RU2782458C2 - Compounds and methods for targeted cleavage of rapidly accelerated fibrosarcoma polypeptides - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to a bifunctional compound of the formula ULM-L-PTM or its pharmaceutically acceptable salt, enantiomer, or stereoisomer, as well as their use for the treatment of a disease or a disorder related to accumulation and aggregation of BRaf in a subject, where the disease or the disorder is: malignant tumor; heart-face-skin syndrome; neurofibromatosis type 1; Costello syndrome; Noonan syndrome; LEOPARD syndrome (lentigo, electrocardiographic pathologies, ocular hypertelorism, pulmonary stenosis, abnormal genitals, retarded growth, deafness) related to accumulation and aggregation of Raf. In the general formula ULM-L-PTM, ULM is a fragment of binding to cerablon E3-ubiquitine ligase (CLM) with a chemical structure represented by a fragment of binding to von Hippel-Lindau E3-ubiquitine ligase with a chemical structure (a), L is a chemical linker group, which is represented by the formula -(A^L)_q-, PTM is a fragment targeting protein of rapidly accelerated fibrosarcoma (RAF), which has a chemical structure represented by PTM-IIa, other values of radicals are specified in the claims.

EFFECT: provision of compounds of ULM-L-PTM having properties of targeted cleavage of BRaf.

23 cl, 4 dwg, 41 tbl, 306 ex

Description

Link to related applications

[0001] This disclosure claims priority to U.S. Provisional Patent Application Serial No. 62/438803, filed December 23, 2016, and U.S. Provisional Patent Application Serial No. 62/582698, filed November 7, 2017; both of which are incorporated herein by reference in their entirety.

Incorporation by reference

[0002] US patent application serial number 15/230354, filed August 5, 2016; and US patent application 15/206497, filed July 11, 2016; and US patent application 15/209648, filed July 13, 2016; and US patent application serial number 62/406888, filed October 11, 2016; and US Patent Application Serial Number 14/686,640, filed April 14, 2015, published as US Patent Application Publication Number 2015/0291562; and US Patent Application Serial Number 14/792414, filed July 6, 2015, published as US Patent Application Publication Number 2016/0058872; and US Patent Application Serial Number 14/371956, filed July 11, 2014, published as US Patent Application Publication Number 2014/0356322; and US Patent Application Serial Number 15/074820, filed March 18, 2016, published as US Patent Application Publication Number 2016/0272639, are incorporated herein by reference in their entirety. Moreover, all references cited herein are incorporated herein by reference in their entirety.

Application for Federally Funded Research

[0003] The present invention was made with government support under grant number NIH R35CA197589, as issued by the National Institutes of Health. The state has certain rights to the present invention.

Field of technology to which the present invention relates

[0004] The present disclosure relates to bifunctional compounds comprising a target protein binding moiety and an E3 ubiquitin ligase binding moiety, as well as methods of use related thereto. Bifunctional compounds are useful as targeted ubiquitination modulators, particularly for rapidly progressing fibrosarcoma (RAF) proteins that are degraded and/or otherwise inhibited by the bifunctional compounds of the present disclosure.

BACKGROUND OF THE INVENTION

[0005] Most small molecule drugs bind enzymes or receptors in narrow and well-defined pockets. On the other hand, protein–protein interactions are known to be difficult to target using small molecules due to their large contact surfaces and the shallow grooves or flat contact regions involved. E3 ubiquitin ligases (hundreds of which are known in humans) confer substrate specificity to ubiquitination and are therefore more attractive therapeutic targets than conventional proteasome inhibitors due to their specificity for certain protein substrates. The development of E3 ligase ligands has proven difficult, in part because they must disrupt protein-protein interactions. However, recent developments have made it possible to obtain specific ligands that bind to these ligases. For example, since the discovery of nutlins, the first small molecule E3 ligase inhibitors, additional compounds that target E3 ligases have been reported, but the area remains underdeveloped. For example, since the discovery of nutlins, the first small molecule inhibitors of the murine minichromosome double homolog 2 (MDM2) E3 ligase, additional compounds have been reported that target the MDM2 (i.e., human minichromosome double homolog 2 or HDM2) E3 ligase (J Di, et al. Current Cancer Drug Targets (2011), 11(8), 987-994).

[0006] The tumor suppressor gene p53 plays an important role in cell growth arrest and apoptosis in response to DNA damage or stress (A. Vazquez, et al. Nat. Rev. Drug. Dis. (2008), 7, 979-982) , and p53 inactivation has been proposed as one of the major pathways for tumor cell survival (A. J. Levine, et al. Nature (2000), 408, 307-310). Approximately 50% of cancer patients have a p53 mutation (M. Hollstein, et al. Science (1991), 233, 49-53), while patients with wild-type p53 often show suppression of p53 by MDM2 through protein-protein interactions p53 and MDM2 (A. Vazquez, et al. Nat. Rev. Drug. Dis. (2008), 7, 979-982). In normal cells without an oncogenic stress signal, MDM2 maintains p53 at low concentrations. In response to DNA damage or cellular stress, p53 increases, which also causes an increase in MDM2 due to a feedback loop from the p53/MDM2 autoregulation system. In other words, p53 regulates MDM2 at the level of transcription, and MDM2 regulates p53 at the level of its activity (A. J. Levine, et al. Genes Dev. (1993)7, 1126-1132).

[0007] Several mechanisms may explain the suppression of p53 by MDM2. First, MDM2 binds to the N-terminal domain of p53 and blocks the expression of p53-responsive genes (J. Momand, et al. Cell (1992), 69, 1237-1245). Second, MDM2 transfers p53 from the nucleus to the cytoplasm to facilitate proteolytic degradation (J. Roth, et al. EMBO J. (1998), 17, 554-564). Finally, MDM2 has intrinsic E3 ligase activity to conjugate ubiquitin to p53 for degradation via the 26s ubiquitin-dependent proteasome system (UPS) (Y. Haupt, et al. Nature (1997) 387, 296-299). Thus, since MDM2 functions as an E3 ligase, the recruitment of MDM2 to the disease-causing protein, as well as its ubiquitination and degradation, is an approach of great interest for drug development.

[0008] One E3 ligase with therapeutic potential of interest is von Hippel-Lindau tumor suppressor (VHL), the substrate recognition subunit of the E3 ligase VCB complex, which also consists of elongins B and C, Cul2 and Rbx1. The primary substrate of VHL is hypoxia-inducible factor 1α (HIF-1α), a transcription factor that activates genes such as the proangiogenic growth factor VEGF and the cytokine erythropoietin, which induces red blood cells in response to low oxygen levels. The first small molecule von Hippel-Lindau (VHL) tumor suppressor ligands were generated for the substrate recognition subunit of E3 ligase, and crystal structures were obtained confirming that the compound mimics the binding mode of the transcription factor HIF-1α, a major substrate of VHL.

[0009] Cereblon is a protein that is encoded by the CRBN gene in humans. CRBN orthologs are highly conserved from plants to humans, highlighting its physiological significance. Cereblon forms an E3 ubiquitin ligase complex with DNA damage binding protein 1 (DDB1), cullin 4A (CUL4A), and regulator of cullin 1 (ROC1). This complex ubiquitinates a number of other proteins. Through a mechanism that is not fully understood, ubiquitination of target proteins by cereblon leads to increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8, in turn, regulates a number of developmental processes, such as the formation of limbs and otic vesicles. The net result is that this ubiquitin ligase complex is essential for limb growth in embryos. In the absence of cereblon, DDB1 forms a complex with DDB2, which functions as a DNA-binding protein.

[0010] Inhibitors of apoptosis proteins (IAPs) are a family of proteins involved in the suppression of apoptosis, i.e. in cell death. The human IAP family includes 8 members, and numerous other organisms contain IAP homologues. IAPs contain an E3 ligase-specific domain and baculovirus 1AP repeat (BFR) domains that recognize substrates and mediate their ubiquitination. IAPs mediate ubiquitination and can directly bind and inhibit caspases. Caspases are proteases (eg, caspase-3, caspase-7, and caspase-9) that mediate apoptosis. Thus, through caspase binding, IAPs inhibit cell death. However, proapoptotic stimuli can lead to the release of the mitochondrial proteins DIABLO (also known as second mitochondria-derived activator of caspases or SMAC) and HTRA2 (also known as Omi). Binding of DIABLO and HTRA2 appears to block IAP activity.

[0011] SMAC interacts with virtually all known IAPs, including XIAP, c-IAP1, c-IAP2, NIL-IAP, Bruce and survivin. The first four amino acids (AVPI) of mature SMAC bind to the IAP moiety, which is believed to be important for blocking the antiapoptotic effects of IAP.

[0012] Bifunctional compounds, such as those described in US Patent Application Publications Nos. 2015-0291562 and 2014-0356322 (incorporated herein by reference), recruit endogenous proteins to E3 ubiquitin ligases for degradation. In particular, the publications describe bifunctional or proteolysis targeting chimeric (PROTAC) compounds that find use as modulators of targeted ubiquitination of a number of polypeptides and other proteins, which are then cleaved and/or otherwise inhibited by the bifunctional compounds.

[0013] There is a continuing need in the art for effective treatments for diseases associated with overexpression or aggregation of rapidly progressing fibrosarcoma protein (RAF) or overactivation of RAF protein (such as constitutively active RAF). For example, current BRaf inhibitors (such as vemurafenib and dabrafenib) target only the V600 mutant of BRaf. Thus, there is a need for treatments for diseases or disorders (such as melanoma, lung cancer, pancreatic cancer and/or colorectal cancer) having various BRaf mutations that are insensitive to existing drugs on the market. In addition, resistance mutations can occur in response to BRaf/MEK inhibitor therapy. For example, a p61 splice variant may appear in melanoma patients treated with BRaf/MEK inhibitor therapy, leaving these patients without clinical options. Currently marketed agents also bind and cause paradoxical activation of wild-type BRaf, leading to clinical complications. In addition, the family of hypoactive class III BRaf mutants, which signal by heterodimerization with CRaf, account for 40% of BRaf mutations in non-small cell lung cancer (NSCLC), and also appear sporadically in other malignancies, may not be the target of any currently approved currently or in clinical trials of BRaf inhibitors.

[0014] Thus, nonspecific effects and the inability to target and modulate RAF remain a barrier to the development of effective treatments. As such, small molecule therapeutics that effectively target RAF (e.g., effectively inhibit and/or cleave mutant forms of BRaf while maintaining wild-type BRaf) and that affect or enhance the substrate specificity of VHL, cereblon, MDM2, and IAP, would be very helpful.

Brief Disclosure of the Present Invention

[0015] The present disclosure relates to bifunctional compounds that function by recruiting endogenous proteins to E3 ubiquitin ligases for degradation, as well as methods of using them. In particular, the present disclosure relates to bifunctional or proteolysis-targeted chimeric (PROTAC) compounds that find use as modulators of targeted ubiquitination of a number of polypeptides and other proteins, which are then cleaved and/or otherwise inhibited by the bifunctional compounds described herein. The advantage of the compounds presented herein is that a wide range of pharmacological activities are possible, consistent with the degradation/inhibition of target polypeptides of virtually any class or family of proteins. In addition, the present disclosure relates to methods of using an effective amount of the compounds described herein to treat or alleviate a disease condition, such as a malignant tumor (e.g., renal cell carcinoma, pancreatic cancer, colorectal cancer, lung cancer, ovarian cancer, thyroid cancer). glands, piloid astrocytoma, prostate cancer, gastric cancer, hepatocellular carcinoma and melanoma), heart-face-skin syndrome, neurofibromatosis type 1, Costello syndrome, Noonan syndrome, LEOPARD syndrome (lentigo, electrocardiographic pathologies, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, slow growth, hearing loss).

[0016] In a further aspect, the present disclosure provides bifunctional compounds or PROTAC compounds that comprise an E3 ubiquitin ligase binding moiety (i.e., an E3 ubiquitin ligase ligand or "ULM" group) and a target protein binding moiety (i.e., a protein/polypeptide targeting ligand or "PTM" group) such that the target protein/polypeptide is placed in close proximity to a ubiquitin ligase to effect cleavage (and inhibition) of that protein. In a preferred embodiment, the ULM (ubiquitin ligase modulator) may be a von Hippel-Lindau (VHL) tumor suppressor E3 ubiquitin ligase binding fragment (VLM), or a cereblon E3 ubiquitin ligase (CLM) binding fragment, or an E3 binding fragment -ubiquitin ligase murine minichromosome double homologue 2 (MDM2) (MLM), or E3 ubiquitin ligase binding fragment IAP (i.e. “ILM”). For example, the structure of bifunctional compounds can be depicted as follows:

[0017] The corresponding positions of PTM and CLM fragments (eg, VLM, CLM, MLM or ILM), as well as the number thereof, illustrated herein are presented by way of example only and are not intended to limit the connections in any way. One skilled in the art will appreciate that the bifunctional compounds described herein can be synthesized such that the number and position of the corresponding functional moieties can be varied as desired.

[0018] In some embodiments, the bifunctional compound may further comprise a chemical linker (“L”). In this example, the structure of bifunctional compounds can be depicted as follows:

wherein PTM is a protein/polypeptide targeting moiety, L is a linker, e.g., a bond or chemical group connecting the PTM to a ULM, and the ULM is an IAP E3 ubiquitin ligase binding moiety, or a von Hippel E3 ubiquitin ligase binding moiety -Lindau (VHL) (VLM), or cereblon E3 ubiquitin ligase binding fragment (CLM), or murine minichromosome double homolog 2 (MDM2) E3 ubiquitin ligase binding fragment (MLM).

[0019] For example, the structure of a bifunctional compound can be depicted as follows:

wherein the PTM is a protein/polypeptide targeting fragment, L is a linker (eg, a bond or chemical linker group) connecting the PTM and at least one of VLM, CLM, MLM, ILM, or a combination thereof; VLM is a von Hippel-Lindau E3 ubiquitin ligase binding fragment that binds to VHL E3 ligase; CLM is a cereblon E3 ubiquitin ligase binding fragment that binds to cereblon; MLM is a binding fragment for the E3 ubiquitin ligase MDM2; and ILM is an IAP binding fragment that binds to the IAP.

[0020] In certain preferred embodiments, the ILM is a tetrapeptide fragment of AVPI. Thus, in accordance with certain additional embodiments, the ILM of the bifunctional compound comprises the amino acids alanine (A), valine (V), proline (P), and isoleucine (I) or other non-naturally occurring mimetics, respectively. In further embodiments, the amino acids of the AVPI tetrapeptide fragment are linked to each other via amide bonds (eg, -C(O)NH- or -NHC(O)-).

[0021] In accordance with certain embodiments, the compounds described herein contain multiple independently selected ULMs, multiple PTMs, multiple chemical linkers, or a combination thereof.

[0022] In accordance with certain embodiments, the ILM contains chemical moieties such as those described herein.

[0023] In accordance with additional embodiments, the VLM may be hydroxyproline or a derivative thereof. Additionally, other proposed VLMs are included in US Patent Application Publication No. 2014/03022523, which, as described above, is incorporated herein in its entirety.

[0024] In accordance with one embodiment, the CLM contains a chemical group derived from an imide, thiomid, amide or thioamide. In accordance with a certain embodiment, the chemical group is a phthalimido group or an analogue or derivative thereof. In accordance with a certain embodiment, the CLM is thalidomide, lenalidomide, pomalidomide, analogs thereof, isosteres thereof, or derivatives thereof. Other proposed CLMs are described in US Patent Application Publication No. 2015/0291562, which is incorporated herein in its entirety.

[0025] In accordance with certain embodiments, the MLM may be nutlin or a derivative thereof. In addition, other proposed MLMs are included in US Patent Application Publication No. 15/206497, filed July 11, 2016, which, as described above, is incorporated herein in its entirety. In certain embodiments, the MLM of the bifunctional compound contains chemical moieties such as substituted imidazolines, substituted spiroindolinones, substituted pyrrolidines, substituted piperidinones, substituted morpholinones, substituted pyrrolopyrimidines, substituted imidazolopyridines, substituted thiazoloimidazolines, substituted pyrrolopyrrolidinones, and substituted isoquinolinones.

[0026] In accordance with additional embodiments, the MLM contains the cow structures mentioned above with additional bis-aryl substitutions arranged in cis or trans configurations.

[0027] In accordance with certain embodiments, "L" represents a link. In further embodiments, the linker "L" is a linker having a number of linear non-hydrogen atoms ranging from 1 to 20. The linker "L" may contain, but is not limited to, functional groups such as ester, amide, alkane, alkene , alkyne, ketone, hydroxyl, carboxylic acid, thioether, sulfoxide and sulfonic. The linker may contain aromatic, heteroaromatic, cyclic, bicyclic and tricyclic moieties. Halogen substitution such as Cl, F, Br and I may be included in the linker. In the case of fluoride substitution, one or more fluorines may be included.

[0028] In certain embodiments, VLM is a trans-3-hydroxyproline derivative wherein both the nitrogen and the carboxylic acid in trans-3-hydroxyproline are functionalized as amides.

[0029] In certain embodiments, CLM is a piperidine-2,6-dione derivative, wherein the piperidine-2,6-dione may be substituted at the 3-position, and the 3-substitution may be bicyclic heteroaromatic compounds with a bond, such as C-N bond or C-C bond. Examples of CLMs include, but are not limited to, pomalidomide, lenalidomide and thalidomide derivatives.

[0030] In accordance with a further aspect, provided herein are therapeutic compositions containing an effective amount of a compound described herein, or a salt thereof, and a pharmaceutically acceptable carrier. Therapeutic compositions modulate protein degradation in a patient or subject, eg, an animal such as a human, and can be used to treat or normalize pathological conditions or conditions that are modulated by protein degradation. In accordance with certain embodiments, the therapeutic compositions described herein can be used to effect the degradation of proteins of interest to treat or alleviate a disease, such as cancer. In accordance with yet another aspect, the present disclosure provides a method for ubiquitination/cleavage of a target protein in a cell. In certain embodiments, the method comprises administering a bifunctional compound as described herein, comprising ILM and PTM, PTM and VLM, or PTM and CLM, or PTM and MLM, preferably linked by a linker moiety otherwise described herein, wherein VLM/ILM/CLM/MLM is linked to the PTM via a linker to target a protein that binds to the PTM for cleavage. Likewise, a PTM can be linked to a VLM or CLM or MLM or TLM via a linker to target a protein or polypeptide for cleavage. Cleavage of the target protein will occur when the target protein is located adjacent to the E3 ubiquitin ligase, thereby resulting in cleavage/inhibition of the effects of the target protein and control of protein levels. The control of protein levels provided by the present disclosure provides treatment for a pathological condition or condition that is modulated by a target protein as a result of a decrease in the level of that protein in the patient's cells.

[0031] In yet another aspect, provided herein are methods of treating or normalizing a disease, disorder, or symptoms thereof in a subject or patient, e.g., an animal such as a human, comprising administering to the subject in need thereof a composition comprising an effective amount, for example, a therapeutically effective amount of a compound described herein, or a salt thereof, and a pharmaceutically acceptable carrier, wherein the composition is effective for treating or normalizing a disease or disorder or symptoms thereof in a subject.

[0032] In another aspect, provided herein are methods for identifying the effects of degradation of proteins of interest in a biological system using compounds of the present disclosure.

[0033] The foregoing general applications are presented by way of example only and are not intended to limit the scope of the present disclosure and the appended claims. Additional objects and advantages associated with the compositions, methods and processes of the present disclosure will be apparent to one skilled in the art in light of the contemplated claims, description and examples. For example, various aspects and embodiments may be used in numerous combinations, all of which are expressly contemplated by the present invention. These additional aspects and embodiments are expressly included within the scope of this disclosure. Publications and other materials used herein to illustrate the prior art of the present invention and, in certain cases, to provide additional information regarding its practical implementation, are incorporated herein by reference.

Brief description of drawings

[0034] The accompanying drawings, which are included and form a part of the description, illustrate several embodiments of the present disclosure, and together with the description are necessary to explain the principles of the present disclosure. The drawings are provided for purposes of illustration of the embodiment only and are not intended to limit the present disclosure. Additional objects, features, and advantages of the present disclosure will be apparent from the following detailed description taken in conjunction with the accompanying drawings, which depict embodiments of the present disclosure in which:

[0035] FIG. 1A and 1B. Illustration of the general operating principle of PROTAC. (A) Exemplary PROTACs contain a protein targeting moiety (PTM; dark box), a ubiquitin ligase binding moiety (ULM; light box), and an optional linker moiety (L; black line) connecting or linking the PTM to ULM. (B) The functional applications of the PROTACs described herein are shown. Briefly, ULM recognizes and binds to a specific E3 ubiquitin ligase, and PTM binds and recruits the target protein, placing it in close proximity to the E3 ubiquitin ligase. Typically, E3 ubiquitin ligase forms a complex with the E2 ubiquitin-conjugating protein, and either alone or with the help of the E2 protein, catalyzes the attachment of ubiquitin (dark circles) to a lysine in the target protein via an isopeptide bond. The polyubiquitinated protein (far right) is then targeted for degradation by the cell's proteasome system.

[0036] FIG. 2. Table 42. Exemplary protein targeting moieties and compounds of the present disclosure.

[0037] FIG. 3. Table 43. Data for exemplary protein-targeting moieties and compounds of the present disclosure.

Detailed Disclosure of the Present Invention

[0038] The following is a detailed description provided to assist those skilled in the art in practicing the present disclosure. Modifications and variations in the embodiments described herein can be made by those skilled in the art without departing from the spirit and scope of the present disclosure. All publications, patent applications, patents, figures and other references mentioned herein are expressly incorporated by reference in their entirety.

[0039] Compositions and methods are now described that relate to the unusual and unexpected discovery that E3 ubiquitin ligase protein (e.g., inhibitors of apoptosis proteins (IAPs), von Hippel-Lindau (VHL) tumor suppressor E3 ubiquitin ligase, cereblon E3 ubiquitin ligase, or E3 ubiquitin ligase murine minichromosome double homologue 2 (MDM2) ubiquitinates the target protein when it and the target protein are located adjacent, using a bifunctional or chimeric construct that links the E3 ubiquitin ligase protein and the target protein. Accordingly, the present invention provides such compounds and compositions comprising an E3 ubiquitin ligase binding moiety ("ULM") coupled to a protein target binding moiety ("PTM"), resulting in ubiquitination of the selected target protein, which results in cleavage of the target protein. proteasome (see Fig. 1). The present disclosure also provides a composition library and a method for using it.

[0040] In certain aspects, the present disclosure provides compounds that contain a ligand, for example, a low molecular weight ligand (i.e., having a molecular weight below 2000, 1000, 500, or 200 daltons) that is capable of binding to a ubiquitin ligase, such as IAP, VHL, MDM2 or Cereblon. The compounds also contain a moiety that is capable of binding to a target protein such that the target protein is positioned adjacent to a ubiquitin ligase to cause degradation (and/or inhibition) of the protein. Small molecule may mean, in addition to the above, that the molecule is non-peptidyl, i.e., not generally considered a peptide, eg, contains less than 4, 3, or 2 amino acids. As used herein, the PTM, ULM, or PROTAC molecule may be a small molecule.

[0041] Unless otherwise noted, all technical and scientific terms used herein have the same meaning as commonly understood by one skilled in the art to which this disclosure pertains. The terminology used herein is used to describe specific embodiments only and is not intended to limit the present disclosure.

[0042] If a range of values is presented, it is understood that each intermediate value up to the tenth unit of the lower limit, unless the context clearly indicates otherwise (for example, as in the case of a group containing a number of carbon atoms, in which case each carbon atom number is represented, which falls within the limit of the range), between the upper and lower limits of such range, and any other specified or intermediate value within the specified range is covered within the scope of this disclosure. Upper and lower limits of such smaller ranges that may be independently included within the smaller ranges are also covered within the scope of this disclosure depending on any specifically excluded limit in the claimed range. If a specified range includes one or both limits, ranges excluding any two such included limits are also included in this disclosure.

[0043] The following terms have been used to describe the present disclosure. Where a term is not specifically defined herein, it is given its meaning within the art by one skilled in the art using such term in the context of its application in describing the present disclosure.

[0044] As used herein and in the claims, the singular forms are used to refer to one or more than one (i.e., at least one) grammatical entity of the description unless the context clearly indicates otherwise. By way of example, "element" means one element or more than one element.

[0045] The expression "and/or" used in the present description and in the claims should be understood to mean "either or both" elements so connected, i.e., elements that are simultaneously present in some cases and separately present in other cases. Many elements listed with "and/or" should be understood in the same way, i.e., "one or more" elements connected in this way. Other elements may not necessarily be present, other than those specifically designated by the “and/or” clause, which are either related or not related to the specifically designated elements. Thus, as a non-limiting example, a reference to “A and/or B,” when used in conjunction with open-ended language such as “comprising,” in one embodiment may refer only to A (not necessarily including elements other than B); according to another embodiment, to B only (optionally including elements other than A); according to yet another embodiment, to both A and B (optionally including other elements); and so on.

[0046] As used herein and in the claims, “or” should be understood to have the same meaning as “and/or” as defined above. For example, if a list contains individual units, “or” or “and/or” should be interpreted as inclusive, i.e., the inclusion of at least one, but also the inclusion of more than one, number or list of items, and optionally additional unlisted units. Only terms clearly defined in the opposite sense, such as “only one of” or “exactly one of” or when used in a claim, “consisting of”, will refer to the inclusion of exactly one element from a number or list of elements. In general, the term "or" when used in the present invention should be interpreted only as meaning exclusive alternatives (i.e., "one or the other, but not both") preceded by exclusive terms such as "either", "one of" , “only one of” or “exactly one of”.

[0047] In the claims, as well as in the description above, all transitional phrases such as “comprising”, “including”, “delivering”, “having”, “comprising”, “involving”, “ holding”, “consisting of”, etc. are understood as open-ended phrases, i.e., meaning inclusive without limitation. Only the transitional phrases “consisting of” and “consisting essentially of” must be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Examination Manual, Section 2111.03.

[0048] As used herein and in the claims, the phrase “at least one” with respect to a list of one or more elements is to be understood to mean at least one element selected from any or more of the elements in the list of elements, but not necessarily including at least one of each individual element specifically listed in the list of elements and without excluding any combinations of elements in the list of elements. This definition also allows that elements other than those specifically defined in the list of elements referred to by the phrase “at least one” may optionally be present, whether or not related to the elements that are specifically identified. Thus, as a non-limiting example, "at least one of A and B" (or equivalent to "at least one of A or B" or equivalent to "at least one A and/or B"), according to one embodiment, may refer to to at least one, optionally including more than one A without B (and optionally including elements other than B); according to another embodiment, to at least one, optionally including more than one B without A (and optionally including elements other than A); according to yet another embodiment, at least one optionally including more than one A and at least one optionally including more than one B (and optionally including other elements); and so on.

[0049] It should also be understood that according to certain methods described in the present invention that include more than one step or action, the order of the steps or actions of the method is not necessarily limited to the order in which the steps or actions of the method are listed, unless the context indicates other.

[0050] The terms “co-administration” and “co-administered” or “combination therapy” refer to both simultaneous administration (administration of two or more therapeutic agents at the same time) and administration at different times (administration of two or more therapeutic agents). agents at a time that is different from the time of administration of the additional therapeutic agent or agents), provided that the therapeutic agents are present in the patient to some extent, preferably in effective amounts, at the same time. In certain preferred aspects, one or more compounds described herein are co-administered in combination with at least one additional biologically active agent, particularly including an anticancer agent. In certain preferred aspects, coadministration of the compounds results in synergistic activity and/or therapy, including anticancer activity.

[0051] As used herein, the term “compound,” unless otherwise noted, refers to any specific compound disclosed herein and includes tautomers, regioisomers, geometric isomers, and optionally stereoisomers, including optical isomers (enantiomers) and others thereof. stereoisomers (diastereomers), as well as their pharmaceutically acceptable salts and derivatives, including their prodrugs and/or deuterated forms, where applicable in the context. Provided deuterated small molecules are those in which one or more hydrogen atoms that are contained in the drug molecule are replaced by deuterium.

[0052] Within its context, the term compound generally refers to a simple compound, and may also include other compounds such as stereoisomers, regioisomers and/or optical isomers (including racemic mixtures), as well as specific enantiomers or enantiomerically enriched mixtures open connections. The term also refers in the context of pharmaceutical dosage forms to compounds that have been modified to facilitate administration and delivery of the compounds to the site of activity. It is noted that in describing the compounds of the present invention, many substituents and variables associated therewith, among other things, are described. Those skilled in the art will appreciate that the molecules that are described in the present invention are stable compounds as generally described herein. If a bond is shown, both the double bond and the single bond are presented or understood within the context of the compound shown and the well-known rules for valence interactions.

[0053] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to a specific substrate protein by targeting the substrate protein for degradation. For example, the ubiquitin ligase protein IAP, which alone or in combination with the E2 ubiquitin-conjugating enzyme, causes the addition of ubiquitin to lysine in the target protein, and subsequently targets specific protein subcountries for degradation by the proteasome. Thus, E3 ubiquitin ligase alone or in complex with the E2 ubiquitin-conjugating enzyme is responsible for the transfer of ubiquitin to target proteins. Typically, a ubiquitin ligase is involved in polyubiquitination such that a second ubiquitin is added to the first; the third joins the second, etc. Polyubiquitination marks proteins for degradation by the proteasome. At the same time, there are some cases of ubiquitination that are limited to monoubiquitination, where only one ubiquitin is added by ubiquitin ligase to a substrate molecule. Monoubiquitinated proteins are not targeted to the proteasome for degradation, but may instead be altered in their cellular location or function, for example by binding to other proteins that have domains capable of binding ubiquitin. Further complicating matters, different lysines in ubiquitin may be targeted by E3 to create chains. The most common lysine is Lys48 in the ubiquitin chain. This is the lysine that is used to create polyubiquitin, which is recognized by the proteasome.

[0054] The term “patient” or “subject” is used throughout this specification to describe an animal, preferably a human or domesticated animal, that is subject to treatment, including prophylactic treatment, with the compositions of the present disclosure. For the treatment of such infections, conditions or pathological conditions that are specific to a particular animal, such as a human patient, the term patient refers to a particular animal, including a domesticated animal such as a dog or cat, or a farm animal such as a horse , cow, sheep, etc. Generally, as used herein, the term patient refers to a human patient unless otherwise stated or the context implies the use of the term.

[0055] The term “effective” is used herein to describe the amount of a compound, composition, or component that, when used in the context of its intended use, produces the intended result. The term effective includes all other terms of effective amount or effective concentration that are otherwise described or used in this application.

[0056] Compounds and compositions

[0057] In one aspect, provided herein are compounds comprising an E3 ubiquitin ligase binding fragment ("ULM"), which is an E3 ubiquitin ligase IAP binding fragment ("ILM"), a cereblon E3 ubiquitin ligase binding fragment ("CLM") ), von Hippel-Lindau (VHL) tumor suppressor E3 ubiquitin ligase binding fragment (VLM) and/or murine minichromosome double homolog 2 (MDM2) E3 ubiquitin ligase binding fragment (MLM). In an exemplary embodiment, the ULM is linked to a target protein binding moiety (PTM) via a chemical linker (L) according to the structure:

(A) PTM-L-ULM,

wherein L represents a chemical linker bond or group, ULM represents an E3 ubiquitin ligase binding moiety, and PTM represents a target protein binding moiety. The number and/or relative positions of moieties in the compounds illustrated herein are provided as an example only. As will be appreciated by one skilled in the art, the compounds described herein can be synthesized using any number/or relative position of appropriate functional moieties.

[0058] The terms ULM, ILM, VLM, MLM and CLM are used in their inclusive sense unless the context clearly indicates otherwise. For example, the term ULM includes all ULMs, including those that bind IAP (i.e. ILM), MDM2 (i.e. MLM), Cereblon (i.e. CLM) and VHL (i.e. ., VLM). In addition, the term TLM includes possible E3 ubiquitin ligase IAP binding fragments, the term MLM includes all possible E3 ubiquitin ligase MDM2 binding fragments, the term VLM includes all possible VHL binding fragments, and the term CLM includes all binding fragments Cereblon.

[0059] In accordance with another aspect, the present disclosure provides bifunctional or multifunctional compounds (eg, PROTAC) useful for regulating the activity of proteins by inducing degradation of a target protein. In accordance with certain embodiments, the compound comprises a TLM or VLM or a CLM or MLM linked, for example, covalently linked, directly or indirectly, to a moiety that binds a protein target (i.e., a protein targeting moiety, or "PTM" ). In accordance with certain embodiments, the ILM/VLM/CLM/MLM and the PTM are linked or joined by a chemical linker (L). ILM binds IAP E3 ubiquitin ligase, VLM binds VHL, CLM binds cereblon E3 ubiquitin ligase and MLM binds MDM2 E3 ubiquitin ligase, and PTM recognizes the target protein and the interaction of the corresponding fragments with their targets facilitates the cleavage of the target protein as a result of the location of the target protein near the protein by the ubiquitin ligase. An exemplary bifunctional compound may be described as follows:

(B) RTM-ILM

(C) RTM CLM

(D) RTM VLM

(E) RTM-MLM

[0060] In accordance with certain embodiments, the bifunctional compound further comprises a chemical linker (“L”). For example, a bifunctional compound can be described as follows:

(F) RTM-L-TLM

(G) RTM-L CLM

(H) RTM-L VLM

(I) RTM-L-MLM,

wherein PTM is a protein/polypeptide targeting fragment, L is a chemical linker, ILM is an IAP E3 ubiquitin ligase binding fragment, CLM is a cereblon E3 ubiquitin ligase binding fragment, VLM is a VHL binding fragment, and MLM is E3 ubiquitin ligase MDM2 binding fragment.

[0061] In certain embodiments, a ULM (e.g., ILM, CLM, VLM, or MLM) has activity on or binds to an E3 ubiquitin ligase (e.g., E3 ubiquitin ligase IAP, E3 ubiquitin ligase cereblon, E3 ubiquitin ligase VHL, or E3 ubiquitin ligase MDM2) to IC ₅₀ less than about 200 µM. IC ₅₀ can be determined in accordance with any method known in the art, for example, fluorescence polarization analysis.

[0062] In certain embodiments, the bifunctional compounds described herein have activity at an IC ₅₀ of less than about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005 , 0.001 mM, or less than about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 μM, or less than about 100, 50, 10, 1, 0 .5, 0.1, 0.05, 0.01, 0.005, 0.001 nM, or less than about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 pM.

[0063] In accordance with certain embodiments, the compounds described herein contain multiple PTMs (targeting the same or different protein targets), multiple ULMs, one or more ULMs (i.e., fragments that bind specifically with several/different E3 ubiquitin ligases, e.g. VHL, IAP, cereblon and/or MDM2) or a combination thereof. In accordance with any of the aspects or embodiments described herein, PTM and ULM (eg, ILM, VLM, CLM and/or MLM) can be linked directly or via one or more chemical linkers or combinations thereof. In further embodiments, if a compound has multiple ULMs, the ULMs may target the same E3 ubiquitin ligase, or each respective ULM may specifically bind to a different E3 ubiquitin ligase. In yet further embodiments, if a compound has multiple PTMs, the PTMs may bind the same target protein, or each respective PTM may specifically bind to a different target protein.

[0064] In accordance with certain embodiments, if a connection contains multiple ULMs, then the ULMs are identical. According to further embodiments, a compound comprising multiple ULMs (e.g., ULM, ULM', etc.) comprises at least one PTM linked to the ULM directly or via a chemical linker (L), or both . According to certain further embodiments, a connection comprising multiple ULMs further comprises multiple PTMs. According to further embodiments, the PTMs are the same or optionally different. In further embodiments, if the PTMs are different, the respective PTMs may bind to the same protein target or specifically bind to a different protein target.

[0065] In accordance with certain embodiments, a connection may contain multiple ULMs and/or multiple ULMs'. According to further embodiments, the compound comprising at least two different ULMs, multiple ULMs, and/or multiple ULMs' further comprises at least one PTM linked to the ULM or ULM' directly or via a chemical linker, or both . In accordance with any of the embodiments described herein, a connection comprising at least two different TLMs may further comprise multiple PTMs. According to further embodiments, the PTMs are the same or optionally different. In further embodiments, if the PTMs are different, the respective PTMs may bind to the same protein target or specifically bind to a different protein target. According to still further embodiments, the PTM itself is a ULM (or ULM'), such as ILM, VLM, CLM, MLM, ILM', VLM', CLM' and/or MLM'.

[0066] In accordance with additional embodiments, provided herein are the compounds described herein, including their enantiomers, diastereomers, solvates, and polymorphs, including their pharmaceutically acceptable salt forms, for example, acid and basic salt forms.

[0067] Exemplary ILMs

[0068] AVPI therapeptide fragments

[0069] In any of the compounds described in the present invention, the ILM may contain an alanine-valine-proline-isoleucine (AVPI) tetrapeptide moiety or non-naturally occurring mimetics thereof. In certain embodiments, the TLM is selected from the group consisting of chemical structures represented by formulas (I), (II), (III), (IV), and (V):

Where:

R ¹ for formulas (I), (II), (III), (IV) and (V) is selected from H or alkyl;

R ² for formulas (I), (II), (III), ((IV) and (V) is selected from H or alkyl;

R ³ for formulas (I), (II), (III), (IV) and (V) is selected from H, alkyl, cycloalkyl and heterocycloalkyl;

R ⁵ and R ⁶ for formulas (I), (II), (III), (IV) and (V) are independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, or more preferably R ⁵ and R ⁶ taken together for formulas (I), (II), (III), (IV) and (V) form a pyrrolidine or piperidine ring, optionally further fused with 1-2 cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings, each of which can then be further fused with another cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring;

R ³ and R ⁵ for formulas (I), (II), (III), (IV) and (V), taken together, can form a 5-8 membered ring, optionally further fused with 1-2 cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings;

R ⁷ for formulas (I), (II), (III), (IV) and (V) is selected from cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, each additionally optionally substituted with 1-3 substituents, selected from halogen, alkyl, haloalkyl, hydroxyl, alkoxy, cyano, (hetero)cycloalkyl or (hetero)aryl, or R ⁷ is -C(O)NH-R ⁴ ; And

R ⁴ is selected from alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, further optionally substituted with 13 substituents as described above.

[0070] As shown above, P1, P2, P3 and P4 of formula (II) are associated with A, V, P and I, respectively, AVPI tetrapeptide moiety or non-naturally occurring mimetics thereof. Similarly, each of formulas (I) and (III) - (V) contains parts associated with A, V, P and I AVPI tetrapeptide fragment or its non-naturally occurring mimetics.

[0071] In any of the compounds described in the present invention, the ILM may have the structure of formula (VI), which is a derivative of the IAP antagonists described in WO publication No. 2008/014236, or their non-naturally occurring mimetics:

Where:

R ₁ of formula (VI) is independently selected from H, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkenyl, C ₁ -C ₄ alkynyl or C ₃ -C _1O cycloalkyl, which are unsubstituted or substituted;

R ₂ of formula (VI) is independently selected from H, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkenyl, C ₁ -C ₄ -alkynyl or C ₃ -C ₁₀ -cycloalkyl, which are unsubstituted or substituted;

R ³ of formula (VI) is independently selected from H, -CF ₃ , -C ₂ H ₅ , C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkenyl, C ₁ -C ₄ -alkynyl, -CH ₂ -Z or any R ₂ and R ₃ together form a heterocyclic ring;

each Z of formula (VI) is independently selected from H, -OH, F, Cl, -CH ₃ , -CF ₃ , -CH ₂ Cl, -CH ₂ F or -CH ₂ OH;

R ₄ of formula (VI) is independently selected from C ₁ -C ₁₆ straight or branched alkyl, C ₁ -C ₁₆ alkenyl, C ₁ -C ₁₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, -(CH ₂ ) _{0- 6} -Z ₁ , -(CH ₂ ) _0-6 -aryl and -(CH ₂ ) _0-6 -het, where alkyl, cycloalkyl and phenyl are unsubstituted or substituted;

R ₅ of formula (VI) is independently selected from H, C _1-10 -alkyl, aryl, phenyl, C _3-7 -cycloalkyl, -(CH ₂ ) _1-6 -C _3-7 -cycloalkyl, -C _1-10 -alkylaryl, -(CH ₂ ) _0-6 -C _3-7 -cycloalkyl-(CH ₂ ) _0-6 -phenyl, -(CH ₂ ) _0-4 -CH[(CH ₂ ) _1-4 -phenyl] ₂ , indanyl, -C(O)-C _1-10 -alkyl, -C(O)-(CH ₂ ) _1-6 -C _3-7 -cycloalkyl, -C(O)-(CH ₂ ) _{0- 6} -phenyl, -(CH ₂ ) _0-6 -C(O)-phenyl, -(CH ₂ ) _0-6 -het, -C(O)-(CH ₂ ) _1-6 -het or R ₅ selected from an amino acid residue wherein the alkyl, nicloalkyl, phenyl and aryl substituents are unsubstituted or substituted;

Z ₁ of formula (VI) is independently selected from -N(R ₁₀ )-C(O)-C _1-10 -alkyl, -N(R _1O )-C(O)-(CH ₂ ) _0-6 -C _{3 -7} -cycloalkyl, -N(R ₁₀ )-C(O)(CH ₂ ) _0-6 -phenyl, -N(R ₁₀ )-C(O)(CH ₂ ) _1-6 -het, -C( O)-N(R ₁₁ )(R ₁₂ ), -C(O)-OC _1-10 -alkyl, -C(O)-O-(CH ₂ ) _1-6 -C _3-7 -cycloalkyl, - C(O)-O-(CH ₂ ) _0-6 -phenyl, -C(O)-O-(CH ₂ ) _1-6 -het, -O-C(O)-C _1-10 -alkyl, -OC(O)-(CH ₂ ) _1-6 -C _3-7 -cycloalkyl, -OC(O)-(CH ₂ ) _0-6 -phenyl, -OC(O)-(CH ₂ ) _1-6 -het, where alkyl, cycloalkyl and phenyl are unsubstituted or substituted;

het of formula (VI) is independently selected from a 5-7 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S, or an 8-12 membered fused ring system containing at least one 5-7 -membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O and S, wherein the heterocyclic ring or fused ring system is unsubstituted or substituted at the carbon or nitrogen atom;

R ₁₀ of formula (VI) is selected from H, -CH ₃ , -CF ₃ , -CH ₂ OH or -CH ₂ Cl;

R ₁₁ and R ₁₂ of formula (VI) are independently selected from H, C _1-4 -alkyl, C _3-7 -cycloalkyl, -(CH ₂ ) _1-6 -C _3-7 -cycloalkyl, (CH ₂ ) _{0- 6} -phenyl, where alkyl, cycloalkyl and phenyl are unsubstituted or substituted; or R ₁₁ and R ₁₂ together with the nitrogen atom form het, and U of formula (VI) is independently represented on formula (VII):

Where:

each n of formula (VII) is independently selected from 0-5;

X of formula (VII) is selected from the group -CH and N;

R _a and R _b of formula (VII) are independently selected from the group of O, S or N or C _0-8 -alkyl atoms, wherein one or more carbon atoms in the alkyl chain are optionally replaced by a heteroatom selected from O, S or N, and where each alkyl is independently either unsubstituted or substituted;

R _d of formula (VII) is selected from the group Re-Q-(R _f ) _p (R _g ) _q and Ar ₁ -D-Ar ₂ ;

R _c of formula (VII) is selected from group II or any R _c and R _d together form cycloalkyl or het; moreover, if R _c and R _d form cycloalkyl or het, R ₅ is attached to the formed ring at the C or N atom;

p and q of formula (VII) are independently selected from 0 or 1;

R _e of formula (VII) is selected from the group of C _1-8 -alkyl and alkylidene, and each Re is either unsubstituted or substituted;

Q is selected from the group N, O, S, S(O) and S(O) ₂ ;

Ar ₁ and Ar ₂ of formula (VII) are independently selected from the group of substituted or unsubstituted aryl and het;

R _f and R _g of formula (VII) are independently selected from H, -C1-10-alkyl, C _1-10 -alkylaryl, -OH, -O-C _1-10 -alkyl, -(CH ₂ ) _0-6 - C _3-7 -cycloalkyl, -O-(CH ₂ ) _0-6 -aryl, phenyl, aryl, phenyl-phenyl, -(CH ₂ ) _1-6 -het, -O-(CH ₂ ) _1-6 - het, -OR ₁₃ , -C(O)-R ₁₃ , -C(O)-N(R ₁₃ )(R ₁₄ ), -N(R ₁₃ )(R ₁₄ ), -SR ₁₃ , -S(O )R ₁₃ , -S(O) ₂ -R ₁₃ , -S(O) ₂ -NR ₁₃ R ₁₄ ; -NR ₁₃ -S(O) ₂ -R ₁₄ , -SC _t-10 -alkyl, aryl-C _1-4 -alkyl or het-C _1-4 -alkyl, where alkyl, cycloalkyl, het and aryl are unsubstituted or substituted, -SO ₂ -C _1-2 -alkyl, -SO ₂ -C _1-2 -alkylphenyl, -O-C _1-4 -alkyl, or any R _g and R _f together form a ring selected from het or aryl ;

D of formula (VII) is selected from the group -CO-, -C(O)-C _1-7 -alkylene or arylene, -CF ₂ -, -O-, -S(O) _r , where r is 0-2 , 1,3-dioxalane or C _1-7 -alkyl-OH; where alkyl, alkylene or arylene are unsubstituted or substituted with one or more halogen atoms, OH, -O-C _1-6 -alkyl, -SC _1-6 -alkyl or -CF ₃ ; or each D is independently selected from N(R _h );

Rh is selected from group H, unsubstituted or substituted C _1-7 -alkyl, aryl, unsubstituted or substituted -O-(C _1-7 -cycloalkyl), -C(O)-C _1-10 -alkyl, -C(O )-C _0-10 -alkylaryl, -C-O-C _01-10 -alkyl, -C-O-C _0-10 -alkylaryl, -SO ₂ -C _1-10 -alkyl or -SO ₂ -(C _0-10 -alkylaryl);

R ₆ , R ₇ , R ₈ and R ₉ of formula (VII) are independently selected from the group H, -C _1-10 -alkyl, -C _1-10 -alkoxy, aryl-C _1-10 -alkoxy, -OH, - O-C _1-10 -alkyl, -(CH ₂ ) _0-6 -C _3-7 -cycloalkyl, -O-(CH ₂ ) _0-6 -aryl, phenyl, -(CH ₂ ) _1-6 -het , -O-(CH ₂ ) _1-6 -het, -OR ₁₃ , -C(O)R ₁₃ , -C(O)-N(R ₁₃ )(R ₁₄ ), -N(R ₁₃ )(R ₁₄ ), -SR ₁₃ , -S(O)-R ₁₃ , -S(O) ₂ - R ₁₃ , -S(O) ₂ -NR ₁₃ R ₁₄ or -NR ₁₃ -S(O) ₂ -R ₁₄ ; wherein each alkyl, cycloalkyl and aryl is unsubstituted or substituted; and any of R ₆ , R ₇ , R ₈ and R ₉ optionally together form a ring system;

R ₁₃ and R ₁₄ of formula (VII) are independently selected from the group H, C _1-10 -alkyl, -(CH ₂ ) _0-6 -C _3-7 -cyloloalkyl, -(CH ₂ ) _0-6 - (CH) _0-1 -(aryl) _1-2 , -C(O)-C _1-10 -alkyl, -C(O)-(CH ₂ ) _1-6 -C _3-7 -cycloalkyl, -C(O) -O-(CH ₂ ) _0-6 -aryl, -C(O)-(CH ₂ ) _0-6 -O-fluorenyl, -C(O)-NH-(CH ₂ ) _0-6 -aryl, - C(O)-(CH ₂ ) _0-6 -aryl, -C(O)-(CH ₂ ) _0⋅6 -het, -C(S)-C _1-10 -alkyl, -C(S)- (CH ₂ ) _1-6 -C _3-7 -cycloalkyl, -C(S)-O-(CH ₂ ) _0-6 -aryl, -C(S)-(CH ₂ ) _0-6 -O-fluorenyl , -C(S)-NH-(CH ₂ ) _0-6 -aryl, -C(S)-(CH ₂ ) _0-6 -aryl or -C(S)-(CH ₂ ) _1-6 -het wherein each alkyl, cycloalkyl and aryl is unsubstituted or substituted: or any R ₁₃ and R ₁₄ together with a nitrogen atom form het;

wherein the alkyl substituents R ₁₃ and R ₁₄ of formula (VII) are unsubstituted or substituted and, if substituted, they are substituted with one or more substituents selected from C _1-10 alkyl, halogen, OH, O-C _1-6 alkyl, - SC _1-6 -alkyl and -CF ₃ ; and substituted phenyl or aryl R ₁₃ and R ₁₄ are substituted with one or more substituents selected from halogen, hydroxyl, C _1-4 -alkyl, C _1-4 -alkoxy, nitro, -CN, -OC(O)-C _{1- 4} -alkyl and -C(O)-OC _1-4 -aryl; or a pharmaceutically acceptable salt or hydrate thereof.

[0072] In certain embodiments, the compound further comprises an independently selected second ILM attached to the ILM of formula (VI), or non-naturally occurring mimetics thereof, via at least one additional independently selected linker group. In an embodiment, the second ILM is a derivative of formula (VI) or non-naturally occurring mimetics thereof. In a certain embodiment, the at least one additional independently selected linker group comprises two additional independently selected linker groups, an ILM chemical linker and a second ILM. In an embodiment, at least one additional linker group for the ILM of formula (VI) or its non-naturally occurring mimetics chemically links groups selected from R ₄ and R ₅ . For example, the ILM of formula (VI) and the second ILM of formula (VI) or their non-naturally occurring mimetics can be related, as shown below:

[0073] In certain embodiments of the ILM, at least one additional independently selected linker group L and the second ILM is characterized by a structure selected from the group consisting of:

which are derivatives of the IAP antagonists described in WO publication No. 2008/014236.

[0074] In any of the compounds described in the present invention, the ILM may have the structure of formula (VIII), which is based on the IAP ligands described in Ndubaku, S., et al. Antagonism of c-IAP and XIAP proteins is required for efficient induction of cell death by small-molecule IAP antagonists, ACS Chem. Biol., 557-566, 4 (7) (2009), or their non-naturally occurring mimetics:

wherein each of A1 and A2 of formula (VIII) is independently selected from optionally substituted monocyclic, fused rings, aryls and heteroaryls; And

R of formula (VIII) is selected from H or Me.

[0075] In a specific embodiment, the linker group L is attached to A1 of formula (VIII). In another embodiment, the linker group L is attached to A2 of formula (VIII).

[0076] In a specific embodiment, the ILM is selected from the group consisting of

[0077] In any of the compounds described in the present invention, the ILM may have the structure of formula (IX), which is obtained from the chemotypes referenced by Mannhold, R., et al. IAP antagonists: promising candidates for cancer therapy, Drug Discov. Today, 15 (5-6), 210-9 (2010), or its non-naturally occurring mimetics:

wherein R ¹ is selected from alkyl, cycloalkyl and heterocycloalkyl and most preferably from isopropyl, tert-butyl, cyclohexyl and tetrahydropyranyl, and R ² of formula (IX) is selected from -OPh or H.

[0078] In any of the compounds described in the present invention, the ILM may have the structure of formula (X), which is obtained from the chemotypes referenced by Mannhold, R., et al. IAP antagonists: promising candidates for cancer therapy, Drug Discov. Today, 15 (5-6), 210-9 (2010), or its non-naturally occurring mimetics:

Where:

R ¹ of formula (X) is selected from H, -CH ₂ OH, --CH ₂ CH ₂ OH, --CH ₂ NH ₂ , --CH ₂ CH ₂ NH ₂ ;

X of formula (X) is selected from S or CH ₂ ;

R ² of formula (X) is selected from:

R ³ and R ⁴ of formula (X) are independently selected from H or Me

[0079] In any of the compounds described in the present invention, the ILM may have the structure of formula (XI), which is obtained from the chemotypes referenced by Mannhold, R., et al. IAP antagonists: promising candidates for cancer therapy, Drug Disc ov. Today, 15 (5-6), 210-9 (2010), or its non-naturally occurring mimetics:

where R ¹ of formula (XI) is selected from H or Me and R ² of formula (XI) is selected from H or

[0080] In any of the compounds described in the present invention, the ILM may have the structure of formula (XII), which is obtained from the chemotypes referenced by Mannhold, R., et al. IAP antagonists: promising candidates for cancer therapy, Drug Discov. Today, 15 (5-6), 210-9 (2010), or its non-naturally occurring mimetics:

Where:

R ¹ of formula (XII) is selected from:

R ² of formula (XII) is selected from:

[0081] In any of the compounds described herein, the E3 ubiquitin ligase IAP binding moiety is selected from the group consisting of:

[0082] In any of the compounds described in the present invention, the ILM may have the structure of formula (XIII), which is based on the IAP ligands summarized in Flygare, J.A., et al. Small-molecule pan-IAP antagonists: a patent review, Expert Opin. Ther. Pat., 20(2), 251-67 (2010), or its non-naturally occurring mimetics:

Where:

Z of formula (XIII) is absent or represents O;

R ¹ of formula (XIII) is selected from:

R ¹⁰ selected from H, alkyl or aryl;

X is selected from CH2 and O; And

is a nitrogen-containing heteroaryl.

[0083] In any of the compounds described in the present invention, the ILM may have a structure of formula (XIV), which is based on the IAP ligands summarized in Flygare, J.A., et al. Small-molecule pan-IAP antagonists: a patent review, Expert Opin. Ther. Pat., 20(2), 251-67 (2010), or its non-naturally occurring mimetics:

Where:

Z of formula (XIV) is absent or represents O;

R ³ and R ⁴ of formula (XIV) are independently selected from H or Me;

R ¹ of formula (XIV) is selected from:

R ¹⁰ selected from H, alkyl or aryl;

X selected from CH2 and O; And

formulas or is a nitrogen-containing heteroaryl.

[0084] In any of the compounds described in the present invention, the ILM is selected from the group consisting of:

which are derivatives of the ligands disclosed in US Patent Publication No. 2008/0269140 and US Patent No. 7244851.

[0085] In any of the compounds described in the present invention, the ILM may have a structure of formula (XV), which is a derivative of the IAP ligand described in WO publication No. 2008/128171, or its non-naturally occurring mimetics:

Where:

Z of formula (XV) is absent or represents O;

R ¹ of formula (XV) is selected from:

R ¹⁰ selected from H, alkyl or aryl;

X selected from CH2 and O; And

formulas or is a nitrogen-containing heteroaryl; And

R ² of formula (XV) is selected from H, alkyl or acyl;

[0086] According to a specific embodiment, the ILM is characterized by the following structure:

[0087] In any of the compounds described in the present invention, the ILM may have a structure of formula (XVI), which is based on the IAP ligand described in WO publication No. 2006/069063, or its non-naturally occurring mimetics:

Where:

R ² of formula (XVI) is selected from alkyl, cycloalkyl and heterocycloalkyl; more preferably isopropyl, tert-butyl, cyclohexyl and tetrahydropyranyl, most preferably cyclohexyl;

formula (XVI) is a 5- or 6-membered nitrogen-containing heteroaryl; more preferably a 5-membered nitrogen heteroaryl and most preferably a thiazole; And

Ar of formula (XVI) is aryl or heteroaryl.

[0088] In any of the compounds described in the present invention, the ILM may have a structure of formula (XVII), which is based on the IAP ligands described in Cohen, F. et al., Antagonists of inhibitors of apoptosis proteins based on thiazole amide isosteres, Bioorg . Med. Chem. Lett., 20(7), 2229-33 (2010), or its non-naturally occurring mimetics:

Where:

R ¹ of formula (XVII) is selected from the group of halogen (for example, fluorine), cyano,

X of formula (XVII) is selected from the group O or CH2.

[0089] In any of the compounds described in the present invention, the ILM may have a structure of formula (XVIII), which is based on the IAP ligands described in Cohen, F. et al., Antagonists of inhibitors of apoptosis proteins based on thiazole amide isosteres, Bioorg . Med. Chem. Lett., 20(7), 2229-33 (2010), or its non-naturally occurring mimetics:

where R of formula (XVIII) is selected from alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or halogen (at various substitution positions).

[0090] In any of the compounds described in the present invention, the ILM may have a structure of formula (XIX), which is based on the IAP ligands described in Cohen, F. et al., Antagonists of inhibitors of apoptosis proteins based on thiazole amide isosteres, Bioorg . Med. Chem. Lett., 20(7), 2229-33 (2010), or its non-naturally occurring mimetics:

Where is a 6-membered heteroaryl with nitrogen.

[0091] According to a certain embodiment, the ILM of the composition is selected from the group consisting of:

[0092] In certain embodiments, the ILM of the composition is selected from the group consisting of:

[0093] In any of the compounds described in the present invention, the ILM may have a structure of formula (XX), which is based on the IAP ligands described in WO publication No. 2007/101347, or its non-naturally occurring mimetics:

where X of formula (XX) is selected from CH ₂ , O, NH or S.

[0094] In any of the compounds described herein, ILM may have the structure of formula (XXI), which is based on the IAP ligands described in US Pat. No. 7,345,081 and US Pat. No. 7,419,975, or non-naturally occurring mimetics thereof:

Where:

R ² of formula (XXI) is selected from:

R ⁵ of formula (XXI) is selected from: And

W of formula (XXI) is selected from CH or N; And

R ⁶ are independently mono- or bicyclic fused aryl or heteroaryl.

[0095] In certain embodiments, the connection ILM is selected from the group consisting of:

[0096] In certain embodiments, the connection ILM is selected from the group consisting of:

which are described in WO Publication No. 2009/060292, US Patent No. 7517906, WO Publication No. 2008/134679, WO Publication No. 2007/130626 and WO Publication No. 2008/128121.

[0097] In any of the compounds described in the present invention, the ILM may have a structure of formula (XXII) or (XXIII), which are derived from the IAP ligands described in WO publication No. 2015/006524 and Perez HL, Discovery of potent heterodimeric antagonists of inhibitor of apoptosis proteins (IAPs) with sustained antitumor activity. J. Med. Chem. 58(3), 1556-62 (2015), or its non-naturally occurring mimetics:

Where:

R ¹ of formula (XXII) or (XXIII) is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, or optionally substituted aryl;

R ² of formula (XXII) or (XXIII) is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, or optionally substituted aryl;

or alternatively, R ¹ and R ² of formula (XXII) or (XXIII) are independently optionally substituted thioalkyl, wherein the substituents attached to the S atom of the thioalkyl are optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted heterocyclyl, -(CH ₂ ) _v COR ²⁰ , -CH ₂ CHR ²¹ COR ²² or -CH ₂ R ²³ ;

Where:

v is an integer from 1 to 3;

R ²⁰ and R ²² formulas -(CH ₂ ) _v COR ²⁰ and -CH ₂ R ²³ ; independently selected from OH, NR ²⁴ R ²⁵ or OR ²⁶ ;

R ²¹ of the formula -CH ₂ CHR ²¹ COR ² is selected from the group NR ²⁴ R ²⁵ ;

R ²³ of the formula -CH ₂ R ²³ is selected from optionally substituted aryl or optionally substituted heterocyclyl, where optional substituents include alkyl and halogen;

R ²⁴ of the formula NR ²⁴ R ²⁵ is selected from hydrogen or optionally substituted alkyl;

R ²⁵ of the formula NR ²⁴ R ²⁵ is selected from hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted arylalkyl, optionally substituted heterocyclyl, -CH ₂ (OCH ₂ CH ₂ O) _m CH ₃ or a polyamine chain such as spermine or spermidine ;

R ²⁶ of formula OR ²⁶ is selected from optionally substituted alkyl, wherein the optional substituents are OH, halogen or NH ₂ ; And

m is an integer from 1 to 8;

R ³ and R ⁴ of formula (XXII) or (XXIII) are independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heteroarylalkyl or optionally substituted heterocycloalkyl, where the substituents are alkyl, halogen or OH;

R ⁵ , R ⁶ , R ⁷ and R ⁸ of formula (XXII) or (XXIII) are independently selected from hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl; And

X is selected from a bond or chemical linker group, and/or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0098] In certain embodiments, X is a link or is selected from the group consisting of:

where "*" is the attachment point of the RTM, L or ULM, for example, ILM.

[0099] In any of the compounds described in the present invention, the ILM may have a structure of formula (XXIV) or (XXVI), which are derived from the IAP ligands described in WO publication No. 2015/006524 and Perez HL, Discovery of potent heterodimeric antagonists of inhibitor of apoptosis proteins (IAPs) with sustained antitumor activity. J. Med. Chem. 58(3), 1556-62 (2015), or its non-naturally occurring mimetics, and a chemical linker with linker group L as shown:

Where:

R ¹ of formula (XXIV), (XXV) or (XXVI) is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted aryl;

R ² of formula (XXIV), (XXV) or (XXVI) is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted aryl;

or alternatively,

R ¹ and R ² of formula (XXIV), (XXV) or (XXVI) are independently selected from optionally substituted thioalkyl, wherein the substituents that are attached to the S atom of the thioalkyl are optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted heterocyclyl, - (CH ₂ ) _v COR ²⁰ , -CH ₂ CHR ²¹ COR ²² or -CH ₂ R ²³ ,

Where:

v is an integer from 1 to 3;

R ²⁰ and R ²² of the formula -(CH ₂ ) _v COR ²⁰ and -CH ₂ R ²³ are independently selected from OH, NR ²⁴ R ²⁵ or OR ²⁶ ;

R ²¹ of the formula -CH ₂ CHR ²¹ COR ² selected from NR ²⁴ R ²⁵ ;

R ²³ of the formula -CH ₂ R ²³ is selected from optionally substituted aryl or optionally substituted heterocyclyl, where optional substituents include alkyl and halogen;

R ²⁴ of the formula NR ²⁴ R ²⁵ is selected from hydrogen or optionally substituted alkyl;

R ²⁵ of the formula NR ²⁴ R ²⁵ is selected from hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted arylalkyl, optionally substituted heterocyclyl, -CH ₂ (OCH ₂ CH ₂ O) _m CH ₃ or a polyamine chain such as spermine or spermidine ;

R ²⁶ of formula OR ²⁶ is selected from optionally substituted alkyl, wherein the optional substituents are OH, halogen or NH ₂ ; And

m is an integer from 1 to 8;

R ³ and R ⁴ of formula (XXIV), (XXV) or (XXVI) are independently optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heteroarylalkyl or optionally substituted heterocycloalkyl, where the substituents are alkyl, halogen or OH;

R ⁵ , R ⁶ , R ⁷ and R ⁸ of formula (XXIV), (XXV) or (XXVI) independently represent hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl; and/or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0100] According to a specific embodiment of the ILM according to formulas (XXII) - (XXVI):

R ⁷ and R ⁸ are selected from H or Me;

R ⁵ and R ⁶ are selected from the group consisting of:

R ³ and R ⁴ are selected from the group containing:

[0101] In any of the compounds described in the present invention, the ILM may have a structure of formula (XXVII) or (XXVII), which are derived from the IAP ligands described in WO publication No. 2014/055461 and Kim, KS, Discovery of tetrahydroisoquinoline-based bivalent heterodimeric IAP antagonists. Bioorg. Med. Chem. Lett. 24(21), 5022-9 (2014), or its non-naturally occurring mimetics:

Where:

R ³⁵ represents 1-2 substituents selected from alkyl, halogen, alkoxy, cyano and haloalkoxy;

R ¹ of formula (XXVII) and (XXVIII) is selected from H or optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted aryl;

R ² of formula (XXVII) and (XXVIII) is selected from H or optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted aryl;

or alternatively

R ¹ and R ² of formula (XXVII) and (XXVIII) are independently selected from optionally substituted thioalkyl-CR ⁶⁰ R ⁶¹ SR ⁷⁰ , where R ⁶⁰ and R ⁶¹ are selected from H or methyl and R ⁷⁰ is selected from optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted heterocyclyl, -(CH ₂ ) _v COR ²⁰ , -CH ₂ CHR ²¹ COR ²² or -CH ₂ R ²³ ,

Where:

v is an integer from 1 to 3;

R ²⁰ and R ²² of the formula -(CH ₂ ) _v COR ²⁰ and -CH ₂ CHR ²¹ COR ²² are independently selected from OH, NR ²⁴ R ²⁵ or OR ²⁶ ;

R ²¹ of the formula -CH ₂ CHR ²¹ COR ²² is selected from NR ²⁴ R ²⁵ ;

R ²³ of the formula -CH ₂ R ²³ is selected from optionally substituted aryl or optionally substituted heterocyclyl, where optional substituents include alkyl and halogen;

R ²⁴ of the formula NR ²⁴ R ²⁵ is selected from hydrogen or optionally substituted alkyl;

R ²⁵ of the formula NR ²⁴ R ²⁵ is selected from hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted arylalkyl, optionally substituted heterocyclyl, -CH ₂ CH ₂ (OCH ₂ CH ₂ ) _m CH ₃ or a polyamine chain -[CH ₂ CH ₂ (CH ₂ ) _δ NH] _ψ CH ₂ CH ₂ (CH ₂ )ϖNH ₂ such as spermine or spermidine;

where δ=0-2, ψ=1-3, ϖ=0-2;

R ²⁶ of the formula OR ²⁶ is an optionally substituted alkyl, wherein the optional substituents are OH, halogen or NH ₂ ; And

m represents an integer from 1 to 8,

R ³ and R ⁴ of formula (XXVII) and (XXVIII) are independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heteroarylalkyl or optionally substituted heterocycloalkyl, where the substituents are alkyl, halogen or OH;

R ⁵ , R ⁶ , R ⁷ and R ⁸ of formula (XXVII) and (XXVIII) are independently selected from hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl;

R ³¹ of formulas (XXVII) and (XXVIII) is selected from alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, optionally further substituted, preferably selected from the group consisting of:

X of formulas (XXVII) and (XXVIII) is selected from -(CR ⁸¹ R ⁸² ) _m -, optionally substituted heteroaryl or heterocyclyl,

Z of formulas (XXVII) is selected from C=O, -O-, -NR, -CONH-, -NHCO- or may be absent;

R ⁸¹ and R ⁸² of the formula -(CR ⁸¹ R ⁸² ) _m - are independently selected from hydrogen, halogen, alkyl or cycloalkyl, or R ⁸¹ and R ⁸² can be taken together to form a carbocyclic ring;

R ¹⁰ and R ¹¹ formulas independently selected from hydrogen, halogen or alkyl;

R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ and R ¹⁶ formulas independently selected from hydrogen, halogen or optionally substituted alkyl or OR ¹⁷ ;

R ¹⁷ is selected from hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl;

m and n formulas -(CR ²¹ R ²² ) _m - and independently represent 0, 1, 2, 3 or 4;

o and p formulas independently represent 0, 1, 2 or 3;

q and t formulas independently represent 0, 1, 2, 3 or 4;

r formulas represents 0 or 1;

and/or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0102] In any of the compounds described in the present invention, the ILM may have a structure of formula (XXIX), (XXX), (XXXI) or (XXXII), which are derived from the IAP ligands described in WO publication No. 2014/055461 and Kim, KS , Discovery of tetrahydroisoquinoline-based bivalent heterodimeric LAP antagonists. Bioorg. Med. Chem. Lett. 24(21), 5022-9 (2014), or its non-naturally occurring mimetics, and a chemical linker with linker group L as shown:

Where:

R ² of formula (XXIX) - (XXXII) is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted aryl; or alternatively

R ¹ and R ² of formula (XXVII) and (XXVIII) are independently selected from H, optionally substituted thioalkyl-CR ⁶⁰ R ⁶¹ SR ⁷⁰ , where R ⁶⁰ and R ⁶¹ are selected from H or methyl, and R ⁷⁰ is optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted heterocyclyl, -(CH ₂ ) _v COR ²⁰ , -CH ₂ CHR ²¹ COR ²² or -CH ₂ R ²³ ;

Where:

v is an integer from 1 to 3;

R ²⁰ and R ²² of the formula -(CH ₂ ) _v COR ²⁰ and -CH ₂ CHR ²¹ COR ²² are independently selected from OH, NR ²⁴ R ²⁵ or OR ²⁶ ;

R ²¹ of the formula -CH ₂ CHR ²¹ COR ²² is selected from NR ²⁴ R ²⁵ ;

R ²³ of the formula -CH ₂ R ²³ is selected from optionally substituted aryl or optionally substituted heterocyclyl, where optional substituents include alkyl and halogen;

R ²⁴ of the formula NR ²⁴ R ²⁵ is selected from hydrogen or optionally substituted alkyl;

R ²⁵ of the formula NR ²⁴ R ²⁵ is selected from hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted arylalkyl, optionally substituted heterocyclyl, -CH ₂ CH ₂ (OCH ₂ CH ₂ ) _m CH ₃ or a polyamine chain [CH ₂ CH ₂ (CH ₂ ) _δ NH] _ψ CH ₂ CH ₂ (CH ₂ )ϖ _r NH ₂ such as spermine or spermidine,

where δ=0-2, ψ=1-3, ϖ=0-2;

R ²⁶ of the formula OR ²⁶ is an optionally substituted alkyl, wherein the optional substituents are OH, halogen or NH ₂ ;

m is an integer from 1 to 8;

R ⁶ and R ⁸ of formula (XXIX) - (XXXII) are independently selected from hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl; And

R ³¹ of formulas (XXIX) - (XXXII) is selected from alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, optionally further substituted, preferably selected from the group consisting of:

[0103] In certain embodiments, the connection ILM is:

[0104] In any of the compounds described in the present invention, ILM may have a structure of formula (XXXIII) derived from the IAP ligands described in WO Publication No. 2014/074658 and WO Publication No. 2013/071035, or its non-naturally occurring mimetics:

Where:

R ² of formula (XXXIII) is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, or optionally substituted aryl;

R ⁶ and R ⁸ of formula (XXXIII) are independently selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl;

R ³² of formula (XXXIII) is selected from (C ₁ -C ₄ alkylene)-R ³³ , where R ³³ is selected from hydrogen, aryl, heteroaryl or cycloalkyl, optionally further substituted;

X formula (XXXIII) selected from:

Z and Z' of formula (XXXIII) are independently selected from:

where is everyone represents the point of attachment to the connection, and both Z and Z' cannot be in any given connection;

Y of formula (XXXIII) is selected from:

where Z and Z' of formula (XXXIII) are the same and Z represents where is everyone represents the attachment point to the connection, X is selected from:

Y of formula (XXXIII) is independently selected from:

Where:

represents the point of attachment to the -C=O portion of the compound;

represents the point of attachment to the -NH portion of the compound;

represents the first attachment point to Z;

represents the second attachment point to Z;

m is an integer from 0 to 3;

n is an integer from 1 to 3;

p is an integer from 0 to 4; And

A represents -C(O)R ³ ;

R ³ is selected from -C(O)R ³ and is OH, NHCN, NHSO ₂ R ¹⁰ , NHOR ¹¹ or N(R ¹² )(R ¹³ );

R ¹⁰ and F ¹¹ of the formula NHSO ₂ R ¹⁰ and NHOR ¹¹ are independently selected from hydrogen, optionally substituted by -C ₁ -C ₄ alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocycloalkyl;

R ¹² and R ¹³ of the formula N(R ¹² )(R ¹³ ) are independently selected from hydrogen, -C ₁ -C ₄ alkyl, -(C ₁ -C ₄ )alkylene)-NH-(C ₁ -C ₄ alkyl) and -(C ₁ -C ₄ alkylene)-O-(C ₁ -C ₄ hydroxyalkyl), or R ¹² and R ¹³ are taken together with the nitrogen atom to which they are normally bonded to form a saturated heterocyclyl, optionally containing one additional heteroatom, selected from N, O and S, and wherein the saturated heterocycle is optionally substituted with methyl.

[0105] In any of the compounds described in the present invention, ILM may have a structure of formula (XXXIV) or (XXXV), which are derived from the IAP ligands described in WO publication No. 2014/047024, or its non-naturally occurring mimetics:

Where:

X of formula (XXXIV) or (XXXV) is absent or represents a group selected from -(CR ¹⁰ R ¹¹ ) _m -, optionally substituted heteroaryl or optionally substituted heterocyclyl,

Y and Z of formula (XXXIV) or (XXXV) are independently selected from C=O, -O-, -NR ⁹ -, -CONH-, -NHCO-, or may be absent;

R ¹ and R ² of formula (XXXIV) or (XXXV) are independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted arylalkyl, optionally substituted aryl, or

R ¹ and R ² of formula (XXXIV) or (XXXV) are independently selected from optionally substituted thioalkyl, wherein the substituents attached to the S atom of the thioalkyl are optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted heterocyclyl, -(CH ₂ ) _v COR ²⁰ , -CH ₂ CHR ²¹ COR ²² or -CH ₂ R ²³ ; Where

v is an integer from 1 to 3;

R ²⁰ and R ²² of the formula -(CH ₂ ) _v COR ²⁰ and -CH ₂ CHR ²¹ COR ²² are independently selected from OH, NR ²⁴ R ²⁵ or OR ²⁶ ;

R ²¹ of the formula -CH ₂ CHR ²¹ COR ²² is selected from NR ²⁴ R ²⁵ ;

R ²³ of the formula -CH ₂ R ²³ is selected from optionally substituted aryl or optionally substituted heterocyclyl, where optional substituents include alkyl and halogen;

R ²⁴ of the formula NR ²⁴ R ²⁵ is selected from hydrogen or optionally substituted alkyl;

R ²⁵ of the formula NR ²⁴ R ²⁵ is selected from hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted arylalkyl, optionally substituted heterocyclyl, -CH ₂ (OCH ₂ CH ²⁰ ) _m CH ₃ or a polyamine chain;

R ²⁶ represents optionally substituted alkyl, wherein the optional substituents are OH, halogen or NH ₂ ;

m of the formula -(CR ¹⁰ R ¹¹ ) _m - represents an integer from 1 to 8;

R ³ and R ⁴ of formula (XXXIV) or (XXXV) are independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heteroarylalkyl or optionally substituted heterocycloalkyl, where the substituents are alkyl, halogen or OH;

R ⁵ , R ⁶ , R ⁷ and R ⁸ of formula (XXXIV) or (XXXV) are independently selected from hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl;

R ¹⁰ and R ¹¹ of the formula -(CR ¹⁰ R ¹¹ ) _m - are independently selected from hydrogen, halogen or optionally substituted alkyl;

R ¹² and R ¹³ formulas independently selected from hydrogen, halogen or optionally substituted alkyl, or R ¹² and R ¹³ can be taken together to form a carbocyclic ring;

R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ formulas independently selected from hydrogen, halogen, optionally substituted alkyl or OR ¹⁹ ;

R ¹⁹ of formula OR ¹⁹ is selected from hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl;

m and n of the formula -(CR ¹⁰ R ¹¹ ) _m - independently represent 0, 1, 2, 3 or 4;

o and p of the formula -(CR ¹⁰ R ¹¹ ) _m - are independently 0, 1, 2 or 3;

q of the formula -(CR ¹⁰ R ¹¹ ) _m - represents 0, 1, 2, 3 or 4; r is 0 or 1;

t of the formula -(CR ¹⁰ R ¹¹ ) _m - represents 1, 2 or 3; and/or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0106] In any of the compounds described in the present invention, the ILM may have a structure of formula (XXXVI), which is derived from the IAP ligands described in WO publication No. 2014/025759, or its non-naturally occurring mimetics:

Where:

And formula (XXXVI) is selected from: or where the dotted line represents an optional double bond;

X of formula (XXXVI) is selected from: -(CR ²¹ R ²² ) _m -,

Y and Z of formula (XXXVI) are independently selected from -O-, -NR ⁶ - or absent;

V of formula (XXXVI) is selected from -N- or -CH-;

W of formula (XXXVI) is selected from -CH- or -N-;

R ¹ of formula (XXXVI) is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted arylalkyl, or optionally substituted aryl;

R ³ and R ⁴ of formula (XXXVI) are independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted heterocycloalkyl;

R ⁵ , R ⁶ , R ⁷ and R ⁸ of formula (XXIV), (XXV) or (XXVI) are independently selected from hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl, or preferably methyl;

R ⁹ and R ¹⁰ formulas independently selected from hydrogen, halogen or optionally substituted alkyl, or R ⁹ and R ¹⁰ can be taken together to form a ring;

R ¹¹ , R ¹² , R ¹³ and R ¹⁴ formulas independently selected from hydrogen, halogen, optionally substituted alkyl or OR ¹⁵ ;

R ¹⁵ of formula OR ¹⁵ is selected from hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl;

m and n formulas -(CR ²¹ R ²² ) _m - and independently selected from 0, 1, 2, 3 or 4;

o and p formulas and independently selected from 0, 1, 2 or 3;

q formulas selected from 0, 1, 2, 3 or 4;

r formulas selected from 0 or 1, and/or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0107] In any of the compounds described in the present invention, ILM may have a structure of formula (XXXVII) or (XXXVIII), which are derived from the IAP ligands described in WO publication No. 2014/011712, or its non-naturally occurring mimetics:

Where:

X of formulas (XXXVII) and (XXXVIII) is -(CR ¹⁶ R ¹⁷ ) _m -, or absent;

Y and Z of formula (XXXVII) and (XXXVIII) are independently selected from -O-, C=O, NR ⁶ or none;

R ¹ and R ² of formula (XXXVII) and (XXXVIII) are selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkylaryl, or optionally substituted aryl;

R ³ and R ⁴ of formula (XXXVII) and (XXXVIII) are independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted arylalkyl, or optionally substituted aryl;

R ⁵ and R ⁶ of formula (XXXVII) and (XXXVIII) are independently selected from optionally substituted alkyl or optionally substituted cycloalkyl;

R ⁷ and R ⁸ of formula (XXXVII) and (XXXVIII) are independently selected from hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl, or preferably methyl;

R ⁹ and R ¹⁰ formulas independently selected from hydrogen, optionally substituted alkyl, or R ⁹ and R ¹⁰ may be taken together to form a ring;

R ¹¹ - R ¹⁴ formulas independently selected from hydrogen, halogen, optionally substituted alkyl or OR ¹⁵ ;

R ¹⁵ of formula OR ¹⁵ is selected from hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl;

R ¹⁶ and R ¹⁷ of the formula -(CR ¹⁶ R ¹⁷ ) _m - are independently selected from hydrogen, halogen or optionally substituted alkyl;

R ⁵⁰ and R ⁵¹ of formula (XXXVII) and (XXXVIII) are independently selected from optionally substituted alkyl or R ⁵⁰ and R ⁵¹ are taken together to form a ring;

m and n formulas (CR ¹⁶ R ¹⁷ ) _m - and independently represent an integer from 0 to 4;

o and p formulas independently represent an integer from 0 to 3;

q formulas represents an integer from 0 to 4; And

r formulas represents an integer from 0 to 1;

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0108] In an embodiment, R ¹ and R ² ILM of formula (XXXVII) or (XXXVIII) are tert-butyl and R ³ and R ⁴ ILM of formula (XXXVII) or (XXXVIII) are tetrahydronaphthalene.

[0109] In any of the compounds described in the present invention, ILM may have a structure of formula (XXXIX) or (XL), which are derived from the IAP ligands described in WO publication No. 2013/071039, or its non-naturally occurring mimetics:

Where:

R ⁴³ and R ⁴⁴ of formulas (XXXIX) and (XL) are independently selected from hydrogen, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, further optionally substituted, and

R ⁶ and R ⁸ of formula (XXXIX) and (XL) are independently selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl.

Each X of formulas (XXXIX) and (XL) is independently selected from:

each Z of formulas (XXXIX) and (XL) is selected from where is everyone represents the point of attachment to a connection; And

each Y is selected from:

Where:

represents the point of attachment to the -C=O portion of the compound;

represents the point of attachment to the amine portion of the compound;

represents the first attachment point to Z;

represents the second attachment point to Z; And

A selected from -C(O)R ³ or

or a tautomeric form of any of the above, where:

R ³ of the formula -C(O)R ³ is selected from OH, NHCN, NHS0 ₂ R ¹⁰ , NHOR ¹¹ or N(R ¹² )(R ¹³ );

R ¹⁰ and R ¹¹ of formula NHS0 ₂ R ¹⁰ and NHOR ¹¹ are independently selected from -C ₁ -C ₄ alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl, any of which is optionally substituted, and hydrogen;

each of R ¹² and R ¹³ of the formula N(R ¹² )(R ¹³ ) is independently selected from hydrogen, -C ₁ -C ₄ alkyl, -(C ₁ -C ₄ alkylene)-NH-(C ₁ -C ₄ alkyl) , benzyl, -(C ₁ -C ₄ alkylene)-C(O)OH, -(C ₁ -C ₄ alkylene)-C(O)CH ₃ , -CH(benzyl)-COOH, -C ₁ -C ₄ alkoxy and -(C ₁ -C ₄ alkylene)-O-(C ₁ -C ₄ hydroxyalkyl); or R ¹² and R ¹³ of the formula N(R ¹² )(R ¹³ ) are taken together with the nitrogen atom to which they are normally bonded to form a saturated heterocyclyl optionally containing one additional heteroatom selected from N, O and S, and where saturated the heterocycle is optionally substituted with methyl.

[0110] In any of the compounds described in the present invention, the ILM may have a structure of formula (XLI), which is derived from the IAP ligands described in WO publication No. 2013/071039, or its non-naturally occurring mimetics:

Where:

W ¹ of formula (XLI) is selected from O, S, NR ^A or C(R ^8a )(R ^8b );

W ² of formula (XLI) is selected from O, S, NR ^A or C(R ^8c )(R ^8d ); provided that W ¹ and W ² are both not O or both are S;

R ¹ of formula (XLI) is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₆ cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted aryl) or -C ₁ -C ₆ alkyl- (substituted or unsubstituted heteroaryl);

if X ¹ is selected from O, NR ^A , S, S(O) or S(O) ₂ then X ² is C(R ^2a R ^2b );

or:

X ¹ of formula (XLI) is selected from CR ^2c R ^2d and X ² is CR ^2a R ^2b , and R ^2c and R ^2a together form a bond;

or:

X ¹ and X ² of formula (XLI) are independently selected from C and N and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring , a fused substituted or unsubstituted 5-10 membered aryl ring or a fused substituted or unsubstituted 5-10 membered heteroaryl ring;

or:

X ¹ of formula (XLI) is selected from CH ₂ and X ² is C=O, C= ^C (RC) ₂ or C=NR ^C ; where each R ^c is independently selected from H, -CN, -OH, alkoxy, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₆ cycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted aryl) or -C ₁ -C ₆ alkyl- (substituted or unsubstituted heteroaryl);

R ^A of the formula NR ^A is selected from H, C ₁ -C ₆ alkyl, -C(=O)C ₁ -C ₂ alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

R ^2a , R ^2b , R ^2c , R ^2d of formula CR ^2c R ^2d and CR ^2a R ^2b are independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₆ cycloalkyl), -C ₁ -C ₆ alkyl -(substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted aryl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted heteroaryl) and -C(=O)R ^B ;

R ^B of the formula -C(=O)R ^B is selected from substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₆ cycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl), -C ₁ -C ₆ alkyl -(substituted or unsubstituted aryl), -C ₁ -C ₆ alkyl-(substituted or unsubstituted heteroaryl) or -NR ^D R ^E ;

R ^D and R ^E of formula NR ^D R ^E are independently selected from H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₆ cycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl), -C ₁ -C ₆ alkyl (substituted or unsubstituted aryl) or -C ₁ -C ₆ alkyl (substituted or unsubstituted heteroaryl);

m of formula (XLI) is selected from 0, 1 or 2;

-U- formula (XLI) selected from -NHC(=O)-, -C(=O)NH-, -NHS(=O) ₂ -, -S(=O) ₂ NH-, -NHC(=O )NH-, -NH(C=O)O-, -O(C=O)NH- or -NHS(=O) ₂ NH-;

R ³ of formula (XLI) is selected from C ₁ -C ₃ alkyl or C ₁ -C ₃ fluoroalkyl;

R ⁴ of formula (XLI) is selected from -NHR ⁵ , -N(R ⁵ )2, -N+(R ⁵ )3 or -OR ⁵ ;

each R ⁵ of the formula -NHR ⁵ , -N(R ⁵ )2, -N+(R ⁵ )3 and -OR ⁵ is independently selected from H, C ₁ -C ₃ alkyl,

C ₁ -C ₃ haloalkyl, C ₁ -C ₃ heteroalkyl and -C ₁ -C ₃ alkyl (C ₃ -C ₅ cycloalkyl);

or:

R ³ and R ⁵ of formula (XLI), together with the atoms to which they are attached, form a substituted or unsubstituted 5-7 membered ring;

or:

R ³ of formula (XLI) is bonded to the nitrogen atom U to form a substituted or unsubstituted 5-7 membered ring;

R ⁶ of formula (XLI) is selected from -NHC(=O)R ⁷ , -C(=O)NHR ⁷ , -NHS(=O)2R ⁷ , -S(=O) ₂ NHR ⁷ ; -NHC(=O)NHR ⁷ , -NHS(=O) ₂ NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHC(=O)R ⁷ , -(C ₁ -C ₃ alkyl)-C(= O)NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHS(=O)2R ⁷ , -(C ₁ -C ₃ alkyl)-S(=O)2NHR ⁷ ; -(C ₁ -C ₃ alkyl)-NHC(=O)NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHS(=O)2NHR ⁷ , substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl or substituted or unsubstituted heteroaryl ;

each R ⁷ of the formula -NHC(=O)R ⁷ , -C(=O)NHR ⁷ , -NHS(=O)2R ⁷ , -S(=O) ₂ NHR ⁷ ; -NHC(=O)NHR ⁷ , -NHS(=O) ₂ NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHC(=O)R ⁷ , -(C ₁ -C ₃ alkyl)-C(= O)NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHS(=O)2R7, -(C ₁ -C ₃ alkyl)-S(=O)2NHR ⁷ ; -(C ₁ -C ₃ alkyl)-NHC(=O)NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHS(=O)2NHR ⁷ independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted C2-C10 heterocycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted aryl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted heteroaryl), -(CH2)p-CH(substituted or unsubstituted aryl)2, -( _CH2 ) _p -CH(substituted or unsubstituted heteroaryl)2, -( _CH2 ) _p -CH(substituted or unsubstituted aryl)(substituted or unsubstituted heteroaryl), -(substituted or unsubstituted aryl)-(substituted or unsubstituted aryl), -(substituted or unsubstituted aryl)-(substituted or unsubstituted heteroaryl), -(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted aryl) or -(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted heteroaryl);

p R ⁷ selected from 0, 1 or 2;

R ^8a , R ^8b , R ^8c and R ^8d formulas C(R ^8a )(R ^8b ) and C(R ^8c )(R ^8d ) are independently selected from H, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ heteroalkyl and substituted or unsubstituted aryl;

or:

R ^8a and R ^8d are defined above and R ^8b and R ^8c together form a bond;

or:

R ^8a and R ^8d are defined above, and R ^8b and R ^8c together with the atoms to which they are attached form a substituted or unsubstituted fused 5-7 membered saturated or partially saturated carbocyclic ring or heterocyclic ring containing 1-3 heteroatoms selected of S, O and N, a substituted or unsubstituted fused 5-10 membered aryl ring or a substituted or unsubstituted fused 5-10 membered heteroaryl ring containing 1-3 heteroatoms selected from S, O and N;

or:

R ^8c and R ^8d are defined above, and R ^8a and R ^8b together with the atoms to which they are attached form a substituted or unsubstituted saturated or partially saturated 3-7 membered spirocycle or heterospirocycle containing 1-3 heteroatoms selected from S, O and N;

or:

R ^8a and R ^8b are defined above, and R ^8c and R ^8d together with the atoms to which they are attached form a substituted or unsubstituted saturated or partially saturated 3-7 membered spirocycle or heterospirocycle containing 1-3 heteroatoms selected from S, O and N;

wherein each substituted alkyl, heteroalkyl, fused ring, spirocycle, heterospirocycle, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is substituted with 1-3 R ⁹ ; And

each R ⁹ of the formula R ^8a , R ^8b , R ^8c and R ^8d is independently selected from halogen, -OH, -SH, (C=O), CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ fluoroalkoxy, -NH ₂ , -NH(C ₁ -C ₄ alkyl), -NH(C ₁ -C ₄ alkyl) ₂ , -C(=O)OH, -C( =O)NH ₂ , -C(=O)C ₁ -C ₃ alkyl, -S(=O) ₂ CH ₃ , -NH(C ₁ -C ₄ alkyl)-OH, -NH(C ₁ -C ₄ alkyl)-O-(C-C ₄ alkyl), -O(C ₁ -C ₄ alkyl)-NH2; -O(C ₁ -C ₄ alkyl)-NH-(C ₁ -C ₄ alkyl) and -O(C ₁ -C ₄ alkyl)-N-(C ₁ -C ₄ alkyl) ₂ , or two R ⁹ together with the atoms to which they are attached form a methylenedioxy or ethylenedioxy ring, substituted or unsubstituted with halogen, -OH or C ₁ -C ₃ alkyl.

