Heterobifunctional molecules as TEAD inhibitors

Abstract

Formula I: Q 1 -Q 2 -Q 3 I (where Q 1 , Q 2 , and Q 3 has the meaning indicated in claim 1) degrades target proteins and can be employed, inter alia, for the treatment of diseases and disorders mediated by such target proteins.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to heterocyclic derivatives, which are useful for therapeutic and / or prophylactic methods in mammals, especially humans. In particular, they are useful as inhibitors and / or degraders of TEAD, and thus may be useful for treating cancer. [Background technology]

[0002] Background of the Invention In recent years, the Hippo pathway has become an interesting target for the treatment of hyperproliferative disorders and diseases, especially cancer (S.A. Smith et al., J. Med. Chem. 2019, 62, 1291-1305; K.C. Lin et al., Annu. Rev. Cancer Biol. 2018, 2:59-79; C.-L. Kim et al., Cells (2019), 8, 468; K.F. Harvey et al., Nature Reviews Cancer, Vol. 13, 246-257 (2013)). The Hippo pathway regulates cell growth, proliferation, and migration. In mammals, the Hippo pathway is thought to act as a tumor suppressor, and dysfunction of Hippo signaling has been frequently observed in human cancers.

[0003] Furthermore, the Hippo pathway plays a role in several biological processes, such as stem and progenitor cell self-renewal and differentiation, wound healing and tissue regeneration, and interactions with other signaling pathways such as Wnt, and its dysfunction may also play a role in human diseases other than cancer (C.-L. Kim et al., Cells (2019), 8, 468; Y. Xiao et al., Genes & Development (2019) 33: 1491-1505; KF Harvey et al., Nature Reviews Cancer, Vol. 13, 246-257 (2013)).

[0004] Although some aspects of the pathway's activity and regulation remain under further investigation, it is well established that in its "switched-on" state, the Hippo pathway involves a cascade of kinases (including Mst1 / 2 and Lats1 / 2) in the cytoplasm, leading to the phosphorylation of two transcriptional coactivators, YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motifs). Phosphorylation of YAP / TAZ leads to their cytoplasmic sequestration and eventual degradation. In contrast, when the Hippo pathway is "switched-off" or dysfunctional, the unphosphorylated, activated YAP / TAZ coactivators are translocated into the cell nucleus. Their primary target transcription factors are four proteins in the transcriptional enhanced associate domain (TEAD) transcription factor family (TEAD1-4). Binding of YAP or TAZ to and activation of TEADs (or other transcription factors) has been shown to induce the expression of several genes, many of which mediate cell survival and proliferation. Thus, activated, unphosphorylated YAP and TAZ can act as oncogenes, whereas activated, switched-on Hippo pathways can act as tumor suppressors by inactivating (i.e., phosphorylating) YAP and TAZ.

[0005] Furthermore, the Hippo pathway may also play a role in resistance mechanisms of cancer cells to oncology and immune-oncology therapy (R. Reggiani et al., BBA - Reviews on Cancer 1873(2020)188341,1-11).

[0006] Consequently, dysfunction or aberrant regulation of the Hippo pathway as a tumor suppressor is thought to be a key event in the development of a wide variety of cancer types and diseases.

[0007] Therefore, inhibition of TEAD and YAP-TEAD or TAZ-TEAD protein-protein interactions through pharmacological intervention appears to be a rational and valuable strategy for preventing and / or treating cancer and other hyperproliferative disorders and diseases associated with Hippo pathway dysfunction.

[0008] Small molecule degraders are increasingly being used as tools to investigate the functional role of proteins and are emerging as novel therapeutic modalities. These molecules, which act at the post-translational level, offer the potential for differentiated biological responses compared to classical inhibitors and expand the repertoire of methods for protein knockdown beyond genetic approaches (e.g., knockout, siRNA).

[0009] Degrader molecules provide an example of chemical genetic techniques that can target the proteome more generally. These chimeric molecules are designed to induce degradation of target proteins via the ubiquitin proteasome system (UPS), thereby eliminating existing proteins. The UPS is the major intracellular pathway for protein degradation, in which a series of enzymes known as E1 (ubiquitin-activating enzymes), E2 (ubiquitin-conjugating enzymes), and E3 (ubiquitin ligases) covalently link ubiquitin, a 9-kDa, 76-amino acid protein, to target proteins. Subsequent enzymatic reactions result in the formation of polyubiquitin chains, which target the protein for degradation by the 26S proteasome.

[0010] Bifunctional degraders (sometimes also referred to as "heterobifunctional degraders") contain an E3 ligase-binding motif linked to a target protein-binding moiety. Consequently, these molecules hijack the cell's own degradation machinery by recruiting E3 ligases to nearby target proteins. Spatial proximity allows for protein ubiquitination and subsequent recognition and depletion by the UPS through the formation of a stable ternary complex.

[0011] Specificity for specific target proteins is associated with E3 ligases, which facilitate the final step of ubiquitin attachment to the target protein (Li W, et al. PLoS One. 2008;3:e1487). First-generation degraders were successfully developed using peptides as E3 ubiquitin ligase recognition motifs, but they were neither cell-permeable nor could be made cell-permeable by adding cell-permeable motifs such as the TAT peptide (Sakamoto KM, et al. Proc Natl Acad Sci U S A. 2001;98:8554-8559; Zhang D, et al. Bioorg Med Chem Lett. 2004;14:645-648; Schneekloth JS Jr. et al. J Am Chem Soc. 2004;126:3748-3754). The poor cell permeability of first-generation bifunctional degraders has been significantly improved by the discovery of small molecules that bind to E3 ligases, such as Von Hippel Lindau (VHL) ligands that bind to VHL ligase (Buckley et al., J. Am. Chem. Soc., 2012, 134(10), pp. 4465-4468; Sosic et al., Chem. Soc. Rev., 2022, 51, pp. 3487-3534) or thalidomide derivatives that bind to CRBN or cereblon E3 ligases (Winter et al., Science 19 Jun 2015: Vol. 348, Issue 6241, pp. 1376-1381; Sosic et al., Chem. Soc. Rev., 2022, 51, pp. 3487-3534).

[0012] Thus, one type of targeted therapy involves bifunctional degrader molecules that exploit the intracellular UPS to selectively degrade target proteins by forming a ternary complex between the target protein, the bifunctional degrader molecule, and an E3 (ubiquitin) ligase, which ultimately provides for degradation of the target protein by the proteasome.

[0013] There is a need for additional and / or improved cancer treatment options that utilize pharmacological targeting of TEADs to provide functional alterations of the Hippo pathway. Bifunctional degrader molecules may be particularly useful. Summary of the Invention

[0014] Description of the invention In one aspect, the present invention provides a compound of formula I Q 1 -Q 2 -Q 3 I During the ceremony Q 1 is a ubiquitin ligase ligand; Q 2 is (i) absent; or (ii) a bivalent linker formed by an unbranched alkylene chain having 2 to 25 C atoms, in which 1 to 8 non-adjacent CH groups in said linker may be replaced, independently of one another, by O, -C(=O)-NH-, -NH-C(=O)-, -C(=O)-N(CH3)-, -N(CH3)-C(=O)-, -CH=CH-, and / or -C≡C-; one or two CH2 groups in said linker may have a methyl substituent; and one CH2 group in said linker may optionally be [ka] wherein the left end of the moiety is a moiety selected from the group consisting of Q 1and the right end of that portion is Q of the compound of formula I. 3 directed to the department; Q 3 teeth, [ka] Indicate, in the formula Ring A is the following ring moiety: [ka] [ka] [ka] represents a 5-membered heteroaromatic ring selected from the group consisting of: During the ceremony R A1 H, D, C 1~6 -Aliphatic, -CH2-Ar A1 , or -CH2-CH2-Ar A1 represents; R A2 H, D, halogen, C 1~6 -Aliphatic, -CH2-Ar A2 , or -CH2-CH2-Ar A2 represents; R A3 H, D, C 1~6 -Aliphatic, -CH2-Ar A3 , or -CH2-CH2-Ar A3 represents; Z 1 is CR Z1 or N; Z 2 is CR Z2 or N; Z 3 is CR Z3 or N; Here Z 1 , Z 2 , and Z 3 At least two of them are not N; W 1 is CR W1or represents N; W 2 is CR W2 or represents N; W 3 is CR W3 or represents N; W 4 is CR W4 or represents N; Here, W 1 , W 2 , W 3 , and W 4 None of the above represents N, or W 1 , W 2 , W 3 , and W 4 Only one of represents N, and simultaneously: and R W1 is H, C 1~6 - represents an aliphatic or halogen; R W2 is H, C 1~6 -Aliphatic; Represents halogen; R W3 is H, C 1~6 -aliphatic, -OC 1~6 -Aliphatic, halogen, -CN, -CH2-Ar W , or -CH2-CH2-Ar W Represents ; R W4 is H, C 1~6 - represents an aliphatic or halogen; R 1 Ar 1 , Hetar 1 , Cyc 1 , Hetcyc 1 , L 1 -Ar 1 , L 1 -Hetar 1 , L 2 -Cyc 1 , L 2 -Hetcyc 1 , unsubstituted or substituted, straight or branched chain C 1~8 -represents aliphatic; R 2 teeth, [ka] represents; Ar A1 , Ar A2 , Ar A3 represent, independently of one another, phenyl, which may be unsubstituted, or, independently of one another, R A11 and / or R A12 may be mono- or di-substituted by; R Z1 , R Z2 , and R Z3 represent, independently of one another, H or halogen; R A11 , R A12 are each independently a halogen or an unsubstituted or substituted, linear or branched C 1~6 -represents aliphatic; Ar W represents phenyl, which may be unsubstituted or, independently of each other, R W11 and / or R W12 may be mono- or di-substituted by; R W11 , R W12 are each independently a halogen or an unsubstituted or substituted, linear or branched C 1~6 -represents aliphatic; Ar 1 is a mono- or bicyclic aryl having 6 or 10 ring carbon atoms, where the aryl may be unsubstituted or may contain a substituent R B1 , R B2 , and / or R B3 (which may be the same or different); Hetar 1 is a monocyclic heteroaryl having 5 or 6 ring atoms, or a bicyclic heteroaryl having 9 or 10 ring atoms, where 1, 2, 3, or 4 of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, and the heteroaryl may be unsubstituted or may contain a substituent R B1 , RB2 , and / or R B2 (which may be the same or different); Cyc 1 is a saturated or partially unsaturated, mono- or bicyclic carbocyclic ring having 3, 4, 5, 6, 7, 8, 9, or 10 ring carbon atoms, where the carbocyclic ring may be unsubstituted or may be substituted with R B4 , R B5 , and / or R B6 (which may be the same or different); Hetcyc 1 is a saturated or partially unsaturated, monocyclic heterocycle having 5 or 6 ring atoms, in which one or two of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, and the heterocycle may be unsubstituted or may be substituted with R B4 , R B5 , and / or R B (which may be the same or different), where if one of the heteroatoms is S, then the heterocycle may also be substituted with R B4 , R B5 , R B6 , R B7 , and R B8 may be substituted; L 1 is -S(=O)2-, -C(=O)-, unsubstituted or substituted, straight or branched chain C 1~6 -Alkylene or C 2~6 -alkenylene (in both of which one of the carbon units of the alkylene or alkenylene chain may be replaced by -O-); L 2 is -S(=O)2-, -C(=O)-, unsubstituted or substituted, straight or branched chain C 1~6 -Alkylene or C 2~6-alkenylene (in both of which one of the carbon units of the alkylene or alkenylene chain may be replaced by -O-); R B1 , R B2 , R B3 are, independently of each other, linear or branched C 1~6 - alkyl, but its C 1~6 -Alkyl may be unsubstituted or monosubstituted with -CN or may be substituted with 1, 2 or 3 halogens, straight or branched C 1~4 -alkoxy, wherein C 1~4 -Alkoxy may be unsubstituted or may contain one, two or three halogens, -O-CH2-C≡CH, straight or branched -SC 1~4 -alkyl, and its -SC 1~4 -Alkyl may be unsubstituted or may contain 1, 2 or 3 halogens, straight or branched C 2~6 -alkenyl, wherein C 2~6 -Alkenyl may be unsubstituted or monosubstituted with -CN or may contain one, two or three halogens, F, Cl, Br, -CN, -S(=O)-C 1~3 -Alkyl, S(=O)2-C 1~3 -Alkyl, -N(C 1~3 -alkyl)2, Ar 2 , -CH2-Ar 2 , Hetar 2 , Cyc 2 , Hetcyc 2 may be substituted with; Or, two adjacent R B1 , R B2 , and / or R B3 together, the divalent -C 3~4 - an alkylene radical, one of whose alkylene carbon units may be replaced by a carbonyl unit (-C(=O)-), or a divalent -OC 2~3 -forming an alkylene radical; R B4 , RB5 , R B6 are independent of each other, F, C 1~4 - alkyl, but its C 1~4 -Alkyl may be unsubstituted or contain 1, 2 or 3 F, C 1~4 -alkoxy, optionally substituted with phenyl; or R B4 , R B5 , and R B6 Two of them are the carbocyclic Cyc 1 or the heterocycle Hetcyc 1 and form a divalent oxo (=O) group; or R B4 and R B5 and R B7 and R B8 are attached to the same sulfur atom of the heterocycle and form two divalent oxo (=O) groups, thereby forming a -S(=O)2- moiety; Ar 2 is phenyl which may be unsubstituted or substituted by two substituents, which substituents are, independently of one another, OH, F, Cl, Br, C 1~4 -alkyl, and C 1~4 -alkoxy, wherein C 1~4 -Alkyl group or C 1~4 - the alkoxy group may be substituted with 1, 2 or 3 F atoms; Hetar 2 is a monocyclic heteroaryl having 5 or 6 ring atoms, wherein 1, 2, 3, 4, 5 of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, wherein the heteroaryl may be unsubstituted or substituted with 1 or 2 substituents, which are, independently of each other, F, Cl, Br, C 1~4 -alkyl, and C 1~4 -alkoxy, wherein C 1~4 -Alkyl group or C 1~4- the alkoxy group may be substituted with 1, 2 or 3 F atoms; Cyc 2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which may be unsubstituted or substituted with one or two substituents, which substituents are, independently of one another, OH, F, Cl, Br, C 1~4 -alkyl, and C 1~4 -alkoxy, wherein C 1~4 -Alkyl group or C 1~4 - the alkoxy group may be substituted with 1, 2 or 3 F atoms and / or 1 hydroxy group; Hetcyc 2 is pyrrolidinyl, piperidinyl, each of which may be unsubstituted or substituted with one or two substituents, which substituents are, independently of one another, OH, F, Cl, Br, C 1~4 -alkyl, and C 1~4 -alkoxy, wherein C 1~4 -Alkyl group or C 1~4 - the alkoxy group may be substituted with 1, 2 or 3 F atoms and / or 1 hydroxy group; Halogens are F, Cl, Br, I; or a pharmaceutically acceptable salt, solvate, tautomer, and / or stereoisomer thereof.

[0015] Any of these specific or even preferred embodiments of the invention as specified below and in the claims refers not only to the compound of the specified formula I, but also to any solvates, tautomers, or stereoisomers thereof, as well as pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all proportions unless otherwise specified.

[0016] In one specific embodiment of the present invention, PE1, the compound of formula I is a compound, or a pharmaceutically acceptable salt, solvate, tautomer, and / or stereoisomer thereof, wherein Q 1 is a ligand for E3 ubiquitin ligase; and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0017] In a further specific embodiment PE1a of PE1, Q 1 is (a) a CRBN (cereblon) ligand, or (b) a VHL (von Hippel-Lindau) ligand, or (c) a different type of E3 ubiquitin ligase ligand (excluding CRBN and VHL ligands).

[0018] In another specific embodiment PE1aa of PE1 or PE1a, Q 1 (a) is a CRBN (cereblon) ligand; and (a) The CRBN (cereblon) ligand is represented by the formula Q1-I, Q1-II, Q1-VII, or Q1-VIII [ka] It has a structure represented by: During the ceremony X 1 represents a single bond, -O-, -NH-, -NCH3-, -CH2-, or -NH-C(=O)-.

[0019] Specific Embodiments of PE1aa PE1aaa, wherein Q 1 (a) is a CRBN (cereblon) ligand; and (a) CRBN (cereblon) ligands are represented by the formulas Q1-I-1, Q1-I-2, Q1-I-3; Q1-I-4, Q1-I-5, Q1-I-6, Q1-II-1, Q1-II-2, Q1-II-3, Q1-II-4, Q1-II-5, Q1-II-6, Q1-II-7, Q1-VII-1, Q1-VII-2, and Q1-VII-3 [ka] [ka] [ka] [ka] It has a structure represented by the following formula:

[0020] Another specific embodiment of PE1aaa: PE1aaaa, wherein Q 1 (a) A CRBN (cereblon) ligand, wherein the CRBN (cereblon) ligand has a structure selected from the structures represented by formulas Q1-I-2, Q1-I-3, Q1-I-5, Q1-I-6, Q1-II-2, Q1-II-3, Q1-II-4, Q1-II-5, and Q1-VII-1.

[0021] Yet another specific embodiment of PE1aaa is PE1aaab, wherein Q 1 (a) a CRBN (cereblon) ligand, wherein the CRBN (cereblon) ligand has a structure selected from the structures represented by formulas Q1-I-1, Q1-I-2, Q1-I-3, Q1-I-4, Q1-I-5, and Q1-I-6. A specific embodiment of PE1aaab is PE1aaaba, wherein the CRBN ligand has a structure selected from the structures represented by formulas Q1-I-2, Q1-I-3, Q1-I-5, and Q1-I-6.

[0022] Yet another specific embodiment of PE1aaa is PE1aaac, wherein Q 1(a) a CRBN (cereblon) ligand, wherein the CRBN (cereblon) ligand has a structure selected from the structures represented by formulas Q1-II-1, Q1-II-2, Q1-II-3, Q1-II-4, Q1-II-5, Q1-II-6, and Q1-II-7. A specific embodiment of PE1aaac is PE1aaaca, wherein the CRBN ligand has a structure selected from the structures represented by formulas Q1-II-2, Q1-II-3, Q1-II-4, and Q1-II-5.

[0023] Another specific embodiment of PE1a is PE1ab, wherein Q 1 is (b) a VHL (von Hippel-Lindau) ligand; and the VHL ligand is of formula Q1-III: [ka] It has a structure represented by: During the ceremony R Q1 denotes H or -C(=O)-CH3; R Q2 indicates H or CH3; All possible stereoisomeric forms of formula Q1-III are included.

[0024] Another specific embodiment of PE1a or PE1ab is PE1aba, wherein Q 1 (b) is a VHL (von Hippel-Lindau) ligand; and VHL ligands are represented by the formulas Q1-III-1, Q1-III-2, Q1-III-3, Q1-III-4, and Q1-III-5 [ka] The structure is selected from:

[0025] Another specific embodiment of PE1aba PE1abaa, wherein the VHL ligand has a structure selected from the structures represented by formulas Q1-III-1 and Q1-III-4.

[0026] Especially Q 1 is represented by the formula Q1-III-1: [ka] It has the structure represented by (PE1abaaa).

[0027] Another specific embodiment of PE1a is PE1ac, wherein Q 1 (c) is a different type of E3 ubiquitin ligase ligand, excluding CRBN ligands and VHL ligands; and the different types of E3 ubiquitin ligase ligands are represented by the formulas Q1-IV, Q1-V, Q1-VI, Q1-XII (particularly Q1-XII-1), Q1-XIII (particularly Q1-XIII-1): [ka] [ka] [ka] The compound has a structure selected from the structures represented by the following formula:

[0028] In another specific embodiment PE2 of the compounds of formula I, Q 2 is a bivalent linker formed by an unbranched alkylene chain having 2 to 25 C atoms, in which 1 to 8 non-adjacent CH groups in said linker may be replaced, independently of one another, by O, -C(=O)-NH-, -NH-C(=O)-, -C(=O)-N(CH)-, -N(CH)-C(=O)-, and / or -C≡C-; one or two CH groups in said linker may have a methyl substituent; and one CH group in said linker is optionally [ka] [ka] wherein the left end of the moiety is a moiety selected from the group consisting of Q 1 and the right end of that portion is Q of the compound of formula I. 3 directed to the department; and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0029] In one specific embodiment of PE2, PE2a, Q 2 is an unbranched alkylene chain having 2 to 10 (i.e., 2, 3, 4, 5, 6, 7, 8, 9, or 10) CH2 (methylene) units.

[0030] In another specific embodiment PE2b of PE2, Q 2 is an unbranched alkylene chain having 4 to 25 CH2 (methylene) units, in which 1, 2, 3, 4, 5, or 6 non-adjacent CH2 groups are replaced by O, thereby forming a polyether linker chain. When more than one CH2 group is replaced by O, typically the two oxygen atoms are separated by at least two CH2 units or three or four CH2 units, thereby forming a polyether unit such as, for example, -CH2-O-CH2-CH2-O-CH2-CH2-O-, -O-CH2-CH2-CH2-O-CH2-CH2-CH2-, -CH2-CH2-O-CH2-CH2-CH2-O-CH2-CH2-, -CH2-CH2-CH2-O-CH2-CH2-CH2-O-, or CH2-CH2-O-CH2-CH2-CH2-CH2-O-. Other suitable polyether linkers may be those utilized in some of the exemplary compounds of the present invention.

[0031] In a further specific embodiment PE2c of PE2, Q 2is an unbranched alkylene chain having 4 to 25 CH2 (methylene) units, in which one CH2 unit is replaced by -C(=O)-NH- or -NH-C(=O)-.

[0032] In a further specific embodiment of PE2, PE2d, PE2b and PE2c are combined, i.e., Q 2 is an unbranched alkylene chain having 4 to 25 CH2 (methylene) units in which (i) 1, 2, 3, 4, 5, or 6 non-adjacent CH2 groups are replaced by O, thereby forming a polyether linker chain, and (ii) another CH2 unit is replaced by -C(=O)-NH- or -NH-C(=O)-; thereby separating the oxygen atom(s) and the -C(=O)-NH- or -NH-C(=O)- moiety by at least two methylene units.

[0033] In yet another specific embodiment PE2e of PE2, Q 2 is an unbranched alkylene chain having 4 to 25 CH2 (methylene) units, the CH2 units in said chain being: [ka] is replaced by a moiety selected from the group consisting of:

[0034] In another specific embodiment of PE2, PE2f, R 2 teeth, [ka] [ka] [ka] [ka] is selected from the group consisting of:

[0035] Specific embodiment of PE2f: PE2fa, wherein Q 2 teeth, [ka] [ka] [ka] is selected from the group consisting of:

[0036] In another specific embodiment of PE2, PE2g, Q 2 is a bivalent linker formed by an unbranched alkylene chain having 2 to 25 C atoms, in which 1 to 8 non-adjacent CH groups in the linker may be replaced, independently of one another, by O, -C(=O)-NH-, -NH-C(=O)-, -C(=O)-N(CH)-, -N(CH)-C(=O)-, and / or -C≡C-; one or two CH groups in the linker may optionally have a methyl substituent; and one CH group in the linker, independently of one another, may optionally be [ka] may be replaced by a moiety selected from the group consisting of:

[0037] In another specific embodiment of PE2, PE2h, Q 2 teeth, [ka] [ka] [ka] [ka] [ka] [ka] is selected from the group consisting of:

[0038] A specific embodiment of PE2h is PE2ha, wherein Q 2 teeth, [ka] [ka] [ka] [ka] is selected from the group consisting of:

[0039] In another specific embodiment PE2-0 of the present invention, Q 2 does not exist, and therefore formula IA Q 1 -Q 3 IA A compound represented by the formula: 1 and the TEAD binding moiety Q 3 are directly linked to each other, i.e., by a suitable linker Q 2 are not separated by

[0040] In another specific embodiment PE3, the compound of the invention is a compound of formula I, wherein Q 3 displays Q3-I or Q3-II; Z 1 is CR Z1 is; Z 2 is CRZ2 is; Z 3 is CR Z3 or N; R Z1 is H or F; especially H; R Z2 is H or F; especially H; R Z3 is H or F; especially H; and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0041] In another specific embodiment of PE3, PE3a, Z 3 is N.

[0042] In yet another specific embodiment PE3b of PE3, Z 3 is CR Z3 is; R Z3 is H.

[0043] In another specific embodiment of PE3, PE3c, Z 1 , Z 2 , and Z 3 Each represents CH; and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0044] In a further specific embodiment PE4, the compound of the invention is a compound of formula I, or a pharmaceutically acceptable salt, solvate, tautomer, and / or stereoisomer thereof, wherein Q 3 is the formula Q3-I [ka] It has a structure represented by: and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0045] In a specific embodiment PE4a of PE4, Q 3 has a structure represented by formula Q3-I; and Ring A is the following ring moiety: [ka] [ka] represents a 5-membered heteroaromatic ring selected from the group consisting of: R A1 is C 1~6 -Aliphatic, -CH2-Ar A1 represents; R A2 is H, C 1~6 -represents aliphatic; R A3 is H, C 1~6 -represents aliphatic; Ar A1 may be unsubstituted or R A11 represents a phenyl which may be mono-substituted by; R A11 represents a halogen; and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0046] In another specific embodiment PE4aa of PE4 or PE4a, R A1 is C optionally substituted with 1, 2, or 3 F atoms or CN; 1~3 -Alkyl, C 2~4 -alkynyl (especially -CH2-C≡CH), -CH2-Ar A1 represents; R A2 is H, C1~6 aliphatic, especially H, C optionally substituted with 1, 2 or 3 F atoms 1~3 -represents alkyl; R A3 represents H; Ar A1 may be unsubstituted or R A11 represents a phenyl which may be mono-substituted by; R A11 represents F; and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0047] In yet another specific embodiment PE4aaa of PE4a or PE4aa, in formula Q3-I Z 1 , Z 2 , and Z 3 Each represents CH.

[0048] In yet another specific embodiment PE4ab of PE4 or PE4a, ring A is selected from the group consisting of rings A-1, A-4, A-7, A-9, A-10, A-12, A-13, A-15, A-17, A-23, and A-24. In another specific embodiment PE4ac of PE4 or PE4a, ring A is ring A-4 or ring A-12, where preferably R A1 is methyl, ethyl, n-propyl, or —CH—C≡CH, more preferably methyl, and R A2 is H (for ring A-4). In yet another specific embodiment of PE4ac, ring A is R A1 is methyl and R A2 is H. In yet another embodiment of PE4ac, PE4acb, ring A is R A1 is ring A-12, which is methyl.

[0049] In yet another specific embodiment PE4ad of PE4 or PE4a, ring A is [ka] [ka] [ka] Rings A-4a or A-12a are particular options.

[0050] In a further specific embodiment PE5, the compound of the invention is a compound of formula I, or a pharmaceutically acceptable salt, solvate, tautomer, and / or stereoisomer thereof, wherein Q 3 is the formula Q3-II [ka] and wherein (a) W 1 is CR W1 represents; W 2 is CR W2 represents; W 3 is CR W3 represents; W 4 is CR W4 represents; R W1 represents H; R W2 represents H; R W3 is C 1~6 -aliphatic, -OC 1~6 -Aliphatic, halogen, -CN, -CH2-Ar W , or -CH2-CH2-Ar W represents; R W4 represents H; Ar W is unsubstituted or R W11 represents a phenyl which may be mono-substituted by; R W11represents halogen; preferably F; or (b) W 1 is CR W1 represents; W 2 is CR W2 represents; W 3 is CR W3 represents; W 4 is CR W4 represents; R W1 represents H; R W2 is C 1~6 -represents aliphatic; R W3 represents H; R W4 represents H; or (c) W 1 is CR W1 represents; W 2 is CR W2 represents; W 3 is CR W3 represents; W 4 is CR W4 represents; R W1 represents H; R W2 represents H; R W3 represents H; R W4 is C 1~6 -represents aliphatic; or (d) W 1 is CR W1 represents; W 2 represents N; W 3 is CR W3 represents; W 4 is CR W4 represents; R W1 represents H; R W3 is C 1~6 -aliphatic, -OC 1~6 -Aliphatic, halogen, -CN, -CH2-Ar W , or -CH2-CH2-Ar W represents; R W4 represents H; Ar W is unsubstituted or R W11 represents a phenyl which may be mono-substituted by; R W11 represents halogen; preferably F; or (e) W 1 is CR W1 represents; W 2 represents N; W 3 is CR W3 represents; W 4 is CR W4 represents; R W1 represents H; R W3 represents H; R W4 is C 1~6 -represents aliphatic; or (f) W 1 is CR W1 represents; W 2 is CR W2 represents; W 3 represents N; W 4 is CR W4 represents; R W1 represents H; R W2 is C 1~6 -represents aliphatic; R W4 represents H; or (g) W 1 is CR W1 represents; W 2 is CR W2 represents; W 3 represents N; W 4 is CR W4 represents; R W1 represents H; R W2 represents H; R W4 is C 1~6 -represents aliphatic; or (h) W 1 is CR W1 represents; W 2 is CR W2 represents; W 3 is CR W3 represents; W 4 represents N; R W1 represents H; R W2 represents H; R W3 is C 1~6 -aliphatic, -OC 1~6 -Aliphatic, halogen, -CN, -CH2-Ar W , or -CH2-CH2-Ar W represents; Ar W is unsubstituted or R W11 represents a phenyl which may be mono-substituted by; R W11 represents halogen; preferably F; and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0051] In another specific embodiment of PE5, PE5a, the compound of the invention is a compound of Formula I, or a pharmaceutically acceptable salt, solvate, tautomer, and / or stereoisomer thereof, wherein: (a) W 1 is CR W1 represents; W 2 is CR W2 represents; W 3 is CR W3 represents; W 4 is CR W4 represents; R W1 represents H; R W2 represents H; R W3 is C 1~6 -aliphatic, -OC 1~6 -Aliphatic, halogen, -CN, -CH2-ArW W , or -CH2-CH2-Ar W ;represents, inter alia, methyl, 2-propyl, trifluoromethyl, methoxy, trifluoromethoxy, F, -CN, -CH2-phenyl, -CH2-(2-fluorophenyl), -C2-(3-fluorophenyl), -CH2-(4-fluorophenyl); R W4 represents H; Ar W is unsubstituted or R W11 represents a phenyl which may be mono-substituted by; R W11 represents halogen; in particular F; or (d) W 1 is CR W1 represents; W 2 represents N; W 3 is CR W3 represents; W 4 is CR W4 represents; RW1 represents H; R W3 is C 1~6 -aliphatic, -OC 1~6 -Aliphatic, halogen, -CN, -CH2-ArW W , or -CH2-CH2-Ar W ;represents, inter alia, methyl, 2-propyl, trifluoromethyl, methoxy, trifluoromethoxy, F, -CN, -CH2-phenyl, -CH2-(2-fluorophenyl), -C2-(3-fluorophenyl), -CH2-(4-fluorophenyl); R W4 represents H; Ar W is unsubstituted or R W11 represents a phenyl which may be mono-substituted by; R W11 represents halogen; in particular F; or (h) W 1 is CR W1 represents; W 2 is CR W2 represents; W 3 is CR W3 represents; W 4 represents N; R W1 represents H; R W2 represents H; R W3 is C 1~6 -aliphatic, -OC 1~6 -Aliphatic, halogen, -CN, -CH2-ArW W , or -CH2-CH2-Ar W ;represents, inter alia, methyl, 2-propyl, trifluoromethyl, methoxy, trifluoromethoxy, F, -CN, -CH2-phenyl, -CH2-(2-fluorophenyl), -C2-(3-fluorophenyl), -CH2-(4-fluorophenyl); Ar W is unsubstituted or R W11represents a phenyl which may be mono-substituted by; R W11 represents halogen; in particular F; and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0052] In another specific embodiment PE5aa of PE5 or PE5a, Z 1 , Z 2 , and Z 3 each represents CH in formula Q3-II.

