JP2022500368A - Polycyclic compounds and methods for targeted degradation of rapidly progressive fibrosarcoma polypeptides - Google Patents

Abstract

The present disclosure finds usefulness as a regulator of Rapidly Accelerated Fibrosarcoma (RAFs such as c-RAF, A-RAF and / or B-RAF; target proteins) of bifunctional compounds. Regarding ULM-L-PTM. In particular, the present disclosure presents von Hippel-Lindau, Cereblon, Inhibitors of Apotosis Proteins, or each, at one end such that the target protein is placed in close proximity to the ubiquitin ligase to result in degradation (and inhibition) of the target protein. Bifunctional compounds containing a mouse double-minute homolog 2 ligand that binds to E3 ubiquitin ligase and a moiety that binds to the target protein RAF at the other end are targeted. The present disclosure presents a wide range of pharmacological activities associated with degradation / inhibition of target proteins. Diseases or disorders resulting from aggregation or accumulation of the target protein, or constitutive activation of the target protein, are treated or prevented with the compounds and compositions of the present disclosure.

Description

Mutual reference to related applications This disclosure claims the priority benefit of US Provisional Patent Application No. 62 / 728,581 filed September 7, 2018, and the US provisional patent filed December 23, 2016. As US Patent Application No. 15 / 853,166 on December 22, 2017, claiming priority to Patent Application No. 62 / 438,803 and US Provisional Patent Application No. 62 / 582,698 filed on November 7, 2017. This is a partial continuation application of US Patent Application Publication No. 2018/0179183A1 filed and published on June 28, 2018. All of these patent applications are incorporated herein by reference in their entirety.

Incorporation by reference
US Patent Application No. 15 / 230,354 filed on August 5, 2016, US Patent Application No. 15 / 206,497 filed on July 11, 2016, and filed on July 13, 2016. Published as US Patent Application No. 15 / 209,648, US Patent Application No. 62 / 406,888 filed October 11, 2016, and US Patent Application Publication No. 2015/0291562, April 14, 2015. US Patent Application No. 14 / 686,640 filed in, and US Patent Application No. 14 / 792,414 filed on July 6, 2015, published as US Patent Application Publication No. 2016/0058872, and. Published as US Patent Application Publication No. 2014/0356322, US Patent Application No. 14 / 371,956 filed on July 11, 2014, and US Patent Application Publication No. 2016/0272639, 2016 US Patent Application No. 15 / 074,820, filed March 18, is incorporated herein by reference in its entirety. In addition, all references cited herein are incorporated herein by reference in their entirety.

Description of Federally Funded Research The invention is government-sponsored under grant number NIH R35CA197589 issued by the National Institutes of Health. Government has specific rights to the invention.

The present specification provides bifunctional compounds and related uses, including a target protein binding moiety and an E3 ubiquitin ligase binding moiety. The bifunctional compound is useful as a regulator of targeted ubiquitination, and is particularly useful for RAF (Rapidly Accelerated Fibrosarcoma) proteins that are degraded and / or otherwise inhibited by the bifunctional compounds according to the present disclosure.

Most small molecule drugs bind closely to enzymes or receptors and in well-defined pockets. On the other hand, it is well known that it is difficult to target protein-protein interactions using small molecules, because of the large contact surface of proteins and the shallow furrows involved. Or because it is a flat interface. E3 ubiquitin ligase, hundreds of which are known in humans, confer substrate specificity on ubiquitination. Therefore, it has specificity for specific protein substrates and is an even more attractive therapeutic target than general-purpose proteasome inhibitors. The development of E3 ligase ligands has proven to be partially difficult due to the fact that they have to disrupt protein-protein interactions. However, recent developments have resulted in specific ligands that bind to these ligases. For example, since the discovery of Natrin, the first small molecule E3 ligase inhibitor, more compounds targeting E3 ligase have been reported, but there are still many undeveloped areas in this area. For example, since the discovery of Natrin, the first small E3 ligase MDM2 (mouse double minute 2 homolog) inhibitor, additional compounds targeting MDM2 (ie, human double minute 2 (HDM2)) E3 ligase have been reported. (J. Di, et al. Current Cancer Drug Targets (2011), 11 (8) 987-994).

The tumor suppressor gene p53 plays an important role in cell proliferation arrest and apoptosis in response to DNA damage or stress ((A. Vazquez, et al. Nat. Rev. Drug. Dis. (2008), 7, 979-982), p53 inactivation has been proposed as one of the important pathways for tumor cell survival (AJ Levine, et al. Nature (2000), 408, 307-310). Sudden p53 in cancer patients. Mutations were found in about 50% (M. Hollstein, et al. Science (1991), 233, 49-53), while patients with wild-type p53 had protein-protein interactions between p53 and MDM2. Many downregulations of p53 by MDM2 have been discovered through action (P. Chene, et al. Nat. Rev. Cancer (2003), 3, 102-109). Normal cells without carcinogenic stress signals. In the above state, MDM2 retains p53 at a low concentration. The level of p53 increases in response to DNA damage and cell stress, and the feedback loop from the auto-control system of p53 / MDM2 also causes an increase in MDM2. In other words, p53 regulates MDM2 at the transcriptional level, and MDM2 regulates p53 at its activity level (AJ Levine, et al. Genes Dev. (1993) 7, 1126-1132).