[0111] In any of the compounds described in the present invention, ILM may have a structure of formula (XLII) derived from the IAP ligands described in WO publication No. 2013/071039, or its non-naturally occurring mimetics:

Where:

W ¹ of formula (XLII) represents O, S, NR or

W ² of formula (XLII) is O, S, NR ^A or C(R ^8c )(R ^8d ); provided that both W ¹ and W ² are not O or both are S;

R ¹ of formula (XLII) is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₆ cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted aryl) or C ₁ -C ₆ alkyl- (substituted or unsubstituted heteroaryl);

if X ¹ of formula (XLII) is NR ^A , then X ² is C=O or CR ^2c R ^2d and X ³ is CR ^2a R ^2b ;

or:

if X ¹ of formula (XLII) is selected from S, S(O) or S(O) ₂ then X ² is CR ^2c R ^2d and X ³ is CR ^2a R ^2b ;

or:

if X ¹ of formula (XLII) represents O, then X ² represents CR ^2c R ^2d and NR ^A and X ³ represents CR ^2a R ^2b ;

or:

if X ¹ of formula (XLII) is CH ₃ then X ² is selected from O, NR ^A , S, S(O) or S(O) ₂ and X ³ is CR ^2a R ^2b ;

if X ¹ of formula (XLII) is CR ^2e R ^2f and X 2 is CR ^2c R ^2d and R ^2e and R ^2c together form a bond and X ³ of formula (VLII) is CR ^2a R ^2b ;

or:

X ¹ and X ³ of formula (XLII) are both CH ₂ and X ² of formula (XLII) is C=O, C=C( ^RC )2 or C=NR ^C ; where each R ^C is independently selected from H, -CN, -OH, alkoxy, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted _C3 - _C6 cycloalkyl, substituted or unsubstituted _C2 - _C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₆ cycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl), -C ₁ -C ₆ alkyl-(substituted or unsubstituted aryl) or -C ₁ -C ₆ alkyl-(substituted or unsubstituted heteroaryl);

or:

X ¹ and X ² of formula (XLII) are independently selected from C and N and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring , a fused substituted or unsubstituted 5-10 membered aryl ring or a fused substituted or unsubstituted 5-10 membered heteroaryl ring and X ³ is CR ^2a R ^2b ;

or:

X ² and X ³ of formula (XLII) are independently selected from C and N and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring , a fused substituted or unsubstituted 5-10 membered aryl ring or a fused substituted or unsubstituted 5-10 membered heteroaryl ring and X ¹ of formula (VLII) is CR ^2e R ^2f ;

R ^A of the formula NR ^A is selected from H, C ₁ -C ₆ alkyl, -C(=O)C ₁ -C ₂ alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

R ^2a , R ^2b , R ^2c , R ^2d , R ^2e and R ^2f of formula CR ^2c R ^2d , CR ^2a R ^2b and CR ^2e R ^2f are independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C ₁ - C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₆ cycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted aryl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted heteroaryl) and -C(=O)R ^B ;

R ^B of the formula -C(=O)R ^B is selected from substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₆ cycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl), -C ₁ -C ₆ alkyl -(substituted or unsubstituted aryl), -C ₁ -C ₆ alkyl-(substituted or unsubstituted heteroaryl) or -NR ^D R ^E ;

R ^D and R ^E of formula NR ^D R ^E are independently selected from H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₆ cycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl), -C ₁ -C ₆ alkyl (substituted or unsubstituted aryl) or -C ₁ -C ₆ alkyl (substituted or unsubstituted heteroaryl);

m of formula (XLII) is selected from 0, 1 or 2;

-U- of formula (XLII) is selected from -NHC(=O)-, -C(=O)NH-, -NHS(=O) ₂ -, -S(=O) ₂ NH-, -NHC(=O )NH-, -NH(C=O)O-, -O(C=O)NH- or -NHS(=O) ₂ NH-;

R ³ of formula (XLII) is selected from C ₁ -C ₃ alkyl or C ₁ -C ₃ fluoroalkyl;

R ⁴ of formula (XLII) is selected from -NHR ⁵ , -N(R ⁵ ) ₂ , -N+(R ⁵ ) ₃ or -OR ⁵ ;

each R ⁵ of the formula -NHR ⁵ , -N(R ⁵ ) ₂ , -N+(R ⁵ ) ₃ and -OR ⁵ is independently selected from H, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ heteroalkyl and -C ₁ -C ₃ alkyl-(C ₃ -C ₅ cycloalkyl);

or:

R ³ and R ⁵ of formula (XLII), together with the atoms to which they are attached, form a substituted or unsubstituted 5-7 membered ring;

or:

R ³ of formula (XLII) is bonded to the U nitrogen atom to form a substituted or unsubstituted 5-7 membered ring;

R ⁶ of formula (XLII) is selected from -NHC(=O)R ⁷ , -C(=O)NHR ⁷ , -NHS(=O)2R ⁷ , -S(=O) ₂ NHR ⁷ ; -NHC(=O)NHR ⁷ , -NHS(=O) ₂ NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHC(=O)R ⁷ , -(C ₁ -C ₃ alkyl)-C(= O)NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHS(=O) ₂ R ⁷ , -(C ₁ -C ₃ alkyl)-S(=O) ₂ NHR ⁷ ; -(C ₁ -C ₃ alkyl)-NHC(=O)NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHS(=O) ₂ NHR ⁷ , substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl or substituted or unsubstituted heteroaryl;

each R ⁷ formulas -NHC(=O)R ⁷ , -C(=O)NHR ⁷ , -NHS(=O)2R7, -S(=O) ₂ NHR ⁷ ; -NHC(=O)NHR ⁷ , -NHS(=O) ₂ NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHC(=O)R ⁷ , -(C ₁ -C ₃ alkyl)-C(= O)NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHS(=O)2R ⁷ , -(C ₁ -C ₃ alkyl)-S(=O)2NHR ⁷ ; -(C ₁ -C ₃ alkyl)-NHC(=O)NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHS(=O)2NHR ⁷ independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted C2-C10 heterocycloalkyl), -C1-C6 alkyl- (substituted or unsubstituted aryl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted heteroaryl), -(CH2)p-CH(substituted or unsubstituted aryl)2, -( _CH2 ) _p -CH(substituted or unsubstituted heteroaryl)2, -( _CH2 ) _p -CH(substituted or unsubstituted aryl)(substituted or unsubstituted heteroaryl ), -(substituted or unsubstituted aryl)-(substituted or unsubstituted aryl), -(substituted or unsubstituted aryl)-(substituted or unsubstituted heteroaryl), -(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted aryl) or -(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted heteroaryl);

p R ⁷ selected from 0, 1 or 2;

R ^8a , R ^8b , R ^8c and R ^8d formulas C(R ^8a )(R ^8b ) and C(R ^8c )(R ^8d ) are independently selected from H, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ heteroalkyl and substituted or unsubstituted aryl;

or:

R ^8a and R ^8d are defined above and R ^8b and R ^8c together form a bond;

or:

R ^8a and R ^8d are defined above and R ^8b and R ^8c together with the atoms to which they are attached form a substituted or unsubstituted fused 5-7 membered saturated or partially saturated carbocyclic ring or heterocyclic ring containing 1-3 heteroatoms selected from S, O and N, a substituted or unsubstituted fused 5-10 membered aryl ring or a substituted or unsubstituted fused 5-10 membered heteroaryl ring containing 1-3 heteroatoms selected from S, O and N; or:

R ^8c and R ^8d are defined above and R ^8a and R ^8b together with the atoms to which they are attached form a substituted or unsubstituted saturated or partially saturated 3-7 membered spirocycle or heterospirocycle containing 1-3 heteroatoms selected from S, O and N;

or:

R ^8a and R ^8b are defined above and R ^8c and R ^8d together with the atoms to which they are attached form a substituted or unsubstituted saturated or partially saturated 3-7 membered spirocycle or heterospirocycle containing 1-3 heteroatoms selected from S, O and N;

wherein each substituted alkyl, heteroalkyl, fused ring, spirocycle, heterospirocycle, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is substituted with 1-3 R ⁹ ; And

each R ⁹ of the formula R ^8a , R ^8b , R ^8c and R ^8d is independently selected from halogen, -OH, -SH, (C=O), CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ fluoroalkoxy, -NH ₂ , -NH(C ₁ -C ₄ alkyl), -NH(C ₁ -C ₄ alkyl) ₂ , -C(=O)OH, -C( =O)NH ₂ , -C(=O)C ₁ -C ₃ alkyl, -S(=O) ₂ CH ₃ , -NH(C ₁ -C ₄ alkyl)-OH, -NH(C ₁ -C ₄ alkyl)-O-(C-C ₄ alkyl), -O(C ₁ -C ₄ alkyl)-NH2; -O(C ₁ -C ₄ alkyl)-NH-(C ₁ -C ₄ alkyl) and -O(C ₁ -C ₄ alkyl)-N-(C ₁ -C ₄ alkyl) ₂ or two R ⁹ together with the atoms to which they are attached form a methylenedioxy or ethylenedioxy ring, substituted or unsubstituted with halogen, -OH or C ₁ -C ₃ alkyl.

[0112] In any of the compounds described in the present invention, ILM may have a structure of formula (XLIII), which is derived from the IAP ligands described in WO publication No. 2013/071039, or its non-naturally occurring mimetics:

Where:

W ¹ of formula (XLIII) is selected from O, S, NR ^A or C(R ^8a )(R ^8b );

W ² of formula (XLIII) is selected from O, S, NR ^A or C(R ^8c )(R ^8d ); provided that both W ¹ and W ² are not O or both are S;

R ¹ of formula (XLIII) is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₆ cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted aryl) or C ₁ -C ₆ alkyl- (substituted or unsubstituted heteroaryl);

if X ¹ of formula (XLIII) is selected from NR ^A , S, S(O) or S(O) ₂ , then X ² of formula (XLIII) is CR ^2c R ^2d and X ³ of formula (XLIII) is CR ^2a R ^2b ;

or:

if X ¹ of formula (XLIII) is O, then X ² of formula (XLIII) is selected from O, NR ^A , S, S(O) or S(O) ₂ and X ³ of formula (XLIII) is CR ^2a R ^2b ;

or:

if X ¹ of formula (XLIII) is CR ^2e R ^2f and X ² of formula (XLIII) is CR ^2c R ^2d and R ^2e and R ^2c together form a bond and X ³ of formula (XLIII) is CR ^2a R ^2b ;

or:

X ¹ and X ² of formula (XLIII) are independently selected from C and N and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring , a fused substituted or unsubstituted 5-10 membered aryl ring or a fused substituted or unsubstituted 5-10 membered heteroaryl ring and X ³ of formula (XLIII) is CR ^2a R ^2b ;

or:

X ² and X ³ of formula (XLIII) are independently selected from C and N and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring , a fused substituted or unsubstituted 5-10 membered aryl ring or a fused substituted or unsubstituted 5-10 membered heteroaryl ring and X ¹ of formula (VLII) is CR ^2e R ^2f ;

R ^A of the formula NR ^A is H, C ₁ -C ₆ alkyl, -C(=O)C ₁ -C ₂ alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

R ^2a , R ^2b , R ^2c , R ^2d , R ^2e and R ^2f of formula CR ^2c R ^2d , CR ^2a R ^2b and CR ^2e R ^2f are independently selected from H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₆ cycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted aryl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted heteroaryl) and -C(=O)R ^B ;

R ^B of formula -C(=O)R ^B is substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₆ cycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl), -C ₁ -C ₆ alkyl - (substituted or unsubstituted aryl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted heteroaryl) or - NR ^D R ^E ;

R ^D and R ^E of formula NR ^D R ^E are independently selected from H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₆ cycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl), -C ₁ -C ₆ alkyl (substituted or unsubstituted aryl) or -C ₁ -C ₆ alkyl (substituted or unsubstituted heteroaryl);

m of formula (XLIII) is 0, 1 or 2;

-U- of formula (XLIII) is -NHC(=O)-, -C(=O)NH-, -NHS(=O) ₂ -, -S(=O) ₂ NH-, -NHC(=O )NH-, -NH(C=O)O-, -O(C=O)NH- or -NHS(=O) ₂ NH-;

R ³ of formula (XLIII) represents C ₁ -C ₃ alkyl or C ₁ -C ₃ fluoroalkyl;

R ⁴ of formula (XLIII) is -NHR ⁵ , -N(R ⁵ ) ₂ , -N+(R ⁵ ) ₃ or -OR ⁵ ;

each R ⁵ of the formula -NHR ⁵ , -N(R ⁵ ) ₂ , -N+(R ⁵ ) ₃ and -OR ⁵ is independently selected from H, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ heteroalkyl and -C ₁ -C ₃ alkyl-(C ₃ -C ₅ cycloalkyl);

or:

R ³ and R ⁵ of formula (XLIII), together with the atoms to which they are attached, form a substituted or unsubstituted 5-7-membered ring;

or:

R ³ of formula (XLIII) is bonded to the U nitrogen atom to form a substituted or unsubstituted 5-7 membered ring;

R ⁶ of formula (XLIII) is selected from -NHC(=O)R ⁷ , -C(=O)NHR ⁷ , -NHS(=O)2R ⁷ , -S(=O) ₂ NHR ⁷ ; -NHC(=O)NHR ⁷ , -NHS(=O) ₂ NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHC(=O)R ⁷ , -(C ₁ -C ₃ alkyl)-C(= O)NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHS(=O) ₂ R ⁷ , -(C ₁ -C ₃ alkyl)-S(=O) ₂ NHR ⁷ ; -(C ₁ -C ₃ alkyl)-NHC(=O)NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHS(=O) ₂ NHR ⁷ , substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl or substituted or unsubstituted heteroaryl;

each R ⁷ of the formula -NHC(=O)R ⁷ , -C(=O)NHR ⁷ , -NHS(=O)2R ⁷ , -S(=O) ₂ NHR ⁷ ; -NHC(=O)NHR ⁷ , -NHS(=O) ₂ NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHC(=O)R ⁷ , -(C ₁ -C ₃ alkyl)-C(= O)NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHS(=O)2R ⁷ , -(C ₁ -C ₃ alkyl)-S(=O)2NHR ⁷ ; -(C ₁ -C ₃ alkyl)-NHC(=O)NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHS(=O)2NHR ⁷ independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted C2-C10 heterocycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted aryl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted heteroaryl), -(CH2)p-CH(substituted or unsubstituted aryl)2, -( _CH2 ) _p -CH(substituted or unsubstituted heteroaryl)2, -( _CH2 ) _p -CH(substituted or unsubstituted aryl)(substituted or unsubstituted heteroaryl), -(substituted or unsubstituted aryl)-(substituted or unsubstituted aryl), -(substituted or unsubstituted aryl)-(substituted or unsubstituted heteroaryl), -(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted aryl) or -(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted heteroaryl);

p R ⁷ is 0, 1 or 2;

R ^8a , R ^8b , R ^8c and R ^8d formulas C(R ^8a )(R ^8b ) and C(R ^8c )(R ^8d ) are independently selected from H, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ heteroalkyl and substituted or unsubstituted aryl;

or:

R ^8a and R ^8d are defined above and R ^8b and R ^8c together form a bond;

or:

R ^8a and R ^8d are defined above and R ^8b and R ^8c together with the atoms to which they are attached form a substituted or unsubstituted fused 5-7 membered saturated or partially saturated carbocyclic ring or heterocyclic ring containing 1-3 heteroatoms selected from S, O and N, a substituted or unsubstituted fused 5-10 membered aryl ring or a substituted or unsubstituted fused 5-10 membered heteroaryl ring containing 1-3 heteroatoms selected from S, O and N; or:

R ^8c and R ^8d are defined above and R ^8a and R ^8b together with the atoms to which they are attached form a substituted or unsubstituted saturated or partially saturated 3-7 membered spirocycle or heterospirocycle containing 1-3 heteroatoms selected from S, O and N;

or:

R ^8a and R ^8b are defined above and R ^8c and R ^8d together with the atoms to which they are attached form a substituted or unsubstituted saturated or partially saturated 3-7 membered spirocycle or heterospirocycle containing 1-3 heteroatoms selected from S, O and N;

wherein each substituted alkyl, heteroalkyl, fused ring, spirocycle, heterospirocycle, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is substituted with 1-3 R ⁹ ; And

each R ⁹ of the formula R ^8a , R ^8b , R ^8c and R ^8d is independently selected from halogen, -OH, -SH, (C=O), CN, C ₁ -C _{4 alkyl, C 1 -C 4} fluoroalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ fluoroalkoxy, -NH ₂ , -NH(C ₁ -C ₄ alkyl), -NH(C ₁ -C ₄ alkyl) ₂ , -C(=O)OH, -C(=O) NH ₂ , -C(=O)C ₁ -C ₃ alkyl, -S(=O) ₂ CH ₃ , -NH(C ₁ -C ₄ alkyl)-OH, -NH(C ₁ -C ₄ alkyl)- O-(C-C ₄ alkyl), -O(C ₁ -C ₄ alkyl)-NH2; -O(C ₁ -C ₄ alkyl)-NH-(C ₁ -C ₄ alkyl) and -O(C ₁ -C ₄ alkyl)-N-(C ₁ -C ₄ alkyl) ₂ or two R ⁹ together with the atoms to which they are attached form a methylenedioxy or ethylenedioxy ring, substituted or unsubstituted with halogen, -OH or C ₁ -C ₃ alkyl.

[0113] In any of the compounds described in the present invention, the ILM may have a structure of formula (XLIV), which is derived from the IAP ligands described in WO publication No. 2013/071039, or its non-naturally occurring mimetics:

Where:

W ¹ of formula (XLIV) is selected from O, S, NR ^A or C(R ^8a )(R ^8b );

W ² of formula (XLIV) is selected from O, S, NR ^A or C(R ^8c )(R ^8d ); provided that both W ¹ and W ² are not O or both are S;

W ³ of formula (XLIV) is selected from O, S, NR ^A or C(R ^8e )(R ^8f ), provided that the ring containing W ¹ , W ² and W ³ does not include two adjacent oxygen atoms or sulfur atom;

R ¹ of formula (XLIV) is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₆ cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted aryl) or -C ₁ -C ₆ alkyl- (substituted or unsubstituted heteroaryl);

if X ¹ of formula (XLIV) is O, then X ² of formula (XLIV) is selected from CR ^2c R ^2d and NR ^A and X ³ of formula (XLIV) is CR ^2a R ^2b ;

or:

if X ¹ of formula (XLIV) is CH ₂ then X ² of formula (XLIV) is selected from O, ^NRA , S, S(O) or S(O) ₂ and X ³ of formula (XLIV) is CR ^2a R ^2b ;

or:

if X ¹ of formula (XLIV) is CR ^2e R ^2f , X ² of formula (XLIV) is CR ^2c R ^2d and R ^2e and R ^2c together form a bond and X ³ of formula (VLIV) is CR ^2a R ^2b ;

or:

X ¹ and X ³ of formula (XLIV) are both CH ₂ and X ² of formula (XLII) is C=O, C=C( ^RC ) ₂ or C=NR ^C ; where each R ^C is independently selected from H, -CN, -OH, alkoxy, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₆ cycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted aryl) or -C ₁ -C ₆ alkyl- (substituted or unsubstituted heteroaryl);

or:

X ¹ and X ² of formula (XLIV) are independently selected from C and N and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring , a fused substituted or unsubstituted 5-10 membered aryl ring or a fused substituted or unsubstituted 5-10 membered heteroaryl ring and X ³ of formula (XLIV) is CR ^2a R ^2b ;

or:

X ² and X ³ of formula (XLIV) are independently selected from C and N and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring , a fused substituted or unsubstituted 5-10 membered aryl ring or a fused substituted or unsubstituted 5-10 membered heteroaryl ring and X ¹ of formula (VLIV) is CR ^2e R ^2f ;

R ^A of the formula NR ^A is selected from H, C ₁ -C ₆ alkyl, -C(=O)C ₁ -C ₂ alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

R ^2a , R ^2b , R ^2c , R ^2d , R ^2e and R ^2f of formula CR ^2c R ^2d , CR ^2a R ^2b and CR ^2e R ^2f are independently selected from H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₆ cycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted aryl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted heteroaryl) and -C(=O)R ^B ;

R ^B of the formula -C(=O)R ^B is selected from substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₆ cycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl), -C ₁ -C ₆ alkyl -(substituted or unsubstituted aryl), -C ₁ -C ₆ alkyl-(substituted or unsubstituted heteroaryl) or -NR ^D R ^E ;

R ^D and R ^E of formula NR ^D R ^E are independently selected from H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₆ cycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted aryl) or -C ₁ -C ₆ alkyl- (substituted or unsubstituted heteroaryl);

m of formula (XLIV) is selected from 0, 1 or 2;

-U- formula (XLIV) is selected from -NHC(=O)-, -C(=O)NH-, -NHS(=O) ₂ -, -S(=O) ₂ NH-, -NHC(=O )NH-, -NH(C=O)O-, -O(C=O)NH- or -NHS(=O) ₂ NH-;

R ³ of formula (XLIV) is selected from C ₁ -C ₃ alkyl or C ₁ -C ₃ fluoroalkyl;

R ⁴ of formula (XLIV) is selected from -NHR ⁵ , -N(R ⁵ ) ₂ , -N+(R ⁵ ) ₃ or -OR ⁵ ;

each R ⁵ of the formula -NHR ⁵ , -N(R ⁵ ) ₂ , -N+(R ⁵ ) ₃ and -OR ⁵ is independently selected from H, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ heteroalkyl and -C ₁ -C ₃ alkyl-(C ₃ -C ₅ cycloalkyl);

or:

R ³ and R ⁵ of formula (XLIV), together with the atoms to which they are attached, form a substituted or unsubstituted 5-7-membered ring;

or:

R ³ of formula (XLIII) is bonded to the U nitrogen atom to form a substituted or unsubstituted 5-7 membered ring;

R ⁶ of formula (XLIII) is selected from -NHC(=O)R ⁷ , -C(=O)NHR ⁷ , -NHS(=O)2R ⁷ , -S(=O) ₂ NHR ⁷ ; -NHC(=O)NHR ⁷ , -NHS(=O) ₂ NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHC(=O)R ⁷ , -(C ₁ -C ₃ alkyl)-C(= O)NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHS(=O) ₂ R ⁷ , -(C ₁ -C ₃ alkyl)-S(=O) ₂ NHR ⁷ ; -(C ₁ -C ₃ alkyl)-NHC(=O)NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHS(=O) ₂ NHR ⁷ , substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl or substituted or unsubstituted heteroaryl;

each R ⁷ of the formula -NHC(=O)R ⁷ , -C(=O)NHR ⁷ , -NHS(=O)2R ⁷ , -S(=O) ₂ NHR ⁷ ; -NHC(=O)NHR ⁷ , -NHS(=O) ₂ NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHC(=O)R ⁷ , -(C ₁ -C ₃ alkyl)-C(= O)NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHS(=O)2R ⁷ , -(C ₁ -C ₃ alkyl)-S(=O)2NHR ⁷ ; -(C ₁ -C ₃ alkyl)-NHC(=O)NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHS(=O)2NHR ⁷ independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted C2-C10 heterocycloalkyl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted aryl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted heteroaryl ), -(CH2)p-CH(substituted or unsubstituted aryl)2, -( _CH2 ) _p -CH(substituted or unsubstituted heteroaryl)2, -( _CH2 ) _p -CH(substituted or unsubstituted aryl)(substituted or unsubstituted heteroaryl), -(substituted or unsubstituted aryl)-(substituted or unsubstituted aryl), -(substituted or unsubstituted aryl)-(substituted or unsubstituted heteroaryl), -(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted aryl) or - (substituted or unsubstituted heteroaryl)-(substituted or unsubstituted heteroaryl);

p R ⁷ selected from 0, 1 or 2;

R ^8a , R ^8b , R ^8c , R ^8d , R ^8e and R ^8f formulas C(R ^8a )(R ^8b ), C(R ^8c )(R ^8d ) and C(R ^8e )(R ^8f ) are independently selected from H, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ heteroalkyl and substituted or unsubstituted aryl;

or:

R ^8a , R ^8d , R ^8e and R ^8f formulas C(R ^8a )(R ^8b ), C(R ^8c )(R ^8d ) and C(R ^8e )(R ^8f ) are defined above and R ^8b and R ^8c together form a bond;

or:

R ^8a , R ^8b , R ^8d and R ^8f formulas C(R ^8a )(R ^8b ), C(R ^8c )(R ^8d ) and C(R ^8e )(R ^8f ) are defined above and R ^8c and R ^8e together form a bond;

or:

R ^8a , R ^8d , R ^8e and R ^8f formulas C(R ^8a )(R ^8b ), C(R ^8c )(R ^8d ) and C(R ^8e )(R ^8f ) are defined above and R ^8b and R ^8c together with the atoms to which they are attached form a substituted or unsubstituted fused 5-7-membered saturated or partially saturated carbocyclic ring or a heterocyclic ring containing 1-3 heteroatoms selected from S, O and N, substituted or unsubstituted fused 5-10- a membered aryl ring or a substituted or unsubstituted fused 5-10 membered heteroaryl ring containing 1-3 heteroatoms selected from S, O and N;

or:

R ^8a , R ^8b , R ^8d and R ^8f formulas C(R ^8a )(R ^8b ), C(R ^8c )(R ^8d ) and C(R ^8e )(R ^8f ) are defined above and R ^8c and R ^8e together with the atoms to which they are attached form a substituted or unsubstituted fused 5-7-membered saturated or partially saturated carbocyclic ring or a heterocyclic ring containing 1-3 heteroatoms selected from S, O and N, substituted or unsubstituted fused 5-10- a membered aryl ring or a substituted or unsubstituted fused 5-10 membered heteroaryl ring containing 1-3 heteroatoms selected from S, O and N;

or:

R ^8c , R ^8d , R ^8e and R ^8f formulas C(R ^8c )(R ^8d ) and C(R ^8c )R ^8f ) are defined above and R ^8a and R ^8b together with the atoms to which they are attached form a substituted or an unsubstituted saturated or partially saturated 3-7 membered spirocycle or heterospirocycle containing 1-3 heteroatoms selected from S, O and N; or:

R ^8a , R ^8b , R ^8e and R ^8f formulas C(R ^8a )(R ^8b ) and C(R ^8e )(R ^8f ) are defined above and R ^8c and R ^8d together with the atoms to which they are attached form a substituted or an unsubstituted saturated or partially saturated 3-7 membered spirocycle or heterospirocycle containing 1-3 heteroatoms selected from S, O and N;

or:

R ^8a , R ^8b , R ^8c , and R ^8d formulas C(R ^8a )(R ^8b ) and C(R ^8c )(R ^8d ) are defined above and R ^8e and R ^8f together with the atoms to which they are attached form substituted or unsubstituted saturated or partially saturated 3-7 membered spirocycle or heterospirocycle containing 1-3 heteroatoms selected from S, O and N; or:

wherein each substituted alkyl, heteroalkyl, fused ring, spirocycle, heterospirocycle, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is substituted with 1-3 R ⁹ ; And

each R ⁹ of the formula R ^8a , R ^8b , R ^8c , R ^8d , R ^8e and R ^8f is independently selected from halogen, -OH, -SH, (C=O), CN, C 1 -C ₄ alkyl, C ₁ -C 4 fluoroalkyl , C ₁ -C ₄ alkoxy, C ₁ -C ₄ fluoroalkoxy, -NH ₂ , -NH(C ₁ -C ₄ alkyl), -NH(C ₁ -C ₄ alkyl)2, - C(=O)OH, -C(=O)NH ₂ , -C(=O)C ₁ -C ₃ alkyl, -S(=O) ₂ CH ₃ , -NH(C ₁ -C ₄ alkyl)-OH, -NH(C ₁ -C ₄ alkyl)-O-(C-C ₄ alkyl), -O(C ₁ -C ₄ alkyl)-NH2; -O(C ₁ -C ₄ alkyl)-NH-(C ₁ -C ₄ alkyl) and -O(C ₁ -C ₄ alkyl)-N-(C ₁ -C ₄ alkyl) ₂ or two R ⁹ together with the atoms to which they are attached form a methylenedioxy or ethylenedioxy ring, substituted or unsubstituted with halogen, -OH or C ₁ -C ₃ alkyl.

[0114] In any of the compounds described in the present invention, the ILM may have a structure of formula (XLV), (XLVI) or (XLVII), which is derived from the IAP ligands described in Vamos, M., et al., Expedient synthesis of highly potent antagonists of inhibitor of apoptosis proteins (MPs) with unique selectivity for ML-IAP, ACS Chem. Biol., 8(4), 725-32 (2013), or its non-naturally occurring mimetics:

Where:

R ² , R ³ and R ⁴ of formula (XLV) are independently selected from H or Me;

X of formula (XLV) is independently selected from O or S; And

R ¹ formula (XLV) selected from:

[0115] According to a specific embodiment, the ILM is characterized by the structure of formula (XLVIII):

where R ³ and R ⁴ of formula (XLVIII) are independently selected from H or Me;

is a 5-membered heterocycle selected from:

[0116] According to a specific embodiment formula XLVIII represents

[0117] In a specific embodiment, the ILM is structured and attached to a linker group L as shown below:

[0118] In a specific embodiment, the ILM is characterized by a structure of formula (XLIX), (L), or (LI):

Where:

R ³ of formula (XLIX), (L) or (LI) are independently selected from H or Me;

is a 5-membered heterocycle selected from:

L formulas (XLIX), (L) or (LI) selected from:

[0119] According to a specific embodiment L of formula (XLIX) (L) or (LI)

[0120] According to a specific embodiment, the ILM is characterized by the structure of formula (LII):

[0121] In a specific embodiment, the ILM according to formula (LII) is chemically coupled to the linker group L in the region indicated and as below:

[0122] In any of the compounds described in the present invention, the ILM may have a structure of formula (LIII) or (LIV), which is based on the IAP ligands described in Hennessy, EJ, et al., Discovery of aminopiperidine-based Smac mimetics as IAP antagonists , Bioorg. Med. Chem. Lett., 22(4), 1960-4 (2012), or its non-naturally occurring mimetics:

Where:

R ¹ of formulas (LIII) and (LIV) is selected from:

R ² of formulas (LIII) and (LIV) is selected from H or Me;

R ³ of formulas (LIII) and (LIV) is selected from:

X is selected from H, halogen, methyl, methoxy, hydroxy, nitro or trifluoromethyl.

[0123] In any of the compounds described in the present invention, ILM can be characterized by the structure and be chemically associated with a linker, as shown in formula (LV) or (LVI), or its non-naturally occurring mimetics:

[0124] In any of the compounds described in the present invention, the ILM may have a structure of formula (LVII), which is based on the IAP ligands described in Cohen, F, et al., Orally bioavailable antagonists of inhibitor of apoptosis proteins based on an azabicyclooctane scaffold, J. Med. Chem., 52(6), 1723-30 (2009), or its non-naturally occurring mimetics:

Where:

R1 formulas (LVII) selected from:

X formulas selected from H, fluorine, methyl or methoxy.

[0125] According to a specific embodiment, the ILM is represented by the following structure:

[0126] In a specific embodiment, the ILM is selected from the group consisting of, and what is shown to be a chemical bond between the ILM and the linker group L:

[0127] In any of the compounds described in the present invention, the ILM is selected from the group consisting of the structures below, which are based on the IAP ligands described in Asano, M, et al., Design, sterioselective synthesis, and biological evaluation of novel tri-cyclic compounds as inhibitor of apoptosis proteins (IAP) antagonists, Bioorg. Med. Chem., 21(18): 5725-37 (2013), or its non-naturally occurring mimetics:

[0128] In a specific embodiment, the ILM is selected from the group consisting of, and what is shown to be a chemical bond between the ILM and the linker group L:

[0129] In any of the compounds described in the present invention, the ILM may have a structure of formula (LVIII), which is based on the IAP ligands described in Asano, M, et al., Design, sterioselective synthesis, and biological evaluation of novel tri-cyclic compounds as inhibitor of apoptosis proteins (IAP) antagonists, Bioorg. Med. Chem., 21(18): 5725-37 (2013), or its non-naturally occurring mimetics:

where X of formula (LVIII) represents one to two substituents independently selected from H, halogen or cyano.

[0130] In any of the compounds described in the present invention, ILM can be characterized by the structure and can be chemically linked to the linker group L, as shown in formula (LIX) or (LX), or its non-naturally occurring mimetics:

wherein X of formula (LIX) and (LX) represents one to two substituents independently selected from H, halogen or cyano, and L of formula (LIX) and (LX) represents a linker group as described in the present invention.

[0131] In any of the compounds described in the present invention, the ILM may have a structure of formula (LXI), which is based on the IAP ligands described in Ardecky, RJ, et al., Design, sysnthesis and evaluation of inhibitor of apoptosis (IAP) antagonists that are highly selective for the BIR2 domain of XIAP, Bioorg. Med. Chem., 23(14): 4253-7 (2013), or its non-naturally occurring mimetics:

Where:

formula (LXI) is a naturally occurring or non-naturally occurring amino acid; And

R ² formula (LXI) selected from:

[0132] In any of the compounds described in the present invention, ILM may have the structure and be chemically associated with the linker group L, as shown in formula (LXII) or (LLXIII), or its non-naturally occurring mimetics:

formula (LXI) is a naturally occurring or non-naturally occurring amino acid; And

L of formula (LXI) represents a linker group as described in the present invention.

[0133] In any of the compounds described herein, the ILM may have a structure selected from the group consisting of the group of IAP-based ligands described in Wang, J, et al., Discovery of novel second mitochondrial-derived activator of caspase mimetics as selective inhibitor or apoptosis protein inhibitors, J. Pharmacol. Exp. Ther., 349(2): 319-29 (2014), or its non-naturally occurring mimetics:

[0134] In any of the compounds described in the present invention, the ILM is characterized by a structure of formula (LXIX), which is based on the IAP ligands described in Hird, AW, et al., Structure-based design and synthesis of tricyclic IAP (Inhibitors of Apoptosis Proteins) inhibitors, Bioorg. Med. Chem. Lett., 24(7): 1820-4 (2014), or its non-naturally occurring mimetics:

where R of formula LIX is selected from the group consisting of:

R1 formulas selected from H or Me;

R2 formulas selected from alkyl or cycloalkyl;

X formulas represents 1-2 substituents independently selected from halogen, hydroxy, methoxy, nitro and trifluoromethyl.

Z formulas represents O or NH;

NO formula is a mono- or fused bicyclic heteroaryl; And

formula (LIX) represents an optional double bond.

[0135] In a specific embodiment, the ILM of a compound is characterized by a chemical structure as represented by:

[0136] In a specific embodiment, the ILM of the compound is characterized by a chemical structure selected from the group consisting of:

[0137] As used herein, the term “independently” means that a variable that is applied independently changes regardless of application to application.

[0138] The term "alkyl" shall mean within its context a straight, branched or cyclic fully saturated hydrocarbon radical or alkyl group, preferably a C ₁ -C ₁₀ , more preferably a C ₁ -C ₆ , alternatively a C ₁ -C ₃ alkyl group , which may optionally be substituted. Examples of alkyl groups are methyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, 2-methylpropyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylethyl, cyclohexylethyl and cyclohexyl, among others. In certain embodiments, the alkyl group is terminated with a halogen group (At, Br, Cl, F, or I). In certain preferred embodiments, compounds of the present disclosure are provided that can be used to covalently link to dehalogenase enzymes. These compounds typically contain a side chain (often linked through a polyethylene glycol group) that terminates in an alkyl group containing a halogen substituent (often chlorine or bromine) at its distal end, resulting in covalent binding of the compound containing such a moiety to the protein.

[0139] The term “alkenyl” refers to straight, branched or cyclic C ₂ -C ₁₀ (preferably C ₂ -C ₆ ) hydrocarbon radicals containing at least one C=C bond.

[0140] The term “alkynyl” refers to straight, branched or cyclic C ₂ -C ₁₀ (preferably C ₂ -C ₆ ) hydrocarbon radicals containing at least one C≡C bond.

[0141] The term “alkylene” as used refers to a -(CH ₂ ) _n group (n is an integer, typically 0 to 6), which may be optionally substituted. If substituted, the alkylene group is preferably substituted on one or more methylene groups with a C ₁ -C ₆ alkyl group (including a cyclopropyl group or tert-butyl group), but may also be substituted with one or more halogen groups, preferably 1 to 3 halogen groups or one or two hydroxyl groups, O-(C ₁ -C ₆ alkyl) groups or amino acid side chains, as otherwise disclosed herein. In certain embodiments, the alkylene group may be substituted with a urethane or alkoxy group (or other group) that is further substituted with a polyethylene glycol chain (1 to 10, preferably 1 to 6, more typically 1 to 4 ethylene glycol units) with which (preferably , but not exclusively at the distal end of the polyethylene glycol chain) an alkyl chain substituted with a simple halogen group, preferably a chlorine group. In other embodiments, the alkylene (often methylene) group may be replaced by an amino acid side group, such as a side chain group of a naturally occurring or non-naturally occurring amino acid, e.g., alanine, β-alanine, arginine, asparagine, aspartic acid, cysteine, cystine , glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan or tyrosine.

[0142] The term "unsubstituted" shall mean substituted only with hydrogen atoms. The range of carbon atoms that includes C ₀ means that the carbon atom is missing and is replaced by H. Thus, the range of carbon atoms that is C ₀ -C ₆ includes carbon atoms 1, 2, 3, 4, 5 and 6 and for C ₀ H stands instead of the carbon atom.

[0143] The term "substituted" or "optionally substituted" shall mean independently (i.e., if more substituents occur, each substituent is independent of the other substituent) one or more substituents (independently up to five substituents, preferably up to three substituents , often 1 or 2 substituents on a moiety in a compound of the present disclosure and may include substituents that themselves may be further substituted) at a carbon (or nitrogen) position anywhere on the molecule within the context, and includes as substituents hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (NO ₂ ), halogen (preferably 1, 2 or 3 halogen, in particular on an alkyl, especially a methyl group such as trifluoromethyl), alkyl group (preferably C ₁ -C ₁₀ , more preferably C ₁ -C ₆ ), aryl (especially phenyl and substituted phenyl, such as benzyl or benzoyl), alkoxy (preferably C ₁ -C ₆ alkyl or aryl, including phenyl and substituted phenyl), thioether (C ₁ -C ₆ alkyl or aryl), acyl (preferably C ₁ -C ₆ acyl), ester or thioester (preferably C ₁ -C ₆ alkyl or aryl), including an alkylene ester (so that the attachment is on the alkylene group, and not with an ester functionality, which is preferably substituted with a C ₁ -C ₆ alkyl or aryl group), preferably a C ₁ -C ₆ alkyl or aryl, halogen (preferably F or Cl), amine (including a five- or six-membered cyclic alkyleneamine, optionally including a C ₁ -C ₆ alkylamine or a C ₁ -C ₆ dialkylamine, wherein the alkyl groups may be substituted by one or two hydroxyl groups) or optionally substituted -N(C ₀ -C ₆ alkyl)C(O)(O- a C ₁ -C ₆ alkyl) group (which may optionally be substituted by a polyethylene glycol chain to which is further linked an alkyl group containing one halogen, preferably a chloride substituent), hydrazine, amido, which is preferably substituted with one or two C ₁ -C ₆ alkyl groups (including a carboxamide that is optionally substituted with one or two C ₁ -C ₆ alkyl groups), an alkanol (preferably a C ₁ -C ₆ alkyl or aryl) or an alkanoic acid (preferably a C ₁ -C ₆ alkyl or aryl). Substituents of the present disclosure may include, for example, -SiR ₁ R ₂ R ₃ groups, wherein each of R ₁ and R ₂ is described in the present invention and R ₃ represents H or a C ₁ -C ₆ alkyl group, preferably R ₁ , R ₂ , R ₃ in this context represent a C ₁ -C ₃ alkyl group (including an isopropyl or tert-butyl group). Each of the above groups may be linked directly to the substituted moiety or, alternatively, the substituent may be linked to the substituted moiety (preferably in the case of an aryl or heteroaryl moiety) via an optionally substituted -(CH ₂ ) _m- or, alternatively, an optionally substituted

-(OSH ₂ ) _m -, -(OSH ₂ CH ₂ ) _m - or -(CH ₂ CH ₂ O) _m is a group that may be substituted by any one or more of the above substituents. Alkylene groups -(CH ₂ ) _m - or -(CH ₂ ) _n - groups or other chains, such as ethylene glycol chains as defined above, can be substituted anywhere on the chain. Preferred substituents on alkylene groups include halogen or C ₁ -C ₆ (preferably C ₁ -C ₃ ) alkyl groups, which may be optionally substituted with one or two hydroxyl groups, one or two ether groups (OC ₁ -C ₆ groups) , up to three halogen groups (preferably F) or amino acid side chains as otherwise described in the present invention, and an optionally substituted amide (preferably a carboxamide substituted as described above) or urethane groups (often with one or two _C0 -With ₆ alkyl substituents, such group(s) may be substituted(s). In certain embodiments, the alkylene group (often a simple methylene group) is substituted with one or two optionally substituted C ₁ -C ₆ alkyl groups, preferably a C ₁ -C ₄ alkyl group, most commonly a methyl or O-methyl group, or an amino acid side chain, as otherwise manner described in the present invention. According to the present disclosure, a moiety in the molecule may optionally be substituted with up to five substituents, preferably with up to three substituents. Most often, according to the present invention, the moieties that are substituted are substituted with one or two substituents.

[0144] The term "substituted" (each substituent is independent of any other substituent) shall also mean, within the context of use, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, amido, carboxamido, sulfone, including sulfonamide, keto , carboxy, C ₁ -C ₆ ester (hydroxy ester or carbonyl ester), C ₁ -C ₆ keto, urethane-OC(O)-NR ₁ R ₂ or -N(R ₁ )-C(O)- OR ₁ , nitro, cyano and amine (especially including C ₁ -C ₆ alkylene-NR ₁ R ₂ , mono- or di-C ₁ -C ₆ alkyl-substituted amines, which may be optionally substituted with one or two hydroxyl groups). Each of these groups contains, unless otherwise noted within the context, from 1 to 6 carbon atoms. In certain embodiments, preferred substituents will include, for example, -NH-, -NHC(O)-, -O-, =O, -(CH ₂ ) _m - (where m and n in context represent 1, 2 , 3, 4, 5 or 6), -S-, -S(O)-, SO ₂ - or -NH-C(O)-NH-, -(CH ₂ ) _n OH, -(CH ₂ ) _n SH, -(CH ₂ ) _n COOH, C ₁ -C ₆ alkyl, -(CH ₂ ) _n O-(C ₁ -C ₆ alkyl), -(CH ₂ ) _n C(O)-(C ₁ -C ₆ alkyl), -(CH ₂ ) _n OC(O)-(C ₁ -C ₆ alkyl), -(CH ₂ ) _n C(O)O-(C ₁ -C ₆ alkyl), -(CH ₂ ) _n NHC(O)-R ₁ -(CH ₂ ) _n C(O)-NR ₁ R ₂ , -(OCH ₂ ) _n OH, -(CH ₂ O) _n COOH, C ₁ -C ₆ alkyl, -( OCH ₂ ) _n O-(C ₁ -C ₆ alkyl), -(CH ₂ O) _n C(O)-(C ₁ -C ₆ alkyl), -(OCH ₂ ) _n NHC(O)-R ₁ , -(CH ₂ O) _n C(O)-NR ₁ R ₂ , -S(O) ₂ -R _S , -S(O)-R _S ( _RS is C ₁ -C ₆ alkyl or -(CH ₂ ) _m -NR ₁ R ₂ group), NO ₂ , CN or halogen (F, Cl, Br, I, preferably F or Cl), depending on the context of use of the substituent. R ₁ and R ₂ each, within the context, represents an H or C ₁ -C ₆ alkyl group (which may be optionally substituted with one or two hydroxyl groups or up to three halogen groups, preferably fluorine). The term “substituted” shall also mean, within the chemical context of the particular compound and substituent used, an optionally substituted aryl or heteroaryl group or an optionally substituted heterocyclic group as otherwise described in the present invention. Alkylene groups may also be substituted, as otherwise described in the present invention, preferably with optionally substituted C ₁ -C ₆ alkyl groups (methyl, ethyl or hydroxymethyl or hydroxyethyl are preferred, thereby providing a chiral center), a side chain of the amino acid group, such as otherwise described in the present invention, an amido group as described above, or a urethane group OC(O)-NR ₁ R ₂ wherein R ₁ and R ₂ are otherwise described in the present invention, although many other groups may also be used as substituents . The various optionally substituted moieties may be substituted with 3 or more substituents, preferably no more than 3 substituents and preferably 1 or 2 substituents. It is noted that in cases in which a substitution is required in a compound at a particular position of the molecule (primarily due to valence) but no substitution is noted, then it is implied or understood that such substituent is H unless the context of the substitution otherwise implies .

[0145] The term "aryl" or "aromatic compound" as used herein refers to a substituted (as otherwise described herein) or unsubstituted monovalent aromatic radical containing a single ring (e.g., benzene, phenyl, benzyl) or fused rings (e.g., naphthyl, anthracenyl, phenanthrenyl, etc.), and may be linked to a compound of the present disclosure at any available stable position on the ring(s) or as otherwise noted in the chemical structure provided. Other examples of aryl groups in context may include heterocyclic aromatic ring systems, "heteroaryl" groups containing one or more nitrogen, oxygen or sulfur atoms on a (monocyclic) ring such as imidazole, furyl, pyrrole, furanyl, thiene, thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole, or fused ring systems such as indole, quinoline, indolizine, azaindolizine, benzofurazan and the like, among others, which may be optionally substituted as described above. Among the heteroaryl groups that may be mentioned are nitrogen-containing heteroaryl groups such as pyrrole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole, indole, isoindole, indolysine, azaindolysine, purine, indazole, quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, quinolysine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine, acridine, phenanthridine, carbazole, carbazoline, pyrimi dine, phenanthroline, phenacene, oxadiazole, benzimidazole, pyrrolopyridine, pyrrolopyrimidine and pyridopyrimidine; sulfur-containing aromatic heterocycles such as thiophene and benzothiophene; oxygen-containing aromatic heterocycles such as furan, pyran, cyclopentapyran, benzofuran and isobenzofuran; and aromatic heterocycles containing 2 or more heteroatoms selected from nitrogen, sulfur and oxygen, such as thiazole, thiadiazole, isothiazole, benzoxazole, benzothiazole, benzothiadiazole, phenothiazine, isoxazole, furazan, phenoxazine, pyrazoloxazole, imidazothiazole, thienofuran, furopyrrole, pyridoxazine, furopyridine, furopyrimidine, thienopyrimidine and oxazole, among others, all of which may be optionally substituted.

[0146] The term “substituted aryl” refers to an aromatic carbocyclic group containing at least one aromatic ring or more fused rings, at least one of which is aromatic, the ring(s) being substituted with one or more substituents. For example, the aryl group may contain substituent(s) selected from: -(CH ₂ ) _n OH, -(CH ₂ ) _n -O-(C ₁ -C ₆ )alkyl, -(CH ₂ ) _n - O-(CH ₂ ) _n -(C ₁ -C ₆ )alkyl, -(CH ₂ ) _n C(O)(C ₀ -C ₆ )alkyl, -(CH ₂ ) _n -C(O)O(C ₀ -C ₆ )alkyl, -(CH ₂ ) _n -OC(O)(C ₀ -C ₆ )alkyl, amine, mono- or di-(C ₁ -C ₆ alkyl)amine, where the alkyl group on the amine is optional substituted with 1 or 2 hydroxyl groups or up to three halogen groups (preferably F, Cl), OH, COOH, C ₁ -C ₆ alkyl, preferably CH ₃ , CF ₃ , OMe, OCF ₃ , NO ₂ or CN groups (each of which may be substituted at the ortho, meta and/or para positions of the phenyl ring, preferably para), an optionally substituted phenyl group (the phenyl group itself is preferably substituted by a linker group attached to an ABM group, including a ULM group), and/ or at least one of F, Cl, OH, COOH, CH ₃ , CF ₃ , OMe, OCF ₃ , NO ₂ or CN group (at the ortho, meta and/or para positions of the phenyl ring, preferably para-) . optionally substituted pyrrole including methyl-substituted pyrrole, optionally substituted imidazole, including methylimidazole, optionally substituted benzimidazole or methoxybenzylimidazole, optionally substituted oximidazole or methyloximidazole, optionally substituted diazole group, including methyldiazole group, optionally substituted triazole group, including methyl-substituted triazole group, optionally substituted pyridine group, including halogen - (preferably F) or a methyl-substituted pyridine group or an oxapyridine group (where the pyridine group is connected to the phenyl group by oxygen), optionally substituted furan, optionally substituted benzofuran, optionally substituted dihydrobenzofuran, optionally substituted indole, indolizine or azaindolizine (2, 3 or 4 -azaindolizine), optionally substituted quinoline and combinations thereof.

[0147] "Carboxyl" means a group -C(O)OR, where R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, and these basic substituents are characterized by meanings that are identical to the definitions of the corresponding groups , defined in the present description.

[0148] The term “heteroaryl” or “hetaryl” may mean, but is not limited to, an optionally substituted quinoline (which may be attached to a pharmacophore or substituted at any carbon atom on the quinoline ring), an optionally substituted indole (including dihydroindole), an optionally substituted indolizine , optionally substituted azaindolysine (2, 3 or 4-azaindolizine), optionally substituted benzimidazole, benzodiazole, benzoxofuran, optionally substituted imidazole, optionally substituted isoxazole, optionally substituted oxazole (preferably methyl substituted), optionally substituted diazole, optionally substituted triazole, tetrazole, optionally substituted benzofuran, optionally substituted thiophene, optionally substituted thiazole (preferably methyl and/or thiol substituted), optionally substituted isothiazole, optionally substituted triazole (preferably 1,2,3-triazole substituted with a methyl group, triisopropylsilyl group, optionally substituted -(CH ₂ ) _m -OC ₁ -C ₆ alkyl group or optionally substituted -(CH ₂ ) _m -C(O)-OC ₁ -C ₆ alkyl group), optionally substituted pyridine (2-, 3 or 4-pyridine) or chemical structure group :

Where:

S ^c represents CHR ^SS , NR ^URE or O;

R ^HET is H, CN, NO ₂ , halogen (preferably Cl or F), optionally substituted C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (e.g. CF ₃ )) , optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or an optionally substituted acetylene group C≡CR _a , where R _a represents H or C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl);

R ^SS is H, CN, NO ₂ , halogen (preferably F or Cl), optionally substituted C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups), optionally substituted O-( C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or optionally substituted -C(O)(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or halogen groups groups of up to three);

R ^URE is H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl) or -C(O)(C ₁ -C ₆ alkyl), each of such groups optionally substituted with one or two hydroxyl groups or up to three halogen atoms, preferably fluorine groups, or an optionally substituted heterocycle, for example piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted, and

Y ^C is N or CR ^YC where R ^YC is H, OH, CN, NO ₂ , halogen (preferably Cl or F), optionally substituted C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or halogen groups up to three (eg CF ₃ )), optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or optionally substituted acetylene group -C≡CR _a where R _a represents H or a C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl).

[0149] The terms “aralkyl” and “heteroarylalkyl” refer to groups that contain both aryl or heteroaryl, as well as alkyl and/or heteroalkyl and/or carbocyclic and/or heterocycloalkyl ring systems according to the above definitions.

[0150] As used herein, the term “arylalkyl” refers to an aryl group as defined above attached to an alkyl group as defined above. The arylalkyl group is attached to the parent moiety through an alkyl group, where the alkyl group consists of one to six carbon atoms. The aryl group in the arylalkyl group may be substituted as defined above.

[0151] The term “heterocycle” refers to a cyclic group that contains at least one heteroatom, such as N, O, or S, and may be aromatic (heteroaryl) or non-aromatic. Thus, heteroaryl moieties relate to the definition of a heterocycle depending on the context of its application. Exemplary heteroaryl groups are described above.

[0152] Exemplary heterocycles include: azetidinyl, benzimidazolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothisnyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxanil, dioxolanil, ethylene urea, 1,3- dioxolane, 1,3-dioxane, 1,4-dioxane, furyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, iidolyl, iidolyl, isochityulinyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, naphthyridinyl, okeazolidinyl, oxazolyl, pyridone , 2- pyrrolidone, pyridine, piperazinyl, N-methylpiperazinyl, piieridinyl, phthalimide, succinimide, pyrazinyl, pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinoline, hyazolidinyl, thiazolyl, thiene silt, tetrahydrothiophene, ocean, oxetanil, oxathiolanyl, thian, among others.

[0153] Heterocyclic groups may optionally be substituted by a member selected from the group consisting of alkoxy, substituted alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, cycloalkyl cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxy, carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic compound, heterocyclooxy, hydroxyami but, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SOaryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, oxo (=O) and -SO2-heteroaryl. Such heterocyclic groups may contain a single ring or several fused rings. Examples of nitrogen heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolysine, isoindole, indole, indazole, purine, quinolysine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, tetrahydrofuranyl, etc., as well as N-alkoxynitrogen-containing heterocycles. The term “heterocyclic” also includes bicyclic groups in which any of the heterocyclic rings are fused to a benzene ring or a cyclohexane ring or other heterocyclic ring (eg, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, etc.).

[0154] The term “cycloalkyl” can mean, without limitation, monovalent groups derived from monocyclic or polycyclic alkyl groups or cycloalkanes as defined herein, for example, saturated monocyclic hydrocarbon groups containing from three to twenty ring carbon atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. The term "substituted cycloalkyl" can mean, but is not limited to, a monocyclic or polycyclic alkyl group and has been substituted with one or more substituents, for example, amino, halogen, alkyl, substituted alkyl, carbiloxy, carbyl mercapto, aryl, nitro, mercapto or sulfo, whereas such typical substituent groups are characterized by meanings that are identical to the definitions of the corresponding groups as defined in this list.

[0155] “Heterocycloalkyl” refers to a monocyclic or polycyclic alkyl group in which at least one ring carbon atom in its cyclic structure is replaced by a heteroatom selected from the group consisting of N, O, S or P. “Substituted heterocycloalkyl” refers to a monocyclic or polycyclic alkyl group in which at least one ring carbon atom in its cyclic structure is replaced by a heteroatom selected from the group consisting of N, O, S or P, and the group contains one or more substituents selected from the group consisting of halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto or sulfo, while such a typical substituent group is characterized by meanings that are identical with the definitions of the corresponding groups as defined in this list.

[0156] The term "hydrocarbyl" is intended to mean a compound that contains carbon and hydrogen and which may be fully saturated, partially unsaturated or aromatic and includes aryl groups, alkyl groups, alkenyl groups and alkynyl groups.

[0157] As used herein, the term “independently” means that a variable used independently varies from application to application.

[0158] The term "lower alkyl" refers to methyl, ethyl or propyl.

[0159] The term "lower alkoxy" refers to methoxy, ethoxy or propoxy.

[0160] In one embodiment described herein, W, X, Y, Z, G, G', R, R', R'', Q1-Q4, A, and Rn may independently be covalently linked to the linker and/ or a linker to which one or more PTM, ULM, ILM or ILM' groups are attached.

[0161] Example MLM

[0162] In certain additional embodiments, the MLM of the bifunctional compound contains chemical moieties such as substituted imidazolines, substituted spiroindolinones, substituted pyrrolidines, substituted piperidinones, substituted morpholinones, substituted pyrrolopyrimidines, substituted imidazolopyridines, substituted thiazoloimidazolines, substituted pyrrolopyrrho lidinones and substituted isoquinolinones.

[0163] In further embodiments, the MLM comprises the basic structures mentioned above with adjacent bis-aryl substitutions arranged in cis or trans configurations.

[0164] In additional embodiments, the MLM comprises a portion of the structural features of RG7112, RG7388, SAR405838, AMG-232, AM-7209, DS-5272, MK-8242, and NVP-CGM-097, and analogs or derivatives thereof.

[0165] In certain preferred embodiments, MLM is a derivative of a substituted imidazoline, represented by formula (A-1), or a thiazoloimidazoline, represented by formula (A-2), or spiroindolinone, represented by formula (A-3), or pyrrolidine, represented as formula (A-4), or piperidinone/morpholinone, represented as formula (A-5), or isoquinolinone, represented as formula (A-6), or pyrrolopyrimidine/imidazolopyridine, represented as formula (A-7), or pyrrolopyrrolidinone/imidazolopyrrolidinone represented by formula (A-8).

where above formula (A-1) is formula (A-8),

X of formula (A-1) to formula (A-8) is selected from the group consisting of carbon, oxygen, sulfur, sulfoxide, sulfone and NR ^a ;

R ^a independently represents H or an alkyl group of 1 to 6 carbon atoms;

Y and Z of formula (A-1) to formula (A-8) are independently carbon or nitrogen;

A, A' and A'' of formula (A-1) through formula (A-8), independently selected from C, N, O or S, may also be one or two atoms forming a fused bicyclic ring or 6,5- and a 5,5-fused aromatic bicyclic group;

R ₁ , R ₂ of formula (A-1) - formula (A-8) are independently selected from the group consisting of an aryl or heteroaryl group, a heteroaryl group containing one or two heteroatoms independently selected from sulfur or nitrogen, wherein aryl or heteroaryl the group may be monocyclic or bicyclic or unsubstituted or substituted with one to three substituents independently selected from the group consisting of:

halogen, -CN, C1-C6 alkyl group, C3-C6 cycloalkyl, -OH, alkoxy with 1-6 carbon atoms, fluorinated alkoxy with 1-6 carbon atoms, sulfoxide with 1-6 carbon atoms, sulfone with 1-6 atoms carbon, ketone with 2-6 carbon atoms, amides with 2-6 carbon atoms and dialkylamine with 2-6 carbon atoms;

R ₃ , R ₄ of formula (A-1) - formula (A-8) are independently selected from the group consisting of H, methyl and C1-C6 alkyl;

R ₅ of formula (A-1) - formula (A-8) is selected from the group consisting of an aryl or heteroaryl group, a heteroaryl group containing one or two heteroatoms independently selected from sulfur or nitrogen, wherein the aryl or heteroaryl group may be monocyclic or bicyclic or unsubstituted or substituted with one to three substituents independently selected from the group consisting of:

halogen, -CN, C1-C6 alkyl group, C3-C6 cycloalkyl, -OH, alkoxy with 1-6 carbon atoms, fluorinated alkoxy with 1-6 carbon atoms, sulfoxide with 1-6 carbon atoms, sulfone with 1-6 atoms carbon, ketone with 2-6 carbon atoms, amides with 2-6 carbon atoms, dialkylamine with 2-6 carbon atoms, alkyl ether (C2-C6), alkyl ketone (C3-C6), morpholinyl, alkyl ester (C3-C6 ), alkyl cyanide (C3-C6);

R ₆ of formula (A-1) - formula (A-8) is H or -C(=O)R ^b , where

R ^b of formula (A-1) - formula (A-8) is selected from the group consisting of alkyl, cycloalkyl, mono-, di- or tri-substituted aryl or heteroaryl, 4-morpholinyl, 1-(3-oxopiperazunyl), 1- piperidinyl, 4- ^NRc -morpholinyl, 4-Rc- ¹ -piperidinyl and 3- ^Rc -1-piperidinyl, where

R ^c of formula (A-1) - formula (A-8) is selected from the group consisting of alkyl, fluoro-alkyl, cyanoalkyl, hydroxyl-alkyl, cycloalkyl, alkoxy alkyl, amidalkyl, alkyl sulfone, alkyl sulfoxide, alkylamide, aryl, heteroaryl, mono -, bis- and trisubstituted aryl or heteroaryl, CH2CH2R ^d and CH2CH2CH2R ^d , where

R ^d of formula (A-1) - formula (A-8) is selected from the group consisting of alkoxy, alkylsulfone, alkylsulfoxide, N-substituted carboxamide, -NHC(O)-alkyl, -NH-SO ₂ -alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl;

R ₇ of formula (A-1) - formula (A-8) is selected from the group consisting of H, C1-C6 alkyl, cyclic alkyl, fluoro-alkyl, cyano-substituted alkyl, 5- or 6-membered heteroaryl or 5-substituted aryl or 6-membered heteroaryl or aryl;

R ₈ of formula (A-1) - formula (A-8) is selected from the group consisting of R ^e -C(O)-R ^f , -R ^e -alkoxy, -R ^e -aryl, -R ^e -heteroaryl and -R ^e -C(O)-R ^f -C(O)-R ^g , where:

R ^e of formula (A-1) - formula (A-8) represents an alkylene with 1-6 carbon atoms or a bond;

R ^f of formula (A-1) - formula (A-8) is substituted with a 4-7 membered heterocycle;

R ^g of formula (A-1) - formula (A-8) is selected from the group consisting of aryl, heteroaryl, substituted aryl or heteroaryl and a 4-7 membered heterocycle;

R ₉ of formula (A-1) - formula (A-8) is selected from the group consisting of mono-, bi- or tri-substituents on the fused bicyclic aromatic ring in formula (A-3), where the substituents are independently selected from the group, consisting of halogen, alkene, alkyne, alkyl, unsubstituted or substituted with Cl or F;

R ₁₀ of formula (A-1) - formula (A-8) is selected from the group consisting of an aryl or heteroaryl group, where the heteroaryl group may contain one or two sulfur or nitrogen heteroatoms, the aryl or heteroaryl group may be monocyclic or bicyclic, aryl or the heteroaryl group may be unsubstituted or substituted with one to three substituents, including halogen, F, Cl, -CN, alkene, alkyne, C1-C6 alkyl group, C1-C6 cycloalkyl, -OH, C1-6 alkoxy, fluorine substituted alkoxy with 1-6 carbon atoms, sulfoxide with 1-6 carbon atoms, sulfone with 1-6 carbon atoms, ketone with 2-6 carbon atoms;

R ₁₁ of formula (A-1) - formula (A-8) is -C(O)-N(R ^h )(R ⁱ ), where R ^h and R ⁱ are selected from the group consisting of the following:

H, C1-C6 alkyl, alkoxy-substituted alkyl, sulfone-substituted alkyl, aryl, heteroaryl, mono-, bis- or tri-substituted aryl or heteroaryl, alkylcarboxylic acid, heteroarylcarboxylic acid, alkylcarboxylic acid, fluorine-substituted alkylcarboxylic acid, aryl-substituted cycloalkyl, heteroaryl-substituted cycloalkyl; Where

R ^h and R ⁱ of formula (A-1) - formula (A-8) are independently selected from the group consisting of H connected to form a ring, 4-hydroxycyclohexane; mono- and dihydroxy-substituted alkyl (C3-C6); 3-hydroxycyclobutane; phenyl-4-carboxylic acid and substituted phenyl-4-carboxylic acid;

R ₁₂ and R ₁₃ of formula (A-1) - formula (A-8) are independently selected from H, lower alkyl (C1-C6), lower alkenyl (C2-C6), lower alkynyl (C2-C6), cycloalkyl (4 , 5 and 6 membered ring), substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, 5 and 6 membered aryl and heteroaryl, R12 and R13 can be combined to form a 5 and 6 membered ring with or without substitution on the ring;

R ₁₄ of formula (A-1) - formula (A-8) is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl , cycloalkenyl and substituted cycloalkenyl;

R ₁₅ of formula (A-1) - formula (A-8) represents CN;

R ₁₆ of formula (A-1) - formula (A-8) is selected from the group consisting of C1-6 alkyl, C1-6 cycloalkyl, C2-6 alkenyl, C1-6 alkyl or C3-6 cycloalkyl with one or more atoms hydrogen replaced by fluorine, alkyl or cycloalkyl with one CH ₂ replaced by S(=O), -S or -S(=O) ₂ , alkyl or cycloalkyl with the final CH ₃ replaced by S(=O) ₂ N(alkyl) (alkyl), -C(=O)N(alkyl)(alkyl), -N(alkyl)S(=O) ₂ (alkyl), -C(=O)2(alkyl), -O(alkyl), C1-6 alkyl or alkylcycloalkyl with a hydrogen atom replaced by a hydroxyl group, 3-7 membered cycloalkyl or heterocycloalkyl, optionally containing

-(C=O)-group, or a 5-6-membered aryl or heteroaryl group, wherein the heterocycloalkyl or heteroaryl group may contain from one to three heteroatoms independently selected from O, N or S, and cycloalkyl, heterocycloalkyl, aryl or the heteroaryl group may be unsubstituted or substituted with one to three substituents independently selected from halogen, C1-6 alkyl groups, hydroxylated C1-6 alkyl, C1-6 alkyl containing thioether, ether, sulfone, sulfoxide, fluoroether or cyano group;

R ₁₇ of formula (A-1) - formula (A-8) is selected from the group consisting of (CH ₂ )nC(O)NR ^k R ¹ , where R ^k and R ¹ are independently selected from H, C1-6 alkyl, hydroxylated C1-6 alkyl, C1-6 alkoxy alkyl, C1-6 alkyl with one or more hydrogen atoms replaced by a fluorine atom, C1-6 alkyl with one carbon atom replaced by S(O), S(O)(O), C1-6 alkoxyalkyl with one or more hydrogen atoms replaced by a fluorine atom, C1-6 alkyl with a hydrogen atom replaced by a cyano group, 5- and 6-membered aryl or heteroaryl, alkylaryl with an alkyl group containing 1-6 carbon atoms, and alkylheteroaryl with an alkyl group containing 1-6 carbon atoms, where the aryl or heteroaryl group may be further substituted;

R ₁₈ of formula (A-1) - formula (A-8) is selected from the group consisting of substituted aryl, heteroaryl, alkyl, cycloalkyl, the substitution is preferably -N(C1-4 alkyl)(cycloalkyl), -N(C1 -4 alkyl)alkylcycloalkyl and -N(C1-4 alkyl)[(alkyl)-(heterocycle-substituted)-cycloalkyl];

R ₁₉ of formula (A-1) to formula (A-8) is selected from the group consisting of aryl, heteroaryl, bicyclic heteroaryl and such aryl or heteroaryl groups may be substituted with halogen, C1-6 alkyl, C1-6 cycloalkyl, CF ₃ , F, CN, alkyne, alkyl sulfone and halogen substitution may be mono-bis or tri-substituted;

R ₂₀ and R ₂₁ of formula (A-1) - formula (A-8) are independently selected from C1-6 alkyl, C1-6 cycloalkyl, C1-6 alkoxy, hydroxylated C1-6 alkoxy and fluoro-substituted C1-6 alkoxy, where R ₂₀ and R ₂₁ may additionally be joined to form a 5-, 6-, and 7-membered cyclic or heterocyclic ring, which may be further substituted;

R ₂₂ of formula (A-1) - formula (A-8) is selected from the group consisting of H, C1-6 alkyl, C1-6 cycloalkyl, carboxylic acid, carboxylic acid ester, amide, reverse amide, sulfonamide, reverse sulfonamide, N-acyl urea, nitrogen-containing 5-membered heterocycle, 5-membered heterocycles can be further substituted with C1-6 alkyl, alkoxy, fluorine-substituted alkyl, CN and alkylsulfone;

R ₂₃ formula (A-1) - formula (A-8) selected from aryl, heteroaryl, -O-aryl, -O-heteroaryl, -O-alkyl, -O-alkylcycloalkyl, -NH-alkyl, -NH-alkylcycloalkyl , -N(H)-apnna, -N(H)-heteroaryl, -N(alkyl)-aryl, -N(alkyl)-heteroaryl, aryl or heteroaryl groups may be substituted with halogen, C1-6 alkyl, hydroxylated C1- 6 alkyl, cycloalkyl, fluoro-substituted C1-6 alkyl, CN, alkoxy, alkylsulfone, amide and sulfonamide;

R ₂₄ of formula (A-1) - formula (A-8) is selected from the group consisting of -CH2-(C1-6 alkyl), -CH2-cycloalkyl, -CH2-aryl, CH2-heteroaryl, where alkyl, cycloalkyl, aryl and heteroaryl may be substituted with halogen, alkoxy, hydroxylated alkyl, cyanoalkyl, cycloalkyl and substituted cycloalkyl;

R ₂₅ of formula (A-1) - formula (A-8) is selected from the group consisting of C1-6 alkyl, C1-6 alkylcycloalkyl, alkoxy-substituted alkyl, hydroxylated alkyl, aryl, heteroaryl, substituted aryl or heteroaryl, 5-, 6 - and 7-membered nitrogen-containing saturated heterocycles, 5,6-fused and 6,6-fused nitrogen-containing saturated heterocycles and these saturated heterocycles can be replaced by C1-6 alkyl, fluorine-substituted C1-6 alkyl, alkoxy, aryl and heteroaryl group;

R ₂₆ of formula (A-1) - formula (A-8) is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, alkyl or cycloalkyl may be substituted with OH, alkoxy, fluoroalkoxy, fluoroalkyl, -NH ₂ , -NH-alkyl, NH-C(O)alkyl, -NH-S(O) ₂ -alkyl and -S(O) ₂ -alkyl;

R ₂₇ of formula (A-1) - formula (A-8) is selected from the group consisting of aryl, heteroaryl, bicyclic heteroaryl, where the aryl or heteroaryl groups may be replaced by C1-6 alkyl, alkoxy, NH2, NH-alkyl, halogen or -CN, and the substitution may independently be mono-, bis-, or tri-substitution;

R ₂₈ of formula (A-1) - formula (A-8) is selected from the group consisting of aryl, 5- and 6-membered heteroaryl, bicyclic heteroaryl, cycloalkyl, saturated heterocycle such as piperidine, piperidinone, tetrahydropyran, N-acylpiperidine wherein cycloalkyl, saturated heterocycle, aryl or heteroaryl may be further substituted with -OH, alkoxy, mono-, bis- or three substituents including halogen, -CN, alkylsulfone and fluoroalkyl groups; And

R _1'' of formula (A-1) to formula (A-8) is selected from the group consisting of alkyl, aryl-substituted alkyl, alkoxy-substituted alkyl, cycloalkyl, aryl-substituted cycloalkyl and alkoxy-substituted cycloalkyl.

[0166] In certain embodiments, the heterocycles in R ^f and R ^g of formula (A-1) through formula (A-8) are substituted pyrrolidine, substituted piperidine, substituted piperisine.

[0167] More specifically, non-limiting examples of MLMs include those shown below, as well as those “hybrid” molecules that result from a combination of 1 or more different features shown in the molecules below.

[0168] Using the MLM in formula A-1 to A-8, the following PROTACs can be prepared to target a specific protein, where "L" represents a connector (i.e., a linker group) and "RTM" represents a ligand, associated with a protein target.

[0169] In certain embodiments, the disclosure provides a bifunctional molecule comprising a structure selected from the group consisting of:

where X, R ^a , Y, Z, A, A', A'', R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ^b , R ^c , R ^d , R ₇ , R ^e , R ^f , R ^g , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ , R ^k , R ¹ , R ₁₈ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R 23 , R ₂₄ , R ₂₅ , R ₂₆ , R _{27 R 28 ,} and R _1'' are defined herein with respect to formulas (A-1) to (A-8).

[0170] In certain embodiments, the disclosure describes bifunctional or chimeric molecules with the structure: PTM-L-MLM, wherein PTM is a protein target binding moiety linked to the MLM by L, wherein L is a linkage (i.e. , absent) or chemical linker. In certain embodiments, the MLM has a structure selected from the group consisting of A-1-1, A-1-2, A-1-3, and A-1-4:

Where:

R1' and R2' of formulas A-1-1 to A-1-4 (i.e., A-1-1, A-1-2, A-1-3 and A-1-4) are independently selected from a group consisting of F, Cl, Br, I, acetylene, CN, CF ₃ and NO ₂ ;

R3' is selected from the group consisting of -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ F, -OCH ₂ CH ₂ OCH ₃ and -OCH(CH ₃ ) ₂ ;

R4' of formulas A-1-1 - A-1-4 is selected from the group consisting of H, halogen, -CH ₃ , -CF ₃ , -OCH ₃ , -C(CH ₃ ) ₃ , -CH(CH ₃ ) ₂ , -cyclopropyl, -CN, -C(CH ₃ ) ₂ OH, -C(CH ₃ ) ₂ OCH ₂ CH ₃ , -C(CH ₃ ) ₂ CH ₂ OH, -C(CH ₃ ) ₂ CH ₂ OCH ₂ CH ₃ , -C(CH ₃ ) ₂ CH ₂ OCH ₂ CH ₂ OH, -C(CH ₃ ) ₂ CH ₂ OCH ₂ CH ₃ , -C(CH ₃ ) ₂ CN, -C(CH ₃ ) ₂ C (O)CH ₃ , -C(CH ₃ ) ₂ C(O)NHCH ₃ , -C(CH ₃ ) ₂ C(O)N(CH ₃ ) ₂ , -SCH ₃ , -SCH ₂ CH ₃ , -S (O) ₂ CH ₃ , -S(O ₂ )CH ₂ CH ₃ , -NHC(CH ₃ ) ₃ , -N(CH ₃ ) ₂ , pyrrolidinyl and 4-morpholinyl;

R5' of formulas A-1-1 to A-1-4 is selected from the group consisting of halogen, -cyclopropyl, -S(O) ₂ CH ₃ , -S(O) ₂ CH ₂ CH ₃ , 1-pyrrolidinyl, - NH ₂ , -N(CH ₃ ) ₂ and -NHC(CH ₃ ) ₃ ; And

R6' of formulas A-1-1 to A-1-4 is selected from the structures presented below, where the point of attachment of the linker is designated as "*".

[0171] Along with R6' as the linker attachment point, R4' can also serve as the linker attachment position. In the case where R4' is the attachment site of a linker, the linker will be connected to the terminal atom of the R4' groups as shown above.

[0172] In certain embodiments, the attachment position of the linker of formulas A-1-1 to A-1-4 is at least one of R4' or R6', or both.

[0173] In certain embodiments, R6' of formulas A-1-1 through A-1-4 is independently selected from the group consisting of H,

where "*" denotes the linker attachment point.

[0174] In certain embodiments, a linker of formula A-4-1 to A-4-6 is attached to at least one R1', R2', R3', R4', R5', R6', or a combination thereof.

[0175] In certain embodiments, the disclosure provides bifunctional or chimeric molecules with the structure: PTM-L-MLM, wherein PTM is a protein target binding moiety linked to the MLM by L, wherein L is a linkage (i.e. , absent) or chemical linker. In certain embodiments, the MLM has a structure selected from the group consisting of A-4-1, A-4-2, A-4-3, A-4-4, A-4-5, and A-4-6:

Where:

R7' of formula A-4-1 - A-4-6 (i.e., A-4-1, A-4-2, A-4-3, A-4-4, A-4-5 and A-4-6) is a member selected from the group consisting of halogen, mono- and di- or tri-halogen;

R8' of formula A-4-1 to A-4-6 is selected from the group consisting of H, -F, -Cl, -Br, -I, -CN, _-NO2 , ethynyl, cyclopropyl, methyl, ethyl, isopropyl , vinyl, methoxy, ethoxy, isopropoxy, -OH, other C1-6 alkyl, other C1-6 alkenyl and C1-6 alkynyl, mono-, di- or tri-substituted;

R9' of formula A-4-1 to A-4-6 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted cycloalkenyl;

Z of formula A-4-1 - A-4-6 is selected from the group consisting of H, -OSH ₃ , -OSH ₂ CH ₃ and halogen;

R10' and R11' of formula A-4-1 to A-4-6 are each independently selected from the group consisting of H, (CH ₂ ) _n -R', (CH ₂ ) _n -NR'R'', (CH ₂ ) _n -NR'COR'', (CH ₂ ) _n -NR'SO ₂ R'', (CH ₂ ) _n -COOH, (CH ₂ ) _n -COOR', (CH) _n -CONR'R'', (CH ₂ ) _n -OR', (CH ₂ ) _n -SR', (CH ₂ ) _n -SOR', (CH ₂ ) _n -CH(OH)-R', (CH ₂ ) _n -COR ', (CH ₂ ) _n -SO ₂ R', (CH ₂ ) _n -SONR'R'', (CH ₂ ) _n -SO ₂ NR'R'', (CH ₂ CH ₂ O) _m -(CH ₂ ) _n -R', (CH ₂ CH ₂ O) _m -(CH ₂ ) _n -OH, (CH ₂ CH ₂ O) _m -(CH ₂ ) _n -OR', (CH ₂ CH ₂ O) _m -(CH ₂ ) _n -NR'R'', (CH ₂ CH ₂ O) _m -(CH ₂ ) _n -NR'COR'', (CH ₂ CH ₂ O) _m (CH ₂ ) _n -NR' SO ₂ R'', (CH ₂ CH ₂ O) _m (CH ₂ ) _n -COOH, (CH ₂ CH ₂ O) _m (CH ₂ ) _n -COOR', (CH ₂ CH ₂ O) _m -(CH ₂ ) _n -CONR'R'', (CH ₂ CH ₂ O) _m -(CH ₂ ) _n -SO ₂ R', (CH ₂ CH ₂ O) _m -(CH ₂ ) _n -COR', (CH ₂ CH ₂ O) _m -(CH ₂ )n-SONR'R'', (CH ₂ CH ₂ O) _m -(CH ₂ ) _n -SO ₂ NR'R'', (CH ₂ ) _p -(CH ₂ CH ₂ O) _m -(CH ₂ ) _n R', (CH ₂ ) _p -(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -OH, (CH ₂ ) _p -(CH ₂ CH ₂ O ) _m -(CH ₂ ) _n -OR', (CH ₂ ) _p -(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -NR'R'', (CH ₂ ) _p -(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -NR'COR'', (CH ₂ ) _p -(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -NR'SO ₂ R'', (CH ₂ ) _p -(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -COOH, (CH ₂ ) _p -(CH ₂ CH ₂ O) _m -(CH2) _n -COOR', (CH ₂ ) _p -(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -CONR'R'', (CH ₂ ) _p -(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -SO ₂ R', (CH ₂ ) _p - (CH ₂ CH ₂ O) _m -(CH ₂ ) _n -COR', (CH ₂ ) _p -(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -SONR'R'', (CH ₂ ) _p -(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -SO ₂ NR'R'', aryl-(CH ₂ ) _n -COOH and heteroarylalkyl-CO-alkyl-NR'R''m, where alkyl can be substituted with OR', and heteroaryl-(CH ₂ ) _n -heterocycle, where the heterocycle may optionally be substituted with alkyl, hydroxyl, COOR' and COR'; where R' and R'' are selected from H, alkyl, halogen-substituted alkyl, hydroxyl, NH2, NH(alkyl), N(alkyl) ₂ , oxo, carboxy, cycloalkyl and heteroaryl;

m, n and p independently represent 0-6;

R12' of formula A-4-1 to A-4-6 is selected from the group consisting of -O-(alkyl), -O-(alkyl)-alkoxy, -C(O)-(alkyl), -C(OH )-alkylalkoxy, -C(O)-NH-(alkyl), -C(O)-N-(alkyl) ₂ , -S(O)-(alkyl), S(O) ₂ -(alkyl), - C(O)-(cyclic amine) and -O-aryl-(alkyl), -O-aryl-(alkoxy);

R1'' of formula A-4-1 to A-4-6 is selected from the group consisting of alkyl, aryl-substituted alkyl, alkoxy-substituted alkyl, cycloalkyl, aryl-substituted cycloalkyl and alkoxy-substituted cycloalkyl.

[0176] In any of the aspects or embodiments described herein, alkyl, alkoxy, or the like may be lower alkyl or lower alkoxy.

[0177] In certain embodiments, the point of attachment of the linker of formula A-4-1 to A-4-6 is at least one of Z, R8', R9', R10', R11'', R12'', or R1'' .

[0178] The method used to formulate chimeric molecules as presented in A-1-1 to A-1-4, A-4-1 to A-4-6 can be applied to MLM with formula A-2, A -3, A-5, A-6, A-7 and A-8, where the hydrophilic area in the MLM can be connected to a linker “L”, which will be attached to the target protein ligand “PTM”, to form a PROTAC.

[0179] Exemplary MDM2 binding fragments include, but are not limited to, the following:

[0180] HDM2/MDM2 inhibitors defined in Vassilev, et al., in vivo activation of the p53 pathway by small-molecule antagonists of MDM2, SCIENCE vol:303, pag:844-848 (2004), and Schneekloth, et al. ., Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics, Bioorg. Med. Chem. Lett. 18 (2008) 5904-5908, including (or additionally) the compounds nutlin-3, nutlin-2 and nutlin-1 (derivatized) as described below, as well as all derivatives and analogs thereof:

(derivatized, where the linker group L or (L-MLM) group is attached, for example, at a methoxy group or as a hydroxyl group);

(derivatized, where the linker group L or (L-MLM) group is attached, for example, at a methoxy group or hydroxyl group); And

(derivatized, where the linker group L or -(L-MLM) group is attached, for example, by a methoxy group or as a hydroxyl group).

[0181] Example CLMs

[0182] Neoimide compounds

[0183] In one aspect, the present invention provides compounds useful for binding and/or inhibiting cereblon. In certain embodiments, the compound is selected from the group consisting of chemical structures:

Where:

W of formulas (a) - (e) is independently selected from the group of CH ₂ , CHR, C=O, SO ₂ , NH and N-alkyl;

X of formulas (a) - (e) is independently selected from the group O, S and H ₂ ;

Y of formulas (a) - (e) is independently selected from the group CH ₂ , -C=CR', NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O and S;

Z of formulas (a)-(e) is independently selected from the group O and S or H ₂ except that both X and Z cannot be H ₂ ;

G and G' of formulas (a) - (e) are independently selected from the group H, alkyl (straight-chain, branched, optionally substituted), OH, R'OCOOR, R'OCONRR'', CH ₂ -heterocyclyl, optionally substituted with R', and benzyl, optionally substituted with R';

Q1-Q4 of formulas (a) - (e) represent a C carbon substituted by a group independently selected from R', N or N-oxide;

A of formulas (a) - (e) is independently selected from the group H, alkyl (straight, branched, optionally substituted), cycloalkyl, Cl and F;

R of formulas (a) - (e) contains without limitation: -CONR'R'', -OR', -NR'R'', -SR', -SO ₂ R', -SO ₂ NR'R'', -CR'R''-, -CR'NR'R''-, (-CR'O) _n R'', -aryl, -hetaryl, -alkyl (straight, branched, optionally substituted), -cycloalkyl, - heterocyclyl, -P(O)(OR')R'', -P(O)R'R'', -OP(O)(OR')R'', -OP(O)R'R'', -Cl, -F, -Br, -I, -CF ₃ , -CN, -NR'SO ₂ NR'R'', -NR'CONR'R'', -CONR'COR'', -NR'C (=N-CN)NR'R'', -C(=N-CN)NR'R'', -NR'C(=N-CN)R'', -NR'C(=C-NO ₂ )NR'R'', -SO ₂ NR'COR'', -NO ₂ , -CO ₂ R', -C(C=N-OR')R'', -CR'=CR'R'', -CCR', -S(C=O)(C=N-R')R'', -SF ₅ and -OCF ₃

R' and R'' of formulas (a) - (e) are independently selected from the bond, H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic compound, -C(=O)R, heterocyclyl, each of which is optionally substituted;

n of formulas (a) - (e) is an integer from 1-10 (for example, 1-4);

formulas (a) - (e) represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific; And

R _n of formulas (a) - (e) contains 1-4 independent functional groups, an optionally substituted alkoxy group (for example, methoxy, ethoxy, butoxy, propoxy, pentoxy or hexoxy; where the alkoxy can be substituted with halogen, cycloalkyl (for example, C3- C6 cycloalkyl) or aryl (for example, C5-C7 aryl)) or atoms.

[0184] Example CLMs

[0185] In any of the compounds described in the present invention, the CLM contains a chemical structure selected from the group:

Where:

W of formulas (a) - (e) is independently selected from the group of CH ₂ , CHR, C=O, SO ₂ , NH and N-alkyl;

X of formulas (a) - (e) is independently selected from the group O, S and H2;

Y of formulas (a) - (e) is independently selected from the group CH ₂ , -C=CR', NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O and S;

Z of formulas (a) - (e) is independently selected from the group O and S or H2, except that both X and Z cannot be H2;

G and G' of formulas (a) - (e) are independently selected from the group H, alkyl (straight, branched), OH, R'OCOOR, R'OCONRR'', CH ₂ -heterocyclyl, optionally substituted with R', and benzyl, optionally substituted R';

Q1-Q4 of formulas (a) - (e) represents a C carbon substituted with a group independently selected from R', N or N-oxide;

A of formulas (a) - (e) is independently selected from the group H, alkyl (straight-chain, branched, optionally substituted), cycloalkyl, Cl and F;

R of formulas (a) - (e) contains without limitation: -CONR'R'', -OR', -NR'R'', -SR', -SO2R', -SO2NR'R'', -CR'R ''-, -CR'NR'R''-, -aryl, -hetaryl, -alkyl (straight, branched, optionally substituted), -cycloalkyl, -heterocyclyl, -P(O)(OR')R'', -P(O)R'R'', -OP(O)(OR')R'', -OP(O)R'R'', -Cl, -F, -Br, -I, -CF3, -CN, -NR'SO2NR'R'', -NR'CONR'R'', -CONR'COR'', -NR'C(=N-CN)NR'R'', -C(=N- CN)NR'R'', -NR'C(=N-CN)R'', -NR'C(=C-NO2)NR'R'', -SO2NR'COR'', -NO2, -CO2R ', -C(C=N-OR')R'', -CR'=CR'R'', -CCR', -S(C=O)(C=N-R')R'', - SF5 and -OCF3

R' and R'' of formulas (a) - (e) are independently selected from the bond, H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic compound, -C(=O)R, heterocyclyl, each of which is optionally substituted;

n of formulas (a) - (e) is an integer from 1 to 10 (for example, 1-4);

formulas (a) - (e) represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific; And

Rn of formulas (a) - (e) contains 1-4 independent functional groups, an optionally substituted alkoxy group (for example, methoxy, ethoxy, butoxy, propoxy, pentoxy or hexoxy; where alkoxy may be substituted with halogen, cycloalkyl (for example, C3-C6 cycloalkyl) or aryl (eg, C5-C7 aryl)) or atom, and optionally one of which is modified to covalently attach to a PTM, a chemical linker group (L), ULM, CLM (or CLM'), or a combination thereof.

[0186] In certain embodiments described herein, the CLM or ULM comprises a chemical structure selected from the group:

Formula (g)

Where:

W of formula (g) is independently selected from the group CH ₂ , C=O, NH and N-alkyl;

R of formula (g) is independently selected from H, methyl, alkyl (eg, or C1-C6 alkyl (straight, branched, optionally substituted));

formula (g) represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific; And

Rn of formula (g) contains 1-4 independently selected functional groups, an optionally substituted alkoxy group (e.g., methoxy, ethoxy, butoxy, propoxy, pentoxy or hexoxy; wherein the alkoxy may be substituted with halogen, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (eg, C5-C7 aryl)), or atoms, and optionally one of which is modified to covalently attach to a PTM, a chemical linker group (L), ULM, CLM (or CLM'), or a combination thereof.

[0187] According to any of the embodiments W, X, Y, Z, G, G', R, R', R'', Q1-Q4, A and Rn of formulas (a) - (g) independently described in the present invention may be covalently attached to a linker and/or a linker to which one or more PTM, ULM, CLM or CLM' groups are attached.

[0188] More specifically, non-limiting examples of CLMs include those shown below, as well as those “hybrid” molecules that result from a combination of 1 or more different features shown in the molecules below.

[0189] In any of the compounds described in the present invention, the CLM contains a chemical structure selected from the group:

Where:

W of formulas (h)-(ab) is independently selected from CH ₂ , CHR, C=O, SO ₂ , NH and N-alkyl;

Q ₁ , Q ₂ , Q ₃ , Q ₄ , Q ₅ of formulas (h)-(ab) independently represent a C carbon substituted by a group independently selected from R', N or N-oxide;

R ¹ of formulas (h)-(ab) is selected from H, CN, C1-C3 alkyl;

R ² of formulas (h)-(ab) is selected from the group H, CN, C1-C3 alkyl, CHF ₂ , CF ₃ , CHO;

R ³ of formulas (h)-(ab) is selected from H, alkyl, substituted alkyl, alkoxy, substituted alkoxy;

R ⁴ of formulas (h)-(ab) is selected from H, alkyl, substituted alkyl;

R ⁵ of formulas (h)-(ab) represents H or lower alkyl;

X of formulas (h)-(ab) represents C, CH or N;

R' of formulas (h)-(ab) is selected from H, halogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy;

R of formulas (h)-(ab) is H, OH, lower alkyl, lower alkoxy, cyano, halogenated lower alkoxy or halogenated lower alkyl

formulas (h)-(ab) represents a single or double bond; And

CLM is covalently linked to PTM, a chemical linker group (L), ULM, CLM (or CLM'), or a combination thereof.

[0190] In any aspect or embodiment described herein, CLM or CLM' is covalently linked to a PTM, a chemical linker group (L), ULM, CLM, CLM', or a combination thereof via an R group (such as R, R ¹ , R ² , ^R3 , ^R4 or R'), W, X or Q group (such as _Q1 , _Q2 , _Q3 , _Q4 or _Q5 ) of formulas (h)-(ab).

[0191] In any of the embodiments described herein, CLM or CLM' is covalently linked to PTM, a chemical linker group (L), ULM, CLM, CLM', or a combination thereof via W, X, R, R ¹ , R ² . R ³ , R ⁴ , R ⁵ , R', Q ₁ , Q ₂ , Q ₃ , Q ₄ , and Q ₅ of formulas (h)-(ab).

[0192] According to any of the embodiments described in the present invention, the implementation of W, X, R ¹ , R ² , R ³ , R ⁴ , R', Q _{1, Q 2 ,} Q ₃ , Q ₄ and Q ₅ of formulas (h)- (ab) may be independently covalently attached to a linker and/or a linker to which one or more PTM, ULM, ULM', CLM or CLM' groups are attached.