[0053] In a further specific embodiment of the present invention, PE6, the compound of the present invention is a compound of formula I, or a pharmaceutically acceptable salt, solvate, tautomer, and / or stereoisomer thereof, wherein Q 3 has a structure represented by formula Q3-I or Q3-II; R 1 Ar 1 , Hetar 1 , Cyc 1 , Hetcyc 1 , L 1 -Ar 1 , L 1 -Hetar 1 , L 2 -Cyc 1 , L 2 -Hetcyc 1 , unsubstituted or substituted, straight or branched chain C 1~6 -Alkyl, C 2~6 -alkenyl, or C 2~6 - represents alkynyl; Ar 1 is a mono- or bicyclic aryl having 6 or 10 ring carbon atoms, where the aryl may be unsubstituted or may contain a substituent R B1 , R B2 , and / or R B3 (which may be the same or different); Hetar 1 is a monocyclic heteroaryl having 5 or 6 ring atoms or a bicyclic heteroaryl having 9 or 10 ring atoms, where 1, 2, or 3 of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, and the heteroaryl may be unsubstituted or may contain a substituent R B1 , R B2 , and / or R B3 (which may be the same or different); preferably, heteroaryl is unsubstituted or is substituted with a substituent R B1 and / or R B2 (which may be the same or different); Cyc 1 is a saturated or partially unsaturated, mono- or bicyclic carbocyclic ring having 3, 4, 5, 6, 7, or 8 ring carbon atoms, where the carbocyclic ring may be unsubstituted or may be substituted with R B4 , R B5 , and / or R B6 (which may be the same or different); Hetcyc 1 is a saturated or partially unsaturated, monocyclic heterocycle having 5 or 6 ring atoms, in which one or two of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, and the heterocycle may be unsubstituted or may be substituted with R B4 , R B5 , and / or R B (which may be the same or different), where if one of the heteroatoms is S, then the heterocycle may also be substituted with R B4 , R B5 , R B6 , R B7 , and R B8 may be substituted; L 1is -S(=O)2-, unsubstituted or substituted, straight or branched chain C 1~6 -Alkylene or C 2~6 -alkenylene (in both of which one of the carbon units of the alkylene or alkenylene chain may be replaced by -O-); L 2 is an unsubstituted or substituted, straight or branched chain C 1~6 -Alkylene or C 2~6 -alkenylene (in both of which one of the carbon units of the alkylene or alkenylene chain may be replaced by -O-); R B1 , R B2 , R B3 are, independently of each other, linear or branched C 1~6 - alkyl, but its C 1~6 -Alkyl may be unsubstituted or monosubstituted with -CN or may be substituted with 1, 2 or 3 halogens, straight or branched C 1~4 -alkoxy, wherein C 1~4 -alkoxy is unsubstituted or substituted with one, two or three halogens, -O-CH-C≡CH, straight or branched -SC 1~4 -alkyl, and its -SC 1~4 -Alkyl is unsubstituted or substituted with one, two or three halogens, F, Cl, Br, -CN, -S(=O)-C 1~3 -Alkyl, S(=O)2-C 1~3 -Alkyl, -N(C 1~3 -alkyl)2, Ar 2 , -CH2-Ar 2 , Hetar 2 , Cyc 2 , Hetcyc 2 may be substituted with; Or, two adjacent R B1 , R B2 , and / or R B3 together, the divalent -C 3~4- an alkylene radical, one of whose alkylene carbon units may be replaced by a carbonyl unit (-C(=O)-), or a divalent -OC 2~3 -forming an alkylene radical; Ar 2 is phenyl; Hetar 2 is a monocyclic heteroaryl having 5 or 6 ring atoms, wherein 1, 2, 3, 4, 5 of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms; Cyc 2 is cyclopropyl, cyclobutyl, cyclopentyl, each of which may be unsubstituted or substituted with one or two substituents, which substituents are, independently of one another, OH, F, Cl, Br, C 1~4 -alkyl, and C 1~4 -alkoxy, wherein C 1~4 -Alkyl group or C 1~4 - the alkoxy group may be substituted with 1, 2 or 3 F atoms and / or 1 hydroxy group; Hetcyc 2 is pyrrolidinyl, piperidinyl, each of which may be unsubstituted or substituted with one or two substituents, which substituents are, independently of one another, OH, F, Cl, Br, C 1~4 -alkyl, and C 1~4 -alkoxy, wherein C 1~4 -Alkyl group or C 1~4 - the alkoxy group may be substituted with 1, 2 or 3 F atoms and / or 1 hydroxy group; R B4 , R B5 , R B6 are independent of each other, F, C 1~2 - alkyl, but its C 1~2 -Alkyl may be unsubstituted or contain 1, 2 or 3 F, C 1~2 -alkoxy, optionally substituted with phenyl; or R B4 , R B5 , R B6 Two of them are the carbocyclic Cyc 1 or the heterocycle Hetcyc 1 and form a divalent oxo (=O) group; or R B4 and R B5 and R B7 and R B8 are attached to the same sulfur atom of the heterocycle and form two divalent oxo (=O) groups, thereby forming a -S(=O)2- moiety; Halogen is F, Cl, Br; and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0054] In another specific embodiment of PE6, PE6a, R 1 Ar 1 , Hetar 1 , Cyc 1 , Hetcyc 1 , L 1 -Ar 1 , L 1 -Hetar 1 , L 2 -Cyc 1 , L 2 -Hetcyc 1 , linear or branched C 1~6 -Alkyl, C 2~6 -alkenyl, or C 2~6 -alkynyl, wherein the C 1~6 -Alkyl, C 2~6 -alkenyl, or C 2~6 -alkynyl is unsubstituted or substituted with 1, 2 or 3 halogens; Ar 1 is phenyl or naphthalenyl, especially phenyl, which may be unsubstituted or may contain the substituent R B1and / or R B2 (which may be the same or different); Hetar 1 is a monocyclic heteroaryl having 5 or 6 ring atoms, or a bicyclic heteroaryl having 9 or 10 ring atoms, where 1, 2, or 3 of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, and the heteroaryl may be unsubstituted or may contain a substituent R B1 and / or R B2 (which may be the same or different); Cyc 1 is a saturated or partially unsaturated, mono- or bicyclic carbocyclic ring having 3, 4, 5, 6, 7, or 8 ring carbon atoms, where the carbocyclic ring may be unsubstituted or may be substituted with R B4 and / or R B5 (which may be the same or different); Hetcyc 1 is a saturated monocyclic heterocycle having 5 or 6 ring atoms, where one of the ring atoms is a heteroatom selected from O and S, and the remainder are carbon atoms, where the heterocycle may be unsubstituted or B8 and / or R B9 (which may be the same or different), where if one of the heteroatoms is S, then the heterocycle may also be substituted with R B4 , R B5 , R B7 , and R B8 may be substituted; L 1 is a divalent radical selected from the group consisting of -S(=O)2-, -CH2-, -CH2-CH2-, -CH2-CH2-C(CH3)H-, -CH2-CH2-C(CH3)2-, -CH2-CH2-O-CH2-, -CH2-CH=CH-; L 2is a divalent radical selected from the group consisting of -CH2-, -CH2-CH2-; R B1 , R B2 are, independently of each other, linear or branched C 1~6 - alkyl, but its C 1~6 -Alkyl may be unsubstituted or monosubstituted with -CN, or may contain one, two, or three halogens (e.g., -CF), straight or branched C 1~4 -alkoxy, wherein C 1~4 -Alkoxy may be unsubstituted or may contain one, two, or three halogens (e.g., -OCF3), -O-CH-C≡CH, straight or branched -SC 1~4 -alkyl, and its -SC 1~4 -Alkyl may be unsubstituted or may contain one, two or three halogens: F, Cl, Br, -CN, -S(=O)-C 1~3 -Alkyl, S(=O)2-C 1~3 -Alkyl, -N(C 1~3 -alkyl)2, Ar 2 , -CH2-Ar 2 , Hetar 2 , Cyc 2 , Hetcyc 2 may be substituted with; Or, two adjacent R B1 , R B2 together, the divalent -C 3~4 - an alkylene radical, one of whose alkylene carbon units may be replaced by a carbonyl unit (-C(=O)-), or a divalent -OC 2~3 -forming an alkylene radical; Ar 2 is phenyl; Hetar 2 is a monocyclic heteroaryl having 5 ring atoms, wherein one of the ring atoms is N and the rest are carbon atoms, or one of the ring atoms is N and one of the ring atoms is S, and the rest are carbon atoms; Cyc 2is cyclopropyl, 1-trifluoromethylcyclopropyl, cyclopentyl; Hetcyc 2 is pyrrolidinyl; R B4 , R B5 are independent of each other, F, C 1~2 - alkyl, but its C 1~2 -Alkyl may be unsubstituted or contain 1, 2 or 3 F, C 1~2 -alkoxy, optionally substituted with phenyl; or R B4 and R B5 is the carbocyclic ring Cyc 1 or the heterocycle Hetcyc 1 and form a divalent oxo (=O) group; or R B4 and R B5 and R B7 and R B8 are attached to the same sulfur atom of the heterocycle and form two divalent oxo (=O) groups, thereby forming a -S(=O)2- moiety; Halogen is F, Cl, Br; and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0055] In yet another specific embodiment PE6aa of PE6 or PE6a, R 1is phenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-difluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-(1,1-difluoroethyl)phenyl, 4-(2,2,2-trifluoroethyl)phenyl, 4-(1-trifluoromethylcyclopropyl)phen-1-yl, 4-cyclopentylphenyl, 4-ethoxyphenyl, 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl bisphenyl, 3-(trifluoromethyl)sulfanylphenyl, 4-(trifluoromethyl)sulfanylphenyl, 3-trifluoromethyl-4-methylphenyl, 2-fluoro-4-trifluoromethylphenyl, 2-fluoro-4-trifluoromethoxyphenyl, 3-fluoro-4-(n-propyl)phenyl, 2,3-dimethyl-4-methoxyphenyl, 6-fluoronaphth-2-yl; 5-trifluoromethylfuran-2-yl; 5-trifluoromethylthiophen-2-yl, 2-trifluoromethyl-1,3-thiazol-4-yl, 3-fluoropyridin-2-yl, 6-methylpyridin-3-yl, 6-methoxypyridin-3-yl, 3-ethylpyridin-2-yl, 6-ethylpyridin-3-yl, 4-difluoromethylpyridin-2-yl, 4-trifluoromethylpyridin-2-yl, 4-trifluoromethoxypyridin-2-yl, 4-cyanopyridin-2-yl, 5-trifluoromethylpyridin-2-yl, 6-trifluoromethylpyridin-2-yl, 6-trifluoromethylpyridin-3-yl, (2-trifluoromethylpyridin- 5-yl), 6-trifluoromethoxypyridin-3-yl, (2-trifluoromethoxypyridin-5-yl), 5-cyanopyridin-2-yl, 5-cyanomethylpyridin-2-yl, 5-methanesulfonylpyridin-2-yl, 6-methoxypyridin-2-yl, 4-methylpyrimidin-2-yl, 4-ethylpyrimidin-2-yl, 4-methylsulfanylpyrimidin-2-yl, 5-cyclopropylpyrimidin-2-yl, 5-ethylpyrimidin-2-yl, 5-difluoromethylpyrimidin-2-yl, 5-trifluoromethylpyrimidine -2-yl, 5-cyanopyrimidin-2-yl, 5-cyano-3-fluoropyridin-2-yl, 5-cyano-6-methylpyridin-2-yl, 3-fluoro-5-(trifluoromethyl)pyridin-2-yl, 5-oxo-5H,6H,7H-cyclopenta[b]pyridin-2-yl, 5,6,7,8-tetrahydroquinolin-2-yl, 5-oxo-5,6,7,8-tetrahydroquinolin-2-yl, 5H,6H,7H-cyclopenta[b]pyridin-2-yl, quinolin-2-yl, isoquinolin-3-yl, 6-methylquinolin-2-yl, 8-Methoxyquinolin-4-yl, furo[3,2-b]pyridin-5-yl, quinazolin-2-yl, 6-fluoroquinazolin-2-yl, 1,5-naphthyridin-2-yl; 3-methylcyclobutyl, cyclopentyl, 3-methylcyclopentyl, 3,3-dimethylcyclopentyl, 3-trifluoromethyl-bicyclo[1.1.1]pentan-1-yl, cyclohexyl, 4-methylcyclohexyl, 4-(trifluoromethyl)cyclohexyl, 4,4-difluorocyclohexyl, cyclohex-1-enyl, 2-oxocycloheptyl, 6,6-Difluorospiro[3.3]heptan-2-yl, 1H-inden-2-yl; benzenesulfonyl (phenylsulfonyl), 3-methylphenylsulfonyl, benzyl, 2-ethoxyphenylmethyl, 3-chlorophenylmethyl, 3-fluorophenylmethyl, 4-chlorophenylmethyl, 3-(pyrrolidin-1-yl)phenylmethyl, 3-methylphenylmethyl, 4-methylphenylmethyl, 3-ethylphenylmethyl, 3-(propan-2-yl)phenylmethyl, 3-tert-butylphenylmethyl, 3-( Difluoromethoxy)phenylmethyl, 2-(difluoromethyl)phenylmethyl, 3-(difluoromethyl)phenylmethyl, 3-(trifluoromethyl)phenylmethyl, 4-(trifluoromethyl)phenyl]methyl, 2-(prop-2-yn-1-yloxy)phenylmethyl, 3-(1,3-thiazol-2-yl)phenylmethyl, 3-(trifluoromethyl)sulfanylphenylmethyl, 3-methanesulfonylphenylmethyl, 3-(dimethylamino)phenylmethyl, 3-(pyrrol-1-yl)phenyl Methyl, 2-methyl-3-methoxyphenylmethyl, 3-trifluoromethyl-5-methylphenylmethyl, 2-methyl-3-(trifluoromethyl)phenylmethyl, 3-trifluoromethyl-4-fluorophenylmethyl, 2-fluoro-5-(trifluoromethoxy)phenylmethyl, 2-methoxy-3-trifluoromethoxyphenylmethyl, 2-fluoro-3-methoxyphenylmethyl, 2-fluoro-3-(trifluoromethyl)phenyl]methyl, 2-fluoro-3-fluoromethoxyphenylmethyl, 2-trifluoromethoxy-5-fluorophenylmethyl, 2-fluoro-5-chloro-phenylmethyl, 3-fluoro-5-methylphenyl)methyl, 3,5-difluorophenylmethyl, 5-fluoro-2-(trifluoromethyl)phenylmethyl, 3-fluoro-5-(trifluoromethyl)phenylmethyl, 2-chloro-3-(trifluoromethyl)phenylmethyl, naphthalen-1-ylmethyl, 5,6,7,8-tetrahydronaphthalen-1-ylmethyl, 2,3-dihydro-1-benzofuran-7-ylmethyl, 3,4-Dihydro-2H-1-benzopyran-8-ylmethyl, 2-phenylethyl, 2-(2-methylphenyl)ethyl, 2-(2-methoxyphenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-(4-methoxyphenyl)ethyl, 2-(2-fluorophenyl)-ethyl, 2-(3-fluorophenyl)-ethyl, 2-(4-fluorophenyl)-ethyl, 2-(2-chlorophenyl)-ethyl, 2-(4-chlorophenyl)-ethyl, 2-(4-bromophenyl)-ethyl, 2-[4-(trifluoromethyl)phenyl]ethyl, 2 -(2,4-difluorophenyl)ethyl, 2-(difluoromethoxy)-5-fluorophenylmethyl, 2-phenylpropyl, 3-phenylpropyl, 3-methyl-3-phenylbutyl, 2-(benzyloxy)ethyl; 5-ethylfuran-2-ylmethyl, 5-(trifluoromethyl)furan-2-ylmethyl, 4-(propan-2-yl)-1,3-thiazol-2-ylmethyl, 2-methyl-1,3-thiazol-4-ylmethyl, 2-trifluoromethyl-1,3-thiazol-4-ylmethyl, 1-ethylpyrazol-5-ylmethyl ethyl, 1-(2-propyl)pyrazol-5-ylmethyl, 1-ethylimidazol-5-ylmethyl, 1-ethylimidazol-2-ylmethyl, 1-propylimidazo-l-2-ylmethyl, 1-benzylimidazo-l-2-yl)methyl, 1-(2-methylpropyl)-1H-imidazo-l-5-ylmethyl, 5-tert-butyl-1,3-oxazol-2-ylmethyl, 3-fluoropyridin-2-ylmethyl, 2-methylpyridin-4-ylmethyl, 4-trifluoromethylpyridin-2-ylmethyl, 6-(fluoromethyl)pyridine -2-ylmethyl, 6-trifluoromethylpyridin-2-ylmethyl, 2-(trifluoromethyl)pyridin-4-ylmethyl, 4-methylpyrimidin-2-ylmethyl, 2-(thiophen-3-yl)ethyl, 5-trifluoromethylthiophen-2-ylmethyl, 1-methyl-1H-indol-6-yl)methyl, 1-benzofuran-3-ylmethyl, 1-benzothiophen-3-ylmethyl, 4H,5H,6H-pyrrolo[1,2-b]pyrazol-3-ylmethyl, pyrazolo[1,5-a]pyridin-7-ylmethyl, pyrazolo[1,5-a]pyridin-3-ylmethyl, imidazo[1,2-a]pyridin-3-ylmethyl, 6-methylimidazo[1,2-a]pyridin-3-ylmethyl, imidazo[1,2-a]pyridin-5-ylmethyl, imidazo[1,5-a]pyridin-1-ylmethyl, imidazo[1,5-a]pyridin-3-ylmethyl, imidazo[1,5-a]pyridin-5-ylmethyl, pyrazolo[1,5-c]pyrimidin-3-ylmethyl, 3-(furan-2-yl)prop-2-en-1-yl; 3-trifluoromethylcyclobutylmethyl, 3-fluoro-3-phenylcyclobutylmethyl, cyclohexylmethyl, 4-methylcyclohexylmethyl, 4-trifluoromethylcyclohexylmethyl, 4-methoxycyclohexylmethyl, 4,4-dimethylcyclohexylmethyl, 4, 4-Difluorocyclohexylmethyl, 3-trifluoromethyl-bicyclo[1.1.1]pentan-1-ylmethyl, bicyclo[2.2.1]heptan-2-ylmethyl, bicyclo[2.2.2]octan-2-ylmethyl, bicyclo[2.2.1]hept-5-en-2-ylmethyl, 6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]methyl; 3,3-dimethyltetrahydrofuran-2-ylmethyl, 1,1-dioxothian-4-ylmethyl, 2-(thian-4-yl)ethyl; 2,2-dimethyl-4,4,4-trifluoropentyl, 4,4,4-trifluorobutyl, 4,4,4-trifluoro-3-methylbutyl, 3,3-dimethyl-4,4,4-trifluorobutyl, 3,3,3-trifluoroprop-1-yn-1-yl; and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0056] In the specific embodiment PE6aaa of PE6, PE6a, or PE6aa, R 1 is selected from the group consisting of 4-methylphenyl, 4-difluoromethylphenyl, 4-trifluoromethylphenyl, 4-fluorophenyl; especially 4-trifluoromethylphenyl (PE6aaaa). In yet another specific embodiment PE6aaaaa of PE6, P6a, PE6aaa, PE6aaa, and / or PE6aaaa, further comprising Z 1 , Z 2 , and Z 3 each represents CH in formula Q3-I or Q3-II.

[0057] In yet another specific embodiment of the invention, PE6b, of PE6, the compound of the invention is a compound of formula I, or any solvate, tautomer, or stereoisomer thereof, and / or any pharmaceutically acceptable salt of each of the above, and mixtures thereof in all proportions, wherein R 1 teeth, [ka] [ka] [ka] selected from the group consisting of: and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0058] In a specific embodiment PE6ba of PE6b, R 1 teeth, [ka] selected from the group consisting of: and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below. In particular, R 1 teeth, [ka] (Specific embodiment PE6baa).

[0059] In yet another specific embodiment PE6baaa of PEb, P6ba, and / or PE6baa, in addition Z 1 , Z 2 , and Z 3 each represents CH in formula Q3-I or Q3-II.

[0060] Another specific embodiment of the present invention, PE7, is a compound of formula I Q 1 -Q 2 -Q 3 I is a compound represented by the formula Q 1 teeth, (a) CRBN (cereblon) ligands; and CRBN (cereblon) ligands are represented by the formulas Q1-I-1, Q1-I-2, Q1-I-3; Q1-I-4, Q1-I-5, Q1-I-6, Q1-II-1, Q1-II-2, Q1-II-3, Q1-II-4, Q1-II-5, and Q1-VII-1 [ka] [ka] [ka] or having a structure selected from the structures represented by (b) VHL (von Hippel-Lindau) ligands; and VHL ligands are represented by the formulas Q1-III-1, Q1-III-2, Q1-III-4, and Q1-III-5: [ka] [ka] having a structure selected from the structures represented by: Q 2 teeth, [ka] [ka] [ka] [ka] selected from the group consisting of: Q 3 is the formula Q3-I [ka] It has a structure represented by: Ring A is ring A-4 or ring A-12 as defined above; R A1 represents methyl; R A2 represents hydrogen; R 1 denotes 4-trifluoromethylphenyl; R 2 teeth, [ka] represents; Z 1 , Z 2 , and Z 3 each represents CH in formula Q3-I; or a pharmaceutically acceptable salt, solvate, tautomer, and / or stereoisomer thereof.

[0061] Specific embodiment of PE7: PE7a, wherein Q 1is (a) a CRBN ligand and has a structure selected from the structures represented by formulas Q1-I-2, Q1-I-3, Q1-I-5, Q1-I-6, Q1-II-2, Q1-II-3, Q1-II-4, and Q1-II-5; or (b) a VHL ligand and has a structure selected from the structures represented by formulas Q1-III-1 and Q1-III-4.

[0062] In yet another specific embodiment, PE8, the compound of the invention is a tricyclic heterocycle selected from the compounds shown in Table 1 below, including Compound Nos. 1-122, or pharmaceutically acceptable salts, solvates, tautomers, and / or stereoisomers thereof. In another specific embodiment, PE8a, of PE8, the compound is a compound selected from Table 1 and represented by Formula I, as described above and in the claims. It is understood that each single compound depicted in Table 1, as well as any pharmaceutically acceptable salt, solvate, tautomer, and / or stereoisomer of such compound, represents a specific embodiment of the invention. In yet another specific embodiment, PE8b, of PE8 or PE8a, the compound is a compound selected from Table 1 and represented by Formula I, as described above and in the claims, within Group A or Group B in the SK-HEP1 TEAD degradation assay and / or within Group A or Group B in the NCI-H226 TEAD degradation assay, as provided in Table 4a below. DETAILED DESCRIPTION OF THE INVENTION

[0063] As used herein, the following definitions shall apply unless otherwise specifically indicated or defined anywhere in the description and / or claims for a particular substituent, radical, residue, group, or moiety.

[0064] The term "ubiquitin ligase ligand" refers to a structural moiety or compound capable of binding to any type of ubiquitin ligase. The term "E3 ubiquitin ligase ligand" refers to a structural moiety or compound capable of binding to an E3 ubiquitin ligase.

[0065] The term "aliphatic" or "aliphatic group," as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain, or a mono-, bi-, or tricyclic hydrocarbon, which is fully saturated or contains one or more units of unsaturation (such as one or more C=C double bond(s) and / or C≡C triple bond(s)), but which is not aromatic (also referred to herein as "carbocycle," "cycloaliphatic," or "cycloalkyl"), which—generally, and unless otherwise defined in this specification or the appended claims—has a single point of attachment to the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1-10 (i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), 1-8 (i.e., 1, 2, 3, 4, 5, 6, 7, or 8), or 1-6 (i.e., 1, 2, 3, 4, 5, or 6) aliphatic carbon atoms (respectively, "C 1~10 -Aliphatic”, “C 1~8 -aliphatic', and 'C 1~6 In some embodiments, the aliphatic group contains 1 to 5 (i.e., 1, 2, 3, 4, or 5) aliphatic carbon atoms ("C 1~5 -aliphatic"). In other embodiments, the aliphatic group contains 1 to 4 (i.e., 1, 2, 3, or 4) aliphatic carbon atoms ("C 1~4 In still other embodiments, the aliphatic group contains 1 to 3 (i.e., 1, 2, or 3) aliphatic carbon atoms ("C 1~3 -aliphatic"), in another embodiment, the aliphatic group contains 1 to 2 aliphatic carbon atoms ("C 1~2 In some embodiments, "cycloaliphatic" ("cycloalkyl") refers to a monocyclic C3-C7 hydrocarbon (i.e., a monocyclic hydrocarbon having 3, 4, 5, 6, or 7 ring carbon atoms) or a bicyclic C5~8

[0013] The term "cycloaliphatic" or "carbocycle" refers to a hydrocarbon (i.e., a bicyclic hydrocarbon having 5, 6, 7, or 8 ring carbon atoms) that is fully saturated or contains one or more units of unsaturation, but which is not aromatic, and that has a single point of attachment to the rest of the molecule. In another embodiment, the term "cycloaliphatic" or "carbocycle" refers to a monocyclic or bicyclic cycloaliphatic ring system that is fused to an aromatic, heteroaromatic, or heterocyclic ring or ring system through two adjacent ring atoms of the aromatic, heteroaromatic, or heterocyclic ring or ring system; in other words, such a carbocycle shares two ring atoms with the ring or ring system to which it is fused, thereby having two points of attachment to the rest of the molecule. In another embodiment, the term "carbocycle" refers to a bicyclic spirocycle in which two monocyclic carbocycles are fused to each other through the same single carbon atom. In general, the term "aliphatic" encompasses, to the extent chemically feasible, straight-chain, i.e., unbranched, and branched hydrocarbon chains, unless otherwise defined in specific instances. In general, the term also encompasses, to the extent chemically feasible, unsubstituted and substituted hydrocarbon moieties, unless otherwise defined in specific instances. Typical substituents for aliphatic groups include, but are not limited to, halogen, particularly F, cyano, hydroxy, alkoxy, unsubstituted or mono- or di-substituted amino, aryl, particularly unsubstituted or substituted phenyl, heteroaryl, particularly unsubstituted or substituted pyridyl or pyrimidinyl, heterocyclyl, particularly unsubstituted or substituted pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0066] The term "alkyl" often refers to saturated aliphatic and acyclic moieties, whereas the term "alkenyl" often refers to unsaturated aliphatic and acyclic moieties with one or more C=C double bonds, and the term "alkynyl" often refers to aliphatic and acyclic moieties with one or more C≡C triple bonds. It is understood that the term "alkenyl" includes all forms of isomers, i.e., E-isomers, Z-isomers, and mixtures thereof (E / Z-isomers). Exemplary aliphatic groups include linear or branched, substituted or unsubstituted C 1~10 -Alkyl group, C 1~8 -Alkyl group, C 1~6 -Alkyl group, C 1~4 -Alkyl group, C 1~3 -Alkyl group, C 1~2 -Alkyl group, C 2~8 -alkenyl group, C 2~6 -alkenyl group, C 2~8 -alkynyl group, C 2~6 -alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0067] In particular, the term "C 1~3 "-alkyl" refers to an alkyl group, i.e., a saturated acyclic aliphatic group having 1, 2, or 3 carbon atoms. Exemplary C 1~3 The alkyl groups are methyl, ethyl, propyl, and isopropyl. 1~4 "-alkyl" refers to an alkyl group having 1, 2, 3, or 4 carbon atoms. Exemplary C 1~4 The alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. 1~6 "-alkyl" refers to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. Exemplary C 1~6 -Alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, and 2-hexyl. 1~8"-alkyl" refers to an alkyl group having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. Exemplary C 1~8 The alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, 2-hexyl, n-heptyl, 2-heptyl, n-octyl, 2-octyl, and 2,2,4-trimethylpentyl. 1~10 "-alkyl" refers to an alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Exemplary C 1~10 - alkyl groups are methyl, ethyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, n-heptyl, 2-heptyl, n-octyl, 2-octyl, 2,2,4-trimethylpentyl and n-decyl, each of which alkyl groups may be linear or - with the exception of C1-alkyl and C2-alkyl - branched and may be unsubstituted or substituted by 1, 2 or 3 substituents which may be the same or different and which, unless specified differently elsewhere in this specification and / or the appended claims, may be selected from the group comprising halogen, especially F, hydroxy, alkoxy, unsubstituted or mono- or di-substituted amino, aryl, especially unsubstituted or substituted phenyl, heteroaryl, especially unsubstituted or substituted pyridyl or pyrimidinyl, heterocyclyl, especially unsubstituted or substituted pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl. Exemplary substituted alkyl groups are difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxymethyl, 2-hydroxyethyl.

[0068] In some cases, C 1~3 -Alkyl group, C 1~4 -Alkyl group, C 1~6 -Alkyl group, C 1~8 -Alkyl group, C 1~10The -alkyl group may also include those residues in which one or two non-terminal, non-adjacent -CH- (methylene) groups are replaced by -O-, -S-, and / or one or two non-terminal, non-adjacent -CH- or -CH- groups are replaced by -NH- or -N-. These replacements illustratively produce (modified) alkyl groups such as -CH-CH-O-CH, -CH-CH-CH-S-CH, CH-CH-NH-CH-CH, CH-CH-O-CH-CH-O-CH, CH-CH-O-CH-CH-O-CH-CH, CH-CH-N(CH)-CH-CH, etc. Further and / or different replacements of -CH- and -CH- groups may be defined elsewhere in the description and / or claims for a particular alkyl substituent or radical. As described above for "unmodified" alkyl groups, these "modified" alkyl groups may be optionally substituted with 1, 2 or 3 substituents which may be the same or different and, unless specified differently elsewhere in this specification and / or the appended claims, may be selected from the group including halogen, especially F, hydroxy, alkoxy, unsubstituted or mono- or di-substituted amino, especially unsubstituted or substituted phenyl, heteroaryl, especially unsubstituted or substituted pyridyl or pyrimidinyl, heterocyclyl, especially unsubstituted or substituted pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl. Exemplary modified alkyl groups are CH2-CH2-O-CH2-CH2-O-CH2-CH2-NH2, CH2-CH2-O-CH2-CH2-O-CH2-CH2-NH-C(=O)-CH3, CH2-CH2-CH2-CH2-CH2-O-CH2-CH2-NH2, CH2-CH2-CH2-CH2-CH2-O-CH2-CH2-NH-C(=O)-CH3, CH2-CH(OH)-CH2-CH2-O-CH2-CH2-O-CH2-CH2-NH2, CHR-CH(OH)-CH2-CH2-O-CH2-CH2-O-CH2-CH2-NH2, where "R" represents another substituent.

[0069] The term “C 3~7 "-cycloalkyl" refers to a cycloaliphatic hydrocarbon, as defined above, having 3, 4, 5, 6, or 7 ring carbon atoms. 3~6 "-cycloalkyl" refers to a cycloaliphatic hydrocarbon having 3, 4, 5, or 6 ring carbon atoms. 3~7 -cycloalkyl", and "C 3~6 As used herein, "cycloalkylalkyl" includes saturated cyclic hydrocarbons or cyclic hydrocarbons containing one or more units of unsaturation, such as a C=C double bond; such cyclic hydrocarbons with at least one unit of unsaturation may also be referred to as "cycloalkenyl" groups. 3~7 - a cycloalkyl group may be unsubstituted or - unless specified otherwise elsewhere in this specification - substituted with 1, 2 or 3 substituents which may be the same or different, and said group may - unless specified otherwise elsewhere in this specification - C 1~6 -Alkyl, OC 1~6 - selected from the group comprising alkyl (alkoxy), halogen, hydroxy, unsubstituted or mono- or di-substituted amino, aryl, especially unsubstituted or substituted phenyl. If substituted, C 3~7 -cycloalkyl includes all possible stereoisomers. 3~7 -Cycloalkyl groups are cyclopropyl, 2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl. The term "bicyclic C 5~8 "-cycloalkyl" refers to a bicyclic cycloaliphatic hydrocarbon as defined above having 5, 6, 7, or 8 ring carbon atoms; it does not include spirocyclic ring systems, i.e., bicyclic C 5~8 -Cycloalkyl includes ring systems in which two carbocyclic rings are attached to each other through the same carbon atom. 5~8-cycloalkyl groups may be unsubstituted or - unless specified otherwise elsewhere in this specification - substituted with 1, 2 or 3 substituents, which may be the same or different, and - unless specified otherwise elsewhere in this specification - C 1~6 -Alkyl, OC 1~6 - alkyl (alkoxy), halogen, hydroxy, unsubstituted or mono- or di-substituted amino. When substituted, bicyclic C 5~8 -cycloalkyl includes all possible stereoisomers. Exemplary bicyclic C 5~8 -Cycloalkyl is spiro[3.3]heptanyl, bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.2]octan-2-yl, bicyclo[2.2.1]hept-5-en-2-ylmethyl, bicyclo[3.1.1]hept-2-en-2-yl.

[0070] The term "aliphatoxy" refers to a saturated or unsaturated aliphatic group or substituent, as defined above, that is connected to another structural moiety through an oxygen atom (-O-). 1~6 "-Aliphatic oxy" refers to an aliphatic oxy radical having 1, 2, 3, 4, 5, or 6 carbon atoms in the aliphatic group. The term "alkoxy" refers to a specific subgroup of saturated aliphatoxy, i.e., alkyl substituents and residues connected to another structural moiety via an oxygen atom (-O-). Sometimes, this is also referred to as "O-alkyl," more specifically "OC 1~2 -alkyl," "OC 1~3 -alkyl," "OC 1~4 -alkyl," "OC 1~6 -alkyl," "OC 1~8 Like similar alkyl groups, it can be straight chain or -O-C. 1~ Alkyl and -OC 2~With the exception of alkyl - which may be branched and may be unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different, and unless specified otherwise elsewhere in this specification, is selected from the group including halogen, unsubstituted or mono- or di-substituted amino. Exemplary alkoxy groups are methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy.

[0071] The term "alkylene" refers to a divalent aliphatic group, especially a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) j -, where j is a positive integer, preferably 1, 2, 3, 4, 5, or 6. In the context of the present invention, "C 1~3 The terms "C-alkylene" and "C-alkylene" refer to alkylene moieties having one, two, and three -CH2- groups, respectively; however, the term "alkylene" includes not only linear alkylene groups, i.e., "alkylene chains," but also branched alkylene groups. 1~6 The term "C-alkylene" refers to an alkylene moiety that is either linear, i.e., an alkylene chain, or branched, and that has 1, 2, 3, 4, 5, or 6 carbon atoms. 2~6 -alkylene" refers to an alkylene moiety with 2, 3, 4, 5, or 6 carbon atoms, whereas "C 3~4 -alkylene" refers to an alkylene moiety having 3 or 4 carbon atoms, and "C 2~3 "-Alkylene" refers to an alkylene moiety having two or three carbon atoms. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms have been replaced by (or with) a substituent. Suitable substituents include those described herein for substituted alkyl groups. In some cases, one or two methylene groups in the alkylene chain may be replaced by, for example, O, S, and / or NH, or NC.1~4 Exemplary alkylene groups are -CH-, -CH-CH-, -CH-CH-CH-CH-, -O-CH-CH-, -O-CH-CH-CH-, -CH-O-CH-CH-, -O-CH-O-, -O-CH-CH-O-, -O-CH-CH-CH-O-, -CH-NH-CH-CH-, -CH-N(CH)-CH-CH-.

[0072] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced by a substituent. Suitable substituents include those described herein for substituted aliphatic groups. The term "alkenylene" refers not only to straight-chain divalent alkenylene radicals, i.e., alkenylene chains, but also to branched alkenylene groups. The term "C 2~6 "-Alkenylene" refers to an alkenylene radical having 2, 3, 4, 5, or 6 carbon atoms.

[0073] The term "alkynylene" refers to a divalent alkynyl group. A substituted alkynylene chain is a polymethylene group containing at least one triple bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described herein for substituted aliphatic groups.

[0074] The term "halogen" means F, Cl, Br, or I.

[0075] The term "heteroatom" means one or more of oxygen (O), sulfur (S), or nitrogen (N), and also includes any oxidized form of nitrogen or sulfur, such as N-oxide, sulfoxide, and sulfone; the quaternized form of any basic or substitutable nitrogen of a heterocyclic or heteroaromatic ring, for example, N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or N-SUB (as in N-substituted pyrrolidinyl), where SUB is a suitable substituent.

[0076] The term "aryl," used alone or as part of a larger moiety, as in "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to monocyclic, bicyclic, and tricyclic ring systems having a total of 5 to 14 ring members (the ring members are carbon atoms), wherein at least one ring in the system is aromatic, i.e., it has (4n+2) π (pi) electrons (where n is an integer selected from 0, 1, 2, and 3), the electrons are delocalized throughout the system, and wherein each ring in the system contains 3 to 7 ring members. Preferably, all rings in an aryl system or the entire ring system are aromatic. The term "aryl" is used interchangeably with the term "aryl ring." In some embodiments of the present invention, "aryl" refers to an "aromatic ring system." More specifically, the aromatic ring systems may be mono-, bi-, or tricyclic, having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring carbon atoms. Even more specifically, the aromatic ring systems may be mono- or bicyclic, having 6, 7, 8, 9, or 10 ring carbon atoms. Exemplary aryl groups are phenyl, biphenyl, naphthyl, anthracyl, and the like, which may be unsubstituted or substituted with one or more of the same or different substituents. Also included within the scope of the terms "aryl" or "aromatic ring system," as used herein, are groups of aromatic rings fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl. In the latter case, the "aryl" group or substituent is attached to its pendant group via the aromatic portion of the ring system.

[0077] The term "benzo" refers to a six-membered aromatic ring (having carbon ring atoms) fused through two adjacent carbon atoms to another ring, which ring is a cycloaliphatic, aromatic, heteroaromatic, or heterocyclic (heteroaliphatic) ring; thus, a ring system having at least two rings is formed in which the benzo ring shares two common carbon atoms with the other ring to which it is fused. For example, when a benzo ring is fused with a phenyl ring, a naphthalene ring system is formed, while when a benzo ring is fused with a pyridine, either a quinoline or an isoquinoline is provided; when a benzo ring is fused with a cyclopentene ring, an indene ring is provided.

[0078] The terms "heteroaryl" and "heteroar-," used alone or as part of a larger moiety, such as "heteroaralkyl" or "heteroaralkoxy," refer to a group having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms (the atoms being carbon atoms and heteroatoms), preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 π (pi) electrons shared in the cyclic array; and having 1, 2, 3, 4, or 5 heteroatoms in addition to the carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes oxidized forms of either nitrogen or sulfur and quaternized forms of any basic nitrogen. In other words, a "heteroaryl" ring or ring system may also be described as an aromatic heterocycle. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, furazanyl, pyridyl(pyridinyl), pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, and pyrrolopyridinyl, especially pyrrolo[2,3-b]pyridinyl. The terms "heteroaryl" and "heteroara-," as used herein, also include groups in which a heteroaromatic ring is fused with one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is preferably on the heteroaromatic or, if present, aryl ring.Non-limiting examples include indolyl, isoindolyl, benzothienyl (benzothiophenyl), benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, 9H-carbazolyl, dibenzofuranyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. For example, the indolyl ring may be attached via one of the ring atoms of a 6-membered aryl ring or one of the ring atoms of a 5-membered heteroaryl ring. The heteroaryl group may optionally be mono-, bi-, or tricyclic. The term "heteroaryl" is used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," all of which terms include unsubstituted rings or rings substituted with one or more of the same or different substituents. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, where the alkyl and heteroaryl portions independently may be optionally substituted.

[0079] A heteroaryl ring can be attached to its pendant group at any heterocyclic or carbon ring atom that results in a stable structure or molecule; any of the ring atoms can be unsubstituted or substituted.

[0080] Exemplary structures of "heteroaryl" substituents, as used herein, are depicted below: [Table A-1] [Table A-2] [Table A-3]

[0081] The heteroaryl substituents may be attached to any pendant group via any of its ring atoms suitable for such attachment.

[0082] As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic radical," and "heterocyclic ring" are used interchangeably and refer to stable mono-, bi-, or tricyclic heterocyclic moieties having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, where 1, 2, 3, 4, or 5 of the ring atoms are heteroatoms, and where the heterocyclic moiety is either saturated or partially unsaturated; heterocyclic moieties that are aromatic rings or ring systems are often referred to as "heteroaryl" moieties, as described hereinabove. Preferably, the heterocycle is a stable saturated or partially unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic, or 7-, 8-, 9-, 10-, or 11-membered bicyclic, or 11-, 12-, 13-, or 14-membered tricyclic heterocyclic moiety.

[0083] When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 1 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen is N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or N-SUB (as in N-substituted pyrrolidinyl), where SUB is a suitable substituent.

[0084] In the context of the term "heterocycle," the term "saturated" refers to a fully saturated heterocyclic system, such as pyrrolidinyl, piperidinyl, morpholinyl, piperidinonyl, tetrahydrofuranyl, thianyl, and dioxothianiyl. With respect to the term "heterocycle," the term "partially unsaturated" refers to (i) a heterocyclic system that contains one or more units of unsaturation (e.g., C=C or C=heteroatom bond) but is not aromatic (e.g., tetrahydropyridinyl); or (ii) a heterocyclic system in which a (saturated or unsaturated, but not aromatic) heterocyclic ring is fused with an aromatic or heteroaromatic ring system, where the "partially unsaturated heterocycle" is attached to the rest of the molecule (its pendant group) through one of the ring atoms of the "heterocyclic" portion of the system, but not through the aromatic or heteroaromatic portion. This first class (i) of "partially unsaturated" heterocycles may also be referred to as "non-aromatic partially unsaturated" heterocycles. This second class (ii) of "partially unsaturated" heterocycles may also be referred to as (bicyclic or tricyclic) "partially aromatic" heterocycles, which indicates that at least one of the heterocycle rings is a saturated or unsaturated, but not aromatic, heterocycle fused to at least one aromatic or heteroaromatic ring system. Typical examples of these "partially aromatic" heterocycles are 1,2,3,4-tetrahydroquinolinyl and 1,2,3,4-tetrahydroisoquinolinyl.

[0085] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms can be unsubstituted or substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydropyranyl, thianyl, dioxothianyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, morpholinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" are used interchangeably herein and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings (such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring). Heterocyclyl groups are optionally mono-, bi-, or tricyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, where the alkyl and heterocyclyl portions are independently unsubstituted or substituted.

[0086] The term "unsaturated," as used herein, means that a moiety or group or substituent has one or more units of unsaturation.

[0087] As used herein with reference to any ring, ring system, ring moiety, etc., the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation. In particular, it encompasses (i) unsaturated (mono-, bi-, or tricyclic) ring systems that lack any aromatic or heteroaromatic moieties; and (ii) bi- or tricyclic ring systems in which one ring of the system is an aromatic or heteroaromatic ring fused to another ring that is neither aromatic nor heteroaromatic (e.g., tetrahydronaphthyl or tetrahydroquinolinyl). The first class (i) of "partially unsaturated" rings, ring systems and ring moieties are sometimes referred to as "non-aromatic partially unsaturated" rings, ring systems and ring moieties, while the second class (ii) is sometimes referred to as "partially aromatic" rings, ring systems and ring moieties.

[0088] As used herein, the terms "bicyclic," "bicyclic ring," or "bicyclic ring system" refer to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or having one or more units of unsaturation (i.e., partially unsaturated or aromatic), with one or more atoms common to the two rings of the ring system. Thus, the term encompasses any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term "heterobicyclic" is a subset of "bicyclic," requiring one or more heteroatoms to be present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions, may be optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, and the like. In some embodiments, bicyclic groups have 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Similarly, the terms "tricyclic," "tricyclic ring," or "tricyclic ring system" refer to any tricyclic ring system, i.e., carbocyclic or heterocyclic, saturated or having one or more units of unsaturation (i.e., partially unsaturated or aromatic), in which a bicyclic ring system (as defined above) is fused to another, third ring. Thus, the term encompasses any permissible ring fusion. As used herein, the term "heterotricyclic" is a subset of "tricyclic," requiring that one or more heteroatoms be present in one or both rings of the tricycle. Such heteroatoms may be present at ring junctions, may be optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc. In some embodiments, tricyclic groups have 10 to 14 ring members and 0 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0089] As described herein, certain compounds of the invention contain "substituted" or "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogens of the specified moiety have been replaced with a suitable substituent. "Substituted" applies to one or more hydrogens from a structure, either explicitly or implicitly. Unless otherwise indicated, a "substituted" or "optionally substituted" group has a suitable substituent at each substitutable position of the group; when more than one position in any given structure is substituted with more than one substituent selected from a specified group, the substituents are either the same or different at each position. When a group, substituent, moiety, or radical is "monosubstituted," it has one (1) substituent. When it is "disubstituted," it has two (2) substituents that are either the same or different; when it is "trisubstituted," it has three (3) substituents, where all three are the same, or two are the same and the third is different, or all three are different from each other. Combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable," as used herein, refers to compounds that are substantially unchanged when subjected to conditions that permit their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0090] Unless otherwise specified elsewhere in this specification or the appended claims, each optional substituent on a substitutable carbon is independently selected from the group consisting of halogen; -(CH) 0~4 R o ;-(CH2) 0~4 OR o ;-O(CH2) 0~4 R o , -O-(CH2) 0~4 C(O)OR o;-(CH2) 0~4 CH(OR o )2;-(CH2) 0~4 SR o ;R ≥ 1 o optionally substituted with -(CH2) 0~4 pH: 1 or higher o optionally substituted with -(CH2) 0~4 O(CH2) 0~1 pH: 1 or higher o -CH=CHPh, optionally substituted with one or more R o optionally substituted with -(CH2) 0~4 O(CH2) 0~1 -pyridyl; -NO2; -CN; -N3; ​​-(CH2) 0~4 N(R o )2;-(CH2) 0~4 N(R o )C(O)R o ;-N(R o )C(S)R o ;-(CH2) 0~4 N(R o )C(O)NR o 2;-N(R o )C(S)NR o 2;-(CH2) 0~4 N(R o )C(O)OR o ;-N(R o )N(R o )C(O)R o ;-N(R o )N(R o )C(O)NR o 2;-N(R o )N(R o )C(O)OR o ;-(CH2) 0~4 C(O)R o ;-C(S)R o ;-(CH2) 0~4 C(O)OR o ;-(CH2) 0~4 C(O)SR o ;-(CH2) 0~4 C(O)OSiR o 3;-(CH2) 0~4 OC(O)R o ;-OC(O)(CH2)0~4 SR-, SC(S)SR o ;-(CH2) 0~4 SC(O)R o ;-(CH2) 0~4 C(O)NR o 2;-C(S)NR o 2;-C(S)SR o ;-SC(S)SR o , -(CH2) 0~4 OC(O)NR o 2;-C(O)N(OR o )R o ;-C(O)C(O)R o ;-C(O)CH2C(O)R o ;-C(NOR o )R o ;-(CH2) 0~4 SSR o ;-(CH2) 0~4 S(O)2R o ;-(CH2) 0~4 S(O)2OR o ;-(CH2) 0~4 OS(O)2R o ;-S(O)2NR o 2;-S(O)(NR o )R o ;-S(O)2N=C(NR o 2)2;-(CH2) 0~4 S(O)R o ;-N(R o )S(O)NR o 2;-N(R o )S(O)2R o ;-N(OR o )R o ;-C(NH)NR o 2;-P(O)2R o ;-P(O)R o 2;-OP(O)R o 2;-OP(O)(OR o )2;SiR o 3;-(C 1~4 Linear or branched alkylene)ON(R o )2; or -(C 1~4 Linear or branched alkylene)C(O)ON(R oIt is understood that "Ph" means phenyl; and "-(CH)" means a monovalent substituent selected from 0~4 " is understood to mean that when the subscript is "0" (zero), there is no alkylene group, or an alkylene group with 1, 2, 3, or 4 CH2 units.

[0091] Each R o are independently hydrogen, halogen, C 1~6 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, -CH2- (a 5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated, or aryl ring (having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur), or, notwithstanding the above definition, independently, two occurrences of R o R taken together with their intervening atom(s) form a 3-12 membered saturated, partially unsaturated, or aryl, monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, selected from =O and =S. o or each R o are independently halogen, -(CH2) 0~2 R ● ,-(Halo R ● ), -(CH2) 0~2 OH, -(CH2) 0~2 OR ● , -(CH2) 0~2 CH(OR ● )2;-O(HaloR ● ), -CN, -N3, -(CH2) 0~2 C(O)R ● , -(CH2) 0~2 C(O)OH, -(CH2) 0~2 C(O)OR ● , -(CH2) 0~2 SR ● , -(CH2) 0~2 SH, -(CH2) 0~2 NH2, -(CH2) 0~2 NHR● , -(CH2) 0~2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● , -(C 1~4 Linear or branched alkylene)C(O)OR ● , or -SSR ● "Ph" means phenyl; "halo" means halogen; and "-(CH) 0~2 " is understood to mean that when the subscript is "0" (zero), there is no alkylene group, or an alkylene group with one or two CH2 units.

[0092] Each R ● independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring (having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur), wherein each R l is unsubstituted or, if preceded by halo, substituted only with one or more halogens; or, where any substituents on the saturated carbon are independently selected from: =O, =S, =NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2~3 O- or -S(C(R * 2)) 2~3 S- or a divalent substituent attached to an adjacent substitutable carbon of an "optionally substituted" group is -O(CR * 2) 2~3 O-, where each R independently * is hydrogen, C 1~6aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings (having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur).

[0093] R * C 1~6 If aliphatic, R * is halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR l , -NR ● 2, or -NO2, where each R ● independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring (having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur), and wherein each R ● is unsubstituted or, if preceded by halo, substituted only with one or more halogens.

[0094] The optional substituents on a substitutable nitrogen are independently -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † where each R † are independently hydrogen, C 1~6an aliphatic, unsubstituted -OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring (having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur), or two independently occurring R † together with their intervening atom(s) form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring (having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur); where R † C 1~6 When it is aliphatic, R † is halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring (having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur), and wherein each R ● is unsubstituted or, if preceded by halo, substituted only with one or more halogens. "Ph" means phenyl; and "halo" is understood to mean halogen.

[0095] The term "solvate" refers to the addition form of the compound of the present invention with a solvent, preferably a pharmaceutically acceptable solvent containing either a stoichiometric amount or a non-stoichiometric amount of solvent.Some compounds have the tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate.When the solvent is water, the solvate formed is a hydrate, for example, a hemi-, mono-, or dihydrate.When the solvent is alcohol, the solvate formed is an alcoholate, for example, a methanolate or an ethanolate.When the solvent is ether, the solvate formed is an etherate, for example, diethyl etherate.