Several mechanisms can explain the downward control of p53 by MDM2. First, MDM2 binds to the N-terminal domain of p53 and inhibits the expression of p53-responsive genes (J. Momand, et al. Cell (1992), 69, 1237-1245). MDM2 then reciprocates p53 from the nucleus to the cytoplasm, facilitating proteolytic degradation (J. Roth, et al. EMBO J. (1998), 17, 554-564). Finally, MDM2 has intrinsic E3 ligase activity that binds ubiquitin to p53 and degrades it through the ubiquitin-dependent 26s proteasome system (UPS) (Y. Haupt, et al. Nature (1997) 387, 296-299). Since MDM2 functions as an E3 ligase, recruiting MDM2 to a disease-causing protein and exerting its ubiquitination and degradation activity is a very interesting drug development method.

One of the attractive therapeutic potential E3 ligases is the von Hippel-Lindau (VHL) tumor suppressor, which is the substrate recognition subunit of the E3 ligase complex VCB and this complex. The body further consists of elongin B and C, Cul2 and Rbx1. The main substrate for VHL is hypoxia-inducible factor 1α (HIF-1α), which upregulates genes such as the angiogenic growth factor VEGF and the erythropoietic cytokine erythropoietin in response to low-level oxygen. It is a transcription factor that rates. The first low molecular weight ligand for von Hippel-Lindou (VHL) for the substrate recognition subunit of E3 ligase was generated and the crystal structure was obtained, and this compound is the transcription factor HIF, which is the main substrate for VHL.
It was confirmed that it mimics the binding mode of -1α.

Cereblon is a protein encoded by the CRBN gene in humans. CRBN orthologs are highly conserved from plants to humans, a clear indication of their physiological importance. Cereblon is a damaged DNA-binding protein 1 (
It forms an E3 ubiquitin ligase complex with DDB1), quince (Cullin) -4A (CUL4A), and quince 1 (Cullins1) regulator (ROC1). This complex ubiquitinates many other proteins. Celebron ubiquitination of the target protein results in increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10) through a mechanism that has not been fully elucidated. FGF8 then regulates a number of developmental processes, such as the formation of limbs and ear follicles. It is finally concluded that this ubiquitin ligase complex is important for limb growth in the embryo. In the absence of cereblon, DDB1 forms a complex with DDB2 and functions as a DNA damage binding protein.

Inhibitor of Apoptosis Proteins (IAP) is a family of proteins involved in apoptosis, or cell death. There are eight species in the human IAP family, and many other organisms also contain IAP homologs. IAP contains an E3 ligase-specific domain and a baculoviral IAP repeat (BIR) domain, which recognize the substrate and promote its ubiquitination. IAP can promote ubiquitination and bind and inhibit caspase directly. Caspases are proteases that perform apoptosis (eg, caspase-3, caspase7, and caspase9). Therefore, through the binding of caspase, IAP inhibits cell death. However, pro-apoptotic stimuli result in the release of the mitochondrial proteins DIABLO (also known as second mitrochondria-derived activator of caspases, or SMAC) and HTRA2 (also known as Omi). The binding of DIABLO to HTRA2 is thought to inhibit IAP activity.

SMAC interacts with essentially 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 a portion of IAP. This is believed to be essential for the inhibition of the anti-apoptotic effect of IAP.

Bifunctional compounds, such as those described in US Patent Application Publication Nos. 2015-0291562 and 2014-0356322 (incorporated herein by reference), recruit endogenous proteins into E3 ubiquitin ligase. Functions to disassemble. In particular, the patent publication describes a bifunctional or proteolysis targeting chimeric (PROTAC) compound, which is used as a regulator of targeted ubiquitination of various polypeptides and other proteins. The usefulness of these is found, and they are degraded and / or inhibited by other means by the bifunctional compound.

There is a continuing need in the art of effective treatment of diseases associated with overexpression or aggregation of RAF (Rapidly Accelerated Fibrosarcoma), or overactivation of RAF (such as constitutively active RAF). For example, current BRaf inhibitors (such as vemurafenib and dabrafenib) may target the V600 mutant BRaf. Therefore, there is a need for diseases or disorders with different BRaf mutations that are insensitive to drugs currently on the market, such as melanoma, lung cancer, pancreatic cancer, and / or colorectal cancer. In addition, resistance mutations may appear in response to BRaf / MEK inhibitor therapy. For example, the p61 splicing variant may appear in melanoma patients treated with BRaf / MEK inhibitor therapy, and these patients remain without clinical options. Drugs currently on the market also lead to and cause bizarre activation of wild-type BRaf, leading to clinical complications. In addition, a family of low-activity class III BRaf mutants signaled through heterodimerization with CRaf is 40% of BRaf mutations in non-small cell lung cancer (NSCLC).
It is not possible to target any currently approved or clinically staged BRaf inhibitors that make up and are sporadic throughout other cancers. Class I BRAF variants (V600E, V600K, V600D) have high kinase activity, are independent of Ras and dimerization, and are sensitive to vemuragenib. Class II BRAF variants have high to moderate kinase activity, are Ras-independent, dimerization-dependent, and insensitive to vemurafenib. Class III BRAF variants have little or no kinase activity, are dependent on Ras and dimerization, and are insensitive to vemurafenib.