[0193] More specifically, non-limiting examples of CLMs include those shown below, as well as those “hybrid” molecules or compounds that result from the combination of 1 or more features of the following compounds:

Where:

W of formulas (ac)-(an) is independently selected from the group of CH ₂ , CHR, C=O, SO ₂ , NH and N-alkyl;

R ¹ of formulas (ac)-(an) is selected from the group H, CN, C1-C3 alkyl;

R ³ of formulas (ac)-(an) is selected from H, alkyl, substituted alkyl, alkoxy, substituted alkoxy;

R of formulas (ac)-(an) represents H;

represents a single or double bond; And

Rn of formulas (ac)-(an) contains a functional group or atom.

[0194] According to any of the embodiments described in the present invention, W, R ¹ , R ² , Q ₁ , Q ₂ , Q ₃ , Q ₄ and Rn of formulas (ac)-(an) can independently be covalently attached to a linker and/ or a linker to which one or more PTM, ULM, ULM', CLM or CLM' groups are attached.

[0195] According to any of the embodiments described in the present invention, R ¹ , R ² , Q ₁ , Q ₂ , Q ₃ , Q ₄ and Rn of formulas (ac)-(an) can independently be covalently attached to a linker and/or linker , to which one or more RTM, ULM, ULM', CLM or CLM' groups are attached.

[0196] According to any of the embodiments described in the present invention, Q ₁ , Q ₂ , Q ₃ , Q ₄ and Rn of formulas (ac)-(an) can independently be covalently attached to a linker and/or a linker to which one or more several RTM, ULM, ULM', CLM or CLM' groups.

[0197] According to any aspect or embodiment described in the present invention, Rn of formulas (ac)-(an) is modified to covalently link to a linker group (L), PTM, ULM, a second CLM having the same chemical structure as the CLM, CLM', a second linker, or any many combinations thereof.

[0198] According to any aspect or embodiment described in the present invention, the CLM is selected from:

where R' represents halogen and R ¹ is described above in relation to formulas (h)-(ab) or (ac)-(an).

[0199] In some cases, CLM may be imides that bind to Cereblon E3 ligase. Such imides and linker attachment point may be, without limitation, the following structures:

where R' represents halogen.

[0200] Example VLMs

[0201] According to certain embodiments of the compounds as described in the present invention, the ULM is a VLM and contains the chemical structure of ULM-a:

Where:

the dotted line represents the attachment of at least one PTM, another ULM or VLM or MLM or ILM or CLM (i.e., ULM' or VLM' or CLM' or ILM' or MLM'), or a chemical linker moiety connecting at least one PTM, ULM' or VLM' or CLM' or ILM' or MLM' with the other end of the linker;

X ¹ , X ² of the ULM-a formula are each independently selected from the bond group, O, NR ^Y3 , CR ^Y3 R ^Y4 , C=O, OS, SO and SO ₂ ;

R ^Y3 , R ^Y4 of formula ULM-a are each independently selected from the group H, straight or branched C _1-6 alkyl, optionally substituted with 1 or more halogen atoms, optionally substituted C _1-6 alkoxy (e.g., optionally substituted with 0-3 RP groups );

R ^P of formula ULM-a represents 1, 2 or 3 groups, each independently selected from H, halogen, -OH, C _1-3 alkyl;

W ³ of formula ULM-a is selected from the group of optionally substituted, optionally substituted -TN(R ^1a R ^1b )X ³ , optionally substituted T-aryl, optionally substituted -T-heteroaryl, optionally substituted -T-heterocycle, optionally substituted -NR ¹ - T-aryl, optionally substituted -NR ¹ -T-heteroaryl or optionally substituted -NR ¹ -T-heterocycle;

X ³ of the formula ULM-a represents C=O, R ¹ , R ^1a , R ^1b ;

R ¹ , R ^1a , R ^1b are each independently selected from the group consisting of H, a straight or branched C ₁ -C ₆ alkyl group, optionally substituted with 1 or more halogen atoms or -OH groups, R ^Y3 C=O, R ^Y3 C =S, R ^Y3 SO, R ^Y3 SO ₂ , N(R ^Y3 R ^Y4 )C=O, N(R ^Y3 R ^Y4 )C=S, N(R ^Y3 R ^Y4 )SO and N(R ^Y3 R ^Y4 ) _SO2 ;

T of formula ULM-a is covalently bonded to X ¹ ;

W ⁴ of formula ULM-a is an optionally substituted -NR1-T-aryl, an optionally substituted -NR1-T-heteroaryl group, or an optionally substituted -NR1-T-heterocycle, wherein -NR ¹ is covalently bonded to X ² and R ¹ is H or CH3, preferably N.

[0202] In any of the embodiments described herein, T is selected from the group of an optionally substituted alkyl, -(CH ₂ ) _n- group, wherein each of the methylene groups is optionally substituted by one or two substituents selected from the group of halogen, methyl, straight-chain or a branched C ₁ -C ₆ alkyl group, optionally substituted with 1 or more halogen atoms or -OH groups or an amino acid side chain, optionally substituted; and n is 0 to 6, often 0, 1, 2 or 3, preferably 0 or 1.

[0203] In certain embodiments, W ⁴ of formula ULM-a is where R _14a , R _14b are each independently selected from the group H, haloalkyl or optionally substituted alkyl.

[0204] In any one of the embodiments, W ⁵ of formula ULM-a is selected from the group of phenyl or 5-10 membered heteroaryl,

R ₁₅ of formula ULM-a is selected from the group H, halogen, CN, OH, NO ₂ , NR _14a R _14b , OR _14a , CONR _14a R _14b , NR _14a COR _14b , SO ₂ NR _14a R _14b , NR _14a SO ₂ R _14b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy; aryl, heteroaryl, cycloalkyl or cycloheteroalkyl;

[0205] In additional embodiments, W ⁴ substituents for use in the present disclosure also specifically include (and without limitation to the specific compound disclosed) W ⁴ substituents that occur in the established compounds disclosed herein. Each of these W ⁴ substituents can be used in conjunction with any number of W ⁴ substituents, which are also disclosed in the present invention.

[0206] In certain additional embodiments, ULM-a is optionally substituted with 0-3 R ^P groups on the pyrrolidine moiety. Each R ^P is independently H, halogen, -OH, C1-3 alkyl, C=O.

[0207] In any of the embodiments described herein, W ³ , W ⁴ of formula ULM-a may independently be covalently attached to a linker that is attached to one or more PTM groups.

and wherein the dotted line denotes the attachment site of at least one PTM, another ULM (ULM'), or a chemical linker moiety connecting at least one PTM or ULM' or both to the ULM.

[0208] In certain embodiments, the ULM is a VHL and is represented by the structure:

ULM-b

Where:

W ³ of formula ULM-b is selected from the group of optionally substituted aryl, optionally substituted heteroaryl, or

R ₉ and R ₁₀ of formula ULM-b are independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl or haloalkyl, or R ₉ , R ₁₀ and the carbon atom to which they are attached form an optionally substituted cycloalkyl ; R ₁₁ of formula ULM-b is selected from the group of optionally substituted heterocyclic compound, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl, or

R ₁₂ of formula ULM-b is selected from the group H or optionally substituted alkyl;

R ₁₃ of formula ULM-b is selected from the group H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl;

R _14a , R _14b of formula ULM-b are each independently selected from the group H, haloalkyl or optionally substituted alkyl;

W ⁵ of formula ULM-b is selected from the group of phenyl or 5-10 membered heteroaryl,

R ₁₅ of formula ULM-b is selected from the group H, halogen, CN, OH, NO ₂ , NR _14a R _14b , OR _14a , CONR _14a R _14b , NR _14a COR _14b , SO ₂ NR _14a R _14b , NR _14a SO ₂ R _14b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy; aryl, heteroaryl, cycloalkyl or cycloheteroalkyl (each optionally substituted);

R ₁₆ of formula ULM-b is independently selected from the group of halogen, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy or optionally substituted haloalkoxy;

o of the formula ULM-b is 0, 1, 2, 3 or 4;

R ₁₈ of formula ULM-b is independently selected from the group H, halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy or a linker; And

p of formula ULM-b is 0, 1, 2, 3 or 4, and wherein the dotted line represents the attachment site of at least one PTM, another ULM (ULM'), or a chemical linker moiety connecting at least one PTM or ULM' or both with ULM.

[0209] In certain embodiments, R ₁₅ of formula ULM-b is where R ₁₇ represents H, halogen, optionally substituted C _3-6 cycloalkyl, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 alkenyl and C _1-6 haloalkyl and Xa represents S or O.

[0210] In certain embodiments, R ₁₇ of formula ULM-b is selected from the group of methyl, ethyl, isopropyl, and cyclopropyl.

[0211] In certain additional embodiments, R ₁₅ of formula ULM-b is selected from the group consisting of:

[0212] In certain embodiments, R ₁₁ of formula ULM-b is selected from the group consisting of:

[0213] In certain embodiments, the ULM is characterized by a chemical structure selected from the group:

Where:

R ₁ of formulas ULM-c, ULM-d and ULM-e is H, ethyl, isopropyl, t-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; optionally substituted alkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl or haloalkyl;

R _14a of formulas ULM-c, ULM-d and ULM-e is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl or cyclopropyl;

R ₁₅ of formulas ULM-c, ULM-d and ULM-e is selected from the group consisting of H, halogen, CN, OH, NO ₂ , optionally substituted heteroaryl, optionally substituted aryl; optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, cycloalkyl or cycloheteroalkyl;

X of formulas ULM-c, ULM-d and ULM-e is C, CH ₂ or C=O

R ₃ of formulas ULM-c, ULM-d and ULM-e is absent or represents a bond or an optionally substituted 5- or 6-membered heteroaryl; And

wherein the dotted line denotes the attachment site of at least one PTM, another ULM (ULM'), or a chemical linker moiety connecting at least one PTM or ULM' or both to the ULM.

[0214] In certain embodiments, the ULM comprises a chemical structure group:

Where:

R _14a of formula ULM-f is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl or cyclopropyl;

R ₉ of formula ULM-f is H;

R ₁₀ of formula ULM-f is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

R ₁₁ of the formula ULM-f is

or optionally substituted heteroaryl;

p of formula ULM-f is 0, 1, 2, 3 or 4;

each R ₁₈ of formula ULM-f independently represents halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy or a linker;

R ₁₂ of the formula ULM-f represents H, C=O;

R ₁₃ of formula ULM-f is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl or optionally substituted aralkyl,

R ₁₅ of formula ULM-f is selected from the group consisting of H, halogen, Cl, CN, OH, NO ₂ , optionally substituted heteroaryl, optionally substituted aryl;

wherein the dotted line of formula ULM-f denotes the attachment site of at least one PTM, another ULM (ULM'), or a chemical linker moiety connecting at least one PTM or ULM' or both to the ULM.

[0215] In certain embodiments, the ULM is selected from the following structures:

where n represents 0 or 1.

[0216] In certain embodiments, the ULM is selected from the following structures:

wherein the phenyl ring in ULM-a1-ULM-a15, ULM-b1-ULM-b12, ULM-c1-ULM-c15 and ULM-d1-ULM-d9 is optionally substituted with fluorine, lower alkyl and alkoxy groups and where the dotted line represents the site of attachment at least one PTM, another ULM (ULM'), or a chemical linker moiety connecting at least one PTM or ULM' or both to ULM-a.

[0217] In one embodiment, the phenyl ring in ULM-a1-ULM-a15, ULM-b1-ULM-b12, ULM-c1-ULM-c15, and ULM-d1-ULM-d9 may be ester functionalized to make it part of a prodrug.

[0218] In certain embodiments, the hydroxyl group on the pyrrolidine ring of ULM-a1-ULM-a15, ULM-b1-ULM-b12, ULM-c1-ULM-c15, and ULM-d1-ULM-d9, respectively, contains an associated complex ether prodrug moiety.

[0219] According to any of the aspects or embodiments of the ULM described herein, and if present, the ULM' is each independently a group of chemical structure:

Where:

R ^1' ULM-g represents an optionally substituted C ₁ -C ₆ alkyl group, optionally substituted -(CH ₂ ) _n OH, optionally substituted -(CH ₂ ) _n SH, optionally substituted (CH ₂ ) _n -O-(C ₁ -C ₆ )alkyl group, optionally substituted (CH ₂ ) _n -WCOCW-(C ₀ -C ₆ )alkyl group containing a WCOCW epoxy moiety, wherein each W independently represents an H or a C ₁ -C ₃ alkyl group, optionally substituted

-(CH ₂ ) _n COOH, optionally substituted -(CH ₂ ) _n C(O)-(C ₁ -C ₆ alkyl), optionally substituted -(CH ₂ ) _n NHC(O)-R ₁ , optionally substituted -( CH ₂ ) _n C(O)-NR ₁ R ₂ , optionally substituted -(CH ₂ ) _n OC(O)-NR ₁ R ₂ , -(CH ₂ O) _n H, optionally substituted -(CH ₂ ) _n OC (O)-(C ₁ -C ₆ alkyl), optionally substituted -(CH ₂ ) _n C(O)-O-(C ₁ -C ₆ alkyl), optionally substituted -(CH ₂ O) _n COOH, optionally substituted -(OCH ₂ ) _n O-(C ₁ -C ₆ alkyl), optionally substituted -(CH ₂ O) _n C(O)-(C ₁ -C ₆ alkyl), optionally substituted -(OCH ₂ ) _n NHC( O)-R ₁ , optionally substituted -(CH ₂ O) _n C(O)-NR ₁ R ₂ , -(CH ₂ CH ₂ O) _n H, optionally substituted -(CH ₂ CH ₂ O) _n COOH, optional substituted -(OSH ₂ CH ₂ ) _n O-(C ₁ -C ₆ alkyl), optionally substituted -(CH ₂ CH ₂ O) _n C(O)-(C ₁ -C ₆ alkyl), optionally substituted -(OCH ₂ CH ₂ ) _n NHC(O)-R ₁ , optionally substituted -(CH ₂ CH ₂ O) _n C(O)-NR ₁ R ₂ , optionally substituted -SO ₂ R _S , optionally substituted S(O)R _S , NO ₂ , CN or halogen (F, Cl, Br, I, preferably F or Cl);

R ₁ and R ₂ ULM-g each independently represent an H or C ₁ -C ₆ alkyl group, which may be optionally substituted with one or two hydroxyl groups or up to three halogen groups (preferably fluorine);

R _S ULM-g represents a C ₁ -C ₆ alkyl group, an optionally substituted aryl, heteroaryl or heterocyclic group or a -(CH ₂ ) _m NR ₁ R ₂ group;

X and X' ULM-g are each independently C=O, C=S, -S(O), S(O) ₂ (preferably X and X' are both C=O);

R ^2' ULM-g represents an optionally substituted -(CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ ) _w alkyl group, optionally substituted -(CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ ) _w NR _1N R _2N group, optionally substituted -(CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ ) _w - aryl, optionally substituted -(CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ ) _w -heteroaryl, optionally substituted -(CH ₂ ) _n -(C=O) _v NR ₁ (SO ₂ ) _w -heterocycle, optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -alkyl, optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -NR _1N R _2N optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -NR ₁ C(O)R _1N , optionally substituted - NR ¹ -(CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ ) _w -aryl, optionally substituted -NR ¹ -(CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ ) _w -heteroaryl or optionally substituted -NR ¹ -(CH ₂ ) _n -(C=O) _v NR ₁ (SO ₂ ) _w -heterocycle, optionally substituted -X ^R2' -alkyl group; an optionally substituted -X ^R2' -aryl group; an optionally substituted -X ^R2' -heteroaryl group; an optionally substituted -X ^R2' -heterocyclic group; optionally substituted;

R ^3' ULM-a is optionally substituted alkyl, optionally substituted -(CH ₂ ) _n -(O) _u (NR ₁ ) _v (SO ₂ ) _w -alkyl, optionally substituted -(CH ₂ ) _n -C(O ) _u (NR ₁ ) _v (SO ₂ ) _w -NR _1N R _2N , optionally substituted -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -NR ₁ C(O)R _1N , optionally substituted -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -C(O)NR ₁ R ₂ , optionally substituted -(CH ₂ ) _n -C(O) _u (NR _i ) _v (SO ₂ ) _w -aryl, optionally substituted -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -heteroaryl, optionally substituted -(CH ₂ ) _n -C (O) _u (NR ₁ ) _v (SO ₂ ) _w -heterocycle, optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -alkyl, optionally substituted - NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -NR _1N R _2N , optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -NR ₁ C(O)R _1N , optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -aryl, optionally substituted - NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -heteroaryl, optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v ( SO ₂ ) _w -heterocycle, optionally substituted -O-(CH ₂ )n-(C=O) _u (NR ₁ ) _v (SO ₂ ) _w -alkyl, optionally substituted -O-(CH ₂ )n-(C =O) _u (NR ₁ ) _v (SO ₂ ) _w -NR _1N R _2N , optionally substituted -O-(CH ₂ )n-(C=O) _u (NR ₁ ) _v (SO ₂ ) _w -NR ₁ C(O)R _1N , optionally substituted -O-(CH ₂ )n-(C=O) _u (NR ₁ ) _v (SO ₂ ) _w -aryl, optionally substituted -O-(CH ₂ ) _n -(C =O) _u (NR ₁ ) _v (SO ₂ ) _w -heteroaryl or optionally substituted -O-(CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ ) _w -heterocycle; -(CH ₂ ) _n -(V) _n' -(CH ₂ ) _n -(V) _n' -alkyl group, optionally substituted -(CH ₂ ) _n -(V) _n' -(CH ₂ ) _n -( V) _n' -aryl group, optionally substituted -(CH ₂ ) _n -(V) _n' -(CH ₂ ) _n -(V) _n' -heteroaryl group, optionally substituted -(CH ₂ ) _n -(V) _n' -(CH ₂ ) _n -(V) _n' -heterocyclic group, optionally substituted -(CH ₂ ) _n -N(R _1' )(C=O) _m' -(V) _n' -alkyl group, optionally substituted -(CH ₂ ) _n -N(R _1' )(C=O) _m' -(V) _n' -aryl group, optionally substituted -(CH ₂ ) _n -N(R _1' )(C= O) _m' -(V) _n' -heteroaryl group, optionally substituted -(CH ₂ ) _n -N(R _1' )(C=O) _m' -(V) _n' -heterocyclic group, optionally substituted -X ^R3' is an alkyl group; an optionally substituted -X ^R3' -aryl group; an optionally substituted -X ^R3' -heteroaryl group; an optionally substituted -X ^R3' heterocyclic group; optionally substituted;

R _1N and R _2N ULM-g are each independently H, C ₁ -C ₆ alkyl, which is optionally substituted with one or two hydroxyl groups and up to three halogen groups, or optionally substituted -(CH ₂ ) _n -aryl, - (CH ₂ ) _n -heteroaryl or -(CH ₂ ) _n -heterocyclic group;

V ULM-g is O, S or NR ₁ ;

R ₁ ULM-g is the same as defined above;

R ¹ and R _1' ULM-g each independently represent an H or a C ₁ -C ₃ alkyl group;

X ^R2' and X ^R3' ULM-g are each independently optionally substituted -CH ₂ ) _n -, -CH ₂ ) _n -CH(X _v )=CH(X _v )- (cis or trans), -CH ₂ ) _n -CH≡CH-, -(CH ₂ CH ₂ O) _n - or a C ₃ -C ₆ cycloalkyl group, where X _v represents H, halogen or a C ₁ -C ₃ alkyl group, which is optionally substituted;

each m ULM-g independently represents 0, 1, 2, 3, 4, 5, 6;

each m' ULM-g is independently 0 or 1;

each n ULM-g independently represents 0, 1, 2, 3, 4, 5, 6;

each n' ULM-g is independently 0 or 1;

each u ULM-g is independently 0 or 1;

each v ULM-g is independently 0 or 1;

each w ULM-g is independently 0 or 1; And

any one or more of R ^1' , R ^2' , R ^3' , X and X' of ULM-g is optionally modified to covalently link to a PTM group via a linker group, where PTM is not ULM', or if PTM is ULM', any one or more of R ^1' , R ^2' , R ^3' , X and X' each of ULM and ULM' are optionally modified to covalently link together directly or via a linker group, or a pharmaceutically acceptable salt thereof , stereoisomer, solvate or polymorph.

[0220] According to any of the aspects or embodiments of the ULMs described herein, and if present, the ULMs' are each independently a group of chemical structure:

Where:

each of R ^1' , R ^2' and R ^3' ULM-h is the same as defined above, and X represents a C=O, C=S, -S(O) group or an S(O) ₂ group, more preferably a C=O group, and any one or more of R ^1' and R ^3' ULM-h are optionally modified to link the linker group to which they are further covalently attached to a PTM group if the PTM is not ULM' or if PTM is a ULM', any one or more of R ^1' , R ^2' and R ^3' of each ULM and ULM' are optionally modified to covalently link to each other directly or via a linker group, or

or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate or polymorph thereof.

[0221] According to any of the aspects or embodiments of the ULM described in the present invention, and if present, the ULM' each independently represents the chemical structure:

Where:

any one or more R ^1' , R ^2' and R ^3' of ULM-I are optionally modified to link the linker group to which they are further covalently linked to a PTM group, wherein the PTM is not a ULM' or where the PTM is a ULM' any one or more R ^1' , R ^2' and R ^3' each ULM and ULM' are optionally modified to covalently link to each other directly or via a linker group, or

a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate or polymorph thereof.

[0222] According to further preferred aspects of the present disclosure, R ^1' ULM-g - ULM-i preferably represents a hydroxyl group or a group that can be metabolized to a hydroxyl or carboxyl group, such that the compound is a prodrug of the active compound. Exemplary preferred R ^1' groups include, for example, -(CH ₂ ) _n OH, (CH ₂ ) _n -O-(C ₁ -C ₆ )alkyl group, -(CH ₂ ) _n COOH, - (CH ₂ O) _n H, optionally substituted -(CH ₂ ) _n OC(O)-(C ₁ -C ₆ alkyl) or optionally substituted -(CH ₂ ) _n C(O)-O-(C ₁ -C ₆ alkyl), where n is 0 or 1. If R ^1' is or contains a carboxylic acid group, a hydroxyl group, or an amine group, the hydroxyl group, carboxylic acid group, or amine (each of which may be optionally substituted) may optionally be chemically modified to form a covalent bond with a linker group to which a PTM group (including a ULM' group) is linked;

[0223] X and X', if present, ULM-g and ULM-h preferably represent a C=O, C=S, -S(O) group or an S(O) ₂ group, more preferably a C=O group;

[0224] R ^2' ULM-g - ULM-i is preferably an optionally substituted -NR ¹ -T-aryl, an optionally substituted -NR ¹ -T-heteroaryl group, or an optionally substituted -NR ¹ -T-heterocycle, wherein R ¹ is H or CH ₃ , preferably H and T is an optionally substituted -(CH ₂ ) _n - group, wherein each of the methylene groups may be optionally substituted with one or two substituents, preferably selected from halogen, an amino acid side chain, or otherwise described in the present invention, or a C ₁ -C ₃ alkyl group, preferably one or two methyl groups, which may be optionally substituted; and n is 0 to 6 (eg 0, 1, 2 or 3, eg 0 or 1). Alternatively, T may also be a -(CH ₂ O) _n group, -(OCH ₂ ) _n group, -(CH ₂ CH ₂ O) _n group, -(OCH ₂ CH ₂ ) _n group, all of these groups are optionally substituted.

[0225] Preferred aryl groups for R ^2' ULM-g - ULM-i include optionally substituted phenyl or naphthyl groups, preferably phenyl groups, wherein the phenyl or naphthyl group is optionally connected to the PTM group by a linker group to which the PTM is attached group (including ULM' group), halogen (preferably F or Cl), amine, monoalkyl or dialkylamine (preferably dimethylamine), F, Cl, OH, COOH, C ₁ -C ₆ alkyl, preferably CH ₃ , CF ₃ , OMe, OCF ₃ , NO ₂ or CN group (each of which may be substituted at the ortho, meta and/or para positions of the phenyl ring, preferably para), an optionally substituted phenyl group (the phenyl group itself is optionally connected to the PTM using a linker group, including a ULM' group), and/or at least one of F, Cl, OH, COOH, CH ₃ , CF ₃ , OMe, OCF ₃ , NO ₂ or CN groups (in ortho-, meta- and/or para-positions of the phenyl ring, preferably para-), naphthyl group, which may be optionally substituted, optionally substituted heteroaryl, preferably optionally substituted isoxazole, including methyl-substituted isoxazole, optionally substituted oxazole, including methyl-substituted oxazole, optionally substituted thiazole, including methyl-substituted thiazole, optionally substituted isothiazole, including methyl-substituted isothiazole, optionally substituted pyrrole, including methyl-substituted pyrrole, optionally substituted imidazole, including methylimidazole, optionally substituted benzimidazole or methoxybenzylimidazole, optionally substituted oximidazole or methyloximidazole, optionally substituted diazole group, including methyl diazole azole group, optionally substituted triazole group including a methyl-substituted triazole group, an optionally substituted pyridine group, including a halo (preferably F) or methyl-substituted pyridine group or an oxapyridine group (where the pyridine group is connected to the phenyl group by oxygen), optionally substituted furan, optionally substituted benzofuran, optionally substituted dihydrobenzofuran, optionally substituted indole, indolizine or azaindolizine (2, 3 or 4-azaindolizine), optionally substituted quinoline, optionally substituted group of chemical structure:

Where:

S ^C ULM-g - ULM-i is CHR ^SS , NR ^URE or O;

R ^HET ULM-g - ULM-i is H, CN, NO ₂ , halogen (preferably Cl or F), optionally substituted C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (eg CF ₃ ), an optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or an optionally substituted acetylene group -C≡CR _a where R _a is H or C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl);

R ^SS ULM-g - ULM-i is H, CN, NO ₂ , halogen (preferably F or Cl), optionally substituted C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups ), optionally substituted O-(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or optionally substituted -C(O)(C ₁ -C ₆ alkyl) (preferably substituted one or two hydroxyl groups or up to three halogen groups);

R ^URE ULM-g - ULM-i is H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl) or -C(O)(C ₁ -C ₆ alkyl), each group optionally substituted one or two hydroxyl groups or up to three halogen atoms, preferably fluorine containing groups or an optionally substituted phenyl group, an optionally substituted heteroaryl or an optionally substituted heterocycle, preferably for example piperidine, morpholine, pyrrolidine, tetrahydrofuran);

R ^PRO ULM-g - ULM-i represents H, optionally substituted C ₁ -C ₆ alkyl or optionally substituted aryl (phenyl or naphthyl), heteroaryl or heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C ₁ -C ₃ alkyl group, preferably a methyl or halogen group, preferably F or Cl), benzofuran, indole, indolysine, azaindolysine;

R ^PRO1 and R ^PRO2 ULM-g - ULM-i each independently represent an H, optionally substituted C ₁ -C ₃ alkyl group or together form a keto group; And

each n ULM-g - ULM-i independently represents 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1) or an optionally substituted heterocycle, preferably tetrahydrofuran, tetrahydrothiene, piperidine, piperazine or morpholine (each of the groups , if substituted, preferably substituted with methyl or halogen (F, Br, Cl), each of the groups may optionally be connected to a PTM group (including a ULM' group) by a linker group.

[0226] According to certain preferred aspects ULM-g - ULM-i is group,

where R ^PRO and n ULM-g - ULM-i are the same as above.

[0227] Preferred heteroaryl groups for R ^2' ULM-g - ULM-i include optionally substituted quinoline (which may be attached to a pharmacophore or substituted at any carbon atom within the quinoline ring), optionally substituted indole, optionally substituted indolizine, optionally substituted azaindolysine, optionally substituted benzofuran, including optionally substituted benzofuran, optionally substituted isoxazole, optionally substituted thiazole, optionally substituted isothiazole, optionally substituted thiophene, optionally substituted pyridine (2-, 3 or 4-pyridine), optionally substituted imidazole, optionally substituted pyrrole , an optionally substituted diazole, an optionally substituted triazole, a tetrazole, an optionally substituted oximidazole, or a group of the chemical structure:

Where:

S ^C ULM-g - ULM-i is CHR ^SS , NR ^URE or O;

R ^HET ULM-g - ULM-i is H, CN, NO ₂ , halogen (preferably Cl or F), optionally substituted C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (eg CF ₃ ), an optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or an optionally substituted acetylene group -C≡CR _a where R _a ULM- g - ULM-i is H or a C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl); R ^SS ULM-g - ULM-i is H, CN, NO ₂ , halogen (preferably F or Cl ), optionally substituted C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups), optionally substituted O-(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or halogen groups up to three) or optionally substituted -C(O)(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or halogen groups up to three);

R ^URE ULM-g - ULM-i is H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl) or -C(O)(C ₁ -C ₆ alkyl), each of these groups optional substituted with one or two hydroxyl groups or up to three halogen atoms, preferably fluorine groups, or an optionally substituted heterocycle, for example piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted, and

Y ^C ULM-g - ULM-i is N or CR ^YC , where R ^YC is H, OH, CN, NO ₂ , halogen (preferably Cl or F), optionally substituted C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (for example, CF ₃ )), optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or optionally a substituted acetylene group-C≡CR _a , where R _a represents H or a C ₁ -C ₆ alkyl group (preferably a C ₁ -C ₃ alkyl), each of these groups may optionally be connected to a PTM group (including a ULM' group) using a linker group.

[0228] Preferred heterocyclic groups for R ^2' ULM-g - ULM-i include tetrahydrofuran, tetrahydrothiene, tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, ocean or thiane, each of these groups may be optionally substituted or a chemical structure group :

preferably group,

Where:

R ^PRO ULM-g - ULM-i represents H, an optionally substituted C ₁ -C ₆ alkyl or an optionally substituted aryl, heteroaryl or heterocyclic group;

R ^PRO1 and R ^PRO2 ULM-g - ULM-i each independently represent an H, optionally substituted C ₁ -C ₃ alkyl group or together form a keto group, and

Each n ULM-g - ULM-i is independently 0, 1, 2, 3, 4, 5 or 6 (often 0 or 1), each of the groups may optionally be connected to a PTM group (including the ULM' group) by linker group.

[0229] Preferred R ^2' substituents ULM-g - ULM-i also specifically include (and without limitation to the specific compound disclosed) R ^2' substituents that occur in the identified compounds disclosed herein (which include specific compounds which are disclosed in this application and in the accompanying figures). Each of these R ^2' substituents can be used in conjunction with any number of R ^3' substituents, which are also disclosed in the present invention.

[0230] R ^3' ULM-g - ULM-i - is preferably optionally substituted -T-aryl, optionally substituted-T-heteroaryl, optionally substituted -T-heterocycle, optionally substituted -NR ¹ -T-aryl, optionally substituted -NR ¹ -T-heteroaryl or optionally substituted -NR ¹ -T-heterocycle. In a preferred embodiment, R ¹ is H or a C ₁ -C ₃ alkyl group, preferably H or CH ₃ , T is an optionally substituted -(CH ₂ ) _n group, wherein each of the methylene groups may be optionally substituted by one or two substituents preferably selected from halogen, a C ₁ -C ₆ alkyl group (straight-chain, branched, optionally substituted) or an amino acid side chain as otherwise described in the present invention, preferably methyl, which may be optionally substituted; and n is 0 to 6, such as 0, 1, 2 or 3 (eg, 0 or 1). Alternatively, T may also be a -(CH ₂ O) _n group, -(OSH ₂ ) _n group, -(CH ₂ CH ₂ O) _n group, (OSH ₂ CH ₂ ) _n group, each of these groups is optionally substituted.

[0231] Preferred aryl groups for R ^3' ULM-g - ULM-i include optionally substituted phenyl or naphthyl groups, preferably phenyl groups, wherein the phenyl or naphthyl group is optionally connected to the PTM group (including the ULM' group) via a linker group and/or a halogen (preferably F or Cl), an amine, a monoalkyl or dialkylamine (preferably a dimethylamine), an amido group (preferably a (CH ₂ ) _m -NR ₁ C(O)R ₂ group, where m, R ₁ and R ₂ are the same as above), halogen (often F or Cl), OH, CH ₃ , CF ₃ , OMe, OCF ₃ , NO ₂ , CN or S(O) _{2 RS} group ( _RS is C _{a 1} -C ₆ alkyl group, an optionally substituted aryl, heteroaryl or heterocyclic group or a -(CH ₂ ) _m NR ₁ R ₂ group, each of which may be substituted at the ortho, meta and/or para positions of the phenyl ring, preferably para-) or aryl (preferably phenyl), heteroaryl or heterocycle. Preferably, said substituted phenyl group is an optionally substituted phenyl group (i.e., the substituted phenyl group itself is preferably substituted by at least one of F, Cl, OH, SH, COOH, CH ₃ , CF ₃ , OMe, OCF ₃ , NO ₂ , CN or a linker group to which a PTM group (including a ULM' group) is attached, the substitution occurring at the ortho, met and/or para positions of the phenyl ring, preferably para), a naphthyl group, which may be optionally substituted, including as described above, optionally substituted heteroaryl (preferably optionally substituted isoxazole, including methyl substituted isoxazole, optionally substituted oxazole, including methyl substituted oxazole, optionally substituted thiazole, including methyl substituted thiazole, optionally substituted pyrrole, including methyl substituted pyrrole, optionally substituted imida ash, including methylimidazole , бензилимидазол или метоксибензилимидазол, оксимидазол или метилоксимидазол), необязательно замещенной диазольной группой, включая метилдиазольную группу, необязательно замещенной триазольной группой, включая метилзамещенную триазольную группу, пиридиновой группой, включая галоген- (предпочтительно F) или метилзамещенную пиридиновую группу, или оксапиридиновой группой (где пиридиновая group is connected to the phenyl group by oxygen) or an optionally substituted heterocycle (tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, morpholine, piperazine, tetrahydroquinoline, ocean or thiane). Each of the aryl, heteroaryl or heterocyclic groups may optionally be connected to a PTM group (including a ULM' group) via a linker group.

[0232] Preferred heteroaryl groups for R ^3' ULM-g - ULM-i include optionally substituted quinoline (which may be attached to a pharmacophore or substituted at any carbon atom on the quinoline ring), optionally substituted indole (including dihydroindole), optionally Subscribed indolizin, not necessarily replaced by azaldolysis (2, 3 or 4 azindolisine), optionally substituted gasymidazole, benzodiazole, benzofuran, optionally substituted imidazole, optionally substituted Isoxazole, optionally replaced oxazole (preferably methyl-membrane), not mandatory diaazole, not necessarily noticeable triasol, teterazol. , optionally substituted benzofuran, optionally substituted thiophene, optionally substituted thiazole (preferably methyl and/or thiol substituted), optionally substituted isothiazole, optionally substituted triazole (preferably 1,2,3-triazole substituted with a methyl group, triisopropylsilyl group, optionally substituted -(CH ₂ ) _m -OC ₁ -C ₆ alkyl group or optionally substituted -(CH ₂ ) _m -C(O)-O-C ₁ -C ₆ alkyl group), optionally substituted pyridine (2-, 3 or 4-pyridine) or chemical structure group:

Where:

S ^C ULM-g - ULM-i is CHR ^SS , NR ^URE or O;

R ^HET ULM-g - ULM-i is H, CN, NO ₂ , halogen (preferably Cl or F), optionally substituted C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (eg CF ₃ ), an optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or an optionally substituted acetylene group -C≡CR _a where R _a is H or C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl);

R ^SS ULM-g - ULM-i is H, CN, NO ₂ , halogen (preferably F or Cl), optionally substituted C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups ), optionally substituted O-(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or optionally substituted -C(O)(C ₁ -C ₆ alkyl) (preferably substituted one or two hydroxyl groups or up to three halogen groups);

R ^URE ULM-g - ULM-i is H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl) or -C(O)(C ₁ -C ₆ alkyl), each of such groups optional substituted with one or two hydroxyl groups or up to three halogen atoms, preferably with fluorine groups, or an optionally substituted heterocycle, for example piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted, and

Y ^C - ULM-g - ULM-i is N or CR ^YC , where R ^YC is H, OH, CN, NO ₂ , halogen (preferably Cl or F), optionally substituted C ₁ -C ₆ alkyl (preferably substituted one or two hydroxyl groups or up to three halogen groups (eg CF ₃ ), optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or optionally substituted an acetylene group -C≡CR _a , where R _a represents H or a C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl).Each of these heteroaryl groups may optionally be connected to a PTM group (including a ULM' group) using a linker group.

[0233] Preferred heterocyclic groups for R ^3' ULM-g - ULM-i include tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, tetrahydrofuran, tetrahydrothiophene, ocean and thiane, each of such groups may be optionally substituted or a chemical structure group :

preferably or group,

Where:

R ^PRO ULM-g - ULM-i represents H, optionally substituted C ₁ -C ₆ alkyl or optionally substituted aryl (phenyl or naphthyl), heteroaryl or heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C ₁ -C ₃ alkyl group, preferably a methyl or halogen group, preferably F or Cl), benzofuran, indole, indolysine, azaindolysine;

R ^PRO1 and R ^PRO2 ULM-g - ULM-i each independently represent an H, optionally substituted C ₁ -C ₃ alkyl group or together form a keto group, and

each n ULM-g - ULM-i is 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1), each of said heterocyclic groups optionally being connected to a PTM group (including a ULM' group) using a linker group.

[0234] Preferred R ^3' substituents ULM-g - ULM-i also specifically include (and without limitation to the specific compound disclosed) R ^3' substituents that occur in the identified compounds disclosed herein (which include specific compounds which are disclosed in this application and in the accompanying figures). Each of these R ^3' substituents can be used in conjunction with any number of R ^2' substituents, which are also disclosed in the present invention.

[0235] In certain alternative preferred embodiments, R ^2' ULM-g - ULM-i is an optionally substituted -NR ₁ -X ^R2' alkyl group, -NR ₁ -X ^R2' aryl group; optionally substituted -NR ₁ -X ^R2' -NO, optionally substituted -NR ₁ -X ^R2' -aryl-NO or optionally substituted -NR ₁ -X ^R2' -NO-aryl,

Where:

R ₁ ULM-g - ULM-i represents H or a C ₁ -C ₃ alkyl group (preferably H);

X ^R2' ULM-g - ULM-i is optionally substituted -CH ₂ ) _n -, -CH ₂ ) _n - CH(X _v )=CH(X _v )- (cis or trans), -(CH ₂ ) _n -CH≡CH-, -(CH ₂ CH ₂ O) _n - or C ₃ -C ₆ cycloalkyl group; And

X _v ULM-g - ULM-i represents H, halogen or a C ₁ -C ₃ alkyl group, which is optionally substituted with one or two hydroxyl groups or up to three halogen groups;

Alkyl ULM-g - ULM-i is an optionally substituted C1- _C10 alkyl (preferably _C1 - _C6 alkyl) group (in certain preferred embodiments, the alkyl group is terminated by a halogen group, often Cl or Br);

Aryl ULM-g - ULM-i is an optionally substituted phenyl or naphthyl group (preferably a phenyl group); And

NO ULM-g - ULM-i is an optionally substituted oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, benzofuran, indole, indolizine, azaindolizine, quinoline (if substituted, each is preferably substituted with a C ₁ -C ₃ alkyl group, preferably a methyl or halogen group, preferably F or Cl) or a group of chemical structure:

S ^c ULM-g - ULM-i is CHR ^SS , NR ^URE or O;

R ^HET ULM-g - ULM-i is H, CN, NO ₂ , halogen (preferably Cl or F), optionally substituted C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (eg CF ₃ ), an optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or an optionally substituted acetylene group -C≡CR _a where R _a is H or C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl);

R ^SS ULM-g - ULM-i is H, CN, NO ₂ , halogen (preferably F or Cl), optionally substituted C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups ), optionally substituted O-(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or optionally substituted -C(O)(C ₁ -C ₆ alkyl) (preferably substituted one or two hydroxyl groups or up to three halogen groups);

R ^URE ULM-g - ULM-i is H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl) or -C(O)(C ₁ -C ₆ alkyl), each of such groups optional substituted with one or two hydroxyl groups or up to three halogen groups, preferably fluorine groups, or an optionally substituted heterocycle, for example piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted;

Y ^C ULM-g - ULM-i is N or CR ^YC , where R ^YC is H, OH, CN, NO ₂ , halogen (preferably Cl or F), optionally substituted C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (eg CF ₃ ), optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or optionally substituted acetylene group -C≡CR _a , where R _a represents H or a C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl);

R ^PRO ULM-g - ULM-i represents H, optionally substituted C ₁ -C ₆ alkyl or optionally substituted aryl (phenyl or naphthyl), heteroaryl or heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C ₁ -C ₃ alkyl group, preferably a methyl or halogen group, preferably F or Cl), benzofuran, indole, indolysine, azaindolysine;

R ^PRO1 and R ^PRO2 ULM-g - ULM-i each independently represent an H, optionally substituted C ₁ -C ₃ alkyl group or together form a keto group, and

each n ULM-g - ULM-i is independently 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1).

[0236] Each of these groups may optionally be connected to a PTM group (including a ULM' group) via a linker group.

[0237] According to certain alternative embodiments of the present disclosure, R ^3' ULM-g - ULM-i is an optionally substituted -(CH ₂ ) _n -(V) _n' -(CH ₂ ) _n -(V) _n' -R ^S3' group, optionally substituted -(CH ₂ ) _n -N(R _1' )(C=O) _m' -(V) _n' -R ^S3' group, optionally substituted -X ^R3' -alkyl group, optionally substituted -X ^R3' -aryl group; an optionally substituted -X ^R3' -NO group, an optionally substituted -X ^R3' -aryl-NO group or an optionally substituted -X ^R3' -NO-aryl group,

Where:

R ^S3' represents an optionally substituted alkyl group (C ₁ -C ₁₀ , preferably C ₁ -C ₆ alkyl), an optionally substituted aryl group or a NO group;

R _1' represents H or a C ₁ -C ₃ alkyl group (preferably H);

V represents O, S or NR _1' ;

X ^R3' represents -(CH ₂ ) _n -, -(CH ₂ CH ₂ O) _n -, -CH ₂ ) _n -CH(X _v )=CH(X _v )- (cis- or trans-), -CH ₂ ) _n -CH≡CH- or C ₃ -C ₆ cycloalkyl group, all optionally substituted;

X _v represents H, halogen or a C ₁ -C ₃ alkyl group, which is optionally substituted with one or two hydroxyl groups or up to three halogen groups;

Alkyl is an optionally substituted C ₁ -C ₁₀ alkyl (preferably C ₁ -C ₆ alkyl) group (in certain preferred embodiments, the alkyl group is terminated by a halogen group, often Cl or Br);

Aryl represents an optionally substituted phenyl or naphthyl group (preferably a phenyl group); And

NO represents an optionally substituted oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, benzofuran, indole, indolizine, azaindolizine , quinoline (if substituted, each is preferably substituted with a C ₁ -C ₃ alkyl group, preferably a methyl or halogen group, preferably F or Cl) or a group of the chemical structure:

S ^c ULM-g - ULM-i is CHR ^SS , NR ^URE or O;

R ^HET ULM-g - ULM-i is H, CN, NO ₂ , halogen (preferably Cl or F), optionally substituted C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (eg CF ₃ ), an optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or an optionally substituted acetylene group -C≡CR _a where R _a is H or C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl);

R ^SS ULM-g - ULM-i is H, CN, NO ₂ , halogen (preferably F or Cl), optionally substituted C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups ), optionally substituted O-(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or optionally substituted -C(O)(C ₁ -C ₆ alkyl) (preferably substituted one or two hydroxyl groups or up to three halogen groups);

R ^URE ULM-g - ULM-i is H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl) or -C(O)(C ₀ -C ₆ alkyl), each of such groups optional substituted with one or two hydroxyl groups or up to three halogen groups, preferably fluorine groups, or an optionally substituted heterocycle, for example piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted;

Y ^C ULM-g - ULM-i is N or CR ^YC , where R ^YC is H, OH, CN, NO ₂ , halogen (preferably Cl or F), optionally substituted C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (eg CF ₃ ), optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or optionally substituted acetylene group -C≡CR _a , where R _a represents H or a C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl);

R ^PRO ULM-g - ULM-i represents H, optionally substituted C ₁ -C ₆ alkyl or optionally substituted aryl (phenyl or naphthyl), heteroaryl or heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C ₁ -C ₃ alkyl group, preferably a methyl or halogen group, preferably F or Cl), benzofuran, indole, indolysine, azaindolysine;

R ^PRO1 and R ^PRO2 ULM-g - ULM-i each independently represent an H, optionally substituted C ₁ -C ₃ alkyl group or together form a keto group;

each n ULM-g - ULM-i is independently 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1);

each m' ULM-g - ULM-i is 0 or 1; And

each n' ULM-g - ULM-i is 0 or 1;

wherein each of these compounds, preferably an alkyl, aryl or Het group, is optionally connected to a PTM group (including a ULM' group) via a linker group.

[0238] In alternative embodiments, R ³ ' ULM-g - ULM-i is -(CH ₂ ) _n -aryl, -(CH ₂ CH ₂ O) _n -aryl, -(CH ₂ ) _n -NO, or - (CH ₂ CH ₂ O) _n -NO,

Where:

said aryl ULM-g - ULM-i is phenyl which is optionally substituted with one or two substituents, said substituent(s) being preferably selected from -(CH ₂ ) _n OH, C ₁ -C ₆ alkyl , which itself is optionally additionally substituted with CN, halogen (up to three halogen groups), OH, -(CH ₂ ) _n O(C ₁ -C ₆ )alkyl, amine, mono- or di-(C ₁ -C ₆ alkyl )amine, wherein the alkyl group on the amine is optionally substituted with 1 or 2 hydroxyl groups or up to three halogen groups (preferably F, Cl) or

the specified aryl group ULM-g - ULM-i is substituted with -(CH ₂ ) _n OH, -(CH ₂ ) _n -O-(C ₁ -C ₆ )alkyl, -(CH ₂ ) _n -O-(CH ₂ ) _n -(C ₁ -C ₆ )alkyl, -(CH ₂ ) _n -C(O)(C ₀ -C ₆ )alkyl, -(CH ₂ ) _n -C(O)O(C ₀ -C ₆ ) alkyl, -(CH ₂ ) _n -OC(O)(C ₀ -C ₆ )alkyl, amine, mono- or di-(C ₁ -C ₆ alkyl)amine, where the alkyl group on the amine is optionally replaced by 1 or 2 hydroxyl groups or halogen groups in an amount up to three (preferably F, Cl), CN, NO ₂ , optionally substituted -(CH ₂ ) _n -(V) _m' -CH ₂ ) _n -(V) _m' -(C ₁ -C ₆ )alkyl group, -(V) _m' -(CH ₂ CH ₂ O) _n -R ^PEG group, where V represents O, S or NR _1' , R _1' represents H or C ₁ -C ₃ alkyl group (preferably H) and R ^PEG is H or a C ₁ -C ₆ alkyl group that is optionally substituted (including optional substitution with a carboxyl group), or

said aryl group ULM-g - ULM-i is optionally substituted with a heterocycle, including a heteroaryl selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene , tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline, benzofuran, indole, indolysine, azaindolysine (if substituted, each is preferably substituted with a C ₁ -C ₃ alkyl group, preferably a methyl or halogen group, preferably F or Cl) or chemical structure groups :

S ^c ULM-g - ULM-i is CHR ^SS , NR ^URE or O;

R ^HET ULM-g - ULM-i is H, CN, NO ₂ , halogen (preferably Cl or F), optionally substituted C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (eg CF ₃ ), an optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or an optionally substituted acetylene group -C≡CR _a where R _a is H or C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl);

R ^SS - ULM-g - ULM-i is H, CN, NO ₂ , halogen (preferably F or Cl), optionally substituted C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or halogen groups up to three), optionally substituted O-(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or optionally substituted -C(O)(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups);

R ^URE ULM-g - ULM-i is H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl) or -C(O)(C ₀ -C ₆ alkyl), each of such groups optional substituted with one or two hydroxyl groups or up to three halogen groups, preferably fluorine groups, or an optionally substituted heterocycle, for example piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted;

Y ^C ULM-g - ULM-i is N or CR ^YC , where R ^YC is H, OH, CN, NO ₂ , halogen (preferably Cl or F), optionally substituted C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (eg CF ₃ ), optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or optionally substituted acetylene group -C≡CR _a , where R _a represents H or a C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl);

R ^PRO ULM-g - ULM-i represents H, optionally substituted C ₁ -C ₆ alkyl or optionally substituted aryl (phenyl or naphthyl), heteroaryl or heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C ₁ -C ₃ alkyl group, preferably a methyl or halogen group, preferably F or Cl), benzofuran, indole, indolysine, azaindolysine;

R ^PRO1 and R ^PRO2 ULM-g - ULM-i each independently represent an H, optionally substituted C ₁ -C ₃ alkyl group or together form a keto group;

NO ULM-g - ULM-i is preferably oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C ₁ -C ₃ alkyl group, preferably a methyl or halogen group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine or a group of the chemical structure:

S ^c ULM-g - ULM-i is CHR ^SS , NR ^URE or O;

R ^HET ULM-g - ULM-i is H, CN, NO ₂ , halogen (preferably Cl or F), optionally substituted C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (eg CF ₃ ), an optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or an optionally substituted acetylene group -C≡CR _a where R _a is H or C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl);

R ^SS ULM-g - ULM-i is H, CN, NO ₂ , halogen (preferably F or Cl), optionally substituted C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups ), optionally substituted O-(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or optionally substituted -C(O)(C ₁ -C ₆ alkyl) (preferably substituted one or two hydroxyl groups or up to three halogen groups);

R ^URE ULM-g - ULM-i is H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl) or -C(O)(C ₀ -C ₆ alkyl), each of such groups optional substituted with one or two hydroxyl groups or up to three halogen groups, preferably fluorine groups, or an optionally substituted heterocycle, for example piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted;

Y ^C ULM-g - ULM-i is N or CR ^YC , where R ^YC is H, OH, CN, NO ₂ , halogen (preferably Cl or F), optionally substituted C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (eg CF ₃ ), optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or optionally substituted acetylene group -C≡CR _a , where R _a represents H or a C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl);

R ^PRO ULM-g - ULM-i represents H, an optionally substituted C ₁ -C ₆ alkyl or an optionally substituted aryl, heteroaryl or heterocyclic group;

R ^PRO1 and R ^PRO2 ULM-g - ULM-i each independently represent an H, optionally substituted C ₁ -C ₃ alkyl group or together form a keto group;

each m' ULM-g - ULM-i is independently 0 or 1; And

each n ULM-g - ULM-i is independently 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1),

wherein each of said compounds, preferably on said aryl or NET groups, is optionally linked to a PTM group (including a ULM' group) via a linker group.

[0239] In further embodiments, preferred compounds include compounds of the chemical structure:

ULM-i

Where:

Where:

R ^1' ULM-i represents OH or a group that is metabolized in the patient or subject to OH;

R ^2' ULM-i is -NH-CH ₂ -aryl-NET (preferably phenyl coupled directly to a methyl-substituted thiazole);

R ^3' ULM-i is a -CHR ^CR3' -NH-C(O)-R ^3P1 group or a -CHR ^CR3' -R ^3P2 group;

R ^CR3' ULM-i represents a C ₁ -C ₄ alkyl group, preferably methyl, isopropyl or tert-butyl;

R ^3P1 ULM-i is a C ₁ -C ₃ alkyl (preferably methyl), an optionally substituted oxetane group (preferably a methyl substituted, -(CH ₂ ) _n OCH ₃ group, where n is 1 or 2 (preferably 2), or a group (the ethyl ether group is preferably meta-substituted on the phenyl moiety), a morpholino group (linked to a carbonyl at the 2- or 3-position);

R ^3P2 ULM-i is a group;

aryl ULM-i is phenyl;

NO ULM-i is an optionally substituted thiazole or isothiazole; And

R ^HET ULM-i represents H or a halogen group (preferably H);

or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof, each of which is optionally linked to a PTM group (including a ULM' group) by a linker group.

[0240] In certain aspects, bifunctional compounds are provided containing an E3 ubiquitin ligase binding moiety (ULM), wherein ULM is a group of the chemical structure:

ULM-j

Where:

each R ₅ and R ₆ ULM-j independently represents OH, SH or optionally substituted alkyl, or R ₅ , R ₆ and the carbon atom to which they are attached form a carbonyl;

R ₇ ULM-j represents H or optionally substituted alkyl;

E ULM-j represents a bond, C=O or C=S;

G ULM-j represents a bond, optionally substituted alkyl, -COOH or C=J;

J ULM-j is O or NR ₈ ;

R ₈ ULM-j is H, CN, optionally substituted alkyl or optionally substituted alkoxy;

M ULM-j is an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclic compound, or

R ₉ and R ₁₀ ULM-j are each independently H; optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted thioalkyl, disulfide-linked ULM, optionally substituted heteroaryl or haloalkyl; or R ₉ , R ₁₀ and the carbon atom to which they are attached form an optionally substituted cycloalkyl;

R ₁₁ ULM-j is an optionally substituted heterocyclic compound, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl, or

R ₁₂ ULM-j represents H or optionally substituted alkyl;

R ₁₃ ULM-j is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; optionally substituted (oxoalkyl)carbamate,

each R ₁₄ ULM-j independently represents H, haloalkyl, optionally substituted cycloalkyl, optionally substituted alkyl, or optionally substituted heterocycloalkyl;

R ₁₅ ULM-j is H, optionally substituted heteroaryl, haloalkyl, optionally substituted aryl, optionally substituted alkoxy or optionally substituted heterocyclyl;

each R ₁₆ ULM-j independently represents halogen, optionally substituted alkyl, optionally substituted haloalkyl, CN or optionally substituted haloalkoxy;

each R ₂₅ ULM-j independently represents H or optionally substituted alkyl; or both R ₂₅ groups can be taken together to form an oxo or optionally substituted cycloalkyl group;

R ₂₃ ULM-j is H or OH;

Z ₁ , Z ₂ , Z ₃ and Z ₄ ULM-j are independently C or N; And

o ULM-j is 0, 1, 2, 3 or 4, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

[0241] In certain embodiments, where G ULM-j is C=J, J is O, R ₇ is H, each R ₁₄ is H, and o is 0.

[0242] In certain embodiments, wherein G ULM-j is C=J, J is O, R ₇ is H, each R ₁₄ is H, R ₁₅ is optionally substituted heteroaryl, and O is 0. In other cases, E represents C=O and M represents

[0243] In certain embodiments, wherein E ULM-j is C=O, R ₁₁ is an optionally substituted heterocyclic compound, or and M represents

[0244] In certain embodiments, where E ULM-j is C=O, M is and R ₁₁ represents each R ₁₈ independently represents halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl or haloalkoxy; and p is 0, 1, 2, 3 or 4.

[0245] In certain embodiments of the ULM, and if present, the ULM' is each independently a group of chemical structure:

ULM-k

Where:

G ULM-k represents C=J, J represents O;

R ₇ ULM-k represents H;

each R ₁₄ ULM-k represents H;

o ULM-k is 0;

The R ₁₅ ULM-k is

R ₁₇ ULM-k represents H, halogen, optionally substituted cycloalkyl, optionally substituted alkyl, optionally substituted alkenyl and haloalkyl.

[0246] In other cases, R ₁₇ ULM-k is alkyl (eg, methyl) or cycloalkyl (eg, cyclopropyl).

[0247] In other embodiments of the ULM, and if present, the ULM' is each independently a group of chemical structure:

Where:

G ULM-k represents C=J, J represents O;

R ₇ ULM-k represents H;

each R ₁₄ ULM-k represents H;

o ULM-k is 0; And

R ₁₅ ULM-k is selected from the group consisting of:

where R ₃₀ ULM-k represents H or optionally substituted alkyl.

[0248] In other embodiments of the ULM, and if present, the ULM' is each independently a group of chemical structure:

ULM-k

Where:

E ULM-k represents C=O;

M ULM-k is And

R ₁₁ ULM-k is selected from the group consisting of:

[0249] According to yet other embodiments, the compound of the chemical structure

ULM-k

where E ULM-k represents C=O;

R ₁₁ ULM-k is a

M ULM-k is

q ULM-k is 1 or 2;

R ₂₀ ULM-k is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or

R ₂₁ ULM-k represents H or optionally substituted alkyl; And

R ₂₂ ULM-k is H, optionally substituted alkyl, optionally substituted alkoxy or haloalkyl.

[0250] According to any embodiment described in the present invention, R ₁₁ ULM-j or ULM-k is selected from the group consisting of:

[0251] In certain embodiments, the R ₁₁ ULM-j or ULM-k is selected from the group consisting of:

[0252] In certain embodiments, the ULM (or if ULM' is present) is a group of the chemical structure:

ULM-l

Where:

X ULM-l is O or S;

Y ULM-l is H, methyl or ethyl;

R ₁₇ ULM-l is H, methyl, ethyl, hydroxymethyl or cyclopropyl;

M ULM-l is optionally substituted aryl, optionally substituted heteroaryl, or

R ₉ ULM-l is H;

R ₁₀ ULM-l is H, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted hydroxyalkyl, optionally substituted thioalkyl or cycloalkyl;

R11 ULM-l is an optionally substituted heteroaromatic compound, an optionally substituted heterocyclic compound, an optionally substituted aryl or

R ₁₂ ULM-l represents H or optionally substituted alkyl; And

R ₁₃ ULM-l is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; optionally substituted (oxoalkyl)carbamate.

[0253] According to some embodiments of the ULM, and if present, the ULM' is each independently a group of chemical structure:

ULM-m

Where:

Y ULM-m is H, methyl or ethyl

R ₉ ULM-m represents H;

R ₁₀ is isopropyl, t-butyl, sec-butyl, cyclopentyl or cyclohexyl;

R ₁₁ ULM-m represents an optionally substituted amide, an optionally substituted isoindolinone, an optionally substituted isoxazole, an optionally substituted heterocycle.

[0254] According to other embodiments of the disclosure, ULMs and if ULMs are present are each independently a group of chemical structure:

ULM-n

Where:

R ₁₇ ULM-n is methyl, ethyl or cyclopropyl; And

R ₉ , R ₁₀ and R ₁₁ ULM-n are defined above. In other cases, R ₉ represents H; And

R ₁₀ ULM-n is H, alkyl or cycloalkyl (preferably isopropyl, t-butyl, sec-butyl, cyclopentyl or cyclohexyl).

[0255] According to any of the aspects or embodiments described in the present invention, ULM (or if ULM' is present) as described in the present invention may be a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate or polymorph thereof. In addition, according to any of the aspects or embodiments described in the present invention, the ULM (or if ULM' is present) as described in the present invention may be connected to the PTM directly through a bond or through a chemical linker.

[0256] According to certain aspects of the ULM disclosure, the fragment is selected from the group consisting of:

wherein VLM can be connected to PTM via a linker as described in the present invention, at any suitable position, including, for example, aryl, heteroaryl, phenyl or phenyl indole group, optionally through any suitable functional group, such as amine, ester, ester , alkyl or alkoxy.

Exemplary Linkers

[0257] In certain embodiments, compounds as described in the present invention include one or more PTMs chemically coupled or associated with one or more ULMs (e.g., at least one of CLM, VLM, MLM, ILM, or a combination thereof ) via a chemical linker (L). In certain embodiments, a linker group L is a group containing one or more covalently linked structural units (for example, -A ^L _l ...(A ^L ) _q - or -(A ^L ) _q -), where A _l is a group, connected to the RTM, and (A ^L ) _q represents a group connected to the ULM.

[0258] In certain embodiments, the linker group L is selected from -(A ^L ) _q -:

(A ^L ) _q represents a group that is connected to a ULM moiety, a PTM moiety, or a combination thereof;

linker q is an integer that is greater than or equal to 1;

each A ^L is independently selected from the group consisting of a link, CR ^L1 R ^L2 , O, S, SO, SO ₂ , NR ^L3 , SO ₂ NR ^L3 , SONR ^L3 , CONR ^L3 , NR ^L3 CONR ^L4 , NR ^L3 SO ₂ NR ^L4 , CO, CR ^L1 =CR ^L2 , C=C, SiR ^L1 R ^L2 , P(O)R ^L1 , P(O)OR ^L1 , NR ^L3 C(=NCN)NR ^L4 , NR ^L3 C(=NCN) , NR ^L3 C(=CNO ₂ )NR ^L4 , C _3-11 cycloalkyl, optionally substituted with 0-6 R ^L1 and/or R ^L2 groups, C _5-13 spirocycloalkyl, optionally substituted with 0-9 R ^L1 and/or groups, C _3-11 heterocyclyl, optionally substituted with 0-6 R ^L1 and/or R ^L2 groups, C _5-13 spiroheterocycloalkyl, optionally substituted with 0-8 R ^L1 and/or R ^L2 groups, aryl, optionally substituted with 0-6 R ^L1 and /or R ^L2 groups, heteroaryl, optionally substituted with 0-6 R ^L1 and/or R ^L2 groups, where R ^L1 or R ^L2 are each independently optionally linked to other groups to form a cycloalkyl and/or heterocyclyl moiety, optionally substituted with 0-4 R ^L5 groups; And

R ^L1 , R ^L2 , R ^L3 , R ^L4 and R ^L5 are each independently H, halogen, C _1-8 alkyl, OC _1-8 alkyl, SC _1-8 alkyl, NHC _1-8 alkyl, N(C _{1 -8} alkyl) ₂ , C _3-11 cycloalkyl, aryl, heteroaryl, C _3-11 heterocyclyl, OS _1-8 cycloalkyl, SC _1-8 cycloalkyl, NHC _1-8 cycloalkyl, N(C _1-8 cycloalkyl) ₂ , N(C _1-8 cycloalkyl)(C _1-8 alkyl), OH, NH ₂ , SH, SO ₂ C _1-8 alkyl, P(O)(OS _1-8 alkyl)(C _1-8 alkyl), P(O)(OS _1-8 alkyl) ₂ , CC-C _1-8 alkyl, CCH, CH=CH(C _1-8 alkyl), C(C _1-8 alkyl)=CH(C _1-8 alkyl ), C(C _1-8 alkyl)=C(C _1-8 alkyl) ₂ , Si(OH) ₃ , Si(C _1-8 alkyl) ₃ , Si(OH)(C _1-8 alkyl) ₂ , SOS _1-8 alkyl, CO ₂ H, halogen, CN, CF ₃ , CHF ₂ , CH ₂ F, NO ₂ , SF5, SO ₂ NHC _1-8 alkyl, SO ₂ N(C _1-8 alkyl) ₂ , SONHC _1-8 alkyl, SON(C _1-8 alkyl) ₂ , CONHC _1-8 alkyl, CON(C _1-8 alkyl) ₂ , N(C _1-8 alkyl)CONH(C _1-8 alkyl), N( C _1-8 alkyl)CON(C _1-8 alkyl) ₂ , NHCONH(C _1-8 alkyl), NHCON(C _1-8 alkyl) ₂ , NHCONH ₂ , N(C _1-8 alkyl)SO ₂ NH( C _1-8 alkyl), N(C _1-8 alkyl) SO ₂ N(C _1-8 alkyl)2, NH SO ₂ NH(C _1-8 alkyl), NH SO ₂ N(C _1-8 alkyl) ₂ , NHSO ₂ NH ₂ .

[0259] In certain embodiments, the linker q is an integer that is greater than or equal to 0. In certain embodiments, q is an integer that is greater than or equal to 1.

[0260] In certain embodiments, for example, where the q of the linker is greater than 2, (A ^L ) _q is a group that is connected to the ULM, and A ^L _l and (A ^L ) _q are connected by linker units (L).

[0261] In certain embodiments, for example, where the q of the linker is 2, (A ^L ) _q is a group that is connected to A ^L _l and to the ULM.

[0262] In certain embodiments, for example, wherein the q of the linker is 1, the structural linker group L is -A ^L _l - and A ^L _l is a group that is connected to the ULM moiety and the PTM moiety.

[0263] In certain embodiments, the linker (L) contains a group represented by a general structure selected from the group consisting of:

-NH(CH ₂ ) _n -(lower alkyl)-, -NR(CH ₂ ) _n -(lower alkoxy)-, -NR(CH ₂ ) _n -(lower alkoxy)-OSH ₂ -, -NH(CH ₂ ) _n -(lower alkoxy)-(lower alkyl)-OSH ₂ -, -NR(CH ₂ ) _n -(cycloalkyl)-(lower alkyl)-OSH ₂ -, -NR(CH ₂ ) _n -(heterocycloalkyl)- , -NR(CH ₂ CH ₂ O) _n -(lower alkyl)-O-CH ₂ -, -NR(CH ₂ CH ₂ O) _n -(heterocycloalkyl)-O-CH ₂ -, -NR(CH ₂ CH ₂ O) _n -aryl-O-CH ₂ -, -NR(CH ₂ CH ₂ O) _n -(heteroaryl)-O-CH ₂ -, -NR(CH ₂ CH ₂ O) _n -(cycloalkyl)-O -(heteroaryl)-O-CH ₂ -, -NR(CH ₂ CH ₂ O) _n -(cycloalkyl)-O-aryl-O-CH ₂ -, -NR(CH ₂ CH ₂ O) _n -(lower alkyl )-NH-aryl-O-CH ₂ -, -NR(CH ₂ CH ₂ O) _n -(lower alkyl)-O-aryl-CH ₂ , -NR(CH ₂ CH ₂ O) _n- cycloalkyl-O- aryl-, -NR(CH ₂ CH ₂ O) _n -cycloalkyl-O-(heteroaryl)l-, -NR(CH ₂ CH ₂ ) _n -(cycloalkyl)-O-(heterocycle)-CH ₂ , -NR( CH ₂ CH ₂ ) _n -(heterocycle)-(heterocycle) _-CH2 , -N(R1R2)-(heterocycle)-CH2;

where n of the linker can be 0-10;

R of the linker may be H, lower alkyl;

R1 and R2 of the linker can form a ring with compound N.

[0264] In certain embodiments, the linker (L) contains a group represented by a general structure selected from the group consisting of:

-N(R)-(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -OCH ₂ -,

-O-(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -OCH2-,

-O-(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -O-;

-N(R)-(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -O-;

-(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -O-;

-(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -OCH2-;

Where

each m, n, o, p, q and r of the linker are independently 0, 1, 2, 3, 4, 5, 6;

if the number is zero, there is no N-O or O-O bond

R of the linker is H, methyl and ethyl;

Linker X represents H and F

where m of the linker can be 2, 3, 4, 5

where each n and m of the linker can independently be 0, 1, 2, 3, 4, 5, 6.

[0265] In some embodiments, the linker (L) is selected from the group consisting of:

where each m and n independently represent 0, 1, 2, 3, 4, 5 or 6.

[0266] In some embodiments, the linker (L) is selected from the group consisting of:

[0267] In some embodiments, the linker (L) is selected from the group consisting of:

where m, n, o, p, q and r are independently 0, 1, 2, 3, 4, 5, 6 or 7.

[0268] In some embodiments, the linker (L) is selected from the group consisting of:

[0269] In further embodiments, the linker (L) comprises a structure selected without limitation from the structure shown below, wherein the dotted line represents the point of attachment to the PTM or ULM moieties:

Where:

W ^L1 and W ^L2 are each independently a 4-8 membered ring with 0-4 heteroatoms, optionally substituted with R ^Q , each R ^Q is independently H, halogen, OH, CN, CF ₃ , C ₁ -C ₆ alkyl ( straight, branched, optionally substituted), C ₁ -C ₆ alkoxy (straight, branched, optionally substituted) or 2 R ^Q groups, taken together with the atom to which they are attached, form a 4-8 membered ring system containing 0- 4 heteroatoms;

Y ^L1 each independently represents a bond, C ₁ -C ₆ alkyl (straight, branched, optionally substituted) and optionally one or more C atoms are replaced by O; or C ₁ -C ₆ alkoxy (straight, branched, optionally substituted);

n represents 0-10; And

the dotted line indicates the point of attachment to the PTM or ULM fragments.

[0270] In further embodiments, the linker (L) comprises a structure selected, without limitation, from the structure shown below, wherein the dotted line represents the point of attachment to the PTM or ULM moieties:

Where:

W ^L1 and W ^L2 are each independently aryl, heteroaryl, cyclic, heterocyclic, C _1-6 alkyl, bicyclic, biaryl, biheteroaryl or biheterocyclic, each optionally substituted with ^RQ , each ^RQ independently representing H, halogen , OH, CN, CF ₃ , hydroxyl, nitro, C≡CH, C _2-6 alkenyl, C _2-6 alkynyl, C ₁ -C ₆ alkyl (unbranched, branched, optionally substituted), C ₁ -C ₆ alkoxy ( straight, branched, optionally substituted), OC _1-3 alkyl (optionally substituted with 1 or more -F), OH, NH ₂ , NR ^Y1 R ^Y2 , CN or 2 R ^Q groups, taken together with the atom to which they are attached, form a 4-8-membered ring system containing 0-4 heteroatoms;

Y ^L1 each independently represents a bond, NR ^YL1 , O, S, NR ^YL2 , CR ^YL1 R ^YL2 , C=O, C=S, SO, SO ₂ , C ₁ -C ₆ alkyl (straight, branched, optionally substituted) and optionally one or more C atoms are replaced by O; C ₁ -C ₆ alkoxy (straight, branched, optionally substituted);

Q ^L is a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms, optionally bridged, optionally substituted with 0-6 R ^Q , each R ^Q independently represents H, C _1-6 alkyl (straight, branched, optionally substituted with 1 or more halogen atoms, C _1-6 alkoxy) or 2 R ^Q groups, taken together with the atom to which they are attached, form a 3-8 membered ring system containing 0-2 heteroatoms);

R ^YL1 , R ^YL2 are each independently H, OH, C _1-6 alkyl (straight, branched, optionally substituted with 1 or more halogen atoms, C _1-6 alkoxy) or R ¹ , R ² together with the atom to which they attached, form a 3-8-membered ring system containing 0-2 heteroatoms);

n represents 0-10; And

the dotted line indicates the point of attachment to the PTM or ULM fragments.

[0271] In further embodiments, the linker group is an optionally substituted (poly)ethylene glycol containing from 1 to about 100 ethylene glycol units, from about 1 to about 50 ethylene glycol units, from 1 to about 25 ethylene glycol units, from about 1 to 10 ethylene glycol units units, from 1 to about 8 ethylene glycol units and from 1 to 6 ethylene glycol units, from 2 to 4 ethylene glycol units or optionally substituted alkyl groups alternate with optionally substituted O, N, S, P or Si atoms. In certain embodiments, the linker is substituted with an aryl, phenyl, benzyl, alkyl, alkylene, or heterocyclic group. In certain embodiments, the linker may be asymmetric or symmetric.

[0272] In any embodiment of the compounds described herein, the linker group may be any suitable moiety as described herein. In one embodiment, the linker is a substituted or unsubstituted polyethylene glycol group with a size ranging from about 1 to about 12 ethylene glycol units, from 1 to about 10 ethylene glycol units, from about 2 to about 6 ethylene glycol units, from about 2 to 5 ethylene glycol units, from about 2 to 4 ethylene glycol units.

[0273] In another embodiment, the present disclosure relates to a compound that contains a PTM group, as described above, that binds to a protein target or polypeptide (eg, RAF) that is ubiquitinated by a ubiquitin ligase and is chemically linked directly to the ULM group or via a linker moiety, L or PTM is alternatively a ULM' group, which is also a ubiquitin ligase binding moiety, which may be the same or different from the ULM group as described above, and is linked directly to the ULM group or via a linker moiety; and L is a linker moiety as described above, which may or may not be present, that chemically (covalently) links ULM to PTM, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate or polymorph thereof.

[0274] In certain embodiments, the linker group L is a group containing one or more covalently linked structural units independently selected from the group consisting of:

X is selected from the group consisting of O, N, S, S(O) and SO ₂ ; n is an integer from 1 to 5, 5; R ^L1 represents hydrogen or alkyl, is a mono- or bicyclic aryl or heteroaryl, optionally substituted with 1-3 substituents selected from alkyl, halogen, haloalkyl, hydroxy, alkoxy or cyano; is a mono- or bicyclic cycloalkyl or heterocycloalkyl, optionally substituted with 1-3 substituents selected from alkyl, halogen, haloalkyl, hydroxy, alkoxy or cyano; and the phenyl ring moiety may be optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy and cyano. In an embodiment, the linker group L contains up to 10 covalently linked structural units, as described above.

[0275] Although the ULM group and PTM group can be covalently linked to the linker group through any group that is appropriate and stable to the linker chemistry, in preferred aspects of the present disclosure the linker is independently covalently linked to the ULM group and PTM group, preferably through an amide ester , thioester, keto group, carbamate (urethane), carbon or ester, each of the groups can be introduced at any location in the ULM group and PTM group to obtain maximum binding to the ULM group on the ubiquitin ligase and the PTM group on the target protein is broken down. (It is noted that in certain aspects where the PTM group is a ULM group, the protein target for degradation may be the ubiquitin ligase itself). In certain preferred aspects, the linker may be connected to an optionally substituted alkyl, alkylene, alkene or alkyne group, aryl group or heterocyclic group on ULM and/or PTM groups.

Illustrative RTMs

[0276] In preferred aspects of the present disclosure, a PTM group is a group that binds to target proteins. The targets of the PTM group are diverse in appearance and are selected from proteins that are expressed in the cell, such that at least a portion of the sequences are found in the cell and can bind to the PTM group. The term “protein” includes oligopeptide and polypeptide sequences of sufficient length to bind to a PTM group in accordance with the present disclosure. Any proteins in a eukaryotic system or microbial system, including a virus, bacteria or fungus, as described elsewhere herein, are targets for ubiquitinylation mediated by the compounds of the present disclosure. Preferably, the target protein is a eukaryotic protein.

[0277] PTM groups according to the present disclosure include, for example, any moiety that specifically binds to a protein (binds to a target protein), and includes the following non-limiting examples of small molecule target protein binding moieties: RAF inhibitors, Hsp90 inhibitors, kinase inhibitors, HDM2 and MDM2 inhibitors, compounds targeting human bromodomain-containing BET proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, nuclear hormone receptor compounds, immunosuppressive compounds and compounds targeting the aryl hydrocarbon receptor (AHR) , among a number of others. The compositions described below illustrate some of these low molecular weight target protein binding fragments. Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates and polymorphs of these compositions, as well as other small molecules that can target the protein of interest. These binding fragments are coupled to an E3 ubiquitin ligase binding fragment, preferably through a linker, to bring the target protein (to which the target protein binding fragment binds) into close proximity to the ubiquitin ligase for ubiquitinylation and degradation.

[0278] Any protein that can bind to a target protein binding moiety or PTM group and is subject to ubiquitin ligase or cleavage by a ubiquitin ligase (eg, RAF) is a target protein according to the present disclosure. In general, target proteins may include, for example, structural proteins, receptors, enzymes, cell surface proteins, proteins related to cell insertion function, including proteins involved in catalytic activity, aromatase activity, motor activity, activity helicases, metabolic processes (anabolism and catabolism), antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, regulatory enzymatic activity, signal transduction activity, activity in in relation to the structure of molecules, binding activity (protein, lipid, carbohydrate), receptor activity, in relation to cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, response to stimulus, behavioral proteins, cell adhesion proteins, proteins, involved in cell death, proteins involved in transport (including protein with transporter activity, nuclear transport, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretory activity, electron transporter activity), in pathogenesis, chaperone regulatory activity , nucleic acid binding activity, transcription regulating activity, extracellular organization and biogenesis activity, translation regulating activity. Proteins of interest may include proteins from eukaryotes (eg, c-RAF, A-RAF and/or B-RAF) and prokaryotes, including humans as targets for drug therapy, other animals, including domestic animals, microbes for identifying targets for antibiotics and other antimicrobials, and plants, and even viruses (for example, v-RAF and/or v-Mil), among several others.

[0279] The present disclosure can be used in the treatment of a number of diseases and/or conditions, including any disease and/or condition in which proteins are dysregulated and in which the patient would benefit from protein breakdown.

[0280] In a further aspect, the present disclosure provides therapeutic compositions comprising an effective amount of a compound described herein, or salt forms thereof, and a pharmaceutically acceptable carrier, additive or excipient and optionally an additional bioactive agent. Therapeutic compositions modulate protein degradation in a patient or subject, eg, an animal such as a human, and can be used to treat or alleviate diseases or conditions that are modulated by protein degradation. In some embodiments, the therapeutic compositions described herein can be used to effect the degradation of proteins of interest to treat or alleviate a disease, for example, cancer, heart-face-skin syndrome, neurofibromatosis type 1, Costello syndrome, Noonan syndrome, LEOPARD. In some additional embodiments, the disease is renal cell carcinoma, pancreatic cancer, colorectal cancer, lung cancer, ovarian cancer, thyroid cancer, piloid astrocytoma, prostate cancer, gastric cancer, hepatocellular carcinoma, and melanoma.

[0281] In alternative aspects, the present disclosure provides a method of treating a disease state or alleviating the symptoms of a disease or condition in a subject, if desired, by degrading a protein or polypeptide by which the disease or condition is modulated, comprising administering to said patient or subject an effective amount, e.g., therapeutically an effective amount of at least one compound described herein above, optionally in combination with a pharmaceutically acceptable carrier, additive or adjuvant and optionally an additional bioactive agent, wherein the composition is effective for treating or alleviating a disease or disorder or a symptom thereof at the subject. The method in accordance with the present disclosure can be used to treat a wide variety of diseases or conditions, including cancer, heart-face-skin syndrome, neurofibromatosis type 1, Costello syndrome, Noonan syndrome, LEOPARD syndrome, by administering effective amounts of at least one compound described in this document. The disease or condition may be a disease caused by a microbial pathogen or other exogenous pathogen, such as a virus (for example, a murine retrovirus or an avian retrovirus such as avian retrovirus MH2), bacteria, fungus, protozoan or other microbe, or may be a disease condition that caused by overexpression of a protein and/or the presence of a protein that is constitutively activated, resulting in a disease and/or condition.

[0282] In another aspect, the present disclosure relates to methods for identifying the effects of degradation of proteins of interest in a biological system using compounds in accordance with the present disclosure.

[0283] The term “target protein” is used to describe a protein or polypeptide that is targeted for binding to a compound in accordance with the present disclosure and cleavage by a ubiquitin ligase in accordance with the present disclosure. Such small molecule target protein binding moiety also includes pharmaceutically acceptable salts, enantiomers, solvates and polymorphs of these compositions, as well as other small molecules that can target the protein of interest. These binding moieties are connected to at least one ULM group (eg VLM, CLM, ILM and/or MLM) through at least one linker group L.

[0284] Target proteins that can be bound to a target protein binding moiety and cleaved by a ligase to which the ubiquitin ligase binding moiety binds include any protein or peptide, including fragments thereof, analogs thereof, and/or homologs thereof. Target proteins include proteins and peptides having any biological function or activity including structural, regulatory, hormonal, enzymatic, genetic, immunological, contractile, storage, transport and signal transduction functions. More specifically, a number of drug targets for human therapeutics are target proteins to which the binding moiety of the target protein can be linked and included in compounds in accordance with the present disclosure. These include proteins that can be used to restore function in numerous polygenic diseases, including, for example, B7.1 and B7, TINFRlm, TNFR2, NADPH oxidase, BclIBax and other partners in the apoptosis pathway, C5a receptor, HMG-CoA reductase , PDE phosphodiesterase type V, PDE IV phosphodiesterase type 4, PDEI, PDEII, PDEIII, squalene cyclase inhibitor, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclooxygenase 1, cyclooxygenase 2, 5HT receptors, dopamine receptors, G proteins, i.e. Gq, histamine receptors, 5-lipoxygenase, serine tryptase, thymidylate synthase, purine nucleoside phosphorylase, trypanosomal GAPDH, glycogen phosphorylase, carbonic anhydrase, chemokine receptors, JAW STAT, RXR and the like, HIV 1 protease, HIV 1 integrase, influenza, neuraminidase, hepatitis virus reverse transcriptase a B , sodium channel, multidrug resistant protein (MDR) and P-glycoprotein (MRP), tyrosine kinase, CD23, CD124, p56 lck tyrosine kinase, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-alphaR, ICAM1 , Cat+ channels, VCAM, VLA-4 integrin, selectins, CD40/CD40L, nevokinins and receptors, inosine monophosphate dehydrogenase, p38 MAP kinase, RaslRaflMEWERK metabolic pathway, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3 RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus type 1 (HSV-I), protease, cytomegalovirus (CMV) protease, poly(ADP-ribose) polymerase, cyclin-dependent kinases, vascular endothelial growth factor, oxytocin receptor, inhibitor of protein transfer through microsomes, bile acid transport inhibitor, 5 alpha reductase inhibitors, angiotensin 11, glycine receptor, norepinephrine reuptake receptor, endothelin receptors, neuropeptide Y and receptor, estrogen receptors, androgen receptors, adenosine receptors, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2 , P2Y4, P2Y6, P2X1-7), farnesyltransferase, geranylgeranyltransferase, TrkA receptor for NGF, beta-amyloid, Flk-IIKDR tyrosine kinase, vitronectin receptor, integrin receptor, Her-21 neu, telomerase inhibitor, cytosolic phospholipase A2 and EGF receptor tyrosine kinase. Additional target proteins include, for example, ecdysone 20-monooxygenase, GABA gate chloride channel, acetylcholinesterase, voltage-gated sodium channel protein, calcium efflux channel, and chloride channels. In addition, additional target proteins include acetyl-CoA carboxylase, adenylosuccinate synthase, protoporphyrinogen oxidase, and enolpyruvyl shikimate phosphate synthase.

[0285] These various target proteins can be used in screens that identify fragments of a compound that bind to the protein, and by incorporating the fragment into compounds according to the present disclosure, the level of activity of the protein can be altered for the ultimate therapeutic outcome.

[0286] The term "target protein binding moiety" or PTM is used to describe a small molecule that binds to a target protein or other protein or polypeptide of interest and places/exposes the protein or polypeptide into close proximity to a ubiquitin ligase so that cleavage of the protein or polypeptide can occur. protein or polypeptide ubiquitin ligase. Non-limiting examples of small molecule target protein binding fragment include RAF inhibitors, Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting human bromodomain BET proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds and compounds targeting the aryl hydrocarbon receptor (AHR), among several others.

[0287] Exemplary target protein fragments according to the present disclosure include RAF inhibitors, haloalkangalegenase inhibitors, Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting human bromodomain-containing BET proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds and compounds targeting the aryl hydrocarbon receptor (AHR).

[0288] The compositions described below illustrate some of these small molecule target protein binding moieties. Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates and polymorphs of these compositions, as well as other small molecules that can target the protein of interest. References cited herein below are incorporated herein by reference in their entirety.

[0289] According to any aspect or embodiment described herein, PTM targets and/or binds RAE. For example, according to any aspect or embodiment described herein, the PTM may include a chemical group selected from the group of chemical structures consisting of PTM-Ia or PTM-Ib:

Where:

dotted double bonds represent aromatic bonds;

V _PTM ; W _PTM ; X _RTM , Y _PTM , Z _PTM is one of the following combinations: C, CH, N, N, C; C, N, N, CH, C; S, O, S, CH, S; C, S, C, CH, C; C, CH, C, O, C; C, CH, C, S, C; C, CH, N, CH, C; N, CH, C, CH, C; C, CH, C, CH, N; N, N, C, CH, C; N, CH, C, N, C; C, CH, C, N, N; C, N, C, CH, N; C, N, C, N, C; and C, N, N, N, C;

X _PTM35 , X _PTM36 , X _PTM37 and X _PTM38 are independently selected from CH and N;

R _PTM1 is covalently attached to a ULM, a chemical linker group (L), CLM, ILM, VLM, MLM, ULM', CLM', ILM', VLM', MLM', or a combination thereof;

R _PTM2 is hydrogen, halogen, aryl, methyl, ethyl, OCH ₃ , NHCH ₃ or M1-CH ₂ -CH ₂ -M2, where M1 is CH ₂ , O and NH and M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle;

R _PTM3 is absent or is hydrogen, aryl, methyl, ethyl, other alkyl, cyclic alkyl, OCH ₃ , NHCH ₃ or M1-CH ₂ -CH ₂ -M ₂ , where M1 is CH ₂ , O and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle;

R _PTM4 is hydrogen, halogen, aryl, methyl, ethyl, OCH ₃ , NHCH ₃ or M1-CH ₂ -CH ₂ -M2, where M1 is CH ₂ , O and NH and M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle; And

R _PTM5 selected from the group consisting of

[0290] According to any aspect or embodiment described in the present invention, the PTM may contain a chemical group selected from the group of chemical structures consisting of PTM-IIa or PTM-IIb:

Where:

X _PTM1 , X _PTM2 ; X _RTM3 , X _RTM4 , X _RTM5 , and X _RTM6 are independently selected from CH or N;

R _PTM5a is selected from the group consisting of: a bond, an optionally substituted amine, an optionally substituted amide (for example, optionally substituted with an alkyl, methyl, ethyl, propyl or butyl group), H,

R _PTM5 selected from the group consisting of

R _PTM6a and R _PTM6b are each independently selected from hydrogen, halogen, or optionally substituted C ₁ -C ₆ alkyl (straight, branched, optionally substituted);

R _PTM6 is absent or is hydrogen, halogen, aryl, methyl, ethyl, OCH ₃ , NHCH ₃ or M1-CH ₂ -CH ₂ -M2, where M1 is CH ₂ , O and NH, and M2 is hydrogen, alkyl , cyclic alkyl, aryl or heterocycle;

R _PTM7 is absent or is hydrogen, halogen, aryl, methyl, ethyl, OCH ₃ , NHCH ₃ or M1-CH ₂ -CH ₂ -M2, where M1 is CH ₂ , O or NH and M2 is hydrogen, alkyl , cyclic alkyl, aryl or heterocycle;

R _PTM8 , R _PTM9 or R _PTM10 are independently absent or selected from the group consisting of hydrogen, halogen, aryl, heteroaryl, alkyl, cycloalkyl, heterocycle, methyl, ethyl, OCH ₃ , NHCH ₃ or M1-CH ₂ -CH ₂ -M2 where M1 represents CH ₂ , O and NH and M2 represents hydrogen, alkyl, cyclic alkyl, aryl or heterocycle;

R _PTM11 is absent or is hydrogen, halogen, methyl, ethyl, OCH ₃ , NH CH ₃ or M1-CH ₂ -CH ₂ -M2, where M1 is CH ₂ , O or NH and M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle; And

at least one of R _PTM8 , R _PTM9 or R _PTM10 is modified to covalently link to a ULM, a chemical linker group (L), CLM, ILM, VLM, MLM, ULM', CLM', ILM', VLM', MLM' or their combination.

[0291] In certain embodiments, the PTM may comprise a chemical group selected from the group of chemical structures consisting of:

where R _PTM5 , R _PTM6a , R _PTM6b , R _PTM6 , R _PTM7 , R _PTM8 , R _PTM9 , R _PTM10 , R _PTM11 are described in the present invention.

[0292] In some embodiments, if R _PTM9 is a covalently linked position, R _PTM7 and R _PTM8 can be linked together via a covalent bond to form a bicyclic group with a ring to which R _PTM7 and RPTM ₈ are attached.

[0293] In other embodiments, if R _PTM8 is a covalently linked position, R _PTM9 and R _PTM10 can be linked together via a covalent bond to form a bicyclic group with a ring to which R _PTM9 and RPTM ₁₀ are attached.

[0294] In further embodiments, if R _PTM10 is a covalently linked position, R _PTM8 and R _PTM9 can be linked together via a covalent bond to form a bicyclic group with a ring to which R _PTM8 and R _PTM9 are attached.

[0295] According to any aspect or embodiment described in the present invention, the PTM may contain a chemical group selected from the group of chemical structures consisting of PTM-III:

Where:

_{X PTM7} , X _PTM8 , X _PTM9 , X _PTM10 , X _PTM11 , X _PTM12 , X _PTM13 , X PTM14, X _PTM15 , X _PTM16 , X _PTM17 , X _PTM18 , X _PTM19 , X _PTM20 independently represent CH or N;

R _PTM12 , R _PTM13 , R _PTM14 , R _PTM15 , R _PTM16 , R _PTM17 , R _PTM18 , R _PTM19 are independently absent or selected from the group consisting of hydrogen, halogen, aryl, heteroaryl, cycloalkyl, heterocycle, methyl, ethyl, other alkyl , OCH ₃ , NHCH ₃ or M1-CH ₂ -CH ₂ -M2, where M1 represents CH ₂ , O and NH, and M2 represents hydrogen, alkyl, cyclic alkyl, aryl or heterocycle;

R _PTM20 is a small group containing less than four non-hydrogen atoms;

R _PTM21 is selected from the group consisting of trifluomethyl, chlorine, bromine, fluorine, methyl, ethyl, propyl, isopropyl, tert-butyl, butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, OCH ₃ , NHCH ₃ , dimethylamino or M1- CH ₂ -CH ₂ -M2, where M1 represents CH ₂ , O or NH, and M2 represents hydrogen, alkyl, cyclic alkyl, aryl or heterocycle; And

at least one of R _PTM12 , R _PTM13 and R _PTM16 is modified to covalently attach to a ULM, chemical linker group (L), CLM, ILM, VLM, MLM, ULM', CLM', ILM', VLM', MLM' or their combinations.