[0096] The compounds of formula I may have one or more centers of chirality, depending on the nature of any substituents they may carry. These may result in various enantiomeric and diastereomeric forms, and may in some cases be racemic or optically active. The present invention therefore also relates to optically active forms, enantiomers, racemates, diastereomers, and mixtures thereof in all proportions, collectively referred to for the purposes of the present invention as "stereoisomers." While the pharmaceutical activity of the racemates or stereoisomers of the compounds according to the present invention may differ, it may be desirable to use a specific stereoisomer, e.g., one specific enantiomer or diastereomer. In these cases, the compounds according to the present invention obtained as racemates—or even intermediates thereof—may be separated into stereoisomeric (enantiomeric, diastereomeric) compounds by chemical or physical means known to those skilled in the art. Another approach that may be applied to obtain one or more specific stereoisomers of the compounds of the invention in enriched or pure form uses stereoselective synthetic procedures, for example, applying starting materials in stereomerically enriched or pure form (illustratively, using pure or enriched (R)- or (S)-enantiomers of particular starting materials having chiral centers), or utilizing chiral reagents or catalysts, especially enzymes. In the context of the present invention, the term "pure enantiomer" often refers to a relative purity of one enantiomer with respect to the other enantiomer (its antipode) that is equal to or greater than 95%, preferably ≧98%, more preferably ≧98.5%, and even more preferably ≧99%.

[0097] Thus, for example, compounds of the present invention which have one or more centers of chirality and which exist as racemates or as mixtures of enantiomers or diastereomers can be fractionated or resolved into their optically pure or enriched isomers, i.e., enantiomers or diastereomers, by methods known per se. The separation of the compounds of the present invention can be carried out by chromatographic methods, for example, column separation on chiral or non-chiral phases, or by recrystallization from any optically active solvent, or by the use of optically active acids or bases, or by derivatization with an optically active reagent (such as, for example, an optically active alcohol), followed by elimination of the radical.

[0098] In the context of the present invention, the term "tautomer" refers to compounds of the present invention that may exist in tautomeric forms and may exhibit tautomerism; for example, carbonyl compounds may exist in their keto and / or enol forms and may exhibit keto-enol tautomerism. These tautomers may exist in their individual forms, for example, in the keto or enol form, or as mixtures thereof, and are claimed individually and together as mixtures in all ratios. The same applies to cis / trans isomers, E / Z isomers, conformers, etc.

[0099] In one embodiment, the compounds of the present invention are in their free base or acid form, as the case may be, i.e., in their non-salt (or salt-free) form. In another embodiment, the compounds of the present invention are in the form of a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt.

[0100] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable base or acid, including inorganic and organic bases or acids. In cases where a compound of the present invention contains one or more acidic or basic groups, the present invention also includes their corresponding pharmaceutically acceptable salts. Thus, compounds of the present invention containing an acidic group, such as a carboxyl group, can exist in the form of a salt and can be used in accordance with the present invention, for example, as an alkali metal salt, alkaline earth metal salt, aluminum salt, or ammonium salt. More precise examples of such salts include lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, barium salts, or salts with ammonia, or salts with organic amines such as ethylamine, ethanolamine, diethanolamine, triethanolamine, piperidine, N-methylglutamine, or amino acids. These salts can be readily obtained by reacting a compound having an acidic group with a suitable base, for example, lithium hydroxide, sodium hydroxide, sodium propoxide, potassium hydroxide, potassium ethoxide, magnesium hydroxide, calcium hydroxide, or barium hydroxide. Other basic salts of the compounds of the present invention include, but are not limited to, copper(I), copper(II), iron(II), iron(III), manganese(II), and zinc salts. Compounds of the present invention that contain one or more basic groups, e.g., groups that can be protonated, can exist in the form of salts and can be used in accordance with the present invention in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, hydrogen iodide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, sulfoacetic acid, trifluoroacetic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, carbonic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, malonic acid, maleic acid, malic acid, embonic acid, mandelic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, taurocholic acid, glutaric acid, stearic acid, glutamic acid or aspartic acid, and other acids known to those skilled in the art.The salts formed include, among others, hydrochloride, chloride, hydrobromide, bromide, iodide, sulfate, phosphate, methanesulfonate (mesylate), tosylate, carbonate, bicarbonate, formate, acetate, sulfoacetate, triflate, oxalate, malonate, maleate, succinate, tartrate, malate, embonate, mandelate, fumarate, lactate, citrate, glutaric acid, stearate, aspartate, and glutamate. Moreover, the stoichiometry of the salts formed from the compounds of the present invention may be an integer multiple of 1 or a non-integer multiple.

[0101] Compounds of the invention containing basic nitrogen-containing groups include (C1-C4) alkyl halides, such as methyl, ethyl, isopropyl, and tert-butyl chlorides, bromides, and iodides; di(C1-C4) alkyl sulfates, such as dimethyl sulfate, diethyl sulfate, and diamyl sulfate; (C 10 ~C 18 ) alkyl halides, such as decyl, dodecyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; and aryl (C1-C4) alkyl halides, such as benzyl chloride and phenethyl bromide. Both water- and oil-soluble compounds according to the invention can be prepared using such salts.

[0102] When the compounds of the present invention contain both acidic and basic groups in the molecule, the present invention also encompasses internal salts or betaines (zwitterions) in addition to the aforementioned salt forms. The respective salts can be obtained by conventional methods known to those skilled in the art, for example, by contacting them with organic or inorganic acids or bases in a solvent or dispersant, or by anion or cation exchange with other salts. The present invention also encompasses all salts of the compounds of the present invention that are not directly suitable for use in medicines due to their low physiological compatibility, but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

[0103] Thus, the following items are also in accordance with the invention: (a) all stereoisomers or tautomers of the compound, including mixtures thereof in all proportions; (b) pharmaceutically acceptable salts of compounds, as well as pharmaceutically acceptable salts of the items referred to under (a); (c) Pharmaceutically acceptable solvates of the compounds and pharmaceutically acceptable solvates of the items referred to under (a) and (b).

[0104] It should be understood that all references hereinbefore to compounds are intended to encompass those items, particularly pharmaceutically acceptable solvates of the compounds, or pharmaceutically acceptable salts thereof.

[0105] Furthermore, the compounds of the present invention are intended to encompass isotopically labeled forms thereof. Isotopically labeled forms of the compounds of Formula I are identical to the compounds except for the fact that one or more atoms of the compound have been replaced by an atom or atoms having an atomic mass or mass number different from the atomic mass or mass number of most naturally occurring atoms. Examples of isotopes that are readily commercially available and can be incorporated into the compounds of the present invention by well-known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example: 2 H(D), 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 33 S, 34 S, 35 S, 36 S, 18 F, and 36CI, respectively. Compounds of Formula I, or pharmaceutically acceptable salts thereof, that contain one or more of the above isotopes and / or other isotopes of other atoms are intended to be part of the present invention. Isotopically labeled compounds of Formula I can be used in a number of beneficial ways, for example: 3 H or 14 Isotopically labeled compounds of the present invention, into which radioactive isotopes such as C are incorporated, are suitable for drug and / or substrate tissue distribution assays. 3 H) and carbon-14 ( 14 C) is particularly preferred due to its simple preparation and excellent detectability. Heavier isotopes (e.g., deuterium ( 2 Incorporation of H) into compounds of Formula I has therapeutic advantages due to the higher metabolic stability of the isotopically labeled compounds. Higher metabolic stability translates directly into increased in vivo half-life or lower dosages, which will represent a preferred embodiment of the present invention under most circumstances. Isotopically labeled compounds of Formula I can generally be prepared by carrying out the procedures disclosed in the synthetic schemes and related descriptions herein, in the Examples section, and in the Preparations section, replacing non-isotopically labeled reactants with readily available isotopically labeled reactants.

[0106] deuterium( 2H;D) can also be incorporated into compounds of Formula I for the purpose of manipulating the oxidative metabolism of the compound through the primary kinetic isotope effect. The primary kinetic isotope effect is the change in the rate of a chemical reaction due to the exchange of an isotope nucleus, which is caused secondarily by the change in the ground state energy required for covalent bond formation after this isotope exchange. The exchange of a heavier isotope usually results in a lowering of the ground state energy for the chemical bond, which in turn causes a reduction in the rate of rate-limiting bond breaking. If the bond breaking occurs in or near a saddle point region along the coordinate of a multi-product reaction, the product distribution ratio can be substantially altered. To illustrate: when deuterium is attached to a carbon atom at a non-exchangeable position, k M / k D A rate difference of 2 to 7 is typical. If this rate difference is successfully applied to an oxidation-prone compound of formula I, the in vivo profile of the compound can be dramatically altered, resulting in improved pharmacokinetic properties.

[0107] When discovering and developing therapeutic agents, those skilled in the art attempt to optimize pharmacokinetic parameters while retaining desirable in vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic profiles are prone to oxidative metabolism. Currently available in vitro liver microsome assays provide valuable information about the course of this type of oxidative metabolism, which in turn allows for the rational design of deuterated compounds of Formula I with improved stability through resistance to such oxidative metabolism. Significant improvements in the pharmacokinetic profile of compounds of Formula I can thereby be obtained, improving in vivo half-life (t), concentration at maximum therapeutic effect (C), and other properties. max ), area under the dose-response curve (AUC), and F; and quantitatively in terms of reduced clearance, dose, and material cost.

[0108] The following is intended to illustrate what has been described above: A compound of Formula I, which has multiple potential attack sites for oxidative metabolism (e.g., benzylic hydrogen atoms and hydrogen atoms attached to nitrogen atoms), is prepared as a series of analogs in which various combinations of hydrogen atoms are replaced with deuterium atoms (so that some, most, or all of these hydrogen atoms can be replaced with deuterium atoms). Determination of the half-life allows for a convenient and accurate determination of the extent to which resistance to oxidative metabolism has been improved. In this way, it is determined that the half-life of the parent compound can be extended by up to 100% as a result of this type of deuterium-hydrogen exchange.

[0109] Deuterium-hydrogen exchange in the compounds of the invention can also be used to achieve favorable modification of the metabolic spectrum of the starting compound to reduce or eliminate undesired toxic metabolites. For example, if a toxic metabolite arises through oxidative carbon-hydrogen (C-H) bond cleavage, it can be reasonably expected that a deuterated analog will significantly reduce or eliminate the production of the unwanted metabolite, even if the specific oxidation is not the rate-limiting step. Further state-of-the-art information on deuterium-hydrogen exchange may be found, for example, in Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990; Reider et al., J. Org. Chem. 52, 3326-3334, 1987; Foster, Adv. Drug Res. 14, 1-40, 1985; Gillette et al., Biochemistry 33(10) 2927-2937, 1994; and Jarman et al. Carcinogenesis 16(4), 683-688, 1995.

[0110] Furthermore, the present invention relates to pharmaceutical compositions comprising at least one compound of Formula I, or a pharmaceutically acceptable salt solvate, tautomer, and / or stereoisomer thereof, as an active ingredient, together with a pharmaceutically acceptable carrier.

[0111] For purposes of the present invention, the term "pharmaceutical composition" (or "pharmaceutical formulation") refers to a composition or product comprising one or more active ingredients and one or more inactive ingredients that constitute the carrier, as well as any product resulting directly or indirectly from the combination, complexation, or aggregation of any two or more of the ingredients, or from the dissociation of one or more of the ingredients, or from any other type of reaction or interaction of one or more of the ingredients. Consequently, pharmaceutical compositions of the present invention encompass any composition made by admixing at least one compound of the present invention with a pharmaceutically acceptable carrier, which may further include pharmaceutically acceptable excipients, auxiliaries, adjuvants, diluents, and / or additional pharmaceutically active substances other than the compounds of the present invention.

[0112] Pharmaceutical compositions include compositions and pharmaceutical formulations suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (eye drops), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and the nature of the active ingredient. These may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.

[0113] The pharmaceutical compositions of the present invention may additionally contain one or more other compounds as active ingredients (drugs), such as one or more additional compounds of the present invention. In specific embodiments, the pharmaceutical compositions further contain a second active ingredient, or derivatives, prodrugs, solvates, tautomers, or stereoisomers thereof, and pharmaceutically acceptable salts of each of the foregoing (including mixtures thereof in any proportion), where the second active ingredient is other than a compound of Formula I; preferably, the second active ingredient is a compound for which the compounds of the present invention are also useful and which is useful for treating, preventing, inhibiting, and / or ameliorating a disease state or condition listed anywhere above or below. Such combinations of two or more active ingredients or drugs may be safer or more effective than either drug or active ingredient alone, or the combination is safer or more effective than would be expected based on the additivity of the individual drugs. Such other drug(s) may be administered contemporaneously or sequentially with the compounds of the present invention by a commonly used route and in an amount thereof. When a compound of the present invention is used contemporaneously with one or more other drugs or active ingredients, a combination product containing such other drug(s) and a compound of the present invention—also referred to as a "fixed-dose combination"—is preferred. However, combination therapy also includes therapy in which a compound of the present invention and one or more other drugs are administered on different, overlapping schedules. It is contemplated that when used in combination with other active ingredients, the compound of the present invention, the other active ingredients, or both, may be effectively used in lower doses than when each is used alone. Consequently, pharmaceutical compositions of the present invention also include those containing one or more other active ingredients in addition to a compound of the present invention.

[0114] The compounds of the present invention - or their pharmaceutically acceptable salts, solvates, tautomers, and / or stereoisomers - can be used as pharmaceuticals. Without wishing to be bound by theory, the compounds of formula I are bifunctional degraders, wherein the structural moiety Q 1functions as a ubiquitin ligase ligand, and the structural moiety Q 3 is the TEAD-binding functional unit (or TEAD ligand), while Q 2 If there is a part Q 1 and Q 3 The compound of Formula I is contemplated as a suitable linker covalently linking the YAP-TEAD and TAZ-TEAD signaling pathways. The compounds of Formula I have been found to exhibit pharmacological activity through binding to and / or inhibiting TEAD, which may include, but is not limited to, inhibiting YAP-TEAD and / or TAZ-TEAD protein-protein interactions, and / or degradation of TEAD. The compounds of Formula I may form a ternary complex comprising (i) the compound of Formula I; (ii) a TEAD protein; and (iii) a ubiquitin ligase, thereby mediating the desired pharmacological activity. It is contemplated that, through this activity, the compounds of the present invention may also restore or antagonize dysfunction of the Hippo pathway. Aside from restoring or antagonizing dysfunction of the Hippo pathway and independent of upstream Hippo regulation, the pharmacological activity of the compounds of the present invention may also be useful in other pathophysiological scenarios in which inhibition, disruption, or degradation of TEAD binding (and / or aberrant YAP-TEAD and / or aberrant TAZ-TEAD signaling) would be beneficial.

[0115] Thus, the compounds of the present invention, which are binders and / or inhibitors and / or degraders of TEAD, are particularly useful for treating, preventing, suppressing, and / or ameliorating hyperproliferative disorders and cancers, particularly tumors, including solid tumors such as breast cancer, lung cancer, mesothelioma, epithelioid hemangioendothelioma, uveal melanoma, liver cancer, ovarian cancer, squamous cell carcinoma, renal cancer, gastric cancer, medulloblastoma, colon cancer, pancreatic cancer, schwannoma, meningioma, glioma, and basal cell carcinoma. Without wishing to subscribe to any particular theory or explanation, it can be assumed that the compounds may achieve this through a direct effect on cancer cells and / or indirectly by modulating the immune system's response to tumors. Furthermore, the compounds of the present invention may also be useful for treating, preventing, suppressing, and / or ameliorating non-cancerous disorders and diseases, such as cardiovascular disease and fibrosis (such as liver fibrosis).

[0116] In particular embodiments, the compounds of the invention are for use in the prevention and / or treatment, in particular, of any of the disorders or diseases listed above, preferably of cancer, especially of tumors including solid tumors, of the specific types of cancer disclosed in the preceding paragraph; or in the treatment of any of the non-cancerous disorders or diseases disclosed in the preceding paragraph.

[0117] Another specific embodiment of the present invention is a method for preventing and / or treating, preferably treating, a disorder or disease selected from the group consisting of hyperproliferative disorders and cancer, especially tumors including solid tumors, or of the specific types of cancer disclosed in the preceding paragraph; or any of the non-cancerous disorders or diseases disclosed in the preceding paragraph.

[0118] Yet another specific embodiment of the present invention is the use of a compound of the present invention - or a solvate, tautomer, or stereoisomer thereof, and / or a pharmaceutically acceptable salt of each of the above, and mixtures thereof in any ratio - for the manufacture of a medicament, especially for preventing and / or treating, preferably treating, a disorder or disease selected from the group consisting of hyperproliferative disorders and cancer, especially tumors including solid tumors, or of the specific types of cancer disclosed in the preceding paragraph; or any of the non-cancerous disorders or diseases disclosed in the preceding paragraph.

[0119] Preferably, the present invention relates to a compound of the present invention for use in the prevention and / or treatment of a disease - or, alternatively, to a method for preventing and / or treating a disease by administering an effective amount of a compound of the present invention; or, in another alternative, to the use of a compound of the present invention for the manufacture of a medicament for the prevention and / or treatment of a disease - wherein the disease is cancer, in particular tumors including solid tumors of the specific types of cancer disclosed in the preceding paragraph; more preferably, wherein the administration of the compound is simultaneous, sequential, or alternating with the administration of at least one other active agent.

[0120] The disclosed compounds of the present invention, particularly the compounds represented by Formula I, can be administered in combination with other known therapeutic agents, including anti-cancer agents. As used herein, the term "anti-cancer agent" refers to any agent administered to a cancer patient for the purpose of treating cancer. The anti-cancer treatment defined above may be applied as a monotherapy, or may involve, in addition to the compounds of the present invention disclosed herein, conventional surgery or radiation therapy or medicinal therapy. Such medicinal therapy (e.g., chemotherapy or targeted therapy) may include one or more of the following anti-tumor agents, preferably one of them:

[0121] Alkylating agents Altretamine, bendamustine, busulfan, carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan, tosilate, lomustine, melphalan, mitobronitol, mitolactol, nimustine, ranimustine, temozolomide, thiotepa, treosulfan, mechlorethamine, carboquone; apaziquone, fotemustine, glufosfamide, palifosfamide, pipobroman, trofosfamide, uramustine, evofosamide, VAL-083 [4] etc;

[0122] platinum compound Carboplatin, cisplatin, eptaplatin, miriplatin hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin, satraplatin, etc.; DNA modifying agents Amrubicin, bisantrene, decitabine, mitoxantrone, procarbazine, trabectedin, clofarabine; Amsacrine, brostallicin, pixantrone, laromustine [1],[3] etc;

[0123] Topoisomerase inhibitors etoposide, irinotecan, razoxane, sobuzoxane, teniposide, topotecan; Amonafide, Belotecan, Elliptinium acetate, Boreloxin, etc.; Microtubule modifiers Cabazitaxel, docetaxel, eribulin, ixabepilone, paclitaxel, vinplastine, vincristine, vinorelbine, vindesine, vinflunine; fosbretabine, tesetaxel, etc.

[0124] anti-metabolite Asparaginase [3], azacitidine, levofolinate calcium, capecitabine, cladribine, cytarabine, enocitabine, floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur; doxifluridine, ellacitabine, raltitrexed, cepacitabine, tegafur [2],[3] , trimethotrexate, etc.;

[0125] Anticancer antibiotics Bleomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, levamisole, miltefosine, mitomycin C, romidepsin, streptozocin, valrubicin, zinostatin, zorubicin, daunorubicin, plicamycin; aclarubicin, peplomycin, pirarubicin, etc.;

[0126] Hormones / antagonists Abarelix, abiraterone, bicalutamide, buserelin, calcitonin, chlorotonianicene, degarelix, dexamethasone, estradiol, flutocortolone, fluoxymesterone, flutamide, fulvestrant, goserelin, histrelin, leuprorelin, megesterol, mitotane, nafarelin, nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen, thyrotropin alfa, toremifene, trilostane, triptorelin, diethylstilbestrol; acolbifene, danazol, deslorelin, epithiostanol, orteronel, enzalutamide [1],[3] etc; Aromatase inhibitors Aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone; formestane, etc.;

[0127] Small Molecule Kinase Inhibitors Crizotinib, dasatinib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib, gefitinib, axitinib; afatinib, alisertib, dabrafenib, dacomitinib, dinaciclib, dovitinib, Enzas Taurine, nintedanib, lenvatinib, linifanib, linsitinib, masitinib, midostaurin, motesanib, neratinib, orantinib, perifosine, ponatinib, radotinib, rigosertib, tepotinib, tipifanib, tivantinib, tivozanib, trametinib, pimasertib, brivanib alaninate, cediranib, apatinib [4] , Cabozantinib S-malate [1],[3] , ibrutinib [1],[3] , icotinib [4] , buparlisib [2] , cipatinib [4] , cobimetinib [1],[3] , idelalisib [1],[3] , fedratinib [1] , tesevatinib, etc.;

[0128] Photosensitizers Methoxsalen [3] ;Porfimer sodium, talaporfin, temoporfin, etc.; antibody Alemtuzumab, besilesomab, brentuximab vedotin, cetuximab, denosumab, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, bevacizumab, pertuzumab [2],[3] Catumaxomab, elotuzumab, epratuzumab, farletuzumab, mogamulizumab, necitumumab, nimotuzumab, obinutuzumab, ocalatuzumab, oregovomab, ramucirumab, rilotumumab, siltuximab, tocilizumab, zalutumumab, zanolimumab, matuzumab, dalotuzumab [1],[2],[3] , onartuzumab [1],[3] , racotumomab [1] , tabalumab [1],[3], EMD-525797 [4] , atezolizumab, durvalumab, pembrolizumab, nivolumab [1],[3] etc;

[0129] cytokines Aldesleukin, interferon alpha 2, interferon alpha 2a [3] , interferon alpha 2b [2][3] ; Celmoleukin, tasonermin, techlereukin, orelvekin [1],[3] , recombinant interferon beta-1a [4] ; Drug conjugates Denileukin diftitox, ibritumomab tiuxetan, iobenguane I123, prednimustine, trastuzumab emtansine, estramustine, gemtuzumab, ozogamicin, aflibercept; syntredequin besudotox, edotreotide, inotuzumab ozogamicin, naptumomab estafenatox, oportuzumab monatox, technitium (99mTc) arcitumomab [1],[3] , vintaphorid [1],[3] etc;

[0130] vaccine Sipuleucel [3] ;Vitespen [3] , Emepepimt-S [3] , OncoVAX [4] , Lindopepimt [3] , troVax [4] , MGN-1601 [4] , MGN-1703 [4] etc; others Alitretinoin, bexarotene, bortezomib, everolimus, ibandronate, imiquimod, lenalidomide, lentinan, metyrosine, mifamurtide, pamidronate, pegaspargase, pentostatin, sipuleucel [3], sizofiran, tamibarotene, temsirolimus, thalidomide, tretinoin, vismodegib, zoledronic acid, vorinostat; celecoxib, cilengitide, entinostat, etanidazole, ganetespib, idronoxyl, iniparib, ixazomib, lonidamine, nimorazole, panobinostat, peretinoin, plitidepsin, pomalidomide, procodazole, ridaforolimus, tasquinimod, telotristat, simalfasin, tirapazamine, tosedostat, travedelsen, ubenimex, valspodar, and gendicine [4] , Picibanil [4] , leiolysin [4] , letaspimycin hydrochloride [1],[3] , trebananib [2],[3] , bilirudin [4] , carfilzomib [1],[3] , endostatin [4] , Immucothel [4] , Belinostat [3] ;

[0131] PARP inhibitors Olaparib, veliparib. MCT1 inhibitors AZD3965 [4] , BAY-8002 [4] . [1] Prop. INN (Proposed International Nonproprietary Name) [2] Rec. INN (Recommended International Nonproprietary Names) [3] USAN (United States Adopted Name) [4] No INN.

[0132] In another aspect of the present invention, there is provided a set or kit comprising a therapeutically effective amount of at least one compound of the present invention and / or at least one pharmaceutical composition as described herein, and a therapeutically effective amount of at least one further pharmacologically active substance other than a compound of the present invention. The set or kit preferably comprises the following separate packs: a) an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, tautomer, and / or stereoisomer thereof; and b) an effective amount of a further active ingredient which is not a compound of Formula I;

[0133] A further aspect of the present invention is a process for the preparation of the pharmaceutical composition of the present invention, characterized in that one or more compounds according to the present invention and one or more compounds selected from the group consisting of solid, liquid or semi-liquid excipients, auxiliaries, adjuvants, diluents, carriers and pharmaceutically active agents other than the compounds according to the present invention are converted into a suitable dosage form.

[0134] The pharmaceutical compositions (formulations) of the present invention may be administered by any means that achieve their intended purpose. For example, administration may be via oral, parenteral, topical, enteral, intravenous, intramuscular, inhalation, nasal, intraarticular, intrathecal, tracheal, ocular, subcutaneous, intraperitoneal, transdermal, or buccal routes. Alternatively, or in parallel, administration may be via the oral route. The administered dosage will depend on the recipient's age, health, and weight, the type of current treatment (if any), the frequency of treatment, and the nature of the desired effect. Parenteral administration is preferred. Oral administration is particularly preferred.

[0135] Suitable dosage forms include, but are not limited to, capsules, tablets, pellets, dragees, semisolids, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, poultices, gels, tapes, eye drops, solutions, syrups, aerosols, suspensions, emulsions, which can be produced according to methods known in the art, for example, as described below:

[0136] Tablets: The active ingredient(s) are mixed with the auxiliaries and the mixture is compressed into tablets (direct compression), optionally granulating part of the mixture before compression.

[0137] Capsules: Mix the active ingredient(s) with the auxiliaries to obtain a free-flowing powder, optionally granulate the powder, fill the powder / granules into open capsules and cap the capsules.

[0138] Semisolids (ointments, gels, creams): The active ingredient(s) are dissolved / dispersed in an aqueous or fatty carrier; the aqueous / fatty phase is then mixed with the complementary fatty / aqueous phase and homogenized (creams only).

[0139] Suppositories (rectal and vaginal): The active ingredient(s) are dissolved / dispersed in a carrier material that has been liquefied by heating (rectal: the carrier material is usually a wax; vaginal: the carrier is usually a heated solution of a gelling agent), the mixture is molded into a suppository form, and the suppository is removed from the annealing mold.

[0140] Aerosol: The active ingredient(s) are dissolved / dispersed in a propellant and the mixture is loaded into an atomizer.

[0141] In general, non-chemical routes for producing pharmaceutical compositions and / or preparations involve processing steps by suitable mechanical means known in the art to convert one or more compounds of the present invention into a dosage form suitable for administration to patients in need of such treatment. Converting one or more compounds of the present invention into such a dosage form usually involves the addition of one or more compounds selected from the group consisting of carriers, excipients, auxiliaries, and pharmaceutically active ingredients other than the compounds of the present invention. Suitable processing steps include, but are not limited to, combining, milling, mixing, granulating, dissolving, dispersing, homogenizing, molding, and / or compressing the active and inactive ingredients, respectively. Mechanical means for carrying out such processing steps are known in the art, for example, from Ullmann's Encyclopedia of Industrial Chemistry, 5th Edition. In this regard, the active ingredients are preferably at least one compound of the present invention and, optionally, one or more additional compounds other than the compounds of the present invention that exhibit valuable pharmaceutical properties, preferably those pharmaceutically active agents disclosed herein other than the compounds of the present invention.

[0142] Particularly suitable for oral use are tablets, pills, coated tablets, capsules, powders, granules, syrups, juices, or drops; suitable for rectal use are suppositories; suitable for parenteral use are solutions, preferably oil-based or aqueous solutions, as well as suspensions, emulsions, or implants; suitable for topical use are ointments, creams, or powders. The compounds of the present invention may also be lyophilized, and the resulting lyophilizates are used, for example, to prepare injection preparations. The indicated preparations may be sterilized and / or contain lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for modifying osmotic pressure, buffer substances, dyes, flavors, and / or several additional active ingredients, such as one or more vitamins.

[0143] Suitable excipients are organic or inorganic substances suitable for enteral (e.g., oral), parenteral, or topical administration, which do not react with the compounds of the invention, such as water, vegetable oils, benzyl alcohol, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose, sucrose, mannitol, sorbitol, or starch (corn starch, wheat starch, rice starch, potato starch), cellulose preparations, and / or calcium phosphates, such as calcium triphosphate or calcium hydrogen phosphate, magnesium stearate, talc, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, and / or vaseline.

[0144] If desired, disintegrants may be added to the above-mentioned starches, such as carboxymethyl-starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof (such as sodium alginate). Auxiliaries include, but are not limited to, flow-regulating agents and lubricants, such as silica, talc, stearic acid or a salt thereof (such as magnesium stearate or calcium stearate), and / or polyethylene glycol. Dragee cores are provided with suitable coatings, which, if desired, are resistant to gastric juices. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol, and / or titanium dioxide, a lacquer solution, and a suitable organic solvent or solvent mixture. To produce a coating resistant to gastric juices or to provide a dosage form offering the advantage of prolonged action, tablets, dragees, or pills can contain an inner dosage and an outer dosage component, the latter in the form of an envelope surrounding the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and allows the inner component to pass intact into the duodenum or be delayed in release. Various materials can be used for such enteric layers or coatings, including a number of polymeric acids, and mixtures of polymeric acids with materials such as shellac, acetyl alcohol, solutions of suitable cellulose preparations (such as acetyl-cellulose phthalate, cellulose acetate, or hydroxypropylmethyl-cellulose phthalate), etc. Dyes or pigments can be added to tablets or dragee coatings, for example, for identification or to characterize active compound dose combinations.

[0145] Suitable carrier materials are organic or inorganic substances suitable for enteral administration (e.g., oral administration) or parenteral administration or topical application that do not react with the novel compounds, such as water, vegetable oils, benzyl alcohol, polyethylene glycol, gelatin, carbohydrates (such as lactose or starch), magnesium stearate, talc, and yellow petroleum jelly. In particular, tablets, coated tablets, capsules, syrups, suspensions, drops, or suppositories are used for enteral administration, solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants are used for parenteral administration, and ointments, creams, or powders are used for topical application. The compounds of the present invention can also be lyophilized, and the resulting lyophilized products can be used, for example, to produce injection preparations.

[0146] Other pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, and soft sealed capsules made of gelatin and plasticizers (such as glycerol or sorbitol). Push-fit capsules can contain the active compound in the form of granules, which may be mixed with fillers such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compound is preferably dissolved or suspended in a suitable liquid such as fatty oils or liquid paraffin. In addition, stabilizers may also be added.

[0147] Liquid forms into which the novel compositions of the present invention may be incorporated for oral administration include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums, for example, tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone, or gelatin.

[0148] Suitable formulations for parenteral administration include aqueous solutions of water-soluble forms of active compounds, such as water-soluble salts and alkaline solutions.In addition, suspensions of active compounds can also be administered as appropriate oily injection suspensions.Suitable lipophilic solvents or vehicles include fatty oils (such as sesame oil) or synthetic fatty acid esters, such as ethyl oleate or triglycerides or polyethylene glycol-400 (this compound is soluble in PEG-400).

[0149] Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, and / or dextran; optionally, the suspension may also contain stabilizers.

[0150] For administration as an inhalation spray, sprays can be used in which the active ingredient is dissolved or suspended in a propellant gas or propellant gas mixture (for example, CO or chlorofluorocarbon).The active ingredient is preferably used here in finely divided form, and in this case, one or more additional physiologically acceptable solvents, such as ethanol, may be present.The inhalation solution can be administered using a conventional inhaler.

[0151] The practicable pharmaceutical preparations that can be used rectally include, for example, suppositories, which are made up of one or more active compounds combined with a suppository base.Suitable suppository bases are, for example, natural or synthetic triglycerides or paraffin hydrocarbons.In addition, gelatin rectal capsules, which are made up of active compounds combined with a base, can also be used.Practicable bases include, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.

[0152] Pharmaceutical preparations can be employed as human medicines and veterinary medicines. As used herein, the term "effective amount" refers to the amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human (which is, for example, being sought by a researcher or clinician). Furthermore, the term also encompasses within its scope a "therapeutically effective amount," which refers to any amount that results in improved treatment, cure, prevention, or amelioration of a disease, disorder, or side effect, or a reduction in the rate of progression of a disease or disorder or symptoms associated with such a disease or disorder, compared to a corresponding subject not receiving such amount; this can also refer to preventing or providing a prophylactic method for a disease or disorder in a subject who has or is at risk of developing a disease disclosed herein. The term also encompasses within its scope an amount effective to enhance normal physiological function. The therapeutically effective amount of one or more compounds of the present invention will be known to those skilled in the art or can be readily determined by standard methods known in the art.

[0153] "Treating" or "treatment," as used herein, means alleviating all or part of the symptoms associated with a disorder or disease, or slowing or halting further progression or worsening of those symptoms, or preventing or prophylaxis of a disease or disorder in a subject at risk of developing the disease or disorder.

[0154] The compound of the present invention and any additional active substance are generally administered in the same manner as commercial preparations.The suitable dosage that is usually therapeutically effective is between 0.0005mg and 1000mg per dosage unit, preferably between 0.005mg and 500mg, particularly between 0.5mg and 100mg.The daily dosage is preferably between about 0.001mg / kg body weight and about 10mg / kg body weight.

[0155] Those skilled in the art will readily understand that dosage levels may vary depending on the specific compound, the severity of the symptoms, and the subject's susceptibility to side effects. Some specific compounds are more potent than others. The preferred dosage for a given compound can be easily determined by those skilled in the art by a variety of means. A preferred means is to measure the physiological potency of a given compound.

[0156] However, the specific dose for an individual patient, and in particular for an individual human patient, depends on numerous factors, such as the potency of the specific compound employed, age, weight, general state of health, sex, type of diet, time and route of administration, excretion rate, type of administration and dosage form administered, drug combination, and the severity of the specific disorder to be treated. The specific therapeutically effective dose for an individual patient can be readily determined by routine experimentation, for example, by the physician or doctor advising or participating in the therapeutic treatment.

[0157] The compounds of the present invention can be prepared by following the procedures of the following schemes, experimental part and examples using appropriate materials, as further illustrated by the following specific examples. They can also be prepared by methods known per se, or more precisely, under known and suitable reaction conditions for the reaction, as described in the literature (e.g., in standard works such as Houben-Weyl, Methoden der Organischen Chemie [Methods of Organic Chemistry], Georg Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York). Variants known per se, but not mentioned in more detail here, can also be used.

[0158] Similarly, the starting materials for the preparation of the compounds of the present invention can be prepared by methods as described in the examples or by methods known per se, as described in the literature of synthetic organic chemistry and known to those skilled in the art, or can be obtained commercially. The starting materials for the claimed and / or utilized processes can also be formed in situ, if desired, not by isolating them from the reaction mixture, but instead by immediately converting them to further compounds of the present invention or intermediate compounds. On the other hand, in general, the reactions can also be carried out stepwise.

[0159] Preferably, the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions. Examples of suitable solvents include, but are not limited to, hydrocarbons such as hexane, petroleum ether, benzene, toluene, or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, chloroform, or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), or dioxane; glycol ethers such as ethylene glycol monomethyl or monoethyl ether, or ethylene glycol dimethyl ether (diglyme); ketones such as acetone or butanone; amides such as acetamide, dimethylacetamide, dimethylformamide (DMF), or N-methylpyrrolidinone (NMP); nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate, or mixtures of such solvents or mixtures with water.

[0160] The reaction temperature is between about -100°C and 300°C, depending on the reaction steps and conditions used.

[0161] The reaction time generally ranges from a few minutes to several days, depending on the reactivity of each compound and the reaction conditions. A suitable reaction time can be easily determined by methods known in the art, such as reaction monitoring. Based on the reaction temperature given above, a suitable reaction time generally ranges from 10 minutes to 48 hours.

[0162] Moreover, by utilizing the procedures described herein, in conjunction with ordinary skill in the art, additional compounds of the present invention claimed herein can be readily prepared. However, the compounds illustrated in the examples should not be construed as forming the only genus that is considered the invention. The examples further provide details for the preparation of compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can also be used to prepare these compounds.

[0163] As will be appreciated by those skilled in the art of organic synthesis, the compounds of the present invention, particularly those represented by Formula I, are readily accessible by a variety of synthetic routes, some of which are exemplified in the accompanying experimental part. Those skilled in the art will readily recognize what kinds of reagents and reaction conditions should be used and how to apply and adapt them in any particular case—wherever necessary or useful—to obtain the compounds of the present invention. Furthermore, certain compounds of the present invention can be readily synthesized by reacting other compounds of the present invention under suitable conditions, for example, by converting certain specific functional groups present in the compounds of the present invention, or suitable precursor molecules thereof, into other ones by applying standard synthetic methods such as reduction, oxidation, addition, or substitution reactions, which are well known to those skilled in the art. Likewise, those skilled in the art will be aware that - whenever necessary or useful - synthetic protecting (or protective) groups; the application of suitable protecting groups as well as methods for introducing and removing them are well known to those skilled in the art of chemical synthesis and are described in more detail, for example, in P.G.M.Wuts, T.W. Greene, "Greene's Protective Groups in Organic Synthesis", 4th edition (2006) (John Wiley & Sons).

[0164] Q of the compound of formula I1 It will be appreciated that several compounds that form the moiety, i.e., ubiquitin ligase ligand, or precursors of those compounds, are commercially available or readily available by well-known synthetic methods, including those described in the experimental section for exemplary compounds. Such compounds or precursors include, but are not limited to, thalidomide and lenalidomide and derivatives thereof.

[0165] Q of the compound of formula I 2 It will further be understood that several compounds forming the moiety, i.e., the bivalent linker, or precursors to those compounds, are commercially available or readily available by well-known synthetic methods, including those described in the experimental part of the exemplary compounds.

[0166] Q of the compound of formula I 3 It will further be appreciated that several compounds forming moieties, i.e., TEAD ligands, or precursors to those compounds, are readily available by well-known synthetic methods, including those described in the experimental section for exemplary compounds.

[0167] Q of the compound of formula I 3 The following general synthetic routes that may be utilized to prepare moiety-forming compounds or precursors to compounds are described in more detail in Schemes A, B, C, and D. [ka] Scheme A (Z 1 , Z 2 , Z 3 , R 1 and ring A is as defined above for formula Q3-I and in the claims; R 2 may be a suitable carboxylic acid derivative, such as the free acid, a suitable salt, ester, or amide thereof.

[0168] Scheme A above depicts a general synthetic route for preparing tricyclic heterocycles of formula pre-Q3-I. In reaction step a, boronic acid B—which is readily available, illustratively by first reacting a bromo-substituted aryl or heteroaryl, respectively, with a suitable organometallic base, such as n-butyllithium, followed by a suitable boronic acid ester, such as B(OCH3)3—is reacted with 1-amino-2-bromo-substituted heterocycle C under typical C-C cross-coupling conditions, such as those typical of Suzuki cross-coupling reactions (illustratively, a solution of B and C in a suitable solvent, such as 1,4-dioxane, in the presence of cesium carbonate and a palladium catalyst, such as Pd(dppf)2Cl2 (1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride)) to produce compound D. It is understood that ring A of the 1-amino-2-bromo-substituted heterocycle C has the same meaning as "ring A" in structure Q3-1, i.e., is selected from the 5-membered heteroaromatic rings A-1 to A-24 as defined above and in the claims. Illustratively, if ring A is selected to be ring A-1, then each compound C has the following formula C-1: [ka] will have.

[0169] Compound D may then be subjected to an intramolecular CN cross-coupling reaction (step b), illustratively under conditions typical of a Hartwig-Buchwald reaction (e.g., reaction with cesium carbonate in a suitable solvent such as 1,4-dioxane in the presence of a suitable palladium catalyst such as di-tert-butyl[2',4',6'-tris(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphane{2'-amino-[1,1'-biphenyl]-2-yl}palladiumylium methanesulfonate), to produce tricyclic heterocycle E. This heterocycle E can then be converted to bromide R in another C-N coupling reaction (step c) under similar conditions, illustratively with cesium carbonate and a suitable palladium catalyst (e.g., chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), X-Phos aminobiphenyl palladium chloride, XPhosPd G2). 1 -Br to provide compounds of formula I of the present invention. 1 , R 2 Depending on the nature of R and ring A, this compound of formula pre-Q3-I may be optionally transformed into further compounds of formula pre-Q3-I. 2 is a carboxyl ester (-C(=O)-OR 2a ), then this ester may be subjected to a saponification reaction using a suitable acid or base, thereby converting the respective carboxylic acid (R 2 = -C(=O)-OH) or a salt thereof (e.g., R 2 = -C(=O)-OCat, where Cat is Li, Na, K, or NH4), or may be subjected to an amidation reaction with a suitable amine derivative to provide the respective amide.

[0170] In some cases, compound D as shown in Scheme A above can be - instead of being subjected to subsequent reaction steps b and c, i.e., two successive C-N coupling reactions - to a suitable compound R 1 -Br under C-N coupling reaction conditions (in the presence of a suitable base such as cesium carbonate or sodium hydride and a suitable palladium catalyst) may directly provide the respective compounds of formula pre-Q3-I.

