one double bond, and are unbranched or branched divalent hydrocarbon chains having 2 to 20 carbon atoms, or more typically 2 to 12 carbon atoms, or 2 to 8 carbon atoms, such as, for example, ethenylene, propenylene, n-butenylene, etc. The alkenylene chain is bonded to the rest of the molecule via a single bond and to the radical group via a double bond or a single bond. The bonding points of the alkenylene chain to the rest of the molecule and the radical group can be via one carbon or any two carbons in the chain.

[0180] "Alkynyl" contains at least one carbon-carbon triple bond and has 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 (alkynyl) refers to an alkyl group having. The term "alkynyl" also includes groups having one triple bond and one double bond.

[0181] "Alkynylene" and "alkynylene chain" refer to unbranched or branched divalent hydrocarbon chains having 2 to 20 carbon atoms, or more typically 2 to 12 carbon atoms, or 2 to 8 carbon atoms, that link the rest of the molecule to a radical group and contain at least one triple bond. Alkynylene chains are bonded to the rest of the molecule via single bonds and to the radical group via double or single bonds. The bonding sites of the alkynylene chain to the rest of the molecule and the radical group can be located via one or any two carbon atoms in the chain.

[0182] "Alkoxy" refers to the "alkyl-O-" group. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexooxy, and 1,2-dimethylbutoxy.

[0183] A "haloalkoxy" refers to an alkoxy group as defined above, in which one or more hydrogen atoms are replaced by halogens.

[0184] "Alkylthio" refers to the "alkyl-S-" group.

[0185] "Amino" is -NR y R y It refers to the base, and here each R y These are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, or heteroaryl, each of which is substituted as necessary as defined herein.

[0186] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings including a condensed system (e.g., bicyclic or tricyclic). As used herein, aryl refers to a ring carbon atom (i.e., C) with 6 to 20 carbon atoms. 6~20 aryl), 6 to 15 carbocyclic atoms (i.e., C 6~15 aryl), or 6 to 10 carbon ring atoms (i.e., C6~10 It has an aryl group. Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. However, aryl does not encompass, nor overlap with, heteroaryls as defined below. When one or more aryl groups are fused with a heteroaryl, the resulting ring system is a heteroaryl. When one or more aryl groups are fused with a heterocyclyl, the resulting ring system is a heterocyclyl.

[0187] "Cyano" refers to the -CN group.

[0188] "Keto" or "oxo" refers to the oxygen group (=O).

[0189] "Carbamoyl" is -OC(O)NR y R z The "O-carbamoyl" group and -NR refer to the group. y C(O)OR z The term "N-carbamoyl" refers to both groups, and here, R y and R z These are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl, each of which may be substituted as needed.

[0190] "Carboxyl" or "carboxylic acid" refers to -C(O)OH.

[0191] "Ester" refers to both -OC(O)R and -C(O)OR, where R is a substituent, each of which may be substituted as necessary as defined herein.

[0192] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings, including fused ring systems, bridging ring systems, and spiro ring systems. The term "cycloalkyl" includes a cycloalkenyl group (i.e., a cyclic group having at least one double bond). As used herein, cycloalkyl refers to a ring with 3 to 15 carbon atoms (i.e., C3~20 Cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3~12 Cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3~10 Cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3~8 Cycloalkyl, or a ring of 3-6 carbon atoms (i.e., C 3~6 It has a cycloalkyl group. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[2.2.2]octan-1-yl. The cycloalkyl group may be attached to the remainder of the molecule by a single ring atom (e.g., as a substituent) or by two ring atoms (e.g., as a linker).

[0193] 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.

[0194] A "propylene glycol unit" refers to a divalent monomer having the structure -CH(CH3)-CH2O-, which can be repeated and extended into longer chains. A linker segment can have up to 12 propylene glycol units, or more typically up to 6.

[0195] "Halogen" or "halo" includes fluoro, chloro, bromo, and iodine.

[0196] A "haloalkyl" refers to an unbranched or branched alkyl group as previously defined, in which one or more hydrogen atoms are replaced by halogens. For example, if a residue is substituted with two or more halogens, that residue may be referred to using a prefix corresponding to the number of halogen moieties it is bound to. Dihaloalkyls and trihaloalkyls refer to alkyl groups substituted with two ("di") or three ("tri") halo groups, whose halo groups may be the same halogen, but are not necessarily the same. Examples of haloalkyls include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0197] A "heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any bonded hydrogen atoms) are independently replaced by 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 by the same or different heteroatoms. Heteroatomic groups include, but are not limited to, -N(R)-, -O-, -S-, -S(O)-, -S(O)2-, etc., where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, or heterocyclyl, each of which may be substituted as necessary. Examples of heteroalkyl groups include -OCH3, -CH2OCH3, -SCH3, -CH2SCH3, -NRCH3, and -CH2NRCH3, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be substituted as necessary. As used herein, a heteroalkyl group comprises 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms, and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0198] "Heteroaryl" refers to a 5- to 15-membered, or more typically 5- to 12-membered aromatic group having a single ring, multiple rings, or multiple fused ring having 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 Heteroaryls), or 3 to 8 carbon ring atoms (i.e., C 3~8 The heteroaryl group comprises a heteroaryl group, as well as 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, prinyl, pyridyl, pyridadinyl, benzothiazolyl, and pyrazolyl. Examples of fused heteroaryl rings, but not limited to, include 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 bonded via any of the rings in the fused system. Any aromatic ring having one or more fused rings and containing at least one heteroatom is considered a heteroaryl, regardless of its bond to the rest of the molecule (i.e., via any one of the fused rings). Heteroaryls do not encompass or overlap with previously defined aryls. Heteroaryls can be attached to the remainder of a molecule by a single ring atom (e.g., as a substituent) or by two ring atoms (e.g., as a linker).

[0199] A "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, bridging heterocyclyl groups, condensed heterocyclyl groups, and spiroheterocyclyl groups. A heterocyclyl may be a single ring or multiple rings, where these multiple rings may be condensed, bridging, or spiro. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the bonding (i.e., it may be bonded via carbon atoms or heteroatoms). Furthermore, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, where those rings may be condensed into an aryl ring or a heteroaryl ring, regardless of bonding with the rest of the molecule. As used herein, a heterocyclyl has 3 to 15 ring atoms (e.g., a 3 to 15-membered heterocyclyl, a 3 to 12-membered heterocyclyl, a 4 to 10-membered heterocyclyl, a 4 to 8-membered heterocyclyl, or a 4 to 6-membered heterocyclyl) and 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. A heterocyclyl may contain one or more oxo groups and / or thioxo groups. Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanil, azetidinyl, azetidinyl, morpholinyl, thiomorpholinyl, 4-7 membered sultams, 4-7 membered cyclic carbamates, 4-7 membered cyclic carbonates, 4-7 membered cyclic sulfides, and morpholinyl.As used herein, a heterocyclyl may include a cross-linked structure (i.e., a “cross-linked heterocyclyl”) in which a 4- to 10-membered cyclic moiety is bonded 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, cross-linked heterocyclyls include 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 further rings, where one or more further rings are 3- to 10-membered cycloalkyls or 3- to 10-membered heterocyclyls, and a single atom of one or more further rings is also an atom of a 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 condensed heterocyclyl rings, but not limited to, include 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 linked via any of the rings in the condensed system. As used herein, a bicyclic heterocyclyl group is a heterocyclyl group bonded at two points to one cyclic group, where the other cyclic group may itself be a heterocyclic or carbocyclic group. A heteroaryl can be bonded to the remainder of the molecule by a single ring atom (e.g., as a substituent) or by two ring atoms (e.g., as a linker).

[0200] "Condensation" refers to a ring that is connected to an adjacent ring and shares two adjacent ring atoms that form a covalent bond.

[0201] "Bridged" refers to a ring condensation in which non-adjacent atoms on a 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.

[0202] "Spiro" refers to a ring substituent linked by two bonds on the same carbon atom. Examples of spiro groups include 1,1-diethylcyclopentane, dimethyl-dioxolane, and 4-benzyl-4-methylpiperidine, where cyclopentane and piperidine are spiro substituents.

[0203] "Hydroxy" or "hydroxyl" refers to the -OH group. "Hydroxyalkyl" refers to an unbranched or branched alkyl group as defined above, in which one or more hydrogen atoms are replaced by hydroxyl groups.

[0204] "Nitro" refers to the -NO2 group.

[0205] "Imino" refers to a group containing a C=N double bond, such as C=NR. y , or =NC(O)R y This refers to R y The imino is selected from the group consisting of hydrogen, alkyl, aryl, cyano, haloalkyl, or heteroaryl, each of which may be substituted as needed. The imino can form a linker segment by bonding to the remainder of the molecule at carbon and nitrogen, respectively.

[0206] "Sulfonyl" refers to the -S(O)2R group, where R is a substituent or a defined group.

[0207] "Alkylsulfonyl" refers to the -S(O)2R group, where R is a substituent or a defined group.

[0208] "Alkylsulfinyl" refers to the -S(O)R group, where R is a substituent or a defined group.

[0209] "Thiocyanate" refers to -SCN.

[0210] "Thiol" refers to the -SR group, where R is a substituent or a defined group.

[0211] "Thioxo" or "thione" refers to a (=S) or (S) group.

[0212] Certain commonly used alternative chemical names may be used. For example, divalent groups, such as divalent "alkyl" groups and divalent "aryl" groups, may also be called "alkylene" or "alkylenyl" groups, or "arylene" or "aryrenyl" groups, respectively. Also, unless otherwise explicitly stated, when a combination of groups is referred to herein as a single part, for example as an arylalkyl group, the last group described contains the atom that bonds that part to the rest of the molecule.

[0213] The terms “as needed” or “as required” mean that the events or circumstances described thereafter may or may not occur, and that this description includes both cases in which such events or circumstances occur and cases in which they do not occur. The term “substituted as required” means that any one or more hydrogen atoms present in the specified atom or group may or may not be replaced by a non-hydrogen part. “Substituted as required” can range from zero to the maximum number of possible substitutions and each occurrence is independent. Where the term “substituted” is used, substitution must occur at the substituteable hydrogen atoms of the specified substituent. A substitution as required may be the same as or different from a (required) substitution.

[0214] Where a part is "substituted as necessary" and refers to a general term, such as any "alkyl," "alkenyl," "alkynyl," "haloalkyl," "cycloalkyl," "aryl," or "heteroaryl," that general term is replaced with any preceding, specifically described term, such as (C 1~3 (Alkyl), (C 4~6 Alkyl), -O(C 1~4 (Alkyl), (C 3~10 Cycloalkyl), O-(C 3~10 This can refer to cycloalkyls, etc. For example, "any aryl" includes both "aryl" and "-O(aryl)", as well as examples of aryls, such as phenyl or naphthyl. Similarly, the term "any heterocyclyl" includes both the terms "heterocyclyl" and "O-(heterocyclyl)", as well as examples of heterocyclyls, such as oxetanyl, tetrahydropyranil, morpholino, and piperidinyl. Likewise, the term "any heteroaryl" includes the terms "heteroaryl" and "O-(heteroaryl)", as well as specific heteroaryls, such as pyridine.

[0215] Some compounds of formula (I) or formula (II) may exist as “stereoisomers” or mixtures of stereoisomers. Stereoiomers refer to compounds made from the same molecules linked by the same bonds but having different, non-interchangeable three-dimensional structures. The compounds of this disclosure, or their pharmaceutically acceptable salts, may contain one or more chiral centers and thus give rise to enantiomers (two stereoisomers having molecules that are mirror images of each other but cannot be superimposed), diastereomers, and other stereoisomers that can be defined as (R)- or (S)- with respect to absolute stereochemistry. This disclosure means to include all such possible isomers, and 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 they can be separated using prior art, e.g., HPLC using a chiral column.

[0216] This disclosure also includes “deuterated analogues” of the compounds of formula (I) or formula (II), in which 1 to n hydrogens (where n is the number of hydrogens in the molecule) bonded to a carbon atom are replaced by deuterium. Such compounds exhibit increased resistance to metabolism and are therefore useful for increasing the half-life of either the compound of formula (I) or formula (II) when administered to mammals, particularly humans. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogens are replaced by deuterium.

[0217] Therapeutic compounds labeled or substituted with deuterium may have improved DMPK (drug metabolism and pharmacokinetic) properties with respect to distribution, metabolism, and elimination (ADME). Substitution with heavier isotopes such as deuterium may result in certain therapeutic advantages, such as increased in vivo half-life, reduced dose requirements, and / or improved therapeutic index, arising from greater metabolic stability. 18 Fluorine-labeled compounds may be useful in PET or SPECT studies. The isotope-labeled compounds of this disclosure can generally be prepared by using readily available isotope-labeling reagents instead of non-isotopically labeled reagents by following the procedures disclosed in the scheme or in the examples and preparations below. In this context, deuterium is understood to be a substituent in the compounds of formula (I) or formula (II).

[0218] The enrichment of such heavier isotopes, specifically deuterium, can be defined by isotopic enrichment factors. In the compounds of this disclosure, any atom not specifically designated as a particular isotope represents any stable isotope of that atom. Unless otherwise stated, where a position is specifically designated as "H" or "hydrogen," that position is understood to contain hydrogen in its naturally occurring isotopic composition. Thus, in the compounds of this disclosure, any atom specifically designated as deuterium (D) represents deuterium.

[0219] In many cases, the compounds of this disclosure can form acid salts and / or base salts in the presence of an amino group and / or a carboxyl group, or a group similar thereto.

[0220] Also provided herein are pharmaceutically acceptable salts, hydrates, or solvates of the compounds described herein. "pharmaceutically acceptable" or "physiologically acceptable" means compounds, salts, compositions, dosage forms, and other materials that are useful for preparing pharmaceutical compositions suitable for veterinary use or use in human pharmaceuticals.

[0221] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological efficacy and properties of the given compound and is desirable both biologically and otherwise. "pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts obtained using inorganic acids and salts obtained using organic acids. In addition, when the compounds described herein are obtained as acid addition salts, the free base can be obtained by making a solution of the acid salt basic. Conversely, if the product is a free base, the 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, following conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize the various synthetic methods that can be used to prepare non-toxic, pharmaceutically acceptable addition salts. pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, but are not limited to, 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)), and di(substituted alkenyl) This includes 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. Specific examples of appropriate amines include, but are not limited to, isopropylamine, trimethylamine, diethylamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, and N-ethylpiperidine.

[0222] The term "substituted" means that any one or more hydrogen atoms present in a given atom or group are replaced by one or more substituents other than hydrogen, provided that the valence of the given atom does not exceed the normal valence of the given atom. One or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amide, amidino, aryl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thion, or combinations thereof. Polymers or similar indeterminate structures reached by defining substituents with an infinite number of further substituents (e.g., a substituted aryl having a substituted alkyl that is itself substituted, with a substituted aryl group further substituted by a substituted heteroalkyl group) are not intended to be included herein. Unless otherwise noted, the maximum number of consecutive substitutions in a compound described herein is three. For example, the sequential substitution of a substituted aryl group having two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definitions are not intended to include unacceptable substitution patterns (e.g., a methyl group substituted with five fluorine atoms or a heteroaryl group having two adjacent oxygen ring atoms). Such unacceptable substitution patterns are well known to those skilled in the art. The term “substituted” may describe other chemical groups as defined herein when used to modify a chemical group. Unless otherwise specified, if a group is described as being substituted as necessary, any substituent of the group itself is unsubstituted. For example, in some embodiments, the term “substituted alkyl” refers to alkyl groups having one or more substituents, including hydroxyl, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl.In other embodiments, one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds, each being substituted. In other embodiments, substituents may be further substituted with unsubstituted halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds, each being unsubstituted. Those skilled in the art will recognize that substituents and other parts of compounds in the general formula herein should be selected to provide compounds that are stable enough to provide pharmaceutically useful compounds that can be formulated into acceptablely stable pharmaceutical compositions. Compounds having such stability are intended to be within the scope of the present invention. It should be understood by those skilled in the art that none of the above definitions and substituent combinations should result in unmanipulable species or compounds.

[0223] As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes all solvents, dispersions, coatings, antimicrobial and antifungal agents, isotonic agents, and absorption retarders. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, its use in a therapeutic composition is intended. Auxiliary active ingredients may also be incorporated into the composition.

[0224] A "solvate" is formed by the interaction of a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided. Targeted HPK1 Degradation

[0225] The compounds disclosed herein are demonstrated by cell-based profiling that degrades HPK1.

[0226] The HiBiT HPK1 jarcut cell line was used in a robust human cell high-throughput format to evaluate the total HPK1 protein levels. The HPK1 levels remaining after treatment with HPK1 CTM were measured at 24 hours. max (Maximum degradation) is reported compared to a vehicle-treated control. As further described in the biological examples, the results indicate that HPK1 CTM can degrade HPK1. These reductions were not a result of cytotoxicity as measured by parallel survival assessment (CTG). See also Table 1. Pharmaceutical compositions and uses of the difunctional compounds of formulas (I) and (II)

[0227] The bifunctional compounds of formula (I) or formula (II) have been demonstrated to degrade HPK1 and are therefore useful for treating disease indications or disorders involving HPK1 function, such as signal transduction or scaffold formation.

[0228] Various embodiments provide pharmaceutical compositions comprising a compound of formula (I) or formula (II), or any one of the substructures or specific compounds of Examples 1 to 97, and a pharmaceutically acceptable carrier.

[0229] Further embodiments provide methods for treating diseases or disorders associated with increased hematopoietic precursor kinase 1 (HPK1) activity, for increasing T cell activation, for treating cancer, for inhibiting the growth or proliferation of cancer cells, for treating or preventing hepatitis B virus (HBV) infection, or for treating or preventing human immunodeficiency virus (HIV) infection, the method comprising the step of administering to a subject in need thereof a therapeutically effective amount of any one of the compounds of formula (I) or formula (II), the substructures or compounds of Examples 1 to 97.

[0230] In a more specific embodiment, the cancer is selected from the group consisting of bladder cancer, breast cancer, colorectal cancer, gastric cancer, head and neck squamous cell carcinoma, Hodgkin 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 carcinoma.

[0231] In some embodiments, a compound of formula (I) or formula (II), or any one of the substructures or specific compounds of Examples 1 to 97, may be administered together with one or more additional therapeutic agents or pharmaceutically acceptable salts thereof in a therapeutically effective amount.

[0232] In further embodiments, one or more additional therapeutic agents include inducible T cell costimulatory molecule (ICOS) agonists, cytotoxic T lymphocyte antigen 4 (CTLA-4) blocking antibodies, PD1 and / or PD-L1 inhibitors, differentiation antigen group 47 (CD47) inhibitors, OX40 agonists, GITR agonists, CD27 agonists, CD28 agonists, CD40 agonists, CD137 agonists, Toll-like receptor 8 (TLR8) agonists, T cell immunoglobulin and mucin domain-3 (TIM-3) inhibitors, lymphocyte activator gene 3 (LAG-3) inhibitors, and CEACAM1 The group consists of inhibitors, T-cell immune receptor (TIGIT) inhibitors having Ig and ITIM domains, V-domain immunoglobulin (Ig)-containing suppressors (VISTA) for T-cell activation, anti-killer IgG-like receptor (KIR) inhibitors, STING agonists, CXC chemokine receptor type 4 (CXCR-4) inhibitors, B7-H3 inhibitors, CD73 inhibitors, inhibitory RNA, IL2 / 15 / 17 fusion proteins, MKNK1 / 2 inhibitors, JAK inhibitors, and PI3K inhibitors, or pharmaceutically acceptable salts of any of the above, or any combination thereof.

[0233] In more specific embodiments, one or more additional therapeutic agents include rituxan, doxorubicin, gemcitabine, nivolumab, pembrolizumab, pidilizumab, PDR001, TSR-001, atezolizumab, durvalumab, avelumab, pidilizumab, TSR-042, BMS-986016, ruxolitinib, N-(cyanomethyl)-4-[2-(4-morpholinoanilino)pyrimidine-4-yl]benzamide, XL147, BKM120, G DC-0941, BAY80-6946, PX-866, CH5132799, XL756, BEZ235, and GDC-0980, Waltmannin, 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-037, AEZS-129, PA799, ZSTK474, AS252424, TGX221, TG100115, IC87114, IPI-549, INCB050465, (S)-2-(1-((9H-purine-6-yl)amino)propyl)-5-fluoro-3-phenylquinazoline-4(3H)-one, (S)-2-(1-((9H-purine-6-yl)amino)ethyl)-6-fluoro-3-phenylquinazoline-4(3H Selected from the group consisting of (S)-one, (S)-2-(1-((9H-purine-6-yl)amino)ethyl)-3-(2,6-difluorophenyl)quinazoline-4(3H)-one, (S)-4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazoline-2-yl)ethyl)amino)pyrimidine-5-carbonitrile, and ipilimumab, or any pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.

[0234] In more specific embodiments, one or more additional therapeutic agents are selected from the group consisting of idelalisib, tirabrutinib, momerotinib, and entospretinib, or pharmaceutically acceptable salts of any of the foregoing, or any combination thereof.

[0235] In further embodiments, one or more additional therapeutic agents include HBV combination drugs, HBV vaccines, HBV DNA polymerase inhibitors, immunomodulators, 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, cyclophyllin inhibitors, HBV virus entry inhibitors, antisense oligonucleotides targeting viral mRNA, short interfering RNA (siRNA) and ddRNAi endonuclease modulators, ribonucleotide (ribonucelotide) reductase inhibitors, and HBV Selected from the group consisting of E antigen inhibitors, covalent closed circular DNA (cccDNA) inhibitors, farnesoid X receptor agonists, HBV antibodies, CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein modulators, retinoic acid-inducible gene 1 stimulants, NOD2 stimulants, phosphatidylinositol 3-kinase (PI3K) inhibitors, indoleamine-2,3-dioxygenase (IDO) pathway inhibitors, PD-1 inhibitors, PD-L1 inhibitors, recombinant thymosin alpha-1 agonists, Bruton's tyrosine kinase (BTK) inhibitors, KDM inhibitors, HBV replication inhibitors, arginase inhibitors, and other HBV drugs, or pharmaceutically acceptable salts of any of the above, or any combination thereof.

[0236] In more specific embodiments, one or more additional therapeutic agents include adefovir (Hepsera®), tenofovir disoproxil fumarate + emtricitabine (Truvada®), tenofovir disoproxil fumarate (Viread®), entecavir (Baraclude®), lamivudine (Epivir-HBV®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, terbivudine (Tyzeka®), Clevudine®, emtricitabine (Emtriva®), pegylated interferon alpha-2b (PEG-Intron®), Multiferon®, interferon alpha-1b (Hapgen®), and interferon alpha-2b (Intron®). A(registered trademark), pegylated interferon alpha-2a (Pegasys(registered trademark)), interferon alpha-n1 (Humoferon(registered trademark)), ribavirin, interferon beta-1a (Avonex(registered trademark)), Bioferon, Ingaron, Inmutag (Inferon), Algeron, Roferon-A, oligotide (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, alfainterferona-2b, Kalferon, Pegnano, Feronsure, PegiHep, Optipeg-A, Realfa-2B, Reliferon, Peginterferon alpha-2b, Reaferon-EC, Proquiferon, Uniferon, Urifron, Interferon alpha-2b, Anterferon, Shanferon, MOR-22, Interleukin-2 (IL-2), Recombinant Human Interleukin-2 (Shenzhen) Selected from the group consisting of Neptunus, Layfferon, Ka Shu Ning, Shang Sheng Lei Tai, Intefen, Sinogen, Fukantai, Alloferon, and celmoleukin, or any pharmaceutically acceptable salt of any of the above, or any combination thereof.