[0296] In some embodiments, if R _PTM12 is a covalently linked position, R _PTM13 and R _PTM14 can be joined together by a covalent bond to form a bicyclic group with a ring to which R _PTM13 and R _PTM14 are attached; and/or R _PTM15 and R _PTM16 can be joined together by a covalent bond to form a bicyclic group with a ring to which R _PTM15 and R _PTM16 are attached.

[0297] In other embodiments, if R _PTM13 is a covalently linked position, R _PTM12 and R _PTM16 can be linked together by a covalent bond to form a bicyclic group with a ring to which R _PTM12 and R _PTM16 are attached; and/or R _PTM15 and R _PTM16 can be joined together by a covalent bond to form a bicyclic group with a ring to which R _PTM15 and R _PTM16 are attached.

[0298] In further embodiments, if R _PTM16 is a covalently linked position, R _PTM12 and R _PTM13 can be linked together by a covalent bond to form a bicyclic group with a ring to which R _PTM12 and R _PTM13 are attached; and/or R _PTM13 and R _PTM14 can be joined together by a covalent bond to form a bicyclic group with a ring to which R _PTM13 and R _PTM14 are attached.

[0299] According to any aspect or embodiment described in the present invention, the PTM may contain a chemical group selected from the group of chemical structures consisting of PTM-IVa or PTM-IVb:

Where:

X _PTM21 , X _PTM22 , X _PTM23 , X _PTM24 , X _PTM25 , X _PTM26 , X _PTM27 , X _PTM28 , X _PTM29, X _PTM30 , X _PTM31 , X _PTM32 , X _PTM33 ; X _PTM34 is independently CH or N;

R _PTM22 selected from the group consisting of

R _PTM25a and R _PTM25b are each independently selected from hydrogen, halogen or C ₁ -C ₆ alkyl (straight, branched, optionally substituted);

R _PTM23 , R _PTM24 , R _PTM28 , R _PTM29 , R _PTM30 , R _PTM31 , R _PTM32 are independently absent or selected from the group consisting of bond, hydrogen, halogen, aryl (optionally substituted), heteroaryl (optionally substituted), cycloalkyl (optional substituted), heterocycle (optionally substituted), methyl, ethyl (optionally substituted), other alkyl (straight, branched, optionally substituted), OCH ₃ , NHCH ₃ or M1-CH ₂ -CH ₂ -M2, where M1 is CH ₂ , O and NH, and M2 is hydrogen, alkyl (straight, branched, optionally substituted), cyclic alkyl (optionally substituted), aryl (optionally substituted) or heterocycle (optionally substituted); And

R _PTM25 is absent or represents hydrogen, halogen, C ₁ -C ₆ alkyl (straight, branched, optionally substituted), OCH3, NHCH ₃ or SCH ₃ ;

R _PTM26 is absent or represents hydrogen, halogen, C ₁ -C ₆ alkyl (straight, branched, optionally substituted), OCH3, NHCH ₃ or SCH ₃ ;

R _PTM27 is absent or selected from the group consisting of hydrogen, halogen, C ₁ -C ₆ alkyl (straight, branched, optionally substituted), OCH ₃ , NHCH ₃ or SCH ₃ ; and at least one of R _PTM24 , R _PTM29 , R _PTM32 is modified to covalently attach to a ULM, chemical linker group (L), CLM, ILM, VLM, MLM, ULM', CLM', ILM', VLM', MLM' or combinations thereof.

[0300] In some embodiments, if R _PTM24 is a covalently linked position, R _PTM31 and R _PTM32 can be joined together by a covalent bond to form a bicyclic group with a ring to which R _PTM31 and R _PTM32 are attached; or R _PTM29 and R _PTM30 can be joined together by a covalent bond to form a bicyclic group with a ring to which R _PTM29 and R _PTM30 are attached.

[0301] In other embodiments, if R _PTM29 is a covalently linked position, R _PTM24 and R _PTM32 can be linked together by a covalent bond to form a bicyclic group with a ring to which R _PTM24 and R _PTM32 are attached; and/or R _PTM31 and R _PTM32 can be joined together by a covalent bond to form a bicyclic group with a ring to which R _PTM31 and R _PTM32 are attached.

[0302] In further embodiments, if R _PTM32 is a covalently linked position, R _PTM24 and R _PTM29 can be linked together via a covalent bond to form a bicyclic group with a ring to which R _PTM24 and R _PTM29 are attached; and/or R _PTM29 and R _PTM30 can be joined together by a covalent bond to form a bicyclic group with a ring to which R _PTM29 and R _PTM30 are attached.

[0303] According to any of the aspects or embodiments described in the present invention, the RTM is selected from the group consisting of the chemical structures RTM-1, RTM-2, RTM-3, RTM-4, RTM-5, RTM-6, RTM-7 and RTM-8:

[0304] According to any aspect or embodiment described in the present invention, the ULM is selected from the group consisting of:

where R _14a represents H, methyl or hydroxymethyl.

Therapeutic compositions

[0305] Pharmaceutical compositions containing combinations of an effective amount of at least one bifunctional compound described herein and one or more of the compounds described elsewhere herein, all of them in effective amounts, in combination with a pharmaceutically effective amount of a carrier , additive or adjuvant, represent an additional aspect of the present disclosure.

[0306] The present disclosure relates, where applicable, to compositions comprising pharmaceutically acceptable salts, particularly acid or base addition salts, of the compounds described herein. The acids that are used to prepare pharmaceutically acceptable acid addition salts of the above basic compounds useful in this aspect are acids that form non-toxic acid addition salts, i.e. salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromic, hydroiodic, nitrate, sulfate, bisulfate, phosphate, hydrophosphate, acetate, lactate, citrate, hydrocitrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate , ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e. 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)] salts, among a number of others.

[0307] Pharmaceutically acceptable base addition salts can also be used to prepare pharmaceutically acceptable salt forms of the compounds or derivatives of the present disclosure. Chemical bases that can be used as reagents to prepare pharmaceutically acceptable base salts of compounds of the present disclosure that are acidic in nature are bases that form non-toxic base salts with these compounds. Such non-toxic base salts include, but are not limited to, salts derived from such pharmacologically acceptable cations as alkali metal cations (eg, potassium and sodium) and alkaline earth metal cations (eg, calcium, zinc and magnesium), ammonium or water-soluble addition salts amine, such as N-methylglucamine (meglumine), and lower alkanolammonium, as well as other basic salts of pharmaceutically acceptable organic amines, among others.

[0308] The compounds described herein in accordance with the present disclosure can be administered in single or divided doses by oral, parenteral or topical routes. Administration of the active compound may range from continuous (intravenous drip) to multiple oral administrations per day (e.g., Q.I.D.) and may include oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include a permeation enhancer), buccal , sublingual administration and administration by suppository, among other routes of administration. Enteric-coated oral tablets can also be used to enhance the bioavailability of compounds via the oral route. The most effective dosage form will depend on the pharmacokinetic parameters of the particular agent chosen, as well as the severity of the disease in the patient. Administration of compounds in the form of sprays, sprays or aerosols for intranasal, intratracheal or pulmonary administration can also be used. The present disclosure, therefore, also relates to pharmaceutical compositions comprising an effective amount of a compound described herein, optionally in combination with a pharmaceutically acceptable carrier, additive or excipient. The compounds of the present disclosure may be administered in immediate release, intermediate release, or sustained or controlled release forms. Sustained or controlled release forms are preferably administered orally, but also in suppository and transdermal or other topical forms. Intramuscular injections in liposomal form may also be used to control or slow the release of the compound at the injection site.

[0309] The compositions described herein can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, and can also be administered in controlled release formulations. Pharmaceutically acceptable carriers that may be used in such pharmaceutical compositions include, but are not limited to, ion exchange agents, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffers such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as prolamine sulfate, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose , polyacrylates, waxes, block polymers of polyethylene and polyoxypropylene, polyethylene glycol and lanolin.

[0310] The compositions described herein may be administered orally, parenterally, by inhalation spray, topical, rectal, nasal, buccal, vaginal, or implanted reservoir. As used herein, the term “parenteral” includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and itracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously.

[0311] Sterile injectable forms of the compositions described herein may be an aqueous or oily suspension. Such suspensions can be formulated according to techniques known in the art, using suitable dispersing or wetting agents as well as suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are traditionally used as a solvent or suspension medium. For this purpose, any finely dispersed non-volatile oil can be used, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful for the preparation of injectable preparations, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylene variants. These oil solutions or suspensions may also contain an alcohol diluent or long chain dispersant such as Ph alcohol. Helv or similar alcohol.

[0312] The pharmaceutical compositions described herein can be administered orally in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions, or solutions. For oral tablets, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also commonly added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral administration, the active ingredient is combined with emulsifying and suspending agents. Certain sweeteners, flavors or colors may also be added if desired.

[0313] Alternatively, the pharmaceutical compositions described herein can be administered in the form of suppositories for rectal administration. They can be prepared by mixing the agent with a suitable non-irritant excipient that is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0314] Pharmaceutical compositions in accordance with the present disclosure can also be administered by topical route. Suitable topical formulations are readily prepared for each of these sites or organs. Topical administration to the lower intestinal tract can be given as a rectal suppository (see above) or in a suitable enema formulation. Transdermal patches suitable for topical administration may also be used.

[0315] For topical use, the pharmaceutical compositions may be formulated as a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. In some preferred aspects of the present disclosure, the compounds can be applied to a stent to be surgically implanted in a patient to inhibit or reduce the likelihood of occlusion occurring in the stent in the patient.

[0316] Alternatively, the pharmaceutical compositions may be formulated into a suitable lotion or cream containing the active ingredients suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl wax esters, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0317] For ophthalmic use, pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, or preferably as solutions in isotonic, pH-adjusted sterile saline, either with or without a preservative such as benzalkonium chloride. preservative. Alternatively, for ophthalmic applications, the pharmaceutical compositions may be formulated as an ointment such as Vaseline.

[0318] Pharmaceutical compositions in accordance with the present disclosure can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as saline solutions using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, hydrofluorocarbons and/or other conventional solubilizing or dispersing agents. funds.

[0319] The amount of compound in the pharmaceutical composition described herein that can be combined with carrier materials to form a unit dosage form will vary depending on the recipient and the disease being treated, the particular route of administration. Preferably, the compositions will be formulated to contain from about 0.05 milligrams to about 750 milligrams or more, more preferably from about 1 milligram to about 600 milligrams, and even more preferably from about 10 milligrams to about 500 milligrams of active ingredient, alone or in combination according to with at least one other compound in accordance with the present disclosure.

[0320] It should also be noted that the specific dosage and treatment regimen for any particular patient will depend on a number of factors, including the potency of the particular compound used, age, body weight, general health, sex, nutrition, time of administration, rate of release , drug combinations and the opinion of the attending physician, as well as the severity of the specific disease or condition being treated.

[0321] A patient or subject in need of therapy using compounds according to the methods described herein can be treated by administering to the patient (subject) an effective amount of a compound according to the present disclosure, including pharmaceutically acceptable salts, solvates, or polymorphs thereof, optionally in a pharmaceutically acceptable carrier or diluent, either alone or in combination with other known erythropoiesis-stimulating agents, as defined elsewhere herein.

[0322] These compounds may be administered by any suitable route, for example, orally, parenterally, intravenously, intradermally, subcutaneously or locally, including transdermally, in liquid, cream, gel or solid or aerosol form.

[0323] The active compound is included in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount for the desired purpose without causing serious toxic effects to the patient being treated. The preferred dose of the active compound for all conditions mentioned herein is in the range from about 10 ng/kg to 300 mg/kg, preferably from 0.1 to 100 mg/kg per day, more often from 0.5 to about 25 mg per kilogram body weight of the recipient/patient per day. A typical dosage for topical administration will range from 0.01-5% w/w in a suitable vehicle.

[0324] The compound is conveniently administered in any suitable unit dosage form, including, but not limited to, containing less than 1 mg, 1 mg to 3000 mg, preferably 5 to 500 mg of active ingredient per unit dosage form. An oral dosage of approximately 25-250 mg is often convenient.

[0325] The active ingredient is preferably administered to achieve peak plasma concentrations of the active compound of about 0.00001-30 mM, preferably about 0.1-30 μM. This can be achieved, for example, by intravenous injection of a solution or formulation of the active ingredient, optionally in saline or aqueous media, or by administration of a bolus of the active ingredient. Oral administration is also suitable for achieving effective plasma concentrations of the active agent.

[0326] The concentration of the active compound in the drug composition will depend on the absorption, distribution, inactivation and release rates of the drug, as well as other factors known to those skilled in the art. It should be noted that dosage values will also vary with the severity of the condition being alleviated. In addition, it should be noted that for any particular subject, specific dosage regimens should be adjusted over time according to individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are provided for exemplary purposes only. and are not intended to limit the scope or implementation of the claimed composition. The active ingredient may be administered all at once or may be divided into several smaller doses to be administered at varying intervals.

[0327] Oral compositions will generally include an inert diluent or edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound or a prodrug derivative thereof can be administered with excipients and used in the form of tablets, lozenges or capsules. Pharmaceutically compatible binders and/or auxiliary materials are included as part of the composition.

[0328] Tablets, pills, capsules, lozenges, etc. may contain any of the following ingredients or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an adjuvant such as starch or lactose, a dispersant such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate or Sterote; a glidant such as colloidal silica; a sweetener such as sucrose or saccharin; or a flavoring agent such as mint, methyl salicylate, or orange flavor. If the unit dosage form is a capsule, it may contain, in addition to the type of material specified above, a liquid carrier such as a fatty oil. In addition, unit dosage forms may contain various other materials that modify the physical form of the dosage unit, such as sugar coatings, shellac, or enteric agents.

[0329] The active compound or a pharmaceutically acceptable salt thereof may be administered as a component of an elixir, suspension, syrup, cachet, chewing gum, or the like. In addition to active compounds, syrup may contain sugar as a sweetener, and some preservatives, dyes and coloring agents, as well as flavorings.

[0330] The active compound or pharmaceutically acceptable salts thereof may also be mixed with other active materials that do not interfere with the desired action, or with materials that complement the desired action, such as erythropoietin stimulating agents, including EPO and darbepoetin alfa, among others. . In certain preferred aspects of the present disclosure, one or more compounds of the present disclosure are administered in conjunction with another bioactive agent, such as an erythropoietin stimulating agent or a wound healing agent, including an antibiotic, as described elsewhere herein.

[0331] Solutions or suspensions used for parenteral, intradermal, subcutaneous or topical use may include the following components: a sterile diluent such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates; and tonicity correctors such as sodium chloride or dextrose. The parenteral drug may be contained in ampoules, disposable syringes, or multiple-dose containers made of glass or plastic.

[0332] For intravenous administration, preferred carriers are physiological saline or phosphate buffered saline (PBS).

[0333] In one embodiment, the active compounds are formulated with carriers that will protect the compound from rapid elimination from the body, for example, in controlled release formulations, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid can be used. Methods for preparing such compositions will be apparent to those skilled in the art.

[0334] Liposomal suspensions can also serve as pharmaceutically acceptable carriers. They can be prepared according to methods known to those skilled in the art, such as those described in US Pat. No. 4,522,811 (which is incorporated herein by reference in its entirety). For example, liposome formulations can be prepared by dissolving a suitable lipid(s) (such as stearoylphosphatidylethanolamine, stearoylphosphatidylcholine, arachadoylphosphatidylcholine and cholesterol) in an inorganic solvent, which is then evaporated, leaving behind a thin film of dried lipid on the surface of the container. The aqueous solution of the active compound is then introduced into the container. The container is then rotated manually to release lipid material from the walls of the container and disperse the lipid aggregates, thereby forming a liposome suspension.

Therapeutic methods

[0335] In a further aspect, the present disclosure provides therapeutic compositions containing an effective amount of a compound described herein, or a salt form thereof, and a pharmaceutically acceptable carrier. Therapeutic compositions modulate protein degradation in a patient or subject, for example, an animal such as a human, and can be used to treat or alleviate disease states or conditions that are modulated by protein degradation.

[0336] As used herein, the terms “treat,” “treatment process,” “treatment,” and the like. refer to any action that provides benefit to a patient to whom the compounds of the present invention may be administered, including the treatment of any disease state or condition that is modulated by the protein to which the compounds of the present invention bind. Diseases or conditions, including malignancy, heart-face-skin syndrome, neurofibromatosis type 1, Costello syndrome, Noonan syndrome, LEOPARD syndrome (lentigo, electrocardiographic abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, slow growth, hearing loss), which can be treated using the compounds of this disclosure are set forth herein above.

[0337] The present disclosure relates to the therapeutic compositions described herein for effecting the degradation of proteins of interest for the purpose of treating or ameliorating a disease, for example, cancer, heart-face-skin syndrome, neurofibromatosis type 1, Costello syndrome, Noonan syndrome or LEOPARD syndrome (lentigo, electrocardiographic pathologies, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retarded growth, hearing loss). In some further embodiments, the disease is multiple myeloma. Thus, in another aspect, the present disclosure relates to a method for ubiquitination/cleavage of a target protein in a cell. In some embodiments, the method comprises administering a bifunctional compound as described herein, comprising, for example, a ULM and a PTM, preferably linked via a linker moiety as described elsewhere herein, wherein the ULM is attached to the PTM and wherein the ULM recognizes a ubiquitin pathway protein (e.g., a ubiquitin ligase, such as E3 ubiquitin ligase, including cereblon, VHL, IAP and/or MDM2), and PTM recognizes the target protein such that degradation of the target protein will occur when the target protein is placed in close proximity to the ubiquitin ligase, thereby leading to degradation/inhibition of the effects of the target protein and control of protein content. Protein control provided by the present disclosure relates to the treatment of a disease state or condition that is modulated by a target protein by reducing the content of that protein in the cells of the patient. In some embodiments, the method comprises administering an effective amount of a compound described herein, optionally with a pharmaceutically acceptable excipient, carrier, adjuvant, other bioactive agent, or a combination thereof.

[0338] In further embodiments, the present disclosure relates to methods of treating or alleviating a disease, disorder, or symptom thereof in a subject or patient, e.g., an animal such as a human, comprising administering to the subject, as needed, a composition containing an effective amount, e.g., a therapeutically effective amount an amount of a compound described herein, or a salt form thereof, and a pharmaceutically acceptable adjuvant, carrier, adjuvant, other bioactive agent, or combinations thereof, wherein the composition is effective in treating or alleviating a disease, disorder, or symptom thereof in a subject.

[0339] In another aspect, the present disclosure relates to methods for identifying the effects of degradation of proteins of interest in a biological system using compounds in accordance with the present disclosure.

[0340] In another embodiment, the present disclosure relates to a method of treating a disease or condition modulated by a protein in a human patient in need thereof, wherein cleavage of the protein will provide a therapeutic effect to the patient, the method comprising administering to the patient in need thereof, an effective amount of a compound according to the present disclosure, optionally in combination with another bioactive agent. The disease or condition may be a disease caused by a microbial pathogen or other exogenous pathogen, such as a virus, bacteria, fungus, protozoan, or other microbe, or may be a disease condition that is caused by overexpression and/or overactivation (eg, constitutive activation) of a protein that leads to a disease and/or condition.

[0341] The term “disease or condition” is used to describe any disease or condition in which a protein is dysregulated (i.e., the amount of protein expressed in the patient is increased) and in which the breakdown of one or more proteins in the patient may provide successful therapy or reduce the patient’s symptoms if necessary. In some cases, the disease or condition can be cured.

[0342] Diseases or conditions that can be treated using the compounds of this disclosure include, for example, asthma, autoimmune diseases such as multiple sclerosis, various malignancies, ciliopathies, cleft palate, diabetes mellitus, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorder, obesity, refractive error, infertility, Angelman syndrome, Canavan disease, celiac disease, Charcot-Marie-Tooth disease, cystic fibrosis, Duchenne muscular dystrophy, hemochromatosis, hemophilia, Klinefelter syndrome, neurofibromatosis, phenylketonuria, polycystic kidney disease, Prader-Willi syndrome (PKD1) or 4 (PKD2), sickle cell disease, Tay-Sachs disease, Turner syndrome.

[0343] The term "neoplasia" or "malignant tumor" is used throughout the specification to refer to a pathological process that results in the formation and growth of cancerous or malignant neoplasms, that is, abnormal tissue that grows by cellular proliferation, often faster than normal, and continues to grow after the cessation of the stimuli that initiated new growth. Malignant neoplasms show a partial or complete lack of structural organization and functional coordination with normal tissue and intensively penetrate into surrounding tissues, metastasize in several places, often recur after attempted removal and cause the death of the patient if adequate treatment is not carried out. As used herein, the term “neoplasia” is used to describe all cancers and includes or covers the pathological process associated with malignant hematogenous, ascitic and solid tumors. Examples of cancers that can be treated with the compounds of the present invention either alone or in combination with at least one additional anticancer agent include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma and renal cell carcinoma, bladder cancer , intestines, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate and stomach; leukemia; benign and malignant lymphomas, especially Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma, hemangiosarcomas, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, glioblastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, tumors Ewing pineal cells, meningioma, meningioma, meningeal sarcoma, neurofibroma and schwannoma; colon cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms tumor and teratocarcinoma. Additional malignancies that may be treated using the compounds of this disclosure include, for example, T-lineage acute lymphoblastic leukemia (T-ALL), T-lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, T -adult cell leukemia, B-cell acute lymphoblastic leukemia of progenitor cells, B-cell lymphomas of progenitor cells, large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome positive ALL and Philadelphia chromosome positive CML.

[0344] The term "bioactive agent" is used to describe an agent, other than a compound of the present disclosure, that is used in combination with compounds of the present invention as an agent with biological activity to provide the intended therapy, inhibition and/or prevention /prophylaxis, for which the compounds according to the present invention are used. Preferred bioactive agents for use herein include those that have pharmacological activity similar to that for which the compounds of the present invention are used or administered, and include, for example, anticancer agents, antiviral agents, e.g. including anti-HIV agents, anti-retroviral and anti-HCV agents, antimicrobial agents, antifungal agents, etc.

[0345] The term “additional anticancer agent” is used to describe an anticancer agent that can be combined with compounds of the present disclosure for the treatment of cancer. Such agents include, for example, everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI -258, GSK461364, AZD 1152, enzastaurine, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitor, androgen receptor inhibitor, VEGFR inhibitor, EGFR TK inhibitor, aurora kinase inhibitor, PIK-1 modulator, Bcl-2 inhibitor, HDAC inhibitor, c-MET inhibitor, PARP inhibitor, Cdk inhibitor, EGFR TK inhibitor, IGFR-TK inhibitor, anti-HGF antibody, PI3 kinase inhibitors, AKT inhibitor, JAK inhibitor /STAT, checkpoint inhibitor 1 or 2, focal adhesion kinase inhibitor, MAP kinase inhibitor (mek), VEGF trap antibody, pemetrexed, erlotinib, dasatanib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifen, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, hemate kan, IL13 -PE38QQR, INO 1001, IPdR ₁ KRX-0402, lucanton, LY317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, this Posid, gemsitabine , doxorubicin, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidine-5- yl)ethyl]-benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258; 3-[5-(methylsulfonylpiperadinemethyl)-indolyl-quinolone, vatalanib, AG-013736, AVE-0005, acetate salt [D-Ser(But)-6-Azgly-10] (pyro-Glu-His-Trp-Ser- Tyr-D-Ser(But)-Leu-Arg-Pro-Azgly-NH ₂ acetate [C ₅₉ H ₈₄ N ₁₈ O ₁₄ -(C ₂ H ₄ O ₂ ) _X ; where x = 1-2.4], goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib , lapatanib, canertinib, ABX- antibody EGF, erbitux, EKB-569, PKI-166, GW-572016, lonafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoyl analide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, zorafenib, KRN9 51, aminoglutethimide , amzacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin vaccine (BCG), adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, Gleevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomi cin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estra mustine, altretamine , floxuridine, 5-deooxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU666 8, EMD121974, interleukin-12, IM862, angiostatin, Vitaxin, droloxifene, idoxifene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox, gefitinib, bortesimibe, paclitaxel, Cremophor-free paclitaxel, docetaxel, epitilone B, BMS-247550 , BMS-310705 , droloxifene, 4-hydroxytamoxifene, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787/ZK 222584, VX-745, PD 184352, rapamycin, 40 -O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, AVT-578, VS-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, P EG-filgrastim, darbepoetin , erythropoietin, granulocyte colony-stimulating factor, zoledronate, prednisone, cetuximab, granulocyte-monocyte colony-stimulating factor, histrelin, pegylated interferon alpha-2a, interferon alpha-2a, pegylated interferon alpha-2b, interferon alpha-2b, azacitidine, PEG-L-asparagine zu , lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, decorazoxan, alemtuzumab, all-transretinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, then zitumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosrorine, liposomal daunorubicin, Edwina-asparaginase, strontium 89, casopitant, netupitant, NK-1 receptor antagonist, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabine ol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa and mixtures thereof.

[0346] The term "anti-HIV agent", "anti-retroviral agent" or "additional anti-HIV agent" includes, for example, nucleoside reverse transcriptase inhibitors (NRTIs), other non-nucleoside reverse transcriptase inhibitors (i.e., those that are not typical of the present disclosure), protease inhibitors, fusion inhibitors, among others, illustrative compounds, which may include, for example, 3TC (lamivudine), AZT (zidovudine), (-)-FTC, ddI (ddidanosine), ddC (zalcitabine), abacavir (ABC), tenofovir (PMPA), D-D4FC (reverset), D4T (stavudine), racivir, L-FddC, L-FD4C, NVP (nevirapine), DLV (delavirdine), EFV (efavirenz) , SQVM (saquinavir mesylate), RTV (ritonavir), IDV (indinavir), SQV (saquinavir), NFV (nelfinavir), APV (amprenavir), LPV (lopinavir), fusion inhibitors such as T20, among others, fuzeon and their mixtures, including anti-HIV compounds currently in clinical trials or in development.

[0347] Other anti-HIV/anti-retroviral agents that may be used in co-administration with other compounds of the present disclosure include, for example, other NNRTIs (i.e., other than the NNRTIs of the present disclosure), which may be selected from the group consisting of nevirapine (BI-R6-587), delavirdine (U-90152S/T), efavirenz (DMP-266), UC-781 (N-[4-chloro-3-(3- methyl-2-butenyloxy)phenyl]-2-methyl-3-furancarbothiamide), etravirine (TMC125), trovirdine (Ly300046.HCl), MKC-442 (emivirine, coactinone), HI-236, HI-240, HI-280 , HI-281, rilpivirine (TMC-278), MSC-127, HBY 097, DMP266, baicalin (TJN-151) ADAM-II (methyl-3',3'-dichloro-4',4''-dimethoxy- 5',5''-bis(methoxycarbonyl)-6,6-diphenylhexenoate), methyl 3-bromo-5-(1-5-bromo-4-methoxy-3-(methoxycarbonyl)phenyl)hept-1-enyl )-2-methoxybenzoate (alkenyldiarylmethane analogue, Adam analogue), (5-chloro-3-(phenylsulfinyl)-2'-indolecarboxamide), AAP-VHAR (U-104489 or PNU-104489), capravirine (AG-1549, S -1153), atevirdine (U-87201E), aurine tricarboxylic acid (SD-095345), 1-[(6-cyano-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine, 1 -[5-[[N-(methyl)methylsulfonylamino]-2-indolylcarbonyl-4-[3-(isopropylamino)-2-pyridinyl]piperazine, 1-[3-(ethylamino)-2-[pyridinyl]-4- [(5-hydroxy-2-indolyl)carbonyl]piperazine, 1-[(6-formyl-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine, (methylsulfonyloxy)-2- indoyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine, U88204E, bis(2-nitrophenyl)sulfone (NSC 633001), calanolide A (NSC675451), calanolide B, 6-benzyl-5-methyl -2-(cyclohexyloxy)pyrimidin-4-one (DABO-546), DPC 961, E-EBU, E-EBU-dm, E-EPSeU, E-EPU, foscarnet (foscavir), HEPT (1-[(2 -hydroxyethoxy)methyl]-6-(phenylthio)thymine), HEPT-M (1-[(2-hydroxyethoxy)methyl]-6-(3-methylphenyl)thio)thymine), HEPT-S (1-[(2 -hydroxyethoxy)methyl]-6-(phenylthio)-2-thiothimine), inophyllum P, L-737,126, michellamine A (NSC650898), michellamine B (NSC649324), michellamine F, 6-(3,5-dimethylbenzyl)-1 -[(2-hydroxyethoxy)methyl]-5-isopropyluracil, 6-(3,5-dimethylbenzyl)-1-(ethoxymethyl)-5-isopropyluracil, NPPS, E-BPTU (NSC 648400), oltipraz (4-methyl- 5-(pyrazinyl)-3H-1,2-dithiol-3-thione), N-{2-(2-chloro-6-fluorophenethyl]-N'-(2-thiazolyl)thiourea (Cl, F derivative of PETT) , N-{2-(2,6-difluorophenethyl]-N'-[2-(5-bromopyridyl)]thiourea {PETT derivative), N-{2-(2,6-difluorophenethyl]-N'-[2 -(5-methylpyridyl)]thiourea {PETT-pyridyl derivative), N-[2-(3-fluorofuranyl)ethyl]-N'-[2-(5-chloropyridyl)]thiourea, N-[2-(2- fluoro-6-ethoxyphenethyl)]-N'-[2-(5-bromopyridyl)]thiourea, N-(2-phenethyl)-N'-(2-thiazolyl)thiourea (LY-73497), L-697,639, L -697.593, L-697.661, 3-[2-(4,7-difluorobenzoxazol-2-yl)ethyl}-5-ethyl-6-methyl(piperidine-2(1H)-thione (2-pyridinone derivative), 3 -[[(2-methoxy-5,6-dimethyl-3-pyridyl)methyl]amine]-5-ethyl-6-methyl(piperidine-2(1H)-thione, R82150, R82913, R87232, R88703, R89439 ( loviride), R90385, S-2720, sodium suramin, TBZ (thiazolebenzimidazole, NSC 625487), thiazolisoindol-5-one, (+)(R)-9b-(3,5-dimethylphenyl-2,3-dihydrothiazolo[2, 3-a]isoindol-5(9bH)-one, tivirapine (R86183), UC-38 and UC-84, among others.

[0348] The term "pharmaceutically acceptable salt" is used throughout the specification to describe, as appropriate, a salt form of one or more compounds described herein that are presented to increase the solubility of the compound in the gastric juices of the gastrointestinal tract of a patient to promote dissolution and bioavailability of compounds. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids, as appropriate. Suitable salts include those derived from alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium, magnesium and ammonium salts, among numerous other acids and bases well known in the pharmaceutical field. Sodium and potassium salts are particularly preferred in the form of neutralizing phosphate salts in accordance with the present disclosure.

[0349] The term "pharmaceutically acceptable derivative" is used throughout this specification to describe any pharmaceutically acceptable prodrug (such as an ester, amide, other prodrug) that, when administered to a patient, directly or indirectly delivers a compound of the present invention or an active metabolite of a compound of the present invention .

General approach to synthesis

[0350] The implementation and optimization of the synthesis of bifunctional molecules described herein can be achieved in a stepwise or modular manner. For example, identifying compounds that bind to target molecules may involve high- or medium-throughput screening approaches when suitable ligands are not immediately available. For parent ligands, there is often a need for iterative design and optimization cycles to improve upon suboptimal aspects identified from in vitro assays, pharmacological assays, and/or ADMET assays. Part of the optimization/SAR approach will be to explore ligand positions that are resistant to substitution and that may be suitable sites for attachment of the linker chemical group previously referred to herein. In case crystallographic or structural data obtained by NMR are available, they can be used to focus such a synthesis attempt.

[0351] Using a very similar approach, E3 ligase ligands, i.e., ULM/ILM/VLM/CLM/ILM, can be identified and optimized.

[0352] Given PTM and ULM (eg, ILM, VLM, CLM and/or ILM), one skilled in the art can use known synthetic methods to combine them with or without a linker moiety. Linker moieties can be synthesized in a range of compositions, lengths and flexibility and functionalized such that PTM and ULM groups can be attached sequentially to the distal ends of the linker. In this way, a library of bifunctional molecules can be generated and profiled in in vitro and in vivo pharmacological studies and ADMET/PK studies. As with the PTM and ULM groups, the final bifunctional molecules can be subjected to iterative design and optimization cycles to identify molecules with the desired properties.

[0353] In some cases, protecting group strategies and/or functional group interconversion (FGI) may be required to facilitate the preparation of the desired substances. Such chemical methods are well known to one skilled in the art of synthetic organic chemistry and many of them can be found in the literature, such as "Greene's Protective Groups in Organic Synthesis" by Peter G.M. Wuts and Theodora W. Greene (Wiley), and “Organic Synthesis: The Disconnection Approach” by Stuart Warren and Paul Wyatt (Wiley).

[0354] List of abbreviations

[0355] AcOH, acetic acid

[0356] aqueous, aqueous

[0357] BINAP, 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene

[0358] Boc, tert-butoxycarbonyl

[0359] Boc ₂ O, di-tert-butyl dicarbonate

[0360] BOP, (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate

[0361] CDCl ₃ , deuteriochloroform

[0362] CD3OD, deuteriomethanol

[0363] CH ₃ CN, acetonitrile

[0364] CH ₃ OH, methanol

[0365] CsF, cesium fluoride

[0366] Cs ₂ CO ₃ , cesium carbonate

[0367] Cu(OAc) ₂ , copper(II) acetate

[0368] Cy ₂ NMe, dicyclohexylmethylamine

[0369] DCM, dichloromethane

[0370] DIAD, diisopropyl azodicarboxylate

[0371] DIEA or DIPEA, diisopropylethylamine

[0372] DMAP, N,N-dimethylaminopyridine

[0373] DMF, N,N-dimethylformamide

[0374] DMSO, dimethyl sulfoxide

[0375] DMSO-d ₆ , hexadeuterodimethyl sulfoxide

[0376] Et ₂ NH, diethylamine

[0377] EtOAc or EA, ethyl acetate

[0378] HCl, hydrochloric acid

[0379] H ₂ O, water

[0380] HPLC, high performance liquid chromatography

[0381] IBX, 2-iodoxybenzoic acid

[0382] KOAc, potassium acetate

[0383] LCMS, liquid chromatography/mass spectrometry

[0384] LiOH, lithium hydroxide

[0385] MeOH, methanol

[0386] MsCl, methane sulfonyl chloride

[0387] N ₂ , nitrogen

[0388] NaH, sodium hydride

[0389] NaBH ₃ CN, sodium cyanoborohydride

[0390] NaBH(OAc) ₃ , sodium triacetoxyborohydride

[0391] NaCl, sodium chloride

[0392] NaHCO ₃ , sodium bicarbonate

[0393] NaI, sodium iodide

[0394] Na ₂ SO ₄ , sodium sulfate

[0395] n-BuLi, n-butyllithium

[0396] NH ₃ , ammonia

[0397] NH ₄ Cl, ammonium chloride

[0398] NH ₂ OH⋅HCl, hydroxylamine hydrochloride

[0399] NMP, N-methylpyrrolidone

[0400] NMR, nuclear magnetic resonance

[0401] O ₂ , oxygen

[0402] Pd(aMPhos)Cl ₂ , bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)

[0403] Pd ₂ (dba) ₃ , tris(dibenzylideneacetone)dipalladium (0)

[0404] Pd(dppf)Cl ₃ , [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)

[0405] Pd(OH) ₂ , palladium hydroxide

[0406] Pd(PPh ₃ ) ₄ , tetrakis(triphenylphosphine) palladium (0)

[0407] PE, petroleum ether

[0408] Ph ₃ P, triphenylphosphine

[0409] Roux, pyridine

[0410] RuBOP, (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate

[0411] room temperature

[0412] TBAF, tetra-n-butylammonium fluoride

[0413] TBDPSCl, tert-butyldiphenylsilyl chloride

[0414] TBS, tert-butyldimethylsilyl

[0415] tBuOK, potassium tert-butoxide

[0416] [tBu ₃ PH]BF ₄ , tri-tert-butylphosphonium tetrafluoroborate

[0417] TEA, triethylamine

[0418] THF, tetrahydrofuran

[0419] TLC, thin layer chromatography

[0420] TMSOTf, trimethylsilyl trifluoromethanesulfonate

[0421] TsCl, para-toluenesulfonyl chloride

[0422] TsOH, para-toluenesulfonic acid

[0423] Scheme 1.

[0424] The compound of formula I can be reacted with reagent II (commercially available or readily prepared using standard reaction techniques known to one skilled in the art) under palladium catalyzed cross-coupling conditions, for example, using a suitable palladium catalyst such as a bis(di- tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), a suitable base such as cesium fluoride, a suitable solvent such as a mixture of 1,4-dioxane and water, at a suitable temperature such as 100°C, with or without microwave irradiation to obtain a compound of formula III. One of M or M' represents a functional group capable of undergoing palladium-catalyzed transmetalation, for example, boronic acid, boronic acid ester or trialkylstannane; the other of M or M' represents a functional group capable of undergoing palladium-catalyzed oxidative addition, for example, iodide, bromide, chloride or trifluoromethanesulfonate; Ar is an aromatic or heteroaromatic ring system; L represents an optional linker or part of a linker, is a primary or secondary amine, optionally cyclized into a 4-8 membered heterocyclic ring, where PG represents a suitable protecting group, including without limitation t-butoxycarbonyl or benzyl. Compounds of formula III can be converted to a compound of formula IV by treatment with a reagent suitable for removing PG, for example hydrogen chloride in 1,4-dioxane if the PG is t-butoxycarbonyl. Compound IV can then be reacted with compound V to produce compound VI, where L' is an optional linker or part of a linker, Y is CH ₂ or C=O, and X is either a suitable leaving group (eg OMs, OTs, Cl, etc. .p.), or aldehyde (CHO). When X represents a leaving group, n represents 0 and suitable reaction conditions are the same as for the alkylation reaction, eg diisopropylethylamine, potassium iodide, DMSO or acetonitrile, 80°C. When X is an aldehyde, n is 1 and suitable reaction conditions are the same as for the reductive amination reaction, eg sodium cyanoborohydride, methanol, dichloromethane, acetic acid, room temperature.

[0425] Scheme 2.

[0426] A compound of formula IV can also be reacted with a compound of formula VII to produce compounds of formula VIII wherein X is a suitable leaving group such as fluorine or chlorine, Y is C=O and the reaction conditions are the same as for nucleophilic aromatic substitution, eg triethylamine, DMSO, 70°C.

[0427] Scheme 3.

[0428] The compound of formula I can be reacted with reagent IX (commercially available or readily prepared using standard reaction techniques known to one skilled in the art) under palladium-catalyzed cross-coupling conditions, for example, as shown in Scheme 1, to produce the compound of formula X. One of M or M' is a functional group capable of undergoing palladium-catalyzed transmetalation, e.g., boronic acid, boronic acid ester or trialkyl stane, and the other of M or M' is a functional group capable of undergoing palladium-catalyzed oxidative addition, e.g., iodide, bromide, chloride or trifluoromethanesulfonate; Ar is an aromatic or heteroaromatic ring system; L is an optional linker or part of a linker and PG is a suitable ester protecting group, for example methyl, ethyl or tert-butyl. Compounds of formula X can be converted to compound of formula XI by treatment with a reagent suitable for removing PG, for example hydrogen chloride in 1,4-dioxane if the PG is tert-butyl. Compound XI can then be reacted with compound XII where Z is an optional substituent, e.g. H, methyl or hydroxymethyl, to give compounds of formula XIII under amide forming conditions, e.g. (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate, diisopropylethylamine, DMF, room temperature temperature.

[0429] Scheme 4.

[0430] Alternatively, a compound of formula IX can be converted to a compound of formula XIV using conditions similar to those for the conversion of compound X to compound XI in Scheme 3. A compound of formula XIV can be converted to a compound of formula XV using conditions similar to those for the conversion compound XI to compound XIII in Scheme 3. The compound of formula XV can then be converted to compound of formula XIII by reacting with a compound of formula I using conditions similar to those for converting compounds I and IX to compound X in scheme 3.

[0431] Scheme 5.

[0432] The compound of formula XVI can be reacted with reagent II' (commercially available or readily prepared using standard reaction techniques known to one skilled in the art) under Chan-Lam cross-coupling reaction conditions, for example copper(II) acetate, pyridine or diethylamine or triethylamine, 100°C, to obtain the compound of formula XVII. M' represents boronic acid or ester of boronic acid; Ar is an aromatic or heteroaromatic ring system; L represents an optional linker, is a primary or secondary amine, optionally cyclized into a 4-8 membered heterocyclic ring, where PG represents a suitable protecting group, including without limitation t-butoxycarbonyl or benzyl. Compounds of formula XVII can react with reagent XVIII under palladium-catalyzed cross-coupling conditions, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, tri-tert-butylphosphine tetrafluoroborate, cesium fluoride, 1,4-dioxane, 90°C , to obtain a compound of formula XIX. M represents a functional group capable of undergoing palladium-catalyzed transmetalation, for example, boronic acid, boronic acid ester or trialkyl stannane and Ar' represents an aromatic or heteroaromatic ring system with optional substituents. The compound of formula XIX can then be converted to the compound of formula XX by treatment with a reagent suitable for removing PG, for example hydrogen chloride in 1,4-dioxane or methanol if the PG is tert-butyl. A compound of formula XX can also be reacted with a compound of formula VII to produce compounds of formula XXI, wherein X is a suitable leaving group such as fluorine or chlorine, Y is C=O, the aromatic ring of compound VII may contain additional optional substituents, and the reaction conditions are as follows: , as for nucleophilic aromatic substitution, for example, triethylamine, DMSO, 80°C. In cases where the Ar' group contains optional substituents, for example a ketone, it can be further functionalized, for example by treatment with hydroxylamine hydrochloride and pyridine at room temperature, to obtain additional compounds of formula XXI.

[0433] Scheme 6.

[0434] Alternatively, a compound of formula XVII can be converted to a compound of formula XXII using conditions similar to those for converting compound XIX to compound XX in Scheme 5. The compound of formula XXII can then be treated with a compound of formula VII as defined in Scheme 5, with obtaining the compound of formula XXIII. The compound of formula XXIII can then be treated with reagent XVIII, as defined in Scheme 5, to obtain the compound of formula XXI. In cases where the Ar' group contains optional substituents, for example a ketone, it can be further functionalized, for example by treatment with hydroxylamine hydrochloride and pyridine at room temperature, to obtain additional compounds of formula XXI.

[0435] Diagram 7.

[0436] A compound of formula XXIV (prepared in a similar manner to preparing compound XVII from compound XVI and II' in Scheme 5, with additional functional group transformations as necessary, which are well known to one skilled in the art) can be reacted with a compound of formula XXV to produce a compound of formula XXVI under reductive amination conditions, e.g. sodium cyanoborohydride, acetic acid, methanol, room temperature. As used herein, Ar represents an aromatic or heteroaromatic ring system; L and L' represent an optional linker or part of a linker, is a primary or secondary amine, optionally cyclized into a 4-8 membered heterocyclic ring, and Y is CH ₂ or C=O. The compound of formula XXVI can then be treated with reagent XVIII, as defined in Scheme 5, to obtain the compound of formula XXVII. In cases where the Ar' group contains optional substituents, for example a ketone, it can be further functionalized, for example by treatment with hydroxylamine hydrochloride and pyridine at room temperature, to obtain additional compounds of formula XVII.

[0437] Diagram 8.

[0438] Alternatively, the compound of formula XXII can be treated with the compound of formula XXVIII under reductive amination conditions, for example, as in Scheme 7, to obtain the compound of formula XXVI'. In the present description, Ar, L, L', and Y are defined in Scheme 7. The compound of formula XXVI' can then be treated with reagent XVIII as defined in Scheme 5 to give the compound of formula XXVII'. In cases where the Ar' group contains optional substituents, for example, a ketone, it can be further functionalized, for example, by treatment with hydroxylamine hydrochloride and pyridine at room temperature, to obtain additional compounds of formula XVII'.

[0439] Diagram 9.

[0440] A compound of formula XIX may be reacted with a compound of formula VII to produce compounds of formula XXX, wherein X is a suitable leaving group such as fluorine or chlorine, Y is C=O, the aromatic ring of compound VII may further contain optional substituents and reactive conditions are the same as for nucleophilic aromatic substitution, eg diisopropylethylamine, NMP, 130° C., with or without microwave irradiation.

[322] Scheme 10.

[0442] Alternatively, a compound of formula XIX can be treated with a compound of formula XXVIII to give a compound of formula XXXI under reductive amination conditions, eg, sodium triacetoxyborohydride, ethanol, dichloromethane, room temperature.

[0443] Diagram 11.

[0444] Alternatively, a compound of formula XXXII, prepared from a compound of formula XIX by simple transformations well known to one skilled in the art, such as alkylation or reductive amination, can be reacted with a compound of formula XII to produce a compound of formula XXXIII under amide-forming conditions, for example (benzotriazole -1-yloxy)tripyrrolidinophosphonium hexafluorophosphate, diisopropylethylamine, DMF, room temperature

[0445] Diagram 12.

[0446] The compound of formula XXXIV can be reacted with reagent XXXV (commercially available or readily prepared using standard reaction techniques known to one skilled in the art) under nucleophilic substitution conditions, for example, potassium carbonate, potassium iodide, DMSO, 60°C, to give compounds of formula XXXVI. Alternatively, the reaction conditions may be the same as for the Mitsunobu reaction, eg triphenylphosphine, diethyl azodicarboxylate, THF. In the present description, Y represents CH ₂ or C=O; one of M or M' represents a functional group capable of undergoing palladium-catalyzed transmetalation, for example, boronic acid, boronic acid ester or trialkylstannane; the other of M or M' represents a functional group capable of undergoing palladium-catalyzed oxidative addition, for example, iodide, bromide, chloride or trifluoromethanesulfonate; Ar is an aromatic or heteroaromatic ring system; and L is a linker. If the reaction is a nucleophilic substitution reaction, X represents a suitable leaving group, for example p-toluenesulfonate, methanesulfonate, iodide, bromide or chloride; if the reaction is a Mitsunobu reaction, X represents OH. The compound of formula XXXVI can then be further transformed by reaction with compound I under palladium-catalyzed cross-coupling conditions, for example using a suitable palladium catalyst such as bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), a suitable base, such as cesium fluoride, a suitable solvent such as a mixture of 1,4-dioxane and water, at a suitable temperature, such as 100°C, with or without microwave irradiation to obtain the compound of formula XXXVII.

[0447] Diagram 13.

[0448] The compound of formula I can react with reagent XXXVIII (easily prepared using standard reaction techniques known to one skilled in the art) under palladium catalyzed cross-coupling conditions, for example [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) , sodium carbonate, in a suitable solvent, such as a mixture of 1,4-dioxane/water, at a suitable temperature, such as 100° C., with or without microwave heating, to obtain the compound of formula XXXIX. One of M or M' represents a functional group capable of undergoing palladium-catalyzed transmetalation, for example, boronic acid, boronic acid ester or trialkylstannane; the other of M or M' represents a functional group capable of undergoing palladium-catalyzed oxidative addition, for example, iodide, bromide, chloride or trifluoromethanesulfonate; Ar is an aromatic or heteroaromatic ring system; L is an optional linker or part of a linker and PG is a suitable ester protecting group, for example methyl, ethyl or tert-butyl. Compounds of formula XXXIX can be converted to compound of formula XL by treatment with a reagent suitable for removing PG, for example sodium hydroxide in methanol and water at 40° C. if the PG is methyl or ethyl. Compound XL can then be reacted with compound XLI, where Z is an optional substituent such as H, methyl or hydroxymethyl, to produce compounds of formula XLII under amide forming conditions, for example N-[(dimethylamino)-1H-1,2,3- triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanamine hexafluorophosphate N-oxide, diisopropylethylamine, DMF, room temperature.

[0449] Diagram 14.

[0450] A compound of formula XLIII can be reacted with reagent XLIV (commercially available or readily prepared using standard reaction techniques known to one skilled in the art) under nucleophilic substitution conditions, e.g., cesium carbonate, DMF, 75°C, to produce a compound of formula XLV . Ar is an aromatic or heteroaromatic ring system; X represents a suitable leaving group, for example p-toluenesulfonate, methanesulfonate, iodide, bromide or chloride; L is an optional linker; and PG is a suitable ester protecting group, for example methyl, ethyl or tert-butyl. Compounds of formula XLV can be converted to compound of formula XLVI by treatment with a reagent suitable for removing PG, for example 3N hydrochloric acid in 1,4-dioxane at room temperature if the PG is t-butyl. Compound XLVI can then be reacted with compounds XII as defined in Scheme 3 to produce compounds of formula XLVII under amide forming conditions, eg (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate, diisopropylethylamine, DMF, room temperature. The compound of formula XLVII can then be treated with reagent XVIII as defined in Scheme 5 to obtain the compound of formula XLVIII. In cases where the Ar' group contains optional substituents, for example a ketone, it can be further functionalized, for example by treatment with hydroxylamine hydrochloride and pyridine at room temperature, to obtain additional compounds of formula XLVIII.

[0451] Intermediate 1: (3R)-N-[3-([5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl1carbonyl)-2.4-difluorophenyl1-3-fluoropyrrolidine-1-sulfonamide

[0452] Stage A:

[0453] 2,6-difluoro-3-nitrobenzoyl chloride

[0454] In a 150 mL round bottom flask, 2,6-difluoro-3-nitrobenzoic acid (15.0 g, 73.8 mmol, 1.0 equiv.), toluene (80 mL), and thionyl chloride (80 mL) were placed. The resulting mixture was stirred at 80°C overnight and concentrated under reduced pressure. This resulted in 14.1 g (86%) of 2,6-difluoro-3-nitrobenzoyl chloride as a brown oil.

[0455] Step B: 5-bromo-3-[(2,6-difluoro-3-nitrophenyl)carbonyl]-1H-pyrrolo[2,3-b]pyridine

[0456] 5-Bromo-1H-pyrrolo[2,3-b]pyridine (11.0 g, 55.8 mmol, 1.1 equiv.) was mixed with 200 ml of chloromethane and aluminum trichloride (42.0 g, 318.2 mmol, 6.4 equiv.). The reaction mixture was stirred at room temperature for 1 hour, and 2,6-difluoro-3-nitrobenzoyl chloride (11.0 g, 49.6 mmol, 1.0 equiv.) was added. The reaction mixture was heated at 50°C overnight, then the reaction mixture was cooled to room temperature, poured into ice water (500 ml) and extracted with ethyl acetate (500 ml x 3). The combined organic layer was washed with brine (500 ml×2) and dried over anhydrous sodium sulfate. The solvent was concentrated to give (5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)(2,6-difluoro-3-nitrophenyl)methanone (12.2 g) as a yellow solid, which used directly in the next step without further purification. LCMS (ES ⁺ ): m/z 381.30 [M+H] ⁺ .

[0457] Step C: 3-([5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl)-2,4-difluoroaniline

[0458] Mixture of (5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)(2,6-difluoro-3-nitrophenyl)-methanone (7.8 g, 20.4 mmol, 1 .0 equiv.), iron (5.6 g, 100.2 mmol, 4.9 equiv.), ammonium chloride (3.6 g, 68 mmol) and hydrochloric acid (25.0 ml) in ethanol (40 ml ) and tetrahydrofuran (40 ml) were refluxed overnight. After cooling to room temperature, the mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/2) to give (3-amino-2,6-difluorophenyl)(5-bromo-1H-pyrrolo[2,3- b]pyridin-3-yl)methanone (4.3 g, 60% yield) as a yellow solid. LCMS (ES ⁺ ): m/z 351.80 [M+H] ⁺ .

[0459] Step D: (R)-3-fluoropyrrolidine-1-sulfonyl chloride

[0460] The oven-dried flask was charged with (R)-3-fluoropyrrolidine hydrochloride (3.0 g, 24 mmol), triethylamine (7.2 g, 72 mmol), and dichloromethane (150 mL). The mixture was stirred for 15 minutes at room temperature and then cooled to approximately -30°C in a dry ice acetonitrile bath for 10 minutes. Sulfuryl chloride (6.0 g, 48 mmol) was added dropwise over 10 minutes. The reaction mixture was stirred at approximately -30°C for one hour and then stirred at room temperature for 5 hours. The reaction mixture was diluted with aqueous HCl (1N, 70 ml). The layers were separated, and the aqueous layers were extracted with dichloromethane (50 ml×3). The combined organic layer was washed with aqueous HCl (1N, 50 ml) and brine (50 ml) and dried over anhydrous sodium sulfate. The solvent was concentrated to give (R)-3-fluoropyrrolidine-1-sulfonyl chloride (4.5 g) as a white solid, which was used directly in the next step without further purification.

[0461] Step E: (3R)-N[3-([5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl)-2,4-difluorophenyl1-3-fluoropyrrolidine-1 -sulfonamide

[0462] To a solution of (3-amino-2,6-difluorophenyl)(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (8.0 g, 22.79 mmol, 1.0 equiv.) in pyridine (25.0 g), (R)-3-fluoropyrrolidine-1-sulfonyl chloride (4.6 g, 24.60 mmol, 1.08 equiv.) and 4-dimethylamino-pyridine ( 560.0 mg, 4.59 mmol, 0.2 equiv.). The reaction mixture was stirred for 12 hours at 40°C. The solvent was removed, water (20 ml) was added, adjusted to pH=7~8 by adding aqueous sodium bicarbonate, and extracted with ethyl acetate (100 ml×2). The combined organic layer was washed with brine (50 ml×2) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (3:1) to give (R)-N-(3-(5-bromo-1H-pyrrolo[2,3- b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (6.4 g) as a yellow solid LCMS (ES ⁺ ): m/z 505.05 [M+H ] ⁺ .

[0463] Intermediate 2: (R)-N-(2,4-difluoro-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H -pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)-3-fluoropyrrolidine-1-sulfonamide

[0464] Step A: (R)-N-(2,4-difluoro-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)-3-fluoropyrrolidine-1-sulfonamide

[0465] To a solution of (R)-N-(3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (1.0 g, 2.0 mmol) in 1,4-dioxane, KOAc (392.0 mg, 4.0 mmol), Pd(dppf)Cl ₂ (163.0 mg, 0.2 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.02 g, 4.0 mmol). The resulting solution was heated to 90°C overnight under N ₂ atmosphere. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography, eluting with ethyl acetate/petroleum ether (1:1). This resulted in 551.0 mg (50%) of (R)-N-(2,4-difluoro-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)-3-fluoropyrrolidine-1-sulfonamide as a light brown solid. LCMS (ES ⁺ ): m/z 551.15 [M+H] ⁺ .

[0466] Intermediate 3: N-(3-[5-bromo-1H-pyrrolo[2,3-b]pyridin-3-carbonyl]-2,4-difluorophenyl)-2-(dimethylamino)ethane-1- sulfonamide

[0467] Step A: N-(3-[5-bromo-1H-pyrrolo[2,3-b]pyridin-3-carbonyl]-2,4-difluorophenyl)-ethene-1-sulfonamide

[0468] Place 3-[5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoroaniline (500 mg, 1.42 mmol, 1 equiv) into a 100 mL round bottom flask .), pyridine (20 ml, 248.47 mmol, 174.99 equiv.), DMAP (35 mg, 0.29 mmol, 0.20 equiv.), ethenesulfonyl chloride (360 mg, 2.84 mmol, 2 .00 equiv.) and dichloromethane (20 ml). The resulting solution was stirred for 0.5 hours at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was applied to a silica gel column, eluting with ethyl acetate/petroleum ether (1:1). This resulted in 300 mg (48%) of N-(3-[5-bromo-1H-pyrrolo[2,3-b]pyridin-3-carbonyl]-2,4-difluorophenyl)ethene-1-sulfonamide as white solid. LCMS (ES ⁺ ): m/z 443.80 [M+H] ⁺ .

[0469] Step B: N-(3-[5-bromo-1H-pyrrolo[2,3-b]pyridin-3-carbonyl]-2,4-difluorophenyl)-2-(dimethylamino)ethane-1-sulfonamide

[0470] Place N-(3-[5-bromo-1H-pyrrolo[2,3-b]pyridin-3-carbonyl]-2,4-difluorophenyl)ethene-1-sulfonamide (300) into a 100 mL round bottom flask mg, 0.68 mmol, 1 equiv.), dichloromethane (20 ml) and dimethylamine (2.0 ml). The resulting solution was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure. This resulted in 360 mg (crude) N-(3-[5-bromo-1H-pyrrolo[2,3-b]pyridin-3-carbonyl]-2,4-difluorophenyl)-2-(dimethylamino)ethane -1-sulfonamide as a white solid. LCMS (ES ⁺ ): m/z 488.85 [M+H] ⁺ .

[0471] Intermediate 4: N-(3-[5-bromo-1H-pyrrolo[2,3-b]pyridin-3-carbonyl]-2,4-difluorophenyl)-2,3-dihydroxypropane-1-sulfonamide

[0472] Step A: N-(3-[5-bromo-1H-pyrrolo[2,3-b]pyridin-3-carbonyl]-2,4-difluorophenyl)-prop-2-ene-1-sulfonamide

[0473] Place 3-[5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoroaniline (500 mg, 1.42 mmol, 1 equiv) into a 25 mL round bottom flask .), pyridine (2 ml, 15 equiv.), prop-2-ene-1-sulfonyl chloride (399.2 mg, 2.84 mmol, 2 equiv.) and DMAP (52.0 mg, 0.43 mmol, 0.3 equiv.). The resulting solution was stirred overnight at 45°C in an oil bath. The resulting mixture was concentrated. The residue was applied to a silica gel column, eluting with ethyl acetate/petroleum ether (1/1). This resulted in 480 mg (74%) N-(3-[5-bromo-1H-pyrrolo[2,3-b]pyridin-3-carbonyl]-2,4-difluorophenyl)prop-2-ene-1 -sulfonamide as a yellow solid.

[0474] Step B: N-(3-[5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl)-2,3-dihydroxypropane-1-sulfonamide

[0475] N-(3-[5-bromo-1H-pyrollo[2,3-b]pyridin-3-carbonyl]-2,4-difluorophenyl)prop-2-ene-1 was placed in a 50 mL round bottom flask -sulfonamide (430 mg, 0.94 mmol, 1 equiv.), acetone (20 ml), N-methylmorpholine-N-oxide (226 mg), water (5 ml) and osmium tetroxide (4 ml). The resulting solution was stirred overnight at room temperature. Then, the reaction mixture was quenched by adding water (20 ml). The resulting solution was extracted with ethyl acetate (30 ml×3). The resulting mixture was washed with saline (20 ml×1), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied to a silica gel column, eluting with ethyl acetate/petroleum ether (1/1). This resulted in 377 mg (82%) N-(3-[5-bromo-1H-pyrrolo[2,3-b]pyridin-3-carbonyl]-2,4-difluorophenyl)-2,3-dihydroxypropane- 1-sulfonamide as a white solid.

[0476] Intermediate 5: (R)-N-(3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1 -carboxamide

[0477] To a solution of (3-amino-2,6-difluorophenyl)(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone (2.0 g, 5.70 mmol, 1 .00 equiv.) and triethylamine (8.6 g, 85.5 mmol, 15.00 equiv.) in dichloromethane (80 ml), a solution of bis(trichloromethyl)carbonate (2.5 g, 8.55 mmol, 1 .50 equiv.) in dichloromethane (40 ml), and then a solution of (R)-3-fluoropyrrolidine (761.0 mg, 8.55 mmol, 1.50 equiv.) in dichloromethane (40 ml). The resulting solution was stirred for 30 minutes at 0°C in an ice-water bath. The resulting solution was quenched by adding aqueous ammonium chloride (40 ml) and extracted with dichloromethane (40 ml×2). Then, the organic layers were combined and concentrated. The residue was applied to a silica gel column, eluting with chloroform/methanol (10:1). This resulted in 541.0 mg (20%) (R)-N-(3-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4-difluorophenyl)- 3-fluoropyrrolidine-1-carboxamide as a tan solid. LCMS (ES ⁺ ): m/z 467.10 [M+H] ⁺ .

[0478] Example of synthesis of compound 86

[0479] Step A: (R)-tert-butyl-4-(4-(3-(2,6-difluoro-3-(3-fluoropyrrolidine-1-sulfonamido)benzoyl)-1H-pyrrolo[2,3 -b]pyridin-5-yl)phenyl)piperazine-1-carboxylate

[0480] To a solution of (R)-N-(3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (0.50 g, 1.0 mmol) in 1,4-dioxane/H ₂ O (20 ml/2 ml) under argon was added tert-butyl-4-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (0.43 g, 1.2 mmol), cesium fluoride (0.23 g, 1.5 mmol) and Pd(aMPhos )Cl ₂ (0.11 g, 0.15 mmol). The mixture was stirred at 100°C for 3 hours. After cooling to room temperature, water was added. The aqueous phase was extracted with ethyl acetate (20 ml×3), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified on silica gel (dichloromethane/methanol = 12:1) to give (R)-tert-butyl-4-(4-(3-(2,6-difluoro-3-(3-fluoropyrrolidine-1-sulfonamido) -benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (0.39 g, 57%) as a yellow solid. LCMS: m/z 685.2 [M+H] ⁺ ; ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.43 (9H, s), 2.06-2.12 (1H, m), 3.18-3.20 (4H, m), 3 .26-3.30 (1H, m), 3.37-3.53 (8H, m), 5.30 (1H, d, J = 52.0 Hz), 7.10 (2H, d, J = 8.8 Hz), 7.28 (1H, t, J = 8.4 Hz), 7.60-7.64 (3H, m), 8.09 (1H, d, J = 2.8 Hz ), 8.55 (1H, br), 8.66 (1H, d, J = 2.4 Hz), 9.87 (1H, s), 12.93 (1H, s).

[0481] Step B: (R)-N-(2,4-difluoro-3-(5-(4-(piperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3 -carbonyl)phenyl)-3-fluoropyrrolidine-1-sulfonamide

[0482] Solution of (R)-tert-butyl-4-(4-(3-(2,6-difluoro-3-(3-fluoropyrrolidine-1-sulfonamido)benzoyl)-1H-pyrrolo[2,3-b ]pyridin-5-yl)phenyl)piperazine-1-carboxylate (0.39 g, 0.57 mmol) in hydrochloric acid in 1,4-dioxane (5 ml, 4.0 N) was stirred at room temperature for 3 hours . Then, the solvent was immediately removed, water (10 ml) was added, and the mixture was adjusted to pH 8-9 by adding saturated sodium bicarbonate. The aqueous phase was extracted with ethyl acetate (10 ml×3), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give (R)-N-(2,4-difluoro-3-(5-(4-( piperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)-3-fluoropyrrolidine-1-sulfonamide (0.30 g, 91%) as a yellow solid.

[0483] Step C: 2-(2-chloroethoxy)ethyl-4-methylbenzenesulfonate

[0484] A mixture of 2-(2-chloroethoxy)ethanol (0.5 g, 4.0 mmol), tosyl chloride (0.8 g, 4.0 mmol) and triethylamine (810 mg, 8.1 mmol) in dichloromethane ( 10 ml) was stirred at room temperature overnight. The mixture was poured into saturated sodium bicarbonate solution (20 ml) and extracted with dichloromethane (20 ml x 3). The combined organic phase was concentrated in vacuo and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to give 2-(2-chloroethoxy)ethyl-4-methylbenzenesulfonate (0.9 g, 80% yield) in the form of a colorless oil. LCMS: m/z 279.1 [M+H] ⁺ .

[0485] Step D: 5-(2-(2-chloroethoxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione

[0486] Mixture of 2-(2-chloroethoxy)ethyl-4-methylbenzenesulfonate (100 mg, 0.36 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione ( 98 mg, 0.36 mmol), ethyldiisopropylamine (93 mg, 0.72 mmol) and potassium iodide (59 mg, 0.36 mmol) in dimethyl sulfoxide (5 ml) were heated at 45°C for 2 hours and then cooled to room temperature. The reaction mixture was poured into water (10 ml) and extracted with dichloromethane (15 ml×3). The combined organic phase was concentrated in vacuo and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 20/1) to give 5-(2-(2-chloroethoxy)ethoxy)-2-(2,6-dioxopiperidine- 3-yl)isoindoline-1,3-dione (48 mg, 35% yield) as a white solid. LCMS: m/z 381.2 [M+H] ⁺ .

[0487] Step E: (3R)-N-(3-(5-(4-(4-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline -5-yloxy)ethoxy)ethyl)piperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide

[0488] Mixture of 5-(2-(2-chloroethoxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (40 mg, 0.11 mmol), (R) -N-(2,4-difluoro-3-(5-(4-(piperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)-3-fluoropyrrolidine -1-sulfonamide (61 mg, 0.11 mmol), ethyldiisopropylamine (28 mg, 0.22 mmol) and potassium iodide (18 mg, 0.11 mmol) in dimethyl sulfoxide (5 ml) were heated at 80°C overnight . The mixture was poured into water (10 ml) and extracted with dichloromethane (10 ml×3). The organic phase was concentrated in vacuo and the residue was purified by preparative HPLC to give (3R)-N-(3-(5-(4-(4-(2-(2-(2-(2,6-dioxopiperidine-3 -yl)-1,3-dioxoisoindolin-5-yloxy)ethoxy)ethyl)piperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4-difluorophenyl) -3-fluoropyrrolidine-1-sulfonamide (31 mg, 30% yield) as a yellow solid. LCMS: m/z 929.3 [M+H] ⁺ ; ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.95-2.10 (3H, m), 2.53-2.59 (8H, m), 3.18-3.23 (4H, m), 3.24-3.31 (2H, m), 3.36-3.39 (2H, m), 3.47 (1H, s), 3.64 (2H, t, J = 6, 0 Hz), 3.80 (2H, t, J = 4.0 Hz), 4.35 (2H, t, J = 4.0 Hz), 5.12 (1H, dd, J = 5.6, 9.6 Hz), 5.29 (1H, d, J = 12.8 Hz), 7.05 (2H, d, J = 8.8 Hz), 7.26 (1H, d, J = 8, 8 Hz), 7.39 (1H, dd, J = 2.0, 8.4 Hz), 7.48 (1H, d, J = 2.4 Hz), 7.58-7.65 (3H, m), 7.85 (1H, d, J = 8.4 Hz), 8.07 (1H, s), 8.53 (1H, d, J = 2.4 Hz), 8.65 (1H, d, J = 2.4 Hz), 9.85 (1H, br), 11.1 (1H, s), 12.9 (1H, s).

[0489] Compounds 87-90 can be prepared in a similar manner.

[0490] Example of synthesis of compound 91

[0491] Step A: 2-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethoxy)-ethanol

[0492] To a solution of 2-(2-chloroethoxy)ethanol (2.0 g, 16.1 mmol) in N,N-dimethylformamide (15.0 mL) was added 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenol (3.54 g, 16.1 mmol), cesium carbonate (10.5 g, 32.2 mmol) and potassium iodide (267 mg, 1.61 mmol) . The reaction mixture was stirred at 60°C overnight. Then, water (50 ml) was added, extracted with ethyl acetate (50 ml x 3), and washed with brine (5 ml x 4). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel (petroleum ether/ethyl acetate = 2:1) to give 2-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethoxy )ethanol (2.1 g, 42%) as a yellow oil. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.28 (12H, s), 3.49-3.52 (4H, m), 3.74 (2H, t, J = 4.8 Hz ), 4.10-4.12 (2H, m), 4.62-4.64 (1H, m), 6.93 (2H, d, J = 9.2 Hz), 7.60 (2H, d, J = 8.4 Hz).

[0493] Step B: 2-(2-(4-(4,4,5,5-tetramethyl-1.3.2-dioxaborolan-2-yl)phenoxy)ethoxy)ethylmethanesulfonate

[0494] To a solution of 2-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethoxy)-ethanol (350 mg, 1.14 mmol ) in dichloromethane (15.0 ml) under nitrogen atmosphere, triethylamine (231 mg, 2.28 mmol) and methanesulfonyl chloride (157 mg, 1.37 mmol) were added. The resulting reaction mixture was stirred at room temperature for 1 hour. Then, water, sodium bicarbonate (20.0 ml) was added, extracted with dichloromethane (20 ml x 3), washed with brine, dried and concentrated in vacuo to give crude 2-(2-(4-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy)ethoxy)ethylmethanesulfonate as a yellow oil, which was used in the next step without further purification. LCMS: m/z 404.2 [M+18] ⁺ .

[0495] Step C: tert-butyl-4-(2-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy)ethoxy)ethyl )piperazine-1-carboxylate

[0496] To a solution of 2-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethoxy)-ethylmethanesulfonate (1.14 mmol) in acetonitrile (20 ml) potassium carbonate (315 mg, 2.28 mmol) and tert-butylpiperazine-1-carboxylate (234 mg, 1.25 mmol) were added. The resulting reaction mixture was stirred at 80°C overnight. The solvent was concentrated under vacuum conditions. The residue was extracted with ethyl acetate (20 ml×3) and water (20 ml). The organic phase was dried and concentrated under vacuum. The residue was purified by preparative TLC (petroleum ether/ethyl acetate = 1:2) to give tert-butyl-4-(2-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)-phenoxy)ethoxy)ethyl)piperazine-1-carboxylate (280 mg, 52% in two batches) as a pale yellow solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.27 (12H, s), 1.38 (9H, s), 2.35 (4H, t, J = 5.2 Hz), 2, 47-2.50 (2H, m), 3.25-3.26 (4H, m), 3.57 (2H, t, J = 6.0 Hz), 3.70-3.73 (2H, m), 4.10-4.12 (2H, m), 6.92 (2H, d, J = 8.8 Hz), 7.59 (2H, d, J = 8.4 Hz).

[0497] Step D: (R)-tert-butyl-4-(2-(2-(4-(3-(2,6-difluoro-3-(3-fluoropyrrolidine-1-sulfonamido)benzoyl)-1H -pyrrolo[2,3-b]pyridin-5-yl)phenoxy)ethoxy)ethyl)piperazine-1-carboxylate

[0498] To a solution of tert-butyl-4-(2-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethoxy)ethyl)piperazine -1-carboxylate (114 mg, 0.238 mmol) in 1,4-dioxane/water (10 ml/1 ml) was added (R)-N-(3-(5-bromo-1H-pyrrolo[2,3-b ]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (120 mg, 0.238 mmol), cesium fluoride (72.4 mg, 0.476 mmol) and Pd(aMPhos)Cl ₂ (16 .9 mg, 0.0238 mmol). The resulting reaction mixture was stirred at 95°C for 16 hours. After cooling, water (20 ml) was added and extracted with ethyl acetate (15 ml×3). The organic phase was dried and concentrated under vacuum. The residue was purified by preparative TLC (dichloromethane/methanol=20:1) to give (R)-tert-butyl-4-(2-(2-(4-(3-(2,6-difluoro-3-(3- fluoropyrrolidine-1-sulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-phenoxy)ethoxy)ethyl)piperazine-1-carboxylate (60 mg, 33%) as a pale yellow solid substances. LCMS: m/z 773.3 [M+H] ⁺ .

[0499] Step E: (R)-N-(2,4-difluoro-3-(5-(4-(2-(2-(piperazin-1-yl)ethoxy)ethoxy)phenyl)-1H-pyrrolo [2,3-b]pyridine-3-carbonyl)phenyl)-3-fluoropyrrolidine-1-sulfonamide hydrochloride

[0500] Solution of (R)-tert-butyl-4-(2-(2-(4-(3-(2,6-difluoro-3-(3-fluoropyrrolidine-1-sulfonamido)benzoyl)-1H-pyrrolo [2,3-b]pyridin-5-yl)phenoxy)ethoxy)ethyl)piperazine-1-carboxylate (60 mg, 0.0517 mmol) in hydrochloric acid in 1,4-dioxane (5 ml, 4 M) stirred at room temperature for 1 hour. The solvent was concentrated in vacuo to give (R)-N-(2,4-difluoro-3-(5-(4-(2-(2-(piperazin-1-yl)ethoxy )-ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)-3-fluoropyrrolidine-1-sulfonamide hydrochloride as a pale yellow solid, which was used in the next step without further purification . LCMS: m/z 673.2 [M+H] ⁺ .

[0501] Step F: (3R)-N-(3-(5-(4-(2-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline -5-yl)piperazin-1-yl)ethoxy)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide

[0502] To a solution of (R)-N-(2,4-difluoro-3-(5-(4-(2-(2-(piperazin-1-yl)ethoxy)ethoxy)phenyl)-1H-pyrrolo[ 2,3-b]pyridin-3-carbonyl)phenyl)-3-fluoropyrrolidine-1-sulfonamide hydrochloride (0.0517 mmol) in dimethyl sulfoxide (3 ml) was added 2-(2,6-dioxopiperidin-3-yl)- 5-fluoroisoindoline-1,3-dione (14.3 mg, 0.0517 mmol) and triethylamine (10.5 mg, 0.104 mmol). The reaction mixture was stirred at 70°C for 24 hours. After cooling to room temperature, water (10 ml) was added and extracted with ethyl acetate (10.0 ml×3). The combined organic phase was washed with brine (2.0 ml×4), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified twice by preparative TLC (dichloromethane/methanol = 20:1) to give (3R)-N-(3-(5-(4-(2-(2-(4-(2-(2,6-dioxopiperidine -3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethoxy)ethoxy)-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4 -difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (6.7 mg, 14%) as a yellow solid. LCMS: m/z 929.3 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.96-2.13 (3H, m), 2.58 (7H, s), 2.83-2.92 (1H, m), 3 .26-3.30 (2H, m), 3.40-3.43 (6H, m), 3.48 (1H, s), 3.63-3.67 (2H, m), 3.76 -3.80 (2H, m), 4.17-4.19 (2H, m), 5.05-5.09 (1H, m), 5.23-5.36 (1H, m), 7 .11 (2H, d, J = 8.4 Hz), 7.24-7.29 (2H, m), 7.34 (1H, s), 7.60-7.69 (4H, m), 8.10 (1H, s), 8.57 (1H, br), 8.66 (1H, d, J = 2.4 Hz), 9.88 (1H, s), 11.09 (1H, s), 12.95 (1H, s).

[0503] Compounds 92-97 can be prepared in a similar manner.

[0504] Example of synthesis of compound 99

[0505] Step A: tert-butyl 4-(4-bromophenyl)piperazine-1-carboxylate

[0506] To a solution of 1,4-dibromobenzene (5.0 g, 21.2 mmol) in toluene (100 mL) was added tert-butylpiperazine-1-carboxylate (3.04 g, 16.3 mmol), Pd ₂ ( dba) ₃ (485 mg, 0.53 mmol), t-BuOK (5.95 g, 53 mmol) and BLNAP (485 mg, 0.53 mmol). The resulting solution was stirred at 90°C for 3 hours under N ₂ atmosphere. After cooling to room temperature, the reaction mixture was quenched by adding H ₂ O (50 ml), and the mixture was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified on silica gel to give the title product (1.2 g, 17% yield) as a white solid. ^1H -NMR (400 MHz, CDCl ₃ ): δ 7.35 (d, J = 8.8 Hz, 2H), 6.78 (d, J = 9.2 Hz, 2H), 3.57 (t , J = 4.8 Hz, 4H), 3.09 (t, J = 4.8 Hz, 4H), 1.48 (s, 9H).

[0507] Step B: tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate

[0508] To a solution of tert-butyl-4-(4-bromophenyl)piperazine-1-carboxylate (1.2 g, 3.53 mmol) in 1,4-dioxane (24 ml) was added 4,4,4', 4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.8 g, 7.06 mmol), Pd(dppf)Cl ₂ (258 mg, 0.35 mmol) and KOAc (1.04 g, 10.59 mmol). The resulting solution was stirred at 90°C overnight under N ₂ atmosphere. Completion of the reaction was detected by TLC. After cooling to room temperature, the reaction mixture was diluted with 50 ml of ethyl acetate, and the mixture was washed with water and brine. The organic phase was dried over anhydrous sodium sulfate. The residue was purified by column chromatography to obtain the target product (1.0 g, 73% yield). LCMS (ES ⁺ ): m/z 482.0.

[0509] Step C: tert-butyl-2-(2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl)piperazine-1 -yl)ethoxy)acetate

[0510] To a solution of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-piperazine-1-carboxylate (550 mg, 1 .42 mmol) to DCM (5 ml) was added TFA (1.5 ml, 20.2 mmol). The resulting solution was stirred at 5°C for 2 hours. The solvent was removed under vacuum to obtain a residue (547 mg, calc.), which was used directly in the next step. To a solution of the residue (547 mg, 1.42 mmol) in anhydrous DMF (5 ml) was added K ₂ CO ₃ (977 mg, 7.08 mmol), KI (470 mg, 2.83 mmol) and tert-butium-2 -(2-chloroethoxy)acetate (550 mg, 2.83 mmol). The resulting solution was stirred at 90°C for 3 hours. After cooling to room temperature, the reaction mixture was quenched by adding 20 ml of saturated NaCl solution, and the mixture was extracted twice with ethyl acetate. The combined organic layer was concentrated in vacuo and the residue was purified on silica gel to give the title product (300 mg, 47% yield in two batches) as an oil. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.70 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 4.01 (m , 3H), 3.69 (m, 4H), 3.30 (m, 4H), 2.68 (m, 6H), 1.48 (s, 9H), 1.32 (s, 12H).

[0511] Step D: (R)-tert-butyl-2-(2-(4-(4-(3-(2,6-difluoro-3-(3-fluoropyrrolidine-1-sulfonamido)benzoyl)-1H -pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-1-yl)ethoxy)-acetate

[0512] To a solution of tert-butyl-2-(2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-1-yl )ethoxy)acetate (100 mg, 0.20 mmol) in 1,4-dioxane/H ₂ O (10 ml/1 ml) was added (3R)-N-[3-([5-bromo-1H-pyrrolo[ 2,3-b]pyridin-3-yl]carbonyl)-2,4-difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide (134 mg, 0.36 mmol), Pd(aMphos)Cl ₂ (15 mg, 0 .02 mmol) and CsF (121 mg, 0.80 mmol). The resulting solution was stirred at 95°C for 3 hours under N ₂ atmosphere. Completion of the reaction was detected by TLC. After cooling to room temperature, the reaction mixture was diluted with 50 ml of ethyl acetate, and the mixture was washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography to obtain the target product (100 mg, 66% yield). LCMS (ES ⁺ ): m/z 743.2 [M+H-16] ⁺ .

[0513] Stage E: (2S,4R)-1-((S)-2-(2-(2-(4-(4-(3-(2,6-difluoro-3-((R)- fluoropyrrolidin-1-sulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-1-yl)ethoxy)-acetamido)-3,3-dimethylbutanoyl)-4-hydroxy- N-(4-(4-methylthiazol-5-yl)benzyl)-pyrrolidine-2-carboxamide

[0514] To a methanol solution of (R)-tert-butyl-2-(2-(4-(4-(3-(2,6-difluoro-3-(3-fluoropyrrolidine-1-sulfonamido)benzoyl)-1H -pyrrolo[2,3-b]pyridin-5-yl)phenyl)-piperazin-1-yl)ethoxy)acetate (100 mg, 0.13 mmol) in 1,4-dioxane (2 ml) was added HCl (gas ) in 1,4-dioxane (1 ml, 8 M). The resulting solution was stirred at 50°C for 3 hours. Completion of the reaction was detected by TLC. After cooling to room temperature, the reaction mixture was concentrated to give the crude product (93 mg, calculated, 100% yield), which was used in the subsequent reaction. To a solution of the crude product (93 mg, 0.13 mmol) in anhydrous NMP (5 mL), (2S,4R)-N-(4-(4-methylthiazol-5-yl)benzyl)-1-((S )-2-amino-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide hydrochloride (91 mg, 0.19 mmol), DIEA (167 mg, 1.30 mmol) and RuBOR (203 mg, 0.39 mmol). The resulting solution was stirred at 10°C for 1 hour. After quenching the reaction mixture by adding brine (20 ml), the mixture was extracted twice with ethyl acetate. The organic layers were concentrated and the residue was purified by silica gel and preparative HPLC to give the title product (39 mg, 27% yield in two batches) as a yellow solid. ¹ H-NMR (400 MHz, CD ₃ OD): δ 8.80 (s, 1H), 8.65 (s, 1H), 8.56 (s, 1H), 7.89 (s, 1H), 7.73 (m, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 7.6 Hz, 2H), 7.36 (d, J = 8 .0 Hz, 2H), 7.07-7.14 (m, 3H), 5.13-5.30 (m, 1H), 4.71 (s, 1H), 4.50-4.65 ( m, 4H), 4.34 (d, J = 15.6 Hz, 1H), 4.12 (m, 2H), 3.78-3.95 (m, 4H), 3.40-3.65 (m, 9H), 3.10 (m, 6H), 2.42 (s, 3H), 2.00-2.30 (m, 4H), 1.04 (s, 9H); LCMS (ES ⁺ ): m/z 550.3 [M/2+H] ⁺ .

[0515] Compounds 98, 100-101, 102, 103-106 and 223-252 can be prepared in a similar manner.

[0516] Example of synthesis of compound 114

[0517] Step A: 1-(azetidin-3-yl)-4-(4-bromophenyl)piperazine hydrochloride

[0518] To a solution of 1-(4-bromophenyl)piperazine hydrochloride (2.0 g, 7.21 mmol) in CH ₃ OH/DCM (v/v = 1/1, 30 ml) was added KOAc at room temperature (1.4 g, 14.4 mmol) and cat. AcOH (0.1 ml). After stirring for 30 minutes, NaBH(OAc) ₃ (7.6 g, 36.1 mmol) was added. The mixture was stirred at 30°C overnight. After quenching the reaction mixture by adding aq. NaHCO ₃ (50 ml), the mixture was extracted with DCM (100 ml×2). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title product (2.5 g) as a light brown solid, which was used in the next step without further purification. To a solution of the above intermediates in methanol (20 ml) was added HCl (gas)/CH ₃ OH (10 ml). The resulting solution was stirred for 2 hours at room temperature. The solvent was removed under vacuum. The residue was triturated with DCM and filtered to give the title 1-(azetidin-3-yl)-4-(4-bromophenyl)-piperazine hydrochloride (2.0 g) as a brown solid.

[0519] Step B: Ethyl 2-(3-(4-(4-bromophenyl)piperazin-1-yl)azetidin-1-yl)acetate

[0520] To a solution of 1-(azetidin-3-yl)-4-(4-bromophenyl)piperazine hydrochloride (2.0 g, 6.01 mmol) in CH ₃ OH/DCM (v/v = 1/ 1, 10 ml) at room temperature, KOAc (1.2 g, 12.1 mmol) and cat. AcOH (0.1 ml). After stirring for 30 minutes, NaBH(OAc) ₃ (6.3 g, 30.1 mmol) was added. The mixture was stirred at 30°C overnight. After quenching the reaction mixture by adding aq. NaHCO ₃ (30 ml), the mixture was extracted with DCM (50 ml×3). The combined organic layer was washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to give the desired ethyl 2-(3-(4-(4-bromophenyl)piperazin-1-yl)azetidin-1-yl )acetate (1.0 g, crude) as a light brown solid, which was used in the next step without further purification. LCMS (ES ⁺ ): m/z 384.1; 382.1 [M+H] ⁺ .

[0521] Step C: Methyl-2-(3-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-piperazin-1-yl )azetidin-1-yl)acetate

[0522] HCl was added to a solution of ethyl 2-(3-(4-(4-bromophenyl)piperazin-1-yl)azetidin-1-yl)acetate (1.0 g, crude) in methanol (20 mL) (gas)/CH ₃ OH (10 ml). The resulting solution was stirred at 60°C for 2 hours. The solvent was removed under vacuum. The residue was taken up in DCM (100 ml), and washed with a mixture of NaHCO ₃ (30 ml×3). The organic phase was concentrated under vacuum conditions. The residue (500 mg) was used in the subsequent reaction without further purification. To a solution of the above intermediates (500 mg, 1.4 mmol) in 1,4-dioxane (20 ml) was added KOAc (267 mg, 2.8 mmol), Pd(dppf)Cl ₂ (190 mg, 0.14 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (700 mg, 2.8 mmol). The resulting solution was purged with N ₂ at room temperature for 10 minutes to remove excess O ₂ . The mixture was stirred at 100°C overnight. After cooling to room temperature, the reaction mixture was taken up in EtOAc. The organic phase was concentrated under vacuum conditions. The residue was purified on silica gel with PE/EA (10~1/1) to obtain the target methyl 2-(3-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)phenyl)piperazin-1-yl)azetidin-1-yl)acetate (300 mg) as a brown solid. LCMS (ES ⁺ ): m/z 416.3 [M+H] ⁺ .

[0523] Step D: (2S,4R)-N-(4-(4-methylthiazol-5-yl)benzyl)-1-((S)-3,3-dimethyl-2-(2-(3- (4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-1-yl)azetidin-1-yl)acetamido)butanoyl)-4- Hydroxypyrrolidine-2-carboxamide

[0524] To a solution of methyl-2-(3-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-piperazin-1-yl) azetidin-1-yl)acetate (300 mg, 0.72 mmol) in H ₂ O/THF (v/v=1/5, 5 ml) was added LiOH (34 mg, 1.5 mmol). The resulting solution was stirred at room temperature for 1 hour. Then, the solvent was removed under vacuum conditions. The residue was used in the subsequent reaction without further purification. To a solution of the above intermediates in DMF (5.0 ml) at room temperature was added DIEA (300 mg, 2.2 mmol), (2S,4R)-N-(4-(4-methylthiazol-5-yl)benzyl )-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide hydrochloride (338 mg, 0.72 mmol) and RuBOR (564 mg, 1.1 mmol). The resulting solution was stirred at 20°C for 2 hours. The reaction mixture was quenched by adding H ₂ O (10 ml), and the mixture was extracted with EtOAc (20 ml×3). The combined organic layer was concentrated in vacuo. The residue was purified by preparative TLC (DCM/CH ₃ OH, 20/1) to obtain the target (2S,4R)-1-((S)-3,3-dimethyl-2-(2-(3-(4-( 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-1-yl)azetidin-1-yl)acetamido)butanoyl)-4-hydroxy-N- (4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (80 mg) as a light brown solid. LCMS (ES ⁺ ): m/z 814.4 [M+H] ⁺ .

[0525] Step E: (2S,4R)-N-(4-(4-methylthiazol-5-yl)benzyl)-1-((5)-2-(2-(3-(4-(4- (3-(2,6-difluoro-3-((R)-3-fluoropyrrolidine-1-sulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1- yl)azetidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidin-2-carboxamide

[0526] To a solution of (2S,4R)-1-((S)-3,3-dimethyl-2-(2-(3-(4-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)piperazin-1-yl)azetidin-1-yl)acetamido)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl) pyrrolidine-2-carboxamide (80 mg, 0.098 mmol) in H ₂ O/1,4-dioxane (v/v = 1/5, 5.0 ml) at room temperature was added CsF (45 mg, 0.29 mmol), Pd(amphos)Cl ₂ (8 mg, 0.01 mmol) and (R)-N-(3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)- 2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (70 mg, 0.14 mmol). The solution was purged with N ₂ at room temperature for 10 minutes to remove excess O ₂ . The resulting solution was stirred at 80°C overnight. After cooling to room temperature, the reaction mixture was taken up in EtOAc. The combined organic layer was concentrated in vacuo. The residue was purified by preparative TLC DCM/CH ₃ OH (20/1) to obtain the target (2S,4R)-1-((S)-2-(2-(3-(4-(4-(3-(2 ,6-difluoro-3-(((R)-3-fluoropyrrolidine)-1-sulfonamido)-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-1-yl) azetidin-1-yl)-acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)-pyrrolidin-2-carboxamide (35 mg) as light -yellow solid. ^1H -NMR (400 MHz, DMSO- _d6 ): δ 9.02 (s, 1H), 8.71-8.75 (m, 2H), 8.68 (br, 1H), 8.12 (s, 1H), 7.61-7.66 (m, 4H), 7.42-7.46 (m, 5H), 7.19-7.21 (m, 2H), 7.06 (d , J = 8.0 Hz, 2H), 5.33-5.35 (m, 0.5H), 5.22-5.23 (m, 0.5 N), 5.16 (d, J = 7.2 Hz, 1H), 4.53 (d, J = 9.6 Hz, 1H), 4.34-4.47 (m, 5H), 4.24-4.29 (m, 1H), 4.04 (s, 1H), 3.65-3.66 (m, 3H), 3.51-.3.61 (m, 5H), 3.22-3.34 (m, 6H), 3 .08 (broad, 3H), 2.41-2.47 (m, 3H), 1.93-2.07 (m, 5H), 0.94 (s, 9H); LCMS (ES ⁺ ): m/z 1111.3 [M+H] ⁺ , 1108.3 [M-H] ⁺ .

[0527] Compounds 107-113, 115, 116 and 253-269 can be prepared in a similar manner.

[0528] Synthesis Example of Compound 117

[0529] Step A: tert-butyl 4-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazine-1-carboxylate

[0530] Mixture of 4-(4-bromo-1H-pyrazol-3-yl)pyridine (5.0 g, 22.3 mmol) (previously described in Bioorg. Med. Chem. Lett. 2008, 18, 4692-4695 ), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (8.7 g, 22.3 mmol) and copper(II) acetate (4.0 g, 22.3 mmol) in pyridine (30 ml) were stirred at 100°C overnight. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to give tert-butyl-4-(4-(4-bromo-3-(pyridin-4-yl)- 1H-pyrazol-1-yl)phenyl)piperazine-1-carboxylate (10.8 g, 70% yield) as a brown solid.