[0171] Furthermore, starting from compound E, compounds of formula pre-Q3-I can be prepared by adding bromo-substituted compounds R 1 It is well understood that R may be synthesized by utilizing a suitable reaction partner other than —Br under suitable reaction conditions. 1 is selected and 1 -Ar or L 1 -Hetar 1 (Here, L 1 is —S(═O)—), then compound E may be reacted with the respective thionyl chloride under suitable reaction conditions to produce the respective sulfonyl derivative represented by formula pre-Q3-I. [ka] Scheme B (Z 1 , Z 2 , Z 3 , R 1 and ring A is as defined above for formula IA and in the claims; R 2 may be a suitable carboxylic acid derivative, such as the free acid, a suitable salt, ester, or amide thereof.

[0172] Scheme B above depicts an alternative synthetic route for making compounds of formula pre-Q3-I, where boronic acid B (or a suitable boronic ester) is reacted with 1-chloro-2-iodo-substituted heterocycle F in a CC cross-coupling reaction (step d) under conditions similar to those described for step a in Scheme A, which produces a dichloro-substituted compound G. Compound G is then reacted with a primary amine R 1 This may be converted to the desired compound represented by pre-Q3-I in a CN coupling reaction with -NH2 (step e) in the presence of a suitable base such as cesium carbonate and a suitable palladium catalyst (as described for Scheme A).

[0173] [ka] Scheme C (Z 1 , Z 2 , Z 3 , R 1 , W 1 , W 2 , W 3 , and W 4 is as defined above for formula Q3-II and in the claims; R 2 may be a suitable carboxylic acid derivative, such as the free acid, a suitable salt, ester, or amide thereof.

[0174] Scheme C above depicts a general synthetic route for preparing compounds of formula pre-Q3-II. In a reaction step, boronic acid BC—which is readily available, for example, by first reacting a bromo-substituted aryl or heteroaryl, respectively, with a suitable organometallic base, such as n-butyllithium, followed by a suitable boronic acid ester, such as B(OCH)—is reacted with 1-amino-2-bromo-substituted phenyl or heterocycle CC under typical CC cross-coupling conditions, for example, conditions typical of Suzuki cross-coupling reactions (for example, by reacting a solution of BC and CC in a suitable solvent, such as 1,4-dioxane, with cesium carbonate in the presence of a palladium catalyst, such as Pd(dppf)Cl(1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride) to produce compound DC. Compound DC may then be subjected to an intramolecular CN cross-coupling reaction (step b), illustratively under conditions typical of a Hartwig-Buchwald reaction (e.g., reaction with cesium carbonate in a suitable solvent such as 1,4-dioxane in the presence of a suitable palladium catalyst such as di-tert-butyl[2',4',6'-tris(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphane{2'-amino-[1,1'-biphenyl]-2-yl}palladiumylium methanesulfonate), to produce the tricyclic heterocycle EC. This heterocycle EC can then be converted to bromide R in another C-N coupling reaction (step c) under similar conditions, illustratively with cesium carbonate and in the presence of a suitable palladium catalyst (e.g., chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), X-Phos aminobiphenylpalladium chloride, XPhosPd G2). 1 -Br to provide a compound of formula pre-Q3-II. 1 , R 2 , and W1 , W 2 , W 3 , and W 4 Depending on the nature of R, this compound of formula pre-Q3-II may optionally be transformed into a further compound of formula I. Illustratively, R 2 is a carboxyl ester (-C(=O)-OR 2a ), then this ester may be subjected to a saponification reaction using a suitable acid or base, thereby converting the respective carboxylic acid (R 2 = -C(=O)-OH) or a salt thereof (e.g., R 2 = -C(=O)-OCat, where Cat is Li, Na, K, or NH4), or may be subjected to an amidation reaction with a suitable amine derivative to provide the respective amide.

[0175] In some cases, compound DC as shown in Scheme C above can be - instead of being subjected to subsequent reaction steps b and c, i.e., two successive C-N coupling reactions - to a suitable compound R 1 -Br under CN reaction conditions (in the presence of a suitable base such as cesium carbonate or sodium hydride and a suitable palladium catalyst) may directly provide the respective compounds of formula pre-Q3-II.

[0176] In some further cases, compound DC—before being converted to either compound EC or compound pre-O3-II—may contain a suitable substituent such as W. 1 , W 2 , W 3 , or W 4 For example, in compound DC, W 3 But Br is R W1 With CR W1 then this bromo-substituted compound may be subjected to a suitable CC coupling reaction to form another substituent R W1 , for example -CH2-Ar Wmay be introduced to provide the respective compound DC.

[0177] Furthermore, starting from compound EC, compounds of formula pre-Q3-II can be prepared by adding a bromo-substituted compound R 1 It is well understood that R may be synthesized by utilizing a suitable reaction partner other than —Br under suitable reaction conditions. 1 is selected and L 1 -Ar or L 1 -Hetar 1 (Here, L 1 is -S(=O)2-), then compound EC may be reacted with the respective thionyl chloride under suitable reaction conditions to produce the respective sulfonyl derivative represented by formula pre-Q3-II.

[0178] [ka] Scheme D (Z 1 , Z 2 , R 1 , W 1 , W 2 , W 3 , and W 4 is as defined above for formula Q3-II and in the claims; R 2 may be a suitable carboxylic acid derivative, such as the free acid, a suitable salt, ester, or amide thereof.

[0179] Scheme D above depicts another synthetic route for making compounds of formula pre-Q3-II. Here, boronic acid BC (or a suitable boronic ester) is reacted with 1-chloro-2-iodo-substituted heterocycle FC in a CC cross-coupling reaction (step d) under conditions similar to those described for step a in Scheme C, which produces a dichloro-substituted compound GC. Compound GC is then converted to a primary amine R 1This may be converted to the desired compound of formula pre-Q3-II in a CN coupling reaction with -NH2 (step e) in the presence of a suitable base such as cesium carbonate and a suitable palladium catalyst (as described for Scheme A).

[0180] Q of the compound of formula I 3 Further synthetic routes and procedures for preparing compounds or precursors of compounds forming the moiety are disclosed in WO 2021 / 224291 A1(Q3-I) and WO 2022 / 018072 A1.

[0181] Also, Part Q 1 , Q 2 , and Q 3 It will also be understood that methods for preparing compounds of Formula I by linking or connecting compounds or precursors of compounds to form the following are generally well known to those skilled in the art. These methods may become apparent from the procedures detailed in the experimental section for the exemplary compounds and include ether formation reactions, esterification reactions, and amidation reactions. Synthetic methods for making bifunctional degraders such as compounds of Formula I and their precursors are also found in Sosic et al., Chem. Soc. Rev., 2022, 51, 3487-3534 and references cited therein.

[0182] Another specific embodiment of the present invention, PE9, includes several compounds that serve as intermediates in the synthesis of compounds of Formula I. Thus, PE9 includes compounds selected from the group consisting of the intermediates depicted in Table INT below, or pharmaceutically acceptable salts, solvates, tautomers, and / or stereoisomers thereof, the syntheses of which are described in the experimental part.

[0183] Table INT [Table B-1]

[0184] [Table B-2]

[0185] [Table B-3]

[0186] [Table B-4]

[0187] [Table B-5]

[0188] It should be noted that, in general, terms, i.e., the singular and plural forms thereof, may be used and read interchangeably - unless specifically stated or the context provides a different meaning. For example, the singular term "compound" may also include or refer to a plurality of compounds, while the plural term "compounds" may also include or refer to a singular compound.

[0189] Examples and Experiments The compounds of the present invention can be prepared according to the procedures of the following schemes and examples using appropriate materials and are further exemplified by the following specific examples. The compounds are listed in Table 1. Analytical data for compounds made according to the following examples is provided with the examples.

[0190] The present invention is illustrated, but not limited, by reference to the specific embodiments described in the following examples. Unless otherwise indicated in the schemes, the variables have the same meanings as described above and in the claims.

[0191] Unless otherwise specified, all starting materials were obtained from commercial suppliers and used without further purification. Unless otherwise specified, all temperatures are expressed in °C and all reactions were performed at room temperature (RT). Compounds were purified by either silica chromatography or preparative HPLC.

[0192] 1 H NMR: 1 H-NMR data for each compound is shown in the experimental section below. to Provided. 1 H NMR spectra were mostly acquired on a Bruker Avance DRX 500, Bruker Avance 400, Bruker DPX 300 NMR, or Bruker Avance III 700 MHz spectrometer under standard conditions using TMS (tetramethylsilane) as the internal standard and DMSO-d6 as the standard solvent, unless otherwise reported. NS (number of scans): 32. TE (temperature): 297 K. Chemical shifts (δ) are reported in ppm relative to the TMS signal. 1 H NMR data are reported as follows: chemical shifts (multiplicities, coupling constants, and hydrogen numbers). Multiplicities are abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets), tt (triplet of triplets), td (triplet of doublets), br (broad), and coupling constants (J) are reported in Hz.

[0193] LC-MS: The LC-MS data provided in the experimental part below for the individual compounds is given in mass in m / z units. The results can be obtained by one of the methods described below.

[0194] synthesis The following abbreviations have the meanings given in parentheses after the particular abbreviation. aq (aqueous), h (hour), g (gram), L (liter), mg (milligram), MHz (megahertz), min. (minute), mm (millimeter), mmol (millimolar), mM (millimolar concentration), mp (melting point), eq (equivalent), mL (milliliter), ACN (acetonitrile), AcOH (acetic acid), CDCl3 (deuterated chloroform), CD3OD (deuterated methanol), CH3CN (acetonitrile), c-hex (cyclohexane), DCC (dicyclohexylcarbodiimide), DCM (dichloromethane), chloromethane), DIC (diisopropylcarbodiimide), DIEA (diisopropylethylamine), DMF (dimethylformamide), DMSO (dimethyl sulfoxide), DMSO-d6 (deuterated dimethyl sulfoxide), DMT-Si (dimercaptotriazine functionalized silica gel), EDC (1-(3-dimethyl-amino-propyl)-3-ethylcarbodiimide), ESI (electrospray ionization), EtOAc (ethyl acetate), Et2O (diethyl ether), EtOH (ethanol HATU (dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluorophosphate), G-II catalyst (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium), HPLC (high-performance liquid chromatography), i-PrOH (2-propanol), KCO (potassium carbonate), LC (liquid chromatography) , MeOH (methanol), MgSO4 (magnesium sulfate), MS (mass spectrometry), MTBE (methyl tert-butyl ether), NaHCO3 (sodium bicarbonate), NaBH4 (sodium borohydride), NMM (N-methylmorpholine), NMR (nuclear magnetic resonance), oNsCl (2-nitrobenzenesulfonyl chloride), Pd(dppf)Cl2 ([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)), Pd(dtbpf)Cl2 (1,1'-bis-(di-tert.-butylphosphino-)ferrocene-palladium dichloride), PyBOP (benzotriazol-1-yl-oxy-tris-pyrrolidine o-phosphonium hexafluorophosphate), RBF (round-bottom flask), RT (room temperature), Rt (retention time), Si-DMT (dimercaptotriazine-functionalized silica gel), SPE (solid-phase extraction), TBTU (2-(1-H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate), TEA (triethylamine), TFA (trifluoroacetic acid), THF (tetrahydrofuran), TLC (thin-layer chromatography), UV (ultraviolet), XPhos Pd G2 (chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)), XPhos Pd G4 ((2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-dimethylamino-1,1'-biphenyl)]palladium(II) methanesulfonate).

[0195] All temperatures are indicated above and below in °C. In the following examples, "conventional work-up" means the following: water is added if necessary, the pH is adjusted if necessary to a value between 2 and 10, the mixture is extracted with ethyl acetate or dichloromethane depending on the composition of the final product, the phases are separated, the organic phase is dried over sodium sulfate and evaporated, and the residue is purified by chromatography on silica gel and / or crystallization. Rf values ​​on silica gel; eluent: ethyl acetate / methanol 9:1.

[0196] All synthetic procedures were carried out under air using analytical grade solvents unless otherwise noted. The use of "water" refers to deionized water. Reaction progress was checked by LC-MS or TLC analysis (using known visualization methods). The following method abbreviations are used in the synthetic procedures to describe the conditions for analytical LC-MS:

[0197] Analytical LC-MS method "Sunfire": Solvent A: H2O+0.05%HCOOH, B: MeCN+0.04%HCOOH+1%H2O, T: 40℃, Flow: 1,4ml / min, MS: 61~1000amu positive (ESI+), Column: SunFire C18 5,0μm 100-3mm, 1%→99%B: 0→2,0min, then 99%B: 2,0→2,7min.

[0198] Analytical LC-MS method "Chromolith": Solvent A: H2O+0,05%HCOOH | B: MeCN+0,04%HCOOH / 4%→100%B: 0→2,8min | 100%B: 2,8→3,3min, T: 40℃, Flow: 3,3mL / min, MS: 100~2000amu positive, Column: Chromolith RP-18e 50-4,6mm.

[0199] Method 1: LC-MS Agilent 1200 Series Chromolith RP-18e 50-4,6mm; 3.3ml / min Solvent A: Water+0.05%HCOOH Solvent B: Acetonitrile+0.04%HCOOH 220nm 0~2.0min: 1%B~99%B 2.0~2.5min: 100%B.

[0200] Method 2: Column: HALO, 3.0*30mm, 2um; Column oven: 40℃; Mobile phase A: water / 0.1%FA; Mobile phase B: acetonitrile / 0.1%FA.

[0201] Method 3: LC-MS Agilent 1200 Series Sunfire C18 100-3mm; 1,4ml / min; Solvent A: Water+0.05%HCOOH; Solvent B: Acetonitrile+0.04%HCOOH 220nm 0~2.0min: 1%B~99%B 2.0~2.7min: 99%B.

[0202] Method 4: Column: Halo C18, 100 mm, 4.6 mm; Column oven: 40°C; Mobile phase A: 6.5 mM NH4HCO3 + NH4OH (pH 0.10), Mobile phase B: acetonitrile.

[0203] Method 5: LC-MS Agilent 1200 Series Cortec T3 30-4,6mm; 0.9ml / min Solvent A: Water+0.05%HCOOH Solvent B: Acetonitrile+0.04%HCOOH 220nm 0~0.8min: 1%B~99%B 0.8~1.05min: 99%B.

[0204] Method 6: UPLC Cortecs T3 30-2,1mm; 0.9ml / min Solvent A: Water+0.05%HCOOH Solvent B: Acetonitrile+0.04%HCOOH 220nm 0~0.6min: 2%B~99%B 0.6~0.8min: 99%B.

[0205] Method 7: Column: HALO, 3.0*30mm, 2um; Mobile phase A: water / 0.05%TFA; Mobile phase B: acetonitrile / 0.05%TFA.

[0206] Method 8: UPLC Kinetex EVO-C18 50-2.1 mm; Solvent A: water + 0.05% HCOOH; Solvent B: acetonitrile + 0.04% HCOOH; Flow 0.9 ml; 1% → 99% B: 0 → 1.0 min | 99% B: 1.0 → 1.3 min.

[0207] Method 9: Column: Agilent HPH, 3.0x50mm, 2.7µm; Mobile phase A: 6.5mM NH4HCO3 + NH4OH (pH=10); Mobile phase B: Acetonitrile; Flow rate: 1.2mL / min; Gradient: 10%B to 95%B in 1.9min, hold for 0.8min; 254nm.

[0208] Method 10: LC-MS Agilent 1200 Series Chromolith RP-18e 50-4.6mm; 3.3ml / min Solvent A: Water + 0.1% TFA Solvent B: Acetonitrile + 0.1% TFA 220nm 0-2.0min: 1%B-99%B 2.0-2.5min: 99%B.

[0209] Method Himass: A: H2O+0,05%HCOOH, B: MeCN+0,04%HCOOH, T: 45℃, flow: 3,3mL / min, MS: 100~2000 amu positive, column: Chromolith HR RP-18e 50-4,6 mm. Gradient: 1%→99%B: 0→2,0min 99%B: 2,0→2,5min.

[0210] Preparative RP-HPLC separations were performed on an AccuPrep machine (Teledyne Isco) using Sunfire or Chromolith columns (ACN / H2O with 0.1% formic acid or TFA as modifiers).

[0211] Method A: Column: Waters XBridge C18 3.5um, 50*4.6mm; Solvent A: Water+0.1%TFA; Solvent: ACN; Flow rate: 1.5ml / min; Time: 6.5min; Gradient: 0.15min: 10%B, 4.5min £0 80%B £4.6min: 95%B, 6.0min: 95%B, 6.1min: 5%B, 6.5min: 5%B.

[0212] Building Block 1 Ethyl 4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (Building Block 1) [ka] Building Block 1

[0213] A solution of 3-bromo-4-chlorobenzoic acid (3000.00 g, 12741.01 mmol, 1.00 equiv) in EtOH (30 L) was placed in a 50-L four-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen. This was followed by the dropwise addition of H2SO4 (1250 g, 12741 mmol) at 0 °C. The resulting solution was stirred at 70 °C for 12 h. The reaction mixture was cooled to 25 °C and then concentrated. The mixture was then quenched by the addition of 5 L of water / ice. The resulting solution was diluted with 10 L of MTBE, and the aqueous phase was extracted with 2 × 5 L of MTBE. The combined organic phase was washed with 1 × 5 L of NaHCO3 (10%), then 1 × 5 L of brine, concentrated to 2 L, and slurried with PE (9 L). This gave 3023 g (90%) of 3-bromo-4-chlorobenzoate as a white solid.

[0214] A solution of 3-bromo-4-chlorobenzoate (3023 g, 11472 mmol), bis(pinacolato)diboron (5826 g, 22943 mmol), KOAc (2252 g, 22943 mmol), and Pd(dppf)Cl (504 g, 688 mmol) in dioxane (30 L) was placed in a 50-L four-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen, then purged three times with N. The resulting solution was stirred at 100 °C for 12 h. The reaction was cooled to 25 °C and quenched by the addition of 3 L of water / ice. The resulting solution was diluted with 3 L of EtOAc. The resulting solution was extracted with 2 × 4 L of ethyl acetate, and the organic layer was washed with 1 × 3 L of brine. The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:1), which gave 2300 g (65%) of ethyl 4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (building block 1) as a yellow solid.

[0215] Building Blocks 2 4-Bromo-1-methylpyrazol-3-amine (Building Block 2) [ka] Building Blocks 2

[0216] A solution of 1-methylpyrazol-3-amine (900 g, 9267 mmol) in DCM (9 L) was placed in a 20-L four-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen. This was followed by the dropwise addition of Br (1407 g, 8803 mmol) and stirring at 15 °C for 2 h. The resulting solution was stirred at 15 °C for 1 h, and then the solid was collected by filtration. The resulting solid was dissolved in 2 L of HO. The pH of the solution was adjusted to 9 with NaOH (1 mol / L). The mixture was extracted with 3 × 3 L of ethyl acetate. The organic layers were combined, washed with 1 × 3 L of brine, and dried over NaSO. The resulting mixture was concentrated to 2 L, and the solid was collected by filtration. This afforded 1100 g (67%) of 4-bromo-1-methylpyrazol-3-amine (building block 2) as a light brown solid. LC-MS: (ES, m / z): 176 [M+H] + 1 H-NMR (300 MHz, DMSO-d6, ppm): δ 7.53 (s, 1H), 4.66 (s, 2H), 3.58 (s, 3H).

[0217] Building Block 3 Ethyl 3-(3-amino-1-methylpyrazol-4-yl)-4-chlorobenzoate (Building Block 3) [ka] Building Block 3

[0218] A solution of building block 2 (1000 g, 5681 mmol) and building block 1 (2294 g, 7386 mmol) in dioxane (10 L) was placed in a 20-L four-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen. A solution of K2CO3 (1570 g, 11363 mmol) and Pd(dppf)Cl2 (457 g, 625 mmol) in HO (1 L) was then added and purged three times with N2. The resulting mixture was stirred at 100 °C for 8 h, then cooled to 25 °C, followed by the addition of 4 L of water / ice. The resulting solution was diluted with 4 L of EtOAc and extracted with 2 × 3 L of ethyl acetate. The organic phase was washed with 1 × 3 L of brine. The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:1). This afforded 730 g (46%) of ethyl 3-(3-amino-1-methylpyrazol-4-yl)-4-chlorobenzoate (building block 3) as a brown solid.

[0219] Building Block 4 Ethyl 2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate (Building Block 4) [ka] Building Block 4

[0220] A mixture of building block 3 (730 g, 2610 mmol), 1-bromo-4-(trifluoromethyl)benzene (881 g, 3915 mmol), CsCO (1701 g, 5220 mmol), and XPhos-Pd-G (233 g, 261 mmol) in dioxane (7.3 L) was placed in a 20-L four-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen, which was then purged three times with N. The resulting mixture was stirred at 100 °C for 8 h and then cooled to 25 °C. The reaction was then quenched by the addition of 3 L of water / ice. The resulting solution was diluted with 3 L of EtOAc. The resulting solution was extracted with 2 × 4 L of ethyl acetate, and the organic layer was washed with 1 × 3 L of brine. The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:1). The crude product was slurried with petroleum ether (3 L). This gave 720 g (71%) of ethyl 2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indole-5-carboxylate as a light brown solid. The solid was dissolved in 3 L of THF, and then Si-DMT (1000 g) was added. The mixture was stirred at 25 °C overnight. The filtrate was collected and evaporated to give 715 g of product (building block 4). LC-MS: (ESI, m / z): 388 [M+H] + 1 H-NMR: (300 MHz, DMSO-d6, ppm): δ 8.44 (d, J = 1.7 Hz, 1H), 8.22 (s, 1H), 8.07 (d, J = 8.5 Hz, 2H), 8.00-7.90 (m, 3H), 7.78 (d, J = 8.7 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 4.03 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H).

[0221] Building Block 5 8-(4-Fluorophenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid (building block 5) [ka] Building Block 5

[0222] A mixture of building block 3 (200 mg; 0.64 mmol), 1-bromo-4-fluorobenzene (135 mg; 0.77 mmol), XPhosPd G2 (56 mg; 0.07 mmol), and Cs2CO3 (629 mg; 1.93 mmol) in 1,4-dioxane (10 mL) was stirred at 120 °C under N2 for 16 h and then filtered. The organic phase was concentrated and purified by chromatography (SiO2, petroleum ether: EtOAc 10:1) to give ethyl 8-(4-fluorophenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate (186 mg; 0.52 mmol; 81%) as a pale yellow solid. To a solution of this ester (180 mg; 0.51 mmol) in EtOH (5 mL) was added 1 M aqueous sodium hydroxide solution (1.70 mL). The mixture was stirred under N at 60 °C for 16 h and then concentrated. H O (15 ml) was added to the residue and adjusted to pH = 1 with 1 N hydrochloric acid. After filtration, the filter cake was washed with H O (10 mL * 3). EtOAc (3 mL) and n-hexane (3 mL) were added to the filter cake and then stirred for 30 min. The suspension was filtered off and the filter cake was dried in vacuo to provide building block 5 (100 mg; 0.31 mmol; 62%) as a white solid. LC-MS: (ESI+, Method A, m / z): 309 [M+H] + . 1 H NMR (400 MHz, DMSO) 12.65 (s, 1H), 8.41 (d, J = 1.4 Hz, 1H), 8.18 (s, 1H), 7.90 (dd, J = 8.7, 1.6 Hz, 1H), 7.83 ¨C 7.77 (m, 2H), 7.54 (d, J = 8.7 Hz, 1H), 7.49 ¨C 7.42 (m, 2H), 4.01 (s, 3H).

[0223] Building Block 6 2-Methyl-8-(4-methylphenyl)-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid (building block 6) [ka] Building Block 6

[0224] A mixture of building block 3 (200 mg; 0.64 mmol), 1-bromo-4-methylbenzene (132 mg; 0.77 mmol), XPhosPd G2 (56 mg; 0.07 mmol), and Cs2CO3 (629 mg; 1.93 mmol) in dioxane-1,4 (10 mL) was stirred at 120 °C under N2 for 16 h. The mixture was filtered, and the organic phase was concentrated and purified by chromatography (SiO2, PE:EA 10:1) to give ethyl 2-methyl-8-(4-methylphenyl)-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate (207 mg; 0.58 mmol; 91%) as a pale yellow solid. To a solution of this ester (200 mg; 0.57 mmol) in EtOH (6 mL) was added 1 M aqueous sodium hydroxide solution (2 mL). The mixture was stirred under N at 60 °C for 2 h and then concentrated. To the residue was added HO (10 mL) and the pH was adjusted to pH = 1 with 1 N hydrochloric acid. The suspension was filtered and the filter cake was washed with HO (15 mL * 3). The filter cake was dried in vacuo to provide building block 6 (160 mg; 0.50 mmol; 87%) as an off-white solid. LC-MS: (ESI+, Method A, m / z): 305 [M+H] + . 1 H NMR (400 MHz, DMSO) 12.60 (s, 1H), 8.40 (d, J = 1.5 Hz, 1H), 8.17 (s, 1H), 7.89 (dt, J = 5.2, 3.3 Hz, 1H), 7.63 (d, J = 8.3 Hz, 2H), 7.54 (d, J = 8.7 Hz, 1H), 7.41 (d, J = 8.2 Hz, 2H), 4.00 (s, 3H), 2.40 (s, 3H).

[0225] Building Block 7 8-{6,6-Difluorospiro[3.3]heptan-2-yl}-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid (building block 7) [ka] Building Block 7

[0226] Step 1. Building block 3 (450.0 mg; 1.419 mmol; 1.00 eq.) and 6,6-difluorospiro[3.3]heptan-2-one (311 mg; 2.128 mmol; 1.50 eq.) were charged to a vial and dissolved in anhydrous DCM (5.625 mL). To the brown solution was added glacial acetic acid (227 μL; 3.972 mmol; 2.80 eq.). The reaction mixture was stirred under argon at 40 °C (heating block temperature) for 1 h. The vial was then cooled to room temperature, and sodium triacetoxyborohydride (633 mg; 2.837 mmol; 2.00 eq.) was added, causing gas evolution. Stirring was continued at room temperature under equal pressure for 2 h. Since the reaction was not complete, additional 6,6-difluorospiro[3.3]heptan-2-one (311 mg; 2.128 mmol; 1.50 eq.), glacial acetic acid (227 μL; 3.972 mmol; 2.80 eq.), and sodium triacetoxyborohydride (633 mg; 2.837 mmol; 2.00 eq.) were added, and stirring was continued at room temperature for 16.5 h. The reaction mixture was neutralized with 5 mL of saturated ammonium chloride solution, diluted with 10 mL of water, and extracted three times with ethyl acetate (10 mL each). The colorless aqueous phase (pH = 5) did not contain any product and was discarded. The combined organic phase (brown) was dried over sodium sulfate, filtered with suction, and evaporated in vacuo. The crude product (1.2491 g brown oil) was fused onto Isolute HM-N® and purified by Isco CombiFlash Rf® (flash chromatography, 12 g SiO2, 0-60% EE). Fractions containing the desired product were combined and evaporated in vacuo. The crude product (971.7 mg yellow-brown oil) was fused onto Isolute HM-N® and purified by Isco CombiFlash Rf® (flash chromatography, 24 g SiO2, 0-20% EE).Fractions containing the desired product were combined and evaporated in vacuo to give ethyl 4-chloro-3-[3-({6,6-difluorospiro[3.3]heptan-2-yl}amino)-1-methyl-1H-pyrazol-4-yl]benzoate (449.4 mg; 1.073 mmol; 68%) as a yellow oil, which crystallized overnight to give a yellow solid. LC-MS (ESI+, Method 10): t R = 1.70 min, m / z 410.1 [M+H] + .

[0227] Step 2. The product from the previous step (399.4 mg; 0.954 mmol; 1.00 eq.) and cesium carbonate (622 mg; 1.907 mmol; 2.00 eq.) were charged into a vial and suspended in anhydrous 1,4-dioxane (6 mL). The pale yellow suspension was placed under an argon atmosphere by three cycles of evacuation, degassing in an ultrasonic bath, and argon flushing. XPhos Pd G4 95% (129.6 mg; 0.143 mmol; 0.15 eq.) was then added. The pale yellow suspension was stirred under an argon atmosphere at 110 °C (heating block temperature) for 17 h. The reaction mixture was filtered through 0.6 g Celite. The residue was washed once with 10 mL ethyl acetate. The black residue was then discarded. The black filtrate was diluted with 10 mL deionized water and 5 mL saturated sodium chloride solution (NaCl), and the phases were separated. The aqueous phase was extracted twice with ethyl acetate (10 mL each). The colorless aqueous phase (pH = 6) did not contain any product and was discarded. The combined organic phases (brown) were dried over sodium sulfate (NaSO), suction filtered, and evaporated in vacuo. The crude product (554.4 mg dark brown oil) was coupled onto Isolute HM-N® and purified by Isco CombiFlash Rf® (flash chromatography, 12 g SiO2, 0-20% EE). Pure fractions containing the desired product were combined and evaporated in vacuo to give ethyl 8-{6,6-difluorospiro[3.3]heptan-2-yl}-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate (369,400 mg; 0,915 mmol; 85,28%) as a brown oil. LC-MS (ESI+, method 10): t R = 1.83 min, m / z 374.1 [M+H] + .

[0228] Step 3. The product from the previous step (369,400 mg; 0.915 mmol; 1.00 eq.) was charged into a vial and dissolved in tetrahydrofuran (3.7 mL). Water (1.85 mL) was added to the yellow-brown solution, causing the formation of a two-phase system. Aq. lithium hydroxide solution (0.035 mL; 3.660 mmol; 4.00 eq.) was then added. The yellow-brown suspension was stirred at 65 °C (heating block temperature) for 16 h, followed by another portion of LiOH solution (0.035 mL; 3.660 mmol; 4.00 eq.) and stirring at 65 °C for 47 h. The cooled reaction mixture was diluted with 50 mL of deionized water and extracted three times with tert-butyl methyl ether (10 mL each). The combined organic phase was washed three times with a mixture of water (10 mL each) and sodium hydroxide solution (NaOH, c = 1 mol / L, 1 mL each). The colorless organic phase did not contain any of the desired product and was discarded. The off-white aqueous phase (suspension) was acidified with 9 mL of hydrochloric acid (HCl, c = 2 mol / L), which thickened the suspension. It was then extracted three times with ethyl acetate (20 mL each). The colorless aqueous phase (pH = 1) did not contain any product and was discarded. The combined organic phases (light yellow) were dried over sodium sulfate (Na2SO4), suction filtered, and evaporated in vacuo to give 8-{6,6-difluorospiro[3.3]heptan-2-yl}-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid (261,300 mg; max. 0,712 mmol; max. 77.83%) as a crude product with insufficient purity. A portion of this crude material (61.3 mg) was purified by RP-HPLC, followed by extraction of the resulting target fraction with EtOAc (3 × 10 mL). The combined organic phases were dried over sodium sulfate (NaSO), suction filtered, and evaporated in vacuo.The beige residue was suspended in 3 mL of methanol, centrifuged under vacuum at 55 °C for 45 min, and dried in a vacuum drying oven at 60 °C and 10-20 mbar for 19 h to give 8-{6,6-difluorospiro[3.3]heptan-2-yl}-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid building block 7 (29.100 mg; 0.084 mmol; 9.21%) as an off-white solid. LC-MS (ESI+, Method 10): t R = 1.50 min, m / z 346.1 [M+H] + .

[0229] TEAD Ligand 1 - Sodium Carboxylate and Free Acid Forms Sodium 2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indole-5-carboxylate (TEAD Ligand 1) and 2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indole-5-carboxylic acid (TEAD Ligand 1 free acid) [ka] TEAD ligands

[0230] A solution of ethyl 2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indole-5-carboxylate (building block 4) (1 g, 2.58 mmol) in 4:1 EtOH / HO (10 mL) and NaOH (0.11 g, 2.75 mmol) was placed in a 25-mL three-neck round-bottom flask purged and maintained under an inert atmosphere of nitrogen. The reaction mixture was stirred at 40 °C for 3 h. After concentrating the reaction mixture, it was diluted with 20 mL of HO. The pH of the solution was adjusted to 3 with HCl (1 N) and then extracted with 2 × 50 mL of ethyl acetate. After evaporation, the crude product was redissolved in 20 mL of acetone, and NaCO (0.27 g, 2.54 mmol) was added. The resulting solution was stirred at 40 °C for 2 h, the excess NaCO was filtered off, and the filtrate was concentrated. This afforded 1 g (99%) of sodium 2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indole-5-carboxylate (TEAD ligand 1) as a light brown solid. LC-MS: (ES, m / z): 360 [M+1] + 1 H-NMR (300 MHz, DMSO-d6, ppm): δ 8.32 (d, J = 1.5 Hz, 1H), 8.19-8.04 (m, 3H).

[0231] The free acid (TEAD Ligand 1 free acid) can be accessed in the following manner: To the residue, HO (15 mL per 200 mg of carboxylate) was added and adjusted to pH = 1 with 1 M aq. hydrochloric acid. After filtration, the filter cake was washed with HO (10 mL per 200 mg of carboxylate * 3). To the filter cake, EtOAc (3 mL per 200 mg of carboxylate) and n-hexane (3 mL per 200 mg of carboxylate) were added, followed by stirring for 30 min. The suspension was filtered off, and the filter cake was dried in vacuo to provide the free acid from the carboxylate form in quantitative yield.

[0232] TEAD Ligand 2 2-Methyl-4-[4-(trifluoromethyl)phenyl]-2H,4H-[1,2,3]triazolo[4,5-b]indole-7-carboxylic acid (TEAD ligand 2) [ka] TEAD Ligand 2

[0233] Step 1. To a solution of 2-methyl-2H-1,2,3-triazol-4-amine (commercially available from Enamine, 9.3 g; 90.00 mmol; 1.20 eq.) in anhydrous DMSO (100.0 mL) was added preparative-grade potassium tert-butylate (25.5 g; 224.99 mmol; 3.00 eq.) under argon. The reaction was stirred at rt for 0.5 h. To the brown precipitate was added 3-bromo-4-fluorobenzonitrile (commercially available from ABCR GmbH, 15.0 g; 75.00 mmol; 1.00 eq.) in anhydrous DMSO (100.0 mL) dropwise, using an ice bath to maintain the internal temperature below 25° C. After the addition was complete, the reaction was stirred at 50° C. for 3 h. The brown suspension was poured into approximately 2 L water and the resulting white precipitate was vacuum filtered, washed with approximately 2×300 ml water and dried in vacuo (50° C., 3 mbar) to give 3-bromo-4-[(2-methyl-2H-1,2,3-triazol-4-yl)amino]benzonitrile (15.0 g, 45.96 mmol, 85%).

[0234] Step 2. To 3-bromo-4-[(2-methyl-2H-1,2,3-triazol-4-yl)amino]benzonitrile (15.0 g; 45.95 mmol; 1.00 eq.) in anhydrous NMP (200.0 ml) was added tetrabutylammonium acetate (52.3 g; 170.03 mmol; 3.70 eq.). The reaction was purged with argon, and Pd(PPh3)2Cl2 (3.3 g; 4.60 mmol; 0.10 eq.) was added. The reaction was stirred at 120 °C for 16 h. HPLC-MS indicated the formation of the desired product as the major compound. The brown suspension was vacuum filtered over Celite, and the mother liquor was poured into 1.5 L of water. The resulting precipitate was vacuum filtered, and the filter cake was washed with water. The aqueous filtrate was discarded. The brown solid was suspended in MTBE / MeCN 1:1 v / v (approximately 200 mL), and the insoluble solid was vacuum filtered, washed with MTBE, and dried in vacuo at 50 °C to give 2-methyl-2H,4H-[1,2,3]triazolo[4,5-b]indole-7-carbonitrile (4.7 g; 23.83 mmol; 52%). The organic filtrate was evaporated to dryness, and the residue was triturated with MTBE / MeCN 1:1 v / v (approximately 100 mL), and the insoluble solid was vacuum filtered, washed with MTBE, and dried in vacuo at 50 °C for 1 h to give 2-methyl-2H,4H-[1,2,3]triazolo[4,5-b]indole-7-carbonitrile (1.6 g; 7.84 mmol; 17%).

[0235] Step 3. To a brown suspension of 2-methyl-2H,4H-[1,2,3]triazolo[4,5-b]indole-7-carbonitrile (4.7 g; 23.83 mmol; 0.75 eq.) in anhydrous 1,4-dioxane (150.0 mL), 4-iodobenzotrifluoride (5.6 mL; 38.01 mmol; 1.20 eq.), N,N'-dimethylethylenediamine, 99% (3.4 mL; 31.7 mmol; 1.0 eq.), CsCO (20.8 g; 63.34 mmol; 2.00 eq.), and CuI (3.0 g; 15.84 mmol; 0.50 eq.) were added under argon. The reaction was stirred at 100 °C for 16 h. The reaction was filtered over Celite and washed with 200 mL EtOAc. The mother liquor was washed 3x with 150 mL water, dried over NaSO, and evaporated to dryness. The resulting solid was triturated with EtOAc / MTBE (approximately 150 mL). The solid was vacuum filtered, washed with hexane, MTBE, and dried under vacuum to give 2-methyl-4-[4-(trifluoromethyl)phenyl]-2H,4H-[1,2,3]triazolo[4,5-b]indole-7-carbonitrile (9.0 g, 26.13 mmol, 83%).

[0236] Step 4. To a suspension of 2-methyl-4-[4-(trifluoromethyl)phenyl]-2H,4H-[1,2,3]triazolo[4,5-b]indole-7-carbonitrile (9.0 g; 26.24 mmol; 1.00 eq.) in ethanol (140.0 ml) / water (140.0 ml), powdered sodium hydroxide (10.8 g; 262.39 mmol; 10.00 eq.) was added and stirred at 80 °C for 16 h. The ethanol was evaporated. The residue was acidified with aq. HCl 37%, diluted with 400 ml EtOAc, washed 3x with 150 mL water, dried over Na2SO4, and evaporated to dryness. The residue was triturated with MTBE / heptane, the solid was vacuum filtered, the filter cake was washed with heptane and dried under vacuum to provide TEAD ligand 2, 2-methyl-4-[4-(trifluoromethyl)phenyl]-2H,4H-[1,2,3]triazolo[4,5-b]indole-7-carboxylic acid (8.6 g, 23.73 mmol, 90%). LC-MS (ESI+, Method 1): R = 1.76 min, m / z 361.0 [M+H] + . 1 H NMR (500 MHz, DMSO) d 12.97 (s, 1H), 8.53 (d, J = 1.7 Hz, 1H), 8.11 - 8.04 (m, 4H), 8.02 (d, J = 8.6 Hz, 2H), 7.93 (d, J = 8.8 Hz, 1H), 4.38 (s, 3H).

[0237] VHL-Lig (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide (VHL-Lig) [ka] Step 1. To a stirred mixture of (2S,4R)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-carboxylic acid (commercially available from Pharmaron, 5.00 g; 13.79 mmol; 1.00 eq.), 1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methanamine hydrochloride (commercially available from Pharmaron, 5.24 g; 20.69 mmol; 1.50 eq.) in DCM (20.00 mL) was added EDCI (5.57 g; 27.58 mmol; 2.00 eq.), EtN (6.05 mL; 41.38 mmol; 3.00 eq.) at room temperature. The resulting mixture was stirred at 25 °C for 16 h.

[0238] The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (1 × 100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to provide tert-butyl N-[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate (6.95 g; 11.90 mmol; 86.3%) as a yellow oil.

[0239] Step 2. To a stirred mixture of tert-butyl N-[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate (5.90 g; 10.10 mmol; 1.00 eq.) in DCM (30.00 ml) was added TFA (10.00 ml) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with HO at room temperature. The mixture was brought to pH 7 with NaHCO (aq.). The resulting mixture was extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (1 x 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide (VHL Lig) (4.16 g; 9.29 mmol; 92.0%) was obtained as a yellow solid. (ESI+, Method 7): R = 0.96 min, m / z 431.0 [M+H] + .

[0240] Intermediate 1 N-{2-[2-(2-aminoethoxy)ethoxy]ethyl}-2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxamide TFA salt (Intermediate 1) [ka]

[0241] An 8 mL vial was charged with TEAD ligand 1 (50 mg; 0.14 mmol) dissolved in dry N,N-dimethylformamide (3 mL) under Ar. This was followed by the addition of 1-(t-butyloxycarbonyl-amino)-3,6-dioxa-8-octanamine (0.07 mL; 0.28 mmol), 4-methylmorpholine (61 μL; 0.56 mmol), and finally HATU (63 mg; 0.17 mmol). The vial was capped and stirred under Ar at RT for 18 h. The reaction mixture was partitioned between MTBE and water, the phases were separated, and the aqueous phase was extracted with additional MTBE (2 × 3 mL). The organic phase was dried over NaSO, filtered, and concentrated by rotary evaporation. The resulting residue was purified by flash chromatography (4 g SiO, 0-10% MeOH in DCM) to give the product as a colorless oil (79 mg, 0.13 mmol, 96%). 59 mg of this product was dissolved in DCM (1 mL) followed by the addition of TFA (1 mL) under stirring. After 30 min, evaporation of the solvent delivered intermediate 1 (49 mg, 0.08 mmol, 81%), which slowly solidified at RT. LC-MS (ESI+, Method Sunfire): R = 1.75 min, m / z 489.9 [M+H] + .