[0237] In more specific embodiments, 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, terbivudine, and lamivudine, or any pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.

[0238] In more specific embodiments, one or more additional therapeutic agents are selected from the group consisting of tenofovir alafenamide, tenofovir alafenamide fumarate, and tenofovir alafenamide hemifumarate, or any pharmaceutically acceptable salt thereof, or any combination thereof.

[0239] In further embodiments, one or more additional therapeutic agents include combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic (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, and HIV vif gene modulators, Vif dimerizing antagonists, HIV-1 virus 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, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocycline modulators, CDK-9 inhibitors, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIVThe group consists of POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein-converting enzyme PC9 stimulants, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic activators, HIV gene therapies, and HIV vaccines, or pharmaceutically acceptable salts of any of the above, or any combination thereof.

[0240] In more specific embodiments, one or more additional therapeutic agents are selected from the group consisting of HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic activators, and other drugs for treating HIV, or pharmaceutically acceptable salts of any of the foregoing, or any combination thereof.

[0241] In more specific embodiments, one or more additional therapeutic agents are selected from the group consisting of 4'-ethinyl-2-fluoro-2'-deoxyadenosine, bictegravir, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, or any pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.

[0242] In more specific embodiments, one or more additional therapeutic agents are selected from the group consisting of 4'-ethinyl-2-fluoro-2'-deoxyadenosine, bictegravir, tenofovir alafenamide, tenofovir alafenamide fumarate or tenofovir alafenamide hemifumarate, or any pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.

[0243] In more specific embodiments, one or more additional therapeutic agents are selected from the group consisting of 4'-ethinyl-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. [Examples]

[0244] Purification procedure Preparative HPLC was performed using columns such as SunFire Prep C18 OBD, XBridge Prep OBD C18, and Xbridge Shield RP18 OBD, and solvent systems such as (water-0.1% formic acid) / acetonitrile, (water-10 mmol / L NH4HCO3) / acetonitrile, or (water-10 mmol / L NH4HCO3) / acetonitrile. Chromatography A refers to purification by elution with a mixture of toluene or toluene in petroleum ether on silica gel in a pre-packed cartridge; Chromatography B refers to elution with a mixture of MeOH in DCM; and Chromatography C refers to elution with a mixture of acetonitrile in water using C18 reversed-phase silica gel. Compounds depicted without stereochemistry were tested as racemic or diasteromeric mixtures in the biological examples. Abbreviation

[0245] The abbreviations used in the examples include: BOP (benzotriazole-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, HATU (N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridine-1-ylmethylene]-N-methylmethaneaminium hexafluorophosphate N-oxide), DMSO (dimethyl sulfoxide), THF (tetrahydrofuran), SiO (ethyl acetate), ACN (acetonitrile), Et2O (diethyl acetate) (methyl), DCM (dichloromethane), MeOH (methanol), EtOH (ethanol), DCE (1,2-dichloroethane), TEA (trimethylamine), DIPEA (N,N-diisopropylethylamine), DMF (N,N-dimethylformamide), NMP (N-methyl-2-pyrrolidone), STAB (sodium triacetoxyborohydride), DMP (des-martin periodinane), TFA (trifluoroacetic acid), rt or RT (room temperature), anh (anhydrous), eq. or equiv. (equivalent). (Example 1)

[0246] 5-((6-(1'-(10-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)decanoyl)-2-oxo-1-((1s,3s)-3-(piperidine-1-yl)cyclobutyl)spiro[indorin-3,4'-piperidine]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridine-4-yl)amino)-4-fluoro-N-isopropyl-2-methylbenzamide [ka]

[0247] The title compound was synthesized according to general procedure F, using intermediate 1 (10 mg) and 10-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-4-yl]aminodecanoic acid (6.3 mg) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (4.0 mg, 24%). LCMS:C 64H 78 FN 11 The required value for O7 is 1132.4, and the measured value is 1133.2 [M+H]. + . (Example 2)

[0248] 5-((6-(1'-(1-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)-3,6,9,12-tetraoxapentadecane-15-oil)-2-oxo-1-((1s,3s)-3-(piperidine-1-yl)cyclobutyl)spiro[indorin-3,4'-piperidine]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridine-4-yl)amino)-4-fluoro-N-isopropyl-2-methylbenzamide [ka]

[0249] The title compound was synthesized according to general procedure F, using intermediate 1 (10 mg) and 1-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-4-yl]amino}-3,6,9,12-tetraoxapentadecane-15-euic acid (7.4 mg) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (4.3 mg, 25%). LCMS:C 65 H 80 FN 11 O 11 Required value: 1209.6, Measured value: 1233.1 [M+Na] + . (Example 3)

[0250] 5-((6-(1'-(8-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)amino)octanoyl)-2-oxo-1-((1s,3s)-3-(piperidine-1-yl)cyclobutyl)spiro[indorin-3,4'-piperidine]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridine-4-yl)amino)-4-fluoro-N-isopropyl-2-methylbenzamide [ka]

[0251] The title compound was synthesized according to general procedure F, using intermediate 1 (10 mg) and 8-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl]aminooctanoic acid (5.9 mg, WO2018089736A1) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (5.1 mg, 32%). LCMS:C 62 H 74 FN 11 The required value for O7 is 1103.6, and the measured value is 1105.3 [M+H]. + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.31 (d, J = 9.3 Hz, 1H), 8.57 (s, 1H), 8.35 (s, 1H), 8.13 (d, J = 7.9 Hz, 1H), 7.87 (s, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 9.7 Hz, 2H), 7.22 - 6.99 (m, 2H), 6.95 (s, 1H), 6.85 (d, J = 8.6 Hz, 1H), 5.32 - 5.20 (m, 1H), 5.02 (dd, J = 12.6, 5.3 Hz, 1H), 4.26 - 4.17 (m, 1H), 4.07 - 3.99 (m, 1H), 3.89 - 3.67 (m, 6H), 3.20 - 3.12 (m, 3H), 3.02 - 2.72 (m, 9H), 2.66 - 2.53 (m, 2H), 2.35 (s, 6H), 2.06 - 1.94 (m, 1H), 1.87 - 1.48 (m, 22H), 1.09 (d, J = 6.6 Hz, 6H). (Example 4)

[0252] 5-((6-(1'-(10-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)amino)decanoyl)-2-oxo-1-((1s,3s)-3-(piperidine-1-yl)cyclobutyl)spiro[indorin-3,4'-piperidine]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridine-4-yl)amino)-4-fluoro-N-isopropyl-2-methylbenzamide [ka]

[0253] Step 1: Synthesis of benzyl 10-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)amino)decanoate. The reaction was carried out according to general procedure A using benzyl 10-aminodecanoate (11.0 g, 39.7 mmol) and 2-(2,6-dioxopiperidine-3-yl)-5-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (9.86 g, 35.7 mmol), followed by chromatography B to obtain the title compound (4.8 g, 25%).

[0254] Step 2: Synthesis of 10-({2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl}aminodecanoic acid. A mixture of benzyl 10-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindolin-5-yl)aminodecanoate (4.8 g, 9.0 mmol), HCl (2 M, 5.0 equivalents in diethyl ether), and 10% Pd / C (20 wt%) was stirred under a hydrogen balloon for 2 hours in THF (0.03 M). After this, the reaction mixture was sparged with nitrogen for 15 minutes and then filtered on a Celite pad. Next, the filtered cake was washed with a mixture of TFA:DCM (9:1), and the filtrate was concentrated under reduced pressure to obtain the product (3.3 g, 83%).

[0255] Step 3: Synthesis of 5-((6-(1'-(10-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)amino)decanoyl)-2-oxo-1-((1s,3s)-3-(piperidine-1-yl)cyclobutyl)spiro[indoline-3,4'-piperidine]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridine-4-yl)amino)-4-fluoro-N-isopropyl-2-methylbenzamide. The title compound was synthesized according to general procedure F, using intermediate 1 (10 mg) and 10-({2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl}amino)decanoic acid (6.3 mg) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (3.7 mg, 23%). LCMS:C 64 H 78 FN 11 The required value for O7 is 1131.6, and the measured value is 1132.9 [M+H]. + . (Example 5)

[0256] 5-((6-(1'-(3-(2-(2-(2-((2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)amino)ethoxy)ethoxy)ethoxy)propanoyl)-2-oxo-1-((1s,3s)-3-(piperidine-1-yl)cyclobutyl)spiro[indorin-3,4'-piperidine]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridine-4-yl)amino)-4-fluoro-N-isopropyl-2-methylbenzamide [ka]

[0257] The title compound was synthesized according to general procedure F, using intermediate 1 (10 mg) and 3-{2-[2-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl]amino}ethoxy)ethoxy]ethoxy}propanoic acid (6.8 mg, WO2020038415A1) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (5.0 mg, 30%). LCMS:C 63 H 76 FN 11 O 10 Required value: 1165.6, Measured value: 1167.3 [M+H] + . (Example 6)

[0258] (2S,4R)-N-(2-((10-(6-(4-((2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridine-6-yl)-2-oxo-1-((1s,3s)-3-(piperidine-1-yl)cyclobutyl)spiro[indoline-3,4'-piperidine]-1'-yl)-10-oxodecyl)oxy)-4-(4-methylthiazole-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide [ka]

[0259] Step 1: Synthesis of tert-butyl10-[2-({[(2S,4R)-1-[(2S)-2-[(1-fluorocyclopropyl)formamide]-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-yl]formamide}methyl)-5-(4-methyl-1,3-thiazole-5-yl)phenoxy]decanoate. (2S,4R)-1-[(2S)-2-[(1-fluorocyclopropyl)formamide]-3,3-dimethylbutanoyl]-4-hydroxy-N-{[2-hydroxy-4-(4-methyl-1,3-thiazole-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide (0.8 g, 1.5 mmol, 1.0 equivalent) was dissolved in anhydrous DMF (15 mL, 0.1 M) to which Cs2CO3 (0.734 g, 2.25 mmol, 1.5 equivalents) and tert-butyl 10-bromodecanoate (0.646 g, 2.10 mmol, 1.4 equivalents) were added. The reaction mixture was purged with argon, sealed, and stirred at 25°C for 16 hours. The solid was filtered, washed with ELISA (5 mL), and discarded. The obtained filtrate was diluted with water (60 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by chromatography A to obtain the title compound (0.99 g, yield 87%).

[0260] Step 2: Synthesis of 10-[2-({[(2S,4R)-1-[(2S)-2-[(1-fluorocyclopropyl)formamide]-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-yl]formamide}methyl)-5-(4-methyl-1,3-thiazole-5-yl)phenoxy]decanoic acid. To a solution of tert-butyl 10-[2-({[(2S,4R)-1-[(2S)-2-[(1-fluorocyclopropyl)formamide]-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-yl]formamide}methyl)-5-(4-methyl-1,3-thiazole-5-yl)phenoxy]decanoate (0.993 g, 1.31 mmol, 1.0 equivalent) in anhydrous DCM (6.5 mL, 0.2 M), TFA (2.00 mL, 26.2 mmol, 20 equivalents) was added. The reaction mixture was stirred at 25°C for 3 hours. The reaction mixture was evaporated under vacuum, and the resulting oily substance was treated with aqueous ammonia solution (20%, 5 mL). After stirring for 1 hour, an oily substance was formed. The supernatant was decanted. The oily substance was dried in a vacuum and purified using chromatography C (20%-60% acetonitrile / 0.1% formic acid aqueous solution) to obtain the title compound as a solid (0.703 g, yield 76%).

[0261] Step 3: Synthesis of (2S,4R)-N-(2-((10-(6-(4-((2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridine-6-yl)-2-oxo-1-((1s,3s)-3-(piperidine-1-yl)cyclobutyl)spiro[indoline-3,4'-piperidine]-1'-yl)-10-oxodecyl)oxy)-4-(4-methylthiazole-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide. The title compound was synthesized according to general procedure F, using intermediate 1 (11 mg) and 10-[2-({[(2S,4R)-1-[(2S)-2-[(1-fluorocyclopropyl)formamide]-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-yl]formamide}methyl)-5-(4-methyl-1,3-thiazole-5-yl)phenoxy]decanoic acid (11 mg) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (3.6 mg, 16%). LCMS:C 77 H 100 F2N 12 The required value for O8S is 1390.7, and the measured value is 1393.2 [M+H]. + . (Example 7)

[0262] (2S,4R)-1-((S)-2-(7-(6-(4-((2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridine-6-yl)-2-oxo-1-((1s,3s)-3-(piperidine-1-yl)cyclobutyl)spiro[indoline-3,4'-piperidine]-1'-yl)-7-oxoheptanamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0263] The title compound was synthesized according to general procedure F, using intermediate 1 (11 mg) and 6-{[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}hexanoic acid (8.9 mg) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (5.2 mg, 28%). LCMS:C 71 H 91 FN 12 O7S required value: 1274.7, measured value: 1277.3 [M+2H] + . (Example 8)

[0264] (2S,4R)-1-((S)-2-(11-(6-(4-((2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridine-6-yl)-2-oxo-1-((1s,3s)-3-(piperidine-1-yl)cyclobutyl)spiro[indoline-3,4'-piperidine]-1'-yl)-11-oxoundecanamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0265] The title compound was synthesized according to general procedure F, using intermediate 1 (11 mg) and 10-{[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}decanoic acid (9.5 mg, WO2019207538A1) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (5.6 mg, 28%). LCMS:C 75 H 99 FN 12 O7S required value: 1330.7, measured value: 1333.3 [M+2H] + . (Example 9)

[0266] (2S,4R)-N-(2-(2-(2-(2-(3-(6-(4-((2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridine-6-yl)-2-oxo-1-((1s,3s)-3-(piperidine-1-yl)cyclobutyl)spiro[indoline-3,4'-piperidine]-1'-yl)-3-oxopropoxy)ethoxy)ethoxy)ethoxy)-4-(4-methylthiazole-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide [ka]

[0267] Step 1: Synthesis of tert-butyl3-[2-(2-{2-[2-({[(2S,4R)-1-[(2S)-2-[(1-fluorocyclopropyl)formamide]-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-yl]formamide}methyl)-5-(4-methyl-1,3-thiazole-5-yl)phenoxy]ethoxy}ethoxy)ethoxy]propanoate. (2S,4R)-1-[(2S)-2-[(1-fluorocyclopropyl)formamide]-3,3-dimethylbutanoyl]-4-hydroxy-N-{[2-hydroxy-4-(4-methyl-1,3-thiazole-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide (0.7 g, 1.31 mmol, 1.0 equivalent) in anhydrous DMF (13 mL, 0.1 M) was mixed with Cs2CO3 (0.642 g, 1.97 mmol, 1.5 equivalents) and tert-butyl 3-{2-[2-(2-bromoethoxy)ethoxy]ethoxy}propanoate (0.897 g, 2.63 mmol, 2.0 equivalents). The reaction mixture was purged with argon and stirred at 25°C for 16 hours. The solid was filtered, washed with ELISA (5 mL), and discarded. The obtained filtrate was diluted with water (60 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by flash chromatography to obtain the title compound as a white foam (0.63 g, yield 61%).

[0268] Step 2: Synthesis of 3-[2-(2-{2-[2-({[(2S,4R)-1-[(2S)-2-[(1-fluorocyclopropyl)formamide]-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-yl]formamide}methyl)-5-(4-methyl-1,3-thiazole-5-yl)phenoxy]ethoxy}ethoxy)ethoxy]propanoic acid. TFA (1.81 g, 15.9 mmol, 20 equivalents) was added to a solution of tert-butyl 3-[2-(2-{2-[2-({[(2S,4R)-1-[(2S)-2-[(1-fluorocyclopropyl)formamide]-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-yl]formamide}methyl)-5-(4-methyl-1,3-thiazole-5-yl)phenoxy]ethoxy}ethoxy)ethoxy]propanoate (0.63 g, 1.3 mmol, 1.0 equivalent) in anhydrous DCM (6.5 mL, 0.2 M). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was evaporated under vacuum, and the resulting oily substance was treated with aqueous ammonia solution (20%, 5 mL). After stirring for 1 hour, an oily substance was formed. The supernatant was decanted, the oily substance was dried under vacuum, and the result was purified using chromatography C (20%-60% acetonitrile / 0.1% formic acid aqueous solution) to obtain the title compound as a white solid (0.502 g, yield 87%).

[0269] Step 3: Synthesis of (2S,4R)-N-(2-(2-(2-(2-(3-(6-(4-((2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridine-6-yl)-2-oxo-1-((1s,3s)-3-(piperidine-1-yl)cyclobutyl)spiro[indoline-3,4'-piperidine]-1'-yl)-3-oxopropoxy)ethoxy)ethoxy)ethoxy)-4-(4-methylthiazole-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide. The title compound was synthesized according to general procedure F, using intermediate 1 (15 mg) and 3-[2-(2-{2-[2-({[(2S,4R)-1-[(2S)-2-[(1-fluorocyclopropyl)formamide]-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-yl]formamide}methyl)-5-(4-methyl-1,3-thiazole-5-yl)phenoxy]ethoxy}ethoxy)ethoxy]propanoic acid (15 mg) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (8.3 mg, 29%). LCMS:C 76 H 98 F2N 12 O 11 Required value for S: 1424.7, Measured value: 1425.1 [M+H] + . (Example 10)

[0270] (2S,4R)-1-((S)-2-(9-(6-(4-((2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridine-6-yl)-2-oxo-1-((1s,3s)-3-(piperidine-1-yl)cyclobutyl)spiro[indoline-3,4'-piperidine]-1'-yl)-9-oxononanamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0271] The title compound was synthesized according to general procedure F, using intermediate 1 (13 mg) and 9-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-9-oxononanoic acid (11 mg, WO2019207538A1) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (11.9 mg, 50%). LCMS:C 73 H 95 FN 12 The required value for O7S is 1302.7, and the measured value is 1303.9 [M+H]. + . 1H NMR (500 MHz, DMSO-d6) δ 9.36 (d, J = 9.9 Hz, 1H), 8.98 (s, 1H), 8.70 (s, 1H), 8.41 (s, 1H), 8.37 (d, J = 7.8 Hz, 1H), 8.14 (d, J = 7.8 Hz, 1H), 7.87 (s, 1H), 7.78 (d, J = 9.3 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.46 - 7.42 (m, 2H), 7.42 - 7.33 (m, 2H), 7.18 (d, J = 12.1 Hz, 1H), 5.30 (t, J = 6.7 Hz, 1H), 4.92 (q, J = 7.1 Hz, 1H), 4.54 - 3.32 (m, 13H), 3.04 - 2.71 (m, 6H), 2.45 (s, 3H), 2.36 (s, 5H), 2.26 (dt, J = 14.7, 7.5 Hz, 1H), 2.12 (dt, J = 14.1, 7.2 Hz, 1H), 2.01 (t, J = 10.5 Hz, 1H), 1.91 - 1.20 (m, 31H), 1.09 (d, J = 6.6 Hz, 6H), 0.94 (s, 9H) (Example 11)

[0272] 5-((6-(1'-(3-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)ethoxy)propanoyl)-2-oxo-1-((1s,3s)-3-(piperidine-1-yl)cyclobutyl)spiro[indorin-3,4'-piperidine]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridine-4-yl)amino)-4-fluoro-N-isopropyl-2-methylbenzamide [ka]

[0273] The title compound was synthesized according to general procedure F, using intermediate 1 (15 mg) and 3-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)ethoxy)propanoic acid (9 mg) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (15.5 mg, 70%). LCMS:C 59 H 68 FN 11 The required value for O8 is 1077.5, and the measured value is 1078.9 [M+H]. + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.36 (d, J = 9.1 Hz, 1H), 8.76 (s, 1H), 8.44 (s, 1H), 8.13 (d, J = 7.8 Hz, 1H), 7.86 (s, 1H), 7.61 (dd, J = 26.4, 7.9 Hz, 4H), 7.48 (d, J = 8.8 Hz, 2H), 7.17 (t, J = 10.9 Hz, 2H), 7.04 (d, J = 7.0 Hz, 1H), 6.61 (s, 1H), 5.36 - 5.29 (m, 1H), 5.04 (dd, J = 12.9, 5.4 Hz, 1H), 4.19 (dd, J = 16.6, 8.4 Hz, 1H), 4.08 - 3.97 (m, 1H), 3.94 - 3.81 (m, 2H), 3.74 (t, J = 6.7 Hz, 4H), 3.64 (t, J = 5.4 Hz, 2H), 3.56 - 3.32 (m, 4H), 3.04 - 2.60 (m, 6H), 2.36 (s, 3H), 2.07 - 1.92 (m, 1H), 1.92 - 1.29 (m, 18H), 1.09 (d, J = 6.5 Hz, 9H). (Example 12)

[0274] 5-((6-(1'-(1-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)-3,6,9,12,15-pentaoxaoctadecane-18-oil)-2-oxo-1-((1s,3s)-3-(piperidine-1-yl)cyclobutyl)spiro[indorin-3,4'-piperidine]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridine-4-yl)amino)-4-fluoro-N-isopropyl-2-methylbenzamide [ka]

[0275] The title compound was synthesized according to general procedure F, using intermediate 1 (15 mg) and 1-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)-3,6,9,12,15-pentaoxaoctadecane-18-euic acid (11 mg) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (19 mg, 52%). LCMS:C 67 H 84 FN 11 O 12 Required value: 1253.6, Measured value: 1255.0 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.35 (s, 1H), 8.65 (d, J = 10.3 Hz, 1H), 8.39 (s, 1H), 8.13 (d, J = 7.8 Hz, 1H), 7.86 (s, 1H), 7.74 - 7.43 (m, 5H), 7.16 (dd, J = 21.5, 10.4 Hz, 2H), 7.09 - 6.98 (m, 1H), 6.60 (s, 1H), 5.36 - 5.24 (m, 1H), 5.05 (dd, J = 12.8, 5.5 Hz, 1H), 4.24 - 4.16 (m, 1H), 4.02 (dd, J = 13.6, 6.8 Hz, 1H), 3.91 - 3.80 (m, 4H), 3.79 - 3.58 (m, 8H), 3.58 - 3.35 (m, 16H), 3.01 - 2.54 (m, 9H), 2.36 (s, 3H), 2.06 - 1.98 (m, 1H), 1.88 - 1.31 (m, 18H), 1.09 (d, J = 6.5 Hz, 6H). (Example 13)

[0276] (2S,4R)-N-(2-((8-(6-(4-((2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridine-6-yl)-2-oxo-1-((1s,3s)-3-(piperidine-1-yl)cyclobutyl)spiro[indoline-3,4'-piperidine]-1'-yl)-8-oxooctyl)oxy)-4-(4-methylthiazole-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide [ka]

[0277] Step 1: Synthesis of tert-butyl 8-[2-({[(2S,4R)-1-[(2S)-2-[(1-fluorocyclopropyl)formamide]-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-yl]formamide}methyl)-5-(4-methyl-1,3-thiazole-5-yl)phenoxy]octanoate. (2S,4R)-1-[(2S)-2-[(1-fluorocyclopropyl)formamide]-3,3-dimethylbutanoyl]-4-hydroxy-N-{[2-hydroxy-4-(4-methyl-1,3-thiazole-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide (1.4 g, 2.6 mmol, 1.0 equivalent) was dissolved in anhydrous DMF (17.5 mL, 0.15 M), to which tert-butyl 8-bromooctanoate (1.03 g, 3.68 mmol, 1.4 equivalents) and Cs2CO3 (1.29 g, 3.94 mmol, 1.5 equivalents) were added. The reaction mixture was sealed and stirred overnight at room temperature. Next, the reaction mixture was diluted with ELISA (20 mL) and filtered. The resulting filtrate was diluted with water (60 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by chromatography B to obtain the title compound as a solid (1.84 g, 96%).