[0531] Step B: tert-butyl-4-(4-(4-(1-oxo-2.3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol- 1-yl)phenyl)piperazine-1-carboxylate

[0532] A mixture of tert-butyl 4-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)-piperazine-1-carboxylate (2.4 g, 5.0 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one (1.3 g , 5.0 mmol), [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium (366 mg, 0.5 mmol), tri-tert-butylphosphine tetrafluoroborate (145 mg, 0.5 mmol) and cesium fluoride ( 2.3 g, 15.0 mmol) in 1,4-dioxane/water (20 ml, 10/1) was stirred at 90°C overnight. The mixture was poured into water (30 ml) and extracted with dichloromethane (30 ml×3). The combined organic phase was concentrated in vacuo and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 20/1) to give tert-butyl-4-(4-(4-(1-oxo-2,3-dihydro- 1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazine-1-carboxylate (1.6 g, 60% yield) as a yellow solid. LCMS: m/z 536.3 [M+H] ⁺ .

[0533] Step C: 5-(1-(4-(piperazin-1-yl)phenyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydro-1H -inden-1-one hydrochloride

[0534] A solution of tert-butyl-4-(4-(4-(1-oxo-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol- 1-yl)phenyl)piperazine-1-carboxylate (1.6 g, 3.0 mmol) in anhydrous hydrogen chloride in methanol (30 ml, 1.0 M) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to give 5-(1-(4-(piperazin-1-yl)phenyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydro -1H-inden-1-one hydrochloride (1.0 g, 80% yield) as a white solid, which was used directly in the next step without further purification.

[0535] Step D: 2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(4-(1-oxo-2,3-ditidro-1H-inden-5-yl) -3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)isoindoline-1,3-dione

[0536] Mixture of 5-(1-(4-(piperazin-1-yl)phenyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydro-1H-indene -1-one hydrochloride (1.0 g, 2.3 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (635 mg, 2.3 mmol) and triethylamine (697 mg, 6.9 mmol) in dimethyl sulfoxide (10 ml) was stirred at 80°C overnight. The mixture was poured into water (20 ml) and extracted with ethyl acetate (20 ml×3). The combined organic phase was concentrated in vacuo and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 20/1) to give 2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-( 4-(1-oxo-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)isoindolin- 1,3-Dione (1.1 g, 70% yield) as a yellow solid. LCMS: m/z 692.3 [M+H] ⁺ .

[0537] Step E: (E)-2-(2.b-dioxopiperidin-3-yl)-5-(4-(4-(4-(1-(hydroxyimino)-2,3-dihydro-1H- inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)isoindoline-1,3-dione

[0538] Mixture of 2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(4-(1-oxo-2,3-dihydro-1H-inden-5-yl)-3 -(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)isoindoline-1,3-dione (300 mg, 0.43 mmol) and hydroxylamine hydrochloride (300 mg, 4. 3 mmol) in pyridine (10 ml) was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum conditions. The residue was purified by preparative HPLC to give (E)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(4-(1-(hydroxyimino)-2,3-dihydro-1H -inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)isoindoline-1,3-dione (182 mg, 60% yield) in as a yellow solid. LCMS: m/z 707.3 [M+H] ⁺ ; ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 2.01-2.07 (1H, m), 2.54-2.61 (2H, m), 2.80-2.89 (3H, m), 2.98-3.02 (2H, m), 3.39 (4H, broad), 3.66 (4H, broad), 5.06-5.11 (1H, m), 7 .16 (2H, d, J = 8.8 Hz), 7.21 (1H, d, J = 7.6 Hz), 7.33-7.35 (1H, m), 7.42 (2H, d, J = 8.0 Hz), 7.47 (2H, dd, J = 5.6, 1.6 Hz), 7.55 (1H, J = 7.6 Hz), 7.72 (1H, d, J = 8.4 Hz), 7.83 (2H, d, J = 8.8 Hz), 8.57 (2H, dd, J = 4.4, 1.2 Hz), 8.73 ( 1H, s), 10.9 (1H, s), 11.0-11.1 (1H. m).

[0539] Compounds 118-132 and 271 can be prepared in a similar manner.

[0540] Example of synthesis of compound 137

[0541] Step A: tert-butyl-(2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)-ethyl)(methyl)carbamate

[0542] To a solution of tert-butylmethyl(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)carbamate (3.57 g, 9. 47 mmol) and 4-(4-bromo-1H-pyrazol-3-yl)pyridine (2.12 g, 9.47 mmol) in DCM (20 ml) was added Et ₂ NH (6.91 g, 94.72 mmol) and Cu(OAc) ₂ (1.72 g, 9.47 mmol). The resulting mixture was stirred at 30°C for 16 hours under 02 atmosphere. The mixture was diluted with DCM (30 ml) and then washed with NH3H2O three times. The organic phase was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (DCM/MeOH = 80/1) to obtain tert-butyl-(2-(4-(4-bromo-3-(pyridin-4-yl) -1H-pyrazol-1-yl)phenoxy)ethyl)(methyl)-carbamate (3.0 g, 66.9% yield) as a brown oil.

[0543] Step B: 2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)-N-methylethan-1-amine

[0544] To a solution of tert-butyl-(2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)-ethyl)(methyl)carbamate (1, 56 g, 3.31 mmol) in MeOH (6 ml) was slowly added HCl in dioxane (6N, 10 ml) at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was evaporated under reduced pressure to obtain 2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)-N-methylethan-1-amine as a colorless solid substances (1.23 g, 100% yield).

[0545] Step C: 5-((2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethyl)-(methyl)amino)-2 -(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0546] To a solution of 2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)-N-methylethan-1-amine (400 mg, 1.07 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (591.9 mg, 2.14 mmol) in NMP (2 ml) was added DIPEA (1.38 g , 10.7 mmol). The resulting mixture was stirred at 130°C for 12 hours under N2 atmosphere. The mixture was diluted with ethyl acetate (30 ml) and then the mixture was washed twice with saline. The organic phase was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc = 1/3) to give 5-((2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl) phenoxy)ethyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (500 mg, 74.1% yield).

[0547] Step D: 2-(2,6-dioxopiperidin-3-yl)-5-(methyl(2-(4-(4-(1-oxo-2,3-dihydro-1H-inden-5- yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethyl)amino)isoindoline-1,3-dione

[0548] To a solution of 5-((2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethyl)-(methyl)amino)-2- (2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (500 mg, 0.79 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)-2,3-dihydro-1H-inden-1-one (307.6 mg, 1.19 mmol) in 1,4-dioxane/H ₂ O (9 ml, 8:1) added t-Bu ₃ PHBF ₄ (92.2 mg, 0.32 mmol), CsF (483.3 mg, 3.18 mmol), Cy ₂ NMe (5 drops) and Pd ₂ (dba) ₃ (145.6 mg, 0. 16 mmol). The resulting mixture was stirred at 100°C for 2 hours under N ₂ atmosphere. The solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate (30 ml) and then the mixture was washed twice with brine. The organic phase was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (PE/DCM/MeOH = 800/200/25) to obtain 2-(2,6-dioxopiperidin-3-yl)-5-(methyl(2 -(4-(4-(1-oxo-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethyl)amino )isoindoline-1,3-dione (500 mg, yield 92.4%).

[0549] Step E: (E)-2-(2,6-dioxopiperidin-3-yl)-5-((2-(4-(4-(1-(hydroxyimino)-2,3-dihydro-1H -inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethyl)(methyl)amino)-isoindoline-1,3-dione

[0550] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-(methyl(2-(4-(4-(1-oxo-2,3-dihydro-1H-inden-5-yl )-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethyl)amino)isoindoline-1,3-dione (200 mg, 0.294 mmol) in CH ₃ CN/Py (3 ml/ 3 ml) NH ₂ OH⋅HCl (200 mg, 2.877 mmol) was added and the mixture was stirred at 40°C for 0.5 hour. The mixture was diluted with DCM (30 ml) and washed twice with saline. The organic layer was evaporated under reduced pressure. The residue was purified by TLC (DCM/EA/MeOH = 50/100/15) to give (E)-2-(2,6-dioxopiperidin-3-yl)-5-

[0551] ((2-(4-(4-(1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1 -yl)phenoxy)ethyl)(methyl)amino)isoindoline-1,3-dione as a yellow-green solid (103 mg, 49.9% yield). ^1H -NMR (400 MHz, CDCl ₃ ): δ 8.56 (d, J = 4.0 Hz, 2H), 8.16 (s, 1H), 7.94 (s, 1H), 7.66 - 7.72 (m, 4H), 7.50 (d, J = 4.8 Hz, 2H), 7.43 (s, 1H), 7.29 (s, 1H), 7.19 - 7, 26 (m, 2H), 6.93 - 6.98 (m, 3H), 4.92 - 4.96 (m, 1H), 4.24 (t, J = 4.8 Hz, 2H), 3 .94 (t, J =10 Hz, 2H), 3.23 (s, 3H), 3.00 - 3.04 (m, 4H), 2.77 - 2.92 (m, AN), 2, 12 - 2.15 (d, J = 8.4 Hz, 1H); LCMS (ES ⁺ ): m/z 696.2 [M+H] ⁺ .

[0552] Compounds 133-136, 138-149 and 273-281 can be prepared in a similar manner.

[0553] Example of synthesis of compound 150

[0554] Step A: 4-(4-bromo-1-(4-(2-(3-((tert-butyldimethylsilyl)oxy)propoxy)ethoxy)phenyl)-1H-pyrazol-3-yl)pyridine

[0555] K ₂ CO ₃ ( 299 mg, 2.16 mmol) and 4-(4-bromo-1H-pyrazol-3-yl)pyridine (342 mg, 1.08 mmol). The resulting solution was stirred at 80°C for 3 hours. The reaction mixture was diluted with ethyl acetate (30 ml) and washed with brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified to give the target 4-(4-bromo-1-(4-(2-(3-((tert-butyldimethylsilyl)oxy)propoxy)ethoxy)phenyl)-1H-pyrazol-3-yl)pyridine ( DCM: MeOH = 20:1) (430 mg) as a colorless solid. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.66 (br., 2H), 7.89-7.93 (m, 3H), 7.55 (d, J=8.8 Hz, 2H ), 6.96-6.98 (m, 2H), 4.04-4.14 (m, 2H), 3.76 (d, J=4.8 Hz, 2H), 3.67 (d, J=6 Hz, 3H), 3.58 (d, J=6.4 Hz, 2H), 1.71-1.79 (m, 2H), 0.84 (s, 9H), 0.0 ( s, 6H).

[0556] Step B: 3-(2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethoxy)-propan-1-ol

[0557] To a solution of 4-(4-bromo-1-(4-(2-(3-((tert-butyldimethylsilyl)oxy)propoxy)-ethoxy)phenyl)-1H-pyrazol-3-yl)pyridine (430 mg, 0.808 mmol) in 1,4-dioxane (2 ml) was added 6 M HCl in 1,4-dioxane (4 ml). The resulting solution was stirred at 25°C for 1 hour. The solvent was removed under reduced pressure to give the crude product 3-(2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethoxy)propane-1- ol (270 mg, crude), which was used in the next step without further purification. LCMS (ES ⁺ ): m/z 420.0 [M+H] ⁺ .

[0558] Step C: 3-(2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethoxy)propanal

[0559] To a solution of 3-(2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethoxy)-propan-1-ol (135 mg, 0.32 mmol) IBX (136 mg, 0.48 mmol) in CH ₃ CN (4 ml) was added at room temperature. The mixture was stirred at 80°C for 2 hours. After completion of the reaction, the mixture was filtered. The filtrate was concentrated in vacuo to give the crude title 3-(2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethoxy)propanal (140 mg, crude .), which was used in the next step without further purification. LCMS (ES ⁺ ): m/z 416.0 [M+H] ⁺ .

[0560] Step D: tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazine-1-carboxylate

[0561] To a solution of tert-butylpiperazin-1-carboxylate (1.35 g, 7.25 mmol) in NMP (10 ml) was added 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1, 3-dione (1 g, 3.62 mmol) and DIEA (1.87 g, 14.5 mmol). The resulting solution was stirred at 90°C in an N ₂ atmosphere for 4 hours. The reaction mixture was diluted with ethyl acetate (30 ml) and washed with brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified to give the target tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-carboxylate (DCM:EA = 1:1) (1.4 g) as a yellow solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 7.73 (d, J=7.2 Hz, 1H), 7.35-7.41 (m, 2H), 5.09-5, 13 (m, 1H), 3.52 (s, 4H), 3.26 (s, 4H), 2.84-2.89 (m, 1H), 2.56-2.63 (m, 2H) , 2.00-2.05 (m, 2H), 1.45 (s, 9H).

[0562] Step E: 2-(2,6-dioxopiperidin-3-yl)-4-(piperazin-1-yl)isoindoline-1,3-dione hydrochloride

[0563] To a solution of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-carboxylate (1.4 g, 3.16 mmol) in 1,4-dioxane (4 ml) was added 6 M HCl in 1,4-dioxane (6 ml). The resulting solution was stirred at 25°C for 1 hour. The solution was concentrated under reduced pressure. The residue yielded the target 2-(2,6-dioxopiperidin-3-yl)-4-(piperazin-1-yl)isoindoline-1,3-dione hydrochloride (1.4 g crude), which was used in the next step without additional cleaning. LCMS (ES ⁺ ): m/z 343.1 [M+H] ⁺ .

[0564] Step F: 4-(4-(3-(2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethoxy)propyl) piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione

[0565] 3-(2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethoxy)-propanal solution (140 mg, crude, 0. 32 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-(piperazin-1-yl)isoindoline-1,3-dione (123 mg, 0.32 mmol), NaBH ₃ CN (41 mg , 0.64 mmol) and acetic acid (3.8 mg, 0.062 mmol) in MeOH were stirred at room temperature overnight. The mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified to obtain the target 4-(4-(3-(2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethoxy)propyl)piperazine- 1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (DCM:MeOH = 15:1) (70 mg) as a yellow solid. LCMS (ES ⁺ ): m/z 742.1 [M+H] ⁺ .

[0566] Step G: 2-(2,6-dioxopiperidin-3-yl)-4-(4-(3-(2-(4-(4-(1-oxo-2,3-dihydro-1H- inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethoxy)propyl)piperazin-1-yl)-isoindolin-1,3-dione

[0567] A solution of 4-(4-(3-(2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethoxy)propyl)piperazine- 1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (70 mg, 0.094 mmol), 5-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one (191 mg, 0.74 mmol), Pd ₂ (dba) ₃ (181 mg, 0.198 mmol), CsF (300 mg , 1.97 mmol), tri-tert-butylphosphine tetrafluoroborate (115 mg, 0.39 mmol) and N,N-dicyclohexylmethylamine (9 mg, 0.047 mmol) in 1,4-dioxane/H ₂ O (6 ml, 10 /1) were subjected to microwave irradiation at 100°C in an N ₂ atmosphere for 2 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified to give the target 2-(2,6-dioxopiperidin-3-yl)-4-(4-(3-(2-(4-(4-(1-oxo-2,3-dihydro-1H-indene -5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethoxy)propyl)piperazin-1-yl)isoindolin-1,3-dione (DCM: MeOH = 20: 1) (33 mg) as a yellow solid. LCMS (ES ⁺ ): m/z 795.3 [M+H] ⁺ .

[0568] Step H: (E)-2-(2,6-dioxopiperidin-3-yl)-4-(4-(3-(2-(4-(4-(1-(hydroxyimino)-2, 3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethoxy)propyl)piperazin-1-yl)isoindolin-1,3- dione

[0569] To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-(4-(3-(2-(4-(4-(1-oxo-2,3-dihydro-1H-indene -5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethoxy)propyl)piperazin-1-yl)isoindolin-1,3-dione (33 mg, 0.042 mmol) in acetonitrile (2 ml) and pyridine (1.5 ml), hydroxylamine hydrochloride (27 mg, 0.42 mmol) was added. The mixture was stirred at 40°C for 20 minutes, diluted with DCM 20 ml and washed with saline (10 ml). The organic layer was concentrated and purified by preparative TLC to give (E)-2-(2,6-dioxopiperidin-3-yl)-4-(4-(3-(2-(4-(4-(1-(hydroxyimino )-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethoxy)propyl)-piperazin-1-yl)isoindolin- 1,3-Dione (22 mg, 66.6% yield) as a yellow solid. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.56 (d, J=5.6 Hz, 2H), 8.37 (s, 1H), 7.94 (s, 1H), 7.68 (d, J=9.2 Hz, 3H), 7.55-7.57 (m, 1H), 7.51 (d, J=5.6 Hz, 2H), 7.38-7.40 ( m, 1H), 7.21-7.28 (m, 2H), 7.15 (d, J=8.4 Hz, 1H), 7.04 (d, J=8.8 Hz, 2H), 4.91-4.98 (m, 1H), 4.18 (d, J=4.8 Hz, 2H), 3.82-3.84 (m, 2H), 3.63 (d, J= 6.4 Hz, 2H), 3.49 (s, 2H), 3.36-3.38 (m, 4H), 3.02 (d, J=10.8 Hz, 4H), 2.69- 2.87 (m, 8H), 2.52-2.56 (m, 2H), 1.85-1.88 (m, 1H); LCMS (ES ⁺ ): m/z 810.2 [M+H] ⁺ .

[0570] Compounds 151-172 and 282-284 can be prepared in a similar manner.

[0571] Example of synthesis of compound 174

[0572] Step A: 4-(benzyloxy)butyl-4-methylbenzenesulfonate

[0573] To a solution of 4-(benzyloxy)butyl-4-methylbenzenesulfonate (5 g, 27.76 mmol), DMAP (0.34 g, 2.78 mmol) and TEA (8.4 g, 83.28 mmol) TsCl (7.94 g, 41.64 mmol) was added in batches to DCM (50 mL). The resulting solution was stirred at 15°C for 2 hours. The reaction mixture was quenched by adding saturated NH ₄ Cl (50 ml). The mixture was extracted with DCM (50 ml×2). The combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified on silica gel to give the title 4-(benzyloxy)butyl-4-methylbenzenesulfonate (5.6 g, 60% yield) as a light yellow oil. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.77 (d, J=8.4 Hz, 2H), 7.26-7.33 (m, 7H), 4.45 (s, 2H) , 4.05 (t, J=6.4 Hz, 2H), 3.42 (t, J=6.4 Hz, 2H), 2.44 (s, 3H), 1.59-1.78 ( m, 4H).

[0574] Step B: (S)-tert-butyl-5-amino-4-(4-(4-(benzyloxy)butoxy)-1,3-dioxoisoindolin-2-yl)-5-oxopentanoate

[0575] To a solution of 4-(benzyloxy)butyl-4-methylbenzenesulfonate (0.63 g, 1.87 mmol) in anhydrous DMF (8.0 mL), K ₂ CO ₃ (0.4 g, 2.88 mmol) and tert-butyl-(S)-5-amino-4-(4-hydroxy-1,3-dioxoisoindolin-2-yl)-5-oxopentanoate (0.5 g, 1.44 mmol). The resulting solution was stirred at 70°C for 2 hours. After cooling to room temperature, the reaction mixture was quenched by adding water (30 ml), and the mixture was extracted with ethyl acetate (40 ml×2). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified on a silica gel column to give (S)-tert-butyl-5-amino-4-(4-(4-(benzyloxy)butoxy)-1,3-dioxoisoindolin-2-yl)-5-oxopentanoate (0 .4 g, yield 55%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.63 (t, J=8.4 Hz, 1H), 7.43 (m, 1H), 7.25-7.40 (m, 5H) , 7.18 (s, 1H), 6.41 (br, 1H), 5.66 (br, 1H), 4.79 (m, 1H), 4.52 (s, 2H), 4, 19 (t, J=6.4 Hz, 2H), 3.58 (t, J=6.4 Hz, 2H), 3.47 (m, 2H), 2.50 (m, 2H), 2, 25 (m, 2H), 2.00 (m, 2H), 1.85 (m, 1H), 1.43 (s, 9H).

[0576] Step C: (S)-2-(2,6-dioxopiperidin-3-yl)-4-(4-hydroxybutoxy)isoindoline-1,3-dione

[0577] To a solution of (S)-tert-butyl-5-amino-4-(4-(4-(benzyloxy)butoxy)-1,3-dioxoisoindolin-2-yl)-5-oxopentanoate (400 mg, 0.784 mmol) in acetonitrile (5 ml) was added TsOH⋅H ₂ O (1.48 g, 7.84 mmol). The resulting solution was stirred at 80°C for 2 hours. The reaction mixture was quenched by adding saturated NaHCO ₃ and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated and purified by a column to give (S)-4-(4-(benzyloxy)-butoxy)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3- dione (370 mg). To a solution of (S)-4-(4-(benzyloxy)butoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (370 mg, 0.85 mmol) in THF/MeOH (4 ml/1 ml) Pd(OH) ₂ (185 mg) and two drops of concentrated HCl were added. The resulting mixture was stirred at 20°C for 1 hour in an atmosphere of H ₂ (1 atm). The resulting solution was filtered and evaporated. The residue was purified by preparative TLC to give the target (S)-2-(2,6-dioxopiperidin-3-yl)-4-(4-hydroxybutoxy)isoindoline-1,3-dione (250 mg, 92% yield in two batches) . LCMS (ES ⁺ , Neg): m/z 345.0 [MH] ⁺ .

[0578] Step D: (S)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-butanal

[0579] To a solution of (S)-2-(2,6-dioxopiperidin-3-yl)-4-(4-hydroxybutoxy)isoindoline-1,3-dione (0.25 g, 0.72 mmol) in CH ₃ CN (5 ml) IBX (607 mg, 2.16 mmol) was added. The resulting solution was stirred at 75°C for 1 hour. After cooling to room temperature, the reaction mixture was filtered and concentrated in vacuo to give the crude title product (240 mg, crude, estimated yield 100%), which was used directly in the next step.

[0580] Step E: (S)-4-(4-(4-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)-piperazine-1 -yl)butoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0581] To a solution of (S)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-oxy)butanal (240 mg, crude, 0. 72 mmol) in MeOH (6 ml) was added 1-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazine (276 mg, 0.72 mmol) and two drops of AcOH. NaBH ₃ CN (134 mg, 2.16 mmol) was then added. The resulting solution was stirred at 18°C for 2 hours. After quenching by adding water (30 ml), the mixture was extracted with ethyl acetate (40 ml×2). The combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column to obtain the target (S)-4-(4-(4-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazine -1-yl)butoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (350 mg, 68% yield in two batches). LCMS (ES ⁺ ): m/z 713.1 [M+H] ⁺ .

[0582] Step F: (S)-2-(2,6-dioxopiperidin-3-yl)-4-(4-(4-(4-(4-(1-oxo-2,3-dihydro-1H -inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)butoxy)-isoindoline-1,3-dione

[0583] To a solution of (S)-4-(4-(4-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)-piperazine-1- yl)butoxy)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (0.35 g, 0.52 mmol) and 5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one (147 mg, 0.57 mmol) in 1,4-dioxane (15 ml)/H ₂ O ( 1.5 ml) CsF (316 mg, 2.08 mmol), Pd ₂ (dba) ₃ (190 mg, 0.21 mmol), tri-tert-butylphosphine tetrafluoroborate (121 mg, 0.42 mmol) and two drops of N-cyclohexyl-N-methylcyclohexane-amine. The reaction mixture was heated to 100°C for 2 hours under N ₂ atmosphere. After cooling to room temperature, the reaction mixture was quenched by adding water (20 ml), and the mixture was extracted with ethyl acetate (30 ml×2). The combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column to obtain the target (S)-2-(2,6-dioxopiperidin-3-yl)-4-(4-(4-(4-(4-(1-oxo-2,3- dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)butoxy)-isoindoline-1,3-dione (0, 3 g, 80% yield) as a yellow solid. LCMS (ES ⁺ ): m/z 382.8 [(M+H)/2] ⁺ .

[0584] Step G: (S,E)-2-(2,6-dioxopiperidin-3-yl)-4-(4-(4-(4-(4-(1-(hydroxyimino)-2,3 -dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)butoxy)isoindoline-1,3-dione

[0585] To a solution of (S)-2-(2,6-dioxopiperidin-3-yl)-4-(4-(4-(4-(4-(1-oxo-2,3-dihydro-1H- inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)butoxy)-isoindoline-1,3-dione (165 mg, 0.22 mmol) in acetonitrile/pyridine (6 ml/3 ml) was added hydroxylamine hydrochloride (150 mg, 2.16 mmol). The mixture was stirred at 45°C for 1 hour. The solvent was removed in vacuo and the residue was purified by preparative TLC (DCM/MeOH, 20/1) to obtain the target (S,E)-2-(2,6-dioxopiperidin-3-yl)-4-(4-( 4-(4-(4-(1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl) piperazin-1-yl)butoxy)isoindoline-1,3-dione (60 mg, 38% yield) as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.11 (s, 1H), 10.88 (d, J=3.6 Hz, 1H), 8.69 (s, 1H), 8 .56 (m, 2H), 7.81 (m, 3H), 7.35-7.62 (m, 6H), 7.20 (s, 1H), 7.09 (m, 2H), 5. 10 (m, 1H), 4.25 (t, J=6.4 Hz, 2H), 3.32 (m, 4H), 3.19 (m, 4H), 2.75-3.05 (m , 5H), 2.40 (m, 2H), 1.60-2.10 (m, 8H); LCMS (ES ⁺ ): m/z 779.3 [M+H] ⁺ .

[0586] Compounds 173 and 175-181 can be prepared in a similar manner.

[0587] Example of synthesis of compound 182

[0588] Step A: N-(3-(5-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)( methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide

[0589] Mixture of N-(2,4-difluoro-3-(5-(methyl(piperidin-4-yl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b] pyridin-1-yl)phenyl)propan-1-sulfonamide (100.0 mg, 0.18 mmol) (previously described in WO 2012/104388), 2-(2,6-dioxopiperidin-3-yl)-4- Fluoroisoindoline-1,3-dione (102 mg, 0.36 mmol) and DIEA (239 mg, 1.80 mmol) in anhydrous NMP (2.0 ml) were microwaved at 130°C for 1 hour. After cooling to room temperature, the reaction mixture was quenched by adding water, and the mixture was extracted with ethyl acetate (10 ml×3). The combined organic layer was washed with water (10 ml×3), brine (20 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC to obtain the target N-(3-(5-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl )(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide (DCM: MeOH = 10:1) (45 mg, yield = 30.6%) as a white solid. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 9.58 (s, 1H), 9.10 (s, 1H), 8.03 (s, 1H), 7.67-7.59 (m, 2H), 7.42 (d, J=7.2 Hz, 1H), 7.34 (d, J=8 Hz, 1H), 7.23-7.18 (m, 1H), 6.66 ( d, J=12 Hz, 1H), 5.02-4.81 (m, 1H), 3.90-3.89 (m, 1H), 3.18-3.14 (m, 3H), 3 .05 (s, 2H), 2.96-2.87 (m, 3H), 2.13 (dd, J=2.8 Hz, 4 Hz, 2H), 2.00-1.90 (m, 3H), 1.30 (s, 8H), 1.09 (t, J=12.0 Hz, 3H), 0.84-.088 (m, 4H); LCMS (ES ⁺ ): m/z 798.2 [M+H] ⁺ .

[0590] Compound 183 can be prepared in a similar manner.

[0591] Example of synthesis of compound 184

[0592] Step A: tert-butyl-(S)-5-amino-4-(4-(2-(benzyloxy)ethoxy)-1,3-dioxoisoindolin-2-yl)-5-oxopentanoate

[0593] Tert-Butyl-(S)-5-amino-4-(4-hydroxy-1,3-dioxoisoindolin-2-yl)-5-oxopentanoate mixture (1.22 g, 3.51 mmol), 2 -(benzyloxy)ethylmethanesulfonate (900 mg, 3.91 mmol) and K ₂ CO ₃ (1.08 g, 7.83 mmol) in DMF (10 ml) were stirred at 70°C for 6 hours. After quenching by adding water, the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified to give the desired tert-butyl(S)-5-amino-4-(4-(2-(benzyloxy)ethoxy)-1,3-dioxoisoindolin-2-yl)-5-oxopentanoate (PE: EtOAc = 1:5) (907 mg).

[0594] Step B: (S)-4-(2-(benzyloxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione

[0595] Tert-Butyl-(S)-5-amino-4-(4-(2-(benzyloxy)ethoxy)-1,3-dioxoisoindolin-2-yl)-5-oxopentanoate solution (907 mg, 1. 88 mmol) and p-TsOH (1.5 g, 7.89 mmol) in MeCN (10 ml) were stirred at 80°C for 8 hours. After quenching by adding water, the mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified to give the target (S)-4-(2-(benzyloxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (PE: EtOAc = 1:1) ( 1.23 g, crude).

[0596] Step C: (S)-2-(2,6-dioxopiperidin-3-yl)-4-(2-hydroxyethoxy)isoindoline-1,3-dione

[0597] (S)-4-(2-(Benzyloxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione solution (1.23 g, 3.01 mmol) , Pd(OH) ₂ /C (0.7 g) and HCl in dioxane (6N, 6 drops) in MeOH/EtOAc (1:1, 40 ml) were stirred at room temperature for 12 hours in an atmosphere of H ₂ (1 atm). The mixture was filtered through Celite and the filtrate was concentrated in vacuo to give the title (S)-2-(2,6-dioxopiperidin-3-yl)-4-(2-hydroxyethoxy)isoindoline-1,3-dione (700 mg, uncleaned).

[0598] Step D: (S)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-acetaldehyde

[0599] To a solution of (S)-2-(2,6-dioxopiperidin-3-yl)-4-(2-hydroxyethoxy)isoindoline-1,3-dione (200 mg, 0.63 mmol) in CH ₃ CN (10 ml) IBX (352 mg, 1.26 mmol) was added. The resulting solution was stirred at 80°C for 2 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo to give the crude title (S)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl )oxy)acetaldehyde (200 mg, crude) as a yellow solid, which was used in the subsequent reaction without further purification.

[0600] Step E: N-(3-(5-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)ethyl )piperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propan-1- sulfonamide

[0601] To a solution of (S)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-oxy)acetaldehyde (200 mg, crude, 0.631 mmol ), N-(2,4-difluoro-3-(5-(methyl-(piperidin-4-yl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridine -1-yl)phenyl)-propane-1-sulfonamide hydrochloride (80 mg, 0.148 mmol) and CH ₃ COOH (3.8 mg, 0.062 mmol) in EtOH/DCM (v/v = 1/1, 20 ml) NaBH(OAc) ₃ (400 mg, 1.88 mmol) was added. The resulting solution was stirred at room temperature overnight. After quenching by adding water, the mixture was extracted with EtOAc. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (DCM/EtOAc/MeOH = 10/1/1) to obtain the target (S)-N-(3-(5-((1-(2-((2-(2,6-dioxopiperidine -3-yl)-1,3-dioxoisoindolin-4-yl)oxy)ethyl)-piperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2 -b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide (20.1 mg) as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 11.07 (s, 1H), 9.80-10.02 (m, 1H), 9.66 (s, 1H), 9.01 (s , 1H), 8.40 (s, 1H), 7.80-7.89 (m, 1H), 7.61-7.63 (m, 2H), 7.44-7.48 (m, 2H ), 6.76 (d, J=9.3 Hz, 1H), 5.08 (dd, J=12.9, 5.2 Hz, 1H), 4.33-4.49 (m, 3H) , 3.45 (s, 6H), 3.06-3.25 (m, 3H), 2.94 (s, 2H), 2.83 (s, 2H), 2.55-2.73 (m , 4H), 2.29 (d, J=10.3 Hz, 2H), 1.77 (m, 2H), 1.68 (d, J=10.1 Hz, 2H), 0.99 (t , J=7.4 Hz, 3H); LCMS: (ES ⁺ ): m/z 842.3 [M+H] ⁺ .

[0602] Compounds 185-189 can be prepared in a similar manner.

[0603] Example of synthesis of compound 191

[0604] Step A: tert-butyl 2-(2-(2-oxoethoxy)ethoxy)acetate

[0605] To a solution of tert-butyl-2-(2-(2-hydroxyethoxy)ethoxy)acetate (1 g, 4.55 mmol) in CH ₃ CN (15 mL) was added IBX (3.8 g, 13.64 mmol). The resulting solution was stirred at 75°C for 1 hour. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo to give the crude title tert-butyl 2-(2-(2-oxoethoxy)ethoxy)acetate (1 g, crude, 100% yield), which was used directly to the next stage. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 9.75 (s, 1H), 4.18 (s, 2H), 4.03 (s, 2H), 3.77 (s, 4H), 1 .48 (s, 9H).

[0606] Step B: tert-butyl-2-(2-(2-(4-((1-(2,6-difluoro-3-(propylsulfonamido)phenyl)-3-(pyrimidin-5-yl)- 1H-pyrrolo[3,2-b]pyridin-5-yl)(methyl)amino)piperidin-1-yl)-ethoxy)ethoxy)acetate

[0607] To a solution of tert-butyl-2-(2-(2-oxoethoxy)ethoxy)acetate (181 mg, crude, 0.83 mmol) in EtOH/DCM (1/1) was added N-(2,4 -difluoro-3-(5-(methyl(piperidin-4-yl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)phenyl)propan- 1-sulfonamide hydrochloride (150 mg, 0.28 mmol) and cat. AcOH. When the pH value was below 5~6, KOAc was added. After stirring for 30 minutes, NaBH(OAc) ₃ (235 mg, 1.11 mmol) was added. The resulting solution was stirred at 30°C for 1 hour. After quenching by adding water (20 ml), the mixture was extracted with DCM (30 ml×2). The combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column to obtain the target 2-(2-(2-(4-((1-(2,6-difluoro-3-(propylsulfonamido)phenyl)-3-(pyrimidin-5-yl)-1H -pyrrolo[3,2-b]pyridin-5-yl)(methyl)amino)piperidin-1-yl)ethoxy)ethoxy)acetate (120 mg, 58% yield). LCMS: (ES ⁺ ): m/z 744.3 [M+H] ⁺ .

[0608] Step C: 2-(2-(2-(4-((1-(2,6-difluoro-3-(propylsulfonamido)phenyl)-3-(pyrimidin-5-yl)-1H-pyrrolo[ 3,2-b]pyridin-5-yl)(methyl)amino)piperidin-1-yl)ethoxy)ethoxy)acetic acid

[0609] To a solution of tert-butyl-2-(2-(2-(4-((1-(2,6-difluoro-3-(propylsulfonamido)phenyl)-3-(pyrimidin-5-yl)-1H -pyrrolo[3,2-b]pyridin-5-yl)(methyl)amino)piperidin-1-yl)-ethoxy)ethoxy)acetate (0.12 g, 0.16 mmol) in DCM (3 ml) was added TFA (1 ml). The resulting solution was stirred at 30°C for 1 hour. The solvent was removed under vacuum to give the target 2-(2-(2-(4-((1-(2,6-difluoro-3-(propylsulfonamido)phenyl)-3-(pyrimidin-5-yl)-1H- pyrrolo[3,2-b]pyridin-5-yl)(methyl)amino)piperidin-1-yl)ethoxy)ethoxy)acetic acid (111 mg, crude, calculations), which was used in the subsequent reaction without further purification . LCMS: (ES ⁺ ): m/z 688.2 [M+H] ⁺ .

[0610] Step D: (2S,4R)-1-((S)-2-(2-(2-(2-(4-((1-(2,6-difluoro-3-(propylsulfonamido)- phenyl)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)(methyl)amino)piperidin-1-yl)ethoxy)ethoxy)acetamido)-3,3 -dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0611] To a solution of 2-(2-(2-(4-((1-(2,6-difluoro-3-(propylsulfonamido)phenyl)-3-(pyrimidin-5-yl)-1H-pyrrolo[3 ,2-b]pyridin-5-yl)(methyl)amino)piperidin-1-yl)ethoxy)ethoxy)acetic acid (111 mg, crude, 0.16 mmol) in DCM (10 ml) was added successively (2S ,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidin-2-carboxamide hydrochloride (150 mg, 0.32 mmol), DIPEA (209 mg, 1.62 mmol) and PyBOP (250 mg, 0.48 mmol). After stirring at 30°C for 1 hour, the reaction mixture was diluted with DCM (30 ml), washed with water (10 ml×2) and saline (10 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was first purified on a column (DCM/MeOH, 19/1) and then further purified by preparative HPLC to obtain the target (2S,4R)-1-((S)-2-(2-(2-(2-(4 -((1-(2,6-difluoro-3-(propylsulfonamido)phenyl)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)(methyl)amino )piperidin-1-yl)ethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidin-2-carboxamide (55 mg, yield 31% in two batches) as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 9.65 (s, 2H), 9.02 (s, 1H), 8.94 (s, 1H), 8.57 (t, J= 4.8 Hz, 1H), 8.40 (m, 1H), 7.55-7.65 (m, 1H), 7.35-7.50 (m, 7H), 6.74 (d, J =9.2 Hz, 1H), 4.57 (d, J=9.6 Hz, 1H), 4.20-4.50 (m, 5H), 4.00 (s, 2H), 3.50 -3.70 (m, 2H), 3.00-3.20 (m, 7H), 2.93 (s, 3H), 2.50-2.70 (m, 4H), 2.43 (s , 3H), 1.60-2.25 (m, 13H), 0.90-1.05 (m, 12H); LCMS: (ES ⁺ ): m/z 1101.4 [M+H] ⁺ .

[0612] Compounds 190 and 192 can be prepared in a similar manner.

[0613] Synthesis Example of Compound 195 [(3R)-N-(3-(5-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yloxy )ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide]

[0614] Step A: Ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)acetate

[0615] To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (5 g, 22.7 mmol) in N,N-dimethylformamide (50 ml) ethyl 2-bromoacetate (4.52 g, 27.2 mmol) and potassium carbonate (6.27 g, 45.4 mmol) were added. The mixture was stirred overnight under nitrogen atmosphere. The reaction mixture was added to water (200 ml) and extracted with ethyl acetate (150 ml×3). The organic layer was washed with saline (100 ml×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)acetate (5.2 g, 75%) as a colorless oil.

[0616] Step B: Methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethanol

[0617] To a solution of ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-acetate (1 g, 3.27 mmol) in tetrahydrofuran /ethanol (10 ml/10 ml), sodium borohydride (124 mg, 3.27 mmol) was added in an ice-water bath. The mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was partitioned between ethyl acetate (100 ml) and water (50 ml). The organic layer was separated, washed with brine (20 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give methyl 2-(4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)phenoxy)ethanol (0.8 g, 93%) as a colorless oil.

[0618] Step C: 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-ethylmethanesulfonate

[0619] To a solution of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethanol (200 mg, 0.76 mmol) and ethyldiisopropylamine (293 mg , 2.27 mol) in dichloromethane (10.0 ml), methanesulfonyl chloride (105 mg, 0.91 mmol) was added while cooling and the mixture was stirred at 0°C for 30 minutes. The mixture was quenched by adding cold water (10.0 ml), the organic layer was washed with sodium bicarbonate solution (10.0 ml×3) and brine (10.0 ml×3), dried over anhydrous saturated sodium sulfate, filtered and concentrated under vacuum to obtain (2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethylmethanesulfonate, which was used directly in the next step.

[0620] Step D: 2-(2,6-dioxopiperidin-3-yl)-5-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )phenoxy)ethoxy)isoindoline-1,3-dione

[0621] A mixture of (2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-ethylmethanesulfonate (260 mg, 0.76 mmol), potassium carbonate ( 210 mg, 1.52 mol), potassium iodide (126 mg, 0.76 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (208 mg, 0. 76 mmol) in dimethyl sulfoxide (10 ml) was stirred at 60°C overnight. The resulting mixture was cooled to room temperature. Water (20 ml) and ethyl acetate (20 ml) were added. The organic layer was separated, washed with brine (10 ml x 2 ), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by preparative TLC (dichloromethane/methanol = 20:1) to give 2-(2,6-dioxopiperidin-3-yl)-5 -(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-ethoxy)isoindoline-1,3-dione (140 mg, 36% in two batches ) as a white solid. LCMS (ES ⁺ ): m/z 521.2 [M+H] ⁺ , 538.2 [M+18] ⁺ .

[0622] Step E: (3R)-N-(3-(5-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yloxy)ethoxy )phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide

[0623] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy)ethoxy)isoindoline-1,3-dione (136 mg, 0.26 mmol), (R)-N-(3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl )-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (120 mg, 0.24 mmol) and CsF (0.18 mg, 0.012 mmol) in 1,4-dioxane (10 ml) and water (2 ml) Pd(aMPhos)Cl ₂ (17 mg, 0.024 mmol) was added under argon and the mixture was stirred at 100°C for 6 hours. After cooling it to room temperature, water (20 ml) was added, the resulting mixture was extracted with ethyl acetate (20 ml×3), washed with brine (10 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC to give (3R)-N-(3-(5-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yloxy) ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (8.1 mg, 4% yield) as a white solid substances. LCMS (ES ⁺ ): m/z 817.2 [M+H] ⁺ ; ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 2.06-2.09 (3H, m), 2.55-2.62 (2H, m), 2.85-2.93 (1H, m), 3.24-3.27 (1H, m), 3.38-3.50 (3H, m), 4.42-4.46 (2H, m), 4.58-4.62 ( 2H, m), 5.12-5.16 (1H, m), 5.23-5.36 (1H, m), 7.15 (2H, d, J=8.8 Hz), 7.25 (1H, t, J=8.8 Hz), 7.45 (1H, dd, J=2.4, 8.4 Hz), 7.55 (1H, d, J=2.0 Hz), 7 .59-7.63 (1H, m), 7.70 (2H, d, J=8.4 Hz), 7.87 (1H, d, J=8.4 Hz), 8.10 (1H, s), 8.58 (1H, s), 8.68 (1H, d, J=2.4 Hz), 9.89 (1H, br), 11.14 (1H, s), 12.96 (1H, wide).

[0624] Compounds 194 and 195 can be prepared in a similar manner.

[0625] Example of the synthesis of compound 285 [(2S,4R)-1-((S)-2-(3-(2-(4-(4-(3-(2,6-difluoro-3-((( R)-3-fluoropyrrolidine)-1-sulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-piperazin-1-yl)ethoxy)isoxazol-5-yl)-3 -methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide] and compounds 286 [(2S,4R)-1-((R)-2-( 3-(2-(4-(4-(3-(2,6-difluoro-3-(((R)-3-fluoropyrrolidine)-1-sulfonamido)benzoyl)-1H-pyrrolo[2,3-b ]pyridin-5-yl)phenyl)piperazin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine -2-carboxamide]

[0626] Step A: 2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoic acid

[0627] In a 100 mL round bottom flask, place 2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoic acid (1.0 g, 5.02 mmol, 1.0 equiv.) and a solution of hydrobromic acid (11.9 g, 147.07 mmol, 29.30 equiv.) in acetic acid (20 ml). The resulting solution was stirred overnight at 60°C in an oil bath. The reaction mixture was concentrated under reduced pressure. This resulted in 650.0 mg (crude) of 2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoic acid as a white solid.

[0628] LCMS (ES ⁺ ): m/z 186.05 [M+H] ⁺ .

[0629] Step B: Ethyl 2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoate

[0630] A solution of 2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoic acid (650.0 mg, 3.51 mmol, 1.00 equiv.) in ethanol (30 ml) and sulfuric acid (1 ml). The resulting solution was stirred overnight at 70°C. Then, the reaction mixture was quenched by adding 20 ml of water and extracted with ethyl acetate (20 ml×2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. This resulted in 720.0 mg (96%) ethyl 2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoate as a light yellow oil.

[0631] Step C: Ethyl 2-[3-(2-bromoethoxy)-1,2-oxazol-5-yl]-3-methylbutanoate

[0632] A solution of ethyl 2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoate (380, 0 mg, 1.78 mmol, 1.00 equiv.) in acetone (15 ml), 1,2-dibromoethane (994.8 mg, 5.30 mmol, 3.00 equiv.) and Cs ₂ CO ₃ (1 .17 g, 3.59 mmol, 2.00 equiv.). The resulting mixture was stirred overnight at room temperature. Then, the reaction mixture was quenched by adding water (15 ml) and extracted with ethyl acetate (20 ml×3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied to a silica gel column, eluting with ethyl acetate/petroleum ether (1:5). This resulted in 450.0 mg (79%) ethyl 2-[3-(2-bromoethoxy)-1,2-oxazol-5-yl]-3-methylbutanoate as a colorless solid.

[0633] Step D: 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine

[0634] A solution of tert-butyl-4-[4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]piperazine-1-carboxylate (1.6 g, 4.12 mmol, 1.00 equiv.) in dichloromethane (40 ml), and then TMSOTf (1.5 g, 6 .75 mmol, 1.60 equiv.) with stirring at 0°C. To the above solution was added 6-dimethylpyridine (132.5 mg, 1.00 mmol, 0.30 equiv.). The resulting solution was stirred for 3 hours at room temperature. Then, the reaction mixture was quenched by adding 50 ml of saturated aqueous sodium bicarbonate. The resulting solution was extracted with ethyl acetate (30 ml×3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied to a silica gel column, eluting with dichloromethane/methanol (10:1). This resulted in 854.0 mg (72%) 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine as an off-white solid . LCMS (ES ⁺ ): m/z 289.15 [M+H] ⁺ .

[0635] Step E: ethyl-3-methyl-2-[3-(2-[4-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-piperazin-1-yl] ethoxy)-1,2-oxazol-5-yl]butanoate

[0636] A solution of ethyl 2-[3-(2-bromoethoxy)-1,2-oxazol-5-yl]-3- was placed into a sealed 30 mL tube that was purged with nitrogen and then maintained under an inert atmosphere of nitrogen. methyl butanoate (576.0 mg, 1.80 mmol, 1.00 equiv.) in N,N-dimethylformamide (6 ml), 1-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl ]piperazine (624.0 mg, 2.17 mmol, 1.20 equiv.), DIEA (17 ml) and NaI (20 mg). The resulting solution was stirred for 16 hours at 130°C. Then, the reaction mixture was quenched by adding 30 ml of water. The resulting solution was extracted with ethyl acetate (30 ml×3). The combined organic layer was washed with brine (30 ml×3), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied to a silica gel column, eluting with ethyl acetate/petroleum ether (1:2). This resulted in 720.0 mg (76%) ethyl 3-methyl-2-[3-(2-[4-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine -1-yl]ethoxy)-1,2-oxazol-5-yl]butanoate as a light yellow solid. LCMS (ES ⁺ ): m/z 528.25 [M+H] ⁺ .

[0637] Step F: Ethyl 2-(3-[2-[4-(4-[3-[(2,6-difluoro-3-[[(3R)-3-fluoropyrrolidinsulfonyl]amino]phenyl)carbonyl ]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl)piperazin-1-yl]ethoxy]-1,2-oxazol-5-yl)-3-methylbutanoate

[0638]

[0639] A solution of ethyl 3-methyl-2-[3-(2-[4-[4-(tetramethyl-1,3 ,2-dioxaborolan-2-yl)phenyl]piperazin-1-yl]ethoxy)-1,2-oxazol-5-yl]butanoate (527.0 mg, 1.00 mmol, 1.00 equiv.) in 20 ml 1,4-dioxane/water (4:1), (3R)-N-[3-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-ylcarbonyl)-2,4-difluorophenyl ]-3-fluoropyrrolidine-1-sulfonamide (503.0 mg, 1.00 mmol, 1.00 equiv.), sodium carbonate (318.0 mg, 3.00 mmol, 3.00 equiv.) and Pd(dppf )Cl ₂ (82.0 mg, 0.10 mmol, 0.10 equiv.). The reaction mixture was treated with microwave radiation for 2 hours at 100°C. Then, the reaction mixture was quenched by adding 20 ml of water. The resulting solution was extracted with ethyl acetate (30 ml×3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied to a silica gel column, eluting with dichloromethane/methanol (10:1). This resulted in 460.0 mg (56%) ethyl 2-(3-[2-[4-(4-[3-[(2,6-difluoro-3-[[(3R)-3-fluoropyrrolidine -1-sulfonyl]amino]phenyl)carbonyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl)piperazin-1-yl]ethoxy]-1,2-oxazol-5-yl) -3-methylbutanoate as a light yellow solid. LCMS (ES ⁺ ): m/z 824.15 [M+H] ⁺ .

Step G: 2-(3-[2-[4-(4-[3-[(2,6-difluoro-3-[[(3R)-3-fluoropyrrolidine-1-sulfonyl]amino]phenyl)carbonyl ]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl)piperazin-1-yl]ethoxy]-1,2-oxazol-5-yl)-3-methylbutanoic acid

[0640] A solution of ethyl 2-(3-[2-[4-(4-[3-[(2,6-difluoro -3-[[(3R)-3-fluoropyrrolidin-1-sulfonyl]amino]phenyl)carbonyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl)piperazin-1-yl]ethoxy] -1,2-oxazol-5-yl)-3-methylbutanoate (420.0 mg, 0.51 mmol, 1.00 equiv.) in methanol (10 ml), and then sodium hydroxide solution (102.0 mg) was added , 2.55 mmol, 5.00 equiv.) in water (2 ml). The resulting solution was stirred at 40°C for 5 hours. The pH value of the solution was adjusted to pH 6 by adding hydrogen chloride (1 M). Solids were collected by filtration. The solid was dried in an oven under reduced pressure. This resulted in 366.0 mg (90%) 2-(3-[2-[4-(4-[3-[(2,6-difluoro-3-[[(3R)-3-fluoropyrrolidine-1 -sulfonyl]amino]phenyl)carbonyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl)piperazin-1-yl]ethoxy]-1,2-oxazol-5-yl)-3- methylbutanoic acid in the form of a solid. LCMS (ES ⁺ ): m/z 796.10 [M+H] ⁺ .

[0641] Stage H: (2S,4R)-1-[2-(3-[2-[4-(4-[3-[(2,6-difluoro-3-[[(3R)-3- fluoropyrrolidin-1-sulfonyl]amino]phenyl)carbonyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl)piperazin-1-yl]ethoxy]-1,2-oxazol-5-yl) -3-methylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenylmethyl]pyrrolidine-2-carboxamide

[0642] To a solution of 2-(3-[2-[4-(4-[3-[(2,6-difluoro-3-[[(3R)-3-fluoropyrrolidine-1-sulfonyl]-amino]phenyl )carbonyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl)piperazin-1-yl]ethoxy]-1,2-oxazol-5-yl)-3-methylbutanoic acid (300.0 mg, 0.38 mmol, 1.00 equiv.) and (2S,4R)-4-hydroxy-N-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methylpyrrolidin-2- carboxamide hydrochloride (199.9 mg, 0.56 mmol, 1.50 equiv.) in N,N-dimethylformamide (10 ml) was added DIEA (3.0 ml) and BOP (200.3 mg, 0.45 mmol, 1.20 equivalent). The resulting mixture was stirred for 1 hour at room temperature. Then, the reaction mixture was quenched by adding 20 ml of water. The resulting solution was extracted with ethyl acetate (30 ml×3). The combined organic layer was washed with brine (30 ml×3), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied to a silica gel column, eluting with dichloromethane/methanol (10:1). This resulted in 265.0 mg (64%) of (2S,4R)-1-[2-(3-[2-[4-(4-[3-[(2,6-difluoro-3-[[ (3R)-3-fluoropyrrolidin-1-sulfonyl]amino]phenyl)-carbonyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl)piperazin-1-yl]ethoxy]-1,2 -oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-pyrrolidine-2-carboxamide in the form solid matter. LCMS (ES ⁺ ): m/z 1095.30 [M+H] ⁺ .

[0643] Step I: (2S,4R)-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-1-(2-[3- [2-(methylamino)ethoxy]-1,2-oxazol-5-yl]butanoyl)pyrrolidine-2-carboxamide

[0644] (2S,4R)-1-[2-(3-[2-[4-(4-[3-[(2,6-difluoro-3-[[(3R)-3-fluoropyrrolidine-1 -sulfonyl]-amino]phenyl)carbonyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl)piperazin-1-yl]ethoxy]-1,2-oxazol-5-yl)-3 -methylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide was separated by chiral HPLC, resulting in:

[0645] 25.7 mg (10%) (2S,4R)-1-((S)-2-(3-(2-(4-(4-(3-(2,6-difluoro-3- (((R)-3-fluoropyrrolidin)-1-sulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-piperazin-1-yl)ethoxy)isoxazol-5-yl )-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. ¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 9.10-8.97 (m, 1H), 8.65 (d, J=2.0 Hz, 1H), 8.60-8, 53 (m, 2H), 8.10-8.07 (m, 1H), 7.70-7.56 (m, 3H), 7.51-7.21 (m, 511), 7.18- 7.07 (m, 211), 6.18-6.12 (m, 111), 5.38-5.21 (m, 1H), 4.44-4.31 (m, 6H), 3, 78 (d, J=8.6 Hz, 1H), 3.62-3.45 (m, 4H), 3.32-3.01 (m, 8H), 2.98-2.60 (m, 4H), 2.55-2.43 (m, 3H), 2.34-1.82 (m, 6H), 0.97-0.62 (m, 6H). LCMS (ES ⁺ ): m/z 1095.60 [M+H] ⁺ .

[0646] 57.5 mg (22%) (2S,4R)-1-((R)-2-(3-(2-(4-(4-(3-(2,6-difluoro-3- (((R)-3-fluoropyrrolidin)-1-sulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-piperazin-1-yl)ethoxy)isoxazol-5-yl )-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. ¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 12.90 (br s, 1H), 9.84 (b s, 1H), 8.99-8.95 (m, 1H), 8.69-8.66 (m, 1H), 8.60-8.53 (m, 2H), 8.07 (s, 1H), 7.70-7.61 (m, 3H), 7. 54-7.39 (m, 4H), 7.387.30 (m, 1H), 7.21-7.08 (m, 2H), 6.18-5.80 (m, 1H), 5.40- 5.15 (m, 1H), 4.74-4.28 (m, 6H), 3.90-3.62 (m, 6H), 3.41-3.22 (m, 7H), 3. 21-2.81 (m, 5H) 2.45-2.42 (m, 3H), 2.32-2.20 (m, 1H), 2.17-1.80 (m, 4H), 0 .95 (d, J=6.5 Hz, 3H), 0.81 (d, J=6.7 Hz, 3H). LCMS (ES ⁺ ): m/z 1095.60 [M+H] ⁺ .

[0647] Exemplary compounds 287 and 288 can be prepared in a similar manner.

[0648] Example of the synthesis of compound 291 [(2S,4R)-4-hydroxy-1-((S)-2-(2-(2-(4-(4-((E)-1-(hydroxyimino)- 2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)-phenoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-N- (4-(4-methylthiazol-5-yl)benzyl)-pyrrolidine-2-carboxamide]

[0649] Step A: tert-butyl-2-(2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)-phenoxy)ethoxy)acetate-ethoxy)acetate

[0650] To a solution of tert-butyl-2-(2-chloroethoxy)acetate (400 mg, 2.06 mmol) and Cs ₂ CO ₃ in DMF (15 ml) was added tert-butyl-4-(4-bromo-3 -(pyridin-4-yl)-1H-pyrazol-1-yl)phenol (525 mg, 1.66 mmol). The mixture was stirred at 75°C for 3 hours. The solution was diluted with ethyl acetate (100 ml). The mixture was washed with water and saline. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-(2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethoxy)acetate ethoxy)acetate (290 mg , 0.62 mmol). LCMS (ES ⁺ ): m/z 475.21 [M+H] ⁺ , 476.1 [M+2H] ⁺ .

[0651] Step B: (2S,4R)-1-((S)-2-(2-(2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1 -yl)phenoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0652] To a solution of 2-(2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethoxy)-acetateethoxy)acetate (290 mg, 0. 61 mmol) in 1,4-dioxane (5 ml) was added HCl (gas) in 1,4-dioxane (3 M, 5 ml). The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in DCM (20 ml). (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidin- 2-carboxamide hydrochloride (394 mg, 0.92 mmol), DIPEA (394 mg, 3.05 mmol) and PyBOP (954 g, 1.83 mmol). After stirring for 30 minutes, the mixture was diluted with DCM (50 ml). The mixture was washed with water and saline. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give (2S,4R)-1-((S)-2-(2-(2-(4-(4-bromo-3-(pyridin-4-yl)-1H- pyrazol-1-yl)phenoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (390 mg, 0 .46 mmol). LCMS (ES ⁺ ): m/z 830.2 [M+H] ⁺ .

[0653] Step C: (2S,4R)-1-((S)-3,3-dimethyl-2-(2-(2-(4-(4-(1-oxo-2,3-dihydro- 1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethoxy)acetamido)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol- 5-yl)benzyl)pyrrolidine-2-carboxamide

[0654] To a solution of (2S,4R)-1-((S)-2-(2-(2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1- yl)phenoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidin-2-carboxamide (390 mg, 0.46 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one (248 mg, 0.92 mmol) in Pd(aMPhos)Cl ₂ (36 mg, 0.046 mmol) and CsF (360 mg, 2.30 mmol) were added successively to 1,4-dioxane/water (20 ml/1 ml). The reaction mixture was stirred at 90°C overnight under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with ethyl acetate (100 ml). The mixture was washed with saline (50 ml x 2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH) to give (2S,4R)-1-((S)-3,3-dimethyl-2-(2-(2-(4-(4-(1- oxo-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethoxy)acetamido)butanoyl)-4-hydroxy-N- (4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (230 mg, 0.26 mmol). LCMS (ES ⁺ ): m/z 882.3 [M+H] ⁺ .

[0655] Step D: (2S,4R)-4-hydroxy-1-((S)-2-(2-(2-(4-(4-((E)-1-(hydroxyimino)-2, 3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-N-(4- (4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0656] To a solution of (2S,4R)-1-((S)-3,3-dimethyl-2-(2-(2-(4-(4-(1-oxo-2,3-dihydro-1H -inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethoxy)acetamido)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5 -yl)benzyl)pyrrolidine-2-carboxamide (230 mg, 0.26 mmol) in CH ₃ CN and pyridine (v/v = 1/1, 5 ml) was added NH ₂ OH⋅HCl (179 mg, 2 .6 mmol). The solution was stirred at 20°C for 3 hours. The mixture was filtered through Celite. The filtrate was concentrated under vacuum conditions. The residue was purified by silica gel column chromatography (DCM/MeOH) to give (2S,4R)-4-hydroxy-1-((S)-2-(2-(2-(4-(4-((E)- 1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethoxy)acetamido)-3,3- dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (21 mg, 0.023 mmol). ^1H -NMR (400 MHz, DMSO- _d6 ): δ 10.89 (s, 1H), 8.97 (s, 1H), 8.72 (s, 1H), 8.56-8.58 ( m, 3H), 7.86 (d, J=8.4 Hz, 2H), 7.49-7.57 (m, 3H), 7.39 (m, 6H), 7.22 (s, 1H ), 7.09-7.12 (m, 2H), 5.17 (m, 1H), 4.52-4.65 (m, 1H), 4.32-4.50 (m, 3H), 4.08-4.29 (s, 4H), 3.95-4.05 (m, 2H), 3.73-3.82 (m, 2H), 3.56-3.70 (m, 2H ), 2.95-3.08 (m, 2H), 2.76-2.85 (s, 2H), 2.40-2.51 (m, 3H), 1.87-2.16 (s , 1H), 0.91-1.07 (s, 9H). LCMS (ES ⁺ ): m/z 898.4 [M+H] ⁺ .

[0657] Exemplary compounds 289, 290, 292 and 293 can be prepared in a similar manner.

[0658] Example 15 - Synthesis Scheme A: Compounds 305, 298, 299, 300, 301, 302 and 303

[0659] tert-Butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)butanoate (1). To a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (209.12 mg, 0.95 mmol) and tert-butyl 4-bromobutanoate (212 mg , 0.95 mmol) in N,N-dimethylformamide (2 ml) was added Cs ₂ CO ₃ (402.47 mg, 1.24 mmol). The reaction mixture was heated at 65°C for 12 hours (overnight). Small amounts of the starting material were detected by TLC (Hex:AcOEt, 7:3). The crude product was purified by flash column chromatography (SiO ₂ -25 g, Hex:AcOEt, gradient 9:1→4:6) to give 198 mg (57% yield) of product as an oil: ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 7.59 (d, J=8.2 Hz, 2H), 6.91 (d, J=7.9 Hz, 2H), 3.99 (t, J=6.3 Hz , 2H), 2.35 (t, J=7.3 Hz, 2H), 1.92 (pent, J=6.7 Hz, 2H), 1.39 (s, 9H), 1.27 (s , 12H). ¹³ C-NMR (101 MHz, DMSO) δ 172.25, 161.56, 136.66, 114.37, 83.77, 80.12, 66.81, 31.72, 28.20, 25.12 , 24.71. LCMS (ESI); m/z [M+Na] ⁺ : Calc. for C ₂₀ H ₃₁ BO ₅ Na, 385.2162. 385.2194 detected.

[0660] tert-Butyl-4-(4-(3-benzoyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenoxy)butanoate (2). A solution of tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-butanoate (72 mg, 0.2 mmol) and (5- Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)phenylmethanone (59.85 mg, 0.2 mmol) in dioxane (6 ml) was degassed under vacuum and purged with argon. K ₂ CO ₃ (82.4 mg, 0.6 mmol) was then added, followed by water (2 ml), the reaction mixture was degassed under vacuum and purged again with argon. Tricyclohexylphosphine (5.57 mg, 0.02 mmol) and Pd(dba) ₂ (5.71 mg, 0.01 mmol) were added to the reaction mixture, the reaction mixture was degassed under vacuum and again purged with argon. Then, the reaction mixture was heated at 90°C for 2 hours. A small amount of starting material was detected by TLC (Hex:AcOEt, 3:7), small amounts of tricyclohexylphosphine (5.57 mg, 0.02 mmol) and Pd(dba) ₂ (5.71 mg, 0.01 mmol) were added twice. , and the reaction mixture was stirred for an additional 2 hours. The reaction mixture was diluted with AcOEt (20 ml), dried (Na ₂ SO ₄ ) and filtered under vacuum through a pad of Celite, the filtrate was dried (Na ₂ SO ₄ ) and concentrated under vacuum. The crude material was diluted with DCM and purified by flash chromatography (SiO ₂ -40 g, Hex:AcOEt gradient, 9:1→100% AcOEt gradient) to obtain 69 mg (68%) of product as an off-white solid. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 12.68 (s, 1H), 8.65 (s, 1H), 8.60 (s, 1H), 8.10 (s, 1H), 7.82 (d, J=7.5 Hz, 2H), 7.58 (dt, J=36.0, 7.9 Hz, 5H), 7.04 (d, J=8.1 Hz, 2H ), 4.16-3.83 (m, 2H), 2.37 (t, J=6.5 Hz, 2H), 1.95 (dd, J=11.4, 5.5 Hz, 2H) , 1.39 (s, 9H). ¹³ C-NMR (126 MHz, DMSO) δ 189.81, 171.86, 158.13, 148.26, 143.24, 139.62, 136.43, 131.45, 130.82, 130.66 , 128.52, 128.48, 128.16, 127.01, 118.77, 115.13, 113.73, 79.68, 66.63, 31.36, 27.77, 24.37. LCMS (ESI); m/z: [M+H] ⁺ Calc. for C ₂₈ H ₂₉ N ₂ O ₄ , 457.2127. 457.2156 detected.

[0661] 4-(4-(3-Benzoyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenoxy)butanoic acid (3). Tert-Butyl 4-(4-(3-(2,6-difluorobenzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenoxy)butanoate solution (30 mg, 0.06 mmol) in a mixture of TFA (1 ml, 13.46 mmol) and dichloromethane (3 ml) was stirred for 1 hour. The solvent was then removed under vacuum and the crude product was dried under high vacuum for 2 hours. The crude product was used in the next step without any further purification (26.5 mg, quantitative yield). LCMS (ESI); m/z: [M+H] ⁺ Calc. for C ₂₄ H ₂₁ N ₂ O ₄ , 401.1501. 401.1420 detected.

[0662] (2S,4R)-1-((S)-2-(4-(4-(3-benzoyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenoxy)-butanamido) -3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)-pyrrolidine-2-carboxamide (compound 305). To a solution of 4-[4-(3-benzoyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-phenoxy]butanoic acid (26.5 mg, 0.07 mmol) and (2S,4R) -1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]-pyrrolidine-2-carboxamide hydrochloride ( 30.91 mg, 0.07 mmol) in DMF (2 ml) TEA (0.2 ml, 1.43 mmol) and PyBOP (37.88 mg, 0.07 mmol) were added at room temperature. The reaction mixture was stirred for 12 hours (overnight) at the same temperature. The absence of starting substances was detected by the TLC method (DCM: MeOH: NH ₄ OH, 90:9:1). DMF was removed under high vacuum conditions. The crude product was filtered through a silica gel carbonate cartridge (1 g) using DCM:MeOH (9:1) as eluent. The filtrate was evaporated in vacuo and the crude product was purified by preparative TLC (MeOH:DCM, 9:1) to obtain 31 mg of product (58% yield). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.70 (s, 1H), 8.97 (s, 1H), 8.68 (d, J=2.2 Hz, 1H), 8, 62 (d, J=2.3 Hz, 1H), 8.60-8.51 (m, 1H), 8.12 (s, 1H), 8.00 (d, J=9.3 Hz, 1H ), 7.90-7.77 (m, 1H), 7.72-7.51 (m, 5H), 7.48-7.29 (m, 4H), 7.07 (d, J=8 .7 Hz, 2H), 5.15 (d, J=3.5 Hz, 1H), 4.59 (d, J=9.3 Hz, 1H), 4.50-4.32 (m, 3H ), 4.22 (dd, J=15.9, 5.4 Hz, 1H), 4.03 (td, J=6.5, 2.6 Hz, 2H), 3.80-3.60 ( m, 2H), 2.44 (s, 3H), 2.48-2.28 (m, 5H), 2.13-1.84 (m, 4H), 0.96 (s, 9H). ¹³ C-NMR (101 MHz, DMSO) δ 189.87, 172.00, 171.63, 169.69, 158.23, 151.48, 148.29, 147.73, 143.29, 139.64 , 139.53, 136.54, 131.52, 131.19, 130.74, 129.65, 128.66, 128.58, 128.55, 128.21, 127.44, 127.05, 118 .81, 115.19, 113.74, 68.93, 67.13, 58.75, 56.47, 48.64, 41.68, 38.01, 35.29, 31.33, 26.43 , 25.08, 15.99. LCMS (ESI); m/z [M+H] ⁺ : Calc. for C ₄₆ H ₄₉ N ₆ O ₆ S, 813.3434. 813.3478 discovered.

[0663] Example 16 - Synthesis Scheme B: Compounds 217, 220 and 221

[0664] tert-Butyl(4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)carbamate (5a). To a solution of tert-butyl-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (50.99 mg, 0.16 mmol) in dioxane (3 ml) N-[3-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4-difluorophenyl]propane-1-sulfonamide (0.06 ml, 0 .13 mmol), K ₂ CO ₃ (55.19 mg, 0.4 mmol), tricyclohexylphosphine (3.73 mg, 0.01 mmol) and water (1 ml). Then, the reaction mixture was degassed under vacuum and purged with argon, Pd(dba) ₂ (3.83 mg, 0.01 mmol) was added, and the reaction mixture was heated at 80°C for 3 hours. Small amounts of starting material were detected by TLC (Hex:AcOEt, 3:7), the reaction mixture was filtered under vacuum through a pad of Celite, the filtrate was poured into saturated aqueous NaCl (20 ml), and the product was extracted with EtOAc (2 x 20 ml). The EtOAc layers were combined, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude material was diluted in DCM and purified by flash chromatography (SiO ₂ -12 g, hexane:AcOEt, gradient 8:2→100% AcOEt) to obtain 47 mg (56%) of product as an off-white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.96 (b s, 1H), 9.77 (b s, 1H), 9.49 (s, 1H), 8.68 (d , J=2.1 Hz, 1H), 8.57 (broad s, 1H), 8.21 (s, 1H), 7.79-7.46 (m, 5H), 7.28 (td, J=8.7, 1.5 Hz, 1H), 3.19-3.07 (m, 2H), 1.74 (d.kv, J=14.9, 7.4 Hz, 2H), 1 .50 (s, 9H), 0.96 (t, J=7.4 Hz, 3H). ¹³ C-NMR (151 MHz, DMSO) δ 180.61, 156.03 (dd, J=246.5, 7.1 Hz), 152.77, 152.34 (dd, J=249.5, 8 .5 Hz), 148.60, 143.76, 139.22, 138.64, 131.66, 131.31, 128.79 (d, J=9.7 Hz), 127.35, 126.38 , 121.94 (dd, J=13.7, 3.6 Hz), 118.66, 118.24 (t, J=23.5 Hz), 117.53, 115.63, 112.35 (dd , J=22.6, 3.9 Hz), 79.19, 53.46, 28.15, 16.85, 12.62. LCMS (ESI); m/z: [M+H] ⁺ Calc. for C ₂₈ H ₂₉ F ₂ N ₄ O ₅ S, 571.1826. 571.1917 discovered.

[0665] N-(3-(5-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (6). Tert-butyl-(4-(3-(2,6-difluoro-3-(propylsulfon-amido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)carbamate solution (30 mg , 0.05 mmol) in TFE (2 ml) was heated at 140°C for 3 hours under microwave assisted conditions. The reaction mixture was evaporated to dryness under vacuum to obtain 23 mg of product in quantitative yield. The crude product was used in the next step without any further purification. LCMS (ESI); m/z: [M+H] ⁺ Calc. for C ₂₃ H ₂₁ F ₂ N ₄ O ₃ S, 471.1302. 471.1351 discovered.

[0666] tert-Butyl-5-((4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amino )-5-oxopentanoate (7). N-(3-(5-(4-aminophenyl)-1H-pyrrolo[2 ,3-b]-pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (10 mg, 0.02 mmol). The resulting suspension was refluxed for 12 hours (overnight). The reaction mixture was evaporated under vacuum and the crude product was purified by preparative TLC (MB:DCM, 4:6) to obtain 10.7 mg of a white powder (79% yield). ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 12.96 (bs, 1H), 10.04 (s, 1H), 9.76 (bs, 1H), 8.69 (d , J=2.2 Hz, 1H), 8.59 (s, 1H), 8.21 (s, 1H), 7.75 (d, J=8.7 Hz, 2H), 7.69 (d , J=8.6 Hz, 2H), 7.59 (td, J=9.0, 5.8 Hz, 1H), 7.28 (t, J=9.2 Hz, 1H), 3.13 (dd, J=8.7, 6.7 Hz, 2H), 2.39 (t, J=7.4 Hz, 2H), 2.28 (t, J=7.4 Hz, 2H), 1 .83 (pent, J=7.4 Hz, 2H), 1.75 (hex, J=7.5 Hz, 2H), 1.41 (s, 9H), 0.96 (t, J=7, 4 Hz, 3H). ¹³ C-NMR (101 MHz, DMSO) δ 181.01, 172.37, 171.16, 156.02 (dd, J=246.3, 7.0 Hz), 152.34 (dd, J=249 ,5, 8.5 Hz), 149.05, 144.18, 139.30, 139.05, 133.00, 131.62, 128.77 (d, J=9.5 Hz), 127.75 , 126.88, 121.96 (dd, J=13.7, 3.5 Hz), 120.04, 118.74-117.84 (m), 117.94, 116.05, 112.34 ( dd, J=22.8, 3.0 Hz). 79.98, 53.89, 35.72, 34.53, 28.20, 20.93, 17.25, 13.02. LCMS (ESI); m/z: [M+H] ⁺ Calc. for C ₃₂ H ₃₅ F ₂ N ₄ O ₆ S, 641.2245. 641.2473 discovered.

[0667] 5-((4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amino)-5- oxopentanoic acid (8). A solution of tert-butyl-5-((4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amino)- 5-oxopentanoate (10.7 mg, 0.02 mmol) in a mixture of TFA (1 ml, 13.46 mmol) and dichloromethane (2 ml) was stirred for 2 hours. The solvent was then removed under vacuum and the crude product was dried under high vacuum for 2 hours. The crude product was used in the next step without any further purification (9.7 mg, quantitative yield). LCMS (ESI); m/z: [M+H] ⁺ Calc. for C ₂₈ H ₂₇ F ₂ N ₄ O ₆ S, 585.1619. 585.1636 detected.

[0668] N1-(4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-N5-((S )-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)-carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2-yl)glutaramide (compound 217). To a solution of 5-((4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amino)-5-oxopentane acid (9.7 mg, 0.02 mmol) and (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4- methylthiazol-5-yl)phenyl]-methyl]pyrrolidine-2-carboxamide hydrochloride (8.52 mg, 0.02 mmol) in DMF (1 ml) was added at room temperature with TEA (0.1 ml, 0.72 mmol) and PyBOP (9.5 mg, 0.02 mmol). The reaction mixture was stirred for 4 hours at the same temperature. The absence of starting substances was detected by the TLC method (DCM: MeOH: NH ₄ OH, 90:9:1). The reaction mixture was diluted with EtOAc (10 ml) and washed with brine (5 ml, 4×), the organic phase was dried (Na ₂ SO ₄ ) and evaporated under vacuum. The crude product was purified by preparative TLC (DCM:MeOH: _NH4OH , 90:9:1) to obtain 4.8 mg of product (29% yield). ^1H -NMR (500 MHz, DMSO- _d6 ) δ 10.02 (s, 1H), 8.97 (s, 1H), 8.68 (d, 1H), 8.64 -8.52 (m , 2H), 8.21 (s, 1H), 7.95 (d, J=9.2 Hz, 1H), 7.72 (dd, J=36.7, 8.5 Hz, 4H), 7 .62-7.54 (m, 1H), 7.40 (dd, 4H), 7.28 (t, J=8.7 Hz, 1H), 5.16 (d, 2H), 4.56 ( d, J=9.3 Hz, 1H), 4.50-4.40 (m, 2H), 4.40-4.33 (m, 1H), 4.22 (dd, J=15.8, 5.3 Hz, 1H), 3.76-3.62 (m, 2H), 3.16-3.05 (m, 2H), 2.44 (s, 3H), 2.41-2.17 (m, 4H), 2.09-2.01 (m, 1H), 1.98-1.80 (m, 3H), 1.74 (d.kv, J=14.9, 7.4 Hz , 2H), 0.96 (s, 9H), 0.95 (t, 3H). ¹³ C-NMR (151 MHz, DMSO) δ 181.06, 172.39, 172.17, 171.46, 170.15, 156.37 (dd, J=246.6, 6.3 Hz), 152 .73 (dd, J=249.4, 8.1 Hz), 151.86, 149.05, 148.13, 144.19, 139.91, 139.37, 139.13, 132.97, 131 .64, 131.59, 130.05, 129.22 (d, J=14.7 Hz), 129.06, 127.84, 127.74, 126.89, 122.47 (d, J=14 ,1 Hz), 120.07, 119.02-118.20 (m), 117.95, 116.06, 112.75 (dd, J=23.4, 2.8 Hz), 69.34, 59.15, 56.90, 56.81, 53.87, 42.08, 38.38, 36.36, 35.63, 34.63, 26.85, 21.91, 17.27, 16, 37, 13.04. LCMS (ESI); m/z [M+H] ⁺ : Calc. for C ₅₀ H ₅₅ F ₂ N ₈ O ₈ S ₂ , 997.3552. 997.3524 discovered.

[0669] Example 17 - Synthesis Scheme C: Compounds 218, 219 and 222

[0670] tert-Butyl-4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)piperazine-1-carboxylate (9a ). A solution of N-[3-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4-difluorophenyl]propane-1-sulfonamide (61 mg, 0.13 mmol) and tert -butylpiperazine-1-carboxylate (37.19 mg, 0.2 mmol) in THF (3 ml) was purged with argon (5×). RuPhos (18.63 mg, 0.04 mmol) and Pd(OAc) ₂ (2.99 mg, 0.01 mmol) were added followed by 1M LHMDS in THF (0.53 ml) The reaction mixture was heated to 60°C and stirred for 6 hours. The reaction mixture was cooled and poured into aqueous oxalic acid (5%, 2 ml), then saturated aqueous NaHCO ₃ (5 ml) was added and the product was extracted with DCM (3 x 10 ml). Organic extracts were combined, dried (Na ₂ SO ₄ ) and evaporated under vacuum. The crude product was purified by preparative TLC (DCM:MeOH: _NH4OH , 90:9:1) (20 mg, 26%). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.61 (b. s, 1H), 9.73 (b. s, 1H), 8.27 (d, J=2.6 Hz, 1H ), 8.03 (s, 1H), 7.94 (broad s, 1H), 7.57 (td, J=9.0, 5.9 Hz, 1H), 7.26 (td, J= 8.7, 1.5 Hz, 1H), 3.63-3.46 (m, 4H), 3.42-3.24 (m, 4H), 3.20-3.06 (m, 2H) , 1.74 (d.kv, J=15.0, 7.4 Hz, 2H), 1.43 (s, 9H), 0.96 (t, J=7.4 Hz, 3H). ¹³ C-NMR (101 MHz, DMSO) δ 180.37, 155.96 (dd, J=246.2, 7.2 Hz), 153.87, 152.31 (dd, J=249.1, 8 .6 Hz), 144.72, 144.31, 138.06, 137.78, 128.59 (d, J=7.8 Hz), 121.94 (dd, J=13.6, 3.7 Hz), 119.35-117.93 (m), 117.56, 115.58, 115.17, 112.25 (dd, J=22.7, 3.8 Hz), 79.01, 53, 49, 50.03, 43.56, 28.07, 16.84, 12.61. LCMS (ESI); m/z: [M+H] ⁺ Calc. for C ₂₆ H ₃₂ F ₂ N ₅ O ₅ S, 564.2092. Detected 564.2

[0671] N-(2,4-difluoro-3-(5-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)phenyl)propane-1-sulfonamide ( 9b). Solution of tert-butyl-4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)piperazine-1-carboxylate (20 mg, 0.04 mmol) in a mixture of DCM:TFA (3 ml: 1 ml) was stirred for 1 hour at room temperature. The absence of the starting material was detected by TLC (DCM: MeOH: NH ₄ OH, 90:9:1). 16.4 mg of product was obtained (quantitative yield), and the crude product was used in the next step without any further purification. LCMS (ESI); m/z [M+H] ⁺ : Calc. for C ₂₁ H ₂₄ F ₂ N ₅ O ₃ S, 464.1567. 464.1712 detected.

[0672] tert-butyl-5-(4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)piperazin-1- yl)-5-oxopentanoate (10). To a solution of N-(2,4-difluoro-3-(5-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-phenyl)propane-1-sulfonamide (16 .4 mg, 0.04 mmol) and 5-(tert-butoxy)-5-oxopentanoic acid (7.99 mg, 0.04 mmol) in DMF (2 ml), TEA (0.1 ml, 0.72 mmol) and PyBOP (20.25 mg, 0.04 mmol). The reaction mixture was stirred for 3 hours at the same temperature. The absence of starting substances was detected by the TLC method (DCM: MeOH: NH ₄ OH, 90:9:1). The reaction mixture was dissolved in EtOAc (10 ml) and washed with saline/water (3×5 ml). The organic extract was concentrated under vacuum and the crude product was purified by preparative TLC (DCM:MeOH: _NH4OH , 90:9:1) to obtain 15.4 mg of product (69% yield). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.67 (b. s, 1H), 9.71 (b. s, 1H), 8.29 (s, 1H), 8.03 (s , 1H), 7.95 (s, 1H), 7.56 (kv, J=8.8 Hz, 1H), 7.26 (t, J=8.7 Hz, 1H), 3.71-3 .57 (m, 4H), 3.24-3.06 (m, 6H), 2.39 (t, J=7.3 Hz, 2H), 2.26 (t, J=7.3 Hz, 2H), 1.84-1.66 (m, 4H), 1.40 (s, 9H), 0.96 (t, J=7.4 Hz, 3H). ¹³ C-NMR (101 MHz, DMSO) δ 180.79, 172.52, 170.57, 156.37 (dd, J=246.4, 7.1 Hz), 152.72 (dd, J=249 ,2, 8.7 Hz), 145.03, 144.70, 138.44, 138.20, 129.01 (d, J=10.4 Hz), 122.34 (dd, J=13.7 , 3.7 Hz), 119.28-118.29 (m), 117.97, 115.84, 115.58, 112.66 (dd, J=22.8, 3.3 Hz), 79, 92, 53.89, 50.66, 45.18, 41.39, 34.57, 31.72, 28.21, 20.83, 17.25, 13.02. LCMS (ESI); m/z [M+H] ⁺ : Calc. for C ₃₀ H ₃₈ F ₂ N ₅ O ₆ S, 634.2510. 634.2621 discovered.

[0673] 5-((4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amino)-5- oxopentanoic acid (11). A solution of tert-butyl-5-((4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amino)- 5-oxopentanoate (10.7 mg, 0.02 mmol) in a mixture of TFA (1 ml, 13.46 mmol) and dichloromethane (2 ml) was stirred for 2 hours at room temperature. The solvent was then removed under vacuum and the crude product was dried under high vacuum for 2 hours. The crude product was used in the next step without any further purification (9.7 mg, quantitative yield). LCMS (ESI); m/z: [M+N] ⁺ Calc. for C ₂₈ H ₂₇ F ₂ N ₄ O ₆ S, 585.1619. 585.1636 detected.

[0674] (2S,4R)-1-((S)-2-(5-(4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3- b]pyridin-5-yl)piperazin-1-yl)-5-oxopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidin-2 -carboxamide (compound 218). To a solution of 5-(4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)piperazin-1-yl)-5- oxopentanoic acid (9.3 mg, 0.02 mmol) and (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4 -methylthiazol-5-yl)-phenyl]methyl]pyrrolidine-2-carboxamide hydrochloride (8.27 mg, 0.018 mmol) in DMF (1 ml) was added at room temperature with TEA (0.1 ml, 0.72 mmol) and PyBOP (9.22 mg, 0.018 mmol). The reaction mixture was stirred for 4 hours at the same temperature. The absence of starting substances was detected by the TLC method (DCM: MeOH: NH ₄ OH, 90:9:1). The reaction mixture was diluted with EtOAc (10 ml) and washed with brine (5 ml, 4×), the organic phase was dried (Na ₂ SO ₄ ) and evaporated under vacuum. By TLC, not the product was detected in the crude mixture, but a certain amount of the starting material VHL (4) (the product is soluble in water). The aqueous extracts were lyophilized overnight and the solid was filtered using DCM:MeOH: _NH4OH (90:9:1, 30 ml). The filtrate was evaporated to dryness and the crude product was purified by preparative TLC (DCM:MeOH: _NH4OH , 90:9:1) to obtain 13 mg of product (81% yield). ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 12.64 (b s, 1H), 9.74 (b s, 1H), 8.97 (s, 1H), 8.62-8 .52 (m, 3H), 8.28 (d, J=2.0 Hz, 1H), 8.00 (s, 1H), 7.95 (broad s, 1H), 7.90 (d, J=9.2 Hz, 1H), 7.59-7.49 (m, 1H), 7.47-7.27 (m, 4H), 7.20 (t, J=8.7 Hz, 1H ), 5.13 (b. s, 1H), 4.56 (d, J=9.3 Hz, 1H), 4.48-4.32 (m, 3H), 4.22 (dd, J= 15.8, 5.3 Hz, 1H), 3.75-3.57 (m, 5H), 3.23-3.02 (m, 7H), 2.44 (s, 3H), 2.41 -2.17 (m, 4H), 2.07-2.01 (m, 1H), 1.96-1.87 (m, 1H), 1.81-1.66 (m, 4H), 0 .95 (s, 9H), 0.94 (t, 3H). ¹³ C-NMR (151 MHz, DMSO) δ 180.70, 171.99, 171.92, 170.44, 169.75, 155.24 (dd, J=248.1, 5.5 Hz), 152 .12 (dd, J=248.8, 8.5 Hz), 151.47, 147.73, 144.63, 144.31, 139.52, 138.02, 137.75, 131.19, 129 ,65, 128.65, 127.98-127.64 (m), 127.44, 123.91-123.09 (m), 118.86-117.72 (m), 117.60, 115, 50, 115.23, 112.02 (dd, J=22.6, 3.2 Hz), 68.92, 58.74, 56.47,56.43, 53.44, 50.31.50, 18.48.63, 44.86, 41.68, 41.00, 37.99, 34.28, 31.80, 26.43, 21.36, 16.99, 15.97, 12.72. LCMS (ESI); m/z [M+H] ⁺ : Calc. for C ₄₈ H ₅₈ F ₂ N ₉ O ₈ S ₂ , 990.3817. 990.3889 discovered.

[0675] Example 18 - Synthesis Scheme D: Compounds 304 and 306

[0676] tert-Butyl-4-[4-[3-[2,6-difluoro-3-(propylsulfonylamino)benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]piperazin-1- yl]butanoate (12). To a solution of methyl-N-[2,4-difluoro-3-(5-piperazin-1-yl-1H-pyrrolo[2,3-b]-pyridin-3-carbonyl)phenyl]propane-1-sulfonamide 2, 2,2-trifluoroacetate (17.4 mg, 0.03 mmol) and tert-butyl-4-iodobutanoate (8.95 mg, 0.03 mmol) in DMF (1 ml) was added TEA (0.03 ml, 0 .15 mmol), and the resulting solution was stirred at 50°C for 16 hours (overnight). The solvent was evaporated under high vacuum, and the residue was filtered through a silica gel carbonate cartridge (1 g) using DCM:MeOH (9:1) as eluent. The filtrate was evaporated under vacuum and the crude product was purified by preparative TLC (DCM:MeOH: _NH4OH , 90:9:1) to obtain 8.8 mg of product (48% yield). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.63 (b s, 1H), 9.73 (b s, 1H), 8.25 (d, J=2.7 Hz, 1H ), 8.00 (s, 1H), 7.89 (b s, 1H), 7.56 (td, J=9.0, 6.0 Hz, 2H), 7.34-7.16 ( m, 1H), 3.25-3.04 (m, 6H), 2.68-2.52 (m, 4H), 2.34 (t, J=7.1 Hz, 2H), 2.24 (t, J=7.2 Hz, 2H), 1.85-1.61 (m, 4H), 1.40 (s, 9H), 0.96 (t, J=7.4 Hz, 3H) . ¹³ C-NMR (151 MHz, DMSO-d ₆ ) δ 180.34, 172.23, 155.99 (dd, J=246.1, 7.0 Hz), 152.31 (dd, J=249, 3, 8.6 Hz), 144.80, 143.96, 137.64, 137.36, 128.60 (d, J=9.9 Hz), 121.91 (dd, J=13.6, 3.7 Hz), 118.41 (t, J=23.8 Hz), 117.63, 115.12, 114.54, 112.26 (dd, J=22.8, 3.7 Hz), 56.95, 53.47, 52.70, 49.72, 32.69, 27.83, 21.79, 16.86, 12.63. LCMS (ESI); m/z: [M+H] ⁺ Calc. for C ₂₉ H ₃₈ F ₂ N ₅ O ₅ S, 606.2561. 606.2504 discovered.

[0677] 4-[4-[3-[2,6-Difluoro-3-(propylsulfonylamino)benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]piperazin-1-yl]butanoic acid (13). Solution of tert-butyl-4-[4-[3-[2,6-difluoro-3-(propylsulfonylamino)benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]piperazin-1-yl] butanoate (8.8 mg, 0.01 mmol) in a mixture of TFA (1 ml, 13.46 mmol) and dichloromethane (3 ml) was stirred for 1 hour. The solvent was then removed under vacuum and the crude product was dried under high vacuum for 2 hours. The crude product was used in the next step without any further purification (7.9 mg, quantitative yield). LCMS (ESI); m/z: [M+N] ⁺ Calc. for C ₂₅ H ₃₀ F ₂ N ₅ O ₅ S, 550.1936. 550.1865 detected.

[0678] (2S,4R)-1-((S)-2-(4-(4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3- b]pyridin-5-yl)piperazin-1-yl)butanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide ( connection 304). To a solution of 4-[4-[3-[2,6-difluoro-3-(propylsulfonylamino)benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]piperazin-1-yl]butanoic acid ( 7.9 mg, 0.01 mmol) and (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methylthiazol- 5-yl)phenyl]methyl]-pyrrolidine-2-carboxamide hydrochloride (7.38 mg, 0.02 mmol) in DMF (1 ml) was added with TEA (0.1 ml, 0.72 mmol) and PyBOP at room temperature (8.23 mg, 0.02 mmol). The reaction mixture was stirred for 12 hours (overnight) at the same temperature. The absence of starting substances was detected by the TLC method (DCM: MeOH: NH ₄ OH, 90:9:1). The reaction mixture was evaporated to dryness. The crude product was filtered through a silica gel carbonate cartridge (1 g) using DCM:MeOH (9:1) as eluent (washed several times, the product had high affinity for the stationary phase). The filtrate was evaporated in vacuo and the crude product was purified by preparative TLC (DCM:MeOH, 9:1) to obtain 7.2 mg of product (52% yield). ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 12.66 (b s, 1H), 9.73 (b s, 1H), 8.96 (s, 1H), 8.61-8 .50 (m, 1H), 8.25 (s, 1H), 8.00 (s, 1H), 7.93 (broad s, 1H), 7.88 (d, J=9.1 Hz, 1H), 7.63-7.49 (m, 1H), 7.40 (dd, 4H), 7.25 (t, J=8.7 Hz, 1H), 5.14 (s, 1H), 4.56 (d, J=9.1 Hz, 1H), 4.46-4.34 (m, 3H), 4.22 (dd, J=15.8, 4.7 Hz, 1H), 3 .75-3.60 (m, 2H), 3.23-3.14 (m, 4H), 3.13-3.08 (m, 2H), 2.65-2.53 (m, 4H) , 2.43 (s, 3H), 2.38-2.31 (m, 2H), 2.31-2.25 (m, 1H), 2.24-2.16 (m, 1H), 2 .07-1.99 (m, 1H), 1.95-1.87 (m, 1H), 1.72 (d.kv, J=16.3, 10.5, 8.9 Hz, 4H) , 0.95 (t, J=5.3 Hz, 3H), 0.95 (s, 9H). ¹³ C-NMR (151 MHz, DMSO-d ₆ ) δ 180.77, 172.43, 172.39, 170.12, 156.38 (dd, J=246.2, 7.1 Hz), 152, 75 (dd, J=249.8, 9.0 Hz), 151.87, 148.13, 145.23, 144.35, 139.92, 138.09, 137.78, 131.59, 130, 05, 129.21-128.76 (m), 127.84, 122.32 (d, J=13.1 Hz), 119.83-118.25 (m), 118.03, 115.53, 114.96, 112.68 (d, J=22.7 Hz), 69.30, 59.13, 57.62, 56.79, 55.33, 53.88, 53.06, 50.11, 42.07, 38.38, 35.68, 33.27, 26.83, 23.09, 17.26, 16.37, 13.04. LCMS (ESI); m/z [M+H] ⁺ : Calc. for C ₄₇ H ₅₈ F ₂ N ₉ O ₇ S ₂ , 962.3868. 962.3986 discovered.