Therefore, non-specific effects and inability to target and regulate RAF remain obstacles to the development of effective therapies. Thus, it effectively targets RAF (eg, keeps wild-type BRaf while effectively inhibiting and / or degrading mutant forms of BRaf), and substrate specificity for VHL, cereblon, MDM2, and IAP. If there is a low molecular weight therapeutic agent that utilizes or enhances the above, it will be very useful.

The present disclosure describes bifunctional compounds that function to recruit and degrade endogenous proteins into E3 ubiquitin ligase, and how to use them. In particular, the present disclosure provides bifunctional or proteolysis targeting chimeric (PROTAC) compounds, which are used as regulators of targeted ubiquitination of various polypeptides and other proteins. Usefulness has been found, and these polypeptides and other proteins are degraded and / or inhibited by alternative means by the bifunctional compounds described herein. The advantages of the compounds provided herein may have a wide range of pharmacological activities and are consistent with the degradation / inhibition of target polypeptides from virtually any protein species or family. In addition, the present specification describes disease states such as cancer (eg, renal cell carcinoma, pancreatic cancer, etc.).
Colon-rectal cancer, lung cancer, ovarian cancer, thyroid cancer, hairy cell stellate cell tumor, prostate cancer, gastric cancer, hepatocellular carcinoma, and melanoma), heart / face / skin syndrome, neurofibromatosis type 1, Costello syndrome , Noonan Syndrome, LEOPARD (Mole, ECG Abnormality, Binocular Isolation, Pulmonary Arterial Valve Narrowing, Genital Abnormality, Growth Delay, Hearing Impairment) Syndrome. Provide a method.

Accordingly, in one embodiment, the present disclosure provides a bifunctional compound or a PROTAC compound, which comprises an E3 ubiquitin ligase binding moiety (ie, a ligand for E3 ubiquitin ligase, or a "ULM" group) and a target protein. Contains a moiety that binds to (ie, a protein / polypeptide targeting ligand, or "PTM" group), whereby the target protein / polypeptide is placed in close proximity to the ubiquitin ligase to degrade (and inhibit) the protein. It works. In a preferred embodiment, ULM (ubiquitinized ligase regulator) is von Hippel-Lindow E3 ubiquitin ligase (VHL) binding moiety (VLM), or Celebron E3 ubiquitin ligase binding moiety (CLM), or MDM2 (mouse double miniute 2 homolog). ) E3 ubiquitin ligase binding moiety (MLM), or IAP E3 ubiquitin ligase binding moiety (ie, "ILM"). For example, the structure of a bifunctional compound can be shown as follows:

The respective positions of the PTM and ULM moieties (eg VLM, CLM, MLM or ILM) exemplified herein, as well as their numbers, are provided for illustrative purposes only and limit the compound in any way. Is not intended. As will be appreciated by those skilled in the art, the bifunctional compounds described herein can be synthesized such that the number and position of each functional moiety can be varied as desired.

In certain embodiments, the bifunctional compound further comprises a chemical linker (L). In this example, the structure of the bifunctional compound can be shown as follows:

In the formula, PTM is a protein / polypeptide targeting moiety, L is a linker, eg, a binding or chemical group that binds PTM to ULM, and ULM is an IAP E3 ubiquitin ligase binding moiety, or von Hippel-Lindow E3. Ubiquitin ligase (VHL) binding moiety (VLM) or Celebron E3 ubiquitin ligase binding moiety (CLM), or MDM2 (mouse double miniute 2 homolog) E3 ubiquitin ligase binding moiety (MLM).

For example, the structure of a bifunctional compound can be shown as follows:

In the formula, PTM is the protein / polypeptide targeting moiety; "L" is a linker (eg, binding) that binds PTM to at least one of VLM, CLM, MLM, ILM, or a combination thereof. , Or a chemical linker group); VLM is the Von Hippel-Lindau E3 ubiquitin ligase binding moiety that binds to VHL E3 ligase; CLM is the Celebron E3 ubiquitin ligase binding moiety that binds to Celebron. Yes; MLM is the MDM2 E3 ubiquitin ligase binding moiety; and ILM is the IAP binding moiety that binds to IAP.

In certain preferred embodiments, the ILM is a tetrapeptide fragment of AVPI. Thus, in certain additional embodiments, the ILM of the bifunctional compound is the amino acids alanine (A), valine (V).
), Proline (P), and isoleucine (I) or their non-natural mimetics, respectively. In additional embodiments, the amino acids of the AVPI tetrapeptide fragment are attached to each other via an amide bond (ie, -C (O) NH- or -NHC (O)-).