[0242] Intermediate 2 5-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]amino}pentanoic acid (Intermediate 2) [ka] Intermediate 2

[0243] Lenalidomide (commercially available) (300 mg; 1.10 mmol) was dissolved in 1-methyl-2-pyrrolidone (NMP) (2 mL) in a 5 mL microwave vial, followed by the addition of 5-bromopentanoic acid tert-butyl ester (0.26 mL; 1.32 mmol) and finally DIPEA (0.59 mL; 3.30 mmol). The vial was capped and the reaction mixture was stirred at 170 °C in a microwave reactor for 1 h and 15 min. The reaction mixture was diluted with water (2 mL). The crude mixture was injected into an MS-coupled preparative RP-HPLC system for purification. The target fraction was lyophilized to give tert-butyl-5-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]amino}pentanoate (167 mg; 0.40 mmol) as a white powder, which was deprotected by dissolving in DCM (3 mL) followed by the addition of TFA (3 mL). The reaction mixture was stirred at RT for 3 h and the volatiles were evaporated to give intermediate 2 as a colorless oil (50 mg, 0.14 mmol), which was used directly in the next step. LC-MS (ESI+, Method Sunfire): R = 1.87 min, m / z 359.9 [M+H] + .

[0244] Intermediate 3 4-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]amino}butanoic acid (Intermediate 3) [ka] Intermediate 3

[0245] Lenalidomide (300 mg; 1.10 mmol) was dissolved in 1-methyl-2-pyrrolidone (NMP) (5 mL), followed by the addition of tert-butyl 4-bromobutanoate (0.25 mL; 1.32 mmol) and N-ethyldiisopropylamine (iPrNEt) (0.56 mL; 3.30 mmol). The vial was capped and heated in a microwave reactor at 110 °C for 12 h. The reaction mixture was purified by preparative HPLC, and the target fraction was lyophilized to give tert-butyl 4-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]amino}butanoate (88 mg; 0.22 mmol, 20%) as a white lyophilisate. This intermediate was deprotected in 33% TFA in DCM (6 mL) at RT for 1 h to give intermediate 3 (quant.) after triple rotary evaporation from the DCM solution. LC-MS (ESI+, Method Sunfire): R = 1.81 min, m / z 345.9 [M+H] + .

[0246] Intermediate 4 7-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]amino}heptanoic acid (Intermediate 4) [ka] Intermediate 4

[0247] A 5 mL microwave reactor was charged with lenalidomide (300 mg; 1.10 mmol) and dissolved in 1-methyl-2-pyrrolidone (NMP) (5.00 mL), followed by the addition of N-ethyldiisopropylamine (iPrNEt) (0.56 mL; 3.30 mmol) and tert-butyl 7-bromoheptanoate (368 mg; 1.32 mmol). The vial was capped and heated in a microwave reactor at 110 °C for 12 h. The cooled reaction mixture was used for purification by preparative RP-HPLC-MS in two consecutive runs (2.5 mL injections) to give tert-butyl 7-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]amino}heptanoate (167 mg, 0.38 mmol, 34%). This was deprotected by treatment with TFA (10 mL) in DCM (15 mL) at RT for 18 h. Volatiles were removed by rotary evaporation to provide intermediate 4 (146 mg, 0.38 mmol, quant.). LC-MS (ESI+, Method Sunfire): R = 2.04 min, m / z 387.9 [M+H] + .

[0248] Intermediate 5 6-{[(2S)-1-[(2S,4S)-4-Hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}hexanoic acid (Intermediate 5) [ka]

[0249] In a 50 mL RBF with a stir bar, pimelic acid (186 mg; 1.16 mmol) and (2S,4S)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide (MeVHL-Lig, commercially available from Sigma-Aldrich or Ambeed) (100 mg; 0.23 mmol) were placed. The mixture was suspended in dichloromethane (DCM) (5 mL) and tetrahydrofuran (THF) (5 mL), followed by the addition of triethylamine (0.11 mL; 0.82 mmol). The resulting solution was cooled to 0 °C, and HATU (106 mg; 0.28 mmol) was added. The reaction mixture was stirred at 0 °C for 2 h and then at RT overnight. The reaction was quenched with water and the mixture was concentrated by rotary evaporation. The remaining residue was dissolved in DMSO and purified by preparative RP-HPLC-MS to give intermediate 5 (70 mg; 0.12 mmol; 53%) after lyophilization. LC-MS (ESI+, Method Sunfire): R = 2.08 min, m / z 572.8 [M+H] + .

[0250] Intermediate 6 6-{[(2S)-1-[(2S,4R)-4-Hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl}pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}hexanoic acid (Intermediate 6) [ka]

[0251] Pimelic acid (166 mg; 1.04 mmol) and (2S,4R)-1-(S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (commercially available from Sigma-Aldrich or Ambeed) (100 mg; 0.21 mmol) were combined in a 50 mL RBF with a stir bar and dissolved in dichloromethane (DCM) (5 mL) and tetrahydrofuran (THF) (5 mL), followed by the addition of triethylamine (0.10 mL; 0.74 mmol). The mixture was cooled to 0° C. in an ice bath, and HATU (95 mg; 0.25 mmol) was added with stirring. The reaction mixture was allowed to warm to RT overnight. Volatiles were removed by rotary evaporation, and the remaining residue was partially redissolved in DMSO (2 mL). The cloudy solution was filtered through a 2 μm filter, and the filtrate was used directly for injection into a preparative RP-HPLC-MS system. The target fraction was lyophilized to give intermediate 6 (77 mg; 0.13 mmol, 63%) as a white lyophilizate. LC-MS (ESI+, Method Sunfire): R = 2,10 min, m / z 586,6 [M+H] + .

[0252] Intermediate 7 tert-Butyl 3-(4-hydroxy-1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-2,6-dioxopiperidine-1-carboxylate (Intermediate 7) [ka] Intermediate 7

[0253] 4-Hydroxythalidomide (1.2 g; 4.38 mmol) was combined with DMAP (535 mg; 4.38 mmol) in 1,4-dioxane (40 ml) and Boc anhydride (1.9 g; 8.75 mmol) addition This was followed by: reactionThe mixture was stirred at RT for 3 h. Piperidine (0.43 ml; 4.38 mmol) was added and the reaction mixture was stirred for 1 h. The reaction mixture was partitioned between water and EtOAc, and the organic phase was filtered over Na2SO4, followed by purification by flash chromatography to give intermediate 7 (1.22 g; 3.26 mmol) as an orange solid. LC-MS (ESI+, Method Sunfire): t R = 2,28 min, m / z 274,9 [M-Boc+H] + .

[0254] Intermediate 8 N-(14-Hydroxy-3,6,9,12-tetraoxatetradecan-1-yl)-2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxamide (Intermediate 8) [ka] Intermediate 8

[0255] TEAD ligand 1 (112 mg; 0.31 mmol) and 14-amino-3,6,9,12-tetraoxatetradecan-1-ol (148 mg; 0.63 mmol) were dissolved in N,N-dimethylformamide (1 ml) in an 8 mL vial with a stir bar, followed by the addition of 4-methylmorpholine (138 μl; 1.25 mmol) and finally HATU (143 mg; 0.38 mmol). The reaction mixture was stirred at RT for 18 h and then directly purified by preparative RP-HPLC-MS to give intermediate 8 (235 mg; 0.39 mmol quant.) after lyophilization. LC-MS (ESI+, Method Sunfire): R = 2.31 min, m / z 578.8 [M+H] + .

[0256] Intermediate 9 N-(2-aminoethyl)-2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxamide (Intermediate 9) [ka] Intermediate 9

[0257] TEAD ligand 1 (500 mg; 1.39 mmol), N-Boc-ethylenediamine (446 mg; 2.78 mmol), HATU (635 mg; 1.67 mmol), and 4-methylmorpholine (612 μL; 5.57 mmol) were dissolved in N,N-dimethylformamide (25 mL) and stirred overnight at room temperature. Water was added, and the resulting precipitate was vacuum filtered. The filter cake was dried under vacuum to provide Boc-intermediate 9 (571 mg; 1.14 mmol, 82%). LC-MS (ESI+, Method Chromolith): R = 1.81 min, m / z 502.00 [M+H] + This material (571 mg; 1.14 mmol) was deprotected in DCM (20 mL) using 4 M HCl (7.12 mL of a solution in 1,4-dioxane) at RT. The resulting precipitate was filtered under vacuum and the filter cake was washed with MTBE, then dried under vacuum to provide intermediate 9 (429 mg; 1.07 mmol, 94%). LC-MS (ESI+, Method Chromolith): R = 1.32 min, m / z 402 [M+H] + .

[0258] Intermediate 10 N-[(2R)-1-aminopropan-2-yl]-8-(4-fluorophenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxamide (Intermediate 10) [ka] Intermediate 10

[0259] To a solution of building block 5 (50 mg; 0.16 mmol) in DMF (3 mL) was added tert-butyl N-[(2R)-2-aminopropyl]carbamate (commercially available from Enamine Ltd., 59 mg; 0.32 mmol), EDC hydrochloride (62 mg; 0.32 mmol), HOBt hydrate (25 mg; 0.16 mmol), and 4-methylmorpholine (0.1 mL). The reaction was stirred overnight at RT and then evaporated to dryness to give crude Boc-intermediate 10 (185 mg; 0.18 mmol, quant.). All of this material was deprotected in DCM (3 mL) using 4 M HCl (1.58 mL of a solution in 1,4-dioxane) at RT. The resulting precipitate was filtered under vacuum, and the filter cake was washed with MTBE and then dried under vacuum. The crude residue was purified by flash chromatography to provide intermediate 10 (78 mg; 0.21 mmol, 85%). LC-MS (ESI+, Method Chromolith): R = 1.20 min, m / z 366.0 [M+H] + .

[0260] Intermediate 11 N-[(2R)-1-aminopropan-2-yl]-2-methyl-8-(4-methylphenyl)-2H,8H-pyrazolo[3,4-b]indole-5-carboxamide (Intermediate 11) [ka] Intermediate 11

[0261] To a solution of building block 6 (50 mg; 0.16 mmol) in DMF (3 ml) was added tert-butyl N-[(2R)-2-aminopropyl]carbamate (commercially available from Enamine Ltd., 60 mg; 0.33 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (63 mg; 0.33 mmol), 1-hydroxybenzotriazole hydrate (25 mg; 0.16 mmol), and 4-methylmorpholine (0.1 mL). The reaction was stirred at RT overnight and then evaporated to dryness. All of this material was dissolved in dichloromethane (3 ml) and added to HCl (4.0 M in dioxane; 1.80 mL) at RT overnight. The resulting precipitate was filtered off, and the filter cake was washed with MTBE and dried in vacuo. The crude residue was purified by flash column chromatography to give intermediate 11 (65 mg; 0.18 mmol, 62%).

[0262] Intermediate 12 1-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]carbamoyl}-2,5,8,11,14-pentaoxahexadecan-16-oic acid (intermediate 12) [ka]

[0263] To a solution of NaH (9.06 g, 226.0 mmol, 60.0% purity, 2.20 eq.) in DMF (200 mL) was added tetraethylene glycol (20.0 g, 103.0 mmol, 17.7 mL, 1.00 eq.) stirred at 15 °C for 2 h. The mixture was then added dropwise to a solution of tert-butyl-2-bromoacetate (80.3 g, 411.0 mmol, 60.9 mL, 4.00 eq.) in DMF (80 mL) at 0 °C, stirred for 30 min, and then warmed to 15 °C for 2 h. The reaction mixture was added sat. NH4Cl (500 mL) and extracted with ethyl acetate (100 mL x 2). The organic layer was washed with sat. NaCl (50 mL x 3). The organic layer was then dried over Na2SO4 and concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate=1:0 to 3:1) to give 3,6,9,12,15-pentaoxaheptadecanedioic acid di-tert-butyl ester (20.0 g, 47.3 mmol, 46.0% yield) as a yellow oil.

[0264] A solution of the ester (20.0 g, 47.3 mmol, 1.00 eq) in HCl / dioxane (4 M, 50 mL, 4.23 eq) was stirred for 10 h at 15° C. The reaction mixture was concentrated to give 3,6,9,12,15-pentaoxaheptadecanedioic acid (12.0 g, 38.7 mmol, 81.7% yield) as a dark brown oil. To a solution of 3,6,9,12,15-pentaoxaheptadecanedioic acid (6.00 g, 19.3 mmol, 1.00 eq) in DCM (30 mL) was added (COCl) (9.82 g, 77.4 mmol, 6.77 mL, 4.00 eq) and stirred at 40 °C for 1 hr, then concentrated and dissolved in THF (30 mL). 4-Aminothalidomide (3.70 g, 13.5 mmol, 0.700 eq) in THF (30 mL) was then added to the reaction and stirred at 70 °C for 3 hr. The reaction mixture was filtered and the cake was washed with MeOH (5 mL × 2), and the filtrate was concentrated to give a residue. The residue was purified by preparative HPLC to give intermediate 12 (2.05 g, 3.44 mmol, 17.8% yield, 95.3% purity) as a yellow solid. LCMS: m / z(M+H+ ) = 566.4

[0265] Intermediate 13 2-{2-[2-({[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]carbamoyl}methoxy)ethoxy]ethoxy}acetic acid (Intermediate 13) [ka]

[0266] To a solution of NaH (16.6 g, 414.0 mmol, 60.0% purity, 2.20 eq) in DMF (200 mL) was added diethylene glycol (20.0 g, 188.0 mmol, 17.9 mL, 1.00 eq) stirred at 15 °C for 2 hr, and the mixture was then added dropwise to a solution of tert-butyl-2-bromoacetate (147.0 g, 753.0 mmol, 111.0 mL, 4.00 eq) in DMF (80 mL) at 0 °C, stirred for 30 min, and then warmed to 15 °C for 2 hr. fartThe mixture was added with sat. NH4Cl (500 mL) and extracted with ethyl acetate (100 mL x 2). The organic layer was washed with sat. NaCl (50 mL x 3), then dried over Na2SO4 and concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 1:0 to 3:1) to give tert-butyl 2-(2-{2-[2-(tert-butoxy)-2-oxoethoxy]ethoxy}ethoxy)acetate (25.0 g, 74.8 mmol, 39.7% yield) as a yellow oil. A solution of tert-butyl 2-(2-{2-[2-(tert-butoxy)-2-oxoethoxy]ethoxy}ethoxy)acetate (25.0 g, 74.8 mmol, 1.00 eq) in HCl (6 M, 50 mL, 4.01 eq) was stirred for 3 h at 15 °C. The reaction mixture was concentrated to give 2-{2-[2-(carboxymethoxy)ethoxy]ethoxy}acetic acid (13.0 g, 58.5 mmol, 78.3% yield) as a brown oil. To a solution of 2-{2-[2-(carboxymethoxy)ethoxy]ethoxy}acetic acid (6.00 g, 27.0 mmol, 1.00 eq) in DCM (20 mL) was added (COCl) (13.7 g, 108.0 mmol, 9.46 mL, 4.00 eq) and stirred at 40 °C for 1 hr, then concentrated and dissolved in THF (20 mL). 4-aminothalidomide (5.17 g, 18.9 mmol, 0.700 eq) in THF (20 mL) was then added to the reaction and stirred at 70 °C for 3 hr. LCMS showed the desired MS was detected. Concentration of the reaction mixture gave a residue. The reaction mixture was purified by preparative HPLC to give intermediate 13 (1.94 g, 3.97 mmol, 14.7% yield, 97.6% purity) as an off-white solid. LC-MS: m / z (M+H + ) = 478.1

[0267] Intermediate 14 1-{[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}-2,5,8,11-tetraoxatridocan-13-oic acid (Intermediate 14) [ka]

[0268] To a solution of NaH (11.7 g, 293.0 mmol, 60.0% purity, 2.20 eq) in DMF (200 mL) was added tetraethylene glycol (20.0 g, 133.0 mmol, 17.9 mL, 1.00 eq) stirred at 15 °C for 2 h. The mixture was then added dropwise to a solution of tert-butyl-2-bromoacetate (103.0 g, 532.0 mmol, 78.7 mL, 4.00 eq) in DMF (80 mL) at 0 °C, stirred for 30 min, and then warmed to 15 °C for 2 h. The reaction mixture was added sat. NH4Cl (500 mL) and extracted with ethyl acetate (100 mL x 2). The organic layer was washed with sat. NaCl (50 mL x 3). The organic layer was then dried over Na2SO4 and concentrated to give a residue. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate = 1:0 to 3:1) to give tert-butyl 2-(2-{2-[2-(tert-butoxy)-2-oxoethoxy]ethoxy}ethoxy)acetate (25.0 g, 66.1 mmol, 49.6% yield) as a yellow oil. A solution of tert-butyl 2-(2-{2-[2-(tert-butoxy)-2-oxoethoxy]ethoxy}ethoxy)acetate (25.0 g, 66.1 mmol, 1.00 eq) in HCl (6 M, 50 mL, 4.54 eq) was stirred at 15 °C for 3 h. The reaction mixture was concentrated to give 2-{2-[2-(carboxymethoxy)ethoxy]ethoxy}acetic acid (15.0 g, 56.3 mmol, 85.3% yield) as a brown oil.

[0269] To a mixture of 2-{2-[2-(carboxymethoxy)ethoxy]ethoxy}acetic acid (5.70 g, 21.4 mmol, 2.50 eq) in DMF (10 mL), HATU (4.88 g, 12.9 mmol, 1.50 eq) and DIEA (3.32 g, 25.7 mmol, 4.48 mL, 3.00 eq) were added and stirred at 15° C. for 0.5 hr, followed by addition of (2S,4R)-1-[(S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[4-(4-methylthiazol-5-yl)benzyl]pyrrolidine-2-carboxamide hydrochloride (4.00 g, 8.56 mmol, 1.00 eq, HCl) in DMF (10 mL) and stirring at 15° C. for 0.5 hr. The reaction mixture was filtered and the filtrate was collected to give a residue. The residue was purified by preparative HPLC to give intermediate 14 (2.31 g, 3.21 mmol, 37.5% yield, 94.3% purity) as a yellow gum.

[0270] Intermediate 15 [ka] Step 1. In a reaction vial with a stir bar, 2-(2,6-dioxo-piperidin-3-yl)-4-fluoroisoindoline-1,3-dione (45.0 mg; 0.163 mmol; 1.00 eq.), tert-butyl 20-amino-3,6,9,12,15,18-hexaoxaikos-1-yl (100.0 mg; 0.236 mmol; 1.45 eq.), and N-ethyldiisopropylamine (73.0 μL; 0.410 mmol; 2.52 eq.) were dissolved in 1-methyl-2-pyrrolidone (1.00 mL; 10.390 mmol; 63.78 eq.) and stirred at 160° C. for 1 h in a Biotage® microwave reactor. The reaction mixture was concentrated under reduced pressure, dissolved in DMSO, and purified by preparative HPLC-MS; the combined product fractions were concentrated under reduced pressure to provide tert-butyl N-(20-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}-3,6,9,12,15,18-hexaoxaicosan-1-yl)carbamate (83.7 mg; 0.109 mmol) as an amorphous residue. LC-MS (ESI+, Method 8): R = 0.49 min, m / z 681.2 [M+H] + .

[0271] Step 2. In an 8 mL reaction vial with a stir bar, tert-butyl N-(20-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}-3,6,9,12,15,18-hexaoxaicosan-1-yl) (83.70 mg; 0.116 mmol; 1.00 eq.) was suspended in a 4 M solution of hydrogen chloride in dioxane (500.00 μL; 2.000 mmol; 17.19 eq.) and stirred at room temperature for 18 h. The mixture was absorbed onto Isolute sorbent and purified by flash chromatography, and the product fractions were concentrated under reduced pressure to provide 4-(21-amino-4,7,10,13,16,19-hexaoxa-1-azaheneicosan-1-yl)-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione dihydrochloride (122.00 mg; 0.186 mmol) as a clear oily residue. LC-MS (ESI+, Method 8): R = 0.34 min, m / z 581.4 [M+H] + .

[0272] Intermediate 16 [ka] In a microwave reaction vial, tert-butyl 3-(5-hydroxy-1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-2,6-dioxopiperidine-1-carboxylate (Intermediate 17) (100.00 mg; 0.251 mmol; 1.00 eq.), tert-butyl-N-(14-hydroxy-3,6,9,12-tetraoxatetradecan-1-yl)carbamate (commercially available from Activate Scientific GmbH, 110.00 mg; 0.310 mmol; 1.23 eq.), and polymer-conjugated triphenylphosphine (392.00 mg; 0.627 mmol; 2.50 eq.) were dissolved in tetrahydrofuran (4.00 mL) at 0° C., followed by diisopropyl azodicarboxylate (123.00 μL; 0.627 mmol; 2.50 eq.). was added. This was stirred at room temperature for 3 days. The reaction mixture was filtered, absorbed onto Isolute sorbent, purified by flash chromatography, and the combined product fractions were concentrated under reduced pressure to provide tert-butyl 3-{5-[(14-{[(tert-butoxy)carbonyl]amino}-3,6,9,12-tetraoxatetradecan-1-yl)oxy]-1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl}-2,6-dioxopiperidine-1-carboxylate (42.0 mg; 0.0076 mmol) as a yellow residue. LC-MS (ESI+, Method 8): R = 0.31 min, m / z 494.3 [M+H] + .

[0273] Intermediate 17 [ka] In a 250 mL round-bottom flask equipped with a stir bar and drying tube, 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (3.00 g; 10.94 mmol; 1.00 eq.) and 4-(dimethylamino)pyridine (1.34 g; 10.94 mmol; 1.00 eq.) were dissolved in DMF (97.50 mL), followed by the addition of di-tert-butyl dicarbonate (4.68 mL; 21.880 mmol; 2.00 eq.). The reaction mixture was stirred at room temperature for 1 hour. Piperidine (1.08 mL; 10.940 mmol; 1.00 eq.) was added, and the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was extracted with deionized water and ethyl acetate. The organic phase was filtered over NaSO, absorbed onto Isolute sorbent, purified by flash chromatography, and the combined product fractions were concentrated under reduced pressure to provide tert-butyl 3-(5-hydroxy-1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-2,6-dioxopiperidine-1-carboxylate (2.77 g; 6.948 mmol) as a yellow solid. LC-MS (ESI+, Method 8): R = 0.47 min, m / z 375.2 [M+H] + .

[0274] Intermediate 20 [ka] In an 8 mL vial with a stir bar, TEAD ligand 1 free acid (106.70 mg; 0.30 mmol; 1.00 eq.) was dissolved in DMF (1.00 mL). 7-Azido-1-heptanamine (46.39 mg; 0.30 mmol; 1.00 eq.), 4-methylmorpholine (0.13 mL; 1.19 mmol; 0.00 eq.), and HATU (135.50 mg; 0.36 mmol; 1.20 eq.) were added. The reaction mixture was stirred at RT. The crude mixture was purified by preparative RP-HPLC-MS. Lyophilization of the target fraction provided N-(7-azidoheptyl)-2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxamide (69.00 mg; 0.14 mmol) as a white solid. LC-MS (ESI+, Method 3): R = 2.81 min, m / z 497.7 [M+H] + .

[0275] Intermediate 21 [ka] In a reaction vial containing a stir bar, oct-7-ynoic acid (15.77 mg; 0.11 mmol; 1.00 eq.), (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide hydrochloride (MeVHL-Lig, commercially available from Ambeed (50.00 mg; 0.11 mmol; 1.00 eq.)), and HATU (51.31 mg; 0.13 mmol; 1.20 eq.) were dissolved in DMF (1.10 mL) at room temperature. 4-Methylmorpholine (50.00 μL; 0.45 mmol; 4.00 eq.) was added, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was purified by preparative HPLC to provide (2S,4R)-1-[(2S)-3,3-dimethyl-2-(oct-7-ynamido)butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (53.1 mg; 0.094 mmol) as a colorless solid. LC-MS (ESI+, Method 3): R = 2.33 min, m / z 567.8 [M+H] + .

[0276] Intermediate 22 [ka] Intermediate 21 was prepared and purified as described, except that intermediate VHL-Lig was used instead of intermediate MeVHL-Lig, to give (2S,4R)-1-[(2S)-3,3-dimethyl-2-(oct-7-ynamido)butanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide (22.1 mg; 0.04 mol) as a colorless solid. LC-MS (ESI+, Method 3): R = 2.27 min, m / z 552.8 [M+H] + .

[0277] Intermediate 29 [ka] Step 1. To a stirred mixture of 2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid (360.00 mg; 0.95 mmol; 1.00 eq.), 3-aminopropan-1-ol (90.00 mg; 1.14 mmol; 1.20 eq.), and EtN (0.26 mL; 1.90 mmol; 2.00 eq.) in DCM (5.00 mL) was added HATU (762.00 mg; 1.90 mmol; 2.00 eq.) at room temperature. The resulting mixture was stirred at 25°C for 16 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with DCM (3 x 150 mL). The combined organic layers were washed with brine (1 x 100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to provide N-(3-hydroxypropyl)-2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxamide (381.00 mg; 0.90 mmol; 94%) as a yellow oil. LC-MS (ESI+, Method 2): R = 1.02 min, m / z 417.0 [M+H] + .

[0278] Step 2. To a solution of NaH (60.00 mg; 1.50 mmol; 2.12 eq.) in DMF (5.00 mL) was added N-(3-hydroxypropyl)-2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxamide (300.00 mg; 0.71 mmol; 1.00 eq.) at 0 °C. The mixture was stirred for 0.5 h. 1-[(3-azidopropoxy)sulfonyl]-4-methylbenzene (228.00 mg; 0.85 mmol; 1.20 eq.) was added and the mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (1x100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to provide N-[3-(3-azidopropoxy)propyl]-2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxamide (220.00 mg; 0.06 mmol; 8.6%) as a colorless oil. LC-MS (ESI+, Method 2): R = 1.09 min, m / z 500.0 [M+H] + .

[0279] Intermediate 30 [ka] Step 1. To a solution of tert-butyl N-(14-amino-3,6,9,12-tetraoxatetradecan-1-yl)carbamate (commercially available from Combi-Blocks, 100.00 mg; 0.30 mmol; 1.00 eq.) in dichloromethanone (DCM) (2.00 ml; 31.3 mmol; 105.4 eq.) in a 5 ml microwave vial, triethylamine (82 μl; 0.59 mmol; 2.00 eq.) was added at RT. o-NsCl (65.9 mg; 0.30 mmol; 1.00 eq.) was then added, and the reaction mixture was stirred for 30 min. After complete conversion of the starting material, the solvent was removed under reduced pressure, and the residue was taken up in DMF (2.00 ml; 25.8 mmol; 86.5 eq.). Then K2CO3 (206.2 mg; 1.49 mmol; 5.00 eq.) was added, followed by MeI (21 μl; 0.33 mmol; 1.10 eq.). The reaction mixture was heated to 60 °C. After 20 min, MeI (21 μl; 0.33 mmol; 1.10 eq.) was added again and the reaction mixture was stirred for 24 h. The mixture was diluted with water (10 mL) and EtOAc (20 mL) and the layers were separated. The aqueous phase was extracted with EtOAc (3 × 20 ml). The combined organic extracts were washed with brine (30 ml) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by HPLC (see attached file).

[0280] Step 2. In a 2 ml microwave vial, tert-butyl N-[14-(N-methyl-2-nitrobenzenesulfonamido)-3,6,9,12-tetraoxatetradecan-1-yl]carbamate (Step 1) (62.7 mg; 0.12 mmol; 1.00 eq.) was dissolved in anhydrous MeCN (1.0 ml) under an argon atmosphere. Cesium carbonate (209.8 mg; 0.64 mmol; 5.50 eq.) and PhSH (16 μl; 0.15 mmol; 1.30 eq.) were added sequentially, and the reaction mixture was heated to 50 °C for 16 h. The reaction mixture was diluted with water (15 ml) and EtOAc (20 ml). The layers were separated, and the aqueous phase was extracted with EtOAc (2 × 20 ml). The combined organic extracts were dried over NaSO, and the solvent was removed under reduced pressure to yield the crude product. The crude product was used immediately in the next step without further purification.

[0281] Step 3. In a 2 ml microwave vial, 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (commercially available from Ambeed Inc., 32.3 mg; 0.12 mmol; 1.00 eq.) and tert-butyl N-(5,8,11,14-tetraoxa-2-azahexadecan-16-yl)carbamate (Step 2) (41.0 mg; 0.12 mmol; 1.00 eq.) were dissolved in anhydrous NMP (1.2 ml). DIPEA (41 μl; 0.23 mmol; 2.00 eq.) was added, and the reaction mixture was heated in a microwave reactor at 130 °C for 1 h. The crude product (as a solution in NMP) was purified by HPLC.

[0282] Step 4. In a 2 ml microwave vial, tert-butyl N-{2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-5,8,11,14-tetraoxa-2-azahexadecan-16-yl}carbamate (Step 3) (18.7 mg; 0.03 mmol; 1.00 eq.) was dissolved in DCM (1.0 ml) and TFA (0.5 ml) was added at RT. After 30 min, the volatiles were removed under reduced pressure. The crude product was used immediately in the next reaction without further purification.

[0283] Intermediate 33 [ka] Intermediate 33 Step 1. To a solution of NaH (0.36 g; 9.00 mmol; 1.53 eq.) in DMF (10.00 ml) was added tert-butyl N-(2-hydroxyethyl)carbamate (1.00 g; 5.89 mmol; 1.00 eq.) at 0° C. The mixture was stirred for 0.5 h. Methyl 7-bromoheptanoate (1.60 g; 6.81 mmol; 1.16 eq.) was added, and the mixture was stirred for 2 h while allowing to warm to room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (1 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to provide crude methyl 7-(2-{[(tert-butoxy)carbonyl]amino}ethoxy)heptanoate (1.62 g; 4.54 mmol; 77.0%) as a colorless oil.

[0284] Step 2. A mixture of methyl 7-(2-{(tert-butoxy)carbonyl]amino}ethoxy)heptanoate (1.62 g; 4.54 mmol; 1.00 eq.) and 4 M HCl in 1,4-dioxane (10.00 ml) was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure to provide crude methyl 7-(2-aminoethoxy)heptanoate (1.05 g; 4.39 mmol; 96.7%) as a yellow oil.

[0285] Step 3. To a stirred mixture of methyl 7-(2-aminoethoxy)heptanoate (300.00 mg; 1.25 mmol; 1.00 eq.), 2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid (TEAD Ligand 1 free acid) (569.00 mg; 1.50 mmol; 1.20 eq.) in DCM (5.00 mL), EtN (0.55 mL; 3.76 mmol; 3.00 eq.) and HATU (1004.00 mg; 2.51 mmol; 2.00 eq.) were added at room temperature. The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with DCM (3 x 150 mL). The combined organic layers were washed with brine (1 × 100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:2) to provide methyl 7-[2-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]heptanoate (430.00 mg; 0.68 mmol; 54%).

[0286] Step 4. To a stirred mixture of methyl 7-[2-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]heptanoate (430.00 mg; 0.68 mmol; 1.00 eq.) in MeOH (10.00 ml), HO (2.00 mL) was added NaOH (143.00 mg; 3.40 mmol; 5.00 eq.) at room temperature. The resulting mixture was stirred at 60 °C for 16 h. The reaction was quenched with HO at room temperature. The mixture was acidified to pH 2 with HCl (aq.). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (1 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give 7-[2-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]heptanoic acid (315.00 mg; 0.54 mmol; 80%) as a white solid. LC-MS (ESI+, Method 7): R = 0.93 min, m / z 531.2 [M+H] + .

[0287] Intermediate 34 4-{2-[2-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]ethoxy}butanoic acid (Intermediate 34) [ka] Intermediate 34

[0288] Step 1. To a stirred mixture of tert-butyl 4-[2-(2-aminoethoxy)ethoxy]butanoate (commercially available from Pharmaron, 200.00 mg; 0.77 mmol; 1.00 eq.) in DCM (10.00 mL), 2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid, TEAD ligand 1 free acid (349.00 mg; 0.92 mmol; 1.20 eq.), HATU (614.00 mg; 1.53 mmol; 2.00 eq.), and EtN (0.28 mL; 1.92 mmol; 2.50 eq.) were added at room temperature. The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with DCM (3 x 150 mL). The combined organic layers were washed with brine (1 × 100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to provide tert-butyl 4-{2-[2-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]ethoxy}butanoate (341.00 mg; 0.56 mmol; 73%) as a colorless oil.

[0289] Step 2. To a stirred mixture of tert-butyl 4-{2-[2-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]ethoxy}butanoate (300.00 mg; 0.49 mmol; 1.00 eq.) in HCl (gas) in 1,4-dioxane (5.00 ml; 20.00 mmol; 40.57 eq.) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with NaHOC3 at room temperature. The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (1 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to provide crude 4-{2-[2-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]ethoxy}butanoic acid (247.00 mg; 0.44 mmol; 88%) as a white solid. LC-MS (ESI+, Method 7): R = 0.82 min, m / z 533.0 [M+H] + .

[0290] Intermediate 35 (2S,4R)-1-[(2S)-2-(2-{3-[2-(2-aminoethoxy)ethoxy]propoxy}acetamido)-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide TFA salt (Intermediate 35) [ka] Intermediate 35

[0291] Step 1. To a stirred solution of methyl 2-(3-hydroxypropoxy)acetate (1.00 g; 6.55 mmol; 1.00 eq.) and I2 (2.56 g; 9.58 mmol; 1.46 eq.) in THF (40.00 ml) was added PPH3 (2.12 g; 7.68 mmol; 1.17 eq.) and 1H-imidazole (0.56 g; 7.81 mmol; 1.19 eq.) at room temperature. The mixture was stirred at room temperature under a nitrogen atmosphere for 1.5 h. The resulting mixture was extracted with HCl and NaHCO3 (3 x 50 mL). The combined organic layers were washed with HO (3 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / hexane (1:10) to afford methyl 2-(3-iodopropoxy)acetate (1.400 g; 5.425 mmol; 83%) as a yellow liquid.

[0292] Step 2. To a stirred solution of tert-butyl N-[2-(2-hydroxyethoxy)ethyl]carbamate (1.000 g; 4.726 mmol; 1.0 eq.) in DMF (30.000 ml), NaH (0.560 g; 14.000 mmol; 3.0 eq.) was added, and methyl 2-(3-iodopropoxy)acetate (1.400 g; 5.425 mmol; 1.1 eq.) was added dropwise at 0 °C. The mixture was stirred at RT for 3 h. The reaction was quenched at room temperature by the addition of HO (50 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase flash chromatography to provide 2-{3-[2-(2-{[(tert-butoxy)carbonyl]amino}ethoxy)ethoxy]propoxy}acetic acid (240.000 mg; 0.747 mmol; 15.8%).

[0293] Step 3. 2-{3-[2-(2-{(tert-butoxy)carbonyl]amino}ethoxy)ethoxy]propoxy}acetic acid (210.000 mg; 0.653 mmol; 4.0 eq.) and (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl] To a stirred solution of {methyl}pyrrolidine-2-carboxamide VHL-Lig (70.000 mg; 0.163 mmol; 1.0 eq.) was added EDCI (35.000 mg; 0.183 mmol; 1.1 eq.), HOBT (25.000 mg; 0.176 mmol; 1.1 eq.), and DIEA (90.000 μL; 0.491 mmol; 3.0 eq.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 18 h. The resulting mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with HO (3 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (9:1) to provide tert-butyl N-(2-{2-[3-({[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methoxy)propoxy]ethoxy}ethyl)carbamate (75.000 mg; 0.102 mmol; 63%) as a white solid.

[0294] Step 4. A mixture of tert-butyl N-(2-{2-[3-({[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl)methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methoxy)propoxy]ethoxy}ethyl)carbamate (75.000 mg; 0.102 mmol; 1.0 eq.) and TFA (1.000 ml) in DCM (5.000 mL) was stirred at room temperature. The resulting mixture was stirred at room temperature for 4 h. The resulting mixture was concentrated under reduced pressure. The result was (2S,4R)-1-[(2S)-2-(2-{3-[2-(2-aminoethoxy)ethoxy]propoxy}acetamido)-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide TFA salt (85.000 mg; 0.095 mmol; 93%) as a crude yellow liquid product. LC-MS (ESI+, Method 3): R = 0.63 min, m / z 634.3 [M+H] + .

[0295] Intermediate 37 N-[2-(4-Azidobutoxy)ethyl]-2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxamide (Intermediate 37) [ka] Intermediate 37

[0296] Step 1. To a stirred mixture of TEAD ligand 1 free acid, 2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid (250.00 mg; 0.66 mmol; 1.00 eq.), 2-aminoethan-1-ol (51.00 mg; 0.79 mmol; 1.20 eq.), and ET3N (0.18 mL; 1.32 mmol; 2.00 eq.) in DCM (3.00 mL), HATU (529.00 mg; 1.32 mmol; 2.00 eq.) was added at room temperature. The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (1 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give N-(2-hydroxyethyl)-2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxamide (252.00 mg; 0.59 mmol; 89%) as a yellow oil.

[0297] Step 2. To a solution of NaH (37.00 mg; 0.93 mmol; 1.97 eq.) in DMF (3.00 ml) was added N-(2-hydroxyethyl)-2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxamide (200.00 mg; 0.47 mmol; 1.00 eq.) at 0 °C. The mixture was stirred for 0.5 h. 1-[(4-azidobutoxy)sulfonyl]-4-methylbenzene (160.00 mg; 0.56 mmol; 1.20 eq.) was added, and the mixture was stirred for 1 h while allowing to warm to room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (1 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to provide N-[2-(4-azidobutoxy)ethyl]-2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxamide (231.00 mg; 0.25 mmol; 53%) as a yellow solid. LC-MS (ESI+, Method 7): R = 0.61 min, m / z 403.0 [M+H] + .

[0298] Intermediate 38 3-{2-[(2-{2-[2-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]ethoxy}ethyl)carbamoyl]ethoxy}propanoic acid (Intermediate 38) [ka] Intermediate 38

[0299] Step 1. A solution of 3-[3-(tert-butoxy)-3-oxopropoxy]propanoic acid (100.00 mg; 0.46 mmol; 1.00 eq.), benzyl N-{2-[2-(2-aminoethoxy)ethoxy]ethyl}carbamate (129.00 mg; 0.46 mmol; 1.00 eq.) and HATU (183.00 mg; 0.46 mmol; 1.00 eq.) in DIEA (177.50 mg; 1.31 mmol; 2.85 eq.) was stirred at room temperature under DCM (8.00 ml) for 2 hours overnight. The crude product was purified by preparative HPLC to provide tert-butyl 3-[2-({2-[2-(2-{[(benzyloxy)carbonyl]amino}ethoxy)ethoxy]ethyl}carbamoyl)ethoxy]propanoate (yellow oil).

[0300] Step 2. A solution of tert-butyl 3-[2-({2-[2-(2-{(benzyloxy)carbonyl]amino}ethoxy)ethoxy]ethyl}carbamoyl]ethoxy]propanoate (50.00 mg; 0.08 mmol; 1.00 eq.) and Pd / C (20.00 mg; 0.02 mmol; 0.23 eq.) in MeOH (5.00 ml) was stirred at about room temperature for 2 hours.

[0301] Step 3. A solution of tert-butyl 3-[2-({2-[2-(2-aminoethoxy)ethoxy]ethyl}carbamoyl)ethoxy]propanoate (100.00 mg; 0.29 mmol; 1.00 eq.), 2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid, TEAD ligand 1 free acid (103.00 mg; 0.29 mmol; 1.00 eq.), and HATU (115.00 mg; 0.29 mmol; 1.00 eq.) in DIEA (111.00 mg; 0.82 mmol; 2.84 eq.) was stirred under DCM (10.00 mL) at room temperature for 2 hours. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with HCl (aq.), NaHCO3 (aq.), NaCl (aq.) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (5:1) to provide tert-butyl 3-{2-[(2-{2-[2-(2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]ethoxy}ethyl)carbamoyl]ethoxy}propanoate (170.00 mg; 0.17 mmol; 59.0%; yellow-brown solid).

[0302] Step 4. The resulting mixture of tert-butyl 3-{2-[(2-{2-[2-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]ethoxy}ethyl)carbamoyl]ethoxy}propanoate (300.00 mg; 0.30 mmol; 1.00 eq.) and HCl (gas) in 1,4-dioxane (10.00 ml; 40.00 mmol; 133.93 eq.). The mixture was stirred at room temperature for 1 h. The resulting solid was dried by lyophilization under reduced pressure / in an infrared oven. 3-{2-[(2-{2-[2-({2-methyl-8-[2-(4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]ethoxy}ethyl)carbamoyl]ethoxy}propanoic acid (200.00 mg; 0.24 mmol; 81.9%; yellow solid). LC-MS (ESI+, Column: XBridge C8, 3.5 μm, 4.6 × 50 mm; Solvent A: water + 0.1% TFA; Solvent B: ACN + 0.1% TFA; Flow: 2 ml / min; Gradient: 0 min: 5% B, 8 min: 100% B, 8.1 min: 100% B, 8.5 min: 5% B, 10 min 5% B): t R = 0.61 min, m / z 403.0 [M+H] + .