[0679] Synthesis example of compound 196: (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(4-(4-(1-(hydroxyimino)-2,3 -dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)butoxy)phenyl)isoindoline-1,3-dione

[0680] Step A: 5-(1-(4-(4-hydroxybutoxy)phenyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydro-1H-indene -1-he

[0681] To a solution of 4-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)butan-1-ol (150 mg, 0.39 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydroinden-1-one (120 mg, 0.46 mmol) in 1,4-dioxane /H ₂ O (10 ml, v/v = 10/1) added t-Bu ₃ PHBF ₄ (44.8 mg, 0.15 mmol), CsF (234.9 mg, 1.54 mmol), Cy ₂ NCH ₃ (5 drops) and Pd ₂ (dba) ₃ (70.7 mg, 0.077 mmol). The resulting solution was stirred at 100°C for 2 hours under N ₂ atmosphere. The solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate (30 ml), and the mixture was washed with brine. The organic phase was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (DCM/MeOH = 80/1) to obtain the desired product (140 mg, 82.4% yield) as a colorless oil.

[0682] Step B: tert-butyl-5-(3-(pyridin-4-yl)-1-(4-(4-(3-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)phenoxy)butoxy)phenyl)-1H-pyrazol-4-yl)-2,3-dihydro-1H-inden-1-one

[0683] To a solution of 5-(1-(4-(4-hydroxybutoxy)phenyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydro-1H-inden- 1-one (140 mg, 0.32 mmol) and triethylamine (96.8 mg, 0.96 mmol) in DCM (10 ml) at 0°C was added MsCl (43.8 mg, 0.38 mmol). After stirring at 30°C for 1 hour, the solvent was removed under vacuum. The residue was diluted with ethyl acetate (30 ml), and the mixture was washed with brine. The organic phase was concentrated to give the mesylate intermediate (180 mg, 0.34 mmol, 109%). To a solution of mesylate (90 mg, 0.17 mmol) in anhydrous DMF (10 ml) was added 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (449.7 mg, 0.22 mmol) and K ₂ CO ₃ (47.9 mg, 0.34 mmol). The resulting mixture was stirred at 68°C for 4 hours. The mixture was diluted with EtOAc (40 ml), washed with brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EtOAc = 1/3) to obtain the target product (80 mg, 71.7% yield). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.65-8.55 (m, 2H), 8.00 (s, 1H), 7.76 (d, J=7.7 Hz, 1H) , 7.68 (d, J=9.1 Hz, 2H), 7.51 (s, 2H), 7.44 (s, 1H), 7.29-7.41 (m, 4H), 7, 02 (d, J=7.0 Hz, 3H), 4.12 (dd, J=14.0, 6.9 Hz, 4H), 3.60-3.67 (m, 1H), 3.13 (s, 2H), 2.74 (s, 2H), 2.01 (s, 2H), 1.34 (s, 12H).

[0684] Step C: tert-butyl-2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(4-(4-(1-oxo-2,3-dihydro-1H -inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)butoxy)phenyl)-isoindoline-1,3-dione

[0685] To a solution of tert-butyl-5-(3-(pyridin-4-yl)-1-(4-(4-(3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenoxy)butoxy)phenyl)-1H-pyrazol-4-yl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.12 mmol) and 5-(3- bromophenyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (46.3 mg, 0.14 mmol) in 1,4-dioxane/H ₂ O (9 ml, 8: 1) added t-Bu ₃ PHBF ₄ (14.5 mg, 0.050 mmol), CsF (75.8 mg, 0.50 mmol), Cy ₂ NMe (1 drop) and Pd ₂ (dba) ₃ (22.8 mg, 0.025 mmol). The resulting mixture was stirred at 100°C for 2 hours under N ₂ atmosphere. The solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate (30 ml), and the mixture was washed with brine. The organic phase was evaporated under reduced pressure. The residue was purified by TLC (PE/EtOAc = 1/8) to obtain the target product (40 mg, 41.5% yield).

[0686] Step D: (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(4-(4-(1-(hydroxyimino)-2,3-dihydro -1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)butoxy)phenyl)-isoindoline-1,3-dione

[0687] To a solution of tert-butyl-2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(4-(4-(1-oxo-2,3-dihydro-1H- inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)butoxy)phenyl)-isoindoline-1,3-dione (40 mg, 0052 mmol) in CH ₃ CN /Py (5 ml/2 ml) NH ₂ OH⋅HCl (40 mg, 0.57 mmol) was added. The reaction mixture was stirred at 40°C for 0.5 hour. The mixture was diluted with EtOAc (30 ml) and washed twice with saline. The organic layer was evaporated under reduced pressure. The residue was purified by preparative HPLC to obtain the title product as a white solid (13.5 mg, 8.6% yield). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.47-8.86 (m, 3H), 8.27 (s, 1H), 8.09 (s, 1H), 7.94 (d, J=4.9 Hz, 3H), 7.68 (d, J=8.7 Hz, 3H), 7.52 (s, 2H), 7.36-7.47 (m, 2H), 7. 29 (s, 1H), 7.21 (s, 1H), 7.15 (s, 1H), 7.02 (d, J=8.4 Hz, 3H), 4.97-5.04 (m , 1H), 4.13 (s, 4H), 2.74-3.12 (m, 8H), 2.21 (d, J=7.7 Hz, 2H), 2.01-2.09 ( m, 3H). LCMS (ES ⁺ ): m/z 787.2 [M+H] ⁺ .

[0688] Example of the synthesis of compound 197: (E)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(2-(4-(4-(1-(hydroxyimino)- 2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethoxy)ethyl)piperazin-1-yl)isoindolin-1,3 -dion

[0689] Step A: 2-(2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethoxy)-ethanol

[0690] To a solution of 4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenol (500 mg, 1.58 mmol) in anhydrous DMF (5 mL), Cs was added sequentially ₂ CO ₃ (1.55 g, 4.75 mmol) and 2-(2-hydroxyethoxy)ethyl-4-methylbenzenesulfonate (1.23 g, 4.75 mmol). The resulting solution was stirred at 70°C for 3 hours. After cooling to room temperature, the reaction mixture was quenched by adding water (20 ml) and extracted with EtOAc (20 ml x 3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by a silica gel column to give the title product (500 mg, 78% yield) as a yellow solid. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.69 (s, 2H), 7.91-7.96 (m, 3H), 7.62 (d, J=8.8 Hz, 2H) , 7.05 (d, J=8.4 Hz, 2H), 4.19 (t, J=4.4 Hz, 2H), 3.90 (t, J=4.0 Hz, 2H), 3 .78 (t, J=4.8 Hz, 2H), 3.70 (t, J=4.4 Hz, 2H).

[0691] Step B: 2-(2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethoxy)ethylmethanesulfonate

[0692] To a solution of 2-(2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethoxy)-ethanol (500 mg, 1.24 mmol ) and TEA (249 mg, 2.47 mmol) in DCM (5 ml) at 0°C, MsCl (169 mg, 1.48 mmol) was added dropwise. The resulting solution was stirred at 5°C for 0.5 hours. After quenching the mixture by adding saturated NaHCO ₃ (20 ml), the mixture was extracted with DCM (20 ml×2). The combined organic layer was dried over anhydrous sodium sulfate and concentrated to give the title product (550 mg, crude, calc.) as an oil, which was used directly in the next step. LCMS (ES+): m/z 482.0 [M+H] ⁺ .

[0693] Step C: tert-butyl-4-(2-(2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethoxy)ethyl) piperazine-1-carboxylate

[0694] To a solution of 2-(2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethoxy)ethylmethanesulfonate (0.5 g, 1, 04 mmol) and tert-butylpiperazine-1-carboxylate (385 mg, 2.08 mmol) in DMF (5 ml) were successively added K ₂ CO ₃ (715 mg, 5.20 mmol) and KI (860 mg, 5.20 mmol). The resulting solution was stirred at 75°C for 3 hours. After cooling to room temperature, the reaction mixture was quenched by adding water (20 ml), and the mixture was extracted with ethyl acetate (30 ml×2). The combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column to give the desired product (0.4 g, 56% yield in two batches) as a brown oil. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.69 (d, J=4.8 Hz, 2H), 7.97 (m, 3H), 7.61 (d, J=9.2 Hz , 2H), 7.01 (d, J=8.8 Hz, 2H), 4.05-4.20 (m, 3H), 3.84 (t, J=4.8 Hz, 2H), 3 .71 (t, J=5.6 Hz, 2H), 3.44 (m, 4H), 2.63 (t, J=5.6 Hz, 2H), 2.45 (m, 4H), 1 .46 (s, 9H).

[0695] Step D: tert-butyl-4-(2-(2-(4-(4-(1-oxo-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4 -yl)-1H-pyrazol-1-yl)phenoxy)ethoxy)ethyl)piperazine-1-carboxylate

[0696] To a solution of tert-butyl-4-(2-(2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)-phenoxy)ethoxy)ethyl) piperazine-1-carboxylate (0.4 g, 0.70 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H -inden-1-one (271 mg, 1.05 mmol) in 1,4-dioxane (15 ml)/H ₂ O (1.5 ml) CsF (425 mg, 2.80 mmol), Pd ₂ were added successively (dba) ₃ (256 mg, 0.28 mmol), tri-tert-butylphosphine tetrafluoroborate (162 mg, 0.56 mmol) and cat. N-cyclohexyl-N-methylcyclohexanamine. The reaction mixture was heated to 100°C for 2 hours under N ₂ atmosphere. After cooling to room temperature, the reaction mixture was quenched by adding water (20 ml), and the mixture was extracted with ethyl acetate (30 ml×2). The combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column to give the desired product (0.4 g crude) as a brown oil. LCMS (ES ⁺ ): m/z 624.7 [M+H] ⁺ .

[0697] Step E: 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(2-(4-(4-(1-oxo-2,3-dihydro-1H- inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethoxy)ethyl)piperazin-1-yl)isoindolin-1,3-dione

[0698] To a solution of tert-butyl-4-(2-(2-(4-(4-(1-oxo-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4- yl)-1H-pyrazol-1-yl)phenoxy)ethoxy)ethyl)piperazine-1-carboxylate (400 mg, 0.64 mmol) in MeOH (5 ml) was added HCl in 1,4-dioxane (5 ml, 8 M). The resulting solution was stirred at 10°C for 1 hour. The solvent was removed under vacuum to obtain the target product (359 mg, calc.), which was used directly in the next step. To a solution of the crude product (359 mg, 0.64 mmol) in NMP (5 mL) DIEA (825 mg, 6.40 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindolin- 1,3-dione (530 mg, 1.92 mmol). The reaction mixture was microwaved at 150°C for 60 minutes. After cooling to room temperature, the reaction mixture was quenched by adding water (20 ml), and the mixture was extracted with ethyl acetate (30 ml×2). The combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column to give the title product (3 g, crude, including NMP) as a brown oil. LCMS (ES+): m/z 780.8 [M+H] ⁺ .

[0699] Step F: (E)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(2-(4-(4-(1-(hydroxyimino)-2, 3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethoxy)ethyl)-piperazin-1-yl)isoindolin-1,3- dione

[0700] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(2-(4-(4-(1-oxo-2,3-dihydro-1H-indene -5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethoxy)ethyl)piperazin-1-yl)isoindolin-1,3-dione (625 mg, 0.64 mmol, calculated) and hydroxylamine hydrochloride (667 mg, 9.60 mmol) in MeOH/DCM (4 ml/1 ml) NaHCO ₃ (1.21 g, 14.4 mmol) was added at 50°C. The mixture was stirred at 50°C for 10 minutes. The residue was purified by preparative TLC (DCM/MeOH = 20/1) and then further purified by preparative HPLC to give the title product (34 mg) as a yellow solid. ^1H -NMR (400 MHz, DMSO- _d6 ): δ 11.09 (s, 1H), 10.93 (s, 1H), 9.93 (br, 1H), 8.79 (s, 1H ), 8.68 (s, 2H), 7.91 (d, J=8.4 Hz, 2H), 7.65-7.80 (m, 3H), 7.58 (d, J=8, 0 Hz, 1H), 7.49 (s, 1H), 7.44 (s, 1H), 7.34 (d, J=8.4 Hz, 1H), 7.25 (d, J=8, 0 Hz, 1H), 7.16 (d, J=8.8 Hz, 2H), 5.09 (m, 1H), 4.25 (m, 4H), 3.88 (m, 4H), 3 .01 (m, 2H), 2.86 (m, 3H), 2.50 (m, 3H), 2.03 (m, 1H); LCMS (ES+): m/z 796.3 [M+H] ⁺ .

[0701] Example of the synthesis of compound 198: (E)-2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-(4-(4-(4-(1-(hydroxyimino)- 2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)ethoxy)ethoxy)isoindoline-1,3 -dion

[0702] Step A: 5-(1-(4-(4-(2-(2-hydroxyethoxy)ethyl)piperazin-1-yl)phenyl)-3-(pyridin-4-yl)-1H-pyrazol- 4-yl)-2,3-dihydro-1H-inden-1-one

[0703] To a solution of tert-butyl-4-(4-(4-(1-oxo-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazole -1-yl)phenyl)piperazine-1-carboxylate (200 mg, 0.37 mmol) in MeOH (3 ml) was added 6 M HCl (gas) in 1,4-dioxane (1 ml). The resulting solution was stirred at 25°C for 1 hour. The solvent was removed under vacuum. The residue was diluted with 20 ml DCM, and adjusted to approximately pH 9 by gradual addition of aqueous NaHCO ₃ solution. The mixture was extracted with DCM. The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain the desired product, which was used directly in the next step. To a solution of the intermediate obtained above (180 mg, crude, 0.37 mmol) in DMF (3 ml) was added 2-(2-hydroxyethoxy)ethyl-4-methylbenzenesulfonate (194 mg, 0.75 mmol) and K ₂ CO ₃ (153.2 mg, 1.11 mmol). The resulting solution was stirred at 70°C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with DCM (20 ml), and the mixture was washed with brine. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by preparative TLC to give the title product (53 mg, 27.2% yield) as a yellow solid. LCMS (ES ⁺ ): m/z 524.2 [M+H] ⁺ .

[0704] Step B: tert-butyl-2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-(4-(4-(4-(1-oxo-2,3- dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)ethoxy)ethoxy)isoindoline-1,3-dione

[0705] To a solution of 5-(1-(4-(4-(2-(2-hydroxyethoxy)ethyl)piperazin-1-yl)phenyl)-3-(pyridin-4-yl)-1H-pyrazol-4 -yl)-2,3-dihydro-1H-inden-1-one (53 mg, 0.10 mmol), Ph ₃ P (78.7 mg, 0.3 mmol) and 2-(2,6-dioxopiperidine DIAD ( _60.7 mg, 0 .3 mmol). The mixture was stirred at 20°C for 1.5 hours. After quenching the mixture by adding H ₂ O (20 ml), the mixture was extracted with DCM (20 ml×3). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by preparative TLC to give the title product (crude, 45 mg, 34.7% yield) as a yellow solid. LCMS (ES ⁺ ): m/z 780.3 [M+H] ⁺ .

[0706] Step C: (E)-2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-(4-(4-(4-(1-(hydroxyimino)-2, 3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)ethoxy)ethoxy)isoindoline-1,3-dione

[0707] To a solution of tert-butyl-2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-(4-(4-(4-(1-oxo-2,3-dihydro -1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-ethoxy)ethoxy)isoindoline-1,3-dione (45 mg, 0.058 mmol) in CH ₃ CN/pyridine (3.0 ml, v/v = 2/1) was added hydroxylamine hydrochloride (40.1 mg, 0.58 mmol). The mixture was stirred at 40°C for 20 minutes. Then, the reaction mixture was diluted with DCM (20 ml), and the mixture was washed with saline (10 ml×3). The combined organic layer was removed under vacuum and the residue was purified by preparative TLC and preparative HPLC to obtain the title product (5.5 mg, 12% yield) as a yellow solid. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.55 (s, 2H), 8.04 (s, 1H), 7.94 (s, 1H), 7.79 (d, J=8, 0 Hz, 1H), 7.65 (d, J=8.8 Hz, 3H), 7.39 (s, 2H), 7.30 (s, 1H), 7.23 (s, 1H), 7 .01 (d, J=8.8 Hz, 2H), 4.98-4.93 (m, 1H), 4.27 (s, 2H), 3.90 (s, 2H), 3.77 ( s, 2H), 3.28 (s, 4H), 3.06-3.01 (m, 4H), 2.93-2.81 (m, 2H), 2.74 (s, 7H), 2 ,17-2.13 (broad, 1H). LCMS (ES ⁺ ): m/z 795.3 [M+H] ⁺ .

[0708] Example of the synthesis of compound 199: (E)-2-(2,6-dioxopiperidin-3-yl)-4-(3-(4-(4-(4-(1-(hydroxyimino)-2,3 -dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)propoxy)isoindoline-1,3-dione

[0709] Step A: 5-(1-(4-(4-(3-hydroxypropyl)piperazin-1-yl)phenyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)- 2,3-dihydro-1H-inden-1-one

[0710] To a solution of tert-butyl-4-(4-(4-(1-oxo-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazole -1-yl)phenyl)piperazine-1-carboxylate (270 mg, 0.50 mmol) in MeOH (5 ml) was added 6 M HCl in 1,4-dioxane (1 ml). The resulting solution was stirred at 25°C for 1 hour. The solvent was removed under vacuum. The residue was diluted with 20 ml DCM and adjusted to pH ~ 9 by adding aqueous NaHCO ₃ . The mixture was extracted with DCM. The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue (240 mg, crude) was used directly in the next step without further purification.

[0711] To a solution of the above intermediate (240 mg, crude, 0.50 mmol) in DMF (5 ml) was added 3-hydroxypropyl-4-methylbenzenesulfonate (230 mg, 1 mmol) and K ₂ CO ₃ (207 mg , 1.5 mmol). The resulting solution was stirred at 70°C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with DCM (20 ml). The mixture was washed with saline and dried over Na ₂ SO ₄ . The solution was filtered and concentrated under reduced pressure. The residue was purified by preparative TLC to obtain the title product (100 mg, 30.5% yield) as a yellow solid. LCMS (ES ⁺ ): m/z 494.3 [M+H] ⁺ .

[0712] Step B: tert-butyl-5-amino-4-(1,3-dioxo-4-(3-(4-(4-(4-(1-oxo-2,3-dihydro-1H- inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)propoxy)-isoindolin-2-yl)-5-oxopentanoate

[0713] To a solution of 5-(1-(4-(4-(3-hydroxypropyl)piperazin-1-yl)phenyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2 ,3-dihydro-1H-inden-1-one (100 mg, 0.20 mmol), triphenylphosphine (157.2 mg, 0.60 mmol) and tert-butyl-5-amino-4-(4-hydroxy- 1,3-Dioxoisoindolin-2-yl)-5-oxopentanoate (104.4 mg, 0.30 mmol) in anhydrous THF (5.0 ml) under N ₂ was added dropwise with DIAD (121.2 mg, 0. 60 mmol). The mixture was stirred at 20°C for 1.5 hours. The reaction mixture was quenched by adding DCM (20 ml), and the mixture was washed with saline (10 ml×3). The organic phase was concentrated under vacuum conditions. The residue was purified by preparative TLC to give the title product (120 mg, 43.1% yield) as a yellow solid. LCMS (ES ⁺ ): m/z 824.3 [M+H] ⁺ .

[0714] Step C: 2-(2,6-dioxopiperidin-3-yl)-4-(3-(4-(4-(4-(1-oxo-2,3-dihydro-1H-inden-5 -yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)propoxy)-isoindoline-1,3-dione

[0715] To a solution of tert-butyl-5-amino-4-(1,3-dioxo-4-(3-(4-(4-(4-(1-oxo-2,3-dihydro-1H-indene -5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)propoxy)-isoindolin-2-yl)-5-oxopentanoate (crude, 120 mg, 0.087 mmol) in acetonitrile (5 ml) was added p-toluenesulfonic acid (45.2 mg, 0.26 mmol). The mixture was stirred at 80°C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with DCM (30 ml), and the mixture was washed with saline (10 ml×2). The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by preparative TLC to obtain the title product (40 mg, 61.1% yield) as a yellow solid. LCMS (ES ⁺ ): m/z 750.3 [M+H] ⁺ .

[0716] Step D: (E)-2-(2,6-dioxopiperidin-3-yl)-4-(3-(4-(4-(4-(1-(hydroxyimino)-2,3-dihydro -1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)propoxy)isoindoline-1,3-dione

[0717] To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-(3-(4-(4-(4-(1-oxo-2,3-dihydro-1H-inden-5- yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)propoxy)-isoindoline-1,3-dione (40 mg, 0.053 mmol) in acetonitrile/pyridine (v/v = 3/1, 4 ml) hydroxylamine hydrochloride (36.8 mg, 0.53 mmol) was added. The mixture was stirred at 40°C for 20 minutes and then diluted with DCM (20 ml). The mixture was washed with saline (10 ml×2). The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by preparative TLC and preparative HPLC to obtain the title product (7.5 mg, 18.4% yield) as a yellow solid. ^1H -NMR (400 MHz, DMSO- _d6 ): δ 11.11 (s, 1H), 10.90 (s, 1H), 8.70 (s, 1H), 8.57-8.56 ( m, 2H), 7.85-7.77 (m, 3H), 7.56 (d, J=8.0 Hz, 2H), 7.49-7.45 (m, 3H), 7.41 (s, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.10-7.08 (m, 2H), 5.12-5.08 (m, 1H), 4, 32-4.28 (m, 2H), 3.22 (s, 5H), 3.03-2.97 (m, 2H), 2.89-2.80 (m, 3H), 2.62- 2.57 (m, 7H), 2.06-1.99 (m, 3H). LCMS (ES ⁺ ): m/z 765.2 [M+H] ⁺ .

[0718] Synthesis Example of Compound 200: (E)-2-(2,6-dioxopiperidin-3-yl)-4-(3-(3-(4-(4-(1-(hydroxyimino)-2,3 -dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)propoxy)phenyl)isoindoline-1,3-dione

[0719] Step A: 3-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)propan-1-ol

[0720] K ₂ CO ₃ (434 mg, 3 .16 mmol) and 3-hydroxypropyl-4-methylbenzenesulfonate (400 mg, 1.74 mmol). The resulting solution was stirred at 80°C for 3 hours. The reaction mixture was diluted with ethyl acetate (30 ml) and washed with brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified (PE:EA = 1:1) to obtain the target 3-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)propan-1-ol ( 400 mg, yield 67%) as a light yellow oil. LCMS (ES ⁺ ): m/z 376.0 [M+H] ⁺ .

[0721] Step B: 3-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)propan-1-ol

[0722] Solution of 3-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)propan-1-ol (400 mg, 1.07 mmol), 5 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one (414 mg, 1.6 mmol), Pd ₂ (dba) ₃ (392 mg, 0.427 mmol), CsF (650 mg, 4.28 mmol). tri-tert-butylphosphine tetrafluoroborate (248 mg, 0.855 mmol) and N,N-dicyclohexylmethylamine (9.0 mg, 0.047 mmol) in 10% water in 1,4-dioxane (10 ml) were microwaved at 100 °C in N ₂ atmosphere for 2 hours. The mixture was cooled to room temperature and quenched by adding water. The mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified (DCM:MeOH = 50:1) to obtain the target 3-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)propan-1-ol ( 450 mg, yield 87%) as a yellow solid. LCMS (ES ⁺ ): m/z 426.1 [M+H] ⁺ .

[0723] Step C: 5-(3-(pyridin-4-yl)-1-(4-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)phenoxy)propoxy)phenyl)-1H-pyrazol-4-yl)-2,3-dihydro-1H-inden-1-one

[0724] To a solution of 3-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)propan-1-ol (450 mg, 1.06 mmol) and TEA (214 mg, 2.12 mmol) in DCM (10.0 mL) was added dropwise with MsCl (145 mg, 1.27 mmol) at 0°C. The resulting solution was stirred at 25°C for 1 hour. The solvent was evaporated and the residue was diluted with ethyl acetate (50 ml). The solution was washed with saturated NaHCO ₃ and saline. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed under vacuum to obtain the crude title product (520 mg, crude), which was used directly in the next step. To a solution of the above target product (520 mg, 1.03 mmol) in anhydrous DMF (10 ml) was added K ₂ CO ₃ (285 mg, 2.07 mmol) and 3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenol (341 mg, 1.55 mmol). The resulting solution was stirred at 70°C overnight. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 ml), and the mixture was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate. The residue was purified by column chromatography to give 5-(3-(pyridin-4-yl)-1-(4-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)phenoxy)-propoxy)phenyl)-1H-pyrazol-4-yl)-2,3-dihydro-1H-inden-1-one (200 g, 32% yield in two batches). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.62 (d, J=6 Hz, 2H), 8.00 (s, 1H), 7.76 (d, J=7.6 Hz, 1H ), 7.68 (d, J=7.6 Hz, 2H), 7.51 (d, J=4.4 Hz, 2H), 7.27-7.44 (m, 4H), 7.02 -7.04 (m, 3H), 4.15-4.22 (m, 3H), 4.11-4.13 (m, 4H), 3.12-3.14 (m, 2H), 2 .72-2.75 (m, 2H), 2.10 (s, 1H), 1.34 (s, 11H), 2.83 (s, 1H).

[0725] Step D: 2-(2,6-dioxopiperidin-3-yl)-4-(3-(3-(4-(4-(1-oxo-2,3-dihydro-1H-inden-5 -yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)propoxy)phenyl)isoindoline-1,3-dione

[0726] To a solution of 4-chloro-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (47 mg, 0.159 mmol) and 5-(3-(pyridin-4-yl)- 1-(4-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propoxy)phenyl)-1H-pyrazol-4-yl)- 2,3-dihydro-1H-inden-1-one (47 mg, 0.159 mmol) in dioxane (5 ml)/H ₂ O (0.5 ml) was added CsF (97 mg, 0.64 mmol) and Pd( aMphos)Cl ₂ (12 mg, 0.016 mmol). After stirring at 100°C for 2 hours under a nitrogen atmosphere, the reaction mixture was diluted with 30 ml of ethyl acetate, and the solution was washed with brine (10 ml x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (DCM/MeOH = 20/1) to obtain the target 2-(2,6-dioxopiperidin-3-yl)-4-(3-(3-(4-(4-(1-oxo- 2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)-propoxy)phenyl)isoindoline-1,3-dione (50 mg , yield 40%) as a yellow solid. LCMS (ES ⁺ ): m/z 758.2 [M+H] ⁺ .

[0727] Step E: (E)-2-(2,6-dioxopiperidin-3-yl)-4-(3-(3-(4-(4-(1-(hydroxyimino)-2,3-dihydro -1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)propoxy)phenyl)-isoindoline-1,3-dione

[0728] To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-(3-(3-(4-(4-(1-oxo-2,3-dihydro-1H-inden-5- yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)propoxy)phenyl)isoindoline-1,3-dione (50 mg, 0.053 mmol) in acetonitrile (2 ml) and pyridine ( 1 ml) hydroxylamine hydrochloride (34 mg, 0.53 mmol) was added. After stirring for 20 minutes at 40°C, the reaction mixture was diluted with DCM (20 ml), and the mixture was washed with saline (10 ml×2). The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by preparative TLC to give (E)-2-(2,6-dioxopiperidin-3-yl)-4-(3-(3-(4-(4-(1-(hydroxyimino)-2,3- Dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)propoxy)phenyl)isoindoline-e-1,3-dione (26 mg, yield 51 %) as a yellow solid. ^1H -NMR (400 MHz, DMSO- _d6 ): δ 11.09 (s, 1H), 10.89 (s, 1H), 8.73 (s, 1H), 8.57 (d, J= 5.2 Hz, 2H), 7.82-7.92 (m, 5H), 7.56 (d, J=8.0 Hz, 1H), 7.48 (d, J=4.8 Hz, 2), 7.37-7.41 (m, 2), 7.09-7.23 (m, 6H), 5.05-5.10 (m, 1H), 4.22-4.29 ( m, 4H), 4.10 (s, 1H), 3.17 (d, J=4.8 Hz, 1H), 2.99-3.01 (m, 2H), 2.81-2.84 (m, 3H), 2.22-2.54 (m, 1H), 2.02-2.08 (m, 1H); LCMS (ES ⁺ ): m/z 773.2 [M+H] ⁺ .

[0729] Example of synthesis of compound 201:

[0730] Step A: 5-fluoro-2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0731] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (500 mg, 1.81 mmol) in anhydrous DMF (10.0 ml) at 0°C NaH (145 mg, 3.62 mmol) was added. After stirring for 0.5 h, CH ₃ I (513.7 mg, 3.62 mmol) was added at 0°C. The resulting solution was stirred for 2 hours. After quenching by adding aq. NH ₄ Cl, the mixture was diluted with 30 ml of ethyl acetate and washed with saline (20 ml×3). The organic phase was dried over Na ₂ SO ₄ and concentrated to give 5-fluoro-2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (500 mg, 95.2% yield) as a brown solid which was used directly in the next step. LCMS (ES ⁺ ): m/z 291.1 [M+H] ⁺ .

[0732] Step B: 2-(1-methyl-2,6-dioxopiperidin-3-yl)-5-(4-(4-(4-(1-oxo-2,3-dihydro-1H-inden- 5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)isoindolin-1,3-dione

[0733] To a solution of tert-butyl-4-(4-(4-(1-oxo-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazole -1-yl)phenyl)piperazine-1-carboxylate (100 mg, 0.19 mmol) in MeOH (3 ml) was added with 6 M HCl in 1,4-dioxane (1 ml). The resulting solution was stirred at 25°C for 1 hour. The solution was concentrated and diluted with 20 ml DCM, and aq. was added. NaHCO ₃ to pH>7. The mixture was extracted with DCM. The organic layer was dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure and used directly in the next step. To a solution of the intermediate obtained above (90 mg, crude, 0.19 mmol) in NMP (5 ml) was added 5-fluoro-2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindolin-1, 3-dione (100 mg, 0.29 mmol) and DIEA (245.1 mg, 1.9 mmol). The resulting solution was subjected to microwave irradiation at 150°C for 2 hours. After cooling to room temperature, the solution was diluted with DCM (20 ml), and the mixture was washed with saline. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by a silica gel column to give 2-(1-methyl-2,6-dioxopiperidin-3-yl)-5-(4-(4-(4-(1-oxo-2,3-dihydro-1H- inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)isoindoline-1,3-dione (43 mg, 26.5% yield) . LCMS (ES ⁺ ): m/z 706.3 [M+H] ⁺ .

[0734] Step C: (E)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(4-(1-(hydroxyimino)-2,3-dihydro-1H- inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)isoindoline-1,3-dione

[0735] To a solution of 2-(1-methyl-2,6-dioxopiperidin-3-yl)-5-(4-(4-(4-(1-oxo-2,3-dihydro-1H-inden-5 -yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)isoindoline-1,3-dione (43 mg, 0.061 mmol) in acetonitrile/pyridine (3 ml, v/v = 2/1), hydroxylamine hydrochloride (42.4 mg, 0.61 mmol) was added at room temperature. The mixture was heated to 40°C for 40 minutes. After cooling to room temperature, the mixture was diluted with DCM (20 ml) and washed with saline (10 ml). The organic phase was concentrated under vacuum conditions. The residue was purified by preparative TLC to give (E)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(4-(1-(hydroxyimino)-2,3-dihydro-1H -inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)-piperazin-1-yl)isoindoline-1,3-dione (23 mg, yield 52.3 %) as a yellow solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 10.90 (s, 1H), 8.73 (s, 1H), 8.58-8.56 (d, J=8.0 Hz, 2H), 7.84-7.82 (d, J=8.8 Hz, 2H), 7.74-7.72 (d, J=8.4 Hz, 1H), 7.56-7.55 (d, J=8.4 Hz, 1H), 7.49-7.48 (m, 2H), 7.43-7.41 (m, 2H), 7.36-7.34 (m, 1H ), 7.22-7.21 (d, J=8.0 Hz, 1H), 7.17-7.15 (d, J=10 Hz, 2H), 5.18-5.14 (m, 1H), 3.66 (s, 4H), 3.42 (s, 4H), 3.02-2.91 (m, 6H), 2.85-2.74 (m, 3H), 2.60 -2.53 (m, 1H), 2.09-2.00 (broad, 1H). LCMS (ES ⁺ ): m/z 721.3 [M+H] ⁺ .

[0736] Synthesis example of compound 202: (3R)-N-(3-(5-(4-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3 -dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4-difluorophenyl)-3- fluoropyrrolidine-1-sulfonamide

[0737] Step A: 1-(4-bromophenyl)-4-(2,2-diethoxyethyl)piperazine

[0738] To a solution of 1-(4-bromophenyl)piperazine (5 g, 20.8 mmol) in anhydrous DMF (50 mL) was added 2-bromo-1,1-diethoxyethane (4.1 g, 20.8 mmol) and K ₂ CO ₃ (8.6 g, 62.4 mmol). The resulting solution was stirred at 90°C for 16 hours. The reaction mixture was diluted with ethyl acetate (50 ml), and the mixture was washed (20 ml×2). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column to obtain the desired product (6 g, 81% yield) as an oil.

[0739] ¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.32 (d, J=9.2 Hz, 2H), 6.77 (d, J=8.8 Hz, 2H), 4, 67 (t, J=5.2 Hz, 1H), 3.69-3.72 (m, 2H), 3.54-3.58 (m, 2H), 3.15 (m, 4H), 2 .68-2.71 (m, 4H), 2.60 (d, J=5.2 Hz, 2H), 1.22 (t, J=7.2 Hz, 6H).

[0740] Step B: 1-(2,2-diethoxyethyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine

[0741] To a solution of 1-(4-bromophenyl)-4-(2,2-diethoxyethyl)piperazine (7.8 g, crude, 21.9 mmol) in 1,4-dioxane (70 mL) was added 4. 4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (8.3 g, 32.8 mmol), Pd(dppf )Cl ₂ (1.6 g, 2.2 mmol) and KOAc (6.4 g, 65.6 mmol). The resulting solution was stirred overnight at 90°C under N ₂ atmosphere. The completion of the reaction was detected by TLC. After cooling to room temperature, the reaction mixture was concentrated and purified by column chromatography to give 1-(2,2-diethoxyethyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)phenyl)piperazine (5 g, 74% yield). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.69 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.4 Hz, 2H), 4.70 (m , 1H), 3.50-3.72 (m, 4H), 3.26 (m, 4H), 2.72 (m, 4H), 2.60 (d, J=5.2 Hz, 2H) , 1.32 (s, 12H), 1.22 (t, J=7.2 Hz, 6H).

[0742] Step C: (R)-N-(3-(5-(4-(4-(2,2-diethoxyethyl)piperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b] pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide

[0743] To a solution of (R)-N-(3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (300 mg, 0.60 mmol) in 1,4-dioxane/H ₂ O (10 ml/2 ml) was added 1-(2,2-diethoxyethyl)-4-(4-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (726 mg, 1.80 mmol), Pd(aMphos)Cl ₂ (42 mg, 0.06 mmol) and CsF (363 mg, 3 .20 mmol). The resulting solution was stirred at 95°C for 3 hours under N ₂ atmosphere. The completion of the reaction was detected by TLC. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 ml), washed with water and brine. The organic layer was dried over anhydrous sodium sulfate. The residue was purified by column chromatography to give (R)-N-(3-(5-(4-(4-(2,2-diethoxyethyl)piperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b ]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (350 mg, 70% yield). LCMS (ES ⁺ ): m/z 701.3 [M+H] ⁺ .

[0744] Step D: (R)-N-(2,4-difluoro-3-(5-(4-(4-(2-oxoethyl)piperazin-1-yl)phenyl)-1H-pyrrolo[2, 3-b]pyridine-3-carbonyl)phenyl)-3-fluoropyrrolidine-1-sulfonamide

[0745] To a solution of (R)-N-(3-(5-(4-(4-(2,2-diethoxyethyl)piperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine -3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (350 mg, 0.50 mmol) in CH ₃ CN (10 ml) was added concentrated HCl (3 ml, which was diluted with 9 ml H ₂ ABOUT). The resulting solution was stirred at 55°C for 16 hours. After cooling to room temperature, we were added to the reaction mixture. NaHCO ₃ to adjust to pH 7~8. A large amount of solid matter was observed. The suspension was extracted with DCM. The organic phase was dried over anhydrous sodium sulfate and concentrated to give (R)-N-(2,4-difluoro-3-(5-(4-(4-(2-oxoethyl)piperazin-1-yl)phenyl)-1H -pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)-3-fluoropyrrolidine-1-sulfonamide (490 mg, crude). LCMS (ES+): m/z 645.2 [M+H+18] ⁺ .

[0746] Step E: (3R)-N(3-(5-(4-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin- 5-yl)piperazin-1-yl)ethyl)piperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1 -sulfonamide

[0747] To a solution of (R)-N-(2,4-difluoro-3-(5-(4-(4-(2-oxoethyl)piperazin-1-yl)phenyl)-1H-pyrrolo[2,3 -b]pyridine-3-carbonyl)phenyl)-3-fluoropyrrolidine-1-sulfonamide (490 mg, crude, 0.80 mmol) in THF/MeOH/DMSO (15 ml, 1/1/1) was added 2- (2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione hydrochloride (364 mg, 0.96 mmol) and two drops of AcOH. NaBH ₃ CN (248 mg, 4.00 mmol) was then added. The resulting solution was stirred at 20°C for 2 hours. The reaction mixture was diluted with 20 ml saturated NaCl solution and extracted with DCM. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was first applied to a silica gel column and then purified by preparative HPLC to obtain the target (3R)-N-(3-(5-(4-(4-(2-(4-(2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl) -2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (75 mg, 16% yield in two batches) as a yellow solid. ^1H -NMR (400 MHz, DMSO- _d6 ): δ 12.92 (s, 1H), 11.08 (s, 1H), 9.80 (br, 1H), 8.54-8.66 (m, 2H), 8.07 (s, 1H), 7.59-7.69 (m, 4H), 7.25-7.35 (m, 3H), 7.07 (d, J=8 .4 Hz, 2H), 5.05-5.36 (m, 2H), 3.22-3.48 (m, 14H), 2.55-3.00 (m, 14H), 1.90- 2.20 (m, 4H); LCMS (ES ⁺ ): m/z 954.3 [M+H] ⁺ .

[0748] Example of the synthesis of compound 203: (E)-2-(2,6-dioxopiperidin-3-yl)-5-(2-(3-(4-(1-(hydroxyimino)-2,3-dihydro- 1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethoxy)isoindoline-1,3-dione

[0749] Step A: 4-(1-(3-(2-(benzyloxy)ethoxy)phenyl)-4-bromo-1H-pyrazol-3-yl)pyridine

[0750] To a solution of 2-(3-(2-(benzyloxy)ethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-

[0751] dioxoborolane (1.2 g, 3.39 mmol) in DCM (50 ml) 4-(4-bromo-1H-pyrazol-3-yl)pyridine (831.53 mg, 3.73 mmol) was added sequentially , Cu(OAc) ₂ (615.6 mg, 3.39 mmol), Et ₂ NH (2.47 g, 33.9 mmol). The resulting solution was stirred at 30°C overnight. The mixture was washed with ammonium hydroxide (30 ml×3). The organic phase was dried over and concentrated under vacuum. The residue was purified on a PE/EA silica gel column to give the target 4-(1-(3-(2-(benzyloxy)ethoxy)phenyl)-4-bromo-1H-pyrazol-3-yl)pyridine (900 mg, yield 59%) as a purple solid. LCMS (ES ⁺ ): m/z 450.1 [M+H] ⁺ .

[0752] Step B: 5-(1-(3-(2-(Benzyloxy)ethoxy)phenyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydro- 1H-inden-1-one

[0753] To a solution of 4-(1-(3-(2-(benzyloxy)ethoxy)phenyl)-4-bromo-1H-pyrazol-3-yl)pyridine (900 mg, 2.0 mmol) in 1.4 -dioxane/H ₂ O (20 ml, v/v = 10/1) 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2 was added successively, 3-dihydro-1H-inden-1-one (774 mg, 3.0 mmol), Pd ₂ (dba) ₃ (183.14 mg, 0.2 mmol), CsF (3.14 g, 20.64 mmol ), [(t-Bu) ₃ PH]BF ₄ (609 mg, 2.1 mmol) and N,N-dicyclohexylmethylamine (503 mg, 2.58 mmol). The resulting solution was stirred at 100°C for 2 hours under N ₂ atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 ml), washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified on a silica gel column to give 5-(1-(3-(2-(benzyloxy)ethoxy)phenyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2,3- dihydro-1H-inden-1-one (750 mg, 74.9% yield) as a yellow solid. LCMS (ES ⁺ ): m/z 502.2 [M+H] ⁺ .

[0754] Step C: 5-(1-(3-(2-hydroxyethoxy)phenyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydro-1H-indene -1-he

[0755] To a solution of 5-(1-(3-(2-(benzyloxy)ethoxy)phenyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydro-1H -inden-1-one (750 mg, 1.50 mmol) in DCM (10 ml) in an atmosphere of N ₂ at -60°C was added dropwise BBr ₃ (1.13 g, 4.50 mmol) in DCM (5 ml). After stirring for 1 hour, the mixture was diluted with DCM (20 ml) and washed with saline (10 ml x 2). The organic phase was concentrated and purified on a silica gel column to give 5-(1-(3-(2-hydroxyethoxy)phenyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2,3- dihydro-1H-inden-1-one (150 mg, 24.4% yield) as a yellow solid. LCMS (ES ⁺ ): m/z 412.1 [M+H] ⁺ .

[0756] Step D: 2-(2,6-dioxopiperidin-3-yl)-5-(2-(3-(4-(1-oxo-2,3-dihydro-1H-inden-5-yl) -3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethoxy)isoindoline-1,3-dione

[0757] To a solution of 5-(1-(3-(2-hydroxyethoxy)phenyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydro-1H-inden- 1-one (150 mg, 0.36 mmol) in DCM (10 ml) and TEA (109.08 mg, 1.08 mmol) at 0°C was added dropwise MsCl (61.56 mg, 0.54 mmol) . The resulting solution was stirred at 25°C for 0.5 hours. Then, water was added and extracted with DCM. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated to give the crude title product (170 mg, crude, 95.5% yield) as a yellow oil, which was used directly in the next step. To a solution of the above target product (170 mg, 0.35 mmol) in DMF (10 ml) was added K ₂ CO ₃ (144.9 mg, 1.05 mmol) and 2-(2,6-dioxopiperidin-3-yl )-5-hydroxyisoindoline-1,3-dione (191.8 mg, 0.70 mmol). The resulting solution was stirred at 70°C for 2 hours. After quenching by adding water, the mixture was extracted with ethyl acetate (30 ml), washed with water and brine. The organic phase was dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 2-(2,6-dioxopiperidin-3-yl)-5-(2-(3-(4-(1-oxo-2,3 -dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethoxy)isoindoline-1,3-dione (60 mg, 25.9% yield ) as a white solid. LCMS (ES ⁺ ): m/z 668.2 [M+H] ⁺ .

[0758] Step E: (E)-2-(2,6-dioxopiperidin-3-yl)-5-(2-(3-(4-(1-(hydroxyimino)-2,3-dihydro-1H- inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethoxy)isoindoline-1,3-dione

[0759] To a solution of S2-(2,6-dioxopiperidin-3-yl)-5-(2-(3-(4-(1-oxo-2,3-dihydro-1H-inden-5-yl)- 3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethoxy)isoindoline-1,3-dione (60 mg, 0.090 mmol) in acetonitrile/pyridine (3.0 ml, v/v = 2/1), hydroxylamine hydrochloride (58.41 mg, 0.90 mmol) was added. The mixture was stirred at 40°C for 20 minutes. Then, the mixture was diluted with DCM (20 ml) and washed with saline (10 ml). The organic phase was concentrated and purified by preparative HPLC to give (E)-2-(2,6-dioxopiperidin-3-yl)-5-(2-(3-(4-(1-(hydroxyimino)-2,3- Dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethoxy)isoindoline-1,3-dione (8 mg, 65.6% yield) as a white solid. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.58 (s, 2H), 8.04 (s, 2H), 7.83-7.81 (d, J=8.4 Hz, 1H) , 7.68-7.66 (d, J=7.6 Hz, 1H), 7.52 (m, 2H), 7.48 (m, 1H), 7.44-7.43 (m, 2H ), 7.41-7.36 (m, 2H), 7.30 (s, 2H), 7.23 (s, 2H), 4.99-4.94 (m, 1H), 4.49 ( s, 4H), 3.05-2.94 (m, 4H), 2.90-2.73 (m, 3H), 2.04-2.00 (m, 1H); LCMS:(ES ⁺ ):m/z 683.2 [M+H] ⁺ .

[0760] Compounds 204 and 205 can be prepared in a manner similar to that described for compound 203.

[0761] Example of the synthesis of compound 206: (E)-2-(2,6-dioxopiperidin-3-yl)-5-(2-(4-(4-(1-(hydroxyimino)-2,3-dihydro- 1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethoxy)isoindoline-1,3-dione

[0762] Step A: tert-butyl 4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0763] Solution of 4-(4-bromo-1H-pyrazol-3-yl)pyridine (5.0 g, 22.4 mmol), tert-butyl-4-bromopiperidine-1-carboxylate (7.1 g, 26 .9 mmol) and Cs ₂ CO ₃ (11.0 g, 33.6 mmol) in DMF (50 ml) were stirred at 55°C overnight. After cooling to room temperature, water (50 ml) was added. The resulting mixture was extracted with ethyl acetate (20 ml×3), the combined organic layer was washed with brine (20 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1) to give tert-butyl-4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)piperidin- 1-carboxylate (3.7 g, 41% yield) as a brown oil. LCMS: m/z 407.1 [M+H] ⁺ .

[0764] Step B: tert-butyl-4-(4-(1-oxo-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1 -yl)piperidine-1-carboxylate

[0765] To a solution of tert-butyl 4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)piperidin-1-carboxylate (2.0 g, 4.9 mmol) , 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one (1.4 g, 5.4 mmol ) and K ₂ CO ₃ (1.4 g, 9.8 mmol) in 1,4-dioxane (40 ml) and water (8 ml) in an Ar atmosphere, Pd(PPh ₃ ) ₄ (200 mg) was added and stirred mixture at 80°C for 2 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate (20 ml×3), the combined organic layer was washed with brine (20 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (petroleum ether/ethyl acetate = 1/10) to give tert-butyl-4-(4-(1-oxo-2,3-dihydro-1H-inden-5-yl)-3- (pyridin-4-yl)-1H-pyrazol-1-yl)piperidin-1-carboxylate (1.9 g, 84% yield) as a yellow oil. LCMS: m/z 459.3 [M+H] ⁺ .

[0766] Step C: 5-(1-(piperidin-4-yl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydro-1H-inden-1- He

[0767] Mixture of tert-butyl-4-(4-(1-oxo-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl )piperidine-1-carboxylate (1.9 g, 4.1 mmol) in HCl in 1,4-dioxane (20 ml) was stirred at room temperature for 2 hours. The solvent was then immediately removed under vacuum to give the crude product (1.6 g, 100% yield) as the hydrochloride, which was used directly in the next step without further purification.

[0768] Step D: 2-(2,6-dioxopiperidin-3-yl)-5-(2-(4-(4-(1-oxo-2,3-dihydro-1H-inden-5-yl) -3-(pyridin-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethoxy)isoindoline-1,3-dione

[0769] Solution of 5-(1-(piperidin-4-yl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydro-1H-inden-1-one ( 440 mg, 1.2 mmol), 5-(2-chloroethoxy)-2-(2,6-dioxopiperidin-3-yl)-isoindolin-1,3-dione (410 mg, 1.2 mmol), KI ( 304 mg, 1.8 mmol) and DIPEA (476 mg, 3.6 mmol) in DMSO (8 ml) were stirred at 100°C overnight. After cooling to room temperature, water (10 ml) was added, the mixture was extracted with ethyl acetate (5 ml×3), the combined organic layer was washed with brine (5 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC (DCM/MeOH = 10/1) to give 2-(2,6-dioxopiperidin-3-yl)-5-(2-(4-(4-(1-oxo-2,3- Dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethoxy)isoindoline-1,3-dione (180 mg, yield 22 %) as a white solid. LCMS: m/z 659.3 [M+H] ⁺ .

[0770] Step E: (E)-2-(2,6-dioxopiperidin-3-yl)-5-(2-(4-(4-(1-(hydroxyimino)-2,3-dihydro-1H- inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethoxy)isoindoline-1,3-dione

[0771] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-(2-(4-(4-(1-oxo-2,3-dihydro-1H-inden-5-yl)- 3-(pyridin-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethoxy)isoindoline-1,3-dione (120 mg, 0.2 mmol) in pyridine (2 ml) added hydroxylamine hydrochloride (126 mg, 1.8 mmol), and the mixture was stirred at room temperature for 2 hours. Then, the solvent was removed under vacuum conditions, and the residue was purified by preparative HPLC to obtain (E)-2-(2,6-dioxopiperidin-3-yl)-5-(2-(4-(4-(1-(hydroxyimino )-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethoxy)-isoindoline-1,3- dione (52 mg, 42% yield). LCMS: m/z 674.2 [M+H] ⁺ ; ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 2.03-2.11 (5H, m), 2.25-2.30 (2H, m), 2.50-2.62 (2H, m), 2.78-2.86 (5H, m), 2.88-2.99 (2H, m), 3.08-3.11 (2H, m), 4.22-4.28 ( 1H, m), 4.33 (2H, t, J=5.2 Hz), 5.12 (1H, dd, J=12.8, 5.2 Hz), 7.12 (1H, d, J =8.0 Hz), 7.30 (1H, s), 7.38-7.40 (3H, m), 7.49-7.52 (2H, m), 7.84 (1H, d, J=8.4 Hz), 8.14 (1H, s), 8.50 (2H, dd, J=4.4, 1.6 Hz), 10.86 (1H, s), 11.10 ( 1H, s).

[0772] Synthesis example of compound 207: (E)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(1-(hydroxyimino)-2,3-dihydro-1H-indene -5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)-1,4'-bipiperidin-1'-yl)isoindolin-1,3-dione

[0773] Step A: tert-butyl-4-(4-(1-oxo-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1 -yl)-1,4'-bipiperidine-1'-carboxylate

[0774] Solution of 5-(1-(piperidin-4-yl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydro-1H-inden-1-one ( 2.5 g, 7.0 mmol), tert-butyl 4-bromopiperidine-1-carboxylate (2.0 g, 7.7 mmol), KI (1.2 g, 7.0 mmol) and K ₂ CO ₃ (2.9 g, 20.9 mmol) in DMF (20 ml) was stirred at 110°C overnight. After cooling to room temperature, water (30 ml) was added. The resulting mixture was extracted with ethyl acetate (20 ml×3), the combined organic layer was washed with brine (20 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH = 20/1) to give tert-butyl-4-(4-(1-oxo-2,3-dihydro-1H-inden-5-yl)-3-( pyridin-4-yl)-1H-pyrazol-1-yl)-1,4'-bipiperidine-1'-carboxylate (360 mg, 10% yield) as a brown oil. LCMS: m/z 542.3 [M+H] ⁺ .

[0775] Step B: 5-(1-(1,4'-bipiperidin-4-yl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydro-1H -inden-1-on

[0776] Mixture of tert-butyl-4-(4-(1-oxo-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl )-1,4'-bipiperidine-1'-carboxylate (360 mg, 0.7 mmol) in HCl in 1,4-dioxane (10 ml) was stirred at room temperature for 30 minutes. The solvent was then immediately removed under vacuum to give the crude product (300 mg, 100% yield) as the hydrochloride, which was used directly in the next step without further purification.

[0777] Step C: 2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(1-oxo-2,3-dihydro-1H-inden-5-yl)-3- (pyridin-4-yl)-1H-pyrazol-1-yl)-1,4'-bipiperidin-1'-yl)isoindolin-1,3-dione

[0778] 5-(1-(1,4'-Bipiperidin-4-yl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydro-1H-indene solution -1-one (290 mg, 0.7 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (183 mg, 0.7 mmol) and Et ₃ N (336 mg, 3.3 mmol) in DMSO (5 ml) was stirred at 80°C overnight. After cooling to room temperature, water (10 ml) was added, the mixture was extracted with ethyl acetate (5 ml×3), the combined organic layer was washed with brine (5 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC (DCM/MeOH = 20/1) to give 2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(1-oxo-2,3-dihydro-1H -inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)-1,4'-bipiperidin-1'-yl)isoindolin-1,3-dione (195 mg, yield 42%) as a white solid. LCMS: m/z 698.3 [M+H] ⁺ .

[0779] Step D: (E)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(1-(hydroxyimino)-2,3-dihydro-1H-inden-5 -yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)-1,4'-bipiperidin-1'-yl)isoindolin-1,3-dione

[0780] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(1-oxo-2,3-dihydro-1H-inden-5-yl)-3-( pyridin-4-yl)-1H-pyrazol-1-yl)-1,4'-bipiperidin-1'-yl)isoindolin-1,3-dione (95 mg, 0.1 mmol) in pyridine (2 ml) hydroxylamine hydrochloride (94 mg, 1.3 mmol) was added and the mixture was stirred at room temperature for 2 hours. Then, the solvent was removed under vacuum conditions, and the residue was purified by preparative HPLC to obtain (E)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(1-(hydroxyimino)-2 ,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)-1,4'-bipiperidin-1'-yl)isoindolin-1,3 -dione (53 mg, 55% yield). LCMS: m/z 713.4 [M+H] ⁺ ; ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.51-1.53 (2H, m), 1.84-1.87 (2H, m), 1.97-2.03 (3H, m), 2.09-2.11 (2H, m), 2.32-2.37 (2H, m), 2.57-2.67 (2H, m), 2.78-2.89 ( 3H, m), 2.90-2.99 (6H, m), 4.11 (2H, d, J=12.8 Hz), 4.20-4.22 (1H, m), 5.06 (1H, dd, J=12.8, 5.6 Hz), 7.12 (1H, d, J=8.8 Hz), 7.25 (1H, d, J=6.0 Hz), 7 .27 (1H, s), 7.30 (1H, s), 7.38 (2H, dd, J=4.8, 1.2 Hz), 7.50 (1H, d, J=8.0 Hz), 7.56 (1H, d, J=8.8 Hz), 8.13 (1H, s), 8.24 (1H, s): 8.50 (2H, dd, J=4.8 , 1.6, Hz), 10.86 (1H, s), 11.08 (1H, s).

[0781] Example of the synthesis of compound 208: (3R)-N-(3-(5-(4-(2-(2-(2-(2-(4-(2-(2,6-dioxopiperidine-3- yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethoxy)ethoxy)-ethoxy)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2, 4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide

[0782] Step A: 2-(2-(2-(2-(4-bromophenoxy)ethoxy)ethoxy)ethoxy)acetaldehyde

[0783] To a solution of 2-(2-(2-(2-(4-bromophenoxy)ethoxy)ethoxy)ethoxy)ethan-1-ol (3.1 g, 8.90 mmol) in acetonitrile (30 ml) was added IBX (3.7 g, 13.40 mmol). The mixture was heated to 80°C for 1 hour. After cooling to room temperature, the mixture was filtered through Celite and concentrated to give the crude title 2-(2-(2-(2-(4-bromophenoxy)ethoxy)ethoxy)ethoxy)acetaldehyde (3.2 g, crude) as oils

[0784] Step B: 5-(4-(2-(2-(2-(2-(4-bromophenoxy)ethoxy)ethoxy)ethoxy)ethyl)piperazin-1-yl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione

[0785] To a solution of 2-(2-(2-(2-(4-bromophenoxy)ethoxy)ethoxy)ethoxy)acetaldehyde (3.2 g, 9.20 mmol) and 2-(2,6-dioxopiperidine-3 -yl)-5-(piperazin-1-yl)isoindolin-1,3-dione hydrochloride (3.1 g, 9.20 mmol) in methanol (100 ml) with two drops of AcOH was added NaBH ₃ CN (0.58 g, 9.20 mmol). The mixture was stirred at room temperature overnight. After quenching by adding water (50 ml), the mixture was extracted with DCM (100 ml×2). The combined organic layer was washed with brine (200 ml), dried over Na ₂ SO ₄ and filtered. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to obtain the target 5-(4-(2-(2-(2-(2-(4-bromophenoxy)ethoxy)ethoxy)ethoxy)ethyl)-piperazine- 1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (1.1 g, 18%) as a yellow solid. LCMS: (ES ⁺ ): m/z 675.1 [M+H] ⁺ .

[0786] Step C: 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(2-(2-(2-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)phenoxy)ethoxy)ethoxy)ethoxy)ethyl)piperazin-1-yl)isoindoline-1,3-dione

[0787] A solution of 5-(4-(2-(2-(2-(2-(4-bromophenoxy)ethoxy)ethoxy)ethoxy)ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin- 3-yl)isoindoline-1,3-dione (400 mg, 0.60 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi( 1,3,2-dioxaborolane) (227 mg, 0.89 mmol), Pd(dppf)Cl ₂ (88 mg, 0.12 mmol) and KOAc (118 mg, 1.20 mmol) in dioxane (10 ml) heated to 90°C overnight under N ₂ atmosphere. After quenching the reaction mixture by adding water (15 ml), the mixture was extracted with DCM (50 ml×2). The combined layers were washed with water and saline. The combined organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(2-(2-(2-(4-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethoxy)ethoxy)ethoxy)ethyl)-piperazin-1-yl)isoindolin-1,3-dione (200 mg, 47%) as a yellow solid substances. LCMS (ES ⁺ ): m/z 721.3 [M+H] ⁺ .

[0788] Step D: (3R)-N-(3-(5-(4-(2-(2-(2-(2-(4-(2-(2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4-difluorophenyl )-3-fluoropyrrolidine-1-sulfonamide

[0789] Solution of 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(2-(2-(2-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)ethoxy)ethoxy)ethoxy)ethyl)piperazin-1-yl)isoindoline-1,3-dione (200 mg, 0.28 mmol), (R)-N- (3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (116 mg, 0.23 mmol), Pd (aMPhos)Cl ₂ (66 mg, 0.09 mmol) and CsF (141 mg, 0.93 mmol) in dioxane/H ₂ O (5 ml/1 ml) were heated to 100°C for 4 hours in an atmosphere of N ₂ . After quenching the reaction mixture by adding water (15 ml), the mixture was extracted with DCM (50 ml×2). The combined layers were washed with water and saline. The combined organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give (3R)-N-(3-(5-(4-(2-(2-(2-(2-(4-(2-(2,6-dioxopiperidine-3- yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethoxy)ethoxy)-ethoxy)ethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2, 4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (40 mg, 17%) as a yellow solid. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 11.23 (b s, 1H), 10.56 (s, 1H), 8.73 (s, 1H), 8.54 (s, 1H) , 7.68-7.62 (m, 3H), 7.44 (s, 1H), 7.28 (s, 1H), 7.09 (d, J=8.8 Hz, 2H), 7, 01 (t, J=8.8 Hz, 1H), 6.84 (s, 1H), 6.54 (d, J=7.6 Hz, 1H), 5.17 (s, 1H), 5, 11-4.95 (m, 1H), 4.23 (s, 2H), 3.92 (s, 2H), 3.77-3.76 (m, 2H), 3.69-3.67 ( m, 4H), 3.64-3.57 (m, 4H), 3.54-3.51 (m, 2H), 3.42-3.39 (m, 2H), 3.13 (s, 4H), 2.93 (s, 3H), 2.50-2.35 (m, 6H), 2.10 (s, 2H); LCMS (ES ⁺ ): m/z 1018.3 [M+H]+.

[0790] Example of synthesis of compound 209:

[0791] Step A: 3-(tert-butyldimethylsilyloxy)cyclohexanol

[0792] To a solution of 1,3-cyclohexanediol (a mixture of cis and trans, 25 g, 0.216 mmol) and imidazole (8.8 g, 0.129 mmol) in a mixture of dichloromethane (150 ml) and tetrahydrofuran (150 ml) at 0°C a solution of tert-butyldimethylsilyl chloride (16.2 g, 0.107 mmol) in a mixture of dichloromethane (40 ml) and tetrahydrofuran (40 ml) was added dropwise. The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The insoluble matter was removed by filtration, and the mother liquor was concentrated under reduced pressure to obtain a residue, which was dissolved in ethyl acetate (300 ml), washed successively with 1N aqueous hydrochloric acid (100 ml), brine (100 ml), saturated sodium hydrogen carbonate in water (100 ml) and saturated sodium chloride (100 ml), and dried over anhydrous sodium sulfate. Evaporation of the solvent gave a residue which was chromatographed on silica gel (ethyl acetate/n-hexane = 1/5) to give 3-(tert-butyldimethylsilyloxy)cyclohexanol (cis/trans mixture) (12.5 g, 51% yield) as colorless oil.

[0793] Step B: 3-(pyridin-4-yloxy)cyclohexanol

[0794] To a mixture of 3-(tert-butyldimethylsilyloxy)cyclohexanol (10 g, 43.4 mmol), pyridin-4-ol (3.9 g, 41.2 mmol) and triphenylphosphine (14.8 g, 56.42 mmol) in THF (40 mL, anhydrous) under nitrogen atmosphere at room temperature, diisopropyl azodicarboxylate (10.5 g, 52.1 mmol) was added dropwise over 0.5 hour. The mixture was stirred for 3 hours at room temperature under a nitrogen atmosphere. Added aq. HCl (70 ml, 1N), and stirred for 0.5 hour. The mixture was extracted with DCM (60 ml×3). The liquid phase was made alkaline by adding KOH and extracted with ethyl acetate (60 ml×4). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 3-(pyridin-4-yloxy)-cyclohexanol (3.3 g, 40% yield) as a yellow oil. LCMS: m/z 194.1 [M+H] ⁺ .

[0795] Step C: 3-(piperidin-4-yloxy)cyclohexanol

[0796] To a solution of 3-(pyridin-4-yloxy)cyclohexanol (3.3 g, 17 mmol) in ethanol (30 ml) was added platinum dioxide (660 mg, 2.9 mmol), sulfuric acid (2.5 g , 26 mmol), and then the reaction mixture was stirred at 50°C for 2 days in a hydrogen atmosphere (2.0 MPa). The mixture was filtered and concentrated, brine (30 ml x 3) was added and extracted with DCM/MeOH (10/1, 30 ml x 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 10/1) to give 3-(piperidin-4-yloxy)cyclohexanol (330 mg, 10% yield) as a pale yellow oil.

[0797] Step C: tert-butyl 4-(3-hydroxycyclohexyloxy)piperidine-1-carboxylate

[0798] Boc ₂ O (436 mg, 2 .0 mmol) and then stirred at room temperature overnight. The solvent was removed under vacuum at room temperature, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 1/1) to give tert-butyl 4-(3-hydroxycyclohexyloxy)piperidine-1-carboxylate (352 mg, yield 71%) as a yellow oil.

[0799] Step D: tert-butyl 4-(3-(methylsulfonyloxy)cyclohexyloxy)piperidine-1-carboxylate

[0800] MsCl ( 162 mg, 1.4 mmol), and the mixture was stirred at 0°C for 1 hour. The mixture was washed successively with aqueous NaHCO ₃ (15 ml×2) and saline (10 ml×2). The organic phase was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give crude tert-butyl 4-(3-(methylsulfonyloxy)-cyclohexyloxy)piperidine-1-carboxylate (351 mg, 79% yield) as pale - yellow oil.

[0801] Step E: cis-tert-butyl-3-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)-cyclohexyloxy)piperidine-1-carboxylate and trans-tert- butyl 3-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)cyclohexyloxy)piperidine-1-carboxylate

[0802] A mixture of tert-butyl 4-(3-(methylsulfonyloxy)cyclohexyloxy)piperidine-1-carboxylate (450 mg, 1.19 mmol), 4-(4-bromo-1H-pyrazol-3-yl)pyridine ( 252 mg, 1.13 mmol) and Cs ₂ CO ₃ (1.16 g, 3.57 mmol) in N,N-dimethylformamide (5 ml) were stirred at 80°C for 2 days. The mixture was diluted with brine (15 ml) and extracted with ethyl acetate (15 ml×3). The combined organic layer was washed with brine (15 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 1/1) to give cis-tert-butyl-3-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl) cyclohexyloxy)piperidine-1-carboxylate (140 mg) and trans-tert-butyl 3-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)cyclohexyloxy)piperidine-1-carboxylate (130 mg) as a pale yellow solid. For cis-tert-butyl-3-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)cyclohexyloxy)piperidine-1-carboxylate: LCMS: m/z 505.3 [M +H] ⁺ ; ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.38 (9H, s), 1.53-1.72 (6H, m), 1.89-2.11 (6H, m), 2.97 -3.04 (2H, m), 3.41-3.47 (1H, m), 3.53-3.55 (1H, m), 3.69 (2H, broad), 4.09- 4.15 (1H, m), 7.52 (1H, s), 7.84 (2H, d, J=6.0 Hz), 8.59 (2H, s). For trans-tert-butyl-3-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)cyclohexyloxy)piperidine-1-carboxylate: LCMS: m/z 505.3 [M +H] ⁺ ; ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.39 (9H, s), 1.42-1.92 (9H, m), 2.05-2.18 (3H, m), 3.04 -3.11 (2H, m), 3.46-3.50 (1H, m), 3.66 (2H, broad), 3.90 (1H, s), 4.42-4.46 ( 1H, m), 7.47 (1H, s), 7.85 (2H, d, J=5.6 Hz), 8.58 (2H, s).

[0803] Step F: tert-butyl-4-((1S,3R)-3-(4-(1-oxo-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4 -yl)-1H-pyrazol-1-yl)cyclohexyloxy)piperidine-1-carboxylate

[0804] A mixture of tert-butyl 4-((1S,3R)-3-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)cyclohexyloxy)piperidine-1-carboxylate ( 40 mg, 0.08 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one (26 mg, 0.1 mmol), K ₂ CO ₃ (33 mg, 0.24 mmol) and tetrakis(triphenylphosphine) palladium (10 mg, 10 M%) were stirred in 1,4-dioxane/water (6 ml, 5/1 ) at 80°C for 2 hours in a nitrogen atmosphere. After cooling the mixture, it was diluted with water (10 ml) and extracted with ethyl acetate (15 ml×3). The combined organic layer was washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 45/55) to give tert-butyl-4-((1S,3R)-3-(4-(1-oxo-2,3-dihydro-1H-indene- 5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)cyclohexyloxy)piperidine-1-carboxylate (20 mg, 44% yield) as a yellow solid. LCMS: m/z 557.3 [M+H] ⁺ .

[0805] Step G: 5-(1-((1R,3S)-3-(piperidin-4-yloxy)cyclohexyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2 ,3-dihydro-1H-inden-1-one

[0806] Tert-Butyl-4-((1S,3R)-3-(4-(1-oxo-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl) solution )-1H-pyrazol-1-yl)cyclohexyloxy)piperidine-1-carboxylate (40 mg, 0.08 mmol) in 4N HCl in 1,4-dioxane (3 ml) was stirred at 0°C for 5 hours. Then, the solvent was immediately removed to obtain 5-(1-((1R,3S)-3-(piperidin-4-yloxy)cyclohexyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl) -2,3-dihydro-1H-inden-1-one (38 mg, crude, 100% yield), which was used directly in the next step without further purification.

[0807] Step H: 2-(2,6-dioxopiperidin-3-yl)-5-(4-((1S,3R-3-(4-(1-oxo-2,3-dihydro-1H-indene -5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)cyclohexyloxy)piperidin-1-yl)isoindolin-1,3-dione

[0808] Mixture of 5-(1-((1R,3S)-3-(piperidin-4-yloxy)cyclohexyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2,3 -dihydro-1H-inden-1-one (20 mg, 0.044 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (18 mg, 0.066 mmol) and DIEA (17 mg, 0.13 mmol) in DMSO (3 ml) was stirred at 80°C overnight. The mixture was diluted with brine (15 ml) and extracted with ethyl acetate (15 ml×3). The combined organic layer was washed with brine (15 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative TLC (DCM/MeOH = 20/1) to give 2-(2,6-dioxopiperidin-3-yl)-5-(4-((1S,3R)-3-(4-(1- oxo-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)cyclohexyloxy)piperidin-1-yl)isoindoline-1,3-dione (15 mg, 50% yield) as a yellow solid. LCMS: m/z 713.3 [M+H] ⁺ .

[0809] Step I: 2-(2,6-dioxopiperidin-3-yl)-5-(4-((1S,3R)-3-(4-((E)-1-(hydroxyimino)-2, 3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)cyclohexyloxy)-piperidin-1-yl)isoindolin-1,3-dione

[0810] A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-(4-((1S,3R)-3-(4-(1-oxo-2,3-dihydro-1H-inden- 5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)cyclohexyloxy)piperidin-1-yl)-isoindoline-1,3-dione (15 mg, 0.021 mmol) and hydroxylamine hydrochloride ( 15 mg, 0.21 mmol) in pyridine (3 ml) was stirred at room temperature overnight. The solvent was immediately removed under vacuum at room temperature, and the residue was purified by preparative HPLC to give 2-(2,6-dioxopiperidin-3-yl)-5-(4-((1S,3R)-3-(4-( (E)-1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)cyclohexyloxy)piperidin-1-yl )isoindoline-1,3-dione (2.8 mg yield, 18%) as a yellow solid. LCMS: m/z 728.3 [M+H] ⁺ ; ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.73-2.08 (12H, m), 2.17-2.19 (1H, m), 2.51-2.53 (1H, m) , 2.66-2.96 (7H, m), 3.17-3.23 (2H, m), 3.48-354 (1H, m), 3.61-3.73 (3H, m) , 4.16-4.22 (1H, m), 4.84-4.89 (1H, m), 6.98 (1H, dd, J=8.4, 2.0 Hz), 7.09 (1H, d, J=8.0 Hz), 7.15 (1H, s), 7.21 (1H, d, J=2.4 Hz), 7.45-7.51 (3H, m) , 7.59 (2H, t, J=8.8 Hz), 8.14 (1H, d, J=12.8 Hz), 8.46 (1H, d, J=4.8 Hz).

[0811] Compound 210 can be prepared in a manner similar to that described for compound 209.

[0812] Example of the synthesis of compound 211: (E)-2-(2,6-dioxopiperidin-3-yl)-5-(3-(1-(2-(4-(4-(1-(hydroxyimino)- 2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethyl)piperidin-4-yl)azetidin-1-yl)isoindoline -1,3-dione

[0813] Step A: tert-butyl-3-(1-(2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethyl)piperidin- 4-yl)azetidine-1-carboxylate

[0814] To a solution of 2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)acetaldehyde (0.34 g, 0.95 mmol) in EtOH/ DCM (6 ml/6 ml) was added tert-butyl-3-(piperidin-4-yl)azetidine-1-carboxylate (272 mg, 1.14 mmol) and cat. AcOH. At pH below 5~6, AcOK was added. NaBH(OAc) ₃ (810 mg, 3.80 mmol) was then added. The resulting solution was stirred at 30°C for 1 hour. After quenching the reaction mixture by adding aq. NaHCO ₃ (20 ml), the mixture was extracted with DCM (30 ml×2). The combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column to obtain the target tert-butyl-3-(1-(2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethyl )-piperidin-4-yl)azetidine-1-carboxylate (270 mg). LCMS: (ES ⁺ ): m/z 583.3 [M+H] ⁺ .

[0815] Step B: 4-(1-(4-(2-(4-(azetidin-3-yl)piperidin-1-yl)ethoxy)phenyl)-4-bromo-1H-pyrazol-3-yl) pyridine

[0816] To a solution of tert-butyl-3-(1-(2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)-phenoxy)ethyl)piperidin- 4-yl)azetidine-1-carboxylate (0.27 g, 0.46 mmol) in DCM (6 ml) was added with TFA (2 ml). The resulting mixture was stirred at 30°C for 1 hour. The solvent was removed in vacuo and the residue was co-evaporated twice with DCM to obtain the target 4-(1-(4-(2-(4-(azetidin-3-yl)piperidin-1-yl)ethoxy)phenyl)-4-bromo -1H-pyrazol-3-yl)pyridine (224 mg crude, calc., 0.46 mmol), which was used in the subsequent reaction without further purification. LCMS: (ES ⁺ ): m/z 482.0 [M+H] ⁺ .

[0817] Step C: 5-(3-(1-(2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethyl)-piperidin- 4-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione

[0818] To a solution of 4-(1-(4-(2-(4-(azetidin-3-yl)piperidin-1-yl)ethoxy)phenyl)-4-bromo-1H-pyrazol-3-yl)pyridine (224 mg, crude, 0.46 mmol) to NMP (5 ml) was added 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (254 mg, 0.92 mmol ) and DIEA (0.6 g, 4.6 mmol). The resulting solution was subjected to microwave irradiation at 150°C for 2 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate (50 ml). The mixture was washed with saline (10 ml×3). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by preparative TLC to give 5-(3-(1-(2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethyl)piperidin- 4-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (60 mg). LCMS (ES+): m/z 739.3 [M+H] ⁺ .

[0819] Step D: 2-(2,6-dioxopiperidin-3-yl)-5-(3-(1-(2-(4-(4-(1-oxo-2,3-dihydro-1H- inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethyl)piperidin-4-yl)azetidin-1-yl)isoindolin-1,3-dione

[0820] To a solution of 5-(3-(1-(2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethyl)-piperidine-4 -yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (60 mg, 0.081 mmol) and 5-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one (84 mg, 0.325 mmol) in dioxane (15 ml)/H ₂ O (3 ml) was added successively CsF (49 mg, 0.325 mmol), Pd ₂ (dba) ₃ (30 mg, 0.033 mmol), tri-tert-butylphosphine tetrafluoroborate (20 mg, 0.066 mmol) and two drops of Cy ₂ NCH ₃ . The resulting solution was heated to 100°C for 16 hours under N ₂ atmosphere. After cooling to room temperature, the reaction mixture was quenched by adding water (20 ml), and the mixture was extracted with ethyl acetate (30 ml×2). The combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC to obtain the target 2-(2,6-dioxopiperidin-3-yl)-5-(3-(1-(2-(4-(4-(1-oxo-2,3-dihydro- 1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethyl)piperidin-4-yl)azetidin-1-yl)isoindolin-1,3-dione (30 mg, 47% yield) as a yellow solid. LCMS: (ES+): m/z 790.3 [M+H] ⁺ .

[0821] Step E: (E)-2-(2,6-dioxopiperidin-3-yl)-5-(3-(1-(2-(4-(4-(1-(hydroxyimino)-2, 3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethyl)piperidin-4-yl)azetidin-1-yl)isoindolin-1 ,3-dione

[0822] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-(3-(1-(2-(4-(4-(1-oxo-2,3-dihydro-1H-indene -5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethyl)piperidin-4-yl)azetidin-1-yl)isoindolin-1,3-dione (30 mg , 0.038 mmol) in CH ₃ CN/pyridine (6 ml/3 ml) was added hydroxylamine hydrochloride (26 mg, 0.38 mmol). The mixture was stirred at 50°C for 1 hour. The solvent was removed in vacuo and the residue was purified by preparative TLC (DCM/MeOH, 15/1) to give the target (E)-2-(2,6-dioxopiperidin-3-yl)-5-(3-(1- (2-(4-(4-(1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy )ethyl)piperidin-4-yl)azetidin-1-yl)isoindoline-1,3-dione (15 mg, 50% yield) as a yellow solid. ^1H -NMR (400 MHz, DMSO- _d6 ): δ 11.07 (s, 1H), 10.91 (s, 1H), 8.75 (s, 1H), 8.57 (d, J= 5.6 Hz, 2H), 7.87 (d, J=8.8 Hz, 2H), 7.65 (d, J=4.8 Hz, 1H), 7.55 (d, J=4, 8 Hz, 1H), 7.49 (d, J=5.6 Hz, 2H), 7.41 (s, 1H), 7.21 (d, J=4.8 Hz, 1H), 7.12 (d, J=9.2 Hz, 2H), 6.77 (s, 1H), 6.63 (d, J=4.4 Hz, 1H), 5.00-5.10 (m, 1H) , 4.05-4.20 (m, 4H), 3.70-3.80 (m, 2H), 2.70-3.10 (m, 7H), 2.55-2.65 (m, 4H), 1.70-2.05 (m, 10H); LCMS: (ES+): m/z 806.3 [M+H] ⁺ .

[0823] Example of the synthesis of compound 213: (E)-2-(2,6-dioxopiperidin-3-yl)-4-(3-(2-(2-((4-(4-(1-(hydroxyimino) -2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)methyl)phenoxy)ethoxy)propoxy)isoindoline-1,3- dione

[0824] Step A: (2-(2-(3-((tert-butyldimethylsilyl)oxy)propoxy)ethoxy)phenyl)-methanol

[0825] To a solution of 2-(3-((tert-butyldimethylsilyl)oxy)propoxy)ethyl-4-methylbenzenesulfonate (1 g, 2.58 mmol) in DMF (10 mL) was added 2-(hydroxymethyl)phenol (0. 38 g, 3.09 mol) and K ₂ CO ₃ (1.07 g, 2.74 mmol). The resulting solution was stirred at 70°C for 3 hours. After cooling to room temperature, the reaction mixture was quenched by adding aq. NH ₄ Cl, and the mixture was extracted with EtOAc. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography to give (2-(2-(3-((tert-butyldimethylsilyl)oxy)propoxy)ethoxy)phenyl)methanol (400 mg, 45.6% yield) as a colorless oil. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.36-7.34 (d, J=7.2 Hz, 1H), 7.18-7.14 (t, J=7.2 Hz, 1H), 6.93-6.90 (m, 2H), 4.90-4.87 (t, J=5.6 Hz, 1H), 4.49-4.47 (m, 2H), 4 .07-4.05 (m, 2H), 3.68-3.61 (m, 4H), 3.52-2.90 (t, J=6.4 Hz, 2H), 1.70-1 .64 (m, 2H), 0.83 (s, 9H), 0.00 (s, 6H).

[0826] Step B: 4-(4-bromo-1-(4-((2-(2-(3-((tert-butyldimethylsilyl)oxy)propoxy)-ethoxy)benzyl)oxy)phenyl)-1H- pyrazol-3-yl)pyridine

[0827] To a solution of (2-(2-(3-((tert-butyldimethylsilyl)oxy)propoxy)ethoxy)phenyl)-methanol (400 mg, 1.18 mmol) in DCM (20 ml) and DIPEA (457 mg , 3.54 mmol) MsCl (268 mg, 2.36 mmol) was added at 0°C. The resulting solution was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM (100 ml), washed with water and brine. The organic phase was dried over anhydrous sodium sulfate, concentrated in vacuo to obtain the crude target product (320 mg, 100% yield), which was used directly in the next step. To a solution of the above target product (320 mg, 0.89 mmol) in anhydrous DMF (20 ml) was added K ₂ CO ₃ (368.5 mg, 2.67 mmol) and 4-(4-bromo-3-(pyridine -4-yl)-1H-pyrazol-1-yl)phenol (309.7 mg, 0.98 mmol). The resulting solution was stirred at 70°C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc (100 ml), washed with water and brine. The organic phase was dried over anhydrous sodium sulfate. The residue was purified by column chromatography to give 4-(4-bromo-1-(4-((2-(2-(3-((tert-butyldimethylsilyl)oxy)-propoxy)ethoxy)benzyl)oxy)phenyl)-1H -pyrazol-3-yl)-pyridine (300 mg, 40.1% yield in two batches) as a red oil. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.73-8.67 (m, 2H), 8.00-7.90 (m, 3H), 7.63-7.59 (d, J =9.2 Hz, 1H), 7.50-7.42 (m, 1H), 7.33-7.27 (m, 2H), 7.12-7.08 (m, 2H), 7. 02-6.91 (m, 2H), 5.20 (s, 2H), 4.22-4.17 (t, J=4.8 Hz, 2H), 3.84-3.76 (t, J=5.2 Hz, 2H), 3.70-3.67 (t, J=6.4 Hz, 2H), 3.62-3.59 (t, J=6.4 Hz, 2H), 1.82-1.75 (m, 2H), 0.87 (s, 9H), 0.02 (s, 6H).

[0828] Step C: 3-(2-(2-((4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)methyl)-phenoxy)ethoxy) propan-1-ol

[0829] To a solution of 4-(4-bromo-1-(4-((2-(2-(3-((tert-butyldimethylsilyl)oxy)propoxy)-ethoxy)benzyl)oxy)phenyl)-1H-pyrazole -3-yl)pyridine (300 mg, 0.47 mmol) in MeOH (10 ml) was added HCl in 1,4-dioxane (1 ml, 6 M, 6 mmol) at room temperature. The resulting solution was stirred at room temperature for 0.5 hours. The solution was concentrated, diluted with 100 ml DCM and washed with NaHCO ₃ (50 ml x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC to obtain the target 3-(2-(2-((4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)methyl)phenoxy)ethoxy )-propan-1-ol (160 mg, 65% yield) as a white solid. LCMS (ES ⁺ ): m/z 524.1 [M+H] ⁺ .

[0830] Step D: tert-butyl-5-amino-4-(4-(3-(2-(2-((4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazole -1-yl)phenoxy)methyl)phenoxy)ethoxy)propoxy)-1,3-dioxoisoindolin-2-yl)-5-oxopentanoate

[0831] To a solution of 3-(2-(2-((4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)methyl)-phenoxy)ethoxy)propane -1-ol (160 mg, 0.31 mmol), PPh ₃ (244 mg, 0.93 mmol) and tert-butyl-5-amino-4-(4-hydroxy-1,3-dioxoisoindolin-2-yl )-5-oxopentanoate (159.4 mg, 0.46 mmol) in anhydrous THF (10 ml) under N ₂ was added DIAD (188 mg, 0.93 mmol). The resulting solution was stirred at room temperature for 2 hours. After quenching by adding water, the mixture was extracted with DCM. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative TLC to obtain the target tert-butyl-5-amino-4-(4-(3-(2-(2-((4-(4-bromo-3-(pyridin-4-yl)-1H -pyrazol-1-yl)phenoxy)methyl)phenoxy)ethoxy)propoxy)-1,3-dioxoisoindolin-2-yl)-5-oxopentanoate (110 mg, 42.2% yield) as a white solid. LCMS (ES ⁺ ): m/z 854.2 [M+H] ⁺ .

[0832] Step D: 4-(3-(2-(2-((4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)-methyl)phenoxy )ethoxy)propoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0833] To a solution of tert-butyl-5-amino-4-(4-(3-(2-(2-((4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol- 1-yl)phenoxy)methyl)phenoxy)ethoxy)propoxy)-1,3-dioxoisoindolin-2-yl)-5-oxopentanoate (80 mg, 0.094 mmol) in acetonitrile (15 ml) was added 4-methylbenzenesulfonic acid (32, 3 mg, 0.28 mmol). The solution was stirred at 60°C for 48 hours. After cooling to room temperature, the reaction mixture was quenched by adding aq. NaHCO ₃ (to pH>7), and the mixture was extracted with DCM (20 ml×3). The combined organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by preparative TLC to obtain the target 4-(3-(2-(2-((4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)methyl) phenoxy)ethoxy)propoxy)-2-(2,6-dioxopiperidin-3-yl)-isoindoline-1,3-dione (40 mg, 54.8% yield) as a white solid. LCMS (ES ⁺ ): m/z 781.1 [M+H] ⁺ .

[0834] Step E: 2-(2,6-dioxopiperidin-3-yl)-4-(3-(2-(2-((4-(4-(1-oxo-2,3-dihydro-1H -inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)methyl)phenoxy)ethoxy)propoxy)isoindoline-1,3-dione

[0835] To a solution of 4-(3-(2-(2-((4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)-methyl)phenoxy) ethoxy)propoxy)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (40 mg, 0.051 mmol) in 1,4-dioxane/H ₂ O (5 ml, v/v . = 10/1) 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one (19.87 mg, 0.077 mmol), Pd ₂ (dba) ₃ (4.67 mg, 0.0051 mmol), CsF (31.0 mg, 0.20 mmol), [(t-Bu) ₃ PH]BF ₄ (0 .59 mg, 0.0020 mmol) and N,N-dicyclohexylmethylamine (0.50 mg, 0.0026 mmol). The resulting solution was stirred at 100°C for 2 hours under N ₂ atmosphere. After cooling to room temperature, the reaction mixture was diluted with DCM (50 ml) and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC to obtain the target 2-(2,6-dioxopiperidin-3-yl)-4-(3-(2-(2-((4-(4-(1-oxo-2,3-dihydro -1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)methyl)phenoxy)ethoxy)propoxy)isoindoline-1,3-dione (30 mg, yield 70.3%) as a white solid. LCMS (ES ⁺ ): m/z 832.3 [M+H] ⁺ .

[0836] Step F: (E)-2-(2,6-dioxopiperidin-3-yl)-4-(3-(2-(2-((4-(4-(1-(hydroxyimino)-2 ,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)methyl)phenoxy)-ethoxy)propoxy)isoindoline-1,3-dione

[0837] To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-(3-(2-(2-((4-(4-(1-oxo-2,3-dihydro-1H- inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)methyl)phenoxy)ethoxy)propoxy)isoindoline-1,3-dione (30 mg, 0.036 mmol) in acetonitrile/pyridine (3 ml, v/v = 2/1), hydroxylamine hydrochloride (25.1 mg, 0.36 mmol) was added. The mixture was stirred at 40°C for 20 minutes, diluted with DCM (20 ml) and washed with saline (10 ml). The organic phase was concentrated under vacuum conditions. The residue was purified by preparative TLC to give (E)-2-(2,6-dioxopiperidin-3-yl)-4-(3-(2-(2-((4-(4-(1-(hydroxyimino)- 2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)methyl)phenoxy)ethoxy)propoxy)isoindoline-1,3-dione (6.2 mg, 20.3% yield) as a white solid. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.57-8.56 (m, 2H), 8.32 (s, 1H), 7.93 (s, 1H), 7.69-7, 63 (m, 3H), 7.57-7.51 (m, 3H), 7.43-7.41 (m, 1H), 7.38-7.36 (d, J=7.2 Hz, 1H), 7.28 (s, 2H), 7.23 (s, 2H), 7.15-7.13 (d, J=7.6 Hz, 1H), 7.08-7.06 (m , 2H), 7.00-6.97 (m, 1H), 6.91-6.89 (d, J=7.6 Hz, 1H), 5.15 (s, 2H), 4.92- 4.88 (m, 1H), 4.26-4.23 (t, J=6.4 Hz, 2H), 4.20-4.17 (t, J=4.4 Hz, 2H), 3 .86-3.84 (t, J=4.8 Hz, 2H), 3.79-3.76 (t, J=6.0 Hz, 2H), 3.08-2.96 (m, 4H ), 2.90-2.82 (m, 1H), 2.81-2.66 (m, 2H), 2.16-2.05 (m, 3H); LCMS (ES ⁺ ): m/z 847.3 [M+H] ⁺ .

[0838] Compound 212 can be prepared in a manner similar to that described for Compound 213.

[0839] Example of the synthesis of compound 215: (E)-2-(2,6-dioxopiperidin-3-yl)-4-(3-(3-((4'-(4-(1-(hydroxyimino)-2 ,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)oxy)propoxy) propoxy)isoindoline-1,3-dione

[0840] Step A: 4-bromo-4'-methoxy-1,1'-biphenyl

[0841] To a solution of (4-methoxyphenyl)boronic acid (5 g, 32.9 mmol) in toluene/MeOH (200 ml/100 ml) was added 1,4-dibromobenzene (11.6 g, 49.4 mmol), Pd(PPh ₃ ) ₄ (1.9 g, 1.65 mmol) and CS ₂ CO ₃ (21.4 g, 65.8 mmol). The resulting solution was stirred at 100°C for 16 hours under N ₂ atmosphere. Completion of the reaction was detected by TLC. After cooling to room temperature, the reaction mixture was diluted with 50 ml of ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography to give 4-bromo-4'-methoxy-1,1'-biphenyl (7.0 g, 80% yield). LCMS (ES+): m/z 263.1 [M+H] ⁺ .