[0278] Step 2: Synthesis of 8-[2-({[(2S,4R)-1-[(2S)-2-[(1-fluorocyclopropyl)formamide]-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-yl]formamide}methyl)-5-(4-methyl-1,3-thiazole-5-yl)phenoxy]octanoic acid. To a solution of tert-butyl 8-[2-({[(2S,4R)-1-[(2S)-2-[(1-fluorocyclopropyl)formamide]-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-yl]formamide}methyl)-5-(4-methyl-1,3-thiazole-5-yl)phenoxy]octanoate (1.84 g, 2.51 mmol, 1.0 equivalent) in anhydrous DCM (12.6 mL, 0.2 M), TFA (1.29 g, 3.94 mmol, 1.5 equivalent) was added under an argon atmosphere. The reaction mixture was stirred at room temperature for 2 hours and evaporated to dryness. The crude residue was polished with aqueous ammonia (10 mL) for 1 hour. The aqueous phase was decanted, the oily substance was dried under vacuum, and purified using chromatography C (20%-60% acetonitrile / 0.1% formic acid aqueous solution) to obtain the title compound (1.32 g, 78%).

[0279] Step 3: Synthesis of (2S,4R)-N-(2-((8-(6-(4-((2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridine-6-yl)-2-oxo-1-((1s,3s)-3-(piperidine-1-yl)cyclobutyl)spiro[indoline-3,4'-piperidine]-1'-yl)-8-oxooctyl)oxy)-4-(4-methylthiazole-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide.

[0280] The title compound was synthesized according to general procedure F, using intermediate 1 (11 mg) and 8-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide)methyl)-5-(4-methylthiazole-5-yl)phenoxy)octanoic acid (11 mg) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (10.7 mg, 53%). LCMS:C 75 H 96 F2N 12 The required value for O8S is 1362.7, and the measured value is 1364.5 [M+2H]. + ; 11H NMR (500 MHz, DMSO-d6) δ 9.33 (d, J = 9.5 Hz, 1H), 8.98 (s, 1H), 8.62 (s, 1H), 8.49 (t, J = 6.0 Hz, 1H), 8.37 (s, 1H), 8.13 (d, J = 7.8 Hz, 1H), 7.87 (s, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.53 - 7.45 (m, 2H), 7.40 (d, J = 7.8 Hz, 1H), 7.28 (dd, J = 9.2, 2.8 Hz, 1H), 7.17 (d, J = 12.2 Hz, 1H), 7.04 - 6.98 (m, 1H), 6.95 (dd, J = 7.8, 1.6 Hz, 1H), 5.28 (p, J = 6.5 Hz, 1H), 4.59 (d, J = 9.2 Hz, 1H), 4.52 (t, J = 8.2 Hz, 1H), 4.38 - 4.16 (m, 4H), 4.10 - 3.98 (m, 4H), 3.89 - 3.59 (m, 5H), 3.02 - 2.73 (m, 7H), 2.46 (s, 3H), 2.36 (s, 5H), 2.08 (t, J = 10.3 Hz, 1H), 1.96 - 1.88 (m, 1H), 1.88 - 1.29 (m, 29H), 1.26 - 1.15 (m, 3H), 1.09 (d, J = 6.6 Hz, 6H), 0.95 (s, 9H). (Example 14)

[0281] (2S,4R)-1-((S)-2-(2-(4-(3-(6-(4-((2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridine-6-yl)-2-oxo-1-((1s,3s)-3-(piperidine-1-yl)cyclobutyl)spiro[indoline-3,4'-piperidine]-1'-yl)-3-oxopropyl)piperidine-1-yl)acetamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0282] Step 1: Synthesis of tert-butyl 3-[1-(2-methoxy-2-oxoethyl)piperidine-4-yl]propanoate. The title compound was synthesized according to general procedure E, using tert-butyl 3-(piperidine-4-yl)propanoate (300 mg, 1.4 mmol) and methyl 2-bromoacetate (230 mg, 1.5 mmol) as starting materials. The title compound was obtained after chromatography C (400 mg, 99%).

[0283] Step 2: Synthesis of {4-[3-(tert-butoxy)-3-oxopropyl]piperidine-1-yl}acetic acid. The title compound was synthesized according to general procedure C, using tert-butyl 3-[1-(2-methoxy-2-oxoethyl)piperidine-4-yl]propanoate (400 mg, 1.4 mmol) as the starting material. The title compound was obtained and used without purification (370 mg, 97%).

[0284] Step 3: Synthesis of tert-butyl 3-[1-({[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methyl)piperidine-4-yl]propanoate. The title compound was synthesized according to general procedure F, using {4-[3-(tert-butoxy)-3-oxopropyl]piperidine-1-yl}acetic acid (113 mg, 0.42 mmol) and (1R,4S)-2-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]cyclopentan-1-carboxamide hydrochloride (200 mg, 0.42 mmol) as starting materials. The crude material was purified by chromatography B to obtain the title compound (280 mg, 96%).

[0285] Step 4: Synthesis of 3-[1-({[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methyl)piperidine-4-yl]propanoic acid. The title compound was synthesized according to general procedure B, using tert-butyl 3-[1-({[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methyl)piperidine-4-yl]propanoate (270 mg, 0.39 mmol) as the starting material. The title compound was obtained and used without purification (220 mg, 89%).

[0286] Step 5: Synthesis of (2S,4R)-1-((S)-2-(2-(4-(3-(6-(4-((2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridine-6-yl)-2-oxo-1-((1s,3s)-3-(piperidine-1-yl)cyclobutyl)spiro[indoline-3,4'-piperidine]-1'-yl)-3-oxopropyl)piperidine-1-yl)acetamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide. The title compound was synthesized according to general procedure F, using intermediate 1 (12 mg) and 3-(1-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)piperidine-4-yl)propanoic acid (10 mg) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (8.1 mg, 28%). LCMS:C 74 H 96 FN 13 O7S required value: 1329.7, measured value: 1331.5 [M+2H] + ; 1H NMR (500 MHz, DMSO-d6) δ 9.49 (s, 2H), 8.99 (s, 1H), 8.73 (d, J = 9.1 Hz, 1H), 8.67 (s, 1H), 8.39 (d, J = 9.3 Hz, 2H), 8.14 (d, J = 7.9 Hz, 1H), 7.87 (s, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.54 - 7.41 (m, 5H), 7.41 - 7.27 (m, 2H), 7.18 (d, J = 12.2 Hz, 1H), 5.33 - 5.25 (m, 1H), 4.92 (t, J = 7.2 Hz, 1H), 4.57 (d, J = 9.1 Hz, 1H), 4.43 (t, J = 8.2 Hz, 1H), 4.31 (s, 1H), 4.24 - 4.16 (m, 1H), 4.07 - 3.93 (m, 1H), 3.67 - 3.28 (m, 4H), 3.08 - 2.71 (m, 9H), 2.47 - 2.32 (m, 8H), 2.08 - 1.99 (m, 1H), 1.93 - 1.32 (m, 33H), 1.15 - 1.04 (m, 6H), 0.96 (d, J = 13.7 Hz, 9H). (Example 15)

[0287] (3R)-1-((1s,3S)-3-(1'-Acetyl-6-(4-((2-Fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridine-6-yl)-2-oxospiro[indoline-3,4'-piperidine]-1-yl)cyclobutyl)-N-(9-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)amino)nonyl)piperidine-3-carboxamide [ka]

[0288] Step 1: Synthesis of 5-((9-aminononyl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione. The reaction was carried out according to general procedure A using tert-butyl 9-aminononyl carbamate (8.2 g, 32 mmol) and 2-(2,6-dioxopiperidine-3-yl)-5-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (8.0 g, 29 mmol). The product of this reaction was subjected to general procedure B to obtain the title compound (3.25 g, 23% over two steps).

[0289] Step 2: Synthesis of (3R)-1-((1s,3S)-3-(1'-acetyl-6-(4-((2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridine-6-yl)-2-oxospiro[indoline-3,4'-piperidine]-1-yl)cyclobutyl)-N-(9-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)amino)nonyl)piperidine-3-carboxamide. The title compound was synthesized according to general procedure F, using intermediate 2 (12 mg) and 5-((9-aminononyl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione (10 mg) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (10.6 mg, 45%). LCMS:C 66 H 81 FN 12 The required value for O8 is 1188.6, and the measured value is 1191.2 [M+2H]. + ; 1H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.56 (s, 1H), 8.64 (s, 1H), 8.38 (s, 1H), 8.22 - 8.09 (m, 1H), 8.05 (t, J = 5.5 Hz, 1H), 7.87 (d, J = 7.5 Hz, 1H), 7.71 - 7.44 (m, 6H), 7.17 (dd, J = 12.1, 6.5 Hz, 2H), 6.93 (s, 2H), 6.84 (dt, J = 8.4, 2.8 Hz, 2H), 5.29 (p, J = 6.7 Hz, 1H), 5.07 - 4.97 (m, 1H), 4.20 (t, J = 8.3 Hz, 1H), 4.03 (dq, J = 13.1, 6.6 Hz, 1H), 3.93 - 3.45 (m, 4H), 3.20 - 2.97 (m, 8H), 2.57 (d, J = 18.8 Hz, 3H), 2.36 (s, 3H), 2.07 (s, 3H), 2.02 - 1.19 (m, 30H), 1.09 (d, J = 6.6 Hz, 6H). (Example 16)

[0290] (R)-1-((1s,3S)-3-(1'-Acetyl-6-(4-((2-Fluoro-5-(Isopropylcarbamoyl)-4-methylphenyl)amino)-3-Isopropyl-3H-Imidazo[4,5-c]pyridine-6-yl)-2-Oxospiro[Indoline-3,4'-piperidine]-1-yl)cyclobutyl)-N-(7-(2-(((2S,4R)-1-((S)-2-(1-Fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-Hydroxypyrrolidine-2-carboxamide)methyl)-5-(4-Methylthiazole-5-yl)phenoxy)heptyl)piperidine-3-carboxamide [ka]

[0291] Step 1: Synthesis of (2S,4R)-N-(2-((7-aminoheptyl)oxy)-4-(4-methylthiazole-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide. The title compound was synthesized using tert-butyl(7-bromoheptyl)carbamate as the starting material in Step 1, following the procedure outlined in Example 9, Steps 1-2.

[0292] Step 2: Synthesis of (R)-1-((1s,3S)-3-(1'-Acetyl-6-(4-((2-Fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridine-6-yl)-2-oxospiro[indoline-3,4'-piperidine]-1-yl)cyclobutyl)-N-(7-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide)methyl)-5-(4-methylthiazole-5-yl)phenoxy)heptyl)piperidine-3-carboxamide. The title compound was synthesized according to general procedure F, using intermediate 2 (12 mg) and (2S,4R)-N-(2-((7-aminoheptyl)oxy)-4-(4-methylthiazole-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide (7.7 mg) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (6.2 mg, 34%). LCMS:C 77 H 99 F2N 13 O9S requirement: 1419.7, measured value: 1422.4 [M+2H] + ; 11H NMR (500 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.98 (s, 1H), 8.76 (s, 1H), 8.50 (t, J = 6.0 Hz, 1H), 8.43 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 8.10 - 8.05 (m, 1H), 7.86 (d, J = 6.5 Hz, 1H), 7.67 - 7.44 (m, 4H), 7.40 (d, J = 7.8 Hz, 1H), 7.28 (dd, J = 9.6, 2.7 Hz, 1H), 7.18 (dd, J = 12.0, 6.7 Hz, 1H), 6.99 (t, J = 2.7 Hz, 1H), 6.95 (dd, J = 7.8, 1.6 Hz, 1H), 5.31 (p, J = 6.6 Hz, 1H), 4.59 (d, J = 9.2 Hz, 1H), 4.51 (t, J = 8.2 Hz, 1H), 4.37 - 4.14 (m, 4H), 4.07 - 3.99 (m, 4H), 3.91 - 3.34 (m, 6H), 3.13 - 2.73 (m, 8H), 2.65 - 2.57 (m, 1H), 2.45 (s, 3H), 2.37 (d, J = 2.2 Hz, 3H), 2.07 (s, 4H), 1.91 (ddd, J = 13.2, 9.2, 4.5 Hz, 3H), 1.86 - 1.56 (m, 14H), 1.56 - 1.15 (m, 14H), 1.09 (d, J = 6.6, 6H), 0.95 (s, 9H). (Example 17)

[0293] (R)-1-((1s,3S)-3-(1'-Acetyl-6-(4-((2-Fluoro-5-(Isopropylcarbamoyl)-4-methylphenyl)amino)-3-Isopropyl-3H-Imidazo[4,5-c]pyridine-6-yl)-2-Oxospiro[Indoline-3,4'-piperidine]-1-yl)cyclobutyl)-N-(9-(2-(((2S,4R)-1-((S)-2-(1-Fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-Hydroxypyrrolidine-2-carboxamide)methyl)-5-(4-Methylthiazole-5-yl)phenoxy)nonyl)piperidine-3-carboxamide [ka]

[0294] Step 1: Synthesis of (2S,4R)-N-(2-((9-aminononyl)oxy)-4-(4-methylthiazole-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide. The title compound was synthesized using tert-butyl(9-bromonol)carbamate as the starting material in Step 1, following the procedure outlined in Example 9, Steps 1-2.

[0295] Step 2: Synthesis of (R)-1-((1s,3S)-3-(1'-Acetyl-6-(4-((2-Fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridine-6-yl)-2-oxospiro[indoline-3,4'-piperidine]-1-yl)cyclobutyl)-N-(9-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide)methyl)-5-(4-methylthiazole-5-yl)phenoxy)nonyl)piperidine-3-carboxamide

[0296] The title compound was synthesized according to general procedure F, using intermediate 2 (12 mg) and (2S,4R)-N-(2-((9-aminononyl)oxy)-4-(4-methylthiazole-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide (7.7 mg) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (5.3 mg, 28%). LCMS:C 79 H 103 F2N 13 O9S requirement: 1447.8, measured value: 1449.5 [M+2H] + ; 11H NMR (500 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.68 (s, 1H), 8.49 (t, J = 6.0 Hz, 1H), 8.39 (s, 1H), 8.12 (d, J = 8.1 Hz, 1H), 8.05 (t, J = 5.9 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.58 (dd, J = 8.3, 4.7 Hz, 1H), 7.50 (d, J = 8.6 Hz, 2H), 7.40 (d, J = 7.8 Hz, 1H), 7.28 (dd, J = 9.2, 2.8 Hz, 1H), 7.18 (dd, J = 12.1, 6.7 Hz, 1H), 7.02 - 6.97 (m, 1H), 6.95 (d, J = 7.8 Hz, 1H), 5.29 (p, J = 6.6 Hz, 1H), 4.59 (d, J = 9.2 Hz, 1H), 4.51 (t, J = 8.2 Hz, 1H), 4.35 (s, 1H), 4.28 (dd, J = 16.5, 6.0 Hz, 1H), 4.19 (dd, J = 16.6, 5.2 Hz, 2H), 4.09 - 3.98 (m, 5H), 3.86 (s, 2H), 3.77 - 3.68 (m, 2H), 3.66 - 3.55 (m, 3H), 3.41 (s, 1H), 3.12 - 2.78 (m, 8H), 2.59 (s, 1H), 2.45 (s, 3H), 2.36 (d, J = 2.4 Hz, 3H), 2.07 (s, 3H), 1.​​​​​(2S,4R)-1-((S)-2-(2-(4-(2-(6-(4-((2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridine-6-yl)-2-oxo-1-((1s,3s)-3-(piperidine-1-yl)cyclobutyl)spiro[indoline-3,4'-piperidine]-1'-yl)-2-oxoethyl)piperazine-1-yl)acetamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0298] Step 1: Synthesis of tert-butyl 4-({[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methyl)piperazine-1-carboxylate. The title compound was synthesized according to general procedure F using [4-(tert-butoxycarbonyl)piperazin-1-yl]acetic acid (900 mg, 3.68 mmol) and (1R,4S)-2-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]cyclopentan-1-carboxamide hydrochloride (1.77 g, 3.68 mmol). The title compound was obtained by chromatography B (2.1 g, 85%).

[0299] Step 2: Synthesis of (2S,4R)-1-[(2S)-3,3-dimethyl-2-[2-(piperazin-1-yl)acetamide]butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide dihydrochloride. The reaction was carried out according to general procedure B using tert-butyl 4-({[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methyl)piperazine-1-carboxylate (2.1 g, 3.13 mmol) to obtain the title compound (2.0 g, 99%).

[0300] Step 3: Synthesis of methyl 2-[4-({[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methyl)piperazine-1-yl]acetate. The title compound was synthesized according to general procedure E, using (2S,4R)-1-[(2S)-3,3-dimethyl-2-[2-(piperazin-1-yl)acetamide]butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide dihydrochloride (1.34 g, 1.57 mmol) and methyl 2-bromoacetate (264 mg, 1.72 mmol) as starting materials. The title compound was obtained by chromatography B (0.590 g, 59%).

[0301] Step 4: Synthesis of [4-({[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methyl)piperazine-1-yl]acetic acid. The reaction was carried out according to general procedure C using methyl 2-[4-({[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methyl)piperazine-1-yl]acetate (589 mg, 0.92 mmol) to obtain the title compound (0.566 g, 98%).

[0302] Step 5: Synthesis of (2S,4R)-1-((S)-2-(2-(4-(2-(6-(4-((2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridine-6-yl)-2-oxo-1-((1s,3s)-3-(piperidine-1-yl)cyclobutyl)spiro[indoline-3,4'-piperidine]-1'-yl)-2-oxoethyl)piperazine-1-yl)acetamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide. The title compound was synthesized according to general procedure F, using intermediate 1 (11.5 mg) and [4-({[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methyl)piperazine-1-yl]acetic acid (10 mg) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (8.2 mg, 36%). LCMS:C 72 H 93 FN 14 O7S required value: 1316.6, measured value: 1317.6 [M+2H]+ ; 1 H NMR (500 MHz, DMSO-d6) δ 9.52 (d, J = 9.5 Hz, 1H), 8.99 (s, 1H), 8.66 (s, 1H), 8.40 (d, J = 8.5 Hz, 2H), 8.14 (d, J = 7.8 Hz, 1H), 7.88 (s, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.53 - 7.40 (m, 4H), 7.37 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 12.1 Hz, 1H), 5.29 (q, J = 6.6 Hz, 1H), 4.91 (t, J = 7.2 Hz, 1H), 4.54 (d, J = 9.4 Hz, 1H), 4.43 (t, J = 8.2 Hz, 1H), 4.33 - 3.32 (m, 22H), 3.03 - 2.92 (m, 1H), 2.92 - 2.76 (m, 6H), 2.45 (s, 3H), 2.36 (s, 3H), 2.05 (t, J = 10.3 Hz, 1H), 1.92 - 1.52 (m, 18H), 1.43 (dd, J = 53.2, 7.0 Hz, 4H), 1.09 (d, J = 6.6 Hz, 6H), 0.97 (s, 9H). (Example 19)

[0303] (2S,4R)-1-((S)-2-(5-(1-(2-(6-(4-((2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridine-6-yl)-2-oxo-1-((1s,3s)-3-(piperidine-1-yl)cyclobutyl)spiro[indoline-3,4'-piperidine]-1'-yl)-2-oxoethyl)piperidine-4-yl)pentanamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0304] Step 1: Synthesis of tert-butyl 4-(4-{[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}butyl)piperidine-1-carboxylate. The title compound was synthesized according to general procedure F, using 5-[1-(tert-butoxycarbonyl)piperidine-4-yl]pentanoic acid (107 mg, 0.37 mmol) and (1R,4S)-2-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]cyclopentan-1-carboxamide hydrochloride (150 mg, 0.31 mmol) as starting materials. The title compound was obtained by chromatography C (0.220 g, 99%).

[0305] Step 2: Synthesis of (2S,4R)-1-[(2S)-3,3-dimethyl-2-[5-(piperidine-4-yl)pentanamide]butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide hydrochloride. The reaction was carried out according to general procedure B using tert-butyl 4-(4-{[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}butyl)piperidine-1-carboxylate (0.220 g, 0.31 mmol) to obtain the title compound (0.194 g, 99%).

[0306] Step 3: Synthesis of methyl 2-[4-(4-{[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}butyl)piperidine-1-yl]acetate. The reaction was carried out according to general procedure E, using (2S,4R)-1-[(2S)-3,3-dimethyl-2-[5-(piperidine-4-yl)pentanamide]butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide hydrochloride (168 mg, 0.26 mmol) and methyl 2-bromoacetate (40 mg, 0.26 mmol). The title compound was obtained by chromatography B (69.9 mg, 39%).

[0307] Step 4: Synthesis of [4-(4-{[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}butyl)piperidine-1-yl]acetic acid. The reaction was carried out according to general procedure C using methyl 2-[4-(4-{[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}butyl)piperidine-1-yl]acetate (69.9 mg, 0.10 mmol) to obtain the title compound (67 mg, 98%).

[0308] Step 5: Synthesis of (2S,4R)-1-((S)-2-(5-(1-(2-(6-(4-((2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridine-6-yl)-2-oxo-1-((1s,3s)-3-(piperidine-1-yl)cyclobutyl)spiro[indoline-3,4'-piperidine]-1'-yl)-2-oxoethyl)piperidine-4-yl)pentanamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide. The title compound was synthesized according to general procedure F, using intermediate 1 (11.5 mg) and [4-(4-{[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}butyl)piperidine-1-yl]acetic acid (10 mg) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (8.2 mg, 46%). LCMS:C 76 H 100 FN 13 O7S required value: 1357.8, measured value: 1359.5 [M+2H] + ; 1H NMR (500 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.99 (s, 1H), 8.61 (s, 1H), 8.40 - 8.33 (m, 2H), 8.13 (d, J = 7.8 Hz, 1H), 7.88 (s, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.52 (s, 1H), 7.49 - 7.32 (m, 6H), 7.17 (d, J = 12.1 Hz, 1H), 5.31 - 5.25 (m, 1H), 4.92 (t, J = 7.2 Hz, 1H), 4.53 (d, J = 9.2 Hz, 1H), 4.45 - 4.27 (m, 6H), 4.24 - 3.30 (m, 17H), 3.22 (s, 1H), 3.02 - 2.73 (m, 10H), 2.45 (s, 4H), 2.36 (s, 3H), 2.31 - 2.23 (m, 1H), 2.13 (d, J = 8.3 Hz, 1H), 2.01 (s, 1H), 1.93 - 1.35 (m, 30H), 1.09 (d, J = 6.6 Hz, 6H), 0.94 (s, 9H). (Example 20)

[0309] (2S,4R)-1-((S)-2-(5-(1-(3-(6-(4-((2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridine-6-yl)-2-oxo-1-((1s,3s)-3-(piperidine-1-yl)cyclobutyl)spiro[indoline-3,4'-piperidine]-1'-yl)-3-oxopropyl)piperidine-4-yl)pentanamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0310] Step 1: Synthesis of methyl 3-[4-(4-{[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}butyl)piperidine-1-yl]propanoate. The reaction was carried out according to general procedure E, using (2S,4R)-1-[(2S)-3,3-dimethyl-2-[5-(piperidine-4-yl)pentanamide]butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide hydrochloride (168 mg, 0.26 mmol) and methyl 3-bromopropanoate (43 mg, 0.26 mmol). The title compound was obtained by chromatography B (47 mg, 26%).