[0303] Intermediate 39 3-{2-[2-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]ethoxy}propanoic acid (Intermediate 39) [ka] Intermediate 39

[0304] Step 1. To a stirred mixture of 2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid (300.00 mg; 0.79 mmol; 1.00 eq.), tert-butyl 3-[2-(2-aminoethoxy)ethoxy]propanoate (233.76 mg; 0.95 mmol; 1.20 eq.) in DCM (10.00 mL), EDCI (320.12 mg; 1.59 mmol; 2.00 eq.), and EtN (0.22 mL; 1.59 mmol; 2.00 eq.) were added at room temperature. The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with DCM (3 x 150 mL). The combined organic layers were washed with brine (1x100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (4:1) to provide tert-butyl 3-{2-[2-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]ethoxy]propanoate (395.00 mg; 0.68 mmol; 86.0%; colorless oil).

[0305] Step 2. To a stirred mixture of tert-butyl 3-{2-[2-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]ethoxy]propanoate (355.00 mg; 0.61 mmol; 1.00 eq.) in 4 M HCl (gas) in 1,4-dioxane (3.00 ml; 12.00 mmol; 19.57 eq.) at room temperature. The resulting mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure to provide 3-{2-[2-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]ethoxy}]propanoic acid (275.00 mg; 0.49 mmol; 79.9%; yellow oil). LC-MS (ESI+, Method 7): R= 0.97 min, m / z 519.0 [M+H] + .

[0306] Intermediate 40 7-(2-{2-[2-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]ethoxy}ethoxy)heptanoic acid (Intermediate 40) [ka] Intermediate 40

[0307] Step 1. To a stirred solution of tert-butyl N-{2-[2-(2-hydroxyethoxy)ethoxy]ethyl}carbamate (1.20 g; 4.67 mmol; 1.07 eq.) in THF (20.00 ml) was added NaH (0.60 g; 15.00 mmol; 3.45 eq.) at 0 °C, and methyl 7-bromoheptanoate (1.00 g; 4.35 mmol; 1.00 eq.) was added dropwise. The resulting mixture was stirred at RT under a nitrogen atmosphere for 3 h. The reaction was quenched at room temperature by the addition of HO. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with HO (3 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The result was methyl 7-{2-[2-(2-{[(tert-butoxy)carbonyl]amino}ethoxy)ethoxy]ethoxy}heptanoate (1.40 g; 2.86 mmol; 65.8%; yellow liquid; crude product).

[0308] Step 2. To a stirred solution of the product from the last step (1.4 g) in DCM (20,000 ml) was added TFA (5,000 ml). The mixture was stirred at RT for 3 h. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 x 50 ml). The combined organic layers were washed with H2O (3 x 50 ml) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The result was methyl 7-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}heptanoate (brown liquid; crude product), assumed quantitative yield.

[0309] Step 3. To a stirred solution of methyl 7-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}heptanoate (1.300 g; 0.892 mmol; 1.6 eq.) and 2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid, TEAD ligand 1 free acid (0.200 g; 0.557 mmol; 1.0 eq.) in DCM (20.000 mL), HATU (233.000 mg; 0.582 mmol; 1.0 eq.) and DIEA (276.000 μL; 1.505 mmol; 2.7 eq.) were added. The resulting mixture was stirred at 25 °C under a nitrogen atmosphere for 2 h. The resulting mixture was extracted with DCM / HO (3 × 50 mL). The combined organic layers were washed with HO (3 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / hexane to provide methyl 7-(2-{2-[2-(2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]ethoxy}ethoxy)heptanoate (170.000 mg; 0.212 mmol; 38.2%; yellow solid; purified product).

[0310] Step 4. To a stirred solution of methyl 7-(2-{2-[2-methyl-8-[2-(4-(trifluoromethyl)phenyl)-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]ethoxy}ethoxy)heptanoate (170.000 mg; 0.212 mmol; 1.0 eq.) in MeOH (20.000 ml) was added NaOH (50.000 mg; 1.188 mmol; 5.6 eq.) in HO (2.000 ml) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 4 h. The resulting mixture was concentrated under reduced pressure. The mixture was acidified to pH 6 with concentrated HCl. The precipitated solid was collected by filtration and washed with HO. The result was 7-(2-{2-[2-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]ethoxy}ethoxy)heptanoic acid (40.000 mg; 0.058 mmol; 27.3%; yellow liquid). LC-MS (ESI+, Method 3): R = 0.92 min, m / z 619.0 [M+H] + .

[0311] Intermediate 41 7-[2-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]heptanoic acid (Intermediate 41) [ka] Intermediate 41

[0312] Step 1. To a solution of NaH (0.71 g; 17.68 mmol; 1.50 eq.) in DMF (20.00 ml) was added tert-butyl N-(2-hydroxyethyl)carbamate (2.00 g; 11.79 mmol; 1.00 eq.) at 0 °C. The mixture was stirred for 0.5 h. Methyl 7-bromoheptanoate (3.32 g; 14.14 mmol; 1.20 eq.) was added and the mixture was stirred for 2 h while being allowed to warm to room temperature.

[0313] The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (1 × 100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to provide methyl 7-(2-{[(tert-butoxy)carbonyl]amino}ethoxy)heptanoate (3.58 g; 10.03 mmol; 85.1%; colorless oil).

[0314] Step 2. To a stirred mixture of methyl 7-(2-{(tert-butoxy)carbonyl]amino}ethoxy)heptanoate (3.54 g; 9.92 mmol; 1.00 eq.) in 4 M HCl (gas) in 1,4-dioxane (20.00 ml) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure to provide methyl 7-(2-aminoethoxy)heptanoate (2.17 g; 9.07 mmol; 91.5%; yellow oil).

[0315] Step 3. To a stirred mixture of methyl 7-(2-aminoethoxy)heptanoate (200.00 mg; 0.84 mmol; 1.00 eq.), 2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid (380.00 mg; 1.00 mmol; 1.20 eq.) in DCM (10.00 ml) was added EtN (260.00 mg; 2.54 mmol; 3.04 eq.) and HATU (670.00 mg; 1.67 mmol; 2.00 eq.) at room temperature. The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with DCM (3 x 150 mL). The combined organic layers were washed with brine (1 x 100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:2) to provide methyl 7-[2-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]heptanoate (382.00 mg; 0.67 mmol; 79.8%; white solid). LC-MS (ESI+, Method 7): t R = 0.97 min, m / z 545.0 [M+H] + .

[0316] Step 4. To a stirred mixture of methyl 7-[2-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]heptanoate (340.00 mg; 0.59 mmol; 1.00 eq.) in MeOH (10.00 ml), HO (2.00 mL) was added NaOH (125.00 mg; 2.97 mmol; 5.00 eq.) at room temperature. The resulting mixture was stirred at 60° C. for 16 h. The reaction was quenched with HO at room temperature. The mixture was acidified to pH 2 with HCl (aq.). The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (1×10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give 7-[2-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]heptanoic acid (297.00 mg; 0.54 mmol; 91.2%; white solid). LC-MS (ESI+, Method 7): R = 0.92 min, m / z 531.0[M+H] + .

[0317] Intermediate 43 1-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)-3,6,9,12-tetraoxahexadecano-16-oic acid (Intermediate 43) [ka] Intermediate 43

[0318] Step 1. A solution of tert-butyl 1-amino-3,6,9,12-tetraoxahexadecan-16-noate (commercially available from Pharmaron, 200.00 mg; 0.57 mmol; 1.00 eq.), 2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid, TEAD ligand 1 free acid (280.00 mg; 0.62 mmol; 1.10 eq.), and HATU (222.00 mg; 0.55 mmol; 0.98 eq.) in DIEA (216.00 mg; 1.59 mmol; 2.80 eq.), DCM (20.00 mL). The mixture was stirred at room temperature under air for 2 hours. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with HCl (aq.), NaHCO3 (aq.), NaCl (aq.) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (5:1) to provide tert-butyl 1-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamide)-3,6,9,12-tetraoxahexadecan-16-noate (300.00 mg; 0.42 mmol; 74.2%; yellow-brown solid).

[0319] Step 2. To a stirred mixture of tert-butyl 1-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamide)-3,6,9,12-tetraoxahexadecan-16-noate (300.00 mg; 0.37 mmol; 1.00 eq.) in 4 M HCl (gas) in 1,4-dioxane (10.00 ml; 40.00 mmol; 107.42 eq.). The mixture was allowed to stand at room temperature for 2 h. The resulting solid was dried under IR radiation in an oven under vacuum / freeze drying. The crude product was purified by preparative HPLC under the following conditions (2#SHIMADZU (HPLC-01)): column, XBridge Shield RP18 OBD column, 19*250 mm, 10 μm; mobile phase, water (0.1% FA) and MeOH- (20% phase B, up to 40% by 8 min); detector, UV 254 nm to provide 1-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamide)-3,6,9,12-tetraoxahexadecan-16-oic acid (200.00 mg; 0.18 mmol; 47.6%; yellow solid). LC-MS (ESI+, Column: XBridge C8, 3.5 μm, 4.6x50 mm; Solvent A: water + 0.1% TFA; Solvent B: ACN + 0.1% TFA; Flow rate: 2 ml / min; Gradient: 0 min: 5% B, 8 min: 100% B, 8.1 min: 100% B, 8.5 min: 5% B, 10 min 5% B.): t R =0.85 min, m / z 621.0 [M+H] + .

[0320] Intermediate 45 7-[methyl(2-{2-[2-({2-methyl-8-[4-(trifluoromethyl)pyridin-2-yl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]ethoxy}ethyl)amino]heptanoic acid (Intermediate 45) [ka] Intermediate 45

[0321] Step 1. To a stirred solution of 7-ethoxy-7-oxoheptanoic acid (2.00 g; 10.41 mmol; 1.00 eq.) and tert-butyl N-{2-[2-(2-aminoethoxy)ethoxy]ethyl}carbamate (2.60 g; 10.26 mmol; 0.99 eq.) in DCM (50.00 ml), HATU (4.50 g; 11.24 mmol; 1.08 eq.) and DIEA (6738.54 μl; 36.75 mmol; 3.53 eq.) were added. The mixture was stirred at 25 °C for 2 h. The resulting mixture was extracted with HCl. The combined organic layers were washed with NaHCO3 and NaCl and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The result was ethyl 6-({2-[2-(2-{(tert-butoxy)carbonyl]amino}ethoxy)ethoxy]ethyl}carbamoyl)hexanoate (7.00 g; 8.36 mmol; 80.3%; yellow liquid).

[0322] Step 2. To a stirred solution of ethyl 6-({2-[2-(2-{[(tert-butoxy)carbonyl]amino}ethoxy)ethoxy]ethyl}carbamoyl)hexanoate (6.95 g; 8.30 mmol; 1.00 eq.) in DCM (120.00 ml; 1879.15 mmol; 226.32 eq.), TFA (8.00 ml) was added. The mixture was stirred at 25 °C for 4 h. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with NaHCO3. After filtration, the filtrate was concentrated under reduced pressure. The result was ethyl 6-({2-[2-(2-aminoethoxy)ethoxy]ethyl}carbamoyl)hexanoate (2.30 g; 7.01 mmol; 84.5%; yellow liquid).

[0323] Step 3. To a stirred solution of 2-methyl-4-[5-(trifluoromethyl)pyridin-2-yl]-2H,4H-[1,2,3]triazolo[4,5-b]indole-7-carboxylic acid (prepared analogously to TEAD Ligand 2, 300.00 mg; 0.78 mmol; 1.00 eq.) and ethyl 6-({2-[2-(2-aminoethoxy)ethoxy]ethyl}carbamoyl)hexanoate (660.00 mg; 2.01 mmol; 2.58 eq.) in DCM (50.00 mL), HATU (380.00 mg; 0.95 mmol; 1.22 eq.) and DIEA (0.50 mL; 2.73 mmol; 3.49 eq.) were added. The mixture was stirred at 25 °C for 2 h. The resulting mixture was extracted with NaHCO (3 x 50 mL). The combined organic layers were washed with NaCl (3 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The result was ethyl 6-[(2-{2-[2-(2-methyl-4-[5-(trifluoromethyl)pyridin-2-yl]-2H,4H-[1,2,3]triazolo[4,5-b]indol-7-yl}formamido)ethoxy]ethoxy}ethyl)carbamoyl]hexanoate (500.00 mg; 0.67 mmol; 85.4%; yellow liquid).

[0324] Step 4. To a stirred solution of ethyl 6-[(2-{2-[2-methyl-4-[5-(trifluoromethyl)pyridin-2-yl]-2H,4H-[1,2,3]triazolo[4,5-b]indol-7-yl}formamido]ethoxy]ethoxy}ethyl)carbamoyl]hexanoate (500.00 mg; 0.67 mmol; 1.00 eq.) in EtOH (30.00 ml) and H2O (2.00 ml), NaOH (200.00 mg; 4.75 mmol; 7.13 eq.) was added. The mixture was stirred at 60 °C for 6 h. The resulting mixture was concentrated under reduced pressure. The mixture was acidified to pH 6 with concentrated HCl. The precipitated solid was collected by filtration and washed with H2O. The result was 6-[(2-{2-[2-(2-methyl-4-[5-(trifluoromethyl)pyridin-2-yl]-2H,4H-[1,2,3]triazolo[4,5-b]indol-7-yl}formamido)ethoxy]ethoxy}ethyl)carbamoyl]hexanoic acid (400.00 mg; 0.63 mmol; 94.7%; yellow liquid). LC-MS (ESI+, Method 3): R = 0.92 min, m / z 531.0 [M+H] + .

[0325] Intermediate 46 7-[methyl(2-{2-[2-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]ethoxy}ethyl)amino]heptanoic acid (Intermediate 46) [ka] Intermediate 46

[0326] Step 1. A solution of tert-butyl 2-[2-(2-aminoethoxy)ethoxy]acetate (225.00 mg; 0.82 mmol; 1.00 eq.), 2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid, TEAD ligand 1 free acid (246.00 mg; 0.65 mmol; 0.79 eq.), and HATU (273.00 mg; 0.68 mmol; 0.83 eq.) in DIEA (265.00 mg; 1.95 mmol; 2.37 eq.) was stirred under DCM (10.00 ml) at room temperature for 2 hours. The crude product was purified by preparative HPLC under the following conditions (2#SHIMADZU (HPLC-01)): column, XBridge Shield RP18 OBD column, 19*250 mm, 10 μm; mobile phase, water (0.1% FA) and MeOH- (20% phase B, up to 40% by 8 min); detector, UV 254 nm to provide tert-butyl 2-{2-{2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]ethoxy}acetate (200.00 mg; 0.36 mmol; 43.5%; white solid).

[0327] Step 2. To a stirred mixture of tert-butyl 2-{2-[2-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]ethoxy}acetate (160.00 mg; 0.23 mmol; 1.00 eq.) and HCl-dioxane (6.00 mL; 24.00 mmol; 105.11 eq.), the mixture was stirred at room temperature for 2 h. The resulting solid was dried under IR radiation in an oven under vacuum / freeze-drying / reduced pressure. The crude product was purified by preparative HPLC to provide 2-{2-[2-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]ethoxy}acetic acid (100.00 mg; 0.20 mmol; 86.8%; white solid). LC-MS (ESI+, Column: XBridge C8, 3.5 μm, 4.6×50 mm; Solvent A: water + 0.1% TFA; Solvent B: ACN + 0.1% TFA; Flow: 2 ml / min; Gradient: 0 min: 5% B, 8 min: 100% B, 8.1 min: 100% B, 8.5 min: 5% B, 10 min 5% B): t R =0.83 min, m / z 505.0 [M+H] + .

[0328] Intermediate 47 7-[methyl(2-{2-[2-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]ethoxy}ethyl]amino]heptanoic acid (Intermediate 47) [ka] Intermediate 47

[0329] Prepared in the same manner as intermediate 45, except using tert-butyl N-(2-{2-[2-(methylamino)ethoxy]ethoxy}ethyl)carbamate (secondary amine) instead of the free primary amine in step 1 and TEAD ligand 1 instead in step 3.

[0330] Intermediate 60 (2S,4R)-1-[(2S)-2-{10-[2-(2-aminoethoxy)ethoxy]decanamido}-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide (Intermediate 60) [ka] Intermediate 60

[0331] Step 1. Phthalic anhydride (1,479 g; 9,987 mmol; 105.00 mol%) and 2-(2-aminoethoxy)ethan-1-ol (commercially available from Acros Organics, 1,000 g; 9,512 mmol; 100.00 mol%) were premixed in a microwave vial and irradiated in a microwave reactor at 150 °C for 2 hr. The reaction mixture was dissolved in water and extracted three times with DCM. The combined organic layers were combined, dried over NaSO and filtered. The concentrated crude product was purified by flash chromatography to give 2-(2-hydroxyethoxy)ethyl]-2,3-dihydro-1H-isoindole-1,3-dione (1,040 g; 4,266 mmol). LC-MS (ESI+, Method 1): R = 1.10 min, m / z 236.1 [M+H] + .

[0332] Step 2. 2-[2-(2-hydroxyethoxy)ethyl]-2,3-dihydro-1H-isoindole-1,3-dione (500,000 mg; 2,075 mmol; 100,00 mol%) was dissolved in DMF (5,000 mL; 64,301 mmol; 3.099,56 mol%) under N2 protection. The mixture was cooled with ice water. Sodium hydride (165,947 mg; 6,224 mmol; 300,00 mol%) was added to the mixture at 0 °C (colorless suspension). Then, tert-butyl 10-bromodecanoate (637,429 mg; 2,075 mmol; 100,00 mol%) was added dropwise. The mixture (off-white suspension) was allowed to warm up to rt and stirred at rt overnight. More tert-butyl 10-bromodecanoate (318,715 mg; 1,037 mmol; 50,00 mol%) was added. The reaction mixture was stirred at rt overnight. The reaction mixture was stirred at rt for another 4 h. The reaction mixture was carefully quenched with water and 1N HCl. The mixture was then extracted three times with EE. The combined organic layers were dried over Na2SO4, filtered and evaporated to give 10-{2-[2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)ethoxy]ethoxy}decanoic acid (865.9 mg, 0.61 mmol, 29%). LC-MS (ESI+, Method 1): t R = 1.88 min, m / z 406 [M+H] + The tert-butylated by-product was deprotected with TFA / DCM (assuming quantitative yield) and used in the next step after evaporation of volatiles and purification by preparative HPLC.

[0333] Step 3. 10-{2-[2-(1,3-Dioxo-2,3-dihydro-1H-isoindol-2-yl)ethoxy]ethoxy}decanoic acid (95,992 mg; 0,232 mmol; 100,00 mol%) was dissolved in DMF (5,000 mL; 64,301 mmol; 27.715,85 mol%) at rt. HATU 97% (176,430 mg; 0,464 mmol; 200,000 μL; 1,547 mmol; 667,01 mol%) and N,N-diisopropylethylamine (200,000 μL; 1,547 mmol; 667,01 mol%) were then added. The reaction mixture was stirred at room temperature for 10 min. A solution of N,N-diisopropylethylamine (200,000 μL) in DMF (5,000 mL; 64,301 mmol; 27.715, 85 mol%) and (2S,4S)-1-(S)-2-amino-3,3-dimethyl-butyryl)-4-hydroxy-pyrrolidine-2-carboxylic acid 4-(4-methyl-thiazol-5-yl)-benzylamide (commercially available from WuXi AppTec) was then added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and purified by preparative HPLC-MS to give (2S,4R)-1-[(2S)-2-(10-{2-[2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)ethoxy]ethoxy}decanamido)-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide (160 mg, 0.18 mmol, 78%) as a colorless gum. LC-MS (ESI+, Method 1): R = 1.79 min, m / z 818.0 [M+H] + .

[0334] Step 4. In a microwave vial, dissolve hydrazinium hydroxide (0.070 mL; 1.438 mmol; 800.00 mol%) in ethanol (2.000 mL). ofThe mixture was irradiated in a microwave reactor at 50 °C for 30 min. After cooling to rt and standing overnight, a precipitate formed. The precipitated phthalhydrazide was filtered off, and the filtrate was evaporated in vacuo to give (2S,4S)-1-[(2S)-2-{10-[2-(2-aminoethoxy)ethoxy]decanamido}-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide (159.4 mg, 0.16 mmol, 89%) as a colorless oil. LC-MS (ESI+, Method 1): R = 1.34 min, m / z 347.7 [M+2H] 2+ .

[0335] Intermediate 68 2-Methyl-4-[(1r,4r)-4-(trifluoromethyl)cyclohexyl]-2H,4H-[1,2,3]triazolo[4,5-b]indole-7-carboxylic acid (Intermediate 68) [ka] Intermediate 68

[0336] Step 1. To a stirred mixture of 4-(trifluoromethyl)cyclohexan-1-ol (303.00 mg; 1.80 mmol; 1.50 eq.), cyanomethylenetributylphosphorane (645.00 mg; 2.41 mmol; 2.00 eq.), and 2-methyl-2H,4H-[1,2,3]triazolo[4,5-b]indole-7-carbonitrile (see Synthesis of TEAD Ligand 2, Step 2) (300.00 mg; 1.20 mmol; 1.00 eq.) in toluene (30.00 ml) at room temperature. The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 16 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with H2O (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to provide 2-methyl-4-[4-(trifluoromethyl)cyclohexyl]-2H,4H-[1,2,3]triazolo[4,5-b]indole-7-carbonitrile (180.00 mg; 0.52 mmol; 43.1%; yellow solid; purified product). LC-MS (ESI+, Method 7): R = 0.73 min, m / z 348.0 [M+H] + .

[0337] Step 2. To a stirred mixture of 2-methyl-4-[4-(trifluoromethyl)cyclohexyl]-2H,4H-[1,2,3]triazolo[4,5-b]indole-7-carbonitrile (170.00 mg; 0.49 mmol; 1.00 eq.) in water (10.00 ml) and EtOH (10.00 ml), NaOH (8488.32 mg; 201.65 mmol; 412.00 eq.) was added at room temperature. The resulting mixture was stirred at 80° C. overnight. The reaction was quenched with H2O at room temperature. The mixture was acidified to pH 2 with concentrated aqueous HCl. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (5:1) to provide 2-methyl-4-[4-(trifluoromethyl)cyclohexyl]-2H,4H-[1,2,3]triazolo[4,5-b]indole-7-carboxylic acid (160.00 mg; 0.44 mmol; 89.2%; white solid; purified product).

[0338] Step 3. The product was separated by column: Xselect CSH OBD column 30*150mm 5um, n; mobile phase A: water (10mmol / L NH4HCO3 + 0.1%NH3.H2O), mobile phase B: ACN; flow rate: 60mL / min; gradient: 35B~55B over 8min. LC-MS (ESI+, Method 7): t R = 0.92 min, m / z 367.0 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) 8.45 (d, J = 1.7 Hz, 1H), 8.08 - 7.99 (m, 1H), 7.72 (d, J = 8.9 Hz, 1H), 4.65 (s, 1H), 4.33 (s, 3H), 2.64 (s, 1H), 2.35 - 2.21 (m, 2H), 2.09 (d, J = 12.8 Hz, 2H), 1.93 (s, 4H).

[0339] Intermediate 71 2-Methyl-8-{[4-(trifluoromethyl)cyclohexyl]methyl}-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid (Intermediate 71) [ka] Intermediate 71

[0340] Step 1. To a stirred solution of ethyl 3-(3-amino-1-methylpyrazol-4-yl)-4-chlorobenzoate (10.00 g, 33.105 mmol, 1.00 equiv, 92.6%) and CsCO (23.28 g, 67.864 mmol, 2.05 equiv, 95%) in dioxane (300 mL) was added t-BuXPhos (2.96 g, 6.621 mmol, 0.20 equiv, 95%) and tBuXPhos Pd G (2.77 g, 3.310 mmol, 0.10 equiv, 95%) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 120° C. under a nitrogen atmosphere overnight. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (2x500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (2:1) to provide ethyl 2-methyl-8H-pyrazolo[3,4-b]indole-5-carboxylate (4.0523 g, 48%) as a white solid. LC-MS (ESI+, Method 3): t R = 0.77 min, m / z 244.1 [M+H] + .

[0341] Step 2. To a solution of ethyl 2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate (60.0 mg; 0.23 mmol; 1.00 aq.) in dry DMF (3.0 ml), sodium hydride suspension (60% suspension in paraffin oil) (28.1 mg; 0.70 mmol; 3.00 aq.) was added and stirred at rt for 0.5 h. Then 1-(bromomethyl)-4-(trifluoromethyl)cyclohexane (69.0 mg; 0.28 mmol; 1.20 aq.) was added and stirred at rt for 16 h. More 1-(bromomethyl)-4-(trifluoromethyl)cyclohexane (69.0 mg; 0.28 mmol; 1.20 aq.) was added and stirred at rt for 16 h. The reaction was added with water and directly purified by preparative HPLC to give the desired 2-methyl-8-{[4-(trifluoromethyl)cyclohexyl]methyl}-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid (30 mg, 0.08 mmol, 32%) in parallel with the corresponding ethyl ester (discarded).

[0342] Intermediate 78 9-{[4-(trifluoromethyl)phenyl]methyl}-9H-pyrido[3,4-b]indole-3-carboxylic acid (Intermediate 78) [ka] Intermediate 78

[0343] Step 1. To 9H-β-carboline-3-carboxylic acid (Merck KGaA, 500.0 mg; 2.36 mmol; 1.00 Eq.) in ethanol (200 ml), thionyl chloride (1709.3 μl; 23.56 mmol; 10.00 Eq.) was added dropwise and stirred at 80° C. for 2 d and 16 hr. Some water was added to the reaction and evaporated to dryness. The residue was basified with NaOH 2N and evaporated with EtOAc (2×). The combined organic layers were washed 2× with water, dried over Na2SO4, and evaporated to dryness. LC-MS (ESI+, Method 1): R = 1.34 min, m / z 241.00 [M+H] + .

[0344] Step 2. To a solution of ethyl 9H-pyrido[3,4-b]indole-3-carboxylate (60.0 mg; 0.25 mmol; 1.00 Eq.) in DMF (3.0 ml), NaH (60% suspension in paraffin oil, 29.8 mg; 0.74 mmol; 3.00 aq.) was added and stirred at RT for 0.5 h. Then (4-trifluoromethyl)benzyl bromide (71.1 mg; 0.30 mmol; 1.20 aq.) was added and stirred at RT for 2 h. Water was added to the reaction, which was directly purified by preparative HPLC to give the desired product after lyophilization. LC-MS (ESI+, Method 1): R = 1.51 min, m / z 371.00 [M+H] + . 1 H NMR (700 MHz, DMSO-d6) 9.26 (s, 1H), 9.09 (s, 1H), 8.55 (d, J = 7.8 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.72 - 7.69 (m, 1H), 7.69 - 7.66 (m, 2H), 7.44 - 7.41 (m, 1H), 7.40 - 7.38 (m, 2H), 6.04 (s, 2H).

[0345] compound 1 N'-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-N-(2-{2-[2-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]ethoxy}ethyl)-3,6,9,12,15-pentaoxaheptadecanediamide (Compound 1) [ka]

[0346] Intermediate 1 (25 mg; 0.05 mmol) was dissolved in dry N,N-dimethylformamide (1 mL) in an 8 mL vial, followed by the addition of Intermediate 12 (29 mg; 0.05 mmol), 4-methylmorpholine (0.06 mL), and HATU (23 mg; 0.06 mmol). The reaction was stirred at RT for 18 h. The crude reaction mixture was partitioned between 10% MeOH in DCM (1 mL) and water (1 mL). The aq. phase was extracted with additional 10% MeOH in DCM (2 × 1 mL). The combined organic phase was filtered over a plug of NaSO and concentrated by rotary evaporation. The crude material was dissolved in DCM (800 μL) and purified by flash chromatography (solution injection, 4 g SiO, 0–10% MeOH in DCM, 13 mL / min). After evaporation of the volatiles, the compound was obtained as an oil, which was redissolved in ACN / HO and lyophilized to give compound 1 (18 mg; 0.02 mmol, 33%) as a white lyophilizate.

[0347] LC-MS (ESI+, method Himass): t R = 1.65 min, m / z 1036.5 [M+H] + . 1H NMR (700 MHz, DMSO-d6) δ 11.15 (s, 1H), 10.33 (s, 1H), 8.73 - 8.68 (m, 1H), 8.52 (t, J = 5.6 Hz, 1H), 8.33 (d, J = 1.9 Hz, 1H), 8.19 (s, 1H), 8.08 (d, J = 8.3 Hz, 2H), 7.96 (d, J = 8.5 Hz, 2H), 7.85 (ddd, J = 8.4, 4.5, 2.6 Hz, 2H), 7.77 (d, J = 8.6 Hz, 1H), 7.65 - 7.60 (m, 2H), 5.16 (dd, J = 13.0, 5.4 Hz, 1H), 4.18 (s, 2H), 4.03 (s, 3H), 3.85 (s, 2H), 3.78 - 3.72 (m, 2H), 3.69 - 3.63 (m, 2H), 3.59 - 3.41 (m, 21H), 3.26 (q, J = 5.9 Hz, 2H), 2.89 (ddd, J = 17.3, 14.0, 5.5 Hz, 1H), 2.61 (ddd, J = 17.4, 4.6, 2.5 Hz, 1H), 2.57 - 2.50 (m, 1H), 2.07 (tdd, J = 8.6, 5.5, 2.8 Hz, 1H).

[0348] compound 2 2-{2-[2-({[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]carbamoyl}methoxy)ethoxy]ethoxy}-N-(2-{2-[2-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]ethyl)acetamide (Compound 2) [ka]

[0349] Intermediate 1 (50 mg; 0.08 mmol) and intermediate 13 (40 mg; 0.08 mmol) were dissolved in N,N-dimethylformamide (1 mL) in an 8 mL vial with a stir bar, followed by the addition of 4-methylmorpholine (0.1 mL) and HATU (41 mg; 0.11 mmol). The reaction mixture was stirred at RT for 8 h, then adsorbed onto Celite and purified by flash chromatography (4 g SiO, 0–10% MeOH in DCM, 13 mL / min) to give the product as an oil. The product was redissolved in ACN / HO and lyophilized to give compound 2 (44 mg; 0.04 mmol, 54%) as an off-white lyophilizate.

[0350] LC-MS (ESI+, method Himass): t R = 1.65 min, m / z 948.5 [M+H] + . 1H NMR (700 MHz, DMSO-d6) δ 11.15 (s, 1H), 10.33 (s, 1H), 9.58 (s, 2H), 8.69 (d, J = 8.4 Hz, 1H), 8.51 (t, J = 5.6 Hz, 1H), 8.33 (d, J = 1.8 Hz, 1H), 8.19 (s, 1H), 8.08 (d, J = 8.3 Hz, 2H), 7.96 (d, J = 8.5 Hz, 2H), 7.87 - 7.81 (m, 2H), 7.76 (d, J = 8.6 Hz, 1H), 7.64 - 7.58 (m, 2H), 5.15 (dd, J = 13.0, 5.5 Hz, 1H), 4.18 (s, 2H), 4.03 (s, 3H), 3.99 - 3.96 (m, 4H), 3.84 (s, 2H), 3.76 (dd, J = 5.8, 3.6 Hz, 2H), 3.68 (dd, J = 5.8, 3.6 Hz, 2H), 3.61 - 3.49 (m, 13H), 3.44 (dt, J = 18.6, 5.9 Hz, 4H), 3.25 (q, J = 5.9 Hz, 2H), 3.06 (s, 4H), 2.93 - 2.86 (m, 1H), 2.81 (s, 6H), 2.64 - 2.58 (m, 1H), 2.57 - 2.51 (m, 1H), 2.07 (ddq, J = 10.6, 5.5, 2.8 Hz, 1H).

[0351] compound 3 N-[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]-N'-(2-{2-[2-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]ethoxy}ethyl)-3,6,9,12-tetraoxatradecanediamide (Compound 3) [ka]

[0352] Intermediate 1 (50 mg; 0.08 mmol) and intermediate 14 were dissolved in N,N-dimethylformamide (1 mL) in an 8 mL vial with a stir bar, followed by the addition of 4-methylmorpholine (0.1 mL) and HATU (41 mg; 0.11 mmol). The reaction mixture was stirred at RT for 18 h and then adsorbed onto Celite for purification by flash chromatography (4 g SiO, 0–10% MeOH in DCM, 13 mL / min) to give the product as an oil. The product was lyophilized but still obtained as an oil. Purification of this oil by preparative RP-HPLC gave compound 3 as a white lyophilizate (33 mg; 0.03 mmol, 35%).

[0353] LC-MS (ESI+, method Sunfire): t R = 2.37 min, m / z 575.4 [M+2H] 2+ . 1H NMR (700 MHz, DMSO-d6) δ 8.97 (s, 1H), 8.59 (t, J = 6.1 Hz, 1H), 8.53 (t, J = 5.6 Hz, 1H), 8.34 (d, J = 1.7 Hz, 1H), 8.20 (s, 1H), 8.08 (d, J = 8.4 Hz, 2H), 7.97 (d, J = 8.4 Hz, 2H), 7.85 (dd, J = 8.7, 1.9 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.64 (t, J = 5.9 Hz, 1H), 7.46 - 7.36 (m, 5H), 5.15 (s, 1H), 4.56 (d, J = 9.6 Hz, 1H), 4.44 (t, J = 8.2 Hz, 1H), 4.39 (dd, J = 15.7, 6.4 Hz, 1H), 4.35 (s, 1H), 4.30 - 4.23 (m, 1H), 4.03 (s, 3H), 3.96 (s, 2H), 3.85 (s, 2H), 3.67 (dd, J = 10.6, 4.0 Hz, 1H), 3.63 - 3.57 (m, 3H), 3.59 - 3.56 (m, 1H), 3.56 (s, 2H), 3.56 (q, J = 2.0 Hz, 3H), 3.55 - 3.49 (m, 10H), 3.45 (dt, J = 18.9, 5.9 Hz, 4H), 3.26 (q, J = 6.0 Hz, 2H), 2.43 (s, 3H), 2.09 - 2.03 (m, 1H), 1.90 (ddd, J = 13.0, 8.8, 4.5 Hz, 1H), 0.94 (s, 9H).

[0354] compound 4 N-[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]-N'-(2-{2-[2-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy}ethyl)heptanediamide (Compound 4) [ka]

[0355] Intermediate 1 (50 mg; 0.08 mmol) and 6-{[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}hexanoic acid (available analogously to Intermediate 5, 47.45 mg; 0.08 mmol) were placed in an 8 mL vial with a stir bar, followed by the addition of 4-methylmorpholine (0.1 mL) and HATU (41 mg; 0.11 mmol). The reaction mixture was stirred at RT for 18 h, then adsorbed onto Celite and purified by flash chromatography. The resulting crude oil was purified by preparative RP-HPLC, followed by lyophilization to give compound 4 (19 mg; 0.02 mmol, 22%) as a white lyophilizate.

[0356] LC-MS (ESI+, method Sunfire): t R = 2.39 min, m / z 522.4 [M+2H] 2+ . 1H NMR (700 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.55 (dt, J = 11.6, 5.8 Hz, 2H), 8.35 (d, J = 1.8 Hz, 1H), 8.21 (s, 1H), 8.09 (d, J = 8.4 Hz, 2H), 7.97 (d, J = 8.4 Hz, 2H), 7.87 - 7.82 (m, 2H), 7.80 (t, J = 5.7 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.42 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 5.13 (s, 1H), 4.53 (d, J = 9.4 Hz, 1H), 4.46 - 4.40 (m, 2H), 4.35 (tt, J = 4.4, 2.4 Hz, 1H), 4.22 (dd, J = 15.8, 5.5 Hz, 1H), 4.03 (s, 3H), 3.69 - 3.62 (m, 2H), 3.59 - 3.53 (m, 4H), 3.53 (dd, J = 5.9, 3.4 Hz, 2H), 3.46 (q, J = 6.0 Hz, 2H), 3.40 (t, J = 6.0 Hz, 2H), 3.18 (q, J = 5.9 Hz, 2H), 2.44 (s, 3H), 2.23 (ddd, J = 14.9, 8.4, 6.9 Hz, 1H), 2.10 (ddd, J = 14.7, 8.6, 6.3 Hz, 1H), 2.03 (t, J = 7.5 Hz, 3H), 1.90 (ddd, J = 12.9, 8.6, 4.7 Hz, 1H), 1.53 - 1.39 (m, 4H), 1.20 (q, J = 7.9 Hz, 2H), 0.93 (s, 9H).

[0357] Compound 4-N N-[(2S)-1-[(2S,4S)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]-N'-(2-{2-[2-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]ethoxy}ethyl)heptanediamide (Compound 4-N) [ka]

[0358] The reaction and purification were carried out similarly to the preparation of compound 4, but using instead the (S,S,S)-configured acid building block (intermediate 5) and a 1 h reaction time. After lyophilization, compound 4-N (50 mg, 0.05 mmol, 39%) was obtained as a transparent film, which was scratched to afford a white solid.

[0359] LC-MS (ESI+, method Chromolith): t R = 1.70 min, m / z 1043.6 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.62 (t, J = 6.1 Hz, 1H), 8.53 (t, J = 5.6 Hz, 1H), 8.35 (d, J = 1.8 Hz, 1H), 8.20 (s, 1H), 8.09 (d, J = 8.3 Hz, 2H), 7.96 (d, J = 8.4 Hz, 2H), 7.89 - 7.74 (m, 4H), 7.40 (q, J = 8.2 Hz, 4H), 5.43 (s, 1H), 4.45 (dd, J = 14.6, 7.6 Hz, 2H), 4.37 (dd, J = 8.6, 6.1 Hz, 1H), 4.25 (ddt, J = 22.3, 11.3, 5.6 Hz, 2H), 4.04 (s, 3H), 3.94 (dd, J = 10.1, 5.6 Hz, 1H), 3.61 - 3.55 (m, 4H), 3.53 (dd, J = 6.1, 3.6 Hz, 2H), 3.51 - 3.38 (m, 5H), 3.19 (q, J = 5.9 Hz, 2H), 2.44 (s, 3H), 2.38 - 2.29 (m, 1H), 2.22 (dt, J = 14.8, 7.6 Hz, 1H), 2.14 - 2.05 (m, 1H), 2.04 (t, J = 7.5 Hz, 2H), 1.76 (dt, J = 12.3, 5.9 Hz, 1H), 1.48 (d, J = 7.8 Hz, 1H), 1.48 - 1.38 (m, 3H), 1.19 (p, J = 7.3 Hz, 2H), 0.95 (s, 9H).

[0360] compound 5 2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]oxy}-N-(2-{2-[2-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]ethoxy}ethyl)acetamide (Compound 5) [ka]

[0361] Intermediate 1 (50 mg; 0.08 mmol) and 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid (available as described in Chem. Commun., 2020, 56, 2881-2884, 28 mg; 0.08 mmol) were dissolved in N,N-dimethylformamide (1 mL) in an 8 mL vial with a stir bar, followed by the addition of 4-methylmorpholine (0.1 mL) and then HATU (41 mg; 0.11 mmol). The reaction mixture was stirred at RT for 18 h, diluted with DMSO (1 mL), and purified by preparative RP-HPLC. The target fraction was lyophilized to give compound 5 (26 mg; 0.03 mmol, 39%) as a white lyophilizate.

[0362] LC-MS (ESI+, method Sunfire): t R = 2.33 min, m / z 803.6 [M+H] + . 1H NMR (700 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.51 (t, J = 5.6 Hz, 1H), 8.33 (d, J = 1.8 Hz, 1H), 8.19 (s, 1H), 8.08 (d, J = 8.4 Hz, 2H), 8.00 (t, J = 5.7 Hz, 1H), 7.96 (d, J = 8.5 Hz, 2H), 7.84 (dd, J = 8.6, 1.9 Hz, 1H), 7.80 - 7.74 (m, 2H), 7.46 (d, J = 7.2 Hz, 1H), 7.37 (d, J = 8.6 Hz, 1H), 5.76 (s, 1H), 5.11 (dd, J = 13.0, 5.4 Hz, 1H), 4.77 (s, 2H), 4.03 (s, 3H), 3.59 - 3.53 (m, 6H), 3.47 (dt, J = 11.8, 5.8 Hz, 4H), 3.31 (q, J = 5.6 Hz, 2H), 2.89 (ddd, J = 17.1, 14.0, 5.4 Hz, 1H), 2.59 (dt, J = 17.0, 3.4 Hz, 1H), 2.57 - 2.50 (m, 1H), 2.03 (dtd, J = 12.9, 5.4, 2.4 Hz, 1H).