In certain embodiments, the compounds described herein include ULMs, PTMs, chemical linkers, or multiples independently selected from a combination thereof.

In certain embodiments, the ILM includes chemical moieties such as those described herein.

In additional embodiments, VLM can be hydroxyproline or a derivative thereof. In addition, another expected VLM is the VLM in US Patent Application Publication No. 2014/03022523, as discussed above, which application is incorporated herein in its entirety.

In certain embodiments, the CLM comprises an imide, thioimide, amide, or a chemical group derived from a thioamide. In certain embodiments, the chemical group is a phthalimide group, or an analog or derivative thereof. In certain embodiments, the CLM is thalidomide,
Lenalidomide, pomalidomide, its analogs, its isostars, or its derivatives. Another expected CLM is the CLM in U.S. Patent Application Publication No. 2015/0291562, which is incorporated herein in its entirety.

In certain embodiments, the MLM can be natrin or a derivative thereof. In addition, other expected MLMs include those in U.S. Patent Application No. 15 / 206,497 filed on July 11, 2016, as discussed above, which is the entire application. Incorporated in the specification. In certain additional embodiments, the MLM of the bifunctional compound may be, for example, substituted imidazoline, substituted spiro-indolinone, substituted pyrrolidine, substituted piperidinone, substituted substituted morpholinone, substituted pyrolopyrimidine, substituted imidazolopyridine, substituted thiazolomidazoline, substituted. Includes chemical moieties such as pyrrolopyrolidinones and substituted isoquinolinones.

In additional embodiments, the MLM comprises the core structure described above with adjacent bis-aryl substitutions positioned as cis or trans configurations.

In certain embodiments, "L" is a bond. In an additional embodiment, the linker "L" is 1
A connector with a linear number of non-hydrogen atoms in the range of ~ 20. "L" of the connector is
It may include, but is not limited to, functional groups such as ethers, amides, alkanes, alkenes, alkynes, ketones, hydroxyls, carboxylic acids, thioethers, sulfoxides, and sulfones. The linker may include aromatic, aromatic heterocyclic, cyclic, bicyclic, and tricyclic parts. Substitutions with halogens such as Cl, F, Br and I may be included in the linker. In the case of fluorine substitution, one or more fluorines may be included.

In certain embodiments, VLM is a derivative of trans-3-hydroxyproline, where both nitrogen and carboxylic acid in trans-3-hydroxyproline are functional as amides.

In certain embodiments, the CLM is a derivative of piperidine-2,6-dione, the piperidine-2,6-dione may be substituted at the 3-position, and the 3-position substitution is CN. It may be a bicyclic hetero-aromatic compound with a bond or a bond as a CC bond. Examples of CLM include, but are not limited to, pomalidomide, lenalidomide and thalidomide and their derivatives.

In an additional aspect, the present specification provides a therapeutic composition comprising an effective amount of a compound described herein or a salt form thereof, and a pharmaceutically acceptable carrier. Therapeutic compositions can be used in a patient or subject, eg, an animal such as a human, to regulate the degradation of a protein and to treat or ameliorate a medical condition or condition regulated via the degraded protein. In certain embodiments, the therapeutic compositions described herein can be used to cause degradation of a protein of interest for the purpose of treating or ameliorating a disease, eg, cancer. In yet another embodiment, the present disclosure provides a method of ubiquitinating / degrading a target protein in a cell. In certain embodiments, the method comprises ILM and PTM, PTM and VLM, or PTM and CLM, or PTM and MLM, preferably coupled via a linker moiety, as described elsewhere herein. Containing the administration of the bifunctional compounds described herein, where VLM / ILM / CLM / MLM are bound to PTM via a linker to target and degrade proteins that bind to PTM. Similarly, PTM can be linked to VLM or CLM or MLM or ILM via a linker to degrade a protein or polypeptide. Degradation of the target protein occurs when the target protein is placed in close proximity to the E3 ubiquitin ligase, resulting in degradation of the target protein / inhibition of the effect of the target protein and regulation of the protein level. The regulation of protein levels provided by the present disclosure provides treatment for a pathological condition or condition, which is regulated via a target protein by lowering the level of that protein in patient cells.

In yet another embodiment, the specification provides a method of treating or ameliorating a disease, disorder or symptom thereof in a subject or patient, such as an animal such as a human, which is described herein. The present invention comprises administering to a subject in need a composition comprising a therapeutically effective amount of the compound or a salt form thereof and a pharmaceutically acceptable carrier, in which case the composition is in the subject. It is effective in treating or ameliorating a disease or disorder or its symptoms.

In another aspect, the present specification provides a method of identifying the degrading effect of a protein of interest in a biological system using the compounds according to the present disclosure.

The above general statement of usefulness is presented for illustrative purposes only and is not intended to limit the scope of this disclosure and attachment claims. Additional objectives and advantages associated with the compositions, methods, and processes of the present disclosure will be apparent to those skilled in the art in light of the claims, detailed description, and examples. For example, the various aspects and embodiments of the present disclosure can be used in many combinations, all of which are expressly expected herein. These additional embodiments and embodiments are expressly included within the scope of the present disclosure. The publications and other materials used herein to explain the background of this disclosure and, in certain cases, to provide additional details with respect to practice, are incorporated by reference.