[0311] Step 2: Synthesis of 3-[4-(4-{[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}butyl)piperidine-1-yl]propanoic acid. The reaction was carried out according to general procedure C using methyl 3-[4-(4-{[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}butyl)piperidine-1-yl]propanoate (47 mg, 0.07 mmol) to obtain the title compound (46 mg, 98%).

[0312] Step 3: Synthesis of (2S,4R)-1-((S)-2-(5-(1-(3-(6-(4-((2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridine-6-yl)-2-oxo-1-((1s,3s)-3-(piperidine-1-yl)cyclobutyl)spiro[indoline-3,4'-piperidine]-1'-yl)-3-oxopropyl)piperidine-4-yl)pentanamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide. The title compound was synthesized according to general procedure F, using intermediate 1 (5.2 mg) and 3-[4-(4-{[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}butyl)piperidine-1-yl]propanoic acid (5 mg) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (2.5 mg, 24%). LCMS:C 77 H 102 FN 13 O7S required value: 1371.8, measured value: 1374.9 [M+3H] + ; 11H NMR (500 MHz, DMSO-d6) δ 9.40 (s, 1H), 8.99 (s, 1H), 8.59 (s, 1H), 8.36 (d, J = 9.3 Hz, 2H), 8.13 (d, J = 7.8 Hz, 1H), 7.88 (s, 1H), 7.80 (d, J = 9.3 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.52 (s, 1H), 7.50 - 7.41 (m, 3H), 7.38 (d, J = 8.2 Hz, 2H), 7.17 (d, J = 12.1 Hz, 1H), 5.31 - 5.25 (m, 1H), 4.95 - 4.88 (m, 1H), 4.53 (d, J = 9.3 Hz, 1H), 4.41 (t, J = 8.0 Hz, 1H), 4.29 (s, 1H), 4.20 (t, J = 8.2 Hz, 1H), 4.07 - 3.99 (m, 1H), 3.96 - 3.30 (m, 12H), 3.02 - 2.73 (m, 11H), 2.45 (s, 3H), 2.36 (s, 3H), 2.31 - 2.23 (m, 1H), 2.12 (dt, J = 13.9, 6.4 Hz, 1H), 2.01 (t, J = 10.4 Hz, 1H), 1.88 - 1.44 (m, 22H), 1.38 (d, J = 7.0 Hz, 3H), 1.34 - 1.18 (m, 6H), 1.09 (d, J = 6.6 Hz, 6H), 0.94 (s, 9H). (Example 21)

[0313] 5-{[6-(1'-{2-[4-(3-{2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl}propyl)piperazine-1-yl]acetyl}-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl)-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl]amino}-4-fluoro-2-methyl-N-(propan-2-yl)benzamide [ka]

[0314] Step 1: Synthesis of tert-butyl 2-[4-(propa-2-in-1-yl)piperazin-1-yl]acetate. 3-bromopropa-1-yin (893 mg, 7.50 mmol) and Cs2CO3 (2.4 g, 7.50 mmol) were added to a solution of tert-butyl 2-(piperazin-1-yl)acetate (1.5 g, 7.5 mmol) in ACN (50.0 mL). The resulting mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was filtered. The filtrate was concentrated under vacuum. The residue was purified by chromatography A to obtain tert-butyl 2-[4-(propa-2-in-1-yl)piperazin-1-yl]acetate (1.1 g, 62%) as a yellow oil.

[0315] Step 2: Synthesis of tert-butyl 2-(4-(3-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)propa-2-inyl)piperazin-1-yl) acetate. To a solution of 4-bromo-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione (1.3 g, 3.86 mmol) in DMF (18.0 mL), tert-butyl 2-(4-(propa-2-inyl)piperazin-1-yl) acetate (1.4 g, 5.6 mmol), Pd(PPh3)2Cl2 (423 mg, 0.60 mmol), DIPEA (12.0 mL), and CuI (251 mg, 1.32 mmol) were added. The resulting mixture was stirred at 75°C for 4 hours. After the reaction was complete, the resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under vacuum. The residue was purified by chromatography B to obtain tert-butyl 2-(4-(3-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)propa-2-inyl)piperazine-1-yl)acetate (2.5 g, 70%) as a solid.

[0316] Step 3: Synthesis of tert-butyl 2-(4-(3-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)propyl)piperazin-1-yl) acetate. To a solution of tert-butyl 2-(4-(3-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)prop-2-inyl)piperazin-1-yl) acetate (2.1 g, 4.25 mmol) in ethanol (50.0 mL), 10% Pd / C (0.42 g, dry) was added. The resulting mixture was stirred under H2 at room temperature for 16 hours. After the reaction was complete, the reaction mixture was filtered. The filtrate was evaporated in a vacuum to obtain tert-butyl 2-(4-(3-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)propyl)piperazine-1-yl) acetate (1.6 g, crude) as a solid.

[0317] Step 4: Synthesis of 2-(4-(3-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)propyl)piperazin-1-yl)acetate 2,2,2-trifluoroacetic acid. 20.0 mL of trifluoroacetic acid was added to a solution of tert-butyl 2-(4-(3-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)propyl)piperazin-1-yl)acetate (2.1 g, 4.2 mmol) in dichloromethane (20.0 mL). The resulting mixture was stirred at room temperature for 4 hours. The resulting mixture was concentrated under vacuum. The residue was purified by preparative HPLC under the following conditions: Column: XSelect CSH Prep C18 OBD column, 5um, 19×150mm; Mobile phase A: Water (0.05% TFA), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 5%B to 20%B over 7 minutes; 254 / 220 nm; Rt: 6.05 minutes to obtain 2-(4-(3-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)propyl)piperazine-1-yl)acetic acid 2,2,2-trifluoroacetic acid (398 mg, 21%) as a solid.

[0318] Step 5: Synthesis of 5-{[6-(1'-{2-[4-(3-{2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl}propyl)piperazine-1-yl]acetyl}-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl)-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl]amino}-4-fluoro-2-methyl-N-(propan-2-yl)benzamide. The title compound was synthesized according to general procedure F, using intermediate 1 (17.9 mg) and 2-(4-(3-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)propyl)piperazine-1-yl)acetic acid 2,2,2-trifluoroacetic acid (10 mg) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (12.4 mg, 46%). LCMS:C 63 H 75 FN 12 The required value for O7 is 1130.6, and the measured value is 1133.3 [M+2H]. + ; 1H NMR (500 MHz, DMSO-d6) δ 11.14 (s, 1H), 9.49 (s, 1H), 8.63 (s, 1H), 8.39 (s, 1H), 8.13 (d, J = 7.8 Hz, 1H), 7.88 (s, 1H), 7.82 (d, J = 6.7 Hz, 2H), 7.75 (dd, J = 6.6, 2.2 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.51 (s, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.17 (d, J = 12.2 Hz, 1H), 5.34 - 5.24 (m, 1H), 5.14 (dd, J = 12.8, 5.5 Hz, 1H), 4.24 - 4.14 (m, 1H), 4.04 (dt, J = 13.8, 6.7 Hz, 1H), 3.96 - 3.07 (m, 10H), 3.01 - 2.72 (m, 13H), 2.65 - 2.52 (m, 3H), 2.36 (s, 4H), 2.10 - 1.92 (m, 4H), 1.91 - 1.50 (m, 16H), 1.48 - 1.38 (m, 1H), 1.09 (d, J = 6.5 Hz, 6H). (Example 22)

[0319] 5-[(6-{1'-[2-(2-{2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl}-2,7-diazaspiro[3,5]nonane-7-yl)acetyl]-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide [ka]

[0320] Step 1: Synthesis of tert-butyl 7-[2-(benzyloxy)-2-oxoethyl]-2,7-diazaspiro[3.5]nonane-2-carboxylate. To a solution of tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (5.0 g, 22 mmol, 1.0 equivalent) in DMF (85 mL, 0.26 M), Cs2CO3 (14.4 g, 44.2 mmol, 2.0 equivalent) and benzyl 2-bromoacetate (5.06 g, 22.1 mmol, 1.0 equivalent) were added. The reaction mixture was stirred at rt for 3 hours. At this point, the DMF was evaporated to dryness, the crude product was dissolved in water, extracted with Et2O (350 mL x 2), washed with brine, and evaporated to dryness to obtain the crude residue, which was then purified by chromatography A to obtain the title compound (6.25 g, 76%).

[0321] Step 2: Synthesis of benzyl 2-{2,7-diazaspiro[3.5]nonane-7-yl}acetate trifluoroacetate. Trifluoroacetic acid (25.5 mL, 114 mmol, 20.0 equivalents) was added to a solution of tert-butyl 7-[2-(benzyloxy)-2-oxoethyl]-2,7-diazaspiro[3.5]nonane-2-carboxylate (6.25 g, 16.7 mmol, 1.0 equivalent) in DCM (56 mL, 0.3 M). The reaction mixture was stirred overnight at RT. Next, the volatile matter was evaporated to dryness, and the crude product was polished with Et2O to obtain 8.23 ​​g of the title compound as the TFA salt (quantitative yield).

[0322] Step 3: Synthesis of benzyl 2-{2-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]-2,7-diazaspiro[3.5]nonan-7-yl}acetate. Benzyl 2-{2,7-diazaspiro[3.5]nonan-7-yl}acetate trifluoroacetate (7.7 g, 30 mmol, 1.1 equivalents) and DIPEA (10.7 mL, 81.4 mmol, 3 equivalents) were added under anhydrous conditions to a solution of 2-(2,6-dioxopiperidine-3-yl)-5-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (7.5 g, 27.1 mmol, 1 equivalent) in DMSO (54.3 mL, 0.5 M). The reaction mixture was stirred at 70°C for 48 hours. The reaction mixture was poured into ice-cold water (250 mL) and extracted with ethyl acetate. The organic layers were combined, washed with ice water (200 mL x 2), dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by chromatography A to obtain 3.6 g (25% yield) of the title compound.

[0323] Step 4: Synthesis of 2-{2-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]-2,7-diazaspiro[3.5]nonan-7-yl}acetate trifluoroacetate. Benzyl 2-{2-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]-2,7-diazaspiro[3.5]nonan-7-yl}acetate (2.5 g, 4.7 mmol) was dissolved in 5% trifluoroacetic acid (47 mL, 0.1 M) in DCM, to which 10% Pd / C (500 mg, 20 wt%) was added. The reaction mixture was purged with argon, followed by purging with hydrogen, and this process was repeated three times. The mixture was then stirred under a hydrogen atmosphere (balloon) for 1 hour. The reaction mixture was filtered through Celite and evaporated to dryness to obtain 2.08 g (80% yield) of the title compound.

[0324] Step 5: Synthesis of 5-[(6-{1'-[2-(2-{2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl}-2,7-diazaspiro[3.5]nonane-7-yl)acetyl]-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide. The title compound was synthesized according to general procedure F, using intermediate 1 (10 mg) and 2-(2-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)-2,7-diazaspiro[3.5]nonane-7-yl)acetic acid (10 mg) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (11.8 mg, 62%). LCMS:C 63 H 73 FN 12 The required value for O7 is 1128.6, and the measured value is 1131.3 [M+2H]. + ; 1H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.63 (s, 1H), 9.52 (s, 1H), 8.61 (s, 1H), 8.39 (s, 1H), 8.13 (d, J = 7.8 Hz, 1H), 7.89 (s, 1H), 7.69 (d, J = 8.1 Hz, 2H), 7.60 (d, J = 8.2 Hz, 1H), 7.52 (s, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.17 (d, J = 12.1 Hz, 1H), 6.81 (d, J = 2.0 Hz, 1H), 6.69 (dd, J = 8.4, 2.1 Hz, 1H), 5.28 (p, J = 6.6 Hz, 1H), 5.06 (dd, J = 12.8, 5.5 Hz, 1H), 4.39 (s, 1H), 4.20 (p, J = 8.4 Hz, 1H), 4.08 - 3.57 (m, 10H), 3.57 - 3.34 (m, 2H), 3.17 - 2.77 (m, 8H), 2.59 (d, J = 17.3 Hz, 1H), 2.54 (s, 3H), 2.36 (s, 3H), 2.23 - 1.95 (m, 4H), 1.94 - 1.53 (m, 15H), 1.42 (q, J = 11.6 Hz, 1H), 1.10 (d, J = 6.6 Hz, 6H). (Example 23)

[0325] 5-[(6-{1'-[2-(4-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl}piperazine-1-yl)acetyl]-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide [ka]

[0326] Step 1: Synthesis of tert-butyl 2-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}acetate. To a solution of tert-butylpiperazine-1-yl acetate dihydrochloride (4.46 g, 16.3 mmol, 1.1 equivalents) in DMSO (29.7 mL, 0.5 M), DIPEA (3.93 mL, 22.5 mmol, 2 equivalents) and 2-(2,6-dioxopiperidine-3-yl)-5-fluoroisoindorin-1,3-dione (4.1 g, 14.8 mmol, 1 equivalent) were added. The reaction mixture was heated under argon at 90°C for 40 hours. The reaction mixture was cooled to rt and 5 mL of water was added dropwise. A bright yellow precipitate formed and was filtered off. Next, the filtered cake was washed twice with water. The filtrate was extracted twice with DCM. The combined DCM layers were concentrated under vacuum and combined with the precipitate. The crude product was purified by chromatography B to obtain the title compound as a yellow solid (5.49 g, yield 81%).

[0327] Step 2: Synthesis of 2-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazin-1-yl}acetate trifluoroacetate. To a solution of tert-butyl 2-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazin-1-yl}acetate (5.49 g, 12.0 mmol, 1 equivalent) in DCM (100 mL, 0.12 M), TFA (50.6 mL, 661 mmol, 55 equivalents) was added. The reaction mixture was stirred at rt for 16 hours and then concentrated under reduced pressure. The resulting bright yellow viscous solid was sonicated with 200 mL of anhydrous diethyl ether and stirred for 1 hour. The resulting precipitate was filtered, washed twice with anhydrous Et2O, and dried under reduced pressure to obtain a bright yellow solid (6.55 g, quantitative).

[0328] Step 3: Synthesis of 5-[(6-{1'-[2-(4-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl}piperazine-1-yl)acetyl]-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide.

[0329] The title compound was synthesized according to general procedure F, using intermediate 1 (10 mg) and 2-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl)acetic acid (10 mg) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (13 mg, 70%). LCMS:C 60 H 69 FN 12 The required value for O7 is 1088.5, and the measured value is 1090.4 [M+2H]. + ; 1H NMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H), 10.18 (s, 1H), 9.53 (s, 1H), 8.62 (s, 1H), 8.39 (s, 1H), 8.14 (d, J = 7.8 Hz, 1H), 7.89 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.72 - 7.65 (m, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.53 - 7.44 (m, 3H), 7.36 (dd, J = 8.7, 2.3 Hz, 1H), 7.17 (d, J = 12.1 Hz, 1H), 5.28 (p, J = 6.7 Hz, 1H), 5.10 (dd, J = 12.7, 5.5 Hz, 1H), 4.46 (s, 1H), 4.26 - 4.11 (m, 1H), 4.08 - 3.18 (m, 10H), 3.04 - 2.73 (m, 8H), 2.64 - 2.54 (s, 4H), 2.36 (s, 3H), 2.10 - 1.99 (m, 1H), 1.92 - 1.52 (m, 17H), 1.41 (d, J = 13.0 Hz, 1H), 1.09 (d, J = 6.5 Hz, 6H). (Example 24)

[0330] 5-[(6-{1'-[1-(1-{2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-4-yl)azetidine-3-carbonyl]-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide [ka]

[0331] Step 1: Synthesis of benzyl 4-{3-[(tert-butoxy)carbonyl]azetidine-1-yl}piperidine-1-carboxylate. To a solution of tert-butylazetidine-3-carboxylate (4.5 g, 29 mmol, 1.0 equivalent) and 1-(benzyloxycarbonyl)-4-piperidinone (7.35 g, 31.5 mmol, 1.10 equivalents) in DCE (136 mL, 0.2 M), acetic acid (2.46 mL, 42.9 mmol, 1.5 equivalents) was added, and the reaction mixture was stirred at RT for 1 hour. Next, NaBH(OAc)3 (9.71 g, 45.8 mmol, 1.6 equivalents) was added, and the mixture was stirred at RT overnight. Then, the reaction mixture was quenched with aqueous NaHCO3, extracted with DCM (3 times), washed with brine, dried over Na2SO4, and concentrated to dryness. The colorless oily substance was purified by chromatography-B to obtain 9.39 g (88% yield) of the title compound.

[0332] Step 2: Synthesis of tert-butyl 1-(piperidine-4-yl)azetidine-3-carboxylate. A solution of benzyl 4-{3-[(tert-butoxy)carbonyl]azetidine-1-yl}piperidine-1-carboxylate (9.39 g, 25.1 mmol, 1.0 equivalent) in MeOH (250 mL, 0.1 M) was degassed and argon was charged three times. Next, Pd(OH)2 (0.7 g, 5.0 mmol, 0.2 equivalents) was added, the mixture was degassed again, and argon was charged three times. Then the reaction mixture was degassed, an H2 balloon was charged, and the mixture was stirred overnight at RT. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated to obtain 5.81 g (yield 96%) of the title compound.

[0333] Step 3: Synthesis of tert-butyl 1-{1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}azetidine-3-carboxylate. To a solution of 2-(2,6-dioxopiperidine-3-yl)-5-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (6.05 g, 21.9 mmol, 1.0 equivalent) in DMSO (43.8 mL, 0.5 M), tert-butyl 1-(piperidine-4-yl)azetidine-3-carboxylate (5.79 g, 24.1 mmol, 1.1 equivalent) and DIPEA (7.63 mL, 43.8 mmol, 2.0 equivalent) were added. Next, the reaction mixture was transferred to a bath preheated to 90°C and stirred overnight under an argon atmosphere. The reaction was quenched with water, extracted with DCM (three times), and the organic phase was washed with ice-cold water. The crude product was purified by elution with DCM:acetone (0-10%) by FC to obtain 6.95 g (yield 64%) of the title compound.

[0334] Step 4: Synthesis of 1-{1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}azetidine-3-carboxylic acid hydrochloride. To a solution of tert-butyl 1-{1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}azetidine-3-carboxylate (4.95 g, 9.97 mmol, 1.0 equivalent) in anhydrous DCM (100 mL, 0.1 M), 2 M HCl (50 mL, 100 mmol, 10.0 equivalent) in Et2O was added. The reaction mixture was then stirred at RT for 2 hours. Further amounts of HCl (50 mL, 100 mmol, 10.0 equivalents) in Et2O were added, and the reaction mixture was stirred for a further 3 hours. The precipitate was filtered off and redissolved in DCM, followed by the addition of 2M HCl (50 mL, 100 mmol, 10.0 equivalents) in Et2O. The reaction mixture was sonicated for 45 minutes. The precipitated solid was filtered off, washed with Et2O, and dried under vacuum to obtain 4.83 g (quantitative yield) of the title compound as the HCl salt.

[0335] Step 5: Synthesis of 5-[(6-{1'-[1-(1-{2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-4-yl)azetidine-3-carbonyl]-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide. The title compound was synthesized according to general procedure F, using intermediate 1 (11.8 mg) and rac-1-(1-{2-[(3R)-2,6-dioxopiperidine-3-yl]-1,3-dioxoisoindole-5-yl}piperidine-4-yl)azetidine-3-carboxylic acid (7 mg) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (6.5 mg, 36%). LCMS:C 63 H 73 FN 12 The required value for O7 is 1128.6, and the measured value is 1130.7 [M+2H]. + ; 1H NMR (500 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.49 (s, 1H), 8.61 (s, 1H), 8.38 (s, 1H), 8.13 (d, J = 7.8 Hz, 1H), 7.88 (s, 1H), 7.76 - 7.65 (m, 2H), 7.60 (dd, J = 8.2, 3.6 Hz, 1H), 7.53 - 7.45 (m, 2H), 7.42 (s, 1H), 7.32 (d, J = 8.2 Hz, 1H), 7.17 (d, J = 12.0 Hz, 1H), 5.37 - 5.20 (m, 1H), 5.08 (dd, J = 12.7, 5.5 Hz, 1H), 4.46 - 4.20 (m, 2H), 4.22 - 4.14 (m, 4H), 4.06 - 3.32 (m, 11H), 3.05 - 2.73 (m, 8H), 2.65 - 2.53 (m, 2H), 2.36 (s, 3H), 2.15 - 1.98 (m, 3H), 1.92 - 1.50 (m, 17H), 1.50 - 1.34 (m, 3H), 1.09 (d, J = 6.6 Hz, 6H). (Example 25)

[0336] 5-[(6-{1'-[1-(1-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl}piperidine-4-carbonyl)pyrroridine-3-carbonyl]-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide [ka]

[0337] Step 1: Synthesis of 1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-4-yl]piperidine-4-carboxylic acid. The reaction was carried out according to general procedure A, using 2-(2,6-dioxopiperidine-3-yl)-4-fluoroisoindole-1,3-dione (400 mg, 1.45 mmol) and tert-butylpiperidine-4-carboxylate (350 mg, 1.89 mmol) as starting materials. The crude material was purified by chromatography B. Using this material, the title compound was obtained (0.378 mg, 68%) according to general procedure B after chromatography C.

[0338] Step 2: Synthesis of 1-(1-{2-[-2,6-dioxopiperidine-3-yl]-1,3-dioxoiisoindole-4-yl}piperidine-4-carbonyl)pyrrolidine-3-carboxylic acid. The reaction was carried out according to general procedure F using 1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoiisoindole-4-yl]piperidine-4-carboxylic acid (50 mg, 0.13 mmol) and tert-butylpyrrolidine-3-carboxylate (27 mg, 0.16 mmol), which were purified using chromatography B. Next, this material was processed according to general procedure B, and the title compound (40 mg, 64%) was isolated after chromatography C.