[0363] compound 6 7-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}-N-(2-{2-[2-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]ethoxy}ethyl)heptanamide (Compound 6) [ka]

[0364] Intermediate 1 (50 mg; 0.08 mmol) and pomalidomide-C6-CO2H (commercially available from Sigma-Aldrich, 33 mg; 0.08 mmol) were dissolved in N,N-dimethylformamide (1 mL) in an 8 mL vial with a stir bar, followed by the addition of 4-methylmorpholine (0.1 mL) and then HATU (41 mg; 0.11 mmol). The reaction mixture was stirred at RT for 18 h. After dilution with DMSO (1 mL), the mixture was injected for purification by preparative RP-HPLC. Lyophilization of the target fraction provided compound 6 (34 mg; 0.04 mmol, 47%) as a golden yellow lyophilizate.

[0365] LC-MS (ESI+, method Sunfire): t R = 2.47 min, m / z 872.6 [M+H] + . 1H NMR (700 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.53 (q, J = 5.8, 5.1 Hz, 1H), 8.34 (d, J = 1.8 Hz, 1H), 8.20 (s, 1H), 8.08 (d, J = 8.4 Hz, 2H), 7.96 (d, J = 8.5 Hz, 2H), 7.85 (dd, J = 8.7, 1.8 Hz, 1H), 7.81 (t, J = 5.7 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.55 (dd, J = 8.5, 7.1 Hz, 1H), 7.05 (d, J = 8.6 Hz, 1H), 7.00 (d, J = 7.0 Hz, 1H), 6.49 (d, J = 6.2 Hz, 1H), 5.05 (dd, J = 12.8, 5.5 Hz, 1H), 4.03 (s, 2H), 3.59 - 3.50 (m, 5H), 3.46 (q, J = 6.0 Hz, 2H), 3.40 (t, J = 5.9 Hz, 2H), 3.24 (q, J = 6.6 Hz, 2H), 3.18 (q, J = 5.8 Hz, 2H), 2.88 (ddd, J = 17.1, 13.9, 5.4 Hz, 1H), 2.62 - 2.53 (m, 1H), 2.09 - 1.99 (m, 3H), 1.50 (dp, J = 40.8, 7.3 Hz, 4H), 1.36 - 1.21 (m, 4H).

[0366] compound 7 2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy}-N-(2-{2-[2-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]ethoxy}ethyl)acetamide (Compound 7) [ka]

[0367] 2-(2,6-Dioxopiperidin-3-yl)-5-hydroxy-2,3-dihydro-1H-isoindole-1,3-dione (1 g; 3.68 mmol) was dissolved in N,N-dimethylformamide (7.5 mL) in a 50 mL RBF with a stir bar. Sodium bicarbonate (766 mg, 9.12 mmol) and tert-butyl bromoacetate (0.7 mL; 4.56 mmol) were added. The reaction mixture was stirred at 60 °C for 18 h. The reaction mixture was cooled to RT and poured into 100 mL water. It was extracted twice with 100 mL EtOAc each time. The combined organic layers were dried over Na SO , filtered, and evaporated under reduced pressure. The residue (1.49 g brown oil) was chromatographed on a 40 g silica gel column using a dichloromethane / methanol gradient. The evaporated target fraction was suspended in MTBE, the suspension was filtered off, and the filter cake was dried under vacuum. The filter cake was washed with 10 ml diethyl ether and dried under vacuum at RT. The compound was deprotected by adding TFA (5 mL) in DCM (10 mL). The reaction mixture was stirred at RT for 4 h, the volatiles were evaporated, the residue was suspended in MTBE, the suspension was filtered off, and the filter cake was dried under vacuum. The filter cake was washed with 10 mL MTBE and dried under vacuum at 50 °C for 2 h to give 2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetic acid (1.03 g; 2.94 mmol; 75% over two steps). LC-MS (ESI+, Method Chromolith): t R = 1.45 min, m / z 389 [M+H] +Intermediate 1 (50 mg; 0.08 mmol) and 2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetic acid (28 mg; 0.08 mmol) were dissolved in N,N-dimethylformamide (1 mL) in an 8 mL vial with a stir bar. The reaction was initiated by the addition of 4-methylmorpholine (0.1 mL) and HATU (41 mg; 0.11 mmol) and stirred at RT for 3 d. The crude mixture was diluted with DMSO (1 mL) and purified by preparative RP-HPLC. Lyophilization of the target fraction gave compound 7 (29 mg; 0.04 mmol, 44%) as a white lyophilizate.

[0368] LC-MS (ESI+, method Sunfire): t R = 2.33 min, m / z 803.6 [M+H] + . 1H NMR (700 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.51 (t, J = 5.6 Hz, 1H), 8.33 (d, J = 1.8 Hz, 1H), 8.19 (s, 1H), 8.08 (d, J = 8.4 Hz, 2H), 8.00 (t, J = 5.7 Hz, 1H), 7.96 (d, J = 8.5 Hz, 2H), 7.84 (dd, J = 8.6, 1.9 Hz, 1H), 7.80 - 7.74 (m, 2H), 7.46 (d, J = 7.2 Hz, 1H), 7.37 (d, J = 8.6 Hz, 1H), 5.76 (s, 1H), 5.11 (dd, J = 13.0, 5.4 Hz, 1H), 4.77 (s, 2H), 4.03 (s, 3H), 3.59 - 3.53 (m, 6H), 3.47 (dt, J = 11.8, 5.8 Hz, 4H), 3.31 (q, J = 5.6 Hz, 2H), 2.89 (ddd, J = 17.1, 14.0, 5.4 Hz, 1H), 2.59 (dt, J = 17.0, 3.4 Hz, 1H), 2.57 - 2.50 (m, 1H), 2.03 (dtd, J = 12.9, 5.4, 2.4 Hz, 1H).

[0369] compound 8 N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-N'-(2-{2-[2-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]ethoxy}ethyl)pentanediamide (Compound 8) [ka]

[0370] To a solution of lenalidomide (1.20 g; 4.63 mmol) in toluene (10 ml) was added glutaric anhydride (634 mg; 5.55 mmol) and the reaction was stirred at 100° C. for 4 h. After cooling to 0° C., the solid was filtered off and washed with cold toluene to give 4-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]carbamoyl}butanoic acid as a pale yellow solid (1.21 g; 3.03 mmol, 66% based on 94% purity by LCMS analysis). LC-MS (ESI+, Method Sunfire): R = 1.67 min, m / z 373.9 [M+H] + Intermediate 1 (50 mg; 0.08 mmol) was dissolved in N,N-dimethylformamide (1 mL) in an 8 mL vial with a stir bar, followed by the addition of 4-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]carbamoyl}butanoic acid (31 mg; 0.08 mmol) and 4-methylmorpholine (0.1 mL). The reaction was initiated by the addition of HATU (41 mg; 0.11 mmol). The reaction mixture was stirred at RT for 18 h, diluted with DMSO (1 mL), and purified by preparative RP-HPLC. The target fraction was lyophilized to give compound 8 (31 mg; 0.04 mmol, 44%) as a white lyophilizate.

[0371] LC-MS (ESI+, method Sunfire): t R = 2,20 min, m / z 844,6 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.73 (s, 1H), 8.49 (t, J = 5.6 Hz, 1H), 8.33 (d, J = 1.8 Hz, 1H), 8.19 (s, 1H), 8.08 (d, J = 8.4 Hz, 2H), 7.96 (d, J = 8.7 Hz, 2H), 7.88 - 7.78 (m, 3H), 7.76 (d, J = 8.6 Hz, 1H), 7.53 - 7.42 (m, 2H), 5.13 (dd, J = 13.3, 5.1 Hz, 1H), 4.44 - 4.29 (m, 2H), 4.03 (s, 3H), 3.61 - 3.50 (m, 6H), 3.44 (dt, J = 18.6, 5.8 Hz, 4H), 3.20 (q, J = 5.9 Hz, 2H), 2.91 (ddd, J = 17.2, 13.5, 5.4 Hz, 1H), 2.65 - 2.56 (m, 1H), 2.42 - 2.27 (m, 3H), 2.15 (t, J = 7.3 Hz, 2H), 2.09 - 1.96 (m, 1H), 1.82 (p, J = 7.5 Hz, 2H).

[0372] compound 9 5-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]amino}-N-(2-{2-[2-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]ethoxy}ethyl)pentanamide (Compound 9) [ka]

[0373] Intermediate 1 (72 mg; 0.12 mmol) and intermediate 2 (43 mg; 0.12 mmol) were combined in an 8 mL vial with a stir bar and dissolved in dimethylformamide (DMF) (1 mL), followed by the addition of 4-methylmorpholine (0.13 mL) and then HATU (59 mg; 0.16 mmol). The reaction mixture was stirred at RT for 1 d. The mixture was then diluted with HO (1 mL) and injected into an MS-coupled preparative HPLC system. The target fraction was lyophilized to provide the product as a white lyophilizate (37 mg, 0.04 mmol, 37%).

[0374] LC-MS (ESI+, method Sunfire): t R = 2.29 min, m / z 830.6 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.53 (t, J = 5.6 Hz, 1H), 8.34 (d, J = 1.8 Hz, 1H), 8.20 (s, 1H), 8.08 (d, J = 8.5 Hz, 2H), 7.96 (d, J = 8.5 Hz, 2H), 7.88 - 7.81 (m, 2H), 7.77 (d, J = 8.7 Hz, 1H), 7.26 (t, J = 7.7 Hz, 1H), 6.92 (d, J = 7.2 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 5.55 (s, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.22 (d, J = 17.1 Hz, 1H), 4.12 (d, J = 17.1 Hz, 1H), 4.03 (s, 3H), 3.59 - 3.53 (m, 4H), 3.52 (dd, J = 5.6, 3.0 Hz, 2H), 3.46 (q, J = 6.0 Hz, 2H), 3.40 (t, J = 5.9 Hz, 2H), 3.19 (q, J = 5.9 Hz, 2H), 3.09 (t, J = 6.7 Hz, 2H), 2.92 (ddd, J = 17.3, 13.6, 5.4Hz, 1H), 2.65 - 2.57 (m, 1H), 2.29 (qd, J = 13.2, 4.5 Hz, 1H), 2.10 (q, J = 8.5, 7.7 Hz, 2H), 2.03 (ddq, J = 10.3, 5.3, 2.6 Hz, 1H), 1.63 - 1.48 (m, 3H).

[0375] compound 10 N-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-17-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamide)-3,6,9,12,15-pentaoxaheptadecanamide (Compound 10) [ka]

[0376] To a mixture of 4-amino-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione (pomalidomide, commercially available from Sigma-Aldrich) (300 mg; 1.08 mmol) in DMF (4 mL) was added 17-{[(tert-butoxy)carbonyl]amino}-3,6,9,12,15-pentaoxaheptadecanoic acid (commercially available from Sigma-Aldrich; 780 mg; 1.93 mmol) at 0° C. Then, pyridine (0.9 mL) and T3P (50% in EtOAc solution (4 mL; 6.73 mmol)) were added at 0° C. After stirring the mixture at 80° C. for 30 min, the resulting mixture was cooled to room temperature and then diluted with water (100 mL) and extracted with EtOAc (30 mL×5). The combined organic layers were concentrated, and the residue was purified by reverse-phase chromatography (column: C18 silica gel; mobile phase A: water (0.1% FA) and B: MeCN; gradient: 5% to 100% over 40 min; detector: 254 / 220 nm) to provide tert-butyl N-(1-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]carbamoyl}-2,5,8,11,14-pentaoxahexadecan-16-yl)carbamate (450 mg; 0.68 mmol; 63%; green solid). To a solution of tert-butyl N-(1-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]carbamoyl}-2,5,8,11,14-pentaoxahexadecan-16-yl)carbamate (300 mg; 0.45 mmol) in DCM (4 mL) was added TFA (1.20 mL) at 0° C. The solution was stirred at RT for 30 min and then concentrated under reduced pressure to provide 17-amino-N-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-3,6,9,12,15-pentaoxaheptadecanamide (220 mg; 0.38 mmol; 85%) as a green solid.TEAD ligand 1 (20 mg; 0.06 mmol), 17-amino-N-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-3,6,9,12,15-pentaoxaheptadecanamide (61 mg; 0.11 mmol), HATU (25 mg; 0.07 mmol), and 4-methylmorpholine (24 μL; 0.22 mmol) were dissolved in DMF (5 mL) and stirred overnight at RT. The reaction mixture was directly purified by preparative RP-HPLC, and the target fraction was released from the solvent in vacuo to give compound 10 (26 mg; 0.03 mmol, 52%).

[0377] LC-MS (ESI+, method Chromolith): t R = 1.68 min, m / z 892.00 [M+H] + . 1 H NMR (700 MHz, DMSO-d6) δ 11.14 (s, 1H), 10.32 (s, 1H), 8.70 (d, J = 8.4 Hz, 1H), 8.51 (t, J = 5.6 Hz, 1H), 8.33 (d, J = 1.9 Hz, 1H), 8.19 (s, 1H), 8.08 (d, J = 8.4 Hz, 2H), 7.96 (d, J = 8.5 Hz, 2H), 7.87 - 7.82 (m, 2H), 7.76 (d, J = 8.6 Hz, 1H), 7.61 (d, J = 7.3 Hz, 1H), 5.15 (dd, J = 13.0, 5.4 Hz, 1H), 4.17 (s, 2H), 4.03 (s, 3H), 3.75 - 3.71 (m, 2H), 3.65 - 3.61 (m, 2H), 3.58 - 3.42 (m, 17H), 2.89 (s, 1H), 2.93 - 2.85 (m, 1H), 2.73 (s, 0H), 2.62 (dd, J = 4.4, 2.5 Hz, 1H), 2.06 (dtt, J = 13.0, 5.5, 2.7 Hz, 1H), 1.99 (s, 1H), 1.17 (t, J = 7.1 Hz, 2H).

[0378] compound 11 (2R,4S)-1-[(2R)-3,3-dimethyl-2-[17-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)-3,6,9,12,15-pentaoxaheptadecanamido]butanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide (Compound 11) [ka]

[0379] 17-{[(tert-butoxy)carbonyl]amino}-3,6,9,12,15-pentaoxaheptadecanoic acid (commercially available from Sigma-Aldrich; 898 mg; 2.27 mmol) was diluted with N,N-dimethylformamide (15 ml) and cooled to 0 °C. HATU (802 mg; 3.41 mmol) was then added, and the mixture was stirred for 5 min. Finally, (2S,4R)-1-((S)-2-amino-3,3-dimethyl-butyryl)-4-hydroxy-pyrrolidine-2-carboxylic acid 4-(4-methyl-thiazol-5-yl)-benzylamide (815 mg; 1.89 mmol) and N-ethyldiisopropylamine (772 μL; 4.54 mmol) were added, and the reaction mixture was stirred at room temperature overnight. HATU (89 mg; 0.38 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethyl-butyryl)-4-hydroxy-pyrrolidine-2-carboxylic acid 4-(4-methyl-thiazol-5-yl)-benzylamide (163 mg; 0.38 mmol) were added, and the mixture was stirred overnight again. The reaction mixture was evaporated to dryness under reduced pressure. The crude product was dissolved in MeOH / DMSO and purified by preparative flash chromatography (Teledyne Isco). The product fractions were combined and evaporated to dryness under reduced pressure. The two main fractions showed impurities via LC-MS analysis. Both fractions were combined and purified again by preparative flash chromatography. The resulting yellow residue was dissolved in dichloromethane (15 mL) and trifluoroacetic acid (7 mL). The mixture was stirred at room temperature overnight. LC-MS showed complete consumption. The mixture was evaporated under reduced pressure and co-evaporated three times with toluene (15 mL each). Finally, (2S,4R)-1-[(2S)-2-(17-amino-3,6,9,12,15-pentaoxaheptadecanamido)-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide (1224.70 mg; 1.73 mmol) was obtained as a colorless solid. LCMS (ESI+, Method Chromolith): R = 1.17 min, m / z 708.4 [M+H] +TEAD ligand 1 (30 mg; 0.08 mmol), (2R,4S)-1-[(2R)-2-(17-amino-3,6,9,12,15-pentaoxaheptadecanamido)-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide (59 mg; 0.08 mmol), HATU (38 mg; 0.10 mmol), and 4-methylmorpholine (37 μL; 0.33 mmol) were dissolved in N,N-dimethylformamide (5 mL) and stirred overnight at room temperature. The reaction mixture was directly purified by preparative RP-HPLC column chromatography, and the target fraction was released from the solvent in vacuo to give compound 11 (23 mg; 0.02 mmol, 25% yield based on 95% purity by LCMS).

[0380] LC-MS (ESI+, method Chromolith): t R = 1.68 min, m / z 525.0 [M+2H] 2+ . 1H NMR (700 MHz, DMSO-d6) δ 8.97 (s, 1H), 8.59 (t, J = 6.1 Hz, 1H), 8.53 (t, J = 5.6 Hz, 1H), 8.34 (d, J = 1.8 Hz, 1H), 8.20 (s, 1H), 8.08 (d, J = 8.6 Hz, 2H), 7.96 (d, J = 8.3 Hz, 2H), 7.85 (dd, J = 8.7, 1.9 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.45 - 7.36 (m, 4H), 5.14 (d, J = 3.6 Hz, 1H), 4.56 (d, J = 9.5 Hz, 1H), 4.44 (t, J = 8.2 Hz, 1H), 4.39 (dd, J = 15.7, 6.4 Hz, 1H), 4.35 (s, 1H), 4.25 (td, J = 15.7, 14.4, 5.6 Hz, 1H), 4.03 (s, 3H), 3.95 (s, 2H), 3.66 (dd, J = 10.7, 4.0 Hz, 1H), 3.62 - 3.55 (m, 3H), 3.57 - 3.52 (m, 5H), 3.54 - 3.48 (m, 7H), 3.48 (d, J = 2.6 Hz, 1H), 3.45 (ddd, J = 11.8, 7.4, 4.3 Hz, 4H), 2.43 (s, 2H), 2.05 (dd, J = 12.8, 7.7 Hz, 1H), 1.90 (ddd, J = 13.0, 8.8, 4.6 Hz, 1H), 0.93 (s, 9H).

[0381] compound 12 (2S,4R)-1-{(2S)-3,3-dimethyl-2-[14-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)-3,6,9,12-tetraoxatetradecanamido]butanoyl}-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide (Compound 12)

change

[0382] To a solution of (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide hydrochloride (commercially available from Sigma-Aldrich; 500 mg; 1.06 mmol) and 14-{[(tert-butoxy)carbonyl]amino}-3,6,9,12-tetraoxatetradecanoic acid (380 mg; 1.07 mmol) in ACN (5 mL) was added N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (360 mg; 1.22 mmol) and N-methylimidazole (0.35 mL; 4.17 mmol). The resulting mixture was stirred at RT for 1 h. The mixture was directly purified via reverse-phase chromatography (column: C18 silica gel; mobile phase A: water (containing 0.1% FA) and B: CH3CN (hold 5% for 5 min, then hold 5% to 100% for 30 min); detector: 2 20 / 254 nm) to provide tert-butyl N-(1-{[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}-2,5,8,11-tetraoxatridecan-13-yl)carbamate (640 mg; 0.84 mmol; 79%) as a colorless oil. TEAD ligand 1 (30 mg; 0.08 mmol), (2S,4R)-1-[(2S)-2-(14-amino-3,6,9,12-tetraoxatetradecanamido)-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide (55 mg; 0.08 mmol), HATU (38 mg; 0.10 mmol), and 4-methylmorpholine (37 μL; 0.33 mmol) were dissolved in N,N-dimethylformamide (5 mL) and stirred overnight at RT. Water and ethyl acetate were added. The layers were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and evaporated to dryness.The crude residue was purified by preparative RP-HPLC. The target fraction was dried under vacuum to give compound 12 (37 mg; 0.03 mmol; 39% based on 87% purity by LCMS).

[0383] LC-MS (ESI+, method Chromolith): t R = 1.69 min, m / z 503.0 [M+2H] 2+ . 1 H NMR (700 MHz, DMSO-d6) δ 8.97 (s, 1H), 8.59 (t, J = 6.2 Hz, 1H), 8.53 (t, J = 5.6 Hz, 1H), 8.34 (d, J = 1.9 Hz, 1H), 8.20 (s, 1H), 8.11 - 8.06 (m, 2H), 7.98 - 7.94 (m, 3H), 7.85 (dd, J = 8.7, 1.9 Hz, 1H), 7.76 (d, J = 8.6 Hz, 1H), 7.42 (dd, J = 15.3, 8.8 Hz, 1H), 7.41 - 7.36 (m, 4H), 5.14 (d, J = 3.6 Hz, 1H), 4.56 (d, J = 9.6 Hz, 1H), 4.44 (t, J = 8.2 Hz, 1H), 4.38 (dd, J = 15.7, 6.4 Hz, 1H), 4.35 (s, 1H), 4.25 (dd, J = 15.7, 5.7 Hz, 1H), 4.03 (s, 4H), 4.03 (q, J = 7.1 Hz, 1H), 3.94 (s, 2H), 3.66 (dd, J = 10.6, 4.0 Hz, 1H), 3.62 - 3.49 (m, 14H), 3.45 (q, J = 6.0 Hz, 2H), 3.02 (s, 1H), 2.43 (s, 3H), 2.08 - 2.03 (m, 1H), 1.99 (s, 2H), 1.90 (ddd, J = 12.9, 8.8, 4.5 Hz, 1H), 1.17 (t, J = 7.1 Hz, 2H), 0.93 (s, 9H).

[0384] compound 13 N-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]-14-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamide)-3,6,9,12-tetraoxatetradecanamide (Compound 13) [ka]

[0385] TEAD ligand 1 (40 mg; 0.11 mmol), 14-amino-N-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]-3,6,9,12-tetraoxatetradecanamide (prepared similarly as described in WO 2020 / 152067 A1; 56 mg; 0.11 mmol), HATU (51 mg; 0.13 mmol), and 4-methylmorpholine (49 mL; 0.45 mmol) were dissolved in N,N-dimethylformamide (5 ml) and stirred overnight at RT. The reaction mixture was directly purified by preparative RP-HPLC. The product fractions were combined and dried under vacuum to provide compound 13 (14 mg, 0.02 mmol, 14% based on 94% purity by LCMS).

[0386] LC-MS (ESI+, method Chromolith): t R = 1.62 min, m / z 848.0 [M+H] + . 1H NMR (700 MHz, DMSO-d6) δ 11.11 (s, 1H), 10.29 (s, 1H), 8.51 (t, J = 5.6 Hz, 1H), 8.33 (d, J = 1.9 Hz, 1H), 8.27 (d, J = 1.9 Hz, 1H), 8.19 (s, 1H), 8.11 - 8.06 (m, 2H), 8.03 - 7.94 (m, 3H), 7.94 - 7.82 (m, 2H), 7.80 - 7.74 (m, 1H), 5.12 (dd, J = 12.9, 5.5 Hz, 1H), 4.15 (s, 2H), 4.06 - 4.00 (m, 4H), 3.68 - 3.64 (m, 2H), 3.61 - 3.57 (m, 2H), 3.59 - 3.52 (m, 10H), 3.45 (q, J = 6.0 Hz, 2H), 2.88 (ddd, J = 17.1, 13.9, 5.5 Hz, 1H), 2.59 (d, J = 21.3 Hz, 1H), 2.04 (dtd, J = 11.1, 6.0, 5.5, 2.8 Hz, 1H), 1.99 (s, 1H), 1.17 (t, J = 7.1 Hz, 1H).

[0387] compound 14 4-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]amino}-N-(2-{2-[2-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]ethoxy}ethyl)butanamide (Compound 14) [ka]

[0388] An 8 mL vial with a stir bar was charged with intermediate 1 (60 mg; 0.10 mmol) and intermediate 3 (34 mg; 0.10 mmol), followed by dissolution in dimethylformamide (DMF) (1 mL) and the addition of 4-methylmorpholine (0.11 mL; 0.99 mmol) and finally HATU (49 mg; 0.13 mmol). The reaction mixture was stirred at RT for 18 h, then diluted with water (2 mL) and purified by MS-coupled preparative RP-HPLC. Lyophilization of the target fraction gave compound 14 (23 mg; 0.03 mmol, 28%) as a white lyophilizate.

[0389] LC-MS (ESI+, method Sunfire): t R = 2.27 min, m / z 816.6 [M+H] + . 1 H NMR (500 MHz, DMSO-d 6) δ 10.99 (s, 1H), 8.53 (t, J = 5.6 Hz, 1H), 8.34 (d, J = 1.8 Hz, 1H), 8.20 (s, 1H), 8.08 (d, J = 8.4 Hz, 2H), 7.96 (d, J = 8.5 Hz, 2H), 7.90 - 7.82 (m, 2H), 7.77 (d, J = 8.7 Hz, 1H), 7.26 (t, J = 7.7 Hz, 1H), 6.92 (d, J = 7.4 Hz, 1H), 6.72 (d, J = 8.1 Hz, 1H), 5.61 (s, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.22 (d, J = 17.1 Hz, 1H), 4.12 (d, J = 17.1 Hz, 1H), 4.03 (s, 3H), 3.59 - 3.53 (m, 4H), 3.52 (dd, J = 5.5, 3.0 Hz, 2H), 3.46 (q, J = 5.9 Hz, 2H), 3.41 (t, J = 5.9 Hz, 2H), 3.21 (q, J = 5.8 Hz, 2H), 3.09 (t, J = 7.1 Hz, 2H), 2.92 (ddd, J = 17.3, 13.6, 5.4 Hz, 1H), 2.61 (dt, J = 17.4, 4.1 Hz, 1H), 2.34 - 2.23 (m, 1H), 2.19 (t, J = 7.3 Hz, 2H), 2.03 (ddq, J = 10.5, 5.5, 3.1, 2.7 Hz, 1H), 1.79 (p, J = 7.2 Hz, 2H).

[0390] compound 15 7-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]amino}-N-(2-{2-[2-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]ethoxy}ethyl)heptanamide (Compound 15) [ka]

[0391] Intermediate 4 (73 mg; 0.19 mmol) and intermediate 1 (114 mg; 0.19 mmol) were dissolved in DMF (2 mL) in an 8 mL vial with a stir bar, followed by the addition of 4-methylmorpholine (0.1 mL; 0.94 mmol) and finally HATU (86 mg; 0.23 mmol). The reaction mixture was stirred at RT for 24 h and then directly injected for purification by preparative RP-HPLC-MS. Lyophilization of the target fraction gave compound 15 (65 mg; 0.08 mmol, 47%) as a white solid.

[0392] LC-MS (ESI+, method Sunfire): t R = 2.47 min, m / z 872.6 [M+H] + . 1H NMR (700 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.53 (q, J = 5.8, 5.1 Hz, 1H), 8.34 (d, J = 1.8 Hz, 1H), 8.20 (s, 1H), 8.08 (d, J = 8.4 Hz, 2H), 7.96 (d, J = 8.5 Hz, 2H), 7.85 (dd, J = 8.7, 1.8 Hz, 1H), 7.81 (t, J = 5.7 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.55 (dd, J = 8.5, 7.1 Hz, 1H), 7.05 (d, J = 8.6 Hz, 1H), 7.00 (d, J = 7.0 Hz, 1H), 6.49 (d, J = 6.2 Hz, 1H), 5.05 (dd, J = 12.8, 5.5 Hz, 1H), 4.03 (s, 2H), 3.59 - 3.50 (m, 5H), 3.46 (q, J = 6.0 Hz, 2H), 3.40 (t, J = 5.9 Hz, 2H), 3.24 (q, J = 6.6 Hz, 2H), 3.18 (q, J = 5.8 Hz, 2H), 2.88 (ddd, J = 17.1, 13.9, 5.4 Hz, 1H), 2.62 - 2.53 (m, 1H), 2.09 - 1.99 (m, 3H), 1.50 (dp, J = 40.8, 7.3 Hz, 4H), 1.36 - 1.21 (m, 4H).

[0393] compound 16 N-(14-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]oxy}-3,6,9,12-tetraoxatetradecan-1-yl)-2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxamide (Compound 16) [ka]

[0394] Triphenylphosphine (56 mg; 0.22 mmol) was placed in a heat-gun-dried 10 mL Schlenk tube with a stir bar under N2, dissolved in dry THF (1 mL), and cooled to 0 °C, followed by the addition of diisopropyl azodicarboxylate (44 mg; 0.22 mmol). The mixture was stirred at 0 °C until the formation of a milky-white precipitate occurred (approximately 20 min). Meanwhile, a solution of intermediate 8 (62 mg; 0.11 mmol) and intermediate 7 (81 mg; 0.22 mmol) in dry THF (3 mL) was prepared. This solution was added to the milky-white precipitate via syringe at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, the ice bath was removed, and the reaction mixture was left stirring at RT for 2 h. The volatiles were removed by rotary evaporation, and the residue was redissolved in DMF (2 mL). The resulting solution was used for purification by preparative RP-HPLC-MS. The target fraction (last peak) was lyophilized to afford Boc-16 (49 mg, 0.05 mmol, 49%) as an amber oil. This intermediate was dissolved in DCM (5 mL), followed by the addition of TFA (5 mL) at room temperature. The reaction mixture was stirred at RT for 45 min. Volatiles were removed by rotary evaporation, and the crude mixture was redissolved in DMF (2 mL). The resulting solution was used for injection into a preparative RP-HPLC-MS system. The target fraction was lyophilized to afford compound 16 (32 mg, 0.04 mmol, 73%) as a white solid.

[0395] LC-MS (ESI+, method Sunfire): t R = 2,40 min, m / z 834,6 [M+H] + . 1H NMR (700 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.52 (t, J = 5.6 Hz, 1H), 8.34 (d, J = 1.9 Hz, 1H), 8.20 (s, 1H), 8.08 (d, J = 8.5 Hz, 2H), 7.96 (d, J = 8.6 Hz, 2H), 7.85 (dd, J = 8.6, 1.9 Hz, 1H), 7.80 - 7.75 (m, 2H), 7.49 (d, J = 8.6 Hz, 1H), 7.44 (d, J = 7.1 Hz, 1H), 5.08 (dd, J = 12.9, 5.4Hz, 1H), 4.32 - 4.26 (m, 2H), 4.03 (s, 3H), 3.79 - 3.74 (m, 2H), 3.61 (dd, J = 5.9, 3.8 Hz, 2H), 3.58 - 3.48 (m, 12H), 3.45 (q, J = 5.9 Hz, 2H), 2.88 (ddd, J = 17.1, 14.0, 5.4 Hz, 1H), 2.58 (dt, J = 17.2, 3.4 Hz, 1H), 2.01 (dtd, J = 13.1, 5.4, 2.3 Hz, 1H).

[0396] compound 17 3-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]carbamoyl}ethoxy)ethoxy]-N-[2-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethyl]propenamide (Compound 17) [ka]

[0397] Intermediate 9 (40 mg; 0.10 mmol) was dissolved in DMF. The reaction was set up with a SynpleChem machine using cartridge P043 (available from SynpleChem AG; see also T. Jiang, et al., Chem. Sci., 2021, 12, 6977-6982). The reaction mixture was evaporated to dryness, and the crude residue was purified by flash column chromatography (4 g SiO2 cartridge, 0-80% MeOH in DCM). Release of the target fraction from the solvent gave compound 17 (29 mg; 0.03 mmol; 32% based on 99% purity by LCMS).

[0398] LC-MS (ESI+, method Chromolith): t R = 1.60 min, m / z 889.00 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 11.13 (s, 1H), 9.84 (s, 1H), 8.54 - 8.46 (m, 2H), 8.32 (d, J = 1.8 Hz, 1H), 8.19 (s, 1H), 8.08 (d, J = 8.4 Hz, 2H), 7.96 (d, J = 8.8 Hz, 3H), 7.86 - 7.74 (m, 3H), 7.58 (dd, J = 7.3, 0.8 Hz, 1H), 5.13 (dd, J = 12.9, 5.4 Hz, 1H), 4.03 (q, J = 7.1 Hz, 1H), 4.03 (s, 3H), 3.71 (t, J = 6.0 Hz, 2H), 3.61 - 3.47 (m, 6H), 3.47 - 3.41 (m, 3H), 3.31 - 3.23 (m, 3H), 2.89 (ddd, J = 17.1, 13.8, 5.4 Hz, 1H), 2.68 (t, J = 6.0 Hz, 2H), 2.64 - 2.52 (m, 1H), 2.31 (t, J = 6.5 Hz, 2H), 1.99 (s, 1H), 1.18 (t, J = 7.1 Hz, 1H).

[0399] compound 18 3-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]carbamoyl}ethoxy)ethoxy)-N-[2-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethyl]propanamide (Compound 18) [ka]

[0400] Intermediate 9 (40 mg; 0.10 mmol) was dissolved in DMF. The reaction was set up with a SynpleChem machine using cartridge P042 (available from SynpleChem AG; see also T. Jiang, et al., Chem. Sci., 2021, 12, 6977-6982). The reaction mixture was evaporated to dryness. The crude residue was purified by flash column chromatography (4 g SiO2 cartridge, 0-70% MeOH in DCM). Product fractions were combined and evaporated to dryness to give compound 18 (40 mg; 0.04 mmol; 44% based on 94% purity by LCMS).

[0401] LC-MS (ESI+, method Chromolith): t R = 1.59 min, m / z 845.00 [M+H] + . 1H NMR (700 MHz, DMSO-d6) δ 11.14 (s, 1H), 9.84 (s, 1H), 8.52 (d, J = 8.3 Hz, 1H), 8.49 (t, J = 5.6 Hz, 1H), 8.32 (d, J = 1.9 Hz, 1H), 8.19 (s, 1H), 8.08 (d, J = 8.3 Hz, 2H), 7.97 (t, J = 8.2 Hz, 3H), 7.83 (dd, J = 8.7, 1.9 Hz, 1H), 7.80 (dd, J = 8.4, 7.3 Hz, 1H), 7.76 (d, J = 8.6 Hz, 1H), 7.58 (dd, J = 7.4, 0.7 Hz, 1H), 5.14 (dd, J = 13.0, 5.5 Hz, 1H), 4.03 (s, 3H), 3.70 (t, J = 6.0 Hz, 2H), 3.60 (t, J = 6.5 Hz, 2H), 3.54 (dd, J = 6.3, 3.9 Hz, 2H), 3.52 - 3.48 (m, 2H), 3.47 - 3.41 (m, 1H), 3.34 (s, 1H), 3.30 (s, 1H), 3.25 (q, J = 6.4 Hz, 2H), 2.89 (ddd, J = 17.3, 13.8, 5.5 Hz, 1H), 2.67 (t, J = 6.0 Hz, 2H), 2.64 - 2.58 (m, 1H), 2.54 (dd, J = 13.1, 4.5 Hz, 1H), 2.31 (t, J = 6.5 Hz, 2H), 2.06 (dtd, J = 12.9, 5.3, 2.3 Hz, 1H), 1.06 (t, J = 7.0 Hz, 1H).

[0402] compound 19 N-(3-{6-[4-(3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]carbamoyl}propyl)piperazin-1-yl]pyridin-3-yl}prop-2-yn-1-yl)-2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxamide, formate (Compound 19) [ka]

[0403] 14-{4-[5-(3-aminoprop-1-yn-1-yl)pyridin-2-yl]piperazin-1-yl}-N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]butanamide hydrochloride (commercially available from Sigma-Aldrich, 53 mg; 0.09 mmol) and TEAD ligand 1 (33 mg; 0.09 mmol) were suspended in dimethylformamide (DMF) (1 mL), followed by the addition of 4-methylmorpholine (0.05 mL). The mixture was vortexed until all components were dissolved. HATU (42 mg; 0.11 mmol) was added, and the reaction mixture was stirred at RT for 18 h. The mixture was directly injected onto a preparative RP-HPLC-M system and the target fraction was lyophilized to give compound 19 (40 mg; 0.04 mmol, 45%) as an off-white solid.

[0404] LC-MS (ESI+, method Sunfire): t R = 1.87 min, m / z 443.00 [M+2H] 2+ . 1H NMR (500 MHz, DMSO-d6) δ 10.97 (s, 1H), 10.22 (s, 1H), 9.01 (t, J = 5.5 Hz, 1H), 8.40 (d, J = 1.8 Hz, 1H), 8.23 ​​- 8.16 (m, 2H), 8.14 (s, 1H), 8.09 (d, J = 8.4 Hz, 2H), 8.01 - 7.94 (m, 3H), 7.90 (dd, J = 8.8, 1.9 Hz, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.59 (dd, J = 8.4, 1.7 Hz, 1H), 7.55 (dd, J = 8.9, 2.4 Hz, 1H), 6.80 (d, J = 9.0 Hz, 1H), 5.08 (dd, J = 13.3, 5.1 Hz, 1H), 4.41 (d, J = 17.2 Hz, 1H), 4.36 (d, J = 5.4 Hz, 2H), 4.28 (d, J = 17.2 Hz, 1H), 4.04 (s, 3H), 3.52 (t, J = 5.1 Hz, 4H), 2.91 (ddd, J = 17.3, 13.6, 5.4 Hz, 1H), 2.60 (dt, J = 15.1, 2.8 Hz, 1H), 2.48 (d, J = 5.1 Hz, 4H), 2.43 (d, J = 7.3 Hz, 2H), 2.42 - 2.31 (m, 3H), 1.99 (dtd, J = 12.7, 5.3, 2.3 Hz, 1H), 1.81 (p, J = 7.2 Hz, 2H).

[0405] compound 20 (2S,4R)-1-[(2S)-3,3-dimethyl-2-[10-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)decanamido]butanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide (Compound 20) [ka]

[0406] ((2S,4R)-1-((S)-2-(10-aminodecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (commercially available from Sigma-Aldrich, 48 mg; 0.08 mmol) and TEAD ligand 1 (27 mg; 0.08 mmol) were dissolved in dimethylformamide (DMF) (1 mL), followed by the addition of 4-methylmorpholine (0.04 mL) and finally HATU (34 mg; 0.09 mmol). The reaction mixture was stirred overnight at RT. The mixture was directly purified by preparative RP-HPLC-MS, and the target fraction was lyophilized to afford compound 20 (44 mg; 0.05 mmol, 62%) as a microcrystalline powder.

[0407] LC-MS (ESI+, method Sunfire): t R = 2.68 min, m / z 471.22 [M+2H] 2+ . 1H NMR (500 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.55 (t, J = 6.1 Hz, 1H), 8.45 (t, J = 5.7 Hz, 1H), 8.33 (d, J = 1.8 Hz, 1H), 8.20 (s, 1H), 8.08 (d, J = 8.4 Hz, 2H), 7.96 (d, J = 8.5 Hz, 2H), 7.87 - 7.80 (m, 2H), 7.76 (d, J = 8.7 Hz, 1H), 7.45 - 7.35 (m, 4H), 4.54 (d, J = 9.4 Hz, 1H), 4.43 (ddd, J = 9.9, 6.7, 3.2 Hz, 2H), 4.35 (tt, J = 4.3, 2.5 Hz, 1H), 4.22 (dd, J = 15.8, 5.5 Hz, 1H), 4.03 (s, 3H), 3.71 - 3.61 (m, 2H), 3.28 (q, J = 6.7 Hz, 2H), 2.44 (s, 3H), 2.26 (dt, J = 14.8, 7.6 Hz, 1H), 2.11 (ddd, J = 14.2, 8.1, 6.3 Hz, 1H), 2.07 - 1.99 (m, 1H), 1.91 (ddd, J = 12.9, 8.5, 4.6 Hz, 1H), 1.50 (ddt, J = 38.5, 13.4, 6.9 Hz, 4H), 1.33 (t, J = 5.0 Hz, 1H), 1.27 (h, J = 9.2, 7.0 Hz, 10H), 0.93 (s, 9H).

[0408] compound 21 10-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}-N-(2-{2-[2-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]ethoxy}ethyl)decanamide (Compound 21) [ka]

[0409] In an 8 mL vial with a stir bar, intermediate 1 (50 mg; 0.08 mmol) and 10-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)decanoic acid (commercially available from Sigma-Aldrich, 37 mg; 0.08 mmol) were dissolved in N,N-dimethylformamide (1 mL), followed by the addition of 4-methylmorpholine (0.1 mL) and finally HATU (41 mg; 0.11 mmol). The reaction mixture was stirred at RT for 18 h. The mixture was used for purification by preparative RP-HPLC to give compound 21 (33 mg; 0.04 mmol, 44%) as a yellow residue after lyophilization of the target fractions.

[0410] LC-MS (ESI+, method Sunfire): t R = 2.63 min, m / z 914.6 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.52 (t, J = 5.6 Hz, 1H), 8.34 (d, J = 1.8 Hz, 1H), 8.19 (s, 1H), 8.08 (d, J = 8.3 Hz, 2H), 7.96 (d, J = 8.4 Hz, 2H), 7.85 (dd, J = 8.7, 1.8 Hz, 1H), 7.77 (d, J = 8.6 Hz, 2H), 7.56 (dd, J = 8.6, 7.1 Hz, 1H), 7.05 (d, J = 8.6 Hz, 1H), 7.00 (d, J = 7.0 Hz, 1H), 6.48 (t, J = 5.9 Hz, 1H), 5.04 (dd, J = 12.8, 5.4 Hz, 1H), 4.03 (s, 3H), 3.60 - 3.54 (m, 4H), 3.52 (dd, J = 6.1, 3.5 Hz, 2H), 3.46 (q, J = 6.0 Hz, 2H), 3.40 (t, J = 5.9 Hz, 2H), 3.24 (q, J = 6.6 Hz, 2H), 3.18 (q, J = 5.8 Hz, 2H), 2.88 (ddd, J = 17.0, 13.8, 5.4 Hz, 1H), 2.63 - 2.52 (m, 2H), 2.02 (t, J = 7.5 Hz, 3H), 1.58 - 1.45 (m, 2H), 1.43 (q, J = 7.2 Hz, 2H), 1.34 - 1.21 (m, 2H), 1.20 (s, 5H).