[0842] Step B: (4'-methoxy-[1,1'-biphenyl]-4-yl)boronic acid

[0843] To a solution of 4-bromo-4'-methoxy-1,1'-biphenyl (2 g, 7.63 mmol) in anhydrous THF (30 ml) at -78°C under N ₂ atmosphere was added n- BuLi (9.2 ml, 22.9 mmol, 2.5 M in hexane). After 1 hour, (CH ₃ O) ₃ B (2.38 g, 22.9 mmol) was added dropwise at -78°C. The resulting solution was stirred for 1 hour at -78°C and overnight at 5°C. After quenching by adding saturated NH ₄ Cl solution, the mixture was extracted with ethyl acetate (30 ml×2.) The combined organic layer was dried over anhydrous sodium sulfate. The residue was purified by column chromatography to give (4'-methoxy-[1,1'-biphenyl]-4-yl)boronic acid (1.0 g, 58% yield). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 8.06 (s, 2H), 7.84 (d, J=7.6 Hz, 2H), 7.63 (d, J=7, 6 Hz, 2H), 7.58 (d, J=7.6 Hz, 2H), 7.02 (d, J=7.6 Hz, 2H), 3.80 (s, 3H).

[0844] Step C: 4-(4-bromo-1-(4'-methoxy-[1,1'-biphenyl-4-yl)-1H-pyrazol-3-yl)pyridine

[0845] To a solution of (4'-methoxy-[1,1'-biphenyl]-4-yl)boronic acid (1 g, 4.39 mmol) in DCM/pyridine (40 ml/4 ml) was added Cu(OAc ) ₂ (0.8 g, 4.39 mmol) and 4-(4-bromo-1H-pyrazol-3-yl)pyridine (1.5 g, 6.58 mmol). The resulting solution was stirred at 5°C for 16 hours in an O ₂ atmosphere. The reaction mixture was washed with ammonia (20 ml×2). The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was applied to a silica gel column to give the target 4-(4-bromo-1-(4'-methoxy-[1,1'-biphenyl]-4-yl)-1H-pyrazol-3-yl)pyridine (1 g crude, yield 56%). LCMS (ES ⁺ ): m/z 407.4 [M+H] ⁺ .

[0846] Step D: 4-(1-(4'-(3-(3-(benzyloxy)propoxy)propoxy)-[1,1'-biphenyl]-4-yl)-4-bromo-1H-pyrazole -3-yl)pyridine

[0847] To a solution of 4-(4-bromo-1-(4'-methoxy-[1,1'-biphenyl]-4-yl)-1H-pyrazol-3-yl)

[0848] pyridine (1 g, 2.46 mmol) in DCM (40 ml) was added dropwise with BBr ₃ (1.85 g, 7.38 mmol). The resulting solution was stirred at 10°C for 2 hours. After quenching with MeOH and concentration, the crude product was applied to a silica gel column to give the target 4'-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)-[1,1'- biphenyl]-4-ol (0.6 g, 62% yield). To a solution of 4'-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-ol (375 mg, 0.96 mmol) in anhydrous DMF (5 ml), Cs ₂ CO ₃ (1.56 g, 4.80 mmol) and 3-(3-(benzyloxy)propoxy)propylmethanesulfonate (0.58 g, 1.92 mmol) were added. The resulting solution was stirred at 75°C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 ml) and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate. The residue was purified by column chromatography to give 4-(1-(4'-(3-(3-(benzyloxy)propoxy)propoxy)-[1,1'-biphenyl]-4-yl)-4-bromo-1H- pyrazol-3-yl)pyridine (400 mg, 70% yield). ^1H -NMR (400 MHz, DMSO- _d6 ): δ 9.02 (s, 1H), 8.73 (br, 2H), 8.00 (m, 2H), 7.80 (d, J =8.0 Hz, 2H), 7.67 (d, J=8.4 Hz, 2H), 7.30 (m, 5H), 7.03 (d, J=8.4 Hz, 2H), 4.45 (m, 2H), 4.06 (t, J=5.6 Hz, 2H), 3.53 (m, 7H), 1.97 (m, 2H), 1.77 (m, 2H ).

[0849] Step E: 5-(1-(4'-(3-(3-hydroxypropoxy)propoxy)-[1,1'-biphenyl]-4-yl)-3-(pyridin-4-yl)- 1H-pyrazol-4-yl)-2,3-dihydro-1H-inden-1-one

[0850] To a solution of 4-(1-(4'-(3-(3-(benzyloxy)propoxy)propoxy)-[1,1'-biphenyl]-4-yl)-4-bromo-1H-pyrazol- 3-yl)pyridine (0.4 g, 0.67 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H -inden-1-one (260 mg, 1.01 mmol) in 1,4-dioxane (15 ml)/H ₂ O (1.5 ml) CsF (328 mg, 2.16 mmol), Pd ₂ were added successively (dba) ₃ (196 mg, 0.216 mmol), tri-tert-butylphosphine tetrafluoroborate (124 mg, 0.43 mmol) and two drops of N-cyclohexyl-N-methylcyclohexanamine. The reaction mixture was heated to 100°C for 2 hours under N ₂ atmosphere. After cooling to room temperature, the reaction mixture was quenched by adding water (20 ml), and the mixture was extracted with ethyl acetate (30 ml×2). The combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column to obtain the target 5-(1-(4'-(3-(3-(benzyloxy)propoxy)propoxy)-[1,1'-biphenyl]-4-yl)-3-(pyridine -4-yl)-1H-pyrazol-4-yl)-2,3-dihydro-1H-inden-1-one (0.4 g, 92% yield) as a brown oil. To a solution of 5-(1-(4'-(3-(3-(benzyloxy)-propoxy)propoxy)-[1,1'-biphenyl]-4-yl)-3-(pyridin-4-yl)- 1H-pyrazol-4-yl)-2,3-dihydro-1H-inden-1-one (400 mg, 0.16 mmol) in THF/MeOH (10 ml/1 ml and two drops of concentrated HCl) was added Pd( OH) ₂ on carbon (200 mg). The mixture was stirred at 5°C for 1 hour under an H ₂ atmosphere (1 atm). The mixture was filtered and the solid was washed with THF. The organic layer was concentrated and purified on a column to give 5-(1-(4'-(3-(3-hydroxypropoxy)propoxy)-[1,1'-biphenyl]-4-yl)-3-(pyridin-4- yl)-1H-pyrazol-4-yl)-2,3-dihydro-1H-inden-1-one (250 mg, 72% yield). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.73 (d, J=5.6 Hz, 2H), 8.64 (s, 3H), 8.10 (m, 2H), 7.85 (m, 3H), 7.68 (d, J=6.0 Hz, 2H), 7.55 (m, 4H), 7.28-7.50 (m, 6H), 7.00 (d, J=8.4 Hz, 2H), 5.68 (m, 1H), 4.49 (s, 2H), 4.15 (m, 3H), 3.45-3.70 (m, 6H), 3.18 (m, 2H), 2.78 (m, 2H).

[0851] Step F: tert-butyl-5-amino-4-(1,3-dioxo-4-(3-(3-((4'-(4-(1-oxo-2,3-dihydro- 1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)oxy)propoxy)-propoxy)isoindolin- 2-yl)-5-oxopentanoate

[0852] To a solution of 5-(1-(4'-(3-(3-hydroxypropoxy)propoxy)-[1,1'-biphenyl]-4-yl)-3-(pyridin-4-yl)-1H -pyrazol-4-yl)-2,3-dihydro-1H-inden-1-one (250 mg, 0.45 mmol), Ph ₃ P (351 mg, 1.35 mmol) and tert-butyl-5- amino-4-(4-hydroxy-1,3-dioxoisoindolin-2-yl)-5-oxopentanoate (233 mg, 0.67 mmol) in anhydrous THF (20 ml) at 0°C, DIAD (266 mg) was added dropwise , 1.35 mmol) in THF (3 ml). The resulting solution was stirred at 0~10°C for 2 hours. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, concentrated and applied to a silica gel column to give tert-butyl-5-amino-4-(1,3-dioxo-4-(3-(3-((4'-(4- (1-oxo-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4- yl)oxy)propoxy)propoxy)-isoindolin-2-yl)-5-oxopentanoate (150 mg, 38% yield) as an oil. LCMS (ES+): m/z 890.4 [M+H] ⁺ .

[0853] Step G: 2-(2,6-dioxopiperidin-3-yl)-4-(3-(3-((4'-(4-(1-oxo-2,3-dihydro-1H-indene -5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)oxy)propoxy)-propoxy)isoindoline-1,3 -dion

[0854] To a solution of tert-butyl-5-amino-4-(1,3-dioxo-4-(3-(3-((4'-(4-(1-oxo-2,3-dihydro-1H -inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)oxy)propoxy)-propoxy)isoindoline-2 -yl)-5-oxopentanoate (150 mg, 0.168 mmol) in CH ₃ CN (5 ml) was added TsOH (289 mg, 1.68 mmol). The resulting solution was stirred at 80°C for 3 hours. The reaction mixture was quenched by adding saturated NaHCO ₃ and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated and purified by preparative TLC to give 2-(2,6-dioxopiperidin-3-yl)-4-(3-(3-((4'-(4-(1-oxo -2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)oxy) propoxy)propoxy)isoindoline-1,3-dione (100 mg, 73% yield). LCMS (ES+): m/z 816.3 [M+H] ⁺ .

[0855] Step H: (E)-2-(2,6-dioxopiperidin-3-yl)-4-(3-(3-((4'-(4-(1-(hydroxyimino)-2,3 -dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)oxy)propoxy)propoxy) isoindoline-1,3-dione

[0856] To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-(3-(3-((4'-(4-(1-oxo-2,3-dihydro-1H-inden- 5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)oxy)propoxy)-propoxy)isoindoline-1,3- dione (100 mg, 0.123 mmol) and hydroxylamine hydrochloride (256 mg, 3.681 mmol) in MeOH/DCM (4 ml/1 ml) NaHCO ₃ (464 mg, 5.521 mmol) was added at 50°C. The mixture was stirred at 50°C for 1 hour. The residue was purified by preparative TLC (DCM/MeOH = 20/1) to obtain the target (E)-2-(2,6-dioxopiperidin-3-yl)-4-(3-(3-((4'-(4 -(1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)-[1,1'-biphenyl] -4-yl)oxy)propoxy)propoxy)-isoindoline-1,3-dione (24 mg, 24% yield) as a yellow solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.09 (s, 1H), 10.90 (s, 1H), 8.90 (s, 1H), 8.59 (d, J= 5.6 Hz, 2H), 8.02 (d, J=8.4 Hz, 2H), 7.79 (m, 3H), 7.38 -7.70 (m, 8H), 7.25 ( d, J=6.0 Hz, 1H), 6.98 (d, J=8.8 Hz, 2H), 5.09 (m, 1H), 4.26 (m, 2H), 4.05 ( m, 2H), 3.60 (m, 4H), 3.05 (m, 2H), 2.86 (m, 3H), 2.50 (m, 3H), 2.03 (m, 5H); LCMS (ES ⁺ ): m/z 831.3 [M+H] ⁺ .

[0857] Compound 214 can be prepared in a manner similar to that described for compound 215.

[0858] Synthesis Example of Compound 100: (2S,4R)-1-((S)-2-(2-(3-(4-(4-(3-(2,6-difluoro-3-((R )-3-fluoropyrrolidin-1-sulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-piperazin-1-yl)propoxy)acetamido)-3,3-dimethylbutanoyl)- 4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0859] Step A: tert-butyl 2-(3-chloropropoxy) acetate

[0860] To a solution of tert-butyl-2-bromoacetate (5.0 g, 26 mmol) and 3-chloropropan-1-ol (2.9 g, 31 mmol) in anhydrous DMF (15 ml) at 0°C was added NaOH (1.2 g, 31 mmol). After stirring for 2 hours at 0°C, the mixture was warmed to room temperature overnight. The reaction mixture was quenched by adding H ₂ O (20 ml) at 0°C, and the mixture was extracted with PE (20 ml x 2). The combined organic layer was washed with water and brine. The organic phase was concentrated in vacuo to give the desired tert-butyl 2-(3-chloropropoxy)acetate (2.8 g, 52% yield) as an oil, which was used directly in the next step. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.97 (s, 2H), 3.65-3.70 (m, 4H), 2.05-2.08 (m, 2H), 1. 49 (s, 9H).

[0861] Step B: tert-butyl-2-(3-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1- yl)propoxy)acetate

[0862] To a solution of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine 2,2,2-trifluoroacetate (530 mg, 1.32 mmol) in anhydrous DMF (5 ml), K ₂ CO ₃ (911 mg, 6.60 mmol), KI (438 mg, 2.64 mmol) and tert-butyl 2-(3-chloropropoxy) acetate (550 mg, 2.64 mmol). The resulting solution was stirred at 90°C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 ml), and the mixture was washed with water and brine. The organic phase was concentrated under vacuum conditions. The residue was purified by preparative TLC to obtain the target tert-butyl-2-(3-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin- 1-yl)propoxy)acetate (300 mg, crude). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.70 (d, J=8.0 Hz, 2H), 6.89 (d, J=8.0 Hz, 2H), 3.96 (br ., 2H), 3.27 (broad, 4H), 3.21 (broad, 2H), 2.60 (broad, 4H), 2.51-2.53 (m, 2H), 1, 82-1.85 (m, 2H), 1.42 (s, 9H), 1.24 (s, 12H).

[0863] Step C: (R)-tert-butyl-2-(3-(4-(4-(3-(2,6-difluoro-3-(3-fluoropyrrolidine-1-sulfonamido)benzoyl)-1H -pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-1-yl)propoxy)acetate

[0864] To a solution of (R)-N-(3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (100 mg, 0.20 mmol) in dioxane/H ₂ O (10 ml/1 ml), tert-butyl-2-(3-(4-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)piperazin-1-yl)propoxy)acetate (200 mg, 0.43 mmol), Pd(aMphos)Cl ₂ (15 mg, 0.02 mmol) and CsF ( 121 mg, 0.80 mmol). The resulting solution was stirred at 95°C for 16 hours under N ₂ atmosphere. Completion of the reaction was detected by TLC. After cooling to room temperature, the reaction mixture was diluted with 50 ml of EA and washed with water and saline. The organic layer was dried over anhydrous sodium sulfate. The residue was purified by preparative TLC to obtain the target (R)-tert-butyl-2-(3-(4-(4-(3-(2,6-difluoro-3-(3-fluoropyrrolidine-1-sulfonamido)-benzoyl )-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-1-yl)propoxy)acetate (80 mg, 53% yield). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 12.00 (br., 1H), 8.87 (s, 1H), 8.60 (s, 1H), 7.75 (s, 2H), 7.54 (d, J=8.0 Hz, 2H), 6.98-7.05 (m, 3H), 5.15-5.30 (m, 1H), 3.97 (s, 2H) , 3.71-3.75 (m, 2H), 3.49-3.65 (m, 6H), 3.28 (s, 4H), 2.58-2.67 (m, 6H), 1 .80-2.30 (m, 3H), 1.49 (s, 9H).

[0865] Stage D: (2S,4R)-1-((S)-2-(2-(3-(4-(4-(3-(2,6-difluoro-3-((R)- 3-fluoropyrrolidin-1-sulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-1-yl)propoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy -N-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0866] To a solution of (R)-tert-butyl-2-(3-(4-(4-(3-(2,6-difluoro-3-(3-fluoropyrrolidine-1-sulfonamido)benzoyl)-1H- pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-1-yl)propoxy)acetate (80 mg, 0.13 mmol) in dioxane (2 ml) added HCl in dioxane (2 ml, 8 M ). The resulting solution was stirred at 50°C for 5 hours. After cooling to room temperature, the solvent was removed under vacuum to give (R)-2-(3-(4-(4-(3-(2,6-difluoro-3-(3-fluoropyrrolidine-1-sulfonamido)benzoyl )-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-1-yl)propoxy)acetic acid (74 mg, calculated, 100% yield). To a solution of (R)-2-(3-(4-(4-(3-(2,6-difluoro-3-(3-fluoropyrrolidine-1-sulfonamido)benzoyl)-1H-pyrrolo[2,3-b ]pyridin-5-yl)phenyl)piperazin-1-yl)-propoxy)acetic acid (74 mg, 0.11 mmol), (2S,4R)-1-((S)-2-amino-3,3 -dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (91 mg, 0.19 mmol) and DIEA (142 mg, 1.10 mmol) in anhydrous NMP (5.0 ml) was added RuBOP (172 mg, 0.33 mmol) at room temperature. After stirring at 10°C for 1 hour, the reaction mixture was quenched by adding brine (20 ml), and the mixture was taken up in ethyl acetate. The organic phase was concentrated under vacuum, and the residue was purified by preparative TLC and preparative HPLC to obtain the target (2S,4R)-1-((S)-2-(2-(3-(4-(4-(3-( 2,6-difluoro-3-((R)-3-fluoropyrrolidin-1-sulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-phenyl)piperazin-1-yl)propoxy )acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (20 mg, 17% yield in two batches) as a white solid substances. ¹ H-NMR (400 MHz, CD ₃ OD): δ 8.82 (s, 1H), 8.65 (s, 1H), 8.59 (s, 1H), 7.89 (s, 1H), 7.74 (m, 1H), 7.59 (d, J=8.8 Hz, 2H), 7.30-7.50 (m, 4H), 7.07-7.20 (m, 3H) , 5.15-5.30 (m, 1H), 4.62 (s, 1H), 4.50-4.60 (m, 3H), 4.30 (d, J=7.8 Hz, 1H ), 4.12 (m, 2H), 3.78-3.95 (m, 2H), 3.40-3.80 (m, 14H), 3.10 (m, 5H), 2.42 ( s, 3H), 1.98-2.30 (m, 8H), 1.03 (s, 9H); LCMS (ES ⁺ ): m/z 1113.3 [M+H] ⁺ .

[0867] Synthesis example of compound 152: (E)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(4-(4-(1-(hydroxyimino)-2,3 -dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethyl)piperazin-1-yl)isoindolin-1,3-dione

[0868] Step A: 2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)acetaldehyde

[0869] To a solution of 4-(4-bromo-1-(4-(2,2-diethoxyethoxy)phenyl)-1H-pyrazol-3-yl)pyridine (1 g, 2.32 mmol) in CH ₃ CN ( 10 ml) added conc. HCl (2 ml, diluted in 6 ml H ₂ O). The resulting solution was stirred at 55°C for 1 hour. After cooling to 0°C, the pH was adjusted to approximately 9 by gradually adding saturated aqueous NaHCO ₃ solution. The solid was filtered and co-evaporated with CH ₃ CN to give 2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)acetaldehyde (0.3 g, yield 66 .9%) as a white solid. LCMS (ES ⁺ ): m/z 358.0, 376.0/378.0 [M+H] ⁺ , [M+18] ⁺ .

[0870] Step B: 5-(4-(2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethyl)-piperazin-1-yl )-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0871] To a solution of 2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)acetaldehyde (0.1 g, 0.28 mmol) in MeOH ( 10 ml) 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione hydrochloride (127 mg, 0.34 mmol) and cat. NOAC. At pH below 5~6, AcOK was added. NaBH ₃ CN (87 mg, 1.40 mmol) was then added. The resulting solution was stirred at 20°C for 1 hour. After quenching by adding saturated NH ₄ Cl (20 ml), the mixture was extracted with DCM (30 ml x 2). The combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC to obtain the target 5-(4-(2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)-phenoxy)-ethyl)piperazin- 1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (90 mg, 35% yield). LCMS (ES ⁺ ): m/z 684.1 /686.1 [M+H] ⁺ .

[0872] Step C: 2-(2.b-dioxopiperidin-3-yl)-5-(4-(2-(4-(4-(1-oxo-2.3-dihydro-1H-inden-5-yl )-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethyl)piperazin-1-yl)isoindoline-1,3-dione

[0873] To a solution of 5-(4-(2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethyl)-piperazin-1-yl) -2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (90 mg, 0.13 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one (37 mg, 0.15 mmol) in dioxane/H ₂ O (10 ml/1 ml) t-Bu ₃ PHBF ₄ was added successively (31 mg, 0.11 mmol), CsF (80 mg, 0.53 mmol), Cy ₂ NMe (5 drops) and Pd ₂ (dba) ₃ (48 mg, 0.05 mmol). The resulting mixture was stirred at 90°C for 2 hours under N2 atmosphere. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate (30 ml) and then the mixture was washed with brine. The organic phase was evaporated under vacuum conditions. The residue was purified by preparative TLC and preparative HPLC to obtain the target 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(4-(4-(1-oxo-2,3-dihydro- 1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethyl)piperazin-1-yl)isoindolin-1,3-dione (60 mg, yield 69%). LCMS (ES ⁺ ): m/z 736.3 [M+H] ⁺ .

[0874] Step D: (E)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(4-(4-(1-(hydroxyimino)-2,3-dihydro -1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethyl)piperazin-1-yl)isoindolin-1,3-dione

[0875] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(4-(4-(1-oxo-2,3-dihydro-1H-inden-5- yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethyl)piperazin-1-yl)isoindoline-1,3-dione (60 mg, 0.08 mmol) in CH ₃ CN/pyridine (6 ml/3 ml) was added NH ₂ OH⋅HCl (57 mg, 0.82 mmol). The mixture was stirred at 45°C for 0.5 hour. The mixture was diluted with DCM (30 ml) and washed with saline. The organic phase was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM/MeOH 15/1) to obtain the target (E)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(4-(4-(1 -(hydroxyimino)-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethyl)piperazin-1-yl)isoindolin- 1,3-Dione as a yellow solid (45 mg, 73% yield). ^1H -NMR (400 MHz, DMSO- _d6 ): δ 11.07 (s, 1H), 10.89 (s, 1H), 8.75 (s, 1H), 8.58 (d, J= 5.6 Hz, 2H), 7.87 (d, J=8.8 Hz, 2H), 7.68 (d, J=8.4 Hz, 1H), 7.55 (d, J=8, 0 Hz, 1H), 7.48 (d, J=4.4 Hz, 2H), 7.20-7.41 (m, 4H), 7.14 (d, J=9.2 Hz, 2H) , 5.08 (m, 1H), 4.21 (t, J=5.6 Hz, 2H), 3.47 (m, 4H), 2.99-3.02 (m, 2H), 2, 67-2.89 (m, 10H), 2.05 (m, 1H); LCMS (ES ⁺ ): m/z 751.3 [M+H] ⁺ .

[0876] Example of the synthesis of compound 216: (2S,4R)-1-((S)-2-(3-(2-(3-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)- 1H-pyrrolo[2,3-b]pyridin-5-yl)phenoxy)ethoxy)-propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-4-(4-methylthiazol-5-yl)benzyl) -pyrrolidine-2-carboxamide

[0877] To a solution of 3-[2-[3-[3-[2,6-difluoro-3-(propylsulfonylamino)benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenoxy]ethoxy ]propanoic acid (22.8 mg, 0.04 mmol) and (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-( 4-methylthiazol-5-yl)-phenyl]methyl]pyrrolidine-2-carboxamide hydrochloride (19.93 mg, 0.043 mmol) in DMF (2 ml) TEA (0.1 ml, 0.72 mmol) was added at room temperature and RuBOR (22.21 mg, 0.043 mmol). The reaction mixture was stirred for 12 hours (overnight) at the same temperature. The absence of starting materials was detected by TLC (DCM:MeOH:NH ₄ OH, 90:9:1). DMF was removed under high vacuum conditions. The crude product was filtered through a silica gel carbonate cartridge using DCM:MeOH (9:1) as eluent. The filtrate was evaporated in vacuo and the crude product was purified by preparative TLC (MeOH:DCM, 1:9, 2×) to obtain 20 mg of product (52% yield). ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 13.00 (bs, 1H), 9.78 (bs, 1H), 8.96 (s, 1H), 8.71 (s , 1H), 8.62 (s, 1H), 8.55 (t, J=5.5 Hz, 1H), 8.23 (s, 1H), 7.96 (d, J=9.2 Hz , 1H), 7.59 (kv, J=8.3 Hz, 1H), 7.52-7.18 (m, 8H), 6.99 (d, J=8.2 Hz, 1H), 5 .13 (d, J=3.8 Hz, 1H), 4.57 (d, J=9.4 Hz, 1H), 4.48-4.32 (m, 3H), 4.23 (d, J=5.5 Hz, 1H), 4.19 (t, J=5.1 Hz, 2H), 3.86-3.57 (m, 6H), 3.19-3.06 (m, 2H ), 2.61 (m, 1H), 2.43 (s, 3H), 2.43-2.37 (m, 1H), 2.08-2.00 (m, 1H), 1.95- 1.87 (m, 1H), 1.80-1.69 (m, 2H), 0.94 (s, 9H), 0.95 (t, 3H). ¹³ C-NMR (151 MHz, DMSO) δ 180.64, 171.95, 169.97, 169.57, 159.10, 156.03 (dd, J=246.6, 6.9 Hz), 152 .34 (dd, J=249.6, 8.4 Hz), 151.42, 148.97, 147.72, 144.17, 139.67, 139.50, 138.81, 131.46, 131 ,17, 130.28, 129.64, 128.94 - 128.71 (m), 128.64, 127.42, 127.17, 121.98 (dd, J=13.6, 3.4 Hz ), 119.57, 118.54 - 117.84 (m), 117.47, 115.72, 113.74, 113.11, 112.53 - 112.23 (m), 68.91, 68, 69, 67.21, 67.13, 58.74, 56.37, 53.46, 41.68, 37.97, 35.70, 35.37, 26.36, 16.86, 15.95, 12.63. LCMS (ESI); m/z [M+H]+: Calc. for C ₅₀ H ₅₆ F ₂ N ₇ O ₉ S ₂ , 1000.3548. 1000.3536 detected.

[0878] Example of the synthesis of compound 217: N1-(4-(3-(2,6-difluoro-3-(propylsulfonamido)-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl) -N5-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3 -dimethyl-1-oxobutan-2-yl)glutaramide

[0879] To a solution of 5-((4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amino)- 5-oxopentanoic acid (9.7 mg, 0.02 mmol) and (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4- (4-methyl-thiazol-5-yl)phenyl]-methyl]pyrrolidine-2-carboxamide hydrochloride (8.52 mg, 0.02 mmol) in DMF (1 ml) was added at room temperature with TEA (0.1 ml, 0.72 mmol) and RuBOR (9.5 mg, 0.02 mmol). The reaction mixture was stirred for 4 hours at the same temperature. TLC meth (DCM:MeOH:NH ₄ OH, 90:9:1) revealed the absence of starting materials. The reaction mixture was diluted with EtOAc (10 ml) and washed with brine (5 ml, 4×), the organic phase was dried (Na ₂ SO ₄ ) and evaporated under vacuum. The crude product was purified by preparative TLC (DCM:MeOH:NH40H, 90:9:1, 2×) to obtain 4.8 mg of product (29% yield). ^1H -NMR (500 MHz, DMSO- _d6 ) δ 10.02 (s, 1H), 8.97 (s, 1H), 8.68 (d, 1H), 8.64-8.52 (m , 2H), 8.21 (s, 1H), 7.95 (d, J=9.2 Hz, 1H), 7.72 (dd, J=36.7, 8.5 Hz, 4H), 7 .62-7.54 (m, 1H), 7.40 (dd, 4H), 7.28 (t, J=8.7 Hz, 1H), 5.16 (d, 2H), 4.56 ( d, J=9.3 Hz, 1H), 4.50-4.40 (m, 2H), 4.40-4.33 (m, 1H), 4.22 (dd, J=15.8, 5.3 Hz, 1H), 3.76-3.62 (m, 2H), 3.16-3.05 (m, 2H), 2.44 (s, 3H), 2.41-2.17 (m, 4H), 2.09-2.01 (m, 1H), 1.98-1.80 (m, 3H), 1.74 (d. sq., J=14.9, 7.4 Hz , 2H), 0.96 (s, 9H), 0.95 (t, 3H). ¹³ C-NMR (151 MHz, DMSO) δ 181.06, 172.39, 172.17, 171.46, 170.15, 156.37 (dd, J=246.6, 6.3 Hz), 152 .73 (dd, J=249.4, 8.1 Hz), 151.86, 149.05, 148.13, 144.19, 139.91, 139.37, 139.13, 132.97, 131 .64, 131.59, 130.05, 129.22 (d, J=14.7 Hz), 129.06, 127.84, 127.74, 126.89, 122.47 (d, J=14 ,1 Hz), 120.07, 119.02-118.20 (m), 117.95, 116.06, 112.75 (dd, J=23.4, 2.8 Hz), 69.34, 59.15, 56.90, 56.81, 53.87, 42.08, 38.38, 36.36, 35.63, 34.63, 26.85, 21.91, 17.27, 16, 37, 13.04. LCMS (ESI); m/z [M+H]+: Calc. for C ₅₀ H ₅₅ F ₂ N ₈ O ₈ S ₂ , 997.3552. 997.3524 discovered.

[0880] Synthesis example of compound 218: (2S,4R)-1-((S)-2-(5-(4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo [2,3-b]pyridin-5-yl)piperazin-1-yl)-5-oxopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl) benzyl)-pyrrolidine-2-carboxamide

[0881] To a solution of 5-(4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)piperazin-1-yl) -5-oxopentanoic acid (9.3 mg, 0.02 mmol) and (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4 -(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide hydrochloride (8.27 mg, 0.018 mmol) in DMF (1 ml) was added TEA (0.1 ml, 0.72 mmol) at room temperature ) and RuBOR (9.22 mg, 0.018 mmol). The reaction mixture was stirred for 4 hours at the same temperature. The absence of starting materials was detected by TLC (DCM:MeOH:NH ₄ OH, 90:9:1). The reaction mixture was diluted with EtOAc (10 ml) and washed with brine (5 ml, 4×), the organic phase was dried (Na ₂ SO ₄ ) and evaporated under vacuum. The TLC method did not detect the product in the crude mixture, but only a certain amount of the starting material (the product is soluble in water). The aqueous extracts were lyophilized overnight and the solid was filtered using (DCM:MeOH:NH ₄ OH, 90:9:1, 30 ml). The filtrate was evaporated to dryness and the crude product was purified by preparative TLC (DCM:MeOH:NH4OH, 90:9:1, 2×) to obtain 13 mg of product (81% yield). ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 12.64 (bs, 1H), 9.74 (bs, 1H), 8.97 (s, 1H), 8.62-8 .52 (m, 3H), 8.28 (d, J=2.0 Hz, 1H), 8.00 (s, 1H), 7.95 (broad s, 1H), 7.90 (d, J=9.2 Hz, 1H), 7.59-7.49 (m, 1H), 7.47-7.27 (m, 4H), 7.20 (t, J=8.7 Hz, 1H ), 5.13 (b. s, 1H), 4.56 (d, J=9.3 Hz, 1H), 4.48-4.32 (m, 3H), 4.22 (dd, J= 15.8, 5.3 Hz, 1H), 3.75-3.57 (m, 5H), 3.23-3.02 (m, 7H), 2.44 (s, 3H), 2.41 -2.17 (m, 4H), 2.07-2.01 (m, 1H), 1.96-1.87 (m, 1H), 1.81-1.66 (m, 4H), 0 .95 (s, 9H), 0.94 (t, 3H). ¹³ C-NMR (151 MHz, DMSO) δ 180.70, 171.99, 171.92, 170.44, 169.75, 155.24 (dd, J=248.1, 5.5 Hz), 152 .12 (dd, J=248.8, 8.5 Hz), 151.47, 147.73, 144.63, 144.31, 139.52, 138.02, 137.75, 131.19, 129 ,65, 128.65, 127.98 - 127.64 (m), 127.44, 123.91 - 123.09 (m), 118.86 - 117.72 (m), 117.60, 115, 50, 115.23, 112.02 (dd, J=22.6, 3.2 Hz), 68.92, 58.74, 56.47, 56.43, 53.44, 50.31, 50, 18, 48.63, 44.86, 41.68, 41.00, 37.99, 34.28, 31.80, 26.43, 21.36, 16.99, 15.97, 12.72. LCMS (ESI); m/z [M+H]+: Calc. for C ₄₈ H ₅₈ F ₂ N ₉ O ₈ S ₂ , 990.3817. 990.3889 discovered.

[0882] Synthesis example of compound 219: (2S,4R)-1-((S)-2-(4-(4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo [2,3-b]pyridin-5-yl)piperazin-1-yl)-4-oxobutanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N(4-(4-methylthiazol-5-yl)benzyl )-pyrrolidine-2-carboxamide

[0883] To a solution of 4-(4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)piperazin-1-yl) -4-oxobutanoic acid (9 mg, 0.016 mmol) and (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4- methylthiazol-5-yl)phenyl]-methyl]pyrrolidine-2-carboxamide hydrochloride (8.2 mg, 0.018 mmol) in DMF (1 ml) was added with TEA (0.1 ml, 0.72 mmol) and RuBOP at room temperature (9.14 mg, 0.018 mmol). The reaction mixture was stirred for 12 hours (overnight) at the same temperature. The absence of starting materials was detected by TLC (DCM:MeOH:NH ₄ OH, 90:9:1). The reaction mixture was evaporated to dryness. The crude product was filtered through a silica gel carbonate cartridge (100 mg) using DCM:MeOH (9:1) as eluent. The filtrate was evaporated in vacuo and the crude product was purified by preparative TLC (DCM:MeOH:NH ₄ OH, 90:9:1, 2×) to obtain 11 mg of product (75% yield). ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 12.66 (bs, 1H), 9.45 (bs, 1H), 8.98 (s, 1H), 8.60 (bs .s, 1H), 8.29 (s, 1H), 8.04 (s, 1H), 8.01-7.88 (m, 2H), 7.62-7.49 (m, 1H), 7.40 (kv, J=8.0 Hz, 4H), 7.26 (t, J=8.8 Hz, 1H), 5.15 (d, J=3.5 Hz, 1H), 4, 54 (d, J=9.3 Hz, 1H), 4.49-4.31 (m, 3H), 4.22 (dd, J=16.1, 5.6 Hz, 1H), 3.81 -3.53 (m, 6H), 3.26-3.03 (m, 6H), 2.73-2.52 (m, 3H), 2.44 (s, 3H), 2.42-2 .33 (m, 1H), 2.09-1.98 (m, 1H), 1.95-1.84 (m, 1H), 1.74 (kV, J=7.5 Hz, 2H), 0.96 (t, 3H), 0.94 (s, 9H). ¹³ C-NMR (126 MHz, DMSO) δ 180.45, 172.02, 171.35, 170.07, 169.64, 156.00 (dd, J=245.9, 6.5 Hz), 152 .34 (dd, J=249.7, 8.3 Hz), 151.52, 147.75, 144.70, 144.30, 139.55, 138.08, 137.91, 131.22, 129 ,66, 128.69, 128.53 (d, J=2.4 Hz), 127.46, 121.96 (d, J=14.1 Hz), 118.61 - 117.82 (m), 117.60, 115.44, 115.20, 112.32 (dd, J=23.0, 3.3 Hz), 68.95, 58.78, 56.50, 56.39, 53.46, 50.25, 50.13, 44.76, 41.69, 41.17, 37.99, 35.43, 30.18, 28.05, 26.44, 16.89, 16.00, 12, 67. LCMS (ESI); m/z [M+H]+: Calc. for C ₄₇ H ₅₆ F ₂ N ₉ O ₈ S ₂ , 976.3661. 976.3712 discovered.

[0884] Synthesis example of compound 220: N1-(4-(3-(2,6-difluoro-3-(propylsulfonamido)-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl) -N4-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3 -dimethyl-1-oxobutan-2-yl)-succinamide. To a solution of 4-((4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amino)-4-oxobutane acid (15 mg, 0.03 mmol) and (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methylthiazol- 5-yl)phenyl]methyl]pyrrolidine-2-carboxamide hydrochloride (13.51 mg, 0.03 mmol) in DMF (1 ml) was added at room temperature with TEA (0.1 ml, 0.72 mmol) and RuBOP ( 15.05 mg, 0.03 mmol). The reaction mixture was stirred for 4 hours at the same temperature. The absence of starting materials was detected by TLC (DCM:MeOH:NH ₄ OH, 90:9:1). The reaction mixture was evaporated to dryness under high vacuum. The crude product was filtered through a silica gel carbonate cartridge (100 mg) using DCM:MeOH (9:1) as eluent. The filtrate was evaporated in vacuo and the crude product was purified by preparative TLC (DCM:MeOH:NH ₄ OH, 90:9:1, 2×) to obtain 12 mg of product (~85% purity). This product was again purified by preparative TLC (DCM:MeOH, 9:1) to obtain 8 mg of product (31% yield). ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 12.97 (bs, 1H), 10.11 (s, 1H), 9.79 (bs, 1H), 8.98 (d , J=2.3 Hz, 0H), 8.69 (s, 1H), 8.66-8.49 (m, 2H), 8.23 (s, 1H), 8.02 (d, J= 9.0 Hz, 1H), 7.84-7.64 (m, 4H), 7.63-7.53 (m, 1H), 7.51-7.33 (m, 4H), 7.29 (t, J=8.4 Hz, 1H), 5.17 (s, 1H), 4.56 (d, J=7.8 Hz, 1H), 4.50-4.39 (m, 2H) , 4.40-4.31 (m, 1H), 4.26-4.16 (m, 1H), 3.66 (kV, J=10.1 Hz, 2H), 3.19-3.06 (m, 2H), 2.72-2.52 (m, 4H), 2.44 (s, 3H), 2.12-1.97 (m, 1H), 1.96-1.84 (m , 1H), 1.74 (d. sq., J=13.2, 8.3, 7.3 Hz, 2H), 0.96 (t, 3H), 0.95 (s, 9H). ¹³ C-NMR (126 MHz, DMSO) δ 180.66, 172.02, 171.24, 170.67, 169.64, 156.05 (dd, J=246.9, 7.0 Hz), 152 .37 (dd, J=249.3, 8.1 Hz), 151.49, 148.66, 147.75, 143.82, 139.53, 139.00, 138.70, 132.54, 131 ,27, 131.22, 129.68, 129.22 - 128.38 (m), 128.69, 127.47, 127.39, 126.53, 121.99 (dd, J=12.9, 4.5 Hz), 119.59, 118.72 - 117.87 (m), 117.57, 115.68, 112.90 - 112.05 (m), 68.95, 58.79, 56, 56, 56.41, 53.51, 41.71, 37.98, 35.45, 31.98, 30.14, 26.43, 16.88, 15.99, 12.65. LCMS (ESI); m/z [M+H]+: Calc. for C ₄₉ H ₅₃ F ₂ N ₈ O ₈ S ₂ , 983.3395. 983.3569 discovered.

[0885] Example of the synthesis of compound 221: N1-(4-(3-(2,6-difluoro-3-(propylsulfonamido)-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl) -N3-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3 -dimethyl-1-oxobutan-2-yl)-malonamide. To a solution of 3-((4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amino)-3-oxopropane acid (16.8 mg, 0.03 mmol) and (2S,4N)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4- methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide hydrochloride (15.5 mg, 0.033 mmol) in DMF (1 ml) was added at room temperature with TEA (0.1 ml, 0.72 mmol) and RuBOP ( 17.28 mg, 0.033 mmol). The reaction mixture was stirred for 12 hours (overnight) at the same temperature. The absence of starting materials was detected by TLC (DCM:MeOH:NH ₄ OH, 90:9:1). The reaction mixture was evaporated to dryness under high vacuum. The crude product was filtered through a silica gel carbonate cartridge (100 mg) using DCM:MeOH (9:1) as eluent. The filtrate was evaporated in vacuo, and the crude product was purified by preparative TLC (DCM:MeOH:NH ₄ OH, 90:9:1, 2×), and the product was purified again by preparative TLC (DCM:MeOH, 9:1) to obtain 19.5 mg of product (yield 67%). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.96 (bs, 1H), 10.23 (s, 1H), 9.75 (bs, 1H), 8.97 (s , 1H), 8.69 (s, 1H), 8.66-8.51 (m, 2H), 8.26 (d, J=9.1 Hz, 1H), 8.22 (s, 1H) , 7.73 (dd, J=8.5 Hz, 4H), 7.59 (kv, J=8.6 Hz, 1H), 7.41 (dd, J=8.0 Hz, 4H), 7 .28 (t, J=8.7 Hz, 1H), 5.16 (d, 1H), 4.59 (d, J=9.2 Hz, 1H), 4.52-4.33 (m, 3H), 4.24 (dd, J=15.7, 5.0 Hz, 1H), 3.68 (kv, J=10.6 Hz, 2H), 3.44 (kv, 2H), 3, 20-3.05 (m, 2H), 2.45 (s, 3H), 2.10-2.01 (m, 1H), 1.96-1.89 (m, 1H), 1.74 ( d. kv, J=14.8, 7.3 Hz, 2H), 0.98 (s, 9H), 0.97 (t, J=8.3 Hz, 3H). ¹³ C-NMR (101 MHz, DMSO) δ 180.62, 171.91, 169.34, 166.16, 166.03, 156.02 (dd, J=246.8, 7.1 Hz), 152 .34 (dd, J=249.4, 8.1 Hz), 151.43, 148.69, 147.73, 143.79, 139.50, 138.69, 138.54, 132.98, 131 ,17, 131.13, 129.68, 129.11 - 128.65 (m), 128.67, 128.01, 127.45, 126.53, 122.21 - 121.73 (m), 119 ,70, 118.63 - 117.89 (m), 117.54, 115.66, 112.35 (dd, J=23.5, 3.0 Hz), 68.93, 58.79, 56, 66, 56.52, 53.49, 44.32, 41.70, 37.97, 35.60, 26.33, 16.85, 15.96, 12.62. LCMS (ESI); m/z [M+H]+: Calc. for C ₄₈ H ₅₁ F ₂ N ₈ O ₈ S ₂ , 969.3239. 969.3272 discovered.

[0886] Synthesis example of compound 222: (2S,4R)-1-((S)-2-(3-(4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo [2,3-b]pyridin-5-yl)piperazin-1-yl)-3-oxopropanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl) benzyl)-pyrrolidine-2-carboxamide. To a solution of 3-(4-(3-(2,6-difluoro-3-(propylsulfonamido)-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)piperazin-1-yl)-3 -oxopropanoic acid (12.5 mg, 0.02 mmol) and (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-( 4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide hydrochloride (11.69 mg, 0.03 mmol) in DMF (1 ml) was added TEA (0.1 ml, 0.72 mmol) at room temperature ) and RuBOR (13.02 mg, 0.03 mmol). The reaction mixture was stirred for 12 hours (overnight) at the same temperature. The absence of starting materials was detected by TLC (DCM:MeOH:NH ₄ OH, 90:9:1). The reaction mixture was evaporated to dryness. The crude product was filtered through a silica gel carbonate cartridge (100 mg) using DCM:MeOH (9:1) as eluent. The filtrate was evaporated in vacuo and the crude product was purified by preparative TLC (MeOH:DCM, 1:9, 2×) to obtain 14.1 mg of product (64% yield). ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 12.71 (bs, 1H), 9.74 (bs, 1H), 8.98 (s, 1H), 8.59 (t , J=5.7 Hz, 1H), 8.29 (s, 1H), 8.26 (d, J=9.1 Hz, 1H), 8.03 (s, 1H), 7.96 (b .s, 1H), 7.57 (kv, J=7.4, 6.3 Hz, 1H), 7.41 (dd, J=8.0 Hz, 4H), 7.26 (t, J= 8.7 Hz, 1H), 5.22-5.05 (m, 1H), 4.58 (d, J=9.3 Hz, 1H), 4.51-4.32 (m, 3H), 4.23 (dd, J=15.8, 5.3 Hz, 1H), 3.67 (kv, J=12.3, 10.6 Hz, 8H), 3.52 (dd, J=53, 7, 15.5 Hz, 2H), 3.27-3.05 (m, 6H), 2.45 (s, 3H), 2.09-2.00 (m, 1H), 1.96-1 .86 (m, 1H), 1.74 (hex, J=7.3 Hz, 2H), 0.97 (s, 9H)., 0.96 (t, 3H). ¹³ C-NMR (101 MHz, DMSO) δ 180.41, 171.91, 169.38, 166.32, 166.06, 156.01 (dd, J=246.5, 6.7 Hz), 152 .34 (dd, J=249.2, 8.3 Hz), 151.44, 147.73, 144.60, 144.28, 139.50, 138.06, 137.84, 131.17, 129 ,66, 128.75 (d, J=8.0 Hz), 128.65, 127.43, 121.86 (dd, J=13.5, 3.5 Hz), 118.34 (m), 117.58, 115.42, 115.18, 112.28 (dd, J=23.1, 3.5 Hz), 68.89, 58.75, 56.54, 56.43, 53.49, 50.10, 45.56, 41.68, 41.19, 40.95, 37.95, 35.52, 26.36, 16.85, 15.96, 12.62. LCMS (ESI); m/z [M+H]+: Calc. for C ₄₆ H ₅₄ F ₂ N ₉ O ₈ S ₂ , 962.3504. 962.3694 discovered.

[0887] Example of the synthesis of compound 294: (E)-2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(4-(1-(hydroxyimino)-2,3-dihydro- 1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)-[1,3'-biazetidin]-1'-yl)isoindolin-1,3- dione

[0888] Step A: tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)azetidine-1-carboxylate

[0889] A mixture of tert-butyl-3-iodazetidine-1-carboxylate (2.8 g, 12.6 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- yl)phenol (3.9 g, 13.8 mmol) and K ₂ CO ₃ (3.5 g, 25.2 mmol) in anhydrous DMF (20 ml) were stirred at 80°C overnight. After cooling to room temperature, DCM (50 ml) and water (25 ml) were added. The layers were separated and the organic phase was washed with water and brine. The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (PE:EA=9:1) to obtain the target product (2.4 g, 65% yield).

[0890] Step B: tert-butyl 3-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)-azetidine-1-carboxylate

[0891] To a solution of tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)azetidine-1-carboxylate (2.4 g, 6.4 mmol) and 4-(4-bromo-1H-pyrazol-3-yl)-pyridine (1.71 g, 7.68 mmol) in DCM (20 ml) was added Et ₂ NH (4.7 g, 64 mmol) and Cu(OAc) ₂ (1.75 g, 9.6 mmol). The resulting mixture was stirred at 30°C for 16 hours in an O ₂ atmosphere. The mixture was diluted with DCM (30 ml), and the mixture was washed with aqueous ammonia (10 ml x 3). The organic phase was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM/MeOH=20/1) to obtain tert-butyl-3-(4-(4-bromo-3-(pyridin-4-yl) -1H-pyrazol-1-yl)phenoxy)-azetidine-1-carboxylate (1.5 g, 50% yield) as a brown oil. LCMS (ES ⁺ ): m/z 471 [M+H] ⁺ .

[0892] Step C: 4-(1-(4-(azetidin-3-yloxy)phenyl)-4-bromo-1H-pyrazol-3-yl)pyridine

[0893] To a solution of tert-butyl-3-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)-azetidine-1-carboxylate (700 mg) in DCM (3 ml) was added with 3 M HCl in 1,4-dioxane (3 ml). The resulting solution was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to give the crude title product (600 mg, crude). LCMS (ES ⁺ ): m/z 371 [M+H] ⁺ .

[0894] Step D: tert-butyl-3-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)-[1,3'-biazetidine]- 1'-carboxylate

[0895] To a solution of 4-(1-(4-(azetidin-3-yloxy)phenyl)-4-bromo-1H-pyrazol-3-yl)pyridine (50 mg, 0.14 mmol) and tert-butyl- 3-oxoazetidine-1-carboxylate (48 mg, 0.28 mmol) in DCE (1.0 ml) was added AcOH (1 drop) and NaBH(OAc) ₃ (74 mg, 0.35 mmol). The resulting solution was stirred at 30°C overnight. The mixture was diluted with ethyl acetate (5 ml), and the mixture was washed three times with aq. _NaHCO3 . The organic phase was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (PE/EA = 1/1) to obtain tert-butyl-3-(4-(4-bromo-3-(pyridin-4-yl) -1H-pyrazol-1-yl)-phenoxy)-[1,3'-biazetidine]-1'-carboxylate (30 mg, 42% yield) as a brown oil. LCMS (ES ⁺ ): m/z 526 [M+H] ⁺ .

[0896] Step E: 5-(3-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)-[1,3'-biazetidine]-1 '-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0897] To a solution of tert-butyl-3-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)-[1,3'-biazetidine]-1 '-carboxylate (160 mg) in DCM (2 ml) was added 3 M HCl in 1,4-dioxane (1 ml). The resulting solution was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to give the desired product (150 mg, crude). To a solution of 3-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)-1,3'-biazetidine (7.0 mg, 0.0165 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (9.0 mg, 0.033 mmol) in NMP (1.0 ml) DIPEA (1 drop) was added. The resulting solution was stirred at 130°C for 1 hour under N ₂ atmosphere. After cooling to RT, the mixture was diluted with ethyl acetate (3 ml), and the mixture was washed twice with brine. The organic phase was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (DCM/MeOH=15/1) to give 5-(3-(4-(4-bromo-3-(pyridin-4-yl)- 1H-pyrazol-1-yl)-phenoxy)-[1,3'-biazetidin]-1'-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (4 mg , yield 36%). LCMS (ES ⁺ ): m/z 682 [M+H] ⁺ .

[0898] Step F: 2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(4-(1-oxo-2,3-dihydro-1H-inden-5-yl) -3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)-[1,3'-biazetidin]-1'-yl)isoindolin-1,3-dione

[0899] To a solution of 5-(3-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)-[1,3'-biazetidine]-1' -yl)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (200 mg, 0.29 mmol) in 1,4-dioxane/H ₂ O (v/v = 10/1, 5 ml) 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one (83 mg, 0.32 mmol), Pd ₂ (dba) ₃ (110 mg, 0.12 mmol), CsF (176 mg, 1.20 mmol), [(t-Bu) ₃ PH]BF ₄ (68 mg, 0.12 mmol) and N,N-dicyclohexylmethylamine (2.9 mg, 0.015 mmol). The resulting solution was heated to 100°C for 2 hours under N ₂ atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (10 ml), and the mixture was washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to give 2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(4-(1-oxo-2,3-dihydro-1H-inden-5-yl )-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)-[1,3'-biazetidin]-1'-yl)isoindolin-1,3-dione (90 mg, yield 41 .9%) as a yellow solid. LCMS (ES ⁺ ): m/z 733 [M+H] ⁺ .

[0900] Step G: (E)-2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(4-(1-(hydroxyimino)-2,3-dihydro-1H- inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)-[1,3'-biazetidine]-1'-yl)isoindolin-1,3-dione

[0901] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(4-(1-oxo-2,3-dihydro-1H-inden-5-yl)- 3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)-[1,3'-biazetidin]-1'-yl)isoindolin-1,3-dione (90 mg, 0.12 mmol ) in acetonitrile/pyridine (v/v = 1/1, 6.0 ml) was added hydroxylamine hydrochloride (83.4 mg, 1.2 mmol). The mixture was stirred at 40°C for 20 minutes. After quenching by adding DCM (20 ml), the mixture was washed with saline (10 ml x 2). The organic phase was concentrated in vacuo and the residue was purified by preparative TLC to give (E)-2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(4-(1-(hydroxyimino) -2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)-[1,3'-biazetidin]-1'-yl )isoindoline-1,3-dione (25 mg, 27% yield) as a yellow solid.

[0902] ¹ H-NMR (400 MHz, CDCl ₃ ): δ 11.06 (s, 1H), 10.89 (s, 1H), 8.73 (s, 1H), 8.57 (d, J =4.8 Hz, 2H), 7.87 (d, J=8.8 Hz, 2H), 7.65 (d, J=8.0 Hz, 1H), 7.56 (d, J=8 ,0 Hz, 1H), 7.48 (d, J=4.8 Hz, 2H), 7.40 (s, 1H), 7.22 (d, J=8.0 Hz, 1H), 7, 03 (d, J=8.8 Hz, 2H), 6.80 (s, 1H), 6.68 (d, J=8.4 Hz, 1H), 5.02-5.07 (m, 1H ), 4.96 (t, J=2.4 Hz, 1H), 4.09 (t, J=8.4 Hz, 2H), 3.80-3.87 (m, 4H), 3.73 (s, 1H), 3.22 (s, 4H), 3.01 (d, J=5.2 Hz, 2H), 2.84 (d, J=5.6 Hz, 2H), 2.01 (d, J=9.2 Hz, 2H); LCMS (ES ⁺ ): m/z 748.79 [M+H] ⁺ .

[0903] Example of the synthesis of compound 226: (2S,4R)-1-((S)-2-(2-(4-((4-(4-(3-(2,6-difluoro-3-(( R)-3-fluoropyrrolidin-1-sulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-piperazin-1-yl)methyl)piperidin-1-yl)acetamido)- 3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0904] Step A: tert-butyl-2-(4-formylpiperidin-1-yl)acetate

[0905] To a solution of tert-butyl-2-(4-(hydroxymethyl)piperidin-1-yl)acetate (1.5 g, 6.55 mmol) in CH ₃ CN (10 ml) was added IBX (2.7 g , 9.85 mmol). The resulting solution was stirred at 80°C for 5 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (30 ml), and the solution was washed with sodium sulfite and sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate. The organic phase was concentrated under vacuum conditions. The residue was purified by silica gel chromatography (PE:EA=5:1) to obtain the target tert-butyl-2-(4-formylpiperidin-1-yl)acetate (350 mg, 25% yield) as a yellow oil. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 9.64 (s, 1H), 3.12 (s, 2H), 2.85-2.89 (m, 2H), 2.31-2, 37 (m, 2H), 2.20-2.26 (m, 1H), 1.89-1.93 (m, 2H), 1.74-1.77 (m, 2H), 1.47 ( s, 9H).

[0906] Step B: tert-butyl-2-(4-((4-(4-bromophenyl)piperazin-1-yl)methyl)piperidin-1-yl)acetate

[0907] To a solution of tert-butyl-2-(4-formylpiperidin-1-yl)acetate (370 mg, 1.54 mmol) and 1-(4-bromophenyl)piperazine (350 mg, 1.54 mmol) in CH ₃ OH/DCM (v/v = 1/1, 10 ml) cat. was added at room temperature. AcOH (0.1 ml). After stirring for 30 minutes, NaBH(OAc) ₃ (1.3 g, 6.17 mmol) was added. The mixture was stirred at 30°C for 1 hour. After quenching by adding aq. NaHCO ₃ (20 ml), the mixture was extracted with DCM (10 ml x 3). The combined organic layer was washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified on silica gel (DCM:MeOH=50:1) to give tert-butyl-2-(4-((4-(4-bromophenyl)piperazin-1-yl)methyl)piperidin-1-yl)acetate (330 mg, yield 47%) as a yellow oil. LCMS (ES ⁺ ): m/z 454.2 [M+H] ⁺ .

[0908] Step C: tert-butyl-2-(4-((4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1 -yl)methyl)piperidin-1-yl)acetate

[0909] To a solution of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (242 mg, 0.951 mmol) and tert-butyl-2-(4-((4-(4-bromophenyl)piperazin-1-yl)methyl)-piperidin-1-yl)-acetate (330 mg, 0.732 mmol) in 1,4-dioxane (5 ml) KOAc (145 mg, 1.46 mmol) and Pd(dppf)Cl ₂ (54 mg, 0.0732 mmol) were added. After stirring at 90°C overnight under nitrogen, the reaction mixture was diluted with 30 ml ethyl acetate, and the solution was washed with brine (10 ml x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified on silica gel (DCM:MeOH=100:3) to obtain the target tert-butyl-2-(4-((4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)acetate (100 mg, 27% yield) as a yellow solid. LCMS (ES ⁺ ): m/z 499.4 [M+H] ⁺ .

[0910] Step D: (R)-tert-butyl-2-(4-((4-(4-(3-(2,6-difluoro-3-(3-fluoropyrrolidine-1-sulfonamido)benzoyl)- 1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-1-yl)methyl)-piperidin-1-yl)acetate

[0911] To a solution of tert-butyl-2-(4-((4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1- yl)methyl)piperidin-1-yl)acetate (100 mg, 0.199 mmol) in H ₂ O/dioxane (v/v = 1/5, 5.0 ml) was added CsF (121 mg, 0.796) at room temperature mmol), Pd(aMPhos)Cl ₂ (14 mg, 0.0199 mmol) and (R)-N-(3-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)- 2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (100 mg, 0.199 mmol). The solution was purged with N ₂ at room temperature for 10 minutes to remove excess O ₂ . The resulting solution was stirred at 100°C for 4 hours. After cooling to room temperature, the reaction mixture was taken up in EtOAc. The combined organic layers were concentrated in vacuo. The residue was purified by preparative TLC (DCM:CH ₃ OH=20:1) to obtain the target (R)-tert-butyl-2-(4-((4-(4-(3-(2,6-difluoro-3 -(3-fluoropyrrolidin-1-sulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)acetate (50 mg, yield 32%) as a light yellow solid. LCMS (ES ⁺ ): m/z 797.6 [M+H] ⁺ .

[0912] Step E: (R)-2-(4-((4-(4-(3-(2,6-difluoro-3-(3-fluoropyrrolidine-1-sulfonamido)-benzoyl)-1H-pyrrolo [2,3-b]pyridin-5-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)acetic acid

[0913] To a solution of (R)-tert-butyl-2-(4-((4-(4-(3-(2,6-difluoro-3-(3-fluoropyrrolidine-1-sulfonamido)benzoyl)-1H -pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-1-yl)methyl)-piperidin-1-yl)acetate (50 mg, 0.0629 mmol) in DCM (1 ml) added TFA (0.5 ml). The resulting solution was stirred for 2 hours at room temperature. The solvent was removed under vacuum. The yellow solid residue was the target (R)-2-(4-((4-(4-(3-(2,6-difluoro-3-(3-fluoropyrrolidine-1-sulfonamido)benzoyl)-1H -pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-1-yl)methyl)-piperidin-1-yl)acetic acid (80 mg, crude). LCMS (ES ⁺ ): m/z 740.2 [M+H] ⁺ .

[0914] Stage G: (2S,4R)-1-((S)-2-(2-(4-((4-(4-(3-(2,6-difluoro-3-((R) -3-fluoropyrrolidin-1-sulfonamido)benzoyl)-1H-pyrrolo[2,3-]pyridin-5-yl)phenyl)piperazin-1-yl)methyl)-piperidin-1-yl)acetamido)-3,3 -dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0915] To a solution of (R)-2-(4-((4-(4-(3-(2,6-difluoro-3-(3-fluoropyrrolidine-1-sulfonamido)-benzoyl)-1H-pyrrolo[ 2,3-b]pyridin-5-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-acetic acid (47 mg, 0.0629 mmol) in DCM (5.0 ml) at room temperature temperature, DIEA (25 mg, 0.189 mmol), (2S,4R)-1-((S)-2-((l3-chloranyl)diazenyl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4 -(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (30 mg, 0.0691 mmol) and RuBOR (40 mg, 0.0755 mmol). The resulting solution was stirred at 20°C for 1 hour. The reaction mixture was quenched by adding H ₂ O (10 ml), and the mixture was extracted with DCM (20 ml x 3). The combined organic layer was concentrated in vacuo. The residue was purified by preparative TLC (OSM:CH ₃ OH=10:1) to obtain the target (2S,4R)-1-((S)-2-(2-(4-((4-(4-(3- (2,6-difluoro-3-((R)-3-fluoropyrrolidin-1-sulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-1-yl)methyl )piperidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidin-2-carboxamide (33 mg) as a white solid substances. ¹ H-NMR (400 MHz, CD ₃ OD): δ 8.77 (s, 1H), 8.59 (s, 1H), 8.49 (s, 1H), 7.79 (s, 1H), 7.61-7.69 (m, 1H), 7.49 (d, J=8.8 Hz, 2H), 7.31-7.39 (m, 4H), 6.98-7.04 ( m, 3H), 5.18 (s, 0.5H), 5.02 (s, 0.5H), 4.56 (s, 1H), 4.41-4.53 (m, 2H), 4 .22-4.29 (m, 1H), 3.76-3.81 (m, 1H), 3.68-3.73 (m, 1H), 3.23-3.52 (m, 4H) , 3.16 (s, 4H), 2.94 (s, 2H), 2.90 (s, 1H), 2.72-2.81 (m, 2H), 2.50 (broad, 4H) , 2.38 (s, 3H), 1.92-2.20 (m, 10H), 1.66-1.79 (m, 2H), 0.95 (s, 9H); LCMS (ES ⁺ ): m/z 1154.3 [M+H] ⁺ .

[0916] Example of the synthesis of compound 227: (2S,4R)-1-((S)-2-(2-(4-((1-(4-(3-(2,6-difluoro-3-(( R)-3-fluoropyrrolidin-1-sulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-piperidin-4-yl)methyl)piperazin-1-yl)acetamido)- 3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0917] Step A: 1-(4-bromophenyl)piperidine-4-carbaldehyde

[0918] To a solution of 1-(4-bromophenyl)-4-(dimethoxymethyl)piperidine (1 g, 3.18 mmol) in MeCN (10 ml) was added hydrochloric acid (3N). The resulting solution was stirred at 50°C for 4 hours. After cooling to room temperature, the mixture was adjusted to pH 8~9 by adding aq. _NaHCO3 . The reaction mixture was diluted with 30 ml of ethyl acetate, and the mixture was washed with sodium sulfite and sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under vacuum conditions. The yellow solid residue was the desired 1-(4-bromophenyl)piperidine-4-carbaldehyde (1 g crude). LCMS (ES ⁺ ): m/z 268.0 [M+H] ⁺ .

[0919] Step B: tert-butyl 4-((1-(4-bromophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate

[0920] To a solution of 1-(4-bromophenyl)piperidine-4-carbaldehyde (1 g, crude) and tert-butylpiperazine-1-carboxylate (590 mg, 3.18 mmol) in CH ₃ OH/DCM (vol. /vol. = 1/1, 10 ml) cat. was added at room temperature. AcOH (0.1 ml). After stirring for 30 minutes, NaBH(OAc) ₃ (2.7 g, 12.7 mmol) was added. The resulting solution was stirred at 30°C overnight. After quenching by adding aq. NaHCO ₃ (20 ml), the mixture was extracted with DCM (10 ml x 3). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified on silica gel with PE/EA (8/1) to give tert-butyl 4-((1-(4-bromophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (800 mg) as yellow oils LCMS (ES ⁺ ): m/z 440.2 [M+H] ⁺ .

[0921] Step C: tert-butyl-2-(4-((1-(4-bromophenyl)piperidin-4-yl)methyl)piperazin-1-yl)acetate

[0922] To a solution of tert-butyl-4-((1-(4-bromophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (800 mg, 1.83 mmol) in DCM (4 ml) was added TFA (2 ml). The resulting solution was stirred for 2 hours at room temperature. The solvent was removed under vacuum to obtain the crude title product (1 g, crude), which was used directly in the next step. To a solution of the crude product obtained above (500 g, crude) and tert-butyl-2-bromoacetate (176 mg, 0.913 mmol) in anhydrous DMF (5 ml) was added K ₂ CO ₃ (190 mg, 1.37 mmol). The resulting solution was stirred at room temperature overnight. The reaction mixture was diluted with 40 ml of ethyl acetate, and the mixture was washed with water and brine. The organic phase was dried over anhydrous sodium sulfate. The yellow oil residue was the desired tert-butyl-2-(4-((1-(4-bromophenyl)piperidin-4-yl)methyl)piperazin-1-yl)acetate (410 mg, crude). LCMS (ES ⁺ ): m/z 453.2 [M+H] ⁺ .

[0923] Step D: tert-butyl-2-(4-((1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-4 -yl)methyl)piperazin-1-yl)acetate

[0924] To a solution of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (300 mg, 1.18 mmol ) and tert-butyl-2-(4-((1-(4-bromophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-acetate (410 mg, 0.913 mmol) in 1,4-dioxane ( 5 ml) KOAc (178 mg, 1.82 mmol) and Pd(dppf)Cl ₂ (67 mg, 0.0913 mmol) were added. After stirring at 90°C overnight under nitrogen, the reaction mixture was diluted with 30 ml ethyl acetate, and the solution was washed with brine (10 ml x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified on silica gel with DCM/MeOH (100/3) to obtain the target tert-butyl-2-(4-((1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)acetate (200 mg, crude) as a yellow solid. LCMS (ES ⁺ ): m/z 500.4 [M+H] ⁺ .

[0925] Step E: (R)-tert-butyl-2-(4-((1-(4-(3-(2.b-difluoro-3-(3-fluoropyrrolidine-1-sulfonamido)benzoyl)- 1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidin-4-yl)methyl)-piperazin-1-yl)acetate

[0926] To a solution of tert-butyl-2-(4-((1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl)piperidin-4 -yl)methyl)piperazin-1-yl)acetate (200 mg, crude) in H ₂ O/dioxane (v/v = 1/5, 5.0 ml) was added CsF (121 mg, 0.796 mmol), Pd(aMPhos)Cl ₂ (14 mg, 0.0199 mmol) and (R)-N-(3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl) -2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (100 mg, 0.199 mmol). The solution was purged with N ₂ at room temperature for 10 minutes to remove excess O ₂ . The resulting solution was stirred at 100°C for 4 hours. After cooling to room temperature, the reaction mixture was taken up in EtOAc. The combined organic layers were concentrated in vacuo. The residue was purified by preparative TLC (DCM/CH ₃ OH 20/1) to obtain the target (R)-tert-butyl-2-(4-((1-(4-(3-(2,6-difluoro-3- (3-fluoropyrrolidin-1-sulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)acetate (110 mg, yield 69%) as a light yellow solid. LCMS (ES ⁺ ): m/z 796.3 [M+H] ⁺ .

[0927] Stage F: (2S,4R)-1-((S)-2-(2-(4-((1-(4-(3-(2,6-difluoro-3-((R) -3-fluoropyrrolidin-1-sulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidin-4-yl)methyl)-piperazin-1-yl)acetamido)-3, 3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0928] To a solution of (R)-tert-butyl-2-(4-((1-(4-(3-(2,6-difluoro-3-(3-fluoropyrrolidine-1-sulfonamido)benzoyl)-1H -pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidin-4-yl)methyl)-piperazin-1-yl)acetate (110 mg, 0.139 mmol) in DCM (3 ml) added TFA (1 .5 ml). The resulting solution was stirred at room temperature for 2 hours. The solvent was removed under vacuum to obtain the crude title product (180 mg, crude), which was used directly in the next step. To a solution of the above acid (180 mg, crude) in DMF (5.0 mL) was added DIEA (54 mg, 0.418 mmol), (2S,4R)-1-((S)-2-(( 13-chloranyl)diazenyl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)-pyrrolidine-2-carboxamide (66 mg, 0.153 mmol) and RuBOP ( 87 mg, 0.167 mmol). The resulting solution was stirred at 20°C for 1 hour. After quenching by adding H ₂ O (10 ml), the mixture was extracted with ethyl acetate (20 ml x 3). The combined organic layer was concentrated in vacuo. The residue was purified by preparative HPLC to give the title product (42 mg) as a yellow solid. ^1H -NMR (400 MHz, MeOD- _d4 ): δ 8.89 (s, 1H), 8.70 (s, 1H), 8.61 (s, 1H), 7.91 (s, 1H) , 7.71-7.80 (m, 1H), 7.60 (d, J=8.4 Hz, 2H), 7.43-7.50 (m, 4H), 7.12-7.16 (m, 3H), 5.23 (s, 0.5H), 5.18 (s, 0.5H), 4.95 (m, 4H), 4.56 (s, 1H), 4.53- 4.66 (m, 4H), 4.35-4.41 (m, 1H), 3.79-3.90 (m, 4H), 3.44-3.60 (m, 6H), 3. 08-3.19 (m, 2H), 2.72-2.81 (m, 10H), 2.50 (s, 3H), 2.03-2.25 (m, 5H), 1.87- 1.92 (m, 3H), 1.52-1.63 (m, 2H), 1.04 (s, 9H); LCMS (ES ⁺ ): m/z 1101.3 [M+H] ⁺ .

[0929] Synthesis example of compound 295: (2S,4R)-1-((3)-2-(2-(4-((4-(4-(3-(2,6-difluoro-3-(( (3S,4S)-3-fluoro-4-hydroxypyrrolidine)-1-sulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-1-yl)methyl)piperidin- 1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0930] Step A: (3S,4S)-3-[(tert-butyldiphenylsilyl)oxy]-4-fluoropyrrolidine

[0931] In a 50 mL round bottom flask, place (3S,4S)-4-fluoropyrrolidin-3-ol (500 mg, 4.76 mmol, 1 equiv.), dichloromethane (10 mL), imidazole (323.8 mg, 4.76 mmol, 1 equiv.) and TBDPSC1 (1307.5 mg, 4.76 mmol, 1 equiv.). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated. The residue was applied to a silica gel column, eluting with dichloromethane/methanol (10/1). This resulted in 470 mg (29%) of (3S,4S)-3-[(tert-butyldiphenylsilyl)oxy]-4-fluoropyrrolidine as a yellow oil.

[0932] Step B: (3S,4S)-3-[(tert-butyldiphenylsilyl)oxy]-4-fluoropyrrolidine-1-sulfonyl chloride

[0933] Place (3S,4S)-3-[(tert-butyldiphenylsilyl)oxy]-4-fluoropyrrolidine (370 mg, 1 equiv.), dichloromethane (5 mL), diisopropylethylamine (279 mg, 1 equiv.) into a 50 mL round bottom flask. 2 equiv.) and dichlorosulfoxide (290 mg, 2 equiv.). The resulting solution was stirred for 4 hours at -30°C. Then, the reaction mixture was quenched by adding water (20 ml). The resulting solution was extracted with dichloromethane (20 ml x 3). The resulting mixture was washed with saline (20 ml×1), dried over anhydrous sodium sulfate and concentrated. This resulted in 450 mg of (3S,4S)-3-[(tert-butyldiphenylsilyl)oxy]-4-fluoropyrrolidine-1-sulfonyl chloride as a yellow oil.

[0934] Step C: (3S,4S)-N-(3-[5-bromo-1H-pyrrolo[2,3-b]pyridin-3-carbonyl]-2,4-difluorophenyl)-3-[( tert-butyldiphenylsilyl)oxy]-4-fluoropyrrolidine-1-sulfonamide

[0935] Place (3S,4S)-3-[(tert-butyldiphenylsilyl)oxy]-4-fluoropyrrolidine-1-sulfonyl chloride (449.4 mg, 1.02 mmol, 2.00) into a 25 mL round bottom flask. equiv.), pyridine (0.7 ml), 3-[5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoroaniline (179 mg, 0.51 mmol, 1 equiv.) and dimethylaminopyridine (18.6 mg, 0.15 mmol, 0.30 equiv.). The resulting solution was stirred for 3 hours at 45°C in an oil bath. The resulting mixture was concentrated. The residue was applied to a silica gel column, eluting with ethyl acetate/petroleum ether (1/1). This resulted in 120 mg (31%) of (3S,4S)-N-(3-[5-bromo-1H-pyrrolo[2,3-b]pyridin-3-carbonyl]-2,4-difluorophenyl)- 3-[(tert-butyldiphenylsilyl)oxy]-4-fluoropyrrolidine-1-sulfonamide as a yellow oil.

[0936] Step D: Synthesis of tert-butyl-2-(4-[[4-(4-[3-[3-([[(3S,4S)-3-[(tert-butyldiphenylsilyl)oxy] -4-fluoropyrrolidin-1-yl]sulfonyl]amino)-2,6-difluorobenzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl)piperazin-1-yl]methyl]piperidine

[0937] Place (3S,4S)-N-(3-[5-bromo-1H-pyrrolo[2,3-b]pyridin-3-carbonyl]-2,4-difluorophenyl)- into a 50 mL round bottom flask. 3-[(tert-butyldiphenylsilyl)-oxy]-4-fluoropyrrolidine-1-sulfonamide (120 mg, 0.16 mmol, 1 equiv.), 1,4-dioxane (5 ml, 0.06 mmol), water ( 0.0 ml, 0.06 mmol), tert-butyl-2-[4-([4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl]piperazin-1-yl]methyl)piperidin-1-yl]acetate (79.1 mg, 0.16 mmol, 1 equiv.), Na ₂ CO ₃ (50.4 mg, 0.48 mmol, 3 equiv. .) and Pd(dppf)Cl ₂ (39 mg). The resulting solution was stirred for 2 hours at 110°C in an oil bath. The resulting mixture was concentrated. The residue was applied to a silica gel column, eluting with dichloromethane/methanol (10/1). This resulted in 90 mg (54%) tert-butyl-2-(4-[[4-(4-[3-[3-([[(3S,4S)-3-[(tert-butyldiphenylsilyl)oxy ]-4-fluoropyrrolidin-1-yl]-sulfonyl]amino)-2,6-difluorobenzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl)piperazin-1-yl]methyl]piperidine in the form of a yellow oil.

[0938] Step E: Synthesis of 2-(4-[[4-(4-[3-[3-([[(3S,4S)-3-[(tert-butyldiphenylsilyl)oxy]-4-fluoropyrrolidine-1 -yl]sulfonyl]amino)-2,6-difluorobenzoyl1-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl)piperazin-1-yl]methyl]piperidin-1-yl)acetic acid

[0939] Place tert-butyl-2-(4-[[4-(4-[3-[3-([[(3S,4S)-3-[(tert-butyldiphenylsilyl)oxy) into a 25 mL round bottom flask ]-4-fluoropyrrolidin-1-yl]sulfonyl]-amino)-2,6-difluorobenzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl)piperazin-1-yl]methyl]piperidine (90 mg, 0.09 mmol, 1 equiv.), dichloromethane (5 ml) and trifluoroacetic acid (2 ml, 0.02 mmol).The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. This resulted in 60 mg (70.43%) of 2-(4-[[4-(4-[3-[3-([[(3S,4S)-3-[(tert-butyldiphenylsilyl)oxy]- 4-fluoropyrrolidin-1-yl]sulfonyl]amino)-2,6-difluorobenzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl)piperazin-1-yl]methyl]-piperidin-1 -yl)acetic acid as a yellow solid.

[0940] Step F: Synthesis of 2-(4-[[4-(4-[3-[2,6-difluoro-3-([[(3S,4S)-3-fluoro-4-hydroxypyrrolidine-1- yl]sulfonyl]amino)benzoyl]-1H-pyrrolo[2,3-b]iridin-5-yl]phenyl)piperazin-1-yl]methyl]piperidin-1-yl)acetic acid

[0941] Place 2-(4-[[4-(4-[3-[3-([[(3S,4S)-3-[(tert-butyldiphenylsilyl)oxy]-4-) into a 25 mL round bottom flask. fluoropyrrolidin-1-yl]sulfonyl]amino)-2,6-difluorobenzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl)piperazin-1-yl]methyl]-piperidin-1-yl )acetic acid (60 mg, 0.06 mmol, 1 equiv.), tetrahydrofuran (3 ml) and TBAF (1 ml, 0.06 equiv.). The resulting solution was stirred for 2 hours at 40°C. The resulting mixture was concentrated under reduced pressure. The residue was applied to a silica gel column, eluting with dichloromethane/methanol (10/1). This resulted in 50 mg (109.62%) of 2-(4-[[4-(4-[3-[2,6-difluoro-3-([[(3S,4S)-3-fluoro-4 -hydroxypyrrolidin-1-yl]sulfonyl]amino)benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl)piperazin-1-yl]methyl]piperidin-1-yl)acetic acid in the form yellow oil.

[0942] Stage G: (2S,4R)-1-((S)-2-(2-(4-((4-(4-(3-(2,6-difluoro-3-(((3S ,4S)-3-fluoro-4-hydroxypyrrolidine)-1-sulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-piperazin-1-yl)methyl)piperidine-1 -yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0943] Place 2-(4-[[4-(4-[3-[2,6-difluoro-3-([[(3S,4S)-3-fluoro-4-hydroxypyrrolidine) into a 25 mL round bottom flask -1-yl]sulfonyl]amino)benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl)piperazin-1-yl]methyl]piperidin-1-yl)acetic acid (50 mg, 0.066 mmol, 1 equiv.), DMF (5 ml), (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 (30.8 mg, 0.066 mmol, 1 equiv.), diisopropylethylamine (34.1 mg, 0.264 mmol, 4.00 equiv. .) and BOR (35 mg, 0.079 mmol, 1.2 equiv.). The resulting solution was stirred for 3 hours at room temperature. Then, the reaction mixture was quenched by adding water (30 ml), extracted with dichloromethane (30 ml x 3), washed with water (30 ml) and concentrated under reduced pressure. The crude product was purified by preparative HPLC. This resulted in 32.6 mg (42%) of (2S,4R)-1-((S)-2-(2-(4-((4-(4-(3-(2,6-difluoro- 3-(((3S,4S)-3-fluoro-4-hydroxypyrrolidine)-1-sulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-piperazin-1-yl )methyl)piperidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidin-2-carboxamide as a yellow solid. ¹ H-NMR (400 MHz, CD ₃ OD): δ 8.87 (s, 1H), 8.69 (s, 1H), 8.58 (s, 1H), 7.89 (s, 1H), 7.73-7.72 (m, 1H), 7.58 (d, J=8.8 Hz, 2H), 7.48-7.40 (m, 4H), 7.10-7.05 ( m, 3H), 4.93 (s, 1H), 4.63 (s, 1H), 4.57 (d, J=6 Hz, 1H), 4.52-4.50 (m, 1H), 4.38-4.34 (m, 2H), 3.87-3.86 (m, 1H), 3.82-3.81 (m, 1H), 3.57-3.50 (m, 3H ), 3.36-3.33 (m, 1H), 3.31-3.20 (m, 5H), 3.02 (s, 2H), 3.01-2.90 (m, 2H), 2.56 (s, 3H), 2.74 (s, 3H), 2.26-2.20 (m, 4H), 2.10-2.01 (m, 1H), 1.82-1.71 ( m, 2H), 1.67-1.61 (m, 3H), 1.44-1.28 (m, 2H), 1.05-1.02 (m, 9H); LCMS (ES ⁺ ): m/z 1168.30 [M+H] ⁺ .

[0944] Synthesis example of compound 298: (2S,4R)-1-((S)-2-(2-(4-(3-(2,6-difluoro-3-propylsulfonamido)benzoyl)-1H-pyrrolo[ 2,3-b]pyridin-5-yl)phenoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)-pyrrolidine-2-carboxamide

[0945] To a solution of 2-[4-[3-[2,6-difluoro-3-(propylsulfonylamino)benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenoxy]acetic acid (10 .8 mg, 0.02 mmol) and (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5 -yl)-phenyl]-methyl]pyrrolidine-2-carboxamide hydrochloride (9.5 mg, 0.02 mmol) in DMF (1 ml) at room temperature was added TEA (0.1 ml, 0.717 mmol) and RuBOP (11 mg, 0.021 mmol). The reaction mixture was stirred for 4 hours at the same temperature. The absence of starting materials was detected by TLC (DCM:MeOH:NH ₄ OH, 90:9:1). DMF was removed under high vacuum conditions. The crude product was filtered through a silica gel carbonate cartridge (100 mg) using DCM:MeOH (90:10) as eluent. The filtrate was evaporated in vacuo and the crude product was purified by preparative TLC (DCM:MeOH:NH ₄ OH, 90:9:1) to obtain 8.5 mg of product (44% yield). ^1H -NMR (500 MHz, DMSO- _d6 ) δ 12.88 (s, 1H), 9.67 (s, 1H), 8.98 (s, 1H), 8.76-8.50 (m , 3H), 8.23 (s, 1H), 7.98 (d, J=9.4 Hz, 1H), 7.69 (d, J=8.6 Hz, 2H), 7.59 (td , J=9.0, 5.8 Hz, 1H), 7.49-7.34 (m, 4H), 7.33-7.20 (m, 1H), 7.10 (d, J=8 .7 Hz, 2H), 5.20 (d, J=3.3 Hz, 1H), 4.72 (s, 2H), 4.62 (d, J=9.4 Hz, 1H), 4.54- 4.34 (m, 3H), 4.25 (dd, J=15.9, 5.5 Hz, 1H), 3.74-3.59 (m, 2H), 3.19-3.07 ( m, 2H), 2.44 (s, 3H), 2.07 (dd, J=12.9, 7.7 Hz, 1H), 1.91 (ddd, J=12.8, 8.8, 4.5 Hz, 1H), 1.80-1.65 (m, 2H), 0.96 (s, 9H), 0.94 (t, 3H). ¹³ C-NMR (151 MHz, DMSO) δ 180.62, 171.82, 169.13, 167.11, 157.51, 156.02 (dd, J=246.1, 7.0 Hz), 152 .34 (dd, J=249.6, 8.5 Hz), 151.45, 148.60, 147.74, 143.80, 139.47, 138.70, 131.16, 129.70, 129 .00 - 128.42 (m), 128.81, 128.69, 128.31, 128.00, 127.48, 126.53, 121.96 (dd, J=13.6, 3.5 Hz ), 118.61 - 117.85 (m), 117.53, 115.63, 115.34, 112.34 (dd, J=22.4, 3.4 Hz), 68.91, 66.58 , 58.80, 56.58, 56.17, 53.45, 41.69, 37.95, 35.79, 26.28, 16.85, 15.96, 12.63. LCMS (ESI); m/z [M+H]+: Calc. for C ₄₇ H ₅₀ F ₂ N ₇ O ₈ S ₂ , 942.3130. 942.3134 discovered.

[0946] Synthesis example of compound 299: (2S,4R)-1-((S)-2-(4-(3-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo [2,3-b]pyridin-5-yl)phenoxy)butanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0947] To a solution of 4-[3-[3-[2,6-difluoro-3-(propylsulfonylamino)benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenoxy]butanoic acid (18 mg, 0.03 mmol) and (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl )phenyl]methyl]-pyrrolidine-2-carboxamide hydrochloride (16.8 mg, 0.036 mmol) in DMF (2 ml) was added with TEA (0.1 ml, 0.72 mmol) and RuBOP (18.48 mg) at room temperature , 0.04 mmol). The reaction mixture was stirred for 4 hours at the same temperature. The absence of starting materials was detected by TLC (DCM:MeOH:NH ₄ OH, 90:9:1). DMF was removed under high vacuum conditions (the product may be partially soluble in water). The crude product was filtered through a silica gel carbonate cartridge using DCM:MeOH (9:1) as eluent. The filtrate was evaporated in vacuo and the crude product was purified by preparative TLC (DCM:MeOH:NH ₄ OH, 90:9:1) followed by repurification by preparative TLC (DCM:MeOH, 9:1) to obtain 8 mg of product ( yield 25%). ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 12.97 (b s, 1H), 9.72 (b s, 1H), 8.97 (s, 1H), 8.71 (d , J=2.1 Hz, 1H), 8.61 (s, 2H), 8.56 (t, J=6.0 Hz, 2H), 8.23 (s, 1H), 7.99 (d , J=9.3 Hz, 1H), 7.59 (td, J=9.0, 5.9 Hz, 1H), 7.50-7.16 (m, 8H), 6.98 (d, J=8.2 Hz, 1H), 5.13 (d, J=3.4 Hz, 1H), 4.58 (d, J=9.3 Hz, 1H), 4.48-4.40 ( m, 2H), 4.35 (s, 1H), 4.22 (dd, J=15.9, 5.5 Hz, 1H), 4.08 (ddt, J=9.6, 7.1, 3.2 Hz, 2H), 3.74-3.62 (m, 2H), 3.15-3.06 (m, 2H), 2.50-2.45 (m, 1H), 2.44 (s, 3H), 2.41-2.33 (m, 1H), 2.09-1.86 (m, 4H), 1.79-1.67 (m, 2H), 0.97 (t , 3H), 0.94 (s, 9H). ¹³ C-NMR (151 MHz, DMSO) δ 181.05, 172.38, 172.05, 170.09, 159.63, 156.44 (dd, J=246.5, 6.8 Hz), 152 .74 (dd, J=249.6, 8.6 Hz), 151.86, 149.36, 148.13, 140.05, 139.92, 139.24, 131.87, 131.59, 130 .71, 130.05, 129.20 (t, J=5.0 Hz), 129.06, 127.84, 127.52, 122.37 (dd, J=13.5, 3.5 Hz) , 119.87, 118.95 - 118.24 (m), 117.88, 116.11, 114.12, 113.60, 112.91 - 112.65 (m), 69.32, 67.53 , 59.14, 56.88, 56.83, 53.86, 42.08, 38.38, 35.67, 31.76, 26.80, 25.52, 17.26, 16.37, 13 .04. LCMS (ESI); m/z [M+H] ⁺ : Calc. for C ₄₉ H ₅₄ F ₂ N ₇ O ₈ S ₂ , 970.3443. 970.3787 discovered.

[0948] Synthesis Example of Compound 300: (2S,4R)-1-((S)-2-(2-(2-(3-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)- 1H-pyrrolo[2,3-b]pyridin-5-yl)phenoxy)ethoxy)-acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl )-pyrrolidine-2-carboxamide

[0949] To a solution of 2-[2-[3-[3-[2,6-difluoro-3-(propylsulfonylaminobenzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenoxy]ethoxy]acetic acid (19.1 mg, 0.03 mmol) and (2S,4R)-l-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4- methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide hydrochloride (17.11 mg, 0.04 mmol) in DMF (2 ml) was added at room temperature with TEA (0.1 ml, 0.72 mmol) and RuBOP (19.06 mg, 0.04 mmol). The reaction mixture was stirred for 2 hours at the same temperature. The absence of starting materials was detected by TLC (DCM:MeOH:NH ₄ OH, 90:9:1). Under high conditions DMF was removed under vacuum (the product may be partially soluble in water). The crude product was filtered through a silica gel carbonate cartridge using DCM:MeOH (9:1) as eluent. The filtrate was evaporated under vacuum, and the crude product was purified by preparative TLC ( DCM:MeOH:NH ₄ OH, 90:9:1) to give 13 mg of product (40% yield): ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.95 (br s, 1H), 9.74 (wide) s, 1H), 8.91 (s, 1H), 8.67 (d, J=2.0 Hz, 1H), 8.55 (dd, J=12.8, 6.8 Hz, 2H), 8.19 (s, 1H), 7.56 (td, J=9.0, 6.0 Hz, 1H), 7.49 (d, J=9.5 Hz, 1H), 7.42-7 .20 (m, 8H), 7.07-7.00 (m, 1H), 5.13 (d, J=3.5 Hz, 1H), 4.58 (d, J=9.6 Hz, 1H), 4.44 (t, J=8.1 Hz, 1H), 4.36 (dd, J=15.8, 6.2 Hz, 2H), 4.30-4.16 (m, 3H ), 4.06 (s, 2H), 3.86 (t, J=4.3 Hz, 2H), 3.13-3.04 (m, 2H), 2.37 (s, 3H), 2 .07-1.99 (m, 1H), 1.94-1.83 (m, 1H), 1.78-1.64 (m, 2H), 0.94 (t, 3H), 0.93 (s, 9H). ¹³ C-NMR (126 MHz, DMSO) δ 181.03, 172.20, 169.60, 168.98, 159.52, 156.46 (dd, J=246.7, 7.1 Hz), 152 .75 (dd), 151.81, 149.36, 148.14, 144.59, 140.08, 139.80, 139.21, 131.85, 131.56, 130.66, 130.08, 129.62 - 128.89 (m), 129.08, 127.82, 122.38 (dd, J=13.5, 3.6 Hz), 120.09, 118.98 - 118.30 ( m), 117.89, 116.15, 114.40, 113.50, 112.78 (dd, J=22.9, 3.8 Hz), 70.05, 70.00, 69.34, 67 .49, 59.18, 57.04, 56.16, 53.89, 42.12, 38.34, 36.22, 26.65, 17.28, 16.32, 13.05. LCMS (ESI); m/z [M+H] ⁺ : Calc. for C ₄₉ H ₅₄ F ₂ N ₇ O ₉ S ₂ , 986.3392. 986.3679 discovered.