[0339] Step 3: 5-[(1-(1-{2-[(3R)-2,6-dioxopiperidine-3-yl]-1,3-dioxoisoindole-4-yl}piperidine-4-carbonyl)pyrrolidine-3-carboxylic acid 6-{1'-[1-(1-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl}piperidine-4 Synthesis of -carbonyl)pyrrolidine-3-carbonyl]-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide. The title compound was synthesized according to general procedure F, using intermediate 1 (10.5 mg) and 1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)piperidine-4-carbonyl)pyrrolidine-3-carboxylic acid (7 mg) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (5.1 mg, 31%). LCMS:C 65 H 75 FN 12 The required value for O8 is 1170.6, and the measured value is 1172.5 [M+2H]. + ; 1H NMR (500 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.34 (s, 1H), 8.68 (s, 1H), 8.40 (s, 1H), 8.13 (dd, J = 7.8, 4.5 Hz, 1H), 7.87 (d, J = 2.9 Hz, 1H), 7.74 - 7.63 (m, 2H), 7.63 - 7.47 (m, 3H), 7.35 (dd, J = 10.7, 6.8 Hz, 2H), 7.18 (d, J = 12.0 Hz, 1H), 5.37 - 5.23 (m, 1H), 5.10 (dd, J = 12.9, 5.3 Hz, 1H), 4.26 - 3.26 (m, 8H), 3.03 - 2.73 (m, 8H), 2.71 - 2.54 (m, 8H), 2.36 (d, J = 6.0 Hz, 4H), 2.22 - 1.98 (m, 3H), 1.92 - 1.50 (m, 21H), 1.50 - 1.36 (m, 1H), 1.09 (dd, J = 6.6, 4.1 Hz, 6H). (Example 26)

[0340] 4-Fluoro-2-methyl-5-[(6-{2-oxo-1'-[1-[(1r,4r)-4-({2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl}amino)cyclohexanecarbonyl]pyrrolidine-3-carbonyl]-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl)amino]-N-(propan-2-yl)benzamide [ka]

[0341] Step 1: Synthesis of (trans)-4-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-4-yl]amino}cyclohexane-1-carboxylic acid. The reaction was carried out according to general procedure A, using 2-(2,6-dioxopiperidine-3-yl)-4-fluoroisoindole-1,3-dione (100 mg, 0.36 mmol) and (trans)-4-aminocyclohexane-1-carboxylic acid (104 mg, 0.72 mmol) as starting materials. The title compound was obtained by chromatography C (40 mg, 28%).

[0342] Step 2: Synthesis of 1-[(trans)-4-({2-[2,6-dioxopiperidine-3-yl]-1,3-dioxoisoindole-4-yl}amino)cyclohexanecarbonyl]pyrrolidine-3-carboxylic acid. The reaction was carried out according to general procedure F using (trans)-4-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-4-yl]amino}cyclohexane-1-carboxylic acid (32 mg, 0.08 mmol) and tert-butylpyrrolidine-3-carboxylate (16.5 mg, 0.10 mmol), which were purified using chromatography C. Next, this material was processed according to general procedure B, and the title compound (23 mg, 58%) was isolated after chromatography C.

[0343] Step 3: Synthesis of 4-fluoro-2-methyl-5-[(6-{2-oxo-1'-[1-[(1r,4r)-4-({2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl}amino)cyclohexanecarbonyl]pyrrolidine-3-carbonyl]-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl}3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl)amino]-N-(propan-2-yl)benzamide. The title compound was synthesized according to general procedure F, using intermediate 1 (10.5 mg) and 1-[(trans)-4-({2-[2,6-dioxopiperidine-3-yl]-1,3-dioxoisoindole-4-yl}amino)cyclohexanecarbonyl]pyrrolidine-3-carboxylic acid (7 mg) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (5.9 mg, 34%). LCMS:C 66 H 77 FN 12 The required value for O8 is 1184.6, and the measured value is 1185.9 [M+H]. + ; 1H NMR (500 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.34 (s, 1H), 8.67 (s, 1H), 8.41 (s, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 2.5 Hz, 1H), 7.78 - 7.48 (m, 5H), 7.33 - 7.14 (m, 2H), 7.05 (d, J = 7.0 Hz, 1H), 6.18 (d, J = 8.1 Hz, 1H), 5.38 - 5.25 (m, 1H), 5.06 (dd, J = 12.8, 5.5Hz, 1H), 4.22 - 3.24 (m, 8H), 3.09 - 2.69 (m, 8H), 2.69 - 2.54 (m, 4H), 2.37 (s, 3H), 2.21 - 1.94 (m, 6H), 1.91 - 1.48 (m, 22H), 1.48 - 1.29 (m, 3H), 1.11 (d, J = 6.4 Hz, 6H). (Example 27)

[0344] 4-Fluoro-2-methyl-5-[(6-{2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1'-[1-[(1s,4s)-4-({2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl}amino)cyclohexanecarbonyl]pyrrolidine-3-carbonyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl)amino]-N-(propan-2-yl)benzamide [ka]

[0345] Step 1: Synthesis of 1-[(cis)-4-({2-[2,6-dioxopiperidine-3-yl]-1,3-dioxoisoindole-4-yl}amino)cyclohexanecarbonyl]pyrrolidine-3-carboxylic acid. The synthesis was started with (cis)-4-aminocyclohexane-1-carboxylic acid and carried out in the same manner as in Example 26, Steps 1 and 2 to obtain the title compound.

[0346] Step 2: Synthesis of 4-fluoro-2-methyl-5-[(6-{2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1'-[1-[(1s,4s)-4-({2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl}amino)cyclohexanecarbonyl]pyrrolidine-3-carbonyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl)amino]-N-(propan-2-yl)benzamide. The title compound was synthesized according to general procedure F, using intermediate 1 (10 mg) and 1-[(cis)-4-({2-[(3RS)-2,6-dioxopiperidine-3-yl]-1,3-dioxoisoindole-4-yl}amino)cyclohexanecarbonyl]pyrrolidine-3-carboxylic acid (7 mg) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (9.7 mg, 58%). LCMS:C 66 H 77 FN 12 The required value for O8 is 1184.6, and the measured value is 1185.9 [M+H]. + ; 1H NMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.36 (s, 1H), 8.69 (s, 1H), 8.41 (s, 1H), 8.14 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 4.5 Hz, 1H), 7.75 - 7.47 (m, 5H), 7.16 (dd, J = 18.2, 10.4 Hz, 2H), 7.05 (d, J = 7.0 Hz, 1H), 6.53 (s, 1H), 5.39 - 5.20 (m, 1H), 5.07 (dd, J = 12.9, 5.4Hz, 1H), 4.24 - 3.21 (m, 9H), 3.03 - 2.73 (m, 8H), 2.65 - 2.52 (m, 5H), 2.36 (s, 3H), 2.16 - 2.02 (m, 2H), 1.90 - 1.50 (m, 26H), 1.41 (q, J = 14.2, 13.6 Hz, 1H), 1.10 (d, J = 6.6 Hz, 6H). (Example 28)

[0347] 5-[(6-{1'-[2-(7-{2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl}-2,7-diazaspiro[3,5]nonane-2-yl)acetyl]-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide [ka]

[0348] Step 1: Synthesis of 2,7-diazaspiro[3.5]nonane-2-ylacetic acid hydrochloride. The synthesis was carried out according to general procedure E, followed by general procedure B, using tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (400 mg, 1.77 mmol) and tert-butyl 2-bromoacetate (379 mg, 1.94 mmol) as starting materials. The title compound (331 mg, 84% across the two steps) was isolated without further purification.

[0349] Step 2: Synthesis of (7-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl]-2,7-diazaspiro[3.5]nonane-2-yl)acetic acid. The reaction was carried out according to general procedure A, using 2,7-diazaspiro[3.5]nonane-2-yl acetate hydrochloride (331 mg, 1.50 mmol) and 2-(2,6-dioxopiperidine-3-yl)-5-fluoroisoindole-1,3-dione (414 mg, 1.50 mmol) as starting materials. The title compound was obtained by chromatography C (50 mg, 8%).

[0350] Step 3: Synthesis of 5-[(6-{1'-[2-(7-{2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl}-2,7-diazaspiro[3,5]nonane-2-yl)acetyl]-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide. The title compound was synthesized according to general procedure F, using intermediate 1 (13.5 mg) and (7-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl]-2,7-diazaspiro[3.5]nonane-2-yl)acetic acid (8 mg) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (6.2 mg, 30%). LCMS:C63 H 73 FN 12 The required value for O7 is 1128.6, and the measured value is 1129.9 [M+H]. + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.07 (d, J = 4.3 Hz, 1H), 10.30 (d, J = 37.2 Hz, 1H), 9.48 (s, 1H), 8.59 (s, 1H), 8.37 (s, 1H), 8.13 (d, J = 7.8 Hz, 1H), 7.89 (s, 1H), 7.70 (t, J = 7.9 Hz, 2H), 7.61 (d, J = 8.3 Hz, 1H), 7.52 (s, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.17 (d, J = 12.2 Hz, 1H), 6.97 - 6.80 (m, 1H), 5.35 - 5.20 (m, 1H), 5.10 - 5.01 (m, 1H), 4.54 (d, J = 17.4 Hz, 1H), 4.25 - 3.13 (m, 9H), 3.04 - 2.68 (m, 9H), 2.65 - 2.52 (m, 6H), 2.36 (s, 3H), 2.23 - 1.52 (m, 22H), 1.41 (d, J = 13.6 Hz, 1H), 1.09 (d, J = 6.4 Hz, 6H). (Example 29)

[0351] 5-{[6-(1'-{2-[(3S)-1-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]pyrrolidine-3-yl}methyl)piperidine-3-yl]acetyl}-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl)-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl]amino}-4-fluoro-2-methyl-N-(propan-2-yl)benzamide [ka]

[0352] Step 1: Synthesis of tert-butyl 3-{[(3S)-3-(2-methoxy-2-oxoethyl)piperidine-1-yl]methyl}pyrrolidine-1-carboxylate. The reaction was carried out according to general procedure D, using tert-butyl 3-formylpyrrolidine-1-carboxylate (1.00 g, 5.02 mmol), methyl 2-[(3S)-piperidine-3-yl]acetate hydrochloride (972 mg, 5.02 mmol), and TEA (1.54 mL, 11.0 mmol) as reagents. After the procedure, the title compound (1.6 g, 94%) was used without further purification.

[0353] Step 2: Synthesis of [(3S)-1-(pyrrolidine-3-ylmethyl)piperidine-3-yl]acetic acid. The saponification reaction was carried out according to general procedure C, using tert-butyl 3-{[(3S)-3-(2-methoxy-2-oxoethyl)piperidine-1-yl]methyl}pyrrolidine-1-carboxylate (1.60 g, 4.70 mmol) as the starting material. The product of this reaction was directly added to general procedure B to obtain the title compound (1.06 g, quantitative).

[0354] Step 3: Synthesis of 2-((3S)-1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidine-3-yl)methyl)piperidine-3-yl)acetic acid. The reaction was carried out according to general procedure A, using [(3S)-1-(pyrrolidine-3-ylmethyl)piperidine-3-yl]acetic acid (328 mg, 0.72 mmol) and 2-(2,6-dioxopiperidine-3-yl)-5-fluoroisoindole-1,3-dione (200 mg, 0.72 mmol) as starting materials. The title compound was obtained by chromatography C (214 mg, 61%).

[0355] Step 4: Synthesis of 5-{[6-(1'-{2-[(3S)-1-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]pyrrolidine-3-yl}methyl)piperidine-3-yl]acetyl}-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl)-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl]amino}-4-fluoro-2-methyl-N-(propan-2-yl)benzamide. The title compound was synthesized according to general procedure F, using intermediate 1 (7.3 mg) and 2-((3S)-1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)piperidine-3-yl)acetic acid (5 mg) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (2.8 mg, 23%). LCMS:C 66 H 79 FN 12 The required value for O7 is 1170.6, and the measured value is 1172.1 [M+H]. + ; 1H NMR (500 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.49 (s, 1H), 8.27 (s, 1H), 8.05 (d, J = 7.9 Hz, 1H), 7.79 (s, 1H), 7.60 (dd, J = 14.7, 8.1 Hz, 2H), 7.52 (d, J = 8.1 Hz, 1H), 7.46 - 7.37 (m, 2H), 7.09 (d, J = 12.2 Hz, 1H), 6.87 (s, 1H), 6.76 (d, J = 8.2 Hz, 1H), 5.23 - 5.11 (m, 1H), 4.98 (dd, J = 13.0, 5.4 Hz, 1H), 4.16 - 4.07 (m, 1H), 4.01 - 3.91 (m, 1H), 3.81 - 3.05 (m, 8H), 2.99 - 2.65 (m, 14H), 2.57 - 2.46 (m, 4H), 2.36 - 2.12 (m, 10H), 2.03 - 1.28 (m, 30H), 1.01 (d, J = 6.6 Hz, 6H). (Example 30)

[0356] 4-Fluoro-2-methyl-5-[(6-{2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1'-[1-[(1s,3s)-3-({2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl}amino)cyclobutanecarbonyl]pyrrolidine-3-carbonyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl)amino]-N-(propan-2-yl)benzamide [ka]

[0357] Step 1: Synthesis of (cis)-3-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-4-yl]amino}cyclobutan-1-carboxylic acid. The reaction was carried out according to general procedure A, using 2-(2,6-dioxopiperidine-3-yl)-4-fluoroisoindole-1,3-dione (150 mg, 0.54 mmol) and (cis)-3-aminocyclobutan-1-carboxylic acid hydrochloride (82 mg, 0.54 mmol) as starting materials. The title compound was obtained by chromatography C (50 mg, 25%).

[0358] Step 2: Synthesis of 1-[(cis)-3-({2-[2,6-dioxopiperidine-3-yl]-1,3-dioxoisoindole-4-yl}amino)cyclobutanecarbonyl]pyrrolidine-3-carboxylic acid. The reaction was carried out according to general procedure F, using (cis)-3-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-4-yl]amino}cyclobutane-1-carboxylic acid (18 mg, 0.05 mmol) and tert-butylpyrrolidine-3-carboxylate (10 mg, 0.06 mmol) as starting materials. The product of this reaction was then subjected to general procedure B, thereby obtaining the title compound after chromatography C (8 mg, 40%).

[0359] Step 3: Synthesis of 4-fluoro-2-methyl-5-[(6-{2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1'-[1-[(1s,3s)-3-({2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl}amino)cyclobutancarbonyl]pyrrolidine-3-carbonyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl)amino]-N-(propan-2-yl)benzamide. The title compound was synthesized according to general procedure F, using intermediate 1 (12.7 mg) and 1-((cis)-3-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)cyclobutan-1-carbonyl)pyrrolidine-3-carboxylic acid (8 mg, 0.02 mmol) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (9.3 mg, 45%). LCMS:C 64 H 73 FN 12 The required value for O8 is 1156.6, and the measured value is 1157.9 [M+H]. + ; 1H NMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.35 (s, 1H), 8.66 (s, 1H), 8.40 (s, 1H), 8.13 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 3.6 Hz, 1H), 7.71 - 7.63 (m, 1H), 7.63 - 7.47 (m, 4H), 7.18 (d, J = 12.1 Hz, 1H), 7.10 - 7.03 (m, 2H), 6.45 (s, 1H), 5.29 (p, J = 6.6 Hz, 1H), 5.06 (dd, J = 12.7, 5.4 Hz, 1H), 4.25 - 3.19 (m, 8H), 3.08 - 2.74 (m, 8H), 2.72 - 2.56 (m, 4H), 2.54 (s, 3H), 2.36 (s, 3H), 2.18 - 2.01 (m, 5H), 1.91 - 1.53 (m, 18H), 1.41 (d, J = 12.9 Hz, 1H), 1.10 (d, J = 6.6 Hz, 6H). (Example 31)

[0360] 5-{[6-(1'-{2-[(3S)-1-{[1-{2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl}pyrrolidine-3-yl]methyl}piperidine-3-yl]acetyl}-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl)-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl]amino}-4-fluoro-2-methyl-N-(propan-2-yl)benzamide [ka]

[0361] Step 1: Synthesis of tert-butyl 3-{[(3S)-3-(2-methoxy-2-oxoethyl)piperidine-1-yl]methyl}pyrrolidine-1-carboxylate. The reaction was carried out according to general procedure D, using tert-butyl 3-formylpyrrolidine-1-carboxylate (1.00 g, 5.02 mmol), methyl 2-[(3S)-piperidine-3-yl]acetate hydrochloride (972 mg, 5.02 mmol), and methyl 2-[(3S)-piperidine-3-yl]acetate hydrochloride (972 mg, 5.02 mmol) as reagents. After the procedure, the title compound (1.6 g, 94%) was used without further purification.

[0362] Step 2: Synthesis of [(3S)-1-(pyrrolidine-3-ylmethyl)piperidine-3-yl]acetic acid. The saponification reaction was carried out according to general procedure C, using tert-butyl 3-{[(3S)-3-(2-methoxy-2-oxoethyl)piperidine-1-yl]methyl}pyrrolidine-1-carboxylate (1.60 g, 4.70 mmol) as the starting material. The product of this reaction was directly added to general procedure B to obtain the title compound (1.06 g, quantitative).

[0363] Step 3: Synthesis of 2-((3S)-1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindolin-4-yl)pyrrolidine-3-yl)methyl)piperidine-3-yl)acetic acid. The reaction was carried out according to general procedure A, using [(3S)-1-(pyrrolidine-3-ylmethyl)piperidine-3-yl]acetic acid (819 mg, 1.81 mmol) and 2-(2,6-dioxopiperidine-3-yl)-4-fluoroisoindole-1,3-dione (500 mg, 1.81 mmol) as starting materials. The title compound was obtained by chromatography C (490 mg, 48%).

[0364] Step 4: Synthesis of 5-{[6-(1'-{2-[(3S)-1-{[1-{2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl}pyrrolidine-3-yl]methyl}piperidine-3-yl]acetyl}-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl)-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl]amino}-4-fluoro-2-methyl-N-(propan-2-yl)benzamide. The title compound was synthesized according to general procedure F, using intermediate 1 (14 mg) and 2-((3S)-1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)pyrrolidine-3-yl)methyl)piperidine-3-yl)acetic acid (10 mg) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (8.1 mg, 29%). LCMS:C 66 H 79 FN 12 The required value for O7 is 1170.6, and the measured value is 1171.8 [M+H]. + ; 1H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.49 (s, 1H), 9.17 (s, 1H), 8.65 (s, 1H), 8.40 (s, 1H), 8.14 (d, J = 7.8 Hz, 1H), 7.87 (s, 1H), 7.69 - 7.54 (m, 3H), 7.49 (d, J = 8.5 Hz, 2H), 7.21 - 7.15 (m, 2H), 7.12 (d, J = 8.8 Hz, 1H), 5.35 - 5.24 (m, 1H), 5.07 (dd, J = 12.8, 5.5 Hz, 1H), 4.20 (dd, J = 16.4, 8.3 Hz, 1H), 4.10 - 3.98 (m, 1H), 3.93 - 3.08 (m, 10H), 3.07 - 2.66 (m, 10H), 2.65 - 2.52 (m, 4H), 2.42 - 2.32 (m, 4H), 2.22 (s, 1H), 2.06 - 1.29 (m, 25H), 1.09 (d, J = 6.5 Hz, 6H). (Example 32)

[0365] 5-({6-[1'-(1-{2-[(3S)-1-{2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl}piperidine-3-yl]acetyl}pyrrolidine-3-carbonyl)-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl]-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl}amino)-4-fluoro-2-methyl-N-(propan-2-yl)benzamide [ka]

[0366] Step 1: Synthesis of [(3S)-1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-4-yl]piperidine-3-yl]acetic acid. The reaction was carried out according to general procedure A, using (3S)-piperidine-3-ylacetic acid (143 mg, 1.00 mmol) and 2-(2,6-dioxopiperidine-3-yl)-4-fluoroisoindole-1,3-dione (276 mg, 1.00 mmol) as starting materials. The title compound was obtained by chromatography C (190 mg, 48%).

[0367] Step 2: Synthesis of 1-{2-[(3S)-1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-4-yl]piperidine-3-yl]acetyl}pyrrolidine-3-carboxylic acid. The reaction was carried out according to general procedure F, using [(3S)-1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-4-yl]piperidine-3-yl]acetic acid (20 mg, 0.05 mmol) and tert-butylpyrrolidine-3-carboxylate (8.6 mg, 0.05 mmol) as starting materials. The crude material from this reaction was directly subjected to general procedure B to obtain the title compound (10 mg, 40%).

[0368] Step 3: Synthesis of 5-({6-[1'-(1-{2-[(3S)-1-{2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl}piperidine-3-yl]acetyl}pyrrolidine-3-carbonyl)-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl]-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl}amino)-4-fluoro-2-methyl-N-(propan-2-yl)benzamide. The title compound was synthesized according to general procedure F, using intermediate 1 (14.5 mg) and 1-(2-((3R)-1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)piperidine-3-yl)acetyl)pyrrolidine-3-carboxylic acid (10 mg) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (7.5 mg, 31%). LCMS:C 66 H 77 FN 12 The required value for O8 is 1184.6, and the measured value is 1185.9 [M+H]. + ; 1H NMR (500 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.34 (s, 1H), 8.70 (d, J = 4.9 Hz, 1H), 8.41 (s, 1H), 8.13 (d, J = 7.7 Hz, 1H), 7.87 (d, J = 2.8 Hz, 1H), 7.71 - 7.62 (m, 2H), 7.61 - 7.46 (m, 3H), 7.41 (t, J = 8.8 Hz, 1H), 7.31 (d, J = 6.9 Hz, 1H), 7.18 (d, J = 12.0 Hz, 1H), 5.30 (p, J = 6.6 Hz, 1H), 5.10 (dd, J = 9.7, 4.5 Hz, 1H), 4.25 - 4.15 (m, 1H), 4.08 - 3.99 (m, 1H), 3.40 (d, J = 11.0 Hz, 10H), 3.03 - 2.65 (m, 8H), 2.54 (s, 3H), 2.36 (s, 3H), 2.31 - 1.91 (m, 8H), 1.93 - 1.50 (m, 20H), 1.41 (q, J = 10.5, 8.2 Hz, 1H), 1.10 (d, J = 6.5 Hz, 6H). (Example 33)

[0369] 5-{[6-(1'-{1-[(1-{2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl}piperidine-4-yl)methyl]azetidine-3-carbonyl}-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl)-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl]amino}-4-fluoro-2-methyl-N-(propan-2-yl)benzamide [ka]

[0370] Step 1: Synthesis of 2-(2,6-dioxopiperidine-3-yl)-4-[4-(hydroxymethyl)piperidine-1-yl]isoindole-1,3-dione. The reaction was carried out according to general procedure A, using piperidine-4-ylmethanol (208 mg, 1.80 mmol) and 2-(2,6-dioxopiperidine-3-yl)-4-fluoroisoindole-1,3-dione (500 mg, 1.81 mmol) as starting materials. The title compound was obtained by chromatography B (500 mg, 74%).

[0371] Step 2: Synthesis of 1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-4-yl]piperidine-4-carbaldehyde. 2-(2,6-dioxopiperidine-3-yl)-4-[4-(hydroxymethyl)piperidine-1-yl]isoindole-1,3-dione (100 mg, 0.27 mmol) was dissolved in DCM (1.35 mL) and DMP (228 mg, 0.54 mmol) was added. After stirring for 90 minutes, silica gel was added to the reactants and the solvent was removed under reduced pressure. The material was then purified by chromatography A to obtain the title compound (32 mg, 32%).