The accompanying drawings that are incorporated into and form part of this specification illustrate some embodiments of the present disclosure and serve to explain the principles of the present disclosure along with the description of the specification. The drawings are for purposes of illustration only of the embodiments of the present disclosure and are not construed as limiting the present disclosure. Further objectives, features and advantages of the present disclosure will become apparent from the following detailed description, along with the accompanying drawings illustrating exemplary embodiments of the present disclosure.

The figure of the general principle of the bifunctional compound of this disclosure. (A) Exemplary bifunctional compounds include protein targeting moieties (PTM; dark shaded rectangles), ubiquitin ligase binding moieties (ULM; bright shaded triangles), and optionally PTM binding or linking to ULM. Includes linker moiety (L; black line). (B) Illustrate the functional uses of the bifunctional compounds described herein. Briefly, ULM recognizes and binds to a particular E3 ubiquitin ligase, and PTM binds to and recruits the target protein, bringing it closer to the E3 ubiquitin ligase. Typically, the E3 ubiquitin ligase is complexed with the E2 ubiquitin-binding protein and catalyzes the ubiquitin binding via isopeptide bond to lysine on the target protein, alone or via the E2 protein (dark color). Circle). The polyubiquitinated protein (far right) is then targeted for degradation by the cell's proteasome mechanism. The figure of the general principle of the bifunctional compound of this disclosure. (A) Exemplary bifunctional compounds include protein targeting moieties (PTM; dark shaded rectangles), ubiquitin ligase binding moieties (ULM; bright shaded triangles), and optionally PTM binding or linking to ULM. Includes linker moiety (L; black line). (B) Illustrate the functional uses of the bifunctional compounds described herein. Briefly, ULM recognizes and binds to a particular E3 ubiquitin ligase, and PTM binds to and recruits the target protein, bringing it closer to the E3 ubiquitin ligase. Typically, the E3 ubiquitin ligase is complexed with the E2 ubiquitin-binding protein and catalyzes the ubiquitin binding via isopeptide bond to lysine on the target protein, alone or via the E2 protein (dark color). Circle). The polyubiquitinated protein (far right) is then targeted for degradation by the cell's proteasome mechanism. [FIG. 2A-1] to [FIG. 2A-88] Table 1A. Exemplary protein targeting moieties and compounds of the present disclosure. [FIG. 2B-1] to [FIG. 2B-117] Table 1B. Exemplary protein targeting moieties and compounds of the present disclosure. [FIG. 2C-1] to [FIG. 2C-40] Table 1C. Exemplary protein targeting moieties and compounds of the present disclosure. [FIG. 2D-1] to [FIG. 2D-6] Table 1D. Exemplary protein targeting moieties and compounds of the present disclosure. [FIG. 3A-1] to [FIG. 3A-71] Table 2A. Data of exemplary protein targeting moieties and compounds of the present disclosure. [FIG. 3B-1] to [FIG. 3B-63] Table 2B. Data of exemplary protein targeting moieties and compounds of the present disclosure. [FIG. 3C-1] to [FIG. 3C-20] Table 2C. Data of exemplary protein targeting moieties and compounds of the present disclosure. [Fig. 3D-1] to [Fig. 3D-4] Table 2D. Data of exemplary protein targeting moieties and compounds of the present disclosure. The figure of the general principle of the bifunctional compound of this disclosure. The exemplary bifunctional compounds of the present disclosure induce mutant-selective degradation of BRAF. The exemplary bifunctional compounds of the present disclosure induce mutant BRAF degradation, inhibit cell proliferation, and suppress MAPK signaling while preserving wild-type BRAF. The exemplary bifunctional compounds of the present disclosure induce mutant BRAF degradation, inhibit cell proliferation, and suppress MAPK signaling while preserving wild-type BRAF. [Fig. 6C-1]-[Fig. 6C-2] The exemplary bifunctional compounds of the present disclosure are wild-type while inducing mutant BRAF degradation, inhibiting cell proliferation, and suppressing MAPK signaling. BRAF preserves. The exemplary bifunctional compounds of the present disclosure induce degradation of the vemurafenib resistant mutant p61. Exemplary bifunctional compounds of the present disclosure induce degradation of mutant BRAF in vivo (a) and reduce tumor volume (B). Exemplary bifunctional compounds of the present disclosure induce degradation of mutant BRAF in vivo (a) and reduce tumor volume (B). The mechanism underlying the selectivity of exemplary bifunctional compounds. The mechanism underlying the selectivity of exemplary bifunctional compounds. Wild-type BRAF cannot recruit Cullin 2 (active E3 ligase).

The following is a detailed description provided to assist those skilled in the art in implementing this disclosure. A person skilled in the art may modify or modify the embodiments described herein without departing from the spirit or scope of the present disclosure. All published documents, patent applications, patents, drawings and other references referred to herein are expressly incorporated by reference in their entirety.