[0950] Example of the synthesis of compound 217: N1-(4-(3-(2,6-difluoro-3-(propylsulfonamido)-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl) -N5-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3 -dimethyl-1-oxobutan-2-yl)glutaramide

[0951] To a solution of 5-((4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amino)- 5-oxopentanoic acid (9.7 mg, 0.02 mmol) and (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4- (4-methylthiazol-5-yl)phenyl]methyl]-pyrrolidine-2-carboxamide hydrochloride (8.52 mg, 0.02 mmol) in DMF (1 ml) was added at room temperature with TEA (0.1 ml, 0. 72 mmol) and RuBOR (9.5 mg, 0.02 mmol). The reaction mixture was stirred for 4 hours at the same temperature. The absence of starting materials was detected by TLC (DCM:MeOH:NH ₄ OH, 90:9:1). The reaction mixture was diluted with EtOAc (10 ml) and washed with brine (5 ml, 4×), the organic phase was dried (Na ₂ SO ₄ ) and evaporated under vacuum. The crude product was purified by preparative TLC (DCM:MeOH:NH ₄ OH, 90:9:1) to obtain 4.8 mg of product (29% yield). ^1H -NMR (500 MHz, DMSO- _d6 ) δ 10.02 (s, 1H), 8.97 (s, 1H), 8.68 (d, 1H), 8.64-8.52 (m , 2H), 8.21 (s, 1H), 7.95 (d, J=9.2 Hz, 1H), 7.72 (dd, J=36.7, 8.5 Hz, 4H), 7 .62-7.54 (m, 1H), 7.40 (dd, 4H), 7.28 (t, J=8.7 Hz, 1H), 5.16 (d, 2H), 4.56 ( d, J=9.3 Hz, 1H), 4.50-4.40 (m, 2H), 4.40-4.33 (m, 1H), 4.22 (dd, J=15.8, 5.3 Hz, 1H), 3.76-3.62 (m, 2H), 3.16-3.05 (m, 2H), 2.44 (s, 3H), 2.41-2.17 (m, 4H), 2.09-2.01 (m, 1H), 1.98-1.80 (m, 3H), 1.74 (d. sq., J=14.9, 7.4 Hz , 2H), 0.96 (s, 9H), 0.95 (t, 3H). ¹³ C-NMR (151 MHz, DMSO) δ 181.06, 172.39, 172.17, 171.46, 170.15, 156.37 (dd, J=246.6, 6.3 Hz), 152 .73 (dd, J=249.4, 8.1 Hz), 151.86, 149.05, 148.13, 144.19, 139.91, 139.37, 139.13, 132.97, 131 .64, 131.59, 130.05, 129.22 (d, J=14.7 Hz), 129.06, 127.84, 127.74, 126.89, 122.47 (d, J=14 ,1 Hz), 120.07, 119.02 - 118.20 (m), 117.95, 116.06, 112.75 (dd, J=23.4, 2.8 Hz), 69.34, 59.15, 56.90, 56.81, 53.87, 42.08, 38.38, 36.36, 35.63, 34.63, 26.85, 21.91, 17.27, 16, 37, 13.04. LCMS (ESI); m/z [M+H] ⁺ : Calc. for C ₅₀ H ₅₅ F ₂ N ₈ O ₈ S ₂ , 997.3552. 997.3524 discovered.

[0952] Synthesis example of compound 218: (2S,4R)-1-((S)-2-(5-(4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo [2,3-b]pyridin-5-yl)piperazin-1-yl)-5-oxopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl) benzyl)pyrrolidine-2-carboxamide

[0953] To a solution of 5-(4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)piperazin-1-yl) -5-oxopentanoic acid (9.3 mg, 0.02 mmol) and (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4 -(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide hydrochloride (8.27 mg, 0.018 mmol) in DMF (1 ml) was added TEA (0.1 ml, 0.72 mmol) at room temperature ) and RuBOR (9.22 mg, 0.018 mmol). The reaction mixture was stirred for 4 hours at the same temperature. The absence of starting materials was detected by TLC (DCM:MeOH:NH ₄ OH, 90:9:1). The reaction mixture was diluted with EtOAc (10 ml) and washed with brine (5 ml, 4×), the organic phase was dried (Na ₂ SO ₄ ) and evaporated under vacuum. By TLC, no product was detected in the crude mixture, but only a small amount of the starting material VHL (4) (the product is soluble in water). The aqueous extracts were lyophilized overnight and the solid was filtered using DCM:MeOH:NH ₄ OH (90:9:1, 30 ml). The filtrate was evaporated to dryness and the crude product was purified by preparative TLC (DCM:MeOH:NH ₄ OH, 90:9:1) to obtain 13 mg of product (81% yield). ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 12.64 (bs, 1H), 9.74 (bs, 1H), 8.97 (s, 1H), 8.62-8 .52 (m, 3H), 8.28 (d, J=2.0 Hz, 1H), 8.00 (s, 1H), 7.95 (br s, 1H), 7.90 (d, J=9.2 Hz, 1H), 7.59-7.49 (m, 1H), 7.47-7.27 (m, 4H), 7.20 (t, J=8.7 Hz, 1H ), 5.13 (b s, 1H), 4.56 (d, J=9.3 Hz, 1H), 4.48-4.32 (m, 3H), 4.22 (dd, J= 15.8, 5.3 Hz, 1H), 3.75-3.57 (m, 5H), 3.23-3.02 (m, 7H), 2.44 (s, 3H), 2.41 -2.17 (m, 4H), 2.07-2.01 (m, 1H), 1.96-1.87 (m, 1H), 1.81-1.66 (m, 4H), 0 .95 (s, 9H), 0.94 (t, 3H). ¹³ C-NMR (151 MHz, DMSO) δ 180.70, 171.99, 171.92, 170.44, 169.75, 155.24 (dd, J=248.1, 5.5 Hz), 152 .12 (dd, J=248.8, 8.5 Hz), 151.47, 147.73, 144.63, 144.31, 139.52, 138.02, 137.75, 131.19, 129 ,65, 128.65, 127.98 - 127.64 (m), 127.44, 123.91 - 123.09 (m), 118.86 - 117.72 (m), 117.60, 115, 50, 115.23, 112.02 (dd, J=22.6, 3.2 Hz), 68.92, 58.74, 56.47, 56.43, 53.44, 50.31, 50, 18, 48.63, 44.86, 41.68, 41.00, 37.99, 34.28, 31.80, 26.43, 21.36, 16.99, 15.97, 12.72. LCMS (ESI); m/z [M+H] ⁺ : Calc. for C ₄₈ H ₅₈ F ₂ N ₉ O ₈ S ₂ , 990.3817. 990.3889 discovered.

[0954] Synthesis example of compound 219: (2S,4R)-1-((S)-2-(4-(4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo [2,3-b]pyridin-5-yl)piperazin-1-yl)-4-oxobutanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl) benzyl)-pyrrolidine-2-carboxamide

[0955] K 4-(4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)piperazin-1-yl)- 4-oxobutanoic acid (9 mg, 0.016 mmol) and (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methylthiazole -5-yl)phenyl]methyl]-pyrrolidine-2-carboxamide hydrochloride (8.2 mg, 0.018 mmol) in DMF (1 ml) was added at room temperature with TEA (0.1 ml, 0.72 mmol) and RuBOP ( 9.14 mg, 0.018 mmol). The reaction mixture was stirred for 12 hours (overnight) at the same temperature. The absence of starting materials was detected by TLC (DCM:MeOH:NH ₄ OH, 90:9:1). The reaction mixture was evaporated to dryness. The crude product was filtered through a silica gel carbonate cartridge (100 mg) using DCM:MeOH (9:1) as eluent. The filtrate was evaporated in vacuo and the crude product was purified by preparative TLC (DCM:MeOH:NH ₄ OH, 90:9:1) to obtain 11 mg of product (75% yield). ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 12.66 (bs, 1H), 9.45 (bs, 1H), 8.98 (s, 1H), 8.60 (bs .s, 1H), 8.29 (s, 1H), 8.04 (s, 1H), 8.01-7.88 (m, 2H), 7.62-7.49 (m, 1H), 7.40 (kv, J=8.0 Hz, 4H), 7.26 (t, J=8.8 Hz, 1H), 5.15 (d, J=3.5 Hz, 1H), 4, 54 (d, J=9.3 Hz, 1H), 4.49-4.31 (m, 3H), 4.22 (dd, J=16.1, 5.6 Hz, 1H), 3.81 -3.53 (m, 6H), 3.26-3.03 (m, 6H), 2.73-2.52 (m, 3H), 2.44 (s, 3H), 2.42-2 .33 (m, 1H), 2.09-1.98 (m, 1H), 1.95-1.84 (m, 1H), 1.74 (kV, J=7.5 Hz, 2H), 0.96 (t, 3H), 0.94 (s, 9H). ¹³ C-NMR (126 MHz, DMSO) δ 180.45, 172.02, 171.35, 170.07, 169.64, 156.00 (dd, J=245.9, 6.5 Hz), 152 .34 (dd, J=249.7, 8.3 Hz), 151.52, 147.75, 144.70, 144.30, 139.55, 138.08, 137.91, 131.22, 129 ,66, 128.69, 128.53 (d, J=2.4 Hz), 127.46, 121.96 (d, J=14.1 Hz), 118.61 - 117.82 (m), 117.60, 115.44, 115.20, 112.32 (dd, J=23.0, 3.3 Hz), 68.95, 58.78, 56.50, 56.39, 53.46, 50.25, 50.13, 44.76, 41.69, 41.17, 37.99, 35.43, 30.18, 28.05, 26.44, 16.89, 16.00, 12, 67. LCMS (ESI); m/z [M+H] ⁺ : Calc. for C ₄₇ H ₅₆ F ₂ N ₉ O ₈ S ₂ , 976.3661. 976.3712 discovered.

[0956] Example of the synthesis of compound 220: N ¹ -(4-(3-(2,6-difluoro-3-(propylsulfonamido)-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl )-N ⁴ -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3 ,3-dimethyl-1-oxobutan-2-yl)succinamide

[0957] To a solution of the synthesis product of compound 218 [(2S,4R)-1-((S)-2-(5-(4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H -pyrrolo[2,3-b]pyridin-5-yl)piperazin-1-yl)-5-oxopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)-pyrrolidine-2-carboxamide]; 4-((4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amino)-4-oxobutanoic acid ( 15 mg, 0.03 mmol) and (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5- yl)phenyl]methyl]pyrrolidine-2-carboxamide hydrochloride (13.51 mg, 0.03 mmol) in DMF (1 ml) was added at room temperature with TEA (0.1 ml, 0.72 mmol) and RuBOP (15, 05 mg, 0.03 mmol). The reaction mixture was stirred for 4 hours at the same temperature. The absence of starting materials was detected by TLC (DCM:MeOH:NH ₄ OH, 90:9:1). The reaction mixture was evaporated to dryness under high vacuum. The crude product was filtered through a silica gel carbonate cartridge (100 mg) using DCM:MeOH (9:1) as eluent. The filtrate was evaporated in vacuo and the crude product was purified by preparative TLC (DCM:MeOH:NH ₄ OH, 90:9:1) to obtain 8 mg of product (31% yield). ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 12.97 (bs, 1H), 10.11 (s, 1H), 9.79 (bs, 1H), 8.98 (d , J=2.3 Hz, 0H), 8.69 (s, 1H), 8.66-8.49 (m, 2H), 8.23 (s, 1H), 8.02 (d, J= 9.0 Hz, 1H), 7.84-7.64 (m, 4H), 7.63-7.53 (m, 1H), 7.51-7.33 (m, 4H), 7.29 (t, J=8.4 Hz, 1H), 5.17 (s, 1H), 4.56 (d, J=7.8 Hz, 1H), 4.50-4.39 (m, 2H) , 4.40-4.31 (m, 1H), 4.26-4.16 (m, 1H), 3.66 (kV, J=10.1 Hz, 2H), 3.19-3.06 (m, 2H), 2.72-2.52 (m, 4H), 2.44 (s, 3H), 2.12-1.97 (m, 1H), 1.96-1.84 (m , 1H), 1.74 (d. kv, J=13.2, 8.3, 7.3 Hz, 2H), 0.96 (t, 3H), 0.95 (s, 9H). ¹³ C-NMR (126 MHz, DMSO) δ 180.66, 172.02, 171.24, 170.67, 169.64, 156.05 (dd, J=246.9, 7.0 Hz), 152 .37 (dd, J=249.3, 8.1 Hz), 151.49, 148.66, 147.75, 143.82, 139.53, 139.00, 138.70, 132.54, 131 ,27, 131.22, 129.68, 129.22 - 128.38 (m), 128.69, 127.47, 127.39, 126.53, 121.99 (dd, J=12.9, 4.5 Hz), 119.59, 118.72 - 117.87 (m), 117.57, 115.68, 112.90 - 112.05 (m), 68.95, 58.79, 56, 56, 56.41, 53.51, 41.71, 37.98, 35.45, 31.98, 30.14, 26.43, 16.88, 15.99, 12.65. LCMS (ESI); m/z [M+H] ⁺ : Calc. for C ₄₉ H ₅₃ F ₂ N ₈ O ₈ S ₂ , 983.3395. 983.3569 discovered.

[0958] Synthesis example of compound 221: N1-(4-(3-(2,6-difluoro-3-(propylsulfonamido)-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl) -N3-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3 -dimethyl-1-oxobutan-2-yl)malonamide

[0959] To a solution of 3-((4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amino)- 3-oxopropanoic acid (16.8 mg, 0.03 mmol) and (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4- (4-methylthiazol-5-yl)phenyl]-methyl]pyrrolidine-2-carboxamide hydrochloride (15.5 mg, 0.033 mmol) in DMF (1 ml) was added TEA (0.1 ml, 0.72 mmol) at room temperature ) and RuBOR (17.28 mg, 0.033 mmol). The reaction mixture was stirred for 12 hours (overnight) at the same temperature. The absence of starting materials was detected by TLC (DCM:MeOH:NH ₄ OH, 90:9:1). The reaction mixture was evaporated to dryness under high vacuum. The crude product was filtered through a silica gel carbonate cartridge (100 mg) using DCM:MeOH (9:1) as eluent. The filtrate was evaporated in vacuo and the crude product was purified by preparative TLC (DCM:MeOH:NH ₄ OH, 90:9:1) to obtain 19.5 mg of product (67% yield). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.96 (bs, 1H), 10.23 (s, 1H), 9.75 (bs, 1H), 8.97 (s , 1H), 8.69 (s, 1H), 8.66-8.51 (m, 2H), 8.26 (d, J=9.1 Hz, 1H), 8.22 (s, 1H) , 7.73 (dd, J=8.5 Hz, 4H), 7.59 (kv, J=8.6 Hz, 1H), 7.41 (dd, J=8.0 Hz, 4H), 7 .28 (t, J=8.7 Hz, 1H), 5.16 (d, 1H), 4.59 (d, J=9.2 Hz, 1H), 4.52-4.33 (m, 3H), 4.24 (dd, J=15.7, 5.0 Hz, 1H), 3.68 (kv, J=10.6 Hz, 2H), 3.44 (kv, 2H), 3, 20-3.05 (m, 2H), 2.45 (s, 3H), 2.10-2.01 (m, 1H), 1.96-1.89 (m, 1H), 1.74 ( d. kv, J=14.8, 7.3 Hz, 2H), 0.98 (s, 9H), 0.97 (t, J=8.3 Hz, 3H). ¹³ C-NMR (101 MHz, DMSO) δ 180.62, 171.91, 169.34, 166.16, 166.03, 156.02 (dd, J=246.8, 7.1 Hz), 152 .34 (dd, J=249.4, 8.1 Hz), 151.43, 148.69, 147.73, 143.79, 139.50, 138.69, 138.54, 132.98, 131 ,17, 131.13, 129.68, 129.11 - 128.65 (m), 128.67, 128.01, 127.45, 126.53, 122.21 - 121.73 (m), 119 ,70, 118.63 - 117.89 (m), 117.54, 115.66, 112.35 (dd, J=23.5, 3.0 Hz), 68.93, 58.79, 56, 66, 56.52, 53.49, 44.32, 41.70, 37.97, 35.60, 26.33, 16.85, 15.96, 12.62. LCMS (ESI); m/z [M+H] ⁺ : Calc. for C ₄₈ H ₅₁ F ₂ N ₈ O ₈ S ₂ , 969.3239. 969.3272 discovered.

[0960] Synthesis example of compound 222: (2S,4R)-1-((S)-2-(3-(4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo [2,3-b]pyridin-5-yl)piperazin-1-yl)-3-oxopropanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl) benzyl)-pyrrolidine-2-carboxamide

[0961] To a solution of 3-(4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)piperazin-1-yl) -3-oxopropanoic acid (12.5 mg, 0.02 mmol) and (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4 -(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide hydrochloride (11.69 mg, 0.03 mmol) in DMF (1 ml) was added at room temperature with TEA (0.1 ml, 0. 72 mmol) and RuBOR (13.02 mg, 0.03 mmol). The reaction mixture was stirred for 12 hours (overnight) at the same temperature. The absence of starting materials was detected by TLC (DCM:MeOH:NH ₄ OH, 90:9:1). The reaction mixture was evaporated to dryness. The crude product was filtered through a silica gel carbonate cartridge (100 mg) using DCM:MeOH (9:1) as eluent. The filtrate was evaporated in vacuo and the crude product was purified by preparative TLC (DCM:MeOH:NH ₄ OH, 90:9:1) to obtain 14.1 mg of product (64% yield). ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 12.71 (bs, 1H), 9.74 (bs, 1H), 8.98 (s, 1H), 8.59 (t , J=5.7 Hz, 1H), 8.29 (s, 1H), 8.26 (d, J=9.1 Hz, 1H), 8.03 (s, 1H), 7.96 (b .s, 1H), 7.57 (kv, J=7.4, 6.3 Hz, 1H), 7.41 (dd, J=8.0 Hz, 4H), 7.26 (t, J= 8.7 Hz, 1H), 5.22-5.05 (m, 1H), 4.58 (d, J=9.3 Hz, 1H), 4.51-4.32 (m, 3H), 4.23 (dd, J=15.8, 5.3 Hz, 1H), 3.67 (kv, J=12.3, 10.6 Hz, 8H), 3.52 (dd, J=53, 7, 15.5 Hz, 2H), 3.27-3.05 (m, 6H), 2.45 (s, 3H), 2.09-2.00 (m, 1H), 1.96-1 .86 (m, 1H), 1.74 (hex, J=7.3 Hz, 2H), 0.97 (s, 9H)., 0.96 (t, 3H). ¹³ C-NMR (101 MHz, DMSO) δ 180.41, 171.91, 169.38, 166.32, 166.06, 156.01 (dd, J=246.5, 6.7 Hz), 152 .34 (dd, J=249.2, 8.3 Hz), 151.44, 147.73, 144.60, 144.28, 139.50, 138.06, 137.84, 131.17, 129 ,66, 128.75 (d, J=8.0 Hz), 128.65, 127.43, 121.86 (dd, J=13.5, 3.5 Hz), 118.34 (m), 117.58, 115.42, 115.18, 112.28 (dd, J=23.1, 3.5 Hz), 68.89, 58.75, 56.54, 56.43, 53.49, 50.10, 45.56, 41.68, 41.19, 40.95, 37.95, 35.52, 26.36, 16.85, 15.96, 12.62. LCMS (ESI); m/z [M+H] ⁺ : Calc. for C ₄₆ H ₅₄ F ₂ N ₉ O ₈ S ₂ , 962.3504. 962.3694 discovered.

[0962] Example of the synthesis of compound 301: (2S,4R)-1-((S)-2-(4-(4-(3-(3-butyramido-2,6-difluorobenzoyl)-1H-pyrrolo[2, 3-b]pyridin-5-yl)phenoxy)butanamido)-3,3-dimethyl-butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0963] To a solution of 4-(4-(3-(3-butyramido-2,6-difluorobenzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenoxy)butanoic acid (27 mg, 0 .05 mmol) and (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl] methyl]pyrrolidine-2-carboxamide hydrochloride (26.6 mg, 0.06 mmol) in DMF (2 ml) was added at room temperature with TEA (0.1 ml, 0.72 mmol) and RuBOP (29.64 mg, 0 .06 mmol). The reaction mixture was stirred for 4 hours at the same temperature. The absence of starting materials was detected by TLC (DCM:MeOH:NH ₄ OH, 90:9:1). DMF was removed under high vacuum conditions. The crude product was filtered through a silica gel carbonate cartridge using DCM:MeOH (9:1) as eluent. The filtrate was evaporated in vacuo and the crude product was purified by preparative TLC (DCM:MeOH:NH ₄ OH, 90:9:1) to obtain 37 mg of product (76% yield). ^1H -NMR (400 MHz, DMSO- _d6 ) δ 12.91 (b, s, 1H), 9.79 (s, 1H), 8.97 (s, 1H), 8.65 (d, J =2.2 Hz, 1H), 8.62-8.47 (m, 2H), 8.15 (s, 1H), 8.06-7.89 (m, 2H), 7.67 (d, J=8.7 Hz, 2H), 7.40 (dd, J=8.3 Hz, 4H), 7.23 (t, J=8.8 Hz, 1H), 7.07 (d, J= 8.8 Hz, 2H), 5.14 (d, J=3.5 Hz, 1H), 4.58 (d, J=9.3 Hz, 1H), 4.49-4.40 (m, 2H), 4.37 (bb s, 1H), 4.22 (dd, J=15.9, 5.4 Hz, 1H), 4.03 (t, J=7.2 Hz, 2H), 3.77-3.62 (m, 2H), 2.44 (s, 3H), 2.43-2.30 (m, 4H), 2.09-1.87 (m, 4H), 1. 61 (hex, J=7.4 Hz, 2H), 0.96 (s, 9H), 0.92 (t, J=7.4 Hz, 3H). ¹³ C-NMR (151 MHz, DMSO) δ 180.92, 171.97, 171.67, 171.61, 169.68, 158.33, 154.61 (dd, J=244.6, 7.1 Hz), 151.44, 150.34 (dd, J=248.8, 8.2 Hz), 148.52, 147.72, 143.71, 139.52, 138.48, 131.32, 131 .17, 130.42, 129.64, 128.65, 128.28, 127.43, 126.50, 126.06 (d, J=10.1 Hz), 123.23 (dd, J=12 ,4, 3.6 Hz), 118.47 - 117.44 (m), 117.55, 115.65, 115.18, 111.60 (d, J=25.0 Hz), 68.92, 67.13, 58.74, 56.48, 56.42, 41.67, 37.99, 37.57, 35.26, 31.32, 26.41, 25.07, 18.56, 15, 96, 13.57. LCMS (ESI); m/z [M+H] ⁺ : Calc. for C ₅₀ H ₅₄ F ₂ N ₇ O ₇ S, 934.3773. 934.2690 discovered.

[0964] Example of the synthesis of compound 302: (2S,4R)-1-((S)-2-(4-(4-(3-(3-amino-2,6-difluorobenzoyl)-1H-pyrrolo[2, 3-b]pyridin-5-yl)phenoxy)butanamido)-3,3-dimethyl-butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0965] To a solution of 4-(4-(3-(3-amino-2,6-difluorobenzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenoxy)butanoic acid (11.5 mg , 0.03 mmol) and (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl) phenyl]methyl]pyrrolidine-2-carboxamide hydrochloride (23.79 mg, 0.05 mmol) in DMF (2 ml) was added with TEA (0.1 ml, 0.72 mmol) and RuBOP (14.58 mg) at room temperature , 0.03 mmol). The reaction mixture was stirred for 4 hours at the same temperature. The absence of starting materials was detected by TLC (DCM:MeOH:NH ₄ OH, 90:9:1). DMF was removed under high vacuum conditions. The crude product was filtered through a silica gel carbonate cartridge (1 g) using DCM:MeOH (9:1) as eluent. The filtrate was evaporated in vacuo and the crude product was purified by preparative TLC (MeOH:DCM, 9:1) to obtain 17.5 mg of product (80% yield). ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 12.68 (b s, 1H), 8.97 (s, 1H), 8.64 (d, J=2.2 Hz, 1H), 8.61-8.47 (m, 2H), 8.06 (s, 1H), 8.00 (d, J=9.3 Hz, 1H), 7.65 (d, J=8.6 Hz , 2H), 7.40 (dd, 4H), 7.07 (d, J=8.7 Hz, 2H), 6.99-6.82 (m, 2H), 5.21 (s, 2H) , 5.15 (d, J=3.6 Hz, 1H), 4.58 (d, J=9.3 Hz, 1H), 4.50-4.40 (m, 2H), 4.37 ( broad s, 1H), 4.23 (dd, J=15.8, 5.3 Hz, 1H), 4.10-3.93 (m, 2H), 3.78-3.54 (m, 2H), 2.58-2.26 (m, 2H), 2.44 (s, 3H), 2.11-1.82 (m, 4H), 0.94 (s, 9H). ¹³ C-NMR (126 MHz, DMSO) δ 182.20, 171.97, 171.63, 169.69, 158.31, 151.43,149.20 (dd, J=234.8, 6.5 Hz) , 148.45, 147.72, 146.01 (dd, J=241.2, 7.9 Hz), 143.55, 139.51, 137.92, 133.42 (dd, J=12.9 , 2.4 Hz), 131.18, 130.49, 129.65, 128.65, 128.24, 127.44, 126.47, 118.32 - 117.22 (m), 117.57, 116.91 - 116.23 (m), 115.84, 115.19, 111.36 (dd, J=22.3, 2.9 Hz), 68.92, 67.14, 58.74, 56 .50, 56.41, 41.68, 37.97, 35.25, 31.33, 26.41, 25.07, 15.95. LCMS (ESI); m/z [M+H] ⁺ : Calc. for C ₄₆ H ₄₈ F ₂ N ₇ O ₆ S, 864.3354. 864.3437 discovered.

[0966] Synthesis example of compound 303: (2S,4R)-1-((S)-2-(4-(4-(3-(2,6-difluorobenzoyl)-1H-pyrrolo[2,3-b] pyridin-5-yl)phenoxy)butanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidin-2-carboxamide

[0967] To a solution of 4-(4-(3-(2,6-difluorobenzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenoxy)-butanoic acid (19.4 mg, 0. 04 mmol) and (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl ]pyrrolidine-2-carboxamide hydrochloride (20.76 mg, 0.04 mmol) in DMF (2 ml) at room temperature was added TEA (0.1 ml, 0.72 mmol) and RuBOP (25.45 mg, 0. 05 mmol). The reaction mixture was stirred for 4 hours at the same temperature. The absence of starting materials was detected by TLC (DCM:MeOH:NH ₄ OH, 90:9:1). DMF was removed under high vacuum conditions. The crude product was filtered through a silica gel carbonate cartridge (1 g) using DCM:MeOH (9:1) as eluent. The filtrate was evaporated in vacuo and the crude product was purified by preparative TLC (DCM:MeOH:NH ₄ OH, 90:9:1) to obtain 29 mg of product (77% yield). ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 12.89 (b s, 1H), 8.97 (s, 1H), 8.65 (d, J=1.9 Hz, 1H), 8.62-8.54 (m, 2H), 8.13 (s, 1H), 8.00 (d, J=9.3 Hz, 1H), 7.75-7.55 (m, 3H) , 7.43 (d, J=8.1 Hz, 3H), 7.38 (d, J=8.1 Hz, 2H), 7.28 (t, J=7.9 Hz, 2H), 7 .07 (d, J=8.6 Hz, 2H), 5.15 (d, J=3.3 Hz, 1H), 4.59 (d, J=9.3 Hz, 1H), 4.49 -4.40 (m, 2H), 4.39-4.33 (m, 1H), 4.23 (dd, J=15.9, 5.4 Hz, 1H), 4.09-3.97 (m, 2H), 3.77-3.61 (m, 2H), ¹ H-NMR (500 MHz, DMSO- _d6 ) δ 2.48-2.31 (m, 2H), 2.44 ( s, 3H), 2.11-1.86 (m, 4H), 0.96 (s, 9H). ¹³ C-NMR (151 MHz, DMSO) δ 181.30, 171.97, 171.61, 169.68, 158.80 (dd, J=247.2, 7.9 Hz), 158.33, 151 ,44, 148.52, 147.72, 143.70, 139.51, 138.38, 132.14 (t, J=9.9 Hz), 131.30, 131.17, 130.44, 129 .64, 128.64, 128.27, 127.43, 126.48, 117.76 (t, J=23.3 Hz), 117.54, 115.78, 115.18, 112.29 (dd , J=21.0, 4.2 Hz), 68.92, 67.13, 58.74, 56.48, 56.42, 41.67, 37.98, 35.26, 31.32, 26 ,41, 25.06, 15.96. LCMS (ESI); m/z [M+H] ⁺ : Calc. for C ₄₆ H ₄₇ F ₂ N ₆ O ₆ S, 849.3245. 849.3378 discovered.

[0968] Synthesis example of compound 304: (2S,4R)-1-((S)-2-(4-(4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo [2,3-b]pyridin-5-yl)piperazin-1-yl)butanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine -2-carboxamide

[0969] To a solution of 4-[4-[3-[2,6-difluoro-3-(propylsulfonylamino)benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]piperazin-1-yl] butanoic acid (7.9 mg, 0.01 mmol) and (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4 -methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide hydrochloride (7.38 mg, 0.02 mmol) in DMF (1 ml) was added TEA (0.1 ml, 0.72 mmol) at room temperature and RuBOR (8.23 mg, 0.02 mmol). The reaction mixture was stirred for 12 hours (overnight) at the same temperature. The absence of starting materials was detected by TLC (DCM:MeOH:NH ₄ OH, 90:9:1). The reaction mixture was evaporated to dryness. The crude product was filtered through a silica gel carbonate cartridge (1 g) using DCM:MeOH (9:1) as eluent (washed several times, the product had high affinity for the stationary phase). The filtrate was evaporated in vacuo and the crude product was purified by preparative TLC (DCM:MeOH, 9:1) to obtain 7.2 mg of product (52% yield). ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 12.66 (bs, 1H), 9.73 (bs, 1H), 8.96 (s, 1H), 8.61-8 .50 (m, 1H), 8.25 (s, 1H), 8.00 (s, 1H), 7.93 (br. s, 1H), 7.88 (d, J=9.1 Hz, 1H), 7.63-7.49 (m, 1H), 7.40 (dd, 4H), 7.25 (t, J=8.7 Hz, 1H), 5.14 (s, 1H), 4.56 (d, J=9.1 Hz, 1H), 4.46-4.34 (m, 3H), 4.22 (dd, J=15.8, 4.7 Hz, 1H), 3 .75-3.60 (m, 2H), 3.23-3.14 (m, 4H), 3.13-3.08 (m, 2H), 2.65-2.53 (m, 4H) , 2.43 (s, 3H), 2.38-2.31 (m, 2H), 2.31-2.25 (m, 1H), 2.24-2.16 (m, 1H), 2 .07-1.99 (m, 1H), 1.95-1.87 (m, 1H), 1.72 (d. sq., J=16.3, 10.5, 8.9 Hz, 4H) , 0.95 (t, J=5.3 Hz, 3H), 0.95 (s, 9H). ¹³ C-NMR (151 MHz, DMSO-d ₆ ) δ 180.77, 172.43, 172.39, 170.12, 156.38 (dd, J=246.2, 7.1 Hz), 152, 75 (dd, J=249.8, 9.0 Hz), 151.87, 148.13, 145.23, 144.35, 139.92, 138.09, 137.78, 131.59, 130, 05, 129.21 - 128.76 (m), 127.84, 122.32 (d, J=13.1 Hz), 119.83 - 118.25 (m), 118.03, 115.53, 114.96, 112.68 (d, J=22.7 Hz), 69.30, 59.13, 57.62, 56.79, 55.33, 53.88, 53.06, 50.11, 42.07, 38.38, 35.68, 33.27, 26.83, 23.09, 17.26, 16.37, 13.04. LCMS (ESI); m/z [M+H] ⁺ : Calc. for C ₄₇ H ₅₈ F ₂ N ₉ O ₇ S ₂ , 962.3868. 962.3986 discovered.

[0970] Synthesis example of compound 305: (2S,4R)-1-((S)-2-(4-(4-(3-benzoyl-1H-pyrrolo[2,3-b]pyridin-5-yl) phenoxy)butanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0971] To a solution of 4-[4-(3-benzoyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-phenoxy]butanoic acid (26.5 mg, 0.07 mmol) and (2S ,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide hydrochloride (30.91 mg, 0.07 mmol) in DMF (2 ml), TEA (0.2 ml, 1.43 mmol) and RuBOP (37.88 mg, 0.07 mmol) were added at room temperature. The reaction mixture was stirred for 12 hours (overnight) at the same temperature. The absence of starting materials was detected by TLC (DCM:MeOH:NH ₄ OH, 90:9:1). DMF was removed under high vacuum conditions. The crude product was filtered through a silica gel carbonate cartridge (1 g) using DCM:MeOH (9:1) as eluent. The filtrate was evaporated in vacuo and the crude product was purified by preparative TLC (MeOH:DCM, 9:1) to obtain 31 mg of product (58% yield). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.70 (s, 1H), 8.97 (s, 1H), 8.68 (d, J=2.2 Hz, 1H), 8, 62 (d, J=2.3 Hz, 1H), 8.60-8.51 (m, 1H), 8.12 (s, 1H), 8.00 (d, J=9.3 Hz, 1H ), 7.90-7.77 (m, 1H), 7.72-7.51 (m, 5H), 7.48-7.29 (m, 4H), 7.07 (d, J=8 .7 Hz, 2H), 5.15 (d, J=3.5 Hz, 1H), 4.59 (d, J=9.3 Hz, 1H), 4.50-4.32 (m, 3H ), 4.22 (dd, J=15.9, 5.4 Hz, 1H), 4.03 (td, J=6.5, 2.6 Hz, 2H), 3.80-3.60 ( m, 2H), 2.44 (s, 3H), 2.48-2.28 (m, 5H), 2.13-1.84 (m, 4H), 0.96 (s, 9H). ¹³ C-NMR (101 MHz, DMSO) δ 189.87, 172.00, 171.63, 169.69, 158.23, 151.48, 148.29, 147.73, 143.29, 139.64 , 139.53, 136.54, 131.52, 131.19, 130.74, 129.65, 128.66, 128.58, 128.55, 128.21, 127.44, 127.05, 118 .81, 115.19, 113.74, 68.93, 67.13, 58.75, 56.47, 48.64, 41.68, 38.01, 35.29, 31.33, 26.43 , 25.08, 15.99. LCMS (ESI); m/z [M+H] ⁺ : Calc. for C ₄₆ H ₄₉ N ₆ O ₆ S, 813.3434. 813.3478 discovered.

[0972] Synthesis example of compound 306: (2S,4R)-1-((S)-2-(2-(2-(4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)- 1H-pyrrolo[2,3-b]pyridin-5-yl)piperazin-1-yl)ethoxy)-acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-methylthiazol-5-yl) benzyl)-pyrrolidine-2-carboxamide

[0973] To a solution of 2-[2-[4-[3-[2,6-difluoro-3-(propylsulfonylamino)benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]piperazin-1 -yl]ethoxy]acetic acid (7.9 mg, 0.01 mmol) and (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[ [4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide hydrochloride (7.18 mg, 0.02 mmol) in DMF (1 ml) was added at room temperature with TEA (0.1 ml, 0.72 mmol) and RuBOR (8 mg, 0.02 mmol). The reaction mixture was stirred for 12 hours (overnight) at the same temperature. The absence of starting materials was detected by TLC (DCM:MeOH:NH ₄ OH, 90:9:1). The reaction mixture was evaporated to dryness under high vacuum. The crude product was evaporated under vacuum and the crude product was purified by preparative TLC (DCM:MeOH:NH ₄ OH, 90:9:1) to obtain 8.1 mg of product (59% yield). ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 12.66 (bs, 1H), 9.72 (bs, 1H), 8.93 (s, 1H), 8.59 (bs .s, 1H), 8.22 (s, 1H), 7.99 (s, 1H), 7.89 (b. s, 1H), 7.56 (d. hept, J=9.1, 3 ,4, 2.9 Hz, 1H), 7.51-7.31 (m, 5H), 7.25 (t, J=8.6 Hz, 1H), 5.17 (s, 1H), 4 .57 (dd, J=9.7, 2.4 Hz, 1H), 4.50-4.33 (m, 3H), 4.28-4.19 (m, 1H), 4.07-3 .92 (m, 2H), 3.65 (d, J=15.4 Hz, 4H), 3.22-3.05 (m, 6H), 2.64 (d, J=21.6 Hz, 6H), 2.42 (s, 3H), 2.11-2.03 (m, 1H), 1.91 (dd, J=13.3, 5.8 Hz, 1H), 1.80-1 .67 (m, 2H), 0.96 (overlap s/t, 12H). ¹³ C-NMR (151 MHz, DMSO-d ₆ ) δ 180.38, 171.80, 169.18, 168.58, 156.01 (dd, J=246.2, 6.8 Hz), 152, 34 (dd, J=249.1, 8.7 Hz), 151.39, 147.73, 144.79, 143.97, 139.43, 137.73, 137.38, 131.16, 129, 70, 128.68, 128.60 (d), 127.47, 121.93 (dd, J=13.8, 3.7 Hz), 118.89 - 118.05 (m), 117.64, 115.15, 114.62, 112.29 (dd, J=22.2, 3.2 Hz), 69.65, 68.94, 68.76, 58.81, 57.13, 56.64, 55.73, 53.49, 53.09, 49.72, 41.71, 37.93, 35.87, 26.24, 16.88, 15.95, 12.65. LCMS (ESI); m/z [M+H] ⁺ : Calc. for C ₄₇ H ₅₈ F ₂ N ₉ O ₈ S ₂ , 978.3817. 978.3933 discovered.

Protein content control

[0974] The present disclosure also relates to methods for monitoring the content of proteins in a cell. It is based on the use of compounds described herein that are known to interact with a specific target protein such that in vivo degradation of the target protein will control the amount of protein in the biological system, preferably for a specific therapeutic effect.

[0975] The following examples are used to facilitate the description of the present disclosure, but they should in no way be construed as limiting the present disclosure.

[0976] The following examples are used to facilitate the description of the present disclosure, but they should in no way be construed as limiting the present disclosure.

EXAMPLES

Analyzes and cleavage data

[0977] Protocol for cell-based target protein cleavage assay (A375 cells).

A375 cells were cultured in ATCC DMEM + 10% FBS in 12-well plates and treated with the indicated compound from Tables 1-41 or vehicle control 0.1% DMSO for 16 hours. Cells were collected in Cell Signaling lysis buffer (cat. no. 9803) supplemented with Roche protease inhibitor tablets (cat. no. 11873580001) and lysates were clarified by microcentrifugation. Proteins were separated by SDS-PAGE and transferred to nitrocellulose membranes using the Invitrogen iBlot system. Immunoblotting was performed for BRAF (Santa Cruz, cat. no. 9002), CRAF (BD, cat. no. 610151), and pErk (Cell Signaling, cat. no. 9106). GAPDH (cat. no.) was used as a loading control. Quantification was performed using BioRad Image Lab 5 software.

[0978] Protocol for In-Cell Western Cellular Target Protein Cleavage Assay (A375 cells). A375 cells were cultured in ATCC DMEM +10% FBS in 96-well plates and treated with the indicated compound from Table 43 or vehicle control 0.1% DMSO for 72 hours. Cells were washed once with PBS and fixed in the plate using 4% PFA in phosphate buffered saline for 15 minutes; washed once and permeabilized with 0.1% Triton-X-100 in PBS for 5 minutes; washed 1 time and blocked with 6 LICOR locator (cat. no. 927-50000) for 1 hour. Cells were then incubated with anti-B-Raf antibody (Santa Cruz, cat. no. 9002) and anti-tubulin antibody (Sigma, cat. no. T6074) in LICOR blocker for 18 hours. Cells were washed 3 times before adding secondary antibodies (LICOR, cat nos. 926-32210 and 926-68071) and incubated for 1 hour. Cells were washed 3 times and imaged using LICOR Odyssey Software.

[0979] The following PROTACs, shown in Tables 1-41 and 42 (FIG. 2), are examples of bifunctional compounds that are described in the claims of this application. Some of these were tested to see if they would exhibit BRAF protein degradation activity in cells, and their results are shown in the DC ₅₀ and D _max columns of these tables. As used herein, DC ₅₀ is the concentration of compound at which the BRAF concentration level reaches the midpoint between the maximum level and the minimum level on a dose-response curve measuring the concentration of BRAF protein in a cell as a function of the concentration of the compound added to the incubation medium of the cell with the compound, a D _max represents the maximum level of protein degradation that can be achieved by varying the concentration of a compound. For many compounds, no DC ₅₀ and _Dmax values or ranges are given in these tables because they either have not been tested or synthesized or are prophetic examples.

Table 42. Exemplary protein targeting moieties and compounds of the present disclosure (see FIG. 2).

Table 43. Decay data for the example compounds in Table 42 (see FIG. 3).

[0980] Specific Embodiments of the Present Disclosure

[0981] The present invention covers the following specific embodiments. The following embodiments may include all of the features listed in the previous embodiment, as indicated. Optionally, the following embodiments may also include features listed in any of the previous embodiments, inclusive or alternative.

[0982] In any aspect or embodiment, provided herein are the following exemplary RAF PROTAC molecules (compounds of Tables 1-43, i.e., any of the compounds of Tables 1, 2, 3, 4, 5, 6, 7 , 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 , 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43 or combinations thereof), including their salts, prodrugs, polymorphs, analogs, derivatives and deuterated forms.

[0983] Thus, the present invention relates to a compound containing the structure of any of the compounds of tables 1-43 (i.e., any of the compounds of tables 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 , 36, 37, 38, 39, 40, 41, 42, 43 or combinations thereof), therapeutic compositions containing them, and methods of use as described in the present invention.

[0984] In one aspect, the present disclosure relates to a bifunctional compound. A bifunctional compound is characterized by its chemical structure:

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or prodrug thereof, wherein: the ULM is a small molecule E3 ubiquitin ligase binding moiety that binds E3 ubiquitin ligase; PTM is a small molecule containing a moiety that targets the rapidly progressing fibrosarcoma (RAF) protein; and L represents a bond or fragment of a chemical bond covalently linking the ULM and PTM.

[0985] In any aspect or embodiment described herein, the E3 ubiquitin ligase binding moiety that targets the E3 ubiquitin ligase is selected from the group consisting of von Hippel-Lindau (VLM), cereblon (CLM), mouse double homolog 2 minichromosomes (MLM) and IAP (ILM).

[0986] According to any aspect or embodiment described in the present invention, PTM is represented by the chemical structure of PTM-Ia or PTM-Ib:

Where:

dotted double bonds represent aromatic bonds;

V _PTM , W _PTM , X _PTM , Y _PTM , Z _PTM is one of the following combinations: C, CH, N, N, C; C, N, N, CH, C; S, O, S, CH, S; C, S, C, CH, C; S, CH, S, O, S; C, CH, C, S, C; C, CH, N, CH, C; N, CH, C, CH, C; C, CH, C, CH, N; N, N, C, CH, C; N, CH, C, N, C; C, CH, C, N, N; C, N, C, CH, N; C, N, C, N, C and C, N, N, N, C;

HRTM35, HRTM36, HRTM37 and HRTM38 were independently selected from CH and N;

R _PTM1 is covalently attached to a ULM, a chemical linker group (L), CLM, ILM, VLM, MLM, ULM', CLM', ILM', VLM', MLM', or a combination thereof;

R _PTM2 is hydrogen, halogen, aryl, methyl, ethyl, OCH ₃ , NHCH ₃ or M1-CH ₂ -CH-M2, where M1 is CH ₂ , O and NH and M2 is hydrogen, alkyl, cyclic alkyl , aryl or heterocycle;

R _PTM3 is absent or represents hydrogen, aryl, methyl, ethyl, other alkyl, cyclic alkyl, OCH ₃ , NHCH ₃ or M1-CH ₂ -CH ₂ -M2, where M1 represents CH ₂ , O and NH, and M2 represents is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle;

R _PTM4 is hydrogen, halogen, aryl, methyl, ethyl, OCH ₃ , NHCH ₃ or M1-CH ₂ -CH ₂ -M2, where M1 is CH ₂ , O and NH and M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle; And

R _PTM5 selected from the group consisting of

[0987] According to any aspect or embodiment described in the present invention, PTM is represented by the chemical structure of PTM-IIa or PTM-IIb:

Where:

X _RTM1 , X _RTM2 , X _RTM3 , X _RTM4 , X _RTM5 and X _RTM6 are independently selected from CH or N;

R _PTM5a is selected from the group consisting of: a bond, an optionally substituted amine, an optionally substituted amide (for example, optionally substituted with an alkyl, methyl, ethyl, propyl or butyl group), H or -NHC(O)R _PTM5 ;

R _PTM5 selected from the group consisting of

R _PTM6a and R _PTM6b are each independently selected from hydrogen, halogen or C ₁ -C ₆ alkyl (straight, branched, optionally substituted; for example, optionally substituted methyl or ethyl);

R _PTM6 represents any of the following groups: none, hydrogen, halogen, aryl, methyl, ethyl, OCH ₃ , NHCH ₃ or M1-CH ₂ -CH ₂ -M2, where M1 represents CH ₂ , O and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle;

R _PTM7 is absent or is hydrogen, halogen, aryl, methyl, ethyl, OCH ₃ , NHCH ₃ or M1-CH ₂ -CH ₂ -M2, where M1 is CH ₂ , O and NH and M2 is hydrogen, alkyl , cyclic alkyl, aryl or heterocycle;

R _PTM8 , R _PTM9 or R _PTM10 are independently absent or selected from the group consisting of hydrogen, halogen, aryl, heteroaryl, alkyl, cycloalkyl, heterocycle, methyl, ethyl, OCH ₃ , NHCH ₃ or M1-CH ₂ -CH ₂ -M2 where M1 represents CH ₂ , O and NH, and M2 represents hydrogen, alkyl, cyclic alkyl, aryl or heterocycle;

R _PTM11 is absent or represents hydrogen, halogen, methyl, ethyl, OCH ₃ , NHCH ₃ or M1-CH ₂ -CH ₂ -M2, in which M1, where CH ₂ , O and NH, and M2 represents hydrogen, alkyl, cyclic alkyl, aryl or heterocycle; And

at least one of R _PTM8 , R _PTM9 or R _PTM10 is modified to covalently attach to a ULM, chemical linker group (L), CLM, ILM, VLM, MLM, ULM', CLM', ILM', VLM', MLM' or their combinations.

[0988] According to any aspect or embodiment described herein, if R _PTM9 is a covalently linked position, R _PTM7 and R _PTM8 are linked together by a covalent bond to form a bicyclic group with a ring to which R _PTM7 and R _PTM8 are attached; or if R _PTM8 is a covalently linked position, R _PTM9 and R _PTM10 are linked together by a covalent bond to form a bicyclic group with a ring to which R _PTM9 and R _PTM10 are attached; or if RPTM10 is a covalently linked position, RPTM8 and RPTM9 are linked together by a covalent bond to form a bicyclic group with a ring to which RPTM8 and RPTM9 are attached.

[0989] According to any aspect or embodiment described in the present invention, PTM is represented by the chemical structure:

or

where R _PTM5 , R _PTM6a , R _PTM6b , R _PTM6 , R _PTM7 , R _PTM8 , R _PTM9 , R _PTM10 , R _PTM11 are described in the present invention.

[0990] According to any aspect or embodiment described in the present invention, PTM is represented by the chemical structure of PTM-III:

Where:

X _RTM7 , X _RTM8 , X _RTM9 , X _RTM10 , X _RTM11 , X _RTM12 , X RTM13, X _RTM14 , X _RTM15 , X _PTM16 , X _RTM17 , X _RTM18 , _{X PTM19 ,} X _RTM20 independently represent CH or N;

R _PTM12 , R _PTM13 , R _PTM14 , R _PTM15 , R _PTM16 , R _PTM17 , R _PTM18 , R _PTM19 are independently absent or selected from the group consisting of hydrogen, halogen, aryl, heteroaryl, cycloalkyl, heterocycle, methyl, ethyl, other alkyl , OCH ₃ , NHCH ₃ or M1-CH ₂ -CH ₂ -M2, where M1 represents CH ₂ , O and NH, and M2 represents hydrogen, alkyl, cyclic alkyl, aryl or heterocycle;

R _PTM20 is a small group containing less than four non-hydrogen atoms;

R _PTM21 is selected from the group consisting of triflutomethyl, chlorine, bromine, fluorine, methyl, ethyl, propyl, isopropyl, tert-butyl, butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, OCH ₃ , NHCH ₃ , dimethylamino or M1- CH ₂ -CH ₂ -M2, where M1 represents CH ₂ , O or NH, and M2 represents hydrogen, alkyl, cyclic alkyl, aryl or heterocycle; And

at least one of R _PTM12 , R _PTM13 and R _PTM16 is modified to covalently attach to a ULM, chemical linker group (L), CLM, ILM, VLM, MLM, ULM', CLM', ILM', VLM', MLM' or their combinations.

[0991] According to any aspect or embodiment described herein, if R _PTM12 is a covalently linked position, R _PTM13 and R _PTM14 are joined together by a covalent bond to form a bicyclic group with a ring to which R _PTM13 and R _PTM14 are attached, and /or R _PTM15 and R _PTM16 are joined together by a covalent bond to form a bicyclic group with a ring to which R _PTM15 and R _PTM16 are attached; if R _PTM13 is a covalently linked position, R _PTM12 and R _PTM16 are linked together by a covalent bond to form a bicyclic group with a ring to which R _PTM12 and R _PTM16 are attached, and/or R _PTM15 and R _PTM16 are linked together by a covalent bond to form a bicyclic group with a ring to which R _PTM15 and R _PTM16 are attached; or if R _PTM16 is a covalently linked position, R _PTM12 and R _PTM13 are linked together by a covalent bond to form a bicyclic group with a ring to which R _PTM12 and R _PTM13 are attached, and/or R _PTM13 and R _PTM14 are linked together by a covalent bond bonds to form a bicyclic group with a ring to which R _PTM13 and R _PTM14 are attached.

[0992] According to any aspect or embodiment described in the present invention, PTM is represented by the chemical structure of PTM-IVa or PTM-IVb:

Where:

X _RTM21 , X _RTM22 , X _RTM23 , X _RTM24 , X _RTM25 , X _RTM26 , X _RTM27 , X _RTM28 , X _RTM29 , X _RTM30 , X _RTM31 , X _RTM32 , X _RTM33 , X _RTM34 independently represent CH or N;

R _PTM22 selected from the group consisting of

R _PTM25a and R _PTM25b are each independently selected from hydrogen, halogen or C ₁ -C ₆ alkyl (straight, branched, optionally substituted);

R _PTM23 , R _PTM24 , R _PTM28 , R _PTM29 , R _PTM30 , R _ptm31 , R _PTM32 are independently absent or selected from the group consisting of bond, hydrogen, halogen, aryl (optionally substituted), heteroaryl (optionally substituted), cycloalkyl (optional substituted), heterocycle (optionally substituted), methyl, ethyl (optionally substituted), other alkyl (straight, branched, optionally substituted), OCH ₃ , NHCH ₃ or M1-CH ₂ -CH ₂ -M2, where M1 is CH ₂ , O and NH and M2 is hydrogen, alkyl (straight, branched, optionally substituted), cyclic alkyl (optionally substituted), aryl (optionally substituted) or heterocycle (optionally substituted); And

R _PTM25 is absent or a small group containing less than four non-hydrogen atoms (eg, absent or selected from hydrogen, halogen, C ₁ -C ₆ alkyl (straight, branched, optionally substituted), OCH 3 , NHCH ₃ or SCH ₃ );

R _PTM26 is absent or is a small group containing less than four non-hydrogen atoms (eg, absent or selected from hydrogen, halogen, C ₁ -C ₆ alkyl (straight, branched, optionally substituted), OCH 3 , NHCH ₃ or SCH ₃ );

RPTM27 is absent or selected from the group consisting of hydrogen, halogen, C ₁ -C ₆ alkyl (straight-line, branched, optionally substituted; for example, optionally substituted methyl or ethyl), OCH ₃ , NHCH ₃ or SCH ₃ ; And

at least one of R _PTM24 , R _PTM29 , R _PTM32 is modified to covalently attach to a ULM, chemical linker group (L), CLM, ILM, VLM, MLM, ULM', CLM', ILM', VLM', MLM', or their combinations.

[0993] According to any aspect or embodiment described herein, if R _PTM24 is a covalently linked position, R _PTM31 and R _PTM32 are joined together by a covalent bond to form a bicyclic group with a ring to which R _PTM31 and R _PTM32 are attached, or R _PTM29 and R _PTM30 are joined together by a covalent bond to form a bicyclic group with a ring to which R _PTM29 and R _PTM30 are attached; or if R _PTM29 is a covalently linked position, R _PTM24 and R _PTM32 are linked together by a covalent bond to form a bicyclic group with a ring to which R _PTM24 and R _PTM32 are attached, and/or R _PTM31 and R _PTM32 are linked together by a covalent bond bonds to form a bicyclic group with a ring to which R _PTM31 and R _PTM32 are attached; or if R _PTM32 is a covalently linked position, R _PTM24 and R _PTM29 are linked together by a covalent bond to form a bicyclic group with a ring to which R _PTM24 and R _PTM29 are attached, and/or R _PTM29 and R _PTM30 are linked together by a covalent bond bonds to form a bicyclic group with a ring to which R _PTM29 and R _PTM30 are attached.

[0994] According to any aspect or embodiment described in the present invention, the RTM is selected from the group consisting of RTM-1, RTM-2, RTM-3, RTM-4, RTM-5, RTM-6, RTM-7, and RTM- 8:

[0995] According to any aspect or embodiment described in the present invention, the ULM is selected from the group consisting of:

where R _14a represents H, methyl or hydroxymethyl.

[0996] According to any aspect or embodiment described in the present invention, the ULM is a von Hippel-Lindau ligase (VHL) binding fragment (VLM) with the chemical structure represented by:

Where:

X ¹ , X ² are each independently selected from the bond group, O, NR ^Y3 , CR ^Y3 R ^Y4 , C=O, C=S, SO and SO ₂ ;

R ^Y3 , R ^Y4 are each independently selected from the group H, straight or branched C _1-6 alkyl (optionally substituted with 1 or more halogen atoms), optionally substituted C _1-6 alkoxy (eg, optionally substituted with 0-3 ^RP groups);

R ^P represents 0, 1, 2 or 3 groups, each independently selected from H, halogen, -OH, C _1-3 alkyl, C=O;

W ³ is selected from the group of optionally substituted -TN(R ^1a R ^1b )X ³ , optionally substituted -TN(R ^1a R ^1b ), optionally substituted T-aryl, optionally substituted -T-heteroaryl, optionally substituted -T-heterocycle, optional substituted -NR ¹ -T-aryl, optionally substituted -NR ¹ -T-heteroaryl or optionally substituted -NR ¹ -T-heterocycle;

X ³ of the formula ULM-a represents C=O, R ¹ , R ^1a , R ^1b ;

R ¹ , R ^1a , R ^1b are each independently selected from the group consisting of H, a straight or branched C ₁ -C ₆ alkyl group, optionally substituted with 1 or more halogen atoms or -OH groups, R ^Y3 C=O, R ^Y3 C =S, R ^Y3 SO, R ^Y3 SO ₂ , N(R ^Y3 R ^Y4 )C=O, N(R ^Y3 R ^Y4 )C=S, N(R ^Y3 R ^Y4 )SO and N(R ^Y3 R ^Y4 ) _SO2 ;

T is selected from the group of optionally substituted alkyl, -(CH ₂ ) _n - group, where each one of the methylene groups is optionally substituted by one or two substituents selected from the group of halogen, methyl, straight or branched C ₁ -C ₆ alkyl group, optionally substituted 1 or more halogen atoms or -OH groups or amino acid side chain, optionally substituted; And

n represents 0 to 6,

W ⁴ represents

R _14a , R _14b are each independently selected from the group H, haloalkyl or optionally substituted alkyl;

W ⁵ is selected from the group of phenyl or 5-10 membered heteroaryl,

R ₁₅ is selected from the group H, halogen, CN, OH, NO ₂ , NR _14a R _14b , OR _14a , CONR _14a R _14b , NR _14a COR _14b , SO ₂ NR _14a R _14b , NR _14a SO ₂ R _14b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxyaryl, heteroaryl, cycloalkyl or cycloheteroalkyl (each optionally substituted);

and wherein the dotted line denotes the attachment site of at least one PTM, another ULM (ULM'), or a chemical linker moiety connecting at least one PTM or ULM' or both to the ULM.

[0997] According to any aspect or embodiment described herein, the ULM is a von Hippel-Lindau ligase (VHL) binding moiety (VLM) with the chemical structure represented by:

Where:

W ³ is selected from the group of optionally substituted aryl, optionally substituted heteroaryl or

R ₉ and R ₁₀ independently represent hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl or haloalkyl, or R ₉ , R ₁₀ and the carbon atom to which they are attached form an optionally substituted cycloalkyl;

R ₁₁ is selected from the group of optionally substituted heterocyclic, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl, or

R ₁₂ is selected from the group H or optionally substituted alkyl;

R ₁₃ is selected from the group H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted alkylcarbonyl, optionally substituted alkylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl;

R _14a , R _14b are each independently selected from the group H, haloalkyl or optionally substituted alkyl;

W ⁵ is selected from the group of phenyl or 5-10 membered heteroaryl,

R ₁₅ is selected from the group H, halogen, CN, OH, NO ₂ , NR _14a R _14b OR _14a , CONR _14a R _14b , NR _14a COR _14b , SO ₂ NR _14a R _14b , NR _14a SO ₂ R _14b , optionally substituted alkyl , optionally substituted haloalkyl, optionally substituted haloalkoxy; aryl, heteroaryl, cycloalkyl or cycloheteroalkyl (each optionally substituted);

R ₁₆ is independently selected from the group of halogen, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy or optionally substituted haloalkoxy;

o represents 0, 1, 2, 3 or 4;

R ₁₈ is independently selected from the group H, halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy or a linker; And

p represents 0, 1, 2, 3 or 4, and where the dotted line represents the attachment site of at least one PTM, another ULM (ULM'), or a chemical linker moiety connecting at least one PTM or ULM' or both to the ULM.

[0998] According to any aspect or embodiment described in the present invention, the ULM is characterized by a chemical structure selected from the group:

Where:

R ₁ is H, ethyl, isopropyl, t-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; optionally substituted alkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl or haloalkyl;

R _14a represents H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl or cyclopropyl;

R ₁₅ is selected from the group consisting of H, halogen, CN, OH, NO ₂ , optionally substituted heteroaryl, optionally substituted aryl; optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, cycloalkyl or cycloheteroalkyl;

X represents C, CH ₂ , or C=O;

R ₃ represents a bond or an optionally substituted 5- or 6-membered heteroaryl; and wherein the dotted line denotes the attachment site of at least one PTM, another ULM (ULM'), or a chemical linker moiety connecting at least one PTM or ULM' or both to the ULM.

[0999] According to any aspect or embodiment described in the present invention, the ULM contains a group according to the chemical structure:

Where:

R _14a represents H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl or cyclopropyl;

R ₉ represents H;

R ₁₀ is H, ethyl, isopropyl, t-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

R ₁₁ represents ; optionally substituted heteroaryl, or

p is 0, 1, 2, 3 or 4; And

each R ₁₈ independently represents halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy or a linker;

R ₁₂ represents H, C=O

R ₁₃ represents H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl or optionally substituted aralkyl,

R ₁₅ is selected from the group consisting of H, halogen, Cl, CN, OH, NO ₂ , optionally substituted heteroaryl, optionally substituted aryl;

and wherein the dotted line denotes the attachment site of at least one PTM, another ULM (ULM'), or a chemical linker moiety connecting at least one PTM or ULM' or both to the ULM.

[1000] According to any aspect or embodiments described in the present invention, the ULM contains a group according to the chemical structure:

Where:

R ^1' ULM-g represents an optionally substituted C ₁ -C ₆ alkyl group, optionally substituted -(CH ₂ ) _n OH, optionally substituted -(CH ₂ ) _n SH, optionally substituted (CH ₂ ) _n -O-(C ₁ -C ₆ )alkyl group, optionally substituted (CH ₂ ) _n -WCOCW-(C ₀ -C ₆ )alkyl group containing a WCOCW epoxy moiety, wherein each W independently represents an H or a C ₁ -C ₃ alkyl group, optionally substituted -(CH ₂ ) _n COOH, optionally substituted -(CH ₂ ) _n C(O)-(C ₁ -C ₆ alkyl), optionally substituted -(CH ₂ ) _n NHC(O)-R ₁ , optionally substituted - (CH ₂ ) _n C(O)-NR ₁ R ₂ , optionally substituted -(CH ₂ ) _n OC(O)-NR ₁ R ₂ , -(CH ₂ O) _n H, optionally substituted -(CH ₂ ) _n OC(O)-(C ₁ -C ₆ alkyl), optionally substituted -(CH ₂ ) _n C(O)-O-(C ₁ -C ₆ alkyl), optionally substituted -(CH ₂ O) _n COOH, optional substituted -(OCH ₂ ) _n O-(C ₁ -C ₆ alkyl), optionally substituted -(CH ₂ O) _n C(O)-(C ₁ -C ₆ alkyl), optionally substituted -(OCH ₂ ) _n NHC (O)-R ₁ , optionally substituted -(CH ₂ O) _n C(O)-NR ₁ R ₂ , -(CH ₂ CH ₂ O) _n H, optionally substituted -(CH ₂ CH ₂ O) _n COOH, optionally substituted -(OCH ₂ CH ₂ ) _n O-(C ₁ -C ₆ alkyl), optionally substituted -(CH ₂ CH ₂ O) _n C(O)-(C ₁ -C ₆ alkyl), optionally substituted -( OCH ₂ CH ₂ ) _n NHC(O)-R ₁ , optionally substituted -(CH ₂ CH ₂ O) _n C(O)-NR ₁ R ₂ , optionally substituted -SO _{2 RS} , optionally substituted S(O)R _S , NO ₂ , CN or halogen (F, Cl, Br, I, preferably F or Cl);

R ₁ and R ₂ ULM-g each independently represent H or a C ₁ -C ₆ alkyl group, which may be optionally substituted with one or two hydroxyl groups or up to three halogen groups (preferably fluorine);

R _S ULM-g represents a C ₁ -C ₆ alkyl group, an optionally substituted aryl, heteroaryl or heterocyclic group or a -(CH ₂ ) _m NR ₁ R ₂ group;

X and X' ULM-g are each independently C=O, C=S, -S(O), S(O) ₂ (preferably X and X' are both C=O);

R ^2' ULM-g represents an optionally substituted -(CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ ) _w alkyl group, optionally substituted -(CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ ) _w NR _1N R _2N group, optionally substituted -(CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ ) _w -aryl, optionally substituted -(CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ ) _w -heteroaryl, optionally substituted -(CH ₂ ) _n -(C=O) _v NR ₁ (SO ₂ ) _w -heterocyclyl, optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -alkyl, optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -NR _1N R _2N , optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -NR ₁ C(O)R _1N , optionally substituted -NR ¹ -(CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ ) _w -aryl, optionally substituted -NR ¹ -(CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ ) _w -heteroaryl or an optionally substituted -NR ¹ -(CH ₂ ) _n -(C=O) _v NR ₁ (SO ₂ ) _w -heteroaryl, an optionally substituted -X ^R2' -alkyl group; an optionally substituted -X ^R2' -aryl group; an optionally substituted -X ^R2' -heteroaryl group; an optionally substituted -X ^R2' -heterocyclic group; optionally substituted;

R ^3' ULM-g is optionally substituted alkyl, optionally substituted -(CH ₂ ) _n -(O) _u (NR ₁ ) _v (SO ₂ ) _w -alkyl, optionally substituted -(CH ₂ ) _n -C(O ) _u (NR ₁ ) _v (SO ₂ ) _w -NR _1N R _2N , optionally substituted -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -NR ₁ C(O)R _1N , optionally substituted -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -C(O)NR ₁ R ₂ , optionally substituted -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -aryl, optionally substituted -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -heteroaryl, optionally substituted -(CH ₂ ) _n -C (O) _u (NR ₁ ) _v (SO ₂ ) _w -heterocycle, optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -alkyl, optionally substituted - NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -NR _1N R _2N , optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -NR ₁ C(O)R _1N , optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -aryl, optionally substituted - NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -heteroaryl, optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v ( SO ₂ ) _w -heterocycle, optionally substituted -O-(CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ ) _w -alkyl, optionally substituted -O-(CH ₂ ) _n -(C =O) _u (NR ₁ ) _v (SO ₂ ) _w -NR _1N R _2N , optionally substituted -O-(CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ ) _w -NR ₁ C(O)R _1N , optionally substituted -O-(CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ ) _w -aryl, optionally substituted -O-(CH ₂ ) _n -(C =O) _u (NR ₁ ) _v (SO ₂ ) _w -heteroaryl or optionally substituted -O-(CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ ) _w -heterocycle; -(CH ₂ ) _n -(V) _n' -(CH ₂ ) _n -(V) _n' -alkyl group, optionally substituted -(CH ₂ ) _n -(V) _n' -(CH ₂ ) _n -( V) _n' -aryl group, optionally substituted -(CH ₂ ) _n -(V) _n' -(CH ₂ ) _n -(V) _n' -heteroaryl group, optionally substituted -(CH ₂ ) _n -(V) _n' -(CH ₂ ) _n -(V) _n' -heterocyclic group, optionally substituted -(CH ₂ ) _n -N(R _1' )(C=O) _m' -(V) _n' -alkyl group, optionally substituted -(CH ₂ ) _n -N(R _1' )(C=O) _m' -(V) _n' -aryl group, optionally substituted -(CH ₂ ) _n -N(R _1' )(C= O) _m' -(V) _n' -heteroaryl group, optionally substituted -(CH ₂ ) _n -N(R _1' )(C=O) _m' -(V) _n' -heterocyclic group, optionally substituted -X ^R3' is an alkyl group; an optionally substituted -X ^R3' -aryl group; an optionally substituted -X ^R3' -heteroaryl group; an optionally substituted -X ^R3' heterocyclic group; optionally substituted;

R _1N and R _2N ULM-g are each independently H, C ₁ -C ₆ alkyl, which is optionally substituted with one or two hydroxyl groups and up to three halogen groups or optionally substituted -(CH ₂ ) _n -aryl, - (CH ₂ ) _n -heteroaryl or -(CH ₂ ) _n -heterocyclic group;

V ULM-g is O, S or NR ₁ ;

R ₁ ULM-g is the same as described above;

R ₁ and R _1' ULM-g each independently represent an H or a C ₁ -C ₃ alkyl group;

X ^R2' and X ^R3' ULM-g are each independently optionally substituted -CH ₂ ) _n -, -CH ₂ ) _n -CH(X _v )=CH(X _v )- (cis or trans), -CH ₂ ) _n -CH≡CH-, -(CH ₂ CH ₂ O) _n - or a C ₃ -C ₆ cycloalkyl group, where X _v represents H, halogen or a C ₁ -C ₃ alkyl group, which is optionally substituted;

each m ULM-g independently represents 0, 1, 2, 3, 4, 5, 6;

each m' ULM-g is independently 0 or 1;

each n ULM-g independently represents 0, 1, 2, 3, 4, 5, 6;

each n' ULM-g is independently 0 or 1;

each u ULM-g is independently 0 or 1;

each v ULM-g is independently 0 or 1;

each w ULM-g is independently 0 or 1; And

any one or more of R ^1' , R ^2' , R ^3' , X and X' of ULM-g is optionally modified to covalently link to a PTM group via a linker group if PTM is not ULM' or if PTM is ULM', any one or more of R ^1' , R ^2' , R ^3' , X and X' of each of ULM and ULM' are optionally modified to covalently link to each other directly or through a linker group, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph.

[1001] In any aspect or embodiment described herein, the ULM is a cereblon E3 ligase (CLM) binding moiety selected from the group consisting of thalidomide, lenalidomide, pomalidomide, analogs thereof, isosteres thereof, or derivatives thereof.

[1002] According to any aspect or embodiment described in the present invention, CLM is characterized by a chemical structure represented by:

Where:

W is selected from the group consisting of CH ₂ , CHR, C=O, SO ₂ , NH and N-alkyl; each X is independently selected from the group consisting of O, S and H ₂ ;

Y is selected from the group consisting of CH ₂ , -C=CR', NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O and S;

Z is selected from the group consisting of O, S and H ₂ ;

G and G' are independently selected from the group consisting of H, alkyl (straight-chain, branched, optionally substituted), OH, R'OCOOR, R'OCONRR'', CH ₂ -heterocyclyl, optionally substituted with R', and benzyl, optionally substituted R';

Q ₁ , Q ₂ , Q ₃ and Q ₄ represent a C carbon substituted by a group independently selected from R', N or N-oxide;

A is independently selected from the group H, alkyl (straight, branched, optionally substituted), cycloalkyl, Cl and F;

R contains -CONR'R'', -OR', -NR'R'', -SR', -SO ₂ R', -SO ₂ NR'R'', -CR'R''-, -CR'NR'R''-,(-CR'O)nR'', -aryl, -hetaryl, -alkyl (straight, branched, optionally substituted), -cycloalkyl, -heterocyclyl, -P(O)(OR')R '', -P(O)R'R'', -OP(O)(OR')R'', -OP(O)R'R'', -Cl, -F, -Br, -I, -CF ₃ , -CN, -NR'SO ₂ NR'R'', -NR'CONR'R'', -CONR'COR'', -NR'C(=N-CN)NR'R'', -C(=N-CN)NR'R'', -NR'C(=N-CN)R'', -NR'C(=C-NO ₂ )NR'R'', -SO ₂ NR'COR'', -NO ₂ , -CO ₂ R', -C(C=N-OR')R'', -CR'=CR'R'', -CCR', -S(C=O)( C=N-R')R'', -SF ₅ and -OCF ₃ ;

R' and R'' are independently selected from the group consisting of a bond, H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic compound, -C(=O)R, heterocyclyl, each of which is optionally substituted;

represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific; And

R _n contains a functional group, an optionally substituted alkoxy group (for example, methoxy, ethoxy, butoxy, propoxy, pentoxy or hexoxy; where the alkoxy may be substituted with halogen, cycloalkyl (for example, C ₃ -C ₆ cycloalkyl) or aryl (for example, C ₅ -With ₇ aryl)) or atom,

where n is an integer from 1 to 10 (for example, 1-4) and where

if n is 1, R _n is modified to be covalently attached to a linker group (L), and

if n is 2, 3 or 4, then one R _n is modified to covalently attach to a linker group (L), and any other R _n is optionally modified to covalently attach to a PTM, CLM, a second CLM having the same chemical structure as and CLM, CLM', a second linker, or any plurality or combination thereof.

[1003] According to any aspect or embodiment described in the present invention, CLM is characterized by a chemical structure represented by:

Where:

W is independently selected from the group CH ₂ , C=O, NH and N-alkyl;

R is independently selected from H, methyl or alkyl (eg, C1-C6 alkyl (straight, branched, optionally substituted));

represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific; And

Rn contains 1-4 independently selected functional groups, an optionally substituted alkoxy group (e.g., methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy; wherein the alkoxy may be substituted with halogen, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)) or atoms, and optionally one of which is modified to covalently link with a PTM, a chemical linker group (L), CLM (or CLM'), or a combination thereof.

[1004] According to any aspect or embodiments described herein, CLM is characterized by a chemical structure represented by:

Where:

W of formulas (h) - (ab) is independently selected from CH ₂ , CHR, C=O, SO ₂ , NH and N-alkyl;

Q ₁ , Q ₂ , Q ₃ , Q ₄ , Q ₅ of formulas (h) - (ab) independently represent a C carbon substituted by a group independently selected from R', N or N-oxide;

R ¹ of formulas (h) - (ab) is selected from H, CN, C1-C3 alkyl;

R ² of formulas (h) - (ab) is selected from the group H, CN, C1-C3 alkyl, CHF ₂ , CF ₃ , CHO;

R ³ of formulas (h) - (ab) is selected from H, alkyl, substituted alkyl, alkoxy, substituted alkoxy;

R ⁴ of formulas (h) - (ab) is selected from H, alkyl, substituted alkyl;

R ⁵ of formulas (h) - (ab) represents H or lower alkyl;

X of formulas (h) - (ab) represents C, CH or N;

R' of formulas (h) - (ab) is selected from H, halogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy;

R of formulas (h) - (ab) is H, OH, lower alkyl, lower alkoxy, cyano, halogenated lower alkoxy or halogenated lower alkyl

formulas (h) - (ab) represents a single or double bond; And

CLM is covalently attached to a PTM, a chemical linker group (L), ULM, CLM (or CLM'), or a combination thereof.

[1005] According to any aspect or embodiment described herein, the ULM is a linking moiety (MDM2) with a chemical moiety selected from the group consisting of substituted imidazolines, substituted spiroindolinones, substituted pyrrolidines, substituted piperidinones, substituted morpholinones, substituted pyrrolopyrimidines, substituted imidazolopyridines, substituted thiazoloimidazolines, substituted pyrrolopyrrolidinones and substituted isoquinolinones.

[1006] According to any aspect or embodiment described herein, the ULM is an E3 IAP ubiquitin ligase binding fragment (ILM) containing the amino acids alanine (A), valine (V), proline (P), and isoleucine (I) or not naturally occurring mimetics.

[1007] In any aspect or embodiment described herein, the ULM is an E3 IAP ubiquitin ligase binding fragment (ILM) containing an AVPI tetrapeptide fragment or a derivative thereof.

[1008] According to any aspect or embodiment described in the present invention, the linker (L) contains a chemical structural unit represented by the formula:

-(A ^L ) _q -,

Where:

(A ^L ) _q represents a group that is connected to a ULM or PTM moiety;

q is an integer that is greater than or equal to 1;

where each A ^L is independently selected from the group consisting of a link, CR ^L1 R ^L2 , O, S, SO, SO ₂ , NR ^L3 , SO ₂ NR ^L3 , SONR ^L3 , CONR ^L3 , NR ^L3 CONR ^L4 , NR ^L3 SO ₂ NR ^L4 , CO, CR ^L1 =CR ^L2 , C≡C, SiR ^L1 R ^L2 , P(O)R ^L1 , P(O)OR ^L1 , NR ^L3 C(=NCN)NR ^L4 , NR ^L3 C(=NCN ), NR ^L3 C(=CNO ₂ )NR ^L4 , C _3-11 cycloalkyl, optionally substituted with 0-6 R ^L1 and/or R ^L2 groups, C _3-11 heterocyclyl, optionally substituted with 0-6 R ^L1 and/or R ^L2 groups, aryl optionally substituted with 0-6 R ^L1 and/or R ^L2 groups, heteroaryl optionally substituted with 0-6 R ^L1 and/or R ^L2 groups, wherein R ^L1 or R ^L2 are each independently optionally combined with other groups to form a cycloalkyl and/or heterocyclyl moiety, optionally substituted with 0-4 R ^L5 groups; And

R ^L1 , R ^L2 , R ^L3 , R ^L4 and R ^L5 are each independently H, halogen, C _1-8 alkyl, OC _1-8 alkyl, SC _1-8 alkyl, NHC _1-8 alkyl, N(C _{1 -8} alkyl) ₂ , C _3-11 cycloalkyl, aryl, heteroaryl, C _3-11 heterocyclyl, OS _1-8 cycloalkyl, SC _1-8 cycloalkyl, NHC _1-8 cycloalkyl, N(C _1-8 cycloalkyl) ₂ , N(C _1-8 cycloalkyl)(C _1-8 alkyl), OH, NH ₂ , SH, SO ₂ C _1-8 alkyl, P(O)(OS _1-8 alkyl)(C _1-8 alkyl), P(O)(OS _1-8 alkyl) ₂ , CC-C _1-8 alkyl, CCH, CH=CH(C _1-8 alkyl), C(C _1-8 alkyl)=CH(C _1-8 alkyl ), C(C _1-8 alkyl)=C(C _1-8 alkyl) ₂ , Si(OH) ₃ , Si(C _1-8 alkyl) ₃ , Si(OH)(C _1-8 alkyl) ₂ , SOS _1-8 alkyl, CO ₂ H, halogen, CN, CF ₃ , CHF ₂ , CH ₂ F, NO ₂ , SF ₅ , SO ₂ NHC _1-8 alkyl, SO ₂ N(C _1-8 alkyl) ₂ , SONHC _1-8 alkyl, SON(C _1-8 alkyl) ₂ , CONHC _1-8 alkyl, CON(C _1-8 alkyl) ₂ , N(C _1-8 alkyl)CONH(C _1-8 alkyl), N (C ₁ - ₈ alkyl)CON(C1-8 alkyl)2, NHCONH(C _1-8 alkyl) _, NHCON(C _1-8 alkyl) ₂ , NHCONH ₂ , N(C _1-8 alkyl)SO ₂ NH(C _1-8 alkyl), N(C _1-8 alkyl) SO ₂ N(C _1-8 alkyl) ₂ , NH SO ₂ NH(C _1-8 alkyl), NH SO ₂ N(C _1-8 alkyl) ₂ , NH SO ₂ NH ₂ .

[1009] According to any aspect or embodiment described in the present invention, the linker (L) contains a group represented by a general structure selected from the group consisting of:

-N(R)-(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -OCH2-,

-O-(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -OCH2-,

-O-(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -O-;

-N(R)-(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -O-;

-(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -O-;

-(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -OCH2-;

where m, n, o, p, q and r independently represent 0, 1, 2, 3, 4, 5, 6, provided that if the number is zero, then there is no NO or O-O bond, R is selected from the groups H, methyl and ethyl and X is selected from the group H and F;

[1010] According to any aspect or embodiment described herein, the linker (L) is selected from the group consisting of:

where each m and n independently represent 0, 1, 2, 3, 4, 5 or 6.

[1011] According to any aspect or embodiment described herein, the linker (L) is selected from the group consisting of:

[1012] According to any aspect or embodiment described herein, the linker (L) is selected from the group consisting of:

, where m, n, o and p are independently 0, 1, 2, 3, 4, 5, 6 or 7.

[1013] According to any aspect or embodiment described herein, the linker (L) is selected from the group consisting of:

[1014] According to any aspect or embodiment described herein, the linker (L) is selected from the group consisting of:

[1015] According to any aspect or embodiment described herein, the linker (L) is selected from the group consisting of:

[1016] According to any aspect or embodiment described in the present invention, the linker (L) contains the following chemical structure:

Where:

W ^L1 and W ^L2 are each independently a 4-8 membered ring with 0-4 heteroatoms, optionally substituted with RQ, each RQ independently represents H, halogen, OH, CN, CF3, C1-C6 alkyl (straight-chain, branched, optional substituted), C1-C6 alkoxy (linear, branched, optionally substituted), or 2 RQ groups, taken together with the atom to which they are attached, form a 4-8 membered ring system containing 0-4 heteroatoms;

Y ^L1 each independently represents a bond, C1-C6 alkyl (straight-chain, branched, optionally substituted) and optionally one or more C atoms are replaced by O; or C1-C6 alkoxy (straight, branched, optionally substituted);

n represents 0-10; And

the dotted line indicates the point of attachment to the PTM or ULM fragments.

[1017] According to any aspect or embodiment described in the present invention, the linker (L) contains the following chemical structure:

Where:

W ^L1 and W ^L2 are each independently aryl, heteroaryl, cyclic, heterocyclic, C _1-6 alkyl, bicyclic, biaryl, biheteroaryl or biheterocyclic, each optionally substituted with ^RQ , each RQ independently representing H, halogen, OH, CN, CF ₃ , hydroxyl, nitro, C≡CH, C _2-6 alkenyl, C _2-6 alkynyl, C ₁ -C ₆ alkyl (straight, branched, optionally substituted), C ₁ -C ₆ alkoxy (straight , branched, optionally substituted), OC _1-3 alkyl (optionally substituted with 1 or more -F), OH, NH ₂ , NR ^Y1 R ^Y2 , CN, or 2 RQ groups, taken together with the atom to which they are attached form 4-8-membered ring system containing 0-4 heteroatoms;

V ^L1 each independently represents a bond, NR ^YL1 , O, S, NR ^YL2 , CR ^YL1 R ^YL2 , C=O, C=S, SO, SO ₂ , C ₁ -C ₆ alkyl (straight, branched, optionally substituted) and optionally one or more C atoms are replaced by O; C ₁ -C ₆ alkoxy (straight, branched, optionally substituted);

Q ^L is a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms, optionally bridged, optionally substituted with 0-6 R ^Q , each R ^Q independently represents H, C _1-6 alkyl (straight, branched, optionally substituted with 1 or more halogen atoms, C _1-6 alkoxy) or 2 R ^Q groups, taken together with the atom to which they are attached, form a 3-8 membered ring system containing 0-2 heteroatoms);

R ^YL1 , R ^YL2 each independently represents H, OH, C _1-6 alkyl (straight, branched, optionally substituted with 1 or more halogen atoms, C _1-6 alkoxy) or R ¹ , R ² together with the atom to which they attached, form a 3-8-membered ring system containing 0-2 heteroatoms);

n represents 0-10; And

the dotted line indicates the point of attachment to the PTM or ULM fragments.

[1018] According to any aspect or embodiment described herein, the linker (L) is selected from the group consisting of:

[1019] According to any aspect or embodiment described in the present invention, the linker (L) is a polyethyleneoxy group, optionally substituted with aryl or phenyl, containing from 1 to 10 ethylene glycol units.

[1020] According to any aspect or embodiment described in the present invention, the linker is selected from tables 1-40.

[1021] According to any aspect or embodiment described herein, the compound comprises multiple ULMs, multiple PTMs, multiple linkers, or any combination thereof.

[1022] According to any aspect or embodiment described in the present invention, the compound is selected from Table 1 to Table 43.

[1023] In any aspect or embodiment described herein, the PTM is a small molecule including a moiety that targets the B-RAF protein.

[1024] In a further aspect, the present disclosure relates to a composition.

The composition includes an effective amount of a bifunctional compound according to the present disclosure and a pharmaceutically acceptable carrier.

[1025] According to any aspect or embodiment described herein, the composition further comprises at least one additional bioactive agent or other bifunctional compound in accordance with the present disclosure.

[1026] In any aspect or embodiment described herein, the additional bioactive agent is an anticancer agent.

[1027] In another aspect, the present disclosure provides a composition comprising a pharmaceutically acceptable carrier and an effective amount of at least one compound according to the present disclosure for treating a disease or disorder in a subject, the method comprising administering the composition to the subject as needed. wherein the compound is effective in treating or alleviating at least one symptom of the disease or disorder.

[1028] According to any aspect or embodiment described herein, the disease or disorder is associated with the accumulation and aggregation of Raf.

[1029] In any aspect or embodiment described herein, the disease or disorder is a cancer; heart-face-skin syndrome; neurofibromatosis type 1; Costello syndrome; Noonan syndrome; or lentigo, electrocardiographic pathology, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retarded growth, hearing loss (LEOPARD) syndrome, associated with Raf accumulation and aggregation.

[1030] In any aspect or embodiment described herein, the cancer is renal cell carcinoma; pancreatic cancer, colorectal cancer; lung cancer; ovarian cancer; thyroid cancer; piloid astrocytoma; prostate cancer; stomach cancer; hepatocellular carcinoma or melanoma.

Claims (179)

1. Bifunctional compound characterized by chemical structure: ULM-L-PTM, or a pharmaceutically acceptable salt, enantiomer or stereoisomer thereof, Where: (i) ULM is a cereblon E3 ubiquitin ligase (CLM) binding fragment with the chemical structure represented by: (a) a von Hippel-Lindau E3 ubiquitin ligase binding fragment with the chemical structure shown as Where W represents CH ₂ or C=O; each X and Z represents an O; G represents hydrogen; Q ₁ , Q ₂ , Q ₃ and Q ₄ are independently N or C substituted with a group independently selected from hydrogen and R; A represents hydrogen; n is an integer from 1 to 4; R represents H, O, N, NH, -OR', -NR'R”, -CR'R”-, 6-membered aryl, 5- or 6-membered heteroaryl, optionally substituted straight or branched C _1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, -Cl, -F, -CF ₃ , -CN, -NO ₂ or -OCF ₃ where R is modified to covalently attach to a chemical linker group (L) ; R' and R” are independently selected from the group consisting of a bond, hydrogen and C _1-6 alkyl, wherein the alkyl is optionally substituted with halogen; And represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific; (ii) L represents a chemical linker group, which is represented by the formula: -(A ^L ) _q -, Where: (A ^L ) _q represents a group connected to the ULM or to the PTM; q is an integer from 1 to 20; each A ^L is independently selected from CR ^L1 R ^L2 , O, NR ^L3 , CO, CR ^L1 =CR ^L2 , C≡C, C _3-8 -cycloalkyl, optionally substituted with 1-6 R ^L1 groups, C _3-8 -heterocyclyl , optionally substituted with 1-6 R ^L1 groups; And each of R ^L1 , R ^L2 , R ^L3 and R ^L5 is independently selected from hydrogen, C _1-8 alkyl, OC _1-8 alkyl, OH, NH ₂ , halogen, CN, CF ₃ , CHF ₂ , CH ₂ F and NO ₂ ; And (iii) PTM is a fragment targeting the rapidly progressing fibrosarcoma protein (RAF), which has the chemical structure represented by PTM-IIa: , Where: X _PTM1 is CH; X _PTM2 , X _PTM3 , X _PTM4 , X _PTM5 and X _PTM6 are independently C or N; R _PTM5a is R _PTM5 selected from the group consisting of , , , , , , And ; R _PTM6a and R _PTM6b are each independently selected from hydrogen and halogen; R _PTM6 is hydrogen; R _PTM7 , R _PTM8 , R _PTM9 , R _PTM10 and R _PTM11 are independently selected from hydrogen, halogen, methyl, ethyl and OCH ₃ ; And at least one of R _PTM8 , R _PTM9 or R _PTM10 is modified to covalently attach to a chemical linker group (L), wherein each heteroaryl or heterocyclyl has at least 1 or 2 heteroatoms independently selected from N, O and S. 2. The bifunctional compound according to claim 1, wherein R _PTM9 represents the covalently linked position. 3. Bifunctional compound according to claim 2, where R _PTM5 is selected from: 4. Bifunctional compound according to any one of paragraphs. 1 or 2, where PTM is selected from the group consisting of: , And . 5. Bifunctional compound according to claim 1 or 2, where PTM is . 6. Bifunctional compound according to any one of paragraphs. 1-5, where ULM is selected from the group consisting of: , , , , And . 7. Bifunctional compound according to any one of paragraphs. 1-5, where CLM is characterized by a chemical structure represented by: 8. Bifunctional compound according to any one of paragraphs. 1-7, wherein the chemical linker group (L) contains a group represented by a structure selected from the group consisting of: ; ; ; ; ; ; ; where each m, n, o, p, q and r in the chemical linker group is independently 0, 1, 2, 3, 4, 5 or 6, provided that if m, n, o, p, q or r is 0, there is no NO or OO bond, R in the chemical linker group is selected from the group of H, methyl and ethyl, and X in the chemical linker group is selected from the group of H and F; wherein R in the chemical linker group is hydrogen, methyl or ethyl; X in a chemical linker group represents hydrogen or fluorine; each of m, n, o, p, q and r in a chemical linker group is independently 0, 1, 2, 3, 4, 5 or 6, provided that if m, n, o, p, q or r is 0, there is no N-O or O-O bond, and the number of units of the chemical linker group -(A ^L ) _q - does not exceed 20. 9. Bifunctional compound according to any one of paragraphs. 1-7, wherein the chemical linker group (L) is selected from the group consisting of: wherein m, n, o, p, q and r of the chemical linker group are each independently 0, 1, 2, 3, 4, 5, 6 or 7, and the number of units of the chemical linker group -(A ^L ) _q - does not exceed 20. 10. Bifunctional compound according to any one of paragraphs. 1-7, wherein the chemical linker group (L) is selected from the group consisting of: ; ; And . 11. Bifunctional compound according to any one of paragraphs. 1-7, wherein the chemical linker group (L) is selected from the group consisting of: ; ; ; where each m, n and o in the chemical linker group is independently equal to 0, 1, 2, 3, 4, 5 or 6, and the number of units of the chemical linker group -(A ^L ) _q - does not exceed 20. 12. Bifunctional compounds according to any one of paragraphs. 1-5, wherein the chemical linker group (L) is selected from the group consisting of: 13. Bifunctional compound according to any one of paragraphs. 1-7, wherein the chemical linker group is selected from the group consisting of: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; And . 14. Bifunctional compound according to claim 1, where: PTM has a chemical structure or CLM has a chemical structure selected from , , , , And , Where represents the point of attachment of the chemical linker group (L); each ^AL is independently selected from CR ^L1 R ^L2 , O, NR ^L3 , CO, C _3-8 cycloalkyl optionally substituted with 1-6 ^RL1 groups, and C _3-8 heterocyclyl optionally substituted with 1-6 ^RL1 groups; And each of R ^L1 , R ^L2 and R ^L3 is independently selected from H, halogen, C _1-8 alkyl, OH, NH ₂ , CN, CF ₃ , CHF ₂ and CH ₂ F. 15. Bifunctional compound according to claim 14, where q is equal to 5. 16. Bifunctional compound according to claim 14, where q is equal to 4. 17. Bifunctional compound according to claim 1, where the compound is selected from: , , , , , , , , , , , And . 18. Bifunctional compound according to claim 1, where the compound is selected from: , , , , , , , , , , , , And . 19. Use of the compound according to any one of paragraphs. 1-18, 22 or 23 for treating a disease or disorder associated with the accumulation and aggregation of BRaf in a subject, wherein the disease or disorder is: (a) malignant tumor; (b) heart-face-skin syndrome; (c) neurofibromatosis type 1; (d) Costello syndrome; (e) Noonan syndrome; (f) LEOPARD syndrome (lentigo, electrocardiographic abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retarded growth, hearing loss), associated with the accumulation and aggregation of Raf. 20. Use according to claim 19, wherein the disease or disorder is a malignant tumor. 21. Use according to claim 20, wherein the malignant tumor is renal cell carcinoma, pancreatic cancer, colorectal cancer, lung cancer, ovarian cancer, thyroid cancer, piloid astrocytoma, prostate cancer, gastric cancer, hepatocellular carcinoma or melanoma. 22. Bifunctional compound according to any one of paragraphs. 1-7, wherein the chemical linker group (L) is selected from the group consisting of where n in the chemical linker group is 0, 1, 2, 3, 4, 5 or 6. 23. Bifunctional compound according to any one of paragraphs. 1-7, wherein the chemical linker group (L) is selected from the group consisting of: where each m, n, o, p, q and r in the chemical linker group is independently 0, 1, 2, 3, 4, 5, 6 or 7, and the number of units of the chemical linker group -(A ^L ) _q - does not exceed 20.