[0372] Step 3: Synthesis of 1-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-4-yl]piperidine-4-yl}methyl)azetidine-3-carboxylic acid. Reductive amination was carried out according to general procedure D, using tert-butylazetidine-3-carboxylate (6.4 mg, 0.04 mmol) and 1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-4-yl]piperidine-4-carbaldehyde (15 mg, 0.04 mmol) as starting materials. The crude material from this reaction was directly treated with general procedure B. After chromatography C, the title compound (8 mg, 43%) was obtained.

[0373] Step 4: Synthesis of 5-{[6-(1'-{1-[(1-{2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl}piperidine-4-yl)methyl]azetidine-3-carbonyl}-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl)-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl]amino}-4-fluoro-2-methyl-N-(propan-2-yl)benzamide. The title compound was synthesized according to general procedure F, using intermediate 1 (12.44 mg) and 1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)piperidine-4-yl)methyl)azetidine-3-carboxylic acid (8 mg) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (8.2 mg, 36%). LCMS:C 64 H 75 FN 12 The required value for O7 is 1142.6, and the measured value is 1144.0 [M+H]. + ; 1H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.45 (s, 1H), 8.62 (s, 1H), 8.39 (s, 1H), 8.13 (d, J = 7.8 Hz, 1H), 7.88 (s, 1H), 7.75 - 7.63 (m, 2H), 7.60 (d, J = 8.1 Hz, 1H), 7.55 - 7.45 (m, 2H), 7.39 - 7.30 (m, 2H), 7.17 (d, J = 12.0 Hz, 1H), 5.29 (q, J = 6.4 Hz, 1H), 5.09 (dd, J = 12.8, 5.5 Hz, 1H), 4.51 - 4.40 (m, 1H), 4.29 - 4.18 (m, 2H), 4.10 - 3.13 (m, 10H), 3.03 - 2.71 (m, 10H), 2.66 - 2.52 (m, 3H), 2.36 (s, 3H), 2.03 (s, 1H), 1.91 - 1.51 (m, 20H), 1.51 - 1.36 (m, 3H), 1.09 (d, J = 6.5 Hz, 6H). (Example 34)

[0374] 5-{[6-(1'-{1-[2-(1-{2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl}piperidine-4-yl)acetyl]azetidine-3-carbonyl}-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl)-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl]amino}-4-fluoro-2-methyl-N-(propan-2-yl)benzamide [ka]

[0375] Step 1: Synthesis of (1-{2-[2,6-dioxopiperidine-3-yl]-1,3-dioxoisoindole-4-yl}piperidine-4-yl)acetic acid. The reaction was carried out according to general procedure A, using piperidine-4-ylacetic acid (273 mg, 1.91 mmol) and 2-(2,6-dioxopiperidine-3-yl)-4-fluoroisoindole-1,3-dione (527 mg, 1.91 mmol) as starting materials. The title compound was obtained by chromatography C (546 mg, 71%).

[0376] Step 2: Synthesis of 1-{2-[(3S)-1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-4-yl]piperidine-3-yl]acetyl}azetidine-3-carboxylic acid. The reaction was carried out according to general procedure F using (1-{2-[2,6-dioxopiperidine-3-yl]-1,3-dioxoisoindole-4-yl}piperidine-4-yl)acetic acid (25 mg, 0.06 mmol) and tert-butylazetidine-3-carboxylate (10 mg, 0.06 mmol). The crude material from this reaction was then directly subjected to general procedure B to obtain the title compound (22 mg, 73%).

[0377] Step 3: Synthesis of 5-{[6-(1'-{1-[2-(1-{2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl}piperidine-4-yl)acetyl]azetidine-3-carbonyl}-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl)-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl]amino}-4-fluoro-2-methyl-N-(propan-2-yl)benzamide. The title compound was synthesized according to general procedure F, using intermediate 1 (10 mg) and 1-(2-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)piperidine-4-yl)acetyl)azetidine-3-carboxylic acid (6.3 mg) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (5.5 mg, 23%). LCMS:C 65 H 75 FN 12 The required value for O8 is 1170.6, and the measured value is 1172.1 [M+H]. + ; 1H NMR (500 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.31 (s, 1H), 8.64 (s, 1H), 8.38 (s, 1H), 8.13 (dd, J = 8.1, 2.3 Hz, 1H), 7.87 (s, 1H), 7.72 - 7.63 (m, 2H), 7.63 - 7.48 (m, 3H), 7.33 (t, J = 7.7 Hz, 2H), 7.18 (d, J = 11.2 Hz, 1H), 5.33 - 5.24 (m, 1H), 5.14 - 5.05 (m, 1H), 4.32 (dd, J = 18.5, 8.1 Hz, 1H), 4.25 - 4.16 (m, 1H), 4.10 - 3.99 (m, 1H), 4.00 - 3.93 (m, 1H), 3.73 - 3.35 (m, 10H), 3.03 - 2.75 (m, 10H), 2.67 - 2.55 (m, 2H), 2.36 (d, J = 4.3 Hz, 4H), 2.13 - 1.97 (m, 3H), 1.93 - 1.52 (m, 18H), 1.41 (q, J = 13.3, 11.2 Hz, 2H), 1.09 (d, J = 4.0 Hz, 6H). (Example 35)

[0378] 5-({6-[1'-(1-{[1-{2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl}pyrrolidine-3-yl]methyl}azetidine-3-carbonyl)-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl]-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl}amino)-4-fluoro-2-methyl-N-(propan-2-yl)benzamide [ka]

[0379] Step 1: Synthesis of 2-(2,6-dioxopiperidine-3-yl)-4-[3-(hydroxymethyl)pyrrolidine-1-yl]isoindole-1,3-dione. The reaction was carried out according to general procedure A, using pyrrolidine-3-ylmethanol (220 mg, 2.17 mmol) and 2-(2,6-dioxopiperidine-3-yl)-4-fluoroisoindole-1,3-dione (500 mg, 1.81 mmol) as starting materials, and heated at 80°C. The title compound was obtained by chromatography B (462 mg, 71%).

[0380] Step 2: Synthesis of 1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-4-yl]pyrrolidine-3-carbaldehyde. 2-(2,6-dioxopiperidine-3-yl)-4-[3-(hydroxymethyl)pyrrolidine-1-yl]isoindole-1,3-dione (100 mg, 0.28 mmol) was dissolved in DCM (1.40 mL) and DMP (237 mg, 0.56 mmol) was added. After stirring for 90 minutes, silica gel was added to the reaction mixture and the solvent was removed under reduced pressure. The material was then purified by chromatography A to obtain the title compound (58 mg, 58%).

[0381] Step 3: Synthesis of 1-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-4-yl]pyrrolidine-3-yl}methyl)azetidine-3-carboxylic acid. The reaction was carried out according to general procedure D, using 1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-4-yl]pyrrolidine-3-carbaldehyde (20 mg, 0.06 mmol) and tert-butylazetidine-3-carboxylate (13.3 mg, 0.08 mmol), with the addition of TEA (0.020 mL, 0.12 mmol). Next, the crude material was treated according to general procedure B. The title compound was obtained by chromatography C (18.3 mg, 74%).

[0382] Step 4: Synthesis of 5-({6-[1'-(1-{[1-{2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl}pyrrolidine-3-yl]methyl}azetidine-3-carbonyl)-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl]-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl}amino)-4-fluoro-2-methyl-N-(propan-2-yl)benzamide. The title compound was synthesized according to general procedure F, using intermediate 1 (28 mg) and 1-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-4-yl]pyrrolidine-3-yl}methyl)azetidine-3-carboxylic acid (18 mg) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (4.4 mg, 9.4%). LCMS:C 63 H 73 FN 12 The required value for O7 is 1128.6, and the measured value is 1130.0 [M+H]. + ; 1H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.49 (s, 1H), 8.60 (d, J = 8.2 Hz, 1H), 8.38 (s, 1H), 8.13 (d, J = 7.9 Hz, 1H), 7.88 (d, J = 2.2 Hz, 1H), 7.70 - 7.64 (m, 1H), 7.61 (dd, J = 8.6, 7.1 Hz, 2H), 7.55 - 7.43 (m, 2H), 7.17 (dt, J = 11.9, 3.7 Hz, 2H), 7.11 (d, J = 8.4 Hz, 1H), 5.27 (q, J = 6.5 Hz, 1H), 5.07 (d, J = 7.3 Hz, 1H), 4.50 - 4.37 (m, 1H), 4.31 - 4.15 (m, 2H), 4.08 - 3.91 (m, 4H), 3.84 - 3.29 (m, 10H), 3.02 - 2.74 (m, 8H), 2.66 - 2.55 (m, 2H), 2.36 (s, 3H), 2.19 - 1.95 (m, 2H), 1.89 - 1.48 (m, 18H), 1.41 (q, J = 11.2, 10.0 Hz, 1H), 1.09 (d, J = 6.5 Hz, 6H). (Example 36)

[0383] 5-{[6-(1'-{1-[2-(1-{2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl}piperidine-4-yl)acetyl]piperidine-4-carbonyl}-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl)-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl]amino}-4-fluoro-2-methyl-N-(propan-2-yl)benzamide [ka]

[0384] Step 1: Synthesis of 1-(2-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-4-yl)piperidine-4-yl)acetyl)piperidine-4-carboxylic acid. The reaction was carried out according to general procedure F using (1-{2-[2,6-dioxopiperidine-3-yl]-1,3-dioxoisoindole-4-yl}piperidine-4-yl)acetic acid (25 mg, 0.06 mmol) and tert-butylpiperidine-4-carboxylate (12 mg, 0.06 mmol). Next, the crude material from this reaction was subjected to general procedure B. The title compound was obtained by chromatography C (22 mg, 69%).

[0385] Step 2: Synthesis of 5-{[6-(1'-{1-[2-(1-{2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl}piperidine-4-yl)acetyl]piperidine-4-carbonyl}-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl)-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl]amino}-4-fluoro-2-methyl-N-(propan-2-yl)benzamide. The title compound was synthesized according to general procedure F, using intermediate 1 (15 mg) and 1-(2-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)piperidine-4-yl)acetyl)piperidine-4-carboxylic acid (10 mg) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (16.4 mg, 68%). LCMS:C 67 H 79 FN 12 The required value for O8 is 1198.6, and the measured value is 1199.9 [M+H]. + ; 1H NMR (500 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.37 (s, 1H), 8.67 (s, 1H), 8.40 (s, 1H), 8.13 (d, J = 7.8 Hz, 1H), 7.87 (s, 1H), 7.71 - 7.64 (m, 2H), 7.59 (d, J = 8.1 Hz, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.33 (dd, J = 10.8, 7.8 Hz, 2H), 7.18 (d, J = 12.1 Hz, 1H), 5.29 (q, J = 6.8 Hz, 1H), 5.09 (dd, J = 12.8, 5.5 Hz, 1H), 4.44 (s, 1H), 4.24 - 4.17 (m, 1H), 4.03 (h, J = 6.8 Hz, 1H), 3.96 - 3.37 (m, 10H), 3.11 (t, J = 12.5 Hz, 1H), 3.00 - 2.71 (m, 9H), 2.70 - 2.55 (m, 2H), 2.36 - 2.29 (m, 4H), 2.06 - 2.00 (m, 1H), 1.88 - 1.33 (m, 27H), 1.10 (d, J = 6.5 Hz, 6H). (Example 37)

[0386] 5-{[6-(1'-{1-[(1-{2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl}piperidine-4-yl)methyl]piperidine-4-carbonyl}-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl)-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl]amino}-4-fluoro-2-methyl-N-(propan-2-yl)benzamide [ka]

[0387] Step 1: Synthesis of 1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-4-yl)piperidine-4-yl)methyl)piperidine-4-carboxylic acid. The reaction was carried out according to general procedure D using 1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-4-yl]piperidine-4-carbaldehyde (15 mg, 0.04 mmol) and tert-butylpiperidine-4-carboxylate (7.5 mg, 0.04 mmol). The crude material from this reaction was then subjected to general procedure B, followed by chromatography C, to obtain the title compound (17.8 mg, 91%).

[0388] Step 2: Synthesis of 5-{[6-(1'-{1-[(1-{2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl}piperidine-4-yl)methyl]piperidine-4-carbonyl}-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl)-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl]amino}-4-fluoro-2-methyl-N-(propan-2-yl)benzamide. The title compound was synthesized according to general procedure F, using intermediate 1 (7.3 mg) and 1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)piperidine-4-yl)methyl)piperidine-4-carboxylic acid (5 mg) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (8.2 mg, 64%). LCMS:C 66 H 79 FN 12 The required value for O7 is 1170.6, and the measured value is 1172.0 [M+H]. + ; 1H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.48 (s, 1H), 8.98 (s, 1H), 8.63 (s, 1H), 8.39 (s, 1H), 8.14 (d, J = 7.8 Hz, 1H), 7.88 (s, 1H), 7.74 - 7.63 (m, 2H), 7.60 (d, J = 8.2 Hz, 1H), 7.52 (d, J = 5.5 Hz, 2H), 7.36 (d, J = 7.6 Hz, 2H), 7.18 (d, J = 12.1 Hz, 1H), 5.32 - 5.18 (m, 1H), 5.09 (dd, J = 12.8, 5.4 Hz, 1H), 4.24 - 3.11 (m, 10H), 3.09 - 2.71 (m, 14H), 2.66 - 2.56 (m 1H), 2.36 (s, 3H), 2.10 - 1.36 (m, 28H), 1.10 (d, J = 6.6 Hz, 6H).. (Example 38)

[0389] 5-[(6-{1'-[1-[(1-{2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl}piperidine-4-yl)methyl]pyrrolidine-3-carbonyl]-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide [ka]

[0390] Step 1: Synthesis of 1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-4-yl)piperidine-4-yl)methyl)pyrrolidine-3-carboxylic acid. The reaction was carried out according to general procedure D using 1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-4-yl]piperidine-4-carbaldehyde (15 mg, 0.04 mmol) and tert-butylpyrrolidine-3-carboxylate (6.8 mg, 0.04 mmol). The crude material from this reaction was then subjected to general procedure B, followed by chromatography C, to obtain the title compound (16.8 mg, 91%).

[0391] Step 2: Synthesis of 5-[(6-{1'-[1-[(1-{2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl}piperidine-4-yl)methyl]pyrrolidine-3-carbonyl]-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide. The title compound was synthesized according to general procedure F, using intermediate 1 (9.5 mg) and 1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)piperidine-4-yl)methyl)pyrrolidine-3-carboxylic acid (6 mg) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (10.5 mg, 61%). LCMS:C 65 H 77 FN 12 The required value for O7 is 1156.6, and the measured value is 1157.9 [M+H]. + ; 1H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.69 - 9.44 (m, 2H), 8.64 (s, 1H), 8.40 (s, 1H), 8.14 (dd, J = 7.9, 2.5 Hz, 1H), 7.89 (d, J = 3.6 Hz, 1H), 7.78 - 7.63 (m, 2H), 7.63 - 7.42 (m, 3H), 7.42 - 7.27 (m, 2H), 7.18 (d, J = 12.2 Hz, 1H), 5.28 (q, J = 6.6 Hz, 1H), 5.09 (dd, J = 12.7, 5.5 Hz, 1H), 4.21 - 3.06 (m, 11H), 3.02 - 2.67 (m, 10H), 2.67 - 2.55 (m, 1H), 2.38 - 2.33 (m, 4H), 2.09 - 1.29 (m, 28H), 1.10 (dd, J = 6.6, 2.4 Hz, 6H). (Example 39)

[0392] 5-[(6-{1'-[1-(1-{2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-4-carbonyl)azetidine-3-carbonyl]-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide [ka]

[0393] Step 1: Synthesis of 1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl]piperidine-4-carboxylic acid. The reaction was carried out according to general procedure A using tert-butylpiperidine-4-carboxylate (402 mg, 2.17 mmol) and 2-(2,6-dioxopiperidine-3-yl)-5-fluoroisoindole-1,3-dione (500 mg, 1.81 mmol). Next, chromatography B was performed, and the resulting material was subjected to general procedure B. The title compound was obtained by chromatography C (440 mg, 63%).

[0394] Step 2: Synthesis of 1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-carbonyl)azetidine-3-carboxylic acid. The reaction was carried out according to general procedure F using 1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl]piperidine-4-carboxylic acid (10 mg, 0.03 mmol) and tert-butylazetidine-3-carboxylate (4 mg, 0.03 mmol). The crude material from this reaction was subjected to general procedure B, followed by chromatography C, to obtain the title compound (10 mg, 82%).

[0395] Step 3: Synthesis of 5-[(6-{1'-[1-(1-{2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-4-carbonyl)azetidine-3-carbonyl]-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide. The title compound was synthesized according to general procedure F, using intermediate 1 (10 mg) and 1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperidine-4-carbonyl)azetidine-3-carboxylic acid (6.8 mg) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (7.2 mg, 44%). LCMS:C 64 H 73 FN 12 The required value for O8 is 1156.6, and the measured value is 1157.8 [M+H]. + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.39 (s, 1H), 8.73 (d, J = 6.2 Hz, 1H), 8.43 (s, 1H), 8.13 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 2.6 Hz, 1H), 7.74 - 7.61 (m, 2H), 7.62 - 7.45 (m, 3H), 7.33 (s, 1H), 7.30 - 7.13 (m, 2H), 5.30 (q, J = 6.5 Hz, 1H), 5.07 (dd, J = 12.7, 5.5Hz, 1H), 4.45 - 4.34 (m, 1H), 4.24 - 3.35 (m, 11H), 3.15 - 2.68 (m, 10H), 2.65 - 2.55 (m, 2H), 2.36 (s, 3H), 2.05 - 1.93 (m, 1H), 1.88 - 1.32 (m, 23H), 1.09 (d, J = 6.5 Hz, 6H). (Example 40)

[0396] 5-[(6-{1'-[1-(1-{2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-4-carbonyl)pyrroridine-3-carbonyl]-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide [ka]

[0397] Step 1: Synthesis of 1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)piperidine-4-carbonyl)pyrrolidine-3-carboxylic acid. The reaction was carried out according to general procedure F using 1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl]piperidine-4-carboxylic acid (10 mg, 0.03 mmol) and tert-butylpyrrolidine-3-carboxylate (4.4 mg, 0.03 mmol). The crude material from this reaction was subjected to general procedure B, followed by chromatography C, to obtain the title compound (10 g, 80%).

[0398] Step 2: Synthesis of 5-[(6-{1'-[1-(1-{2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-4-carbonyl)pyrrolidine-3-carbonyl]-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide. The title compound was synthesized according to general procedure F, using intermediate 1 (10 mg) and 1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperidine-4-carbonyl)pyrrolidine-3-carboxylic acid (8.4 mg) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (12.1 mg, 75%). LCMS:C 65 H 75 FN 12 The required value for O8 is 1170.6, and the measured value is 1172.0 [M+H]. + ; 1H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.37 (s, 1H), 8.70 (s, 1H), 8.41 (s, 1H), 8.14 (d, J = 7.5 Hz, 1H), 7.87 (d, J = 4.8 Hz, 1H), 7.67 (dd, J = 8.4, 4.5 Hz, 2H), 7.62 - 7.46 (m, 3H), 7.34 (t, J = 2.5 Hz, 1H), 7.25 (dd, J = 8.6, 2.7 Hz, 1H), 7.18 (d, J = 12.1 Hz, 1H), 5.30 (p, J = 6.6 Hz, 1H), 5.07 (dd, J = 12.7, 5.4 Hz, 1H), 4.24 - 3.26 (m, 11H), 3.15 - 2.73 (m, 11H), 2.64 - 2.53 (m, 2H), 2.37 - 2.34 (m, 3H), 2.19 - 1.51 (m, 25H), 1.41 (d, J = 13.0 Hz, 1H), 1.11 - 1.07 (m, 6H). (Example 41)

[0399] 5-[(6-{1'-[1-(1-{2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-4-carbonyl)piperidine-4-carbonyl]-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide [ka]

[0400] Step 1: Synthesis of 1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)piperidine-4-carbonyl)piperidine-4-carboxylic acid. The reaction was carried out according to general procedure F using 1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl]piperidine-4-carboxylic acid (10 mg, 0.03 mmol) and tert-butylpiperidine-4-carboxylate (4.6 mg, 0.03 mmol). The crude material from this reaction was subjected to general procedure B, followed by chromatography C, to obtain the title compound (8.4 g, 66%).

[0401] Step 2: Synthesis of 5-[(6-{1'-[1-(1-{2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-4-carbonyl)piperidine-4-carbonyl]-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide. The title compound was synthesized according to general procedure F, using intermediate 1 (10 mg) and 1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperidine-4-carbonyl)piperidine-4-carboxylic acid (8.4 mg) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (8.8 mg, 54%). LCMS:C 66 H 77 FN 12 The required value for O8 is 1184.6, and the measured value is 1185.9 [M+H]. + ; 1H NMR (500 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.37 (s, 1H), 8.72 (s, 1H), 8.42 (s, 1H), 8.14 (d, J = 7.8 Hz, 1H), 7.88 (s, 1H), 7.67 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 8.1 Hz, 1H), 7.52 (d, J = 11.0 Hz, 2H), 7.34 (d, J = 2.2 Hz, 1H), 7.25 (dd, J = 8.8, 2.3 Hz, 1H), 7.18 (d, J = 12.1Hz, 1H), 5.34 - 5.25 (m, 1H), 5.07 (dd, J = 12.8, 5.4 Hz, 1H), 4.45 - 4.38 (m, 1H), 4.25 - 4.15 (m, 1H), 4.12 - 3.29 (m, 10H), 3.20 - 2.72 (m, 13H), 2.69 - 2.55 (m, 2H), 2.37 (s, 3H), 2.07 - 1.97 (m, 1H), 1.89 - 1.46 (m, 24H), 1.47 - 1.35 (m, 2H), 1.10 (d, J = 6.6 Hz, 6H). (Example 42)

[0402] 5-{[6-(1'-{1-[2-(7-{2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl}-2,7-diazaspiro[3,5]nonane-2-yl)acetyl]piperidine-4-carbonyl}-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl)-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl]amino}-4-fluoro-2-methyl-N-(propan-2-yl)benzamide [ka]

[0403] Step 1: Synthesis of 2,7-diazaspiro[3.5]nonane-2-ylacetic acid hydrochloride. The reaction was carried out according to general procedure E, using tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (400 mg, 1.77 mmol) and tert-butyl 2-bromoacetate (379 mg, 1.94 mmol) as starting materials. The crude residue was then treated according to general procedure B to obtain the title compound (300 mg, 77%).

[0404] Step 2: Synthesis of (7-{2-[(2,6-dioxopiperidine-3-yl]-1,3-dioxoisoindole-5-yl}-2,7-diazaspiro[3.5]nonane-2-yl)acetic acid. The reaction was carried out according to general procedure A, using 2-(2,6-dioxopiperidine-3-yl)-5-fluoroisoindole-1,3-dione (414 mg, 1.50 mmol) and 2,7-diazaspiro[3.5]nonane-2-yl acetate hydrochloride (330 mg, 1.50 mmol) as starting materials. The title compound was obtained by chromatography C (50 mg, 8%).