E3 ubiquitin ligase protein and a bifunctional or chimeric construct that binds to the target protein, such as E3 ubiquitin ligase protein (eg, apoptosis inhibitor (IAP), von hippel-lindow E3 ubiquitin ligase (VHL), celebrone E3 ubiquitin ligase, or mouse A composition and method for the surprising and unexpected finding of ubiquitinating a target protein when the double minute 2 homolog (MDM2) E3 ubiquitin ligase) and the target protein are placed in close proximity are described herein. Accordingly, the present disclosure provides compounds and compositions such as those comprising an E3 ubiquitin ligase binding moiety (ULM) bound to a protein target binding moiety (PTM), which results in ubiquitination of the selective target protein. This leads to the degradation of the target protein by the proteasome (Fig. 1).
See). The present disclosure also provides a library of compositions and their use.

In certain embodiments, the present disclosure discloses a ligand, eg, a small molecule ligand (ie, 2,000).
Compounds comprising daltons (having a molecular weight of less than daltons, 1,000 daltons, 500 daltons, or 200 daltons) are provided, and the compounds can be attached to ubiquitin ligases such as IAP, VHL, MDM2 or cereblon. The compound also includes a moiety capable of placing the target protein in close proximity to the ubiquitin ligase and binding to the target protein in such a way as to cause degradation (and / or inhibition) of the protein. In addition to the above, a small molecule can mean that the molecule is non-peptidyl. That is, they are often not considered peptides, for example containing less than 4, 3, or 2 amino acids. According to the present specification, the PTM, ULM, or PROTAC molecule may be a small molecule.

Unless otherwise defined, all technical and scientific terms used herein are.
It has the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. The terminology used herein is for illustration purposes only and is not intended to limit this disclosure.

If a range of values is provided, unless explicitly stated otherwise in the context (eg, for groups containing a certain number of carbon atoms, each carbon atom number within that range is provided). And it should be understood that each intervening value up to one tenth of the lower bound unit, between the upper and lower bounds of any other designated range, or the intervening value within that specified range is included within the scope of the invention. The upper and lower limits of these smaller ranges may be independently included in the smaller range, which is also included within the present disclosure and is any specifically excluded boundary value within the specified range. If the specified range includes one or both of the boundary values, then any of the included boundary values, or a range that excludes both, is also included in the present disclosure.

The following terms are used to describe this disclosure. If a term is not specifically defined herein, the term is given a meaning recognized in the art by those skilled in the art applying the term at the discretion of its use in the description of the present disclosure.

As used herein, the articles "a" and "an" shall be one or more (ie, at least one) of the grammatical objects of the article, unless expressly indicated otherwise by the context. As used herein to refer to one). As an example, "element" means one element or multiple elements.

As used herein and in the claims, the phrase "and / or" is to be understood to mean "either or both" of the elements so combined. That is, in some examples the elements are connected and in others they are not. Multiple elements listed using "and / or" should be interpreted in the same way. That is, "one or more" of the elements are so combined. Other elements other than those specifically specified by the "and / or" clause may optionally exist, whether or not they are related to those specifically specified elements. Thus, as a non-limiting example, when used in conjunction with open-ended wording, such as "contains," the reference to "A and / or B" refers only to A in one embodiment. May (optionally include elements other than B); in another embodiment it may refer only to B (optionally includes elements other than A); in yet another embodiment A and B May refer to both (optionally, including other elements); etc.

As used herein and in the claims, "or" should be understood to have the same meaning as "and / or" as defined above. For example, "or" or "and / or" shall be construed as comprehensive when separating items in a list. That is, it contains many elements, or at least one of a list of elements, but also more than one, and optionally additional items not listed. Only terms that clearly suggest the opposite, for example "only one of" or "exactly one of", or "consisting of" when used in the claims. , Many elements, or the inclusion of exactly one element in the list of elements. As used herein in general, the term "or" means, for example, "any", "one of", "only one of", or "exactly of". It should be construed to indicate an exclusive option (ie, "one or other, but not both") only if it is preceded by an exclusive term such as "one".

In the claims, as well as in the specification described above, "comprising,""including,""carrying,""having," and "containin."
All transitional phrases such as "g)", "involving", "holding", and "composed of" are non-limiting, i.e. including but not limited. Please understand that it means. Only the transitional phrases "consisting of" and "consisting essentially of" shall be limited or semi-restricted transitional phrases, respectively, which is the US Patent Examination Standard. It is described in Section 2111.03 of.

As used herein, in the specification and claims, with respect to a list of one or more elements, the phrase "at least one" is selected from any one or more of the elements in the element list. It should be understood to mean at least one element that is, but does not necessarily include at least one of all the elements specifically listed in the element list, but any of the elements in the element list. It does not exclude the combination of. In addition, this definition can optionally include elements other than those specifically identified in the element list pointed to by the phrase "at least one", with or without the relevance of those specifically identified elements. Allow it to exist. Thus, as a non-limiting example, "at least one of A and B (or equivalently, at least one of A or B", or equivalently, "at least of A and / or B". "One") may refer to at least one in one embodiment, in which B is absent (and optionally contains elements other than B) and optionally comprises a plurality of A's; another embodiment. May refer to at least one in which A does not exist (and optionally contains elements other than A), optionally contains more than one B; and in yet another embodiment optionally contains more than one A. May refer to at least one, and optionally at least one (and optionally other elements), including more than one B. Such.