[0411] compound 22 N-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-N'-[(2R)-2-{[8-(4-fluorophenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indol-5-yl]formamido}propyl]-3,6,9,12,15-pentaoxaheptadecanediamide (Compound 22) [ka]

[0412] To intermediate 10 (40 mg; 0.11 mmol) in DMF (3 ml) was added 1-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]carbamoyl}-2,5,8,11,14-pentaoxahexadecan-16-oic acid (available analogously to compound 24 in ACS Chem. Biol. 2017, 12, 2570-2578 (Supplementary Information); 62 mg; 0.11 mmol), EDC hydrochloride (42 mg; 0.22 mmol), HOBT hydrate (17 mg; 0.11 mmol), and 4-methylmorpholine (0.06 mL; 0.55 mmol). The reaction was stirred overnight at RT and then evaporated to dryness. The crude residue was purified by preparative RP-HPLC. The product fractions were combined and dried under vacuum to give compound 22 (15 mg; 0.02 mmol; 15%).

[0413] LC-MS (ESI+, method Chromolith): t R = 1.52 min, m / z 457.00 [M+2H] 2+ . 1H NMR (500 MHz, DMSO-d6) δ 11.13 (s, 1H), 10.32 (s, 1H), 8.70 (d, J = 8.4 Hz, 1H), 8.29 (d, J = 1.8 Hz, 1H), 8.19 (d, J = 7.9 Hz, 1H), 8.15 (s, 1H), 7.84 (dd, J = 8.5, 7.3 Hz, 1H), 7.84 - 7.75 (m, 4H), 7.64 - 7.59 (m, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.48 - 7.39 (m, 2H), 5.15 (dd, J = 12.9, 5.4 Hz, 1H), 4.22 - 4.12 (m, 3H), 4.00 (s, 3H), 3.87 (s, 2H), 3.73 (dd, J = 5.8, 3.5 Hz, 2H), 3.68 - 3.61 (m, 2H), 3.56 - 3.43 (m, 7H), 3.43 (s, 4H), 3.28 (s, 1H), 3.23 (dd, J = 13.4, 6.7 Hz, 1H), 2.89 (ddd, J = 17.0, 13.9, 5.4 Hz, 1H), 2.65 - 2.52 (m, 2H), 2.13 - 2.03 (m, 1H), 1.15 (d, J = 6.7 Hz, 3H).

[0414] compound 23 N-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-N'-[(2R)-2-{[2-methyl-8-(4-methylphenyl)-2H,8H-pyrazolo[3,4-b]indol-5-yl]formamido}propyl]-3,6,9,12,15-pentaoxaheptadecanediamide (Compound 23) [ka]

[0415] To intermediate 11 (40 mg; 0.11 mmol) in DMF (3 ml) was added 1-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]carbamoyl}-2,5,8,11,14-pentaoxahexadecan-16-oic acid (available analogously to compound 24 in ACS Chem. Biol. 2017, 12, 2570-2578 (Supplementary Information); 63 mg; 0.11 mmol), EDC hydrochloride (42 mg; 0.22 mmol), HOBt hydrate (17 mg; 0.11 mmol), and 4-methylmorpholine (0.06 mL; 0.55 mmol). The reaction was stirred overnight at RT. The mixture was evaporated to dryness. The crude residue was purified by preparative RP-HPLC. The product fractions were combined and dried under vacuum to give compound 23 (25 mg; 0.03 mmol; 25%).

[0416] LC-MS (ESI+, method Chromolith): t R = 1.52 min, m / z 455.00 [M+2H] 2+ . 1H NMR (500 MHz, DMSO-d6) δ 11.13 (s, 1H), 10.32 (s, 1H), 8.70 (d, J = 8.4 Hz, 1H), 8.28 (d, J = 1.8 Hz, 1H), 8.18 (d, J = 7.9 Hz, 1H), 8.13 (s, 1H), 7.88 - 7.75 (m, 3H), 7.62 (td, J = 6.9, 1.4 Hz, 3H), 7.52 (d, J = 8.6 Hz, 1H), 7.43 - 7.37 (m, 2H), 5.15 (dd, J = 12.9, 5.4 Hz, 1H), 4.21 - 4.12 (m, 3H), 4.00 (s, 3H), 3.87 (s, 2H), 3.72 (dd, J = 5.8, 3.5 Hz, 2H), 3.63 (dd, J = 5.8, 3.6 Hz, 2H), 3.56 - 3.42 (m, 6H), 3.43 (s, 3H), 3.22 (dd, J = 13.4, 6.7 Hz, 1H), 2.89 (ddd, J = 17.0, 13.8, 5.4 Hz, 1H), 2.62 (d, J = 3.2 Hz, 1H), 2.39 (s, 3H), 1.14 (d, J = 6.6 Hz, 3H).

[0417] compound 24 N'-[(2S)-1-[(2S,4R)-4-hydroxy-2-{[[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl}pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]-N-(2-{2-[2-[2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]ethoxy}ethyl)heptanediamide (Compound 24) [ka]

[0418] Intermediate 6 (39 mg; 0.06 mmol), intermediate 1 (40 mg; 0.06 mmol), and 4-methylmorpholine (0.03 mL) were dissolved in dimethylformamide (DMF) (1 mL), followed by the addition of HATU (30 mg; 0.08 mmol) in a 100 mL RBF with a stir bar. The reaction mixture was stirred at RT for 1 h, at which time the crude mixture was injected into a preparative RP-HPLC-MS system to give compound 24 (32 mg, 0.03 mmol, 46%).

[0419] LC-MS (ESI+, method Sunfire): t R = 2.43 min, m / z 529.40 [M+2H] 2+ . 1H NMR (500 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.60 (t, J = 5.6 Hz, 1H), 8.43 (d, J = 7.8 Hz, 1H), 8.35 (d, J = 1.7 Hz, 1H), 8.22 (s, 1H), 8.09 (d, J = 8.4 Hz, 2H), 7.98 (d, J = 8.7 Hz, 2H), 7.90 - 7.81 (m, 3H), 7.78 (d, J = 8.7 Hz, 1H), 7.46 - 7.40 (m, 2H), 7.40 - 7.30 (m, 2H), 5.15 (s, 1H), 4.91 (p, J = 7.1 Hz, 1H), 4.51 (d, J = 9.4 Hz, 1H), 4.41 (t, J = 8.1 Hz, 1H), 4.28 (q, J = 3.3 Hz, 1H), 4.04 (s, 3H), 3.62 - 3.50 (m, 8H), 3.17 (q, J = 5.9 Hz, 2H), 2.45 (s, 3H), 2.22 (dt, J = 14.8, 7.7 Hz, 1H), 2.14 - 2.05 (m, 1H), 2.02 (q, J = 8.3, 7.8 Hz, 3H), 1.77 (ddd, J = 13.0, 8.7, 4.6 Hz, 1H), 1.51 - 1.38 (m, J = 6.7, 5.9 Hz, 4H), 1.36 (d, J = 7.0 Hz, 3H), 1.19 (dq, J = 14.5, 8.7, 7.0 Hz, 2H), 0.92 (s, 9H).

[0420] compound 25 (3R,5S)-1-[(2S)-3,3-dimethyl-2-{6-[(2-{2-[2-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)ethoxy]ethoxy}ethyl)carbamoyl]hexanamido}butanoyl]-5-{[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl}pyrrolidin-3-yl acetate (Compound 25) [ka]

[0421] Intermediate 6 (39 mg; 0.06 mmol), Intermediate 1 (40 mg; 0.06 mmol), and 4-methylmorpholine (0.03 mL; 0.26 mmol) were dissolved in dimethylformamide (DMF) (1 mL), and the mixture was added to a 100 mL flask with a stir bar. This was followed by the addition of HATU (30 mg; 0.08 mmol) in RBF. The reaction mixture was stirred at RT for 1 h, followed by the addition of acetic anhydride (12 μL; 0.13 mmol) at RT for 15 min. No reaction was observed by LC-MS analysis. DMAP (7 mg, 0.06 mmol) was then added, followed by additional AcCl (10 μL, 0.14 mmol). The reaction mixture was stirred for 6 h, after which LC-MS analysis indicated the formation of the product. The reaction mixture was diluted with water and DMSO (1 mL each) and directly injected into a preparative RP-HPLC-MS system to give compound 25 (12 mg, 0.01 mmol, 17%) as a white film after lyophilization.

[0422] LC-MS (ESI+, method Chromolith): t R = 1.78 min, m / z 1100.50 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.60 (t, J = 5.6 Hz, 1H), 8.46 (d, J = 7.6 Hz, 1H), 8.35 (d, J = 1.8 Hz, 1H), 8.22 (s, 1H), 8.09 (d, J = 8.4 Hz, 2H), 7.98 (d, J = 8.4 Hz, 2H), 7.90 - 7.83 (m, 3H), 7.78 (d, J = 8.7 Hz, 1H), 7.46 - 7.40 (m, 2H), 7.39 - 7.31 (m, 2H), 5.17 (s, 1H), 4.90 (p, J = 7.2 Hz, 1H), 4.44 (dd, J = 9.1, 7.7 Hz, 1H), 4.33 (d, J = 8.7 Hz, 1H), 4.03 (s, 3H), 3.95 (d, J = 11.7 Hz, 1H), 3.72 (dd, J = 11.8, 4.1 Hz, 1H), 3.59 - 3.50 (m, 6H), 3.46 (s, 1H), 3.17 (q, J = 5.9 Hz, 2H), 2.45 (s, 3H), 2.21 (tt, J = 14.8, 7.5 Hz, 2H), 2.14 - 1.92 (m, 6H), 1.44 (h, J = 8.0 Hz, 4H), 1.36 (d, J = 7.1 Hz, 3H), 1.25 - 1.12 (m, 3H), 0.94 (s, 9H).

[0423] compound 26 (2S,4R)-1-[(2S)-3,3-dimethyl-2-[4-(4-{5-[3-({2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indol-5-yl}formamido)prop-1-yn-1-yl]pyridin-2-yl}piperazin-1-yl)butanamido]butanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide, bis-TFA salt (Compound 26) [ka]

[0424] In an 8 mL vial with a stir bar, (2S,4R)-1-[(2S)-2-(4-{4-[5-(3-aminoprop-1-yn-1-yl)pyridin-2-yl]piperazin-1-yl}butanamido)-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide hydrochloride (commercially available from Sigma-Aldrich, 52 mg; 0.07 mmol) and TEAD ligand 1 (25 mg; 0.07 mmol) were dissolved in dimethylformamide (DMF) (1 mL). The reaction was initiated by the addition of 4-methylmorpholine (0.03 mL; 0.28 mmol) followed by HATU (32 mg; 0.08 mmol). The reaction mixture was stirred at room temperature for 18 h, filtered through a 0.2 μm membrane filter, and the filtrate was directly injected into a preparative RP-HPLC-MS system using a TFA modifier. The target fraction was lyophilized to give compound 26 (43 mg; 0.03 mmol, 48% based on 99% purity by LCMS analysis) as a yellowish solid.

[0425] LC-MS (ESI+, method Chromolith): t R = 1.56 min, m / z 1055.50 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 9.84 (s, 1H), 9.10 (t, J = 5.5 Hz, 1H), 9.02 (s, 1H), 8.64 (t, J = 6.1 Hz, 1H), 8.41 (d, J = 1.8 Hz, 1H), 8.28 - 8.22 (m, 2H), 8.17 (d, J = 9.3 Hz, 1H), 8.10 (d, J = 8.4 Hz, 2H), 7.98 (d, J = 8.6 Hz, 2H), 7.91 (dd, J = 8.8, 1.9 Hz, 1H), 7.81 (d, J = 8.7 Hz, 1H), 7.68 (dd, J = 8.9, 2.4 Hz, 1H), 7.43 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 6.96 (d, J = 8.9 Hz, 1H), 4.57 (d, J = 9.3 Hz, 1H), 4.45 (ddd, J = 18.6, 9.5, 6.0 Hz, 4H), 4.37 (s, 1H), 4.22 (dd, J = 15.9, 5.4 Hz, 1H), 4.05 (s, 3H), 3.68 (dd, J = 10.6, 3.9 Hz, 1H), 3.64 (d, J = 10.7 Hz, 1H), 3.59 (d, J = 11.8 Hz, 2H), 3.18 (d, J = 12.5 Hz, 1H), 3.12 (t, J = 9.3 Hz, 3H), 3.07 (s, 2H), 3.06 - 3.00 (m, 1H), 2.45 (s, 3H), 2.38 (dt, J = 14.9, 7.3 Hz, 1H), 2.29 (dt, J = 14.9, 7.1 Hz, 1H), 2.06 (dd, J = 12.9, 7.8 Hz, 1H), 1.91 (ddt, J = 14.6, 9.5, 5.1 Hz, 3H), 0.96 (s, 9H).

[0426] compound 27 N-{6-[2-(2-{4-[4-(N-benzyl-2-chloroacetamido)phenoxy]phenoxy}ethoxy)ethoxy]hexyl}-2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxamide (Compound 27) [ka]

[0427] N-{4-[4-(2-{2-[(6-aminohexyl)oxy]ethoxy}ethoxy)phenoxy]phenyl}-N-benzyl-2-chloroacetamide; trifluoroacetic acid (51 mg; 0.08 mmol; freshly prepared by Boc-deprotection of tert-butyl (6-(2-(2-(4-(4-(N-benzyl-2-chloroacetamido)phenoxy)phenoxy)ethoxy)ethoxy)hexyl)carbamate (commercially available from Sigma-Aldrich) in 50% TFA in DCM for 30 min at 0 °C, followed by evaporation of volat...

Claims

1. Formula I Q 1 -Q 2 -Q 3 I During the ceremony Q 1 is a ubiquitin ligase ligand; Q 2 is (i) absent; or (ii) a bivalent linker formed by an unbranched alkylene chain having 2 to 25 C atoms, wherein there are 1 to 8 non-adjacent CH 2 The groups are, independently of one another, O, -C(=O)-NH-, -NH-C(=O)-, -C(=O)-N(CH 3 )-, -N(CH 3 )-C(=O)-, -CH=CH-, and / or -C≡C-; one or two CH 2 The group may optionally have a methyl substituent; and one CH 2 The base is 【Chemistry 1】 【Chemistry 2】 wherein the left end of the moiety is a moiety selected from the group consisting of Q 1 and the right end of that portion is directed to the Q 3 directed to the department; Q 3 teeth, 【Transformation 3】 wherein ring A is a ring moiety as follows: 【Chemistry 4】 【Transformation 5】 【Transformation 6】 【Transformation 7】 wherein the formula represents a 5-membered heteroaromatic ring selected from the group consisting of R A1 H, D, C 1～6 -aliphatic, -CH 2 -Ar A1 , or -CH 2 -CH 2 -Ar A1 represents; R A2 H, D, halogen, C 1～6 -aliphatic, -CH 2 -Ar A2 , or -CH 2 -CH 2 -Ar A2 represents; R A3 H, D, C 1～6 -aliphatic, -CH 2 -Ar A3 , or -CH 2 -CH 2 -Ar A3 represents; Z 1 is CR Z1 or N; Z 2 is CR Z2 or N; Z 3 is CR Z3 or N; Here Z 1 , Z 2 , and Z 3 At least two of them are not N; W 1 is CR W1 or represents N; W 2 is CR W2 or represents N; W 3 is CR W3 or represents N; W 4 is CR W4 or represents N; Here, W 1 , W 2 , W 3 , and W 4 None of the above represents N, or W 1 , W 2 , W 3 , and W 4 Only one of represents N, and simultaneously: and R W1 is H, C 1～6 - represents an aliphatic or halogen; R W2 is H, C 1～6 -Aliphatic; Represents halogen; R W3 is H, C 1～6 -aliphatic, -OC 1～6 -Aliphatic, halogen, -CN, -CH 2 -Ar W , or -CH 2 -CH 2 -Ar W represents; R W4 is H, C 1～6 - represents an aliphatic or halogen; R 1 Ar 1 , Hetar 1 , Cyc 1 , Hetcyc 1 , L 1 -Ar 1 , L 1 -Hetar 1 , L 2 -Cyc 1 , L 2 -Hetcyc 1 , unsubstituted or substituted, straight or branched chain C 1～8 -represents aliphatic; R 2 teeth, 【Transformation 8】 represents; Ar A1 , Ar A2 , Ar A3 represent, independently of one another, phenyl, which may be unsubstituted, or, independently of one another, R A11 and / or R A12 may be mono- or di-substituted by; R Z1 , R Z2 , and R Z3 represent, independently of one another, H or halogen; R A11 , R A12 are each independently a halogen or an unsubstituted or substituted, linear or branched C 1～6 -represents aliphatic; Ar W represents phenyl, which may be unsubstituted or, independently of each other, R W11 and / or R W12 may be mono- or di-substituted by; R W11 , R W12 are each independently a halogen or an unsubstituted or substituted, linear or branched C 1～6 -represents aliphatic; Ar 1 is a mono- or bicyclic aryl having 6 or 10 ring carbon atoms, where the aryl may be unsubstituted or may contain a substituent R B1 , R B2 , and / or R B3 (which may be the same or different); Hetar 1 is a monocyclic heteroaryl having 5 or 6 ring atoms, or a bicyclic heteroaryl having 9 or 10 ring atoms, where 1, 2, 3, or 4 of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, and the heteroaryl may be unsubstituted or may contain a substituent R B1 , R B2 , and / or R B2 (which may be the same or different); Cyc 1 is a saturated or partially unsaturated, mono- or bicyclic carbocyclic ring having 3, 4, 5, 6, 7, 8, 9, or 10 ring carbon atoms, where the carbocyclic ring may be unsubstituted or may be substituted with R B4 , R B5 , and / or R B6 (which may be the same or different); Hetcyc 1 is a saturated or partially unsaturated, monocyclic heterocycle having 5 or 6 ring atoms, in which one or two of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, and the heterocycle may be unsubstituted or may be substituted with R B4 , R B5 , and / or R B (which may be the same or different), where if one of the heteroatoms is S, then the heterocycle may also be substituted with R B4 , R B5 , R B6 , R B7 , and R B8 may be substituted; L 1 is -S(=O) 2 -, -C(=O)-, unsubstituted or substituted, straight or branched chain C 1～6 -Alkylene or C 2～6 -alkenylene (in both of which one of the carbon units of the alkylene or alkenylene chain may be replaced by -O-); L 2 is -S(=O) 2 -, -C(=O)-, unsubstituted or substituted, straight or branched chain C 1～6 -Alkylene or C 2～6 -alkenylene (in both of which one of the carbon units of the alkylene or alkenylene chain may be replaced by -O-); R B1 , R B2 , R B3 are, independently of each other, linear or branched C 1～6 - alkyl, but its C 1～6 -Alkyl may be unsubstituted or monosubstituted with -CN or may be substituted with 1, 2 or 3 halogens, straight or branched C 1～4 -alkoxy, wherein C 1～4 -alkoxy may be unsubstituted or may contain one, two or three halogens, -O-CH 2 -C≡CH, linear or branched -SC 1～4 -alkyl, and its -SC 1～4 -Alkyl may be unsubstituted or may contain 1, 2 or 3 halogens, straight or branched C 2～6 -alkenyl, wherein C 2～6 -Alkenyl may be unsubstituted or monosubstituted with -CN or may contain one, two or three halogens, F, Cl, Br, -CN, -S(=O)-C 1～3 -Alkyl, S(=O) 2 -C 1～3 -Alkyl, -N(C 1～3 -alkyl) 2 , Ar 2 , -CH 2 -Ar 2 , Hetar 2 , Cyc 2 , Hetcyc 2 may be substituted with; Or, two adjacent R B1 , R B2 , and / or R B3 together, the divalent -C 3～4 - an alkylene radical, one of whose alkylene carbon units may be replaced by a carbonyl unit (-C(=O)-), or a divalent -OC 2～3 -forming an alkylene radical; R B4 , R B5 , R B6 are independent of each other, F, C 1～4 - alkyl, but its C 1～4 -Alkyl may be unsubstituted or contain 1, 2 or 3 F, C 1～4 -alkoxy, optionally substituted with phenyl; or R B4 , R B5 , and R B6 Two of them are the carbocyclic Cyc 1 or the heterocycle Hetcyc 1 and form a divalent oxo (=O) group; or R B4 and R B5 and R B7 and R B8 are attached to the same sulfur atom of the heterocycle and form two divalent oxo (=O) groups, thereby forming -S(=O) 2 -Parts are formed; Ar 2 is phenyl which may be unsubstituted or substituted by two substituents, which substituents are, independently of one another, OH, F, Cl, Br, C 1～4 -alkyl, and C 1～4 -alkoxy, wherein C 1～4 -Alkyl group or C 1～4 - the alkoxy group may be substituted with 1, 2 or 3 F atoms; Hetar 2 is a monocyclic heteroaryl having 5 or 6 ring atoms, wherein 1, 2, 3, 4, 5 of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, wherein the heteroaryl may be unsubstituted or substituted with 1 or 2 substituents, which are, independently of each other, F, Cl, Br, C 1～4 -alkyl, and C 1～4 -alkoxy, wherein C 1～4 -Alkyl group or C 1～4 - the alkoxy group may be substituted with 1, 2 or 3 F atoms; Cyc 2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which may be unsubstituted or substituted with one or two substituents, which substituents are, independently of one another, OH, F, Cl, Br, C 1～4 -alkyl, and C 1～4 -alkoxy, wherein C 1～4 -Alkyl group or C 1～4 - the alkoxy group may be substituted with 1, 2 or 3 F atoms and / or 1 hydroxy group; Hetcyc 2 is pyrrolidinyl, piperidinyl, each of which may be unsubstituted or substituted with one or two substituents, which substituents are, independently of one another, OH, F, Cl, Br, C 1～4 -alkyl, and C 1～4 -alkoxy, wherein C 1～4 -Alkyl group or C 1～4 - the alkoxy group may be substituted with 1, 2 or 3 F atoms and / or 1 hydroxy group; Halogens are F, Cl, Br, I; or a pharmaceutically acceptable salt, solvate, tautomer, and / or stereoisomer thereof.

2. Q 1 is (a) a CRBN (cereblon) ligand, or (b) a VHL (von Hippel-Lindau) ligand, or (c) a different type of E3 ubiquitin ligase ligand excluding a CRBN ligand and a VHL ligand, or a pharmaceutically acceptable salt, solvate, tautomer, and / or stereoisomer thereof.

3. (a) CRBN (cereblon) ligands have a structure represented by formula Q1-I, Q1-II, Q1-VII, or Q1-VIII; (b) VHL ligands have a structure represented by formula Q1-III; (c) different types of E3 ubiquitin ligase ligands have a structure represented by formula Q1-IV, Q1-V, Q1-VI, Q1-XII, or Q1-XIII: 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 During the ceremony X 1 represents a single bond, -O-, -NH-, -NCH 3 -, -CH 2 - or -NH-C(=O)-; R Q1 is H or -C(=O)-CH 3 Show; R Q2 is H or CH 3 Show; 3. The compound of claim 2, or a pharmaceutically acceptable salt, solvate, tautomer, and / or stereoisomer thereof.

4. Q 1 is a CRBN (cereblon) ligand; and the CRBN (cereblon) ligand is represented by the formula Q1-I-1, Q1-I-2, Q1-I-3; Q1-I-4, Q1-I-5, Q1-I-6, Q1-II-1, Q1-II-2, Q1-II-3, Q1-II-4, Q1-II-5, Q1-II-6, Q1-II-7, Q1-VII-1, Q1-VII-2, and Q1-VII-3. 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 3. The compound of claim 1 or 2, having the structure:

5. Q 1 is a VHL (von Hippel-Lindau) ligand; and VHL ligands are represented by the formulas Q1-III-1, Q1-III-2, Q1-III-3, Q1-III-4, and Q1-III-5 【Chemistry 17】 [Chemistry 18] 3. The compound of claim 1 or 2, having a structure selected from:

6. Q 2 but, 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 10. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, tautomer, and / or stereoisomer thereof.

7. Q 3 has a structure represented by formula Q3-I; Ring A is the following ring moiety: 【Chemistry 25】 【Chemistry 26】 represents a 5-membered heteroaromatic ring selected from the group consisting of: R A1 But C 1～6 -aliphatic, -CH 2 -Ar A1 represents; R A2 But H, C 1～6 -represents aliphatic; R A3 But H, C 1～6 -represents aliphatic; Ar A1 Even if unsubstituted or R A11 represents a phenyl which may be mono-substituted by; R A11 represents a halogen; Z 1 , Z 2 , and Z 3 Each represents CH; 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, and / or stereoisomer thereof.

8. Q 3 has a structure represented by formula Q3-I; Ring A is ring A-4 or ring A-12; R A1 is methyl; R A2 is H; Z 1 , Z 2 , and Z 3 Each represents CH; 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, and / or stereoisomer thereof.

9. Q 3 has a structure represented by formula Q3-II; and (a) W 1 But, CR W1 represents; W 2 But, CR W2 represents; W 3 But, CR W3 represents; W 4 But, CR W4 represents; R W1 represents H; R W2 represents H; R W3 But C 1～6 -aliphatic, -OC 1～6 -Aliphatic, halogen, -CN, -CH 2 -Ar W , or -CH 2 -CH 2 -Ar W represents; R W4 represents H; Ar W is unsubstituted or R W11 represents a phenyl which may be mono-substituted by; R W11 represents halogen; preferably F; or (b) W 1 But, CR W1 represents; W 2 But, CR W2 represents; W 3 But, CR W3 represents; W 4 But, CR W4 represents; R W1 represents H; R W2 But C 1～6 -represents aliphatic; R W3 represents H; R W4 represents H; or (c) W 1 But, CR W1 represents; W 2 But, CR W2 represents; W 3 But, CR W3 represents; W 4 But, CR W4 represents; R W1 represents H; R W2 represents H; R W3 represents H; R W4 But C 1～6 -represents aliphatic; or (d) W 1 But, CR W1 represents; W 2 represents N; W 3 But, CR W3 represents; W 4 But, CR W4 represents; R W1 represents H; R W3 But C 1～6 -aliphatic, -OC 1～6 -Aliphatic, halogen, -CN, -CH 2 -Ar W , or -CH 2 -CH 2 -Ar W represents; R W4 represents H; Ar W is unsubstituted or R W11 represents a phenyl which may be mono-substituted by; R W11 represents halogen; preferably F; or (e) W 1 But, CR W1 represents; W 2 represents N; W 3 But, CR W3 represents; W 4 But, CR W4 represents; R W1 represents H; R W3 represents H; R W4 But C 1～6 -represents aliphatic; or (f) W 1 But, CR W1 represents; W 2 But, CR W2 represents; W 3 represents N; W 4 But, CR W4 represents; R W1 represents H; R W2 But C 1～6 -represents aliphatic; R W4 represents H; or (g) W 1 But, CR W1 represents; W 2 But, CR W2 represents; W 3 represents N; W 4 But, CR W4 represents; R W1 represents H; R W2 represents H; R W4 But C 1～6 -represents aliphatic; or (h) W 1 But, CR W1 represents; W 2 But, CR W2 represents; W 3 But, CR W3 represents; W 4 represents N; R W1 represents H; R W2 represents H; R W3 But C 1～6 -aliphatic, -OC 1～6 -Aliphatic, halogen, -CN, -CH 2 -Ar W , or -CH 2 -CH 2 -Ar W represents; Ar W is unsubstituted or R W11 represents a phenyl which may be mono-substituted by; R W11 represents halogen; preferably F; Z 1 , Z 2 , and Z 3 Each represents CH; 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, and / or stereoisomer thereof.

10. R 1 phenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-difluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-(1,1-difluoroethyl)phenyl, 4-(2,2,2-trifluoroethyl)phenyl, 4-(1-trifluoromethylcyclopropyl)phen-1-yl, 4-cyclopentylphenyl, 4-ethoxyphenyl, 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl bisphenyl, 3-(trifluoromethyl)sulfanylphenyl, 4-(trifluoromethyl)sulfanylphenyl, 3-trifluoromethyl-4-methylphenyl, 2-fluoro-4-trifluoromethylphenyl, 2-fluoro-4-trifluoromethoxyphenyl, 3-fluoro-4-(n-propyl)phenyl, 2,3-dimethyl-4-methoxyphenyl, 6-fluoronaphth-2-yl; 5-trifluoromethylfuran-2-yl; 5-trifluoromethylthiophen-2-yl, 2-trifluoromethyl-1,3-thiazol-4-yl, 3-fluoropyridin-2-yl, 6-methylpyridin-3-yl, 6-methoxypyridin-3-yl, 3-ethylpyridin-2-yl, 6-ethylpyridin-3-yl, 4-difluoromethylpyridin-2-yl, 4-trifluoromethylpyridin-2-yl, 4-trifluoromethoxypyridin-2-yl, 4-cyanopyridin-2-yl, 5-trifluoromethylpyridin-2-yl, 6-trifluoromethylpyridin- 2-yl, 6-trifluoromethylpyridin-3-yl, (2-trifluoromethylpyridin-5-yl), 6-trifluoromethoxypyridin-3-yl, (2-trifluoromethoxypyridin-5-yl), 5-cyanopyridin-2-yl, 5-cyanomethylpyridin-2-yl, 5-methanesulfonylpyridin-2-yl, 6-methoxypyridin-2-yl, 4-methylpyrimidin-2-yl, 4-ethylpyrimidin-2-yl, 4-methylsulfani pyrimidin-2-yl, 5-cyclopropylpyrimidin-2-yl, 5-ethylpyrimidin-2-yl, 5-difluoromethylpyrimidin-2-yl, 5-trifluoromethylpyrimidin-2-yl, 5-cyanopyrimidin-2-yl, 5-cyano-3-fluoropyridin-2-yl, 5-cyano-6-methylpyridin-2-yl, 3-fluoro-5-(trifluoromethyl)pyridin-2-yl, 5-oxo-5H,6H,7H-cyclopenta[b]pyridin-2-yl, quinolin-2-yl, 5,6,7,8-tetrahydroquinolin-2-yl, 5-oxo-5,6,7,8-tetrahydroquinolin-2-yl, 5H,6H,7H-cyclopenta[b]pyridin-2-yl, quinolin-2-yl, isoquinolin-3-yl, 6-methylquinolin-2-yl, 8-methoxyquinolin-4-yl, furo[3,2-b]pyridin-5-yl, quinazolin-2-yl, 6-fluoroquinazolin-2-yl, 1,5-naphthyridin-2-yl; 3-Methylcyclobutyl, cyclopentyl, 3-methylcyclopentyl, 3,3-dimethylcyclopentyl, 3-trifluoromethyl-bicyclo[1.1.1]pentan-1-yl, cyclohexyl, 4-methylcyclohexyl, 4-(trifluoromethyl)cyclohexyl, 4,4-difluorocyclohexyl, cyclohex-1-enyl, 2-oxocycloheptyl, 6,6-Difluorospiro[3.3]heptan-2-yl, 1H-inden-2-yl; benzenesulfonyl (phenylsulfonyl), 3-methylphenylsulfonyl, benzyl, 2-ethoxyphenylmethyl, 3-chlorophenylmethyl, 3-fluorophenylmethyl, 4-chlorophenylmethyl, 3-(pyrrolidin-1-yl)phenylmethyl, 3-methylphenylmethyl, 4-methylphenylmethyl, 3-ethylphenylmethyl, 3-(propan-2-yl)phenylmethyl, 3-tert-butylphenylmethyl, 3-( Difluoromethoxy)phenylmethyl, 2-(difluoromethyl)phenylmethyl, 3-(difluoromethyl)phenylmethyl, 3-(trifluoromethyl)phenylmethyl, 4-(trifluoromethyl)phenyl]methyl, 2-(prop-2-yn-1-yloxy)phenylmethyl, 3-(1,3-thiazol-2-yl)phenylmethyl, 3-(trifluoromethyl)sulfanylphenylmethyl, 3-methanesulfonylphenylmethyl, 3-(dimethylamino)phenylmethyl, 3-(pyrrol-1-yl)phenyl Methyl, 2-methyl-3-methoxyphenylmethyl, 3-trifluoromethyl-5-methylphenylmethyl, 2-methyl-3-(trifluoromethyl)phenylmethyl, 3-trifluoromethyl-4-fluorophenylmethyl, 2-fluoro-5-(trifluoromethoxy)phenylmethyl, 2-methoxy-3-trifluoromethoxyphenylmethyl, 2-fluoro-3-methoxyphenylmethyl, 2-fluoro-3-(trifluoromethyl)phenyl]methyl, 2-fluoro-3-fluoromethoxyphenylmethyl, 2-trifluoromethoxy-5-fluorophenylmethyl, 2-fluoro-5-chloro-phenylmethyl, 3-fluoro-5-methylphenyl)methyl, 3,5-difluorophenylmethyl, 5-fluoro-2-(trifluoromethyl)phenylmethyl, 3-fluoro-5-(trifluoromethyl)phenylmethyl, 2-chloro-3-(trifluoromethyl)phenylmethyl, naphthalen-1-ylmethyl, 5,6,7,8-tetrahydronaphthalen-1-ylmethyl, 2,3-dihydro-1-benzofuran-7-ylmethyl, 3,4-dihydro-2H-1-benzopyran-8-ylmethyl, 2-phenylethyl, 2-(2-methylphenyl)ethyl, 2-(2-methoxyphenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-(4-methoxyphenyl)ethyl, 2-(2-fluorophenyl)-ethyl, 2-(3-fluorophenyl)-ethyl, 2-(4-fluorophenyl)-ethyl, 2-(2-chlorophenyl)-ethyl, 2-(4-chlorophenyl)-ethyl, 2-(4-bromophenyl)-ethyl, 2-[4-(trifluoromethyl)phenyl]ethyl, 2-(2,4-difluorophenyl)ethyl, 2-(difluoromethoxy)-5-fluorophenylmethyl, 2-phenylpropyl, 3-phenylpropyl, 3-methyl-3-phenylbutyl, 2-(benzyloxy)ethyl; 5-Ethylfuran-2-ylmethyl, 5-(trifluoromethyl)furan-2-ylmethyl, 4-(propan-2-yl)-1,3-thiazol-2-ylmethyl, 2-methyl-1,3-thiazol-4-ylmethyl, 2-trifluoromethyl-1,3-thiazol-4-ylmethyl, 1-ethylpyrazol-5-ylmethyl, 1-(2-propyl)pyrazol-5-ylmethyl, 1-ethylimidazol-5-ylmethyl, 1-ethylimidazol-2-ylmethyl, 1-propylimidazo-2-ylmethyl, 1-benzylimidazo-2-yl)methyl, 1-(2-methylpropyl)-1H-imidazo-5-ylmethyl, 5-tert-butyl-1,3-oxazol-2-ylmethyl, 3-fluoro- pyrrolo[1,2-b]pyrazol-3-ylmethyl, 2-methylpyridin-4-ylmethyl, 4-trifluoromethylpyridin-2-ylmethyl, 6-(fluoromethyl)pyridin-2-ylmethyl, 6-trifluoromethylpyridin-2-ylmethyl, 2-(trifluoromethyl)pyridin-4-ylmethyl, 4-methylpyrimidin-2-ylmethyl, 2-(thiophen-3-yl)ethyl, 5-trifluoromethylthiophen-2-ylmethyl, 1-methyl-1H-indol-6-yl)methyl, 1-benzofuran-3-ylmethyl, 1-benzothiophen-3-ylmethyl, 4H,5H,6H-pyrrolo[1,2-b]pyrazol-3-ylmethyl, pyrazolo[1,5-a]pyridin-7-ylmethyl, pyrazolo[1,5-a]pyridin-3-ylmethyl, imidazo[1,2-a]pyridin-3-ylmethyl, 6-methylimidazo[1,2-a]pyridin-3-ylmethyl, imidazo[1,2-a]pyridin-5-ylmethyl, imidazo[1,5-a]pyridin-1-ylmethyl, imidazo[1,5-a]pyridin-3-ylmethyl, imidazo[1,5-a]pyridin-5-ylmethyl, pyrazolo[1,5-c]pyrimidin-3-ylmethyl, 3-(furan-2-yl)prop-2-en-1-yl; 3-trifluoromethylcyclobutylmethyl, 3-fluoro-3-phenylcyclobutyl Methyl, cyclohexylmethyl, 4-methylcyclohexylmethyl, 4-trifluoromethylcyclohexylmethyl, 4-methoxycyclohexylmethyl, 4,4-dimethylcyclohexylmethyl, 4,4-difluorocyclohexylmethyl, 3-trifluoromethyl-bicyclo[1.1.1]pentan-1-ylmethyl, bicyclo[2.2.1]heptan-2-ylmethyl, bicyclo[2.2.2]octan-2-ylmethyl, bicyclo[2.2.1]hept-5-en-2-ylmethyl, 6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]methyl; 3,3-dimethyltetrahydrofuran-2-ylmethyl, 1,1-dioxothian-4-ylmethyl, 2-(thian-4-yl)ethyl; 2,2-dimethyl-4,4,4-trifluoropentyl, 4,4,4-trifluorobutyl, 4,4,4-trifluoro-3-methylbutyl, 3,3-dimethyl-4,4,4-trifluorobutyl, 3,3,3-trifluoroprop-1-yn-1-yl; 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, and / or stereoisomer thereof.

11. R 1 represents 4-methylphenyl, 4-difluoromethylphenyl, 4-trifluoromethylphenyl, 4-fluorophenyl, or a pharmaceutically acceptable salt, solvate, tautomer, and / or stereoisomer thereof.

12. Q 3 has a structure represented by formula Q3-I; Ring A is ring A-4 or ring A-12; R A1 is methyl; R A2 is H; R 1 is 4-trifluoromethylphenyl; R 2 but, 【Chemistry 27】 represents; Z 1 , Z 2 , and Z 3 Each represents CH; 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, and / or stereoisomer thereof.

13. Q 1 but, (a) is a CRBN (cereblon) ligand; and the CRBN (cereblon) ligand is represented by the formula Q1-I-1, Q1-I-2, Q1-I-3; Q1-I-4, Q1-I-5, Q1-I-6, Q1-II-1, Q1-II-2, Q1-II-3, Q1-II-4, Q1-II-5, and Q1-VII-1 【Chemistry 28】 【Chemistry 29】 【Transformation 30】 or having a structure selected from the structures represented by (b) VHL (von Hippel-Lindau) ligands; and VHL ligands are represented by the formulas Q1-III-1, Q1-III-2, Q1-III-4, and Q1-III-5: 【Chemistry 31】 having a structure selected from the structures represented by: Q 2 but, 【Chemistry 32】 【Transformation 33】 【Transformation 34】 【Chemistry 35】 selected from the group consisting of: Q 3 But Q3-I; Ring A is ring A-4 or ring A-12; R A1 represents methyl; R A2 represents hydrogen; R 1 displays 4-trifluoromethylphenyl; R 2 but, 【Transformation 36】 represents; Z 1 , Z 2 , and Z 3 Each represents CH; 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, and / or stereoisomer thereof.

14. Q 1 or a pharmaceutically acceptable salt, solvate, tautomer, and / or stereoisomer thereof, wherein: (a) is a CRBN ligand and has a structure selected from the structures represented by formulas Q1-I-2, Q1-I-3, Q1-I-5, Q1-I-6, Q1-II-2, Q1-II-3, Q1-II-4, and Q1-II-5; or (b) is a VHL ligand and has a structure selected from the structures represented by formulas Q1-III-1 and Q1-III-4.

15. 2. The compound of claim 1, wherein the compound is selected from Table 1, or a pharmaceutically acceptable salt, solvate, tautomer, and / or stereoisomer thereof.

16. 10. The compound of claim 1 for use as a pharmaceutical.

17. 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, and / or stereoisomer thereof, for use in the treatment and / or prevention of a disease or condition selected from the group consisting of cancer, particularly breast cancer, lung cancer, liver cancer, ovarian cancer, squamous cell carcinoma, renal cancer, gastric cancer, medulloblastoma, colon cancer, pancreatic cancer, tumors (including solid tumors); cardiovascular disease and fibrosis, particularly liver fibrosis.

18. 10. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt solvate, tautomer, and / or stereoisomer thereof, as an active ingredient, together with a pharmaceutically acceptable carrier.

19. 19. The pharmaceutical composition of claim 18, further comprising a second active ingredient, or a pharmaceutically acceptable salt solvate, tautomer, and / or stereoisomer thereof, wherein the second active ingredient is other than a compound of Formula I as defined in claim 1.

20. 10. A method for degrading a TEAD protein, comprising contacting the TEAD protein with a compound as defined in claim 1.

21. (i) a compound according to claim 1; (ii) TEAD protein; and (iii) ubiquitin ligase A ternary complex comprising:

22. A compound selected from the group consisting of the intermediates depicted in Table INT, or a pharmaceutically acceptable salt, solvate, tautomer, and / or stereoisomer thereof.

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