[0405] Step 3: Synthesis of 1-(2-(7-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)-2,7-diazaspiro[3.5]nonane-2-yl)acetyl)piperidine-4-carboxylic acid. The reaction was carried out according to general procedure F, using (7-{2-[(2,6-dioxopiperidine-3-yl]-1,3-dioxoisoindole-5-yl}-2,7-diazaspiro[3.5]nonane-2-yl)acetic acid (20 mg, 0.05 mmol) and tert-butylpiperidine-4-carboxylate (9.2 mg, 0.05 mmol) as starting materials. The crude material from this reaction was then subjected to general procedure B, followed by chromatography C, to obtain the title compound (10 mg, 40%).

[0406] Step 4: Synthesis of 5-{[6-(1'-{1-[2-(7-{2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl}-2,7-diazaspiro[3,5]nonane-2-yl)acetyl]piperidine-4-carbonyl}-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl)-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl]amino}-4-fluoro-2-methyl-N-(propan-2-yl)benzamide. The title compound was synthesized according to general procedure F, using intermediate 1 (10 mg) and 1-(2-(7-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)-2,7-diazaspiro[3.5]nonane-2-yl)acetyl)piperidine-4-carboxylic acid (7.2 mg) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (6.7 mg, 39%). LCMS:C 69 H 82 FN 13 The required value for O8 is 1239.6, and the measured value is 1240.9 [M+H]. + ; 1H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 10.28 -10.07 (m, 1H), 9.44 (s, 1H), 8.62 (s, 1H), 8.38 (s, 1H), 8.14 (d, J = 7.8 Hz, 1H), 7.88 (s, 1H), 7.73 - 7.63 (m, 2H), 7.60 (d, J = 8.5 Hz, 1H), 7.50 (d, J = 11.5 Hz, 2H), 7.39 - 7.26 (m, 1H), 7.17 (d, J = 12.1 Hz, 1H), 6.97 - 6.78 (m, 1H), 5.28 (q, J = 6.7 Hz, 1H), 5.07 (dd, J = 13.0, 5.0 Hz, 1H), 4.61 - 4.28 (m, 2H), 4.25 - 4.15 (m, 1H), 4.08 - 3.99 (m, 2H), 3.97 - 2.69 (m, 20H), 2.65 - 2.55 (m, 1H), 2.36 (s, 3H), 2.20 - 1.33 (m, 30H), 1.12 - 0.99 (m, 6H). (Example 43)

[0407] 5-[(6-{1'-[23-({2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl}amino)-3,6,9,12,15,18,21-heptaoxatricosan-1-yl]-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide [ka]

[0408] Step 1: Synthesis of 2-(2,6-dioxopiperidine-3-yl)-4-((23-hydroxy-3,6,9,12,15,18,21-heptaoxatricosyl)amino)isoindoline-1,3-dione. The reaction was carried out according to general procedure A, using 23-amino-3,6,9,12,15,18,21-heptaoxatricosane-1-ol (1.34 g, 3.62 mmol) and 2-(2,6-dioxopiperidine-3-yl)-4-fluoroisoindole-1,3-dione (1.0 g, 3.62 mmol) as starting materials. The title compound was obtained by chromatography B (700 mg, 31%).

[0409] Step 2: Synthesis of 23-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-4-yl)amino)-3,6,9,12,15,18,21-heptaoxatricosyl 4-methylbenzenesulfonate. 2-(2,6-dioxopiperidine-3-yl)-4-((23-hydroxy-3,6,9,12,15,18,21-heptaoxatricosyl)amino)isoindoline-1,3-dione (2.5 g, 4.0 mmol) and pyridine (316 mg, 4.0 mmol) were mixed in DCM (15 mL), to which p-toluenesulfonyl chloride (838 mg, 4.4 mmol) was added. The reaction mixture was then stirred overnight, and water was added. The organic phase was removed, and the aqueous phase was extracted with DCM (twice). The combined organic layers were then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The title compound was obtained by chromatography B (220 mg, 7%).

[0410] Step 3: Synthesis of 5-[(6-{1'-[23-({2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl}amino)-3,6,9,12,15,18,21-heptaoxatricosane-1-yl]-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide. The title compound was synthesized by combining intermediate 1 (19.7 mg, 1 equivalent), 23-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)-3,6,9,12,15,18,21-heptaoxatricosyl 4-methylbenzenesulfonate (23 mg, 1 equivalent), sodium iodide (3.97 mg, 1 equivalent), and dipotassium carbonate (18.3 mg, 5 equivalents) in ACN (0.05 M). The reaction mixture was heated at 80°C for 16 hours. The reaction mixture was filtered and purified by reverse-phase HPLC to obtain the title compound (15.1 mg, 33%). LCMS:C 70 H 92 FN 11 O 13 Required value: 1313.7, Measured value: 1315.0 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.65 - 9.39 (m, 2H), 8.61 (d, J = 3.6 Hz, 1H), 8.39 (d, J = 21.9 Hz, 1H), 8.14 (d, J = 7.9 Hz, 1H), 7.90 (d, J = 25.4 Hz, 1H), 7.77 - 7.48 (m, 4H), 7.26 - 7.06 (m, 3H), 7.04 (d, J = 7.0 Hz, 1H), 6.59 (s, 1H), 5.28 (s, 1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 4.27 - 3.29 (m, 36H), 2.99 - 2.75 (m, 8H), 2.58 (d, J = 19.6 Hz, 2H), 2.38 - 2.25 (m, 5H), 2.17 (s, 1H), 2.05 - 1.48 (m, 16H), 1.41 (q, J = 11.9, 10.7 Hz, 1H), 1.10 (d, J = 6.5 Hz, 6H). (Example 44)

[0411] 5-({6-[1'-(2-{4-[4-({[2-({2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl}amino)ethyl]carbamoyl}methyl)phenyl]piperazine-1-yl}acetyl)-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl]-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl}amino)-4-fluoro-2-methyl-N-(propan-2-yl)benzamide [ka]

[0412] Step 1: Synthesis of ethyl 2-(4-{4-[2-(tert-butoxy)-2-oxoethyl]piperazin-1-yl}phenyl) acetate. Tert-butyl(piperazin-1-yl) acetate (0.89 g, 4.4 mmol, 1.2 equivalents), palladium(II) acetate (0.083 g, 0.37 mmol, 0.1 equivalent), and Xphos (0.176 g, 0.37 mmol, 0.1 equivalent) were added under argon to a stirred solution of ethyl 4-bromophenyl (0.90 g, 3.7 mmol, 1.0 equivalent) in toluene (22 mL, 0.2 M). The reaction mixture was then purged with argon for 3 minutes, transferred to a bath preheated to 100°C, and stirred for 16 hours. Formation of the title compound was shown by UPLC. The mixture was diluted with water (20 mL) and then extracted with ethyl acetate (three times). The combined organic fraction was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography A to obtain 0.9 g (67% yield) of the title compound.

[0413] Step 2: Synthesis of potassium 2-{4-[4-(2-ethoxy-2-oxoethyl)phenyl]piperazin-1-yl}acetate. Ethyl 2-(4-{4-[2-(tert-butoxy)-2-oxoethyl]piperazin-1-yl}phenyl)acetate (0.61 g, 1.7 mmol, 1.0 equivalent) was dissolved in THF (12 mL, 0.14 M), and potassium trimethylsilanolate (0.216 g, 1.68 mmol, 1.0 equivalent) was added. The reaction mixture was stirred overnight (the progress was monitored by UPLC). The precipitated white solid was filtered off and dried to obtain 415 mg (72% yield) of the title compound.

[0414] Step 3: Synthesis of {4-[4-({[2-({2-[2,6-dioxopiperidine-3-yl]-1,3-dioxoisoindole-4-yl}amino)ethyl]carbamoyl}methyl)phenyl]piperazine-1-yl}acetic acid. The reaction was carried out according to general procedure F, using potassium 2-{4-[4-(2-ethoxy-2-oxoethyl)phenyl]piperazine-1-yl}acetate (57 mg, 0.17 mmol) and 4-[(2-aminoethyl)amino]-2-[2,6-dioxopiperidine-3-yl]isoindole-1,3-dione hydrochloride (60 mg, 0.17 mmol) as starting materials. The crude material from this reaction was subjected to general procedure B and purified according to chromatography C to obtain the title compound (40 mg, 41%).

[0415] Step 4: Synthesis of 5-({6-[1'-(2-{4-[4-({[2-({2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl}amino)ethyl]carbamoyl}methyl)phenyl]piperazine-1-yl}acetyl)-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl]-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl}amino)-4-fluoro-2-methyl-N-(propan-2-yl)benzamide. The title compound was synthesized according to general procedure F, using intermediate 1 (10 mg) and {4-[4-({[2-({2-[2,6-dioxopiperidine-3-yl]-1,3-dioxoisoindole-4-yl}amino)ethyl]carbamoyl}methyl)phenyl]piperazine-1-yl}acetic acid (10 mg) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (14.1 mg, 80%). LCMS:C 70 H 81 FN 14 The required value for O8 is 1264.6, and the measured value is 1266.9 [M+2H]. + ; 1H NMR (500 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.99 (s, 1H), 9.50 (s, 1H), 8.66 (s, 1H), 8.41 (s, 1H), 8.23 ​​(t, J = 5.7 Hz, 1H), 8.14 (d, J = 7.9 Hz, 1H), 7.89 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.64 - 7.42 (m, 4H), 7.25 - 7.08 (m, 5H), 7.04 (d, J = 7.0 Hz, 1H), 6.92 (d, J = 8.4 Hz, 2H), 6.74 (s, 1H), 5.36 - 5.21 (m, 1H), 5.07 (dd, J = 12.8, 5.4 Hz, 1H), 4.54 - 3.04 (m, 17H), 3.04 - 2.72 (m, 8H), 2.68 - 2.55 (m, 1H), 2.36 (s, 3H), 2.04 (dd, J = 10.2, 4.9 Hz, 1H), 1.92 - 1.38 (m, 21H), 1.10 (d, J = 6.6 Hz, 6H). (Example 45)

[0416] 5-{[6-(1'-{1-[(1-{2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-4-yl)methyl]piperidine-4-carbonyl}-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl)-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl]amino}-4-fluoro-2-methyl-N-(propan-2-yl)benzamide [ka]

[0417] Step 1: Synthesis of 1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-4-yl)piperidine-4-yl)methyl)piperidine-4-carboxylic acid. The reaction was carried out according to general procedure D using 1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl]piperidine-4-carbaldehyde (15 mg, 0.04 mmol) and tert-butylpiperidine-4-carboxylate (7.4 mg, 0.04 mmol). The crude material from this reaction was then subjected to general procedure B, followed by chromatography C, to obtain the title compound (15.4 mg, 80%).

[0418] Step 2: Synthesis of 5-{[6-(1'-{1-[(1-{2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-4-yl)methyl]piperidine-4-carbonyl}-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl)-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl]amino}-4-fluoro-2-methyl-N-(propan-2-yl)benzamide. The title compound was synthesized according to general procedure F, using intermediate 1 (10 mg) and 1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperidine-4-yl)methyl)piperidine-4-carboxylic acid (6.5 mg) as starting materials. The crude material was purified by reverse-phase HPLC to obtain the title compound (14.3 mg, 74.1%). LCMS:C 66 H 79 FN 12 The required value for O7 is 1170.6, and the measured value is 1171.4 [M+H]. + ; 1H NMR (500 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.49 (s, 1H), 8.99 (s, 1H), 8.64 (s, 1H), 8.40 (s, 1H), 8.14 (d, J = 7.8 Hz, 1H), 7.88 (s, 1H), 7.68 (dd, J = 10.1, 8.0 Hz, 2H), 7.59 (d, J = 8.2 Hz, 1H), 7.51 (d, J = 6.1 Hz, 2H), 7.37 (d, J = 2.2 Hz, 1H), 7.28 (dd, J = 8.8, 2.1 Hz, 1H), 7.17 (d, J = 12.2 Hz, 1H), 5.37 - 5.20 (m, 1H), 5.07 (dd, J = 12.8, 5.4 Hz, 1H), 4.25 - 3.36 (m, 12H), 3.19 - 2.74 (m, 8H), 2.66 - 2.53 (m, 2H), 2.36 (s, 3H), 2.20 - 1.49 (m, 27H), 1.47 - 1.21 (m, 4H), 1.10 (d, J = 6.6 Hz, 6H). (Example 46)

[0419] N-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-4-yl)amino)ethyl)-7-(2-(6-(4-((2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridine-6-yl)-2-oxo-1-((1s,3s)-3-(piperidine-1-yl)cyclobutyl)spiro[indoline-3,4'-piperidine]-1'-yl)-2-oxoethyl)-7-azaspiro[3.5]nonane-2-carboxamide [ka]

[0420] Step 1: Synthesis of N-[2-({2-[2,6-dioxopiperidine-3-yl]-1,3-dioxoisoindole-4-yl}amino)ethyl]-7-azaspiro[3.5]nonane-2-carboxamide. The reaction was carried out according to general procedure F using 4-[(2-aminoethyl)amino]-2-[2,6-dioxopiperidine-3-yl]isoindole-1,3-dione hydrochloride (55 mg, 0.16 mmol) and 7-(tert-butoxycarbonyl)-7-azaspiro[3.5]nonane-2-carboxylic acid (46 mg, 0.17 mmol). The crude material from this reaction was then subjected to general procedure B, followed by chromatography C, to obtain the title compound (56 mg, 77%).

[0421] Step 2: Synthesis of (2-{[2-({2-[2,6-dioxopiperidine-3-yl]-1,3-dioxoisoindole-4-yl}amino)ethyl]carbamoyl}-7-azaspiro[3.5]nonane-7-yl)acetic acid. The title compound was synthesized according to general procedure E using N-[2-({2-[2,6-dioxopiperidine-3-yl]-1,3-dioxoisoindole-4-yl}amino)ethyl]-7-azaspiro[3.5]nonane-2-carboxamide (28 mg, 0.06 mmol) and tert-butyl 2-bromoacetate (12 mg, 0.06 mmol). The crude material from this reaction was then subjected to general procedure B, followed by chromatography C, to obtain the title compound (28 mg, 89%).

[0422] Step 3: Synthesis of N-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-4-yl)amino)ethyl)-7-(2-(6-(4-((2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridine-6-yl)-2-oxo-1-((1s,3s)-3-(piperidine-1-yl)cyclobutyl)spiro[indoline-3,4'-piperidine]-1'-yl)-2-oxoethyl)-7-azaspiro[3.5]nonane-2-carboxamide. The title compound was synthesized according to general procedure F using intermediate 1 (12.7 mg, 0.02 mmol) and (2-{[2-({2-[2,6-dioxopiperidine-3-yl]-1,3-dioxoisoindole-4-yl}amino)ethyl]carbamoyl}-7-azaspiro[3.5]nonane-7-yl)acetic acid (9.0 mg, 0.02 mmol), followed by reverse-phase HPLC to obtain the title compound (4.9 mg, 20%). LCMS:C 67 H 80 FN 13 The required value for O8 is 1213.6, and the measured value is 1214.7 [M+H]. + ; 1 H NMR (500 MHz, Methanol-d4) δ 8.73 (s, 1H), 8.08 - 7.97 (m, 1H), 7.82 - 7.67 (m, 2H), 7.63 (s, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.19 - 7.11 (m, 2H), 7.08 (d, J = 7.0 Hz, 1H), 5.29 (p, J = 6.5 Hz, 1H), 5.10 - 5.02 (m, 1H), 4.40 - 4.03 (m, 4H), 4.03 - 3.87 (m, 2H), 3.72 - 3.57 (m, 2H), 3.57 - 3.38 (m, 9H), 3.15 - 2.62 (m, 11H), 2.43 (s, 3H), 2.22 - 1.48 (m, 26H), 1.14 (d, J = 6.6 Hz, 6H). (Example 47)

[0423] (2S,4R)-1-[(2S)-2-(2-{4-[4-(2-{6-[4-({2-fluoro-4-methyl-5-[(propan-2-yl)carbamoyl]phenyl}amino)-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-6-yl]-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl}-2-oxoethyl)phenyl]piperazine-1-yl}acetamide)-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide [ka]

[0424] Step 1: Synthesis of tert-butyl 2-(4-(4-(2-ethoxy-2-oxoethyl)phenyl)piperazin-1-yl)acetate. Tert-butyl (piperazin-1-yl)acetate (0.89 g, 4.4 mmol, 1.2 equivalents), palladium(II) acetate (0.083 g, 0.37 mmol, 0.1 equivalent), and Xphos (0.176 g, 0.37 mmol, 0.1 equivalent) were added under argon to a stirred solution of ethyl 4-bromophenyl (0.90 g, 3.7 mmol, 1.0 equivalent) in anhydrous toluene (22 mL, 0.2 M). The reaction mixture was then purged with argon for 3 minutes, transferred to a bath preheated to 100°C, and stirred for 16 hours. Formation of the title compound was shown by UPLC. The mixture was diluted with water (20 mL) and then extracted with ethyl acetate (three times). The combined organic fraction was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography A to obtain 0.9 g (67% yield) of the title compound.

[0425] Step 2: Synthesis of 2-{4-[4-(2-ethoxy-2-oxoethyl)phenyl]piperazin-1-yl}acetic acid. Tert-butyl 2-(4-(4-(2-ethoxy-2-oxoethyl)phenyl)piperazin-1-yl) acetate (0.13 g, 0.36 mmol, 1.0 equivalent) was dissolved in anhydrous DCM (1.3 mL), followed by the addition of TFA (0.275 mL, 10.0 equivalents), and the mixture was stirred at RT for 4 hours. UPLC showed that SM remained. Another 10 equivalents of TFA were added, and the reaction mixture was stirred for a further 2 hours. The reaction mixture was evaporated to dryness to obtain 0.13 g (yield 86%) of the title compound as the TFA salt.

[0426] Step 3: Synthesis of ethyl 2-{4-[4-({[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methyl)piperazine-1-yl]phenyl}acetate. The title compound was synthesized according to general procedure F using (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide hydrochloride (50 mg, 0.10 mmol) and {4-[4-(2-ethoxy-2-oxoethyl)phenyl]piperazine-1-yl}acetic acid (53 mg, 0.12 mmol). The crude material was purified by chromatography B to obtain the title compound (75 mg, 98%).

[0427] Step 4: Synthesis of {4-[4-({[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methyl)piperazine-1-yl]phenyl}acetic acid. The title compound was synthesized using ethyl 2-{4-[4-({[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methyl)piperazine-1-yl]phenyl}acetate (75 mg, 0.10 mmol). This material was used without purification.

[0428] Step 5: Synthesis of (2S,4R)-1-[(2S)-2-{2-[4-(4-{2-[6-(4-{[2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl]amino}-3-isopropylimidazo[4,5-c]pyridine-6-yl)-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]spiro[indole-3,4'-piperidine]-1'-yl]-2-oxoethyl}phenyl)piperazine-1-yl]acetamide}-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide. The title compound was synthesized according to general procedure F using intermediate 1 (15.8 mg, 0.02 mmol) and {4-[4-({[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methyl)piperazine-1-yl]phenyl}acetic acid (15 mg, 0.02 mmol), followed by reverse-phase HPLC to obtain the title compound (13 mg, 44%). LCMS:C 78 H 97 FN14 The required value for O7S is 1392.7, and the measured value is 1393.8 [M+H]. + ; 1 H NMR (500 MHz, Methanol-d4) δ 8.92 - 8.80 (m, 2H), 8.08 - 8.01 (m, 1H), 7.80 - 7.67 (m, 2H), 7.64 - 7.53 (m, 1H), 7.49 - 7.25 (m, 7H), 7.19 - 7.02 (m, 2H), 5.30 (p, J = 6.6 Hz, 1H), 5.02 (t, J = 6.9 Hz, 1H), 4.61 - 4.24 (m, 2H), 4.21 - 3.39 (m, 23H), 3.19 - 2.81 (m, 7H), 2.50 - 2.37 (m, 6H), 2.26 - 2.18 (m, 1H), 2.07 - 1.45 (m, 22H), 1.15 - 1.06 (m, 15H). (Example 48)

[0429] (2S,4R)-1-((2S)-2-(2-(3-(3-(6-(4-((2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridine-6-yl)-2-oxo-1-((1s,3s)-3-(piperidine-1-yl)cyclobutyl)spiro[indoline-3,4'-piperidine]-1'-yl)-3-oxopropyl)piperidine-1-yl)acetamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0430] Step 1: Synthesis of ethyl 3-[1-({[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methyl)piperidine-3-yl]propanoate. The reaction was carried out according to general procedure F, using (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide hydrochloride (110 mg, 0.23 mmol) and [3-(3-ethoxy-3-oxopropyl)piperidine-1-yl]acetic acid (56 mg, 0.23 mmol) as starting materials. The title compound was obtained by purification using chromatography B (128 mg, 83%).

[0431] Step 2: Synthesis of 3-[1-({[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methyl)piperidine-3-yl]propanoic acid. The reaction was carried out according to general procedure C, using ethyl 3-[1-({[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methyl)piperidine-3-yl]propanoate (128 mg, 0.19 mmol) as the starting material. The residue was used in the next step without purification.

[0432] Step 3: Synthesis of (2S,4R)-1-[(2S)-2-{2-[(3RS)-3-(3-{6-[4-({2-fluoro-4-methyl-5-[(propan-2-yl)carbamoyl]phenyl}amino)-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-6-yl]-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl}-3-oxopropyl)piperidine-1-yl]acetamide}-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide. The title compound was synthesized according to general procedure F using intermediate 1 (12 mg, 0.02 mmol) and 3-[1-({[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methyl)piperidine-3-yl]propanoic acid (10 mg, 0.02 mmol), followed by reverse-phase HPLC to obtain the title compound (10.9 mg, 43%). LCMS:C 74 H 96 FN 13 O7S required value: 1329.5, measured value: 1331.2 [M+2H] + ; 1H NMR (500 MHz, Acetonitrile-d3) δ 8.84 - 8.73 (m, 1H), 8.67 (s, 1H), 8.06 - 7.96 (m, 1H), 7.96 - 7.86 (m, 1H), 7.75 - 7.67 (m, 1H), 7.53 - 7.13 (m, 10H), 6.68 (d, J = 7.8 Hz, 1H), 5.23 - 5.10 (m, 1H), 4.96 (s, 1H), 4.71 - 4.57 (m, 1H), 4.57 - 4.45 (m, 1H), 4.44 - 4.32 (m, 1H), 4.32 - 4.00 (m, 3H), 3.98 - 3.58 (m, 8H), 3.58 - 3.39 (m, 6H), 3.09 - 2.39 (m, 10H), 2.12 (d, J = 5.1 Hz, 2H), 1.92 - 1.38 (m, 28H), 1.16 (d, J = 6.6 Hz, 8H), 1.02 (d, J = 8.4 Hz, 10H). (Example 49)

[0433] 5-[(6-{1'-[1-{1-[2-({2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl}amino)acetyl]piperidine-4-carbonyl}pyrroridine-3-carbonyl]-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide [ka]

[0434] Step 1: Synthesis of benzyl 1-[2-({2-[2,6-dioxopiperidine-3-yl]-1,3-dioxoisoindole-4-yl}amino)acetyl]piperidine-4-carboxylate. The title compound was synthesized according to general procedure F using ({2-[-2,6-dioxopiperidine-3-yl]-1,3-dioxoisoindole-4-yl}amino)acetic acid (175 mg, 0.39 mmol) and benzylpiperidine-4-carboxylate (86 mg, 0.39 mmol). The crude material was purified by chromatography B to obtain the title compound (200 mg, 96%).