In certain methods described herein that include multiple steps or actions, the order of the steps or actions of the method is not necessarily the order in which the steps or actions of the method are listed, unless otherwise indicated by the context. Not limited.

"Co-administration" and "co-administering"
) ”Or“ combination therapy ”is the time between simultaneous administration (simultaneous administration of two or more therapeutic agents) and the simultaneous presence of the therapeutic agent in the patient's body to some extent, preferably at the same time. (To administer one or more therapeutic agents at a time different from the time of administration of the additional therapeutic agent). In certain preferred embodiments, one or more of the compounds described herein are co-administered in combination with at least one additional bioactive agent, particularly including an anti-cancer agent. In a particularly preferred embodiment, co-administration of the compounds results in synergistic activity and / or treatment, including anti-cancer activity.

As used herein, unless otherwise indicated, the term "compound" refers to any specific chemical compound disclosed herein, a metavariant, a positional isomer, and the like. Geometric isomers, and steric isomers, including optical isomers (mirror isomers) and other steric isomers (diasteromers) where appropriate, and their prodrugs and / or weights where appropriate in the context. Includes pharmaceutically acceptable salts and derivatives, including hydrides. The expected deuterated small molecule is a small molecule in which one or more of the hydrogen atoms contained in the drug molecule is replaced with deuterium.

Within its use in the context, the term compound generally refers to a single compound, such as stereoisomers, positional isomers and / or optical isomers (including racemic mixtures) and specific enantiomers of the disclosed compounds. Other compounds, such as isomers or mixtures enriched with specific enantiomers, may be included. The term also refers in the context of a prodrug form of a compound modified to facilitate administration and deliver the compound to the active site. It should be noted that in the description of this compound, many substituents, and in particular the variables associated with them, are mentioned. Those skilled in the art will appreciate that the molecules described herein are stable compounds as outlined below. Where binding is indicated, both double and single bonds are expressed or understood in the context of the compounds shown and known rules for valence interactions.

The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to a particular substrate protein and target that substrate protein for degradation. For example, the IAP E3 ubiquitin ligase protein, which adds ubiquitin to lysine on a target protein, either in combination with or alone with E2 ubiquitin ligase, and then targets that particular protein substrate for proteasome degradation. Thus, in complex with E2 ubiquitin-binding enzyme, or alone, E3 ubiquitin ligase is involved in the transfer of ubiquitin to the targeted protein. In general, ubiquitin ligase is involved in polyubiquitination, whereby a second ubiquitin is added to the first ubiquitin; a third ubiquitin is added to the second ubiquitin. Polyubiquitination marks the protein against proteasome degradation. However, there are some ubiquitination events that are limited to monoubiquitination, in which case only one ubiquitin is added to the substrate molecule by ubiquitin ligase. Monoubiquitinated proteins do not target the degradation of the proteasome, but instead alter their intracellular location and function through binding to other proteins that have domains to which ubiquitin can bind, for example. May cause you to. Further complicating the problem is that another lysine on ubiquitin can be targeted by E3 to form a chain. The most common lysine is Lys48 on the ubiquitin chain. It is the lysine used to produce the polyubiquitin recognized by the proteasome.

The term "patient" or "subject" is used throughout the specification to describe an animal, preferably a human or livestock, for which treatment is provided, including prophylactic treatment with the compositions according to the present disclosure. With respect to the treatment of an infectious disease, condition or condition specific to a particular animal, for example a human patient, the term patient refers to domestic animals such as dogs or cats, or agricultural animals such as horses, cows, sheep. Refers to a specific animal, including. In general, the term patient in the present disclosure refers to a human patient unless otherwise indicated or implied by the circumstances in which the term is used.

The term "effective" is used to describe the amount of compound, composition, or component that, when used within the context of its intended use, produces the intended result. The term valid includes all other terms of effective amount or concentration, which are described or used separately in this application.

Compounds and Compositions In one embodiment, the specification herein is IAP E3 ubiquitin ligase binding moiety (ILM), Celebron E3 ubiquitin ligase binding moiety (CLM), von Hippel-Lindau E3 ubiquitin ligase binding moiety (VLM), And / or a compound comprising an E3 ubiquitin ligase binding moiety (ULM), which is a mouse double minute 2 homologue (MDM2) E3 ubiquitin ligase binding moiety (MLM). In an exemplary embodiment, ULM is linked to a target protein binding moiety (PTM) via a chemical linker (L) according to the following structure:
(A) PTM-L-ULM
In the formula, L is a binding or chemical linker group, ULM is an E3 ubiquitin ligase binding moiety, and PTM is a target protein binding moiety. The number and / or relative positions of the moieties in the compounds described herein are provided for illustrative purposes only. As will be appreciated by those of skill in the art, the compounds described herein can be synthesized with any desired number of each functional group moiety and / or at relative positions of each functional group moiety.