[0435] Step 2: Synthesis of 1-[2-({2-[2,6-dioxopiperidine-3-yl]-1,3-dioxisoindole-4-yl}amino)acetyl]piperidine-4-carboxylic acid. The title compound was synthesized by adding carbon-supported palladium (15 mg, 10 wt%) to benzyl 1-[2-({2-[2,6-dioxopiperidine-3-yl]-1,3-dioxisoindole-4-yl}amino)acetyl]piperidine-4-carboxylate (200 mg, 0.38 mmol). Next, ethyl acetate (2 mL) and ethanol (2 mL) were added, and the mixture was subsequently stirred and bubbling with H2 gas for 5 minutes. The reaction mixture was then stirred under an H2 balloon for 5 hours, purged with nitrogen, filtered through Celite, and washed with ethyl acetate. The filtrate was concentrated and purified according to chromatography to obtain the title compound (120 mg, 72%).

[0436] Step 3: Synthesis of 1-{1-[2-({2-[2,6-dioxopiperidine-3-yl]-1,3-dioxoiisoindole-4-yl}amino)acetyl]piperidine-4-carbonyl}pyrrolidine-3-carboxylic acid. The title compound was synthesized according to general procedure F using 1-[2-({2-[2,6-dioxopiperidine-3-yl]-1,3-dioxoiisoindole-4-yl}amino)acetyl]piperidine-4-carboxylic acid (44 mg, 0.10 mmol) and tert-butylpyrrolidine-3-carboxylate (19 mg, 0.11 mmol). The crude material was purified using chromatography C, followed by general procedure B, to obtain the title compound (22 mg, 41%).

[0437] Step 4: Synthesis of 5-[(6-{1'-[1-{1-[2-({2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl}amino)acetyl]piperidine-4-carbonyl}pyrroridine-3-carbonyl]-2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl)amino]-4-fluoro-2-methyl-N-(propan-2-yl)benzamide. The title compound was synthesized according to general procedure F using intermediate 1 (13 mg, 0.02 mmol) and 1-{1-[2-({2-[2,6-dioxopiperidine-3-yl]-1,3-dioxoisoindole-4-yl}amino)acetyl]piperidine-4-carbonyl}pyrrolidine-3-carboxylic acid (10 mg, 0.02 mmol), followed by reverse-phase HPLC to obtain the title compound (13.6 mg, 60%). LCMS:C 67 H 78 FN 13 The required value for O9 is 1227.6, and the measured value is 1230.0 [M+2H]. + ; 1H NMR (500 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.31 (s, 1H), 8.64 (s, 1H), 8.39 (s, 1H), 8.14 (d, J = 7.9 Hz, 1H), 7.89 (d, J = 4.6 Hz, 1H), 7.68 (d, J = 6.8 Hz, 1H), 7.62 (t, J = 8.2 Hz, 2H), 7.60 - 7.50 (m, 2H), 7.19 (d, J = 12.0 Hz, 1H), 7.15 - 7.01 (m, 3H), 5.30 (p, J = 7.6, 7.1 Hz, 1H), 5.08 (dd, J = 12.8, 5.4 Hz, 1H), 4.42 (d, J = 12.0 Hz, 1H), 4.22 (q, J = 19.3, 17.2 Hz, 5H), 4.08 - 4.01 (m, 2H), 3.49 - 3.22 (m, 8H), 3.20 - 2.69 (m, 13H), 2.62 (d, J = 3.7 Hz, 1H), 2.37 (s, 3H), 2.20 - 2.03 (m, 3H), 1.93 - 1.54 (m, 17H), 1.50 - 1.33 (m, 2H), 1.11 (d, J = 6.6Hz, 6H). (Example 50)

[0438] 4-Fluoro-2-methyl-5-[(6-{2-oxo-1-[(1s,3s)-3-(piperidine-1-yl)cyclobutyl]-1'-[(1s,4s)-4-[4-({2-[2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl}amino)piperidine-1-carbonyl]cyclohexanecarbonyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-6-yl}-3-(propan-2-yl)-3H-imidazo[4,5-c]pyridine-4-yl)amino]-N-(propan-2-yl)benzamide [ka]

[0439] Step 1: Synthesis of tert-butyl 4-[[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-4-yl]amino]piperidine-1-carboxylate: In DMSO (20 mL), a mixture of 2-(2,6-dioxopiperidine-3-yl)-4-fluoroisoindole-1,3-dione (4.0 g, 14 mmol, 1 equivalent) and tert-butyl 4-aminopiperidine-1-carboxylate (3.48 g, 17.3 mmol, 1.2 equivalents) was mixed with DIPEA (5.61 g, 43.4 mmol, 3 equivalents). The resulting mixture was stirred overnight at 80°C and then cooled to rt. The precipitated solid was collected by filtration and washed with water (3 × 50 mL). This yielded the title compound as a solid (4.0 g, 61%).

[0440] Step 2: Synthesis of 2-(2,6-dioxopiperidine-3-yl)-4-(piperidine-4-ylamino)isoindole-1,3-dione: The title compound was obtained according to general procedure B, using tert-butyl 4-[[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-4-yl]amino]piperidine-1-carboxylate (4.0 g, 8.8 mmol) as the starting material. After chromatography C, the title compound was isolated (2.4 g, 77%).

[0441] Step 3: Synthesis of (1s,4s)-4-[4-([2-[2,6-dioxopiperidine-3-yl]-1,3-dioxoisoindole-4-yl]amino)piperidine-1-carbonyl]cyclohexane-1-carboxylic acid: (1s,4s)-cyclohexane-1,4-dicarboxylic acid (0.63 g, 3.7 mmol, 1 equivalent) was added to a mixture of 2-(2,6-dioxopiperidine-3-yl)-4-(piperidine-4-ylamino)isoindole-1,3-dione (1.3 g, 3.65 mmol, 1 equivalent) and TEA (2.21 g, 21.9 mmol, 6 equivalents) in DMF (8 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 30 minutes. T3P (3.48 g, 5.47 mmol, 1.5 equivalents, 50 w / w% in ethy...

Claims

1. Structure of formula (Ic) 【Chemistry 166】 A compound having or a pharmaceutically acceptable salt thereof, Here, L is a linker moiety having 2 to 24 continuously covalently bonded atoms of a length selected from the group consisting of C, O, N, and S, and LHM is the ligase harness portion, which is a compound or pharmaceutically acceptable salt thereof that targets CRBN or VHL.

2. L, 【Chemistry 167】 And in the formula, t is 0, 1, 2, 3, 4, 5, 6, or 7, q is 0, 1, 2, 3, 4, 5, 6, or 7, L １ However, it is a direct bond, -C(O)NH-, or -C(O)-, L ２ However, it is -C(O)NH-, -O-, or -NH- The compound according to claim 1.

3. L has the following structure 【Chemical 168】 【Chemistry 169】 The compound according to claim 2, having one of the above.

4. L, 【Chemistry 170】 And in the formula, w is 1, 2, or 3, v is 1 or 2, p is 1, 2, 3, 4, or 5, Y １ However, direct bonding, -(CH ２ ) ｐ -, or -O-, Y ２ is directly bonded by -(CH ２ ) ｐ -, -C(O)-, or -C(O)-CH ２ -, and X ３ and X ４ However, independently, N or C(R), and R is either H or C １～３ It is alkyl, L ４ However, it is either a direct bond, -NH-, -NHC(O)-, or L ４ but, 【Chemistry 171】 The compound according to claim 1.

5. L has the following structure 【Chemistry 172】 【Chemistry 173】 【Chemistry 174】 The compound according to claim 4, having one of the above.

6. L has the following structure 【Chemistry 175】 【Chemistry 176】 The compound according to claim 1, which is one of the following.

7. The LHM targets CRBN, and has the structure of formula (Id). 【Chemistry 177】 A compound according to any one of claims 1 to 6, having [In the formula, W is -C(R ｇ ) - or -N-, Z １ -C(O)-, -C(S)-, -C(NR ｇ )-,-C(R ｇ ) ２ -, -C(R ｇ ) ２ -C(O)-, -C(O)-N(R ｇ )-,-CR ｇ =CR ｇ -, -C(R ｇ ) = N-, -C(R ｇ ) ２ -C(S)-, or -C(R ｇ ) ２ -C(R ｇ ) ２ - and q is 0, 1 or 2, R ｇ is hydrogen or C １～６ It is alkyl, R ａ C １～６ alkyl, halo, halo C １～６ Alkyl, -N(R ｇ ) ２ , CN, nitro, -O-C １～４ [It is alkyl or hydroxyl.]

8. The LHM has the following structure 【Chemistry 178】 The compound according to claim 7, having one of the above.

9. The LHM targets VHL and has the structure of formula (Ie) or (If). 【Chemistry 179】 A compound according to any one of claims 1 to 6, having [In the formula, p is either 0 or 1, R ｊ This is an unsubstituted 5-6 member heteroaryl or 1-3 R ｋ It is a 5-6 member heteroaryl substituted with, Each R ｋ These are independently: halo, oxo, -CN, -OH, C １～６ Alkyl, C ３～８ Cycloalkyl, or -O-C １～６ It is alkyl, Each R ｅ These are, independently, hydrogen and C １～６ Alkyl or C ３～８ It is a cycloalkyl, R ｂ is hydrogen or hydroxyl, R ｃ is -C(O)R ｆ And R ｆ is an unsubstituted C １～６ C substituted with alkyl, halo, or -CN １～６ Alkyl or unsubstituted C ３～８ C substituted with cycloalkyl, halo, or -CN ３～８ It is a cycloalkyl, and R g is hydrogen.

10. The LHM has the following structure 【Chemistry 180】 The compound according to claim 9, having one of the above.

11. The following: 【Chemistry 11-11】 [Chemistry 11-12] [Chemistry 11-13] [Chemistry 11-14] 【Chemistry 11-15】 【Chemistry 11-16】 [Chemistry 11-17] [Chemistry 11-18] [Chemistry 11-19] [Chemistry 11-20] 【Chemistry 11-21】 [Chemistry 11-22] [Chemistry 11-23] [Chemistry 11-24] [Chemistry 11-25] [Chemistry 11-26] A compound according to claim 1, selected from the group consisting of the following.

12. Structure of formula (IIc) 【Chemistry 185】 A compound having or a pharmaceutically acceptable salt thereof, Here, L is a linker moiety having 2 to 24 continuously covalently bonded atoms of a length selected from the group consisting of C, O, N, and S, and LHM is the ligase harness portion, which targets CRBN or VHL. A compound or a pharmaceutically acceptable salt thereof.

13. L, 【Chemical 186】 And in the formula, t is 0, 1, 2, 3, 4, 5, 6, or 7, q is 0, 1, 2, 3, 4, 5, 6, or 7, L １ However, it is a direct bond, -C(O)NH-, or -C(O)-, L ２ However, it is -C(O)NH-, -O-, or -NH- The compound according to claim 12.

14. t is 0, q is 5 or 7, L １ However, it is -C(O)NH- and L ２ The compound according to claim 13, wherein the compound is -O- or -NH-.

15. The aforementioned LHM targets VHL, and has the structure of formula (If). 【Chemistry 187】 A compound according to any one of claims 12 to 14, having [In the formula, p is either 0 or 1, R ｊ This is an unsubstituted 5-6 member heteroaryl or 1-3 R ｋ It is a 5-6 member heteroaryl substituted with, Each R ｋ These are independently: halo, oxo, -CN, -OH, C １～６ Alkyl, C ３～８ Cycloalkyl, or -O-C １～６ It is alkyl, Each R ｅ These are, independently, hydrogen and C １～６ Alkyl or C ３～８ It is a cycloalkyl, R ｂ is hydrogen or hydroxyl, R ｃ is -C(O)R ｆ And R ｆ is an unsubstituted C １～６ C substituted with alkyl, halo, or -CN １～６ Alkyl or unsubstituted C ３～８ C substituted with cycloalkyl, halo, or -CN ３～８ It is a cycloalkyl, and R g is hydrogen.

16. The aforementioned LHM is one of the following structures 【Chemical 188】 【Chemical 189】 The compound according to claim 15, having the following characteristics.

17. The LHM targets CRBN, and has the structure of formula (Id). 【Chemistry 190】 A compound according to any one of claims 12 to 14, having [In the formula, W is -C(R ｇ ) - or -N-, Z １ is -C(O)-, -C(S)-, -C(NR ｇ ), -C(R ｇ ), ２ -C(R ｇ ), ２ -C(O)-, -C(O)-N(R ｇ ), -CR ｇ =CR ｇ -, -C(R ｇ )=N-, -C(R ｇ ), ２ -C(S)-, or -C(R ｇ ), ２ -C(R ｇ ), ２ -, where q is 0, 1 or 2, R ｇ is hydrogen or C １～６ It is alkyl, R ａ is C １～６ alkyl, halo, halo C １～６ alkyl, -N(R ｇ ) ２ , CN, nitro, hydroxyl, or -O-C １～４ alkyl].

18. W is -CH-, Z １ However, -C(O)-, -CH ２ -ien-CH ２ The compound according to claim 17, wherein it is -C(O)- or -CH=CH-.

19. The aforementioned LHM is one of the following structures 【Chemistry 191】 The compound according to claim 18, having the following characteristics.

20. The following: 【Chemistry 20】 A compound according to claim 12, selected from the above.

21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

22. The pharmaceutical composition according to claim 21, further comprising one or more additional therapeutic agents or pharmaceutically acceptable salts thereof.

23. A composition comprising a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for use in a method for treating a disease or disorder associated with increased hematopoietic precursor kinase 1 (HPK1) activity.

24. A composition comprising a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for use in a method for increasing T cell activation.

25. A composition comprising a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer.

26. The composition according to claim 25, 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 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 carcinoma.

27. A composition comprising a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for use in a method for inhibiting the growth or proliferation of cancer cells.

28. Furthermore, the composition according to any one of claims 23 to 27 is combined with one or more additional therapeutic agents or pharmaceutically acceptable salts thereof in a therapeutically effective amount.

29. The one or more additional therapeutic agents include inducible T cell costimulatory molecule (ICOS) agonists, cytotoxic T lymphocyte antigen 4 (CTLA-4) blocking antibodies, PD1 and / or PD-L1 inhibitors, differentiation antigen group 47 (CD47) inhibitors, OX40 agonists, GITR agonists, CD27 agonists, CD28 agonists, CD40 agonists, CD137 agonists, Toll-like receptor 8 (TLR8) agonists, T cell immunoglobulin and mucin domain-3 (TIM-3) inhibitors, lymphocyte activator gene 3 (LAG-3) inhibitors, CEACAM1 inhibitors, Ig and ITI The composition according to claim 28, selected from the group consisting of M-domain T cell immune receptor (TIGIT) inhibitors, V-domain immunoglobulin (Ig)-containing suppressors (VISTA) for T cell activation, anti-killer IgG-like receptor (KIR) inhibitors, STING agonists, C-X-C chemokine receptor 4 (CXCR-4) inhibitors, B7-H3 inhibitors, CD73 inhibitors, inhibitory RNA, IL2 / 15 / 17 fusion proteins, MKNK1 / 2 inhibitors, JAK inhibitors, and PI3K inhibitors, or pharmaceutically acceptable salts of any of the above, or any combination thereof.

30. The one or more additional therapeutic agents mentioned above include Rituxan, Doxorubicin, Gemcitabine, Nivolumab, Pembrolizumab, Pidilizumab, PDR001, TSR001, Atezolizumab, Durvalumab, Avelumab, Pidilizumab, TSR-042, BMS-986016, Ruxolitinib, N-(cyanomethyl)-4-[2-(4-morpholinoanilino)pyrimidine-4-yl]benzamide, XL147, BKM120, GDC-0941, and BAY8. 0-6946, PX-866, CH5132799, XL756, BEZ235, and GDC-0980, Waltmannin, LY294002, TGR-1202, AMG-319, GSK2269557, X-339, X-414, RP5090, KAR4141, XL499, OXY111A, IPI-145, IPI-443, GSK2636771, BAY10824391, Buparlicib, BYL719, RG7604, MLN1117, WX- 037, AEZS-129, PA799, ZSTK474, AS252424, TGX221, TG100115, IC87114, IPI-549, INCB050465, (S)-2-(1-((9H-purine-6-yl)amino)propyl)-5-fluoro-3-phenylquinazoline-4(3H)-one, (S)-2-(1-((9H-purine-6-yl)amino)ethyl)-6-fluoro-3-phenylquinazoline-4(3H)-one, (S)-2-( The composition according to claim 29, selected from the group consisting of 1-((9H-purine-6-yl)amino)ethyl)-3-(2,6-difluorophenyl)quinazoline-4(3H)-one, (S)-4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazoline-2-yl)ethyl)amino)pyrimidine-5-carbonitrile, and ipilimumab, or any pharmaceutically acceptable salt thereof, or any combination thereof.

31. The composition according to claim 29, wherein the one or more additional therapeutic agents are selected from the group consisting of idelalisib, tirabrutinib, momerotinib, and entospretinib, or pharmaceutically acceptable salts of any of the foregoing, or any combination thereof.

32. A composition comprising a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for use in a method for treating or preventing hepatitis B virus (HBV) infection.

33. The composition according to claim 32, further comprising a therapeutically effective amount of one or more additional therapeutic agents or pharmaceutically acceptable salts thereof.

34. The one or more additional therapeutic agents mentioned above include HBV combination drugs, HBV vaccines, HBV DNA polymerase inhibitors, immunomodulators, 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, cyclophyllin inhibitors, HBV virus entry inhibitors, antisense oligonucleotides targeting viral mRNA, short interfering RNA (siRNA) and ddRNAi endonuclease modulators, ribonucleotide reductase inhibitors, and HBV The composition according to claim 33, selected from the group consisting of E antigen inhibitors, covalent closed circular DNA (cccDNA) inhibitors, farnesoid X receptor agonists, HBV antibodies, CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein modulators, retinoic acid-inducible gene 1 stimulants, NOD2 stimulants, phosphatidylinositol 3-kinase (PI3K) inhibitors, indoleamine-2,3-dioxygenase (IDO) pathway inhibitors, PD-1 inhibitors, PD-L1 inhibitors, recombinant thymosin alpha-1 agonists, Bruton's tyrosine kinase (BTK) inhibitors, KDM inhibitors, HBV replication inhibitors, arginase inhibitors, and other HBV drugs, or pharmaceutically acceptable salts of any of the above, or any combination thereof.

35. The aforementioned one or more additional therapeutic agents include adefovir (Hepsera®), tenofovir disoproxil fumarate + emtricitabine (Truvada®), tenofovir disoproxil fumarate (Viread®), entecavir (Baraclude®), lamivudine (Epivir-HBV®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, and tenofovir. Alafenamide fumarate, tenofovir alafenamide hemifumarate, terbivudine (Tyzeka®), Clevudine®, emtricitabine (Emtriva®), pegylated interferon alpha-2b (PEG-Intron®), Multiferon®, interferon alpha-1b (Hapgen®), interferon alpha-2b (Intron) A (registered trademark), pegylated interferon alpha-2a (Pegasys (registered trademark)), interferon alpha-n1 (Humoferon (registered trademark)), ribavirin, interferon beta-1a (Avonex (registered trademark)), bioferon, ingaron, immutag (inferon), algeron, loferon-A, oligotide, zutectra, shaferon, interferon alpha-2b (Axxo), alphaferon, interferon alpha-2b, feron, interferon-alpha-2 (CJ), bevac, raferonam, vipe Blauferon-B, Blauferon-A, Intermax Alpha, Realjiron, Lanstion, Pegaferon, PDferon-B, Alpha Interferon 2b, Carferon, Pegnano, Feron Sle, Pegihep, OptiPeg A, Real Alpha 2B, Reliferon, Peginterferon Alpha-2b, Rareferon-EC, Prociferon, Uniferon, Ulifron, Interferon Alpha-2b, Antarferon, Chanferon, MOR-22, Interleukin-2 (IL-2), Recombinant Human Interleukin-2 (Shenzhen)The composition according to any one of claims 33 or 34, selected from the group consisting of Neptunus), Liferon, Ka-Shu-Nin, Shan-Shen-Lei-Tai, Intefen, Sinogen, Fukan-Tai, Aloferon, and Sermoloykin, or any pharmaceutically acceptable salt thereof, or any combination thereof.

36. The composition according to any one of claims 33 to 35, 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, terbivudine, and lamivudine, or any pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.

37. The composition according to any one of claims 33 to 36, 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 any pharmaceutically acceptable salt thereof, or any combination thereof.

38. A composition comprising a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for use in methods for treating or preventing human immunodeficiency virus (HIV) infection.

39. The composition according to claim 38, further comprising a therapeutically effective amount of one or more additional therapeutic agents or pharmaceutically acceptable salts thereof.

40. The aforementioned one or more additional therapeutic agents include: combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversal 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 modulator, vif dimerizing antagonist, HIV-1 virus infectivity factor inhibitor, TAT protein inhibitor, HIV-1 Nef modulator, Hck tyrosine kinase modulator, mixed lineage kinase-3 (MLK-3) inhibitor, HIV-1 splicing inhibitor, Rev protein inhibitor, integrin antagonist, nucleoprotein inhibitor, splicing factor modulator, COMM domain-containing protein 1 modulator, HIV ribonuclease H inhibitor, retrocyclin modulator, CDK-9 inhibitor, dendritic ICAM-3-binding nonintegrin 1 inhibitor, HIV GAG protein inhibitor, HIV The composition according to claim 39, selected from the group consisting of a POL protein inhibitor, a complement factor H modulator, a ubiquitin ligase inhibitor, a deoxycytidine kinase inhibitor, a cyclin-dependent kinase inhibitor, a proprotein-converting enzyme PC9 stimulant, an ATP-dependent RNA helicase DDX3X inhibitor, a reverse transcriptase priming complex inhibitor, a G6PD and NADH-oxidase inhibitor, a pharmacokinetic activator, an HIV gene therapy, and an HIV vaccine, or a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.

41. The composition according to any one of claims 39 to 40, wherein the one or more additional therapeutic agents are selected from the group consisting of HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic activators, and other drugs for treating HIV, or pharmaceutically acceptable salts of any of the foregoing, or any combination thereof.

42. The composition according to any one of claims 38 to 41, wherein the one or more additional therapeutic agents are selected from the group consisting of 4'-ethinyl-2-fluoro-2'-deoxyadenosine, bictegravir, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, or any pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.

43. The composition according to any one of claims 38 to 42, wherein the one or more additional therapeutic agents are selected from the group consisting of 4'-ethinyl-2-fluoro-2'-deoxyadenosine, bictegravir, tenofovir alafenamide, tenofovir alafenamide fumarate, or tenofovir alafenamide hemifumarate, or any pharmaceutically acceptable salt thereof, or any combination thereof.

44. The composition according to any one of claims 38 to 43, wherein the one or more additional therapeutic agents are selected from the group consisting of 4'-ethinyl-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.

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