The terms ULM, ILM, VLM, MLM and CLM are used in their comprehensive sense unless the context suggests otherwise. For example, the term ULM includes all ULMs that bind to IAP (ie ILM), MDM2 (ie MLM), cereblon (ie CLM), and VHL (ie VLM). In addition, the term ILM includes all possible IAP E3 ubiquitin ligase binding moieties, the term MLM includes all possible MDM2 E3 ubiquitin ligase binding moieties, and the term VLM includes all possible MDM2 E3 ubiquitin ligase binding moieties. Includes one VHL binding moiety, and the term CLM includes all cereblon binding moieties.

In another aspect, the present disclosure provides bifunctional or polyfunctional compounds (eg, PROTAC) useful for controlling protein activity by inducing degradation of a target protein. In certain embodiments, the compound comprises an ILM or VLM or CLM or MLM that is directly or indirectly bound to a moiety that binds to a target protein (ie, a protein targeting moiety or "PTM"), eg, by covalent bond. include. In certain embodiments, ILM / VLM / CLM / MLM and PTM are linked or linked via a chemical linker (L). ILM binds to IAP E3 ubiquitin ligase, VLM binds to VHL, CLM binds to cereblon E3 ubiquitin ligase,
And MLM binds to MDM2 E3 ubiquitin ligase, and PTM recognizes the target protein, and by placing the target protein and the ubiquitin ligase protein in close proximity, the interaction between each moiety and its target is targeted. Promotes protein degradation. Exemplary bifunctional compounds can be shown as:
(B) PTM-ILM
(C) PTM-CLM
(D) PTM-VLM
(E) PTM-MLM
In certain embodiments, the bifunctional compound further comprises a chemical linker (L). For example, a bifunctional compound can be shown as:
(F) PTM-L-ILM
(G) PTM-L-CLM
(H) PTM-L-VLM
(I) PTM-L-MLM
In the formula, PTM is the protein / polypeptide targeting moiety, L is the chemical linker, and ILM.
Is the IAP E3 ubiquitin ligase binding moiety, CLM is the cereblon E3 ubiquitin ligase binding moiety, VLM is the VHL binding moiety, and MLM is the MDM2 E3 ubiquitin ligase binding moiety.

In certain embodiments, ULM (eg, ILM, CLM, VLM, or MLM) is an E3 ubiquitin ligase (eg, IAP E3 ubiquitin ligase, cereblon E3 ubiquitin ligase, VHL, or MDM2 E3 ubiquitin ligase _{) with an IC 50 of less than about 200 μM.} ) Shows or binds to. The IC ₅₀ can be determined according to any method known in the art, such as, for example, a fluorescent polarization assay.

In certain additional embodiments, the bifunctional compounds described herein are about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, less than 0.001 mM, or about 100, 50, 10. , 1, 0.5, 0.1, 0.05, 0.01, 0.005, less than 0.001 μM, or about 100, 50, 10, 1, 1, 0.5, 0.1, 0.05, 0.01, 0.005, less than 0.001 nM, or about 100, 50, 10, 1 , 0.5, 0.1, 0.05, 0.01, 0.005, show activity _{of IC 50 below 0.001 pM.}

In certain embodiments, the compounds described herein are multiple PTMs (targeting the same or different protein targets), multiple ULMs, one or more ULMs (ie, multiple / different E3 ubiquitin ligases, eg). VHL, IAP, cereblon, and / or moieties that specifically bind to MDM2) or combinations thereof. In any of the embodiments or embodiments described herein, PTM and ULM (eg, ILM, VLM, CLM, and / or MLM) are linked directly or via one or more chemical linkers, or a combination thereof. can do. In additional embodiments, if the compound has multiple ULMs, those ULMs may be for the same E3 ubiquitin ligase, or each ULM may specifically bind to another E3 ubiquitin ligase. .. In a further embodiment, if the compound has multiple PTMs, those PTMs may bind to the same target protein, or each PTM may specifically bind to another target protein.

In certain embodiments, if the compound comprises more than one ULM, those ULMs are the same. In additional embodiments, the compound comprises at least one PTM that is attached to ULM by multiple ULMs (eg ULM, ULM'), directly or via a chemical linker (L), or both. In certain additional embodiments, a compound containing multiple ULMs further comprises multiple PTMs. In a further additional embodiment, the PTMs are the same or optionally different. In a further embodiment, if the PTMs are different, each PTM may bind to the same protein target or may specifically bind to a different protein target.

In certain embodiments, the compound may comprise more than one ULM and / or more than one ULM'. In a further embodiment, a compound containing at least two different ULMs, multiple ULMs, and / or multiple ULMs were attached to ULMs or ULMs directly, via a chemical linker, or both. Further includes at least one PTM. In any of the embodiments described herein, a compound comprising at least two different ILMs may further comprise a plurality of PTMs. In a further additional embodiment, the PTMs are the same or optionally different. In a further embodiment, if the PTMs are different, each PTM may bind to the same protein target or may specifically bind to a different protein target. In a further embodiment, the PTM itself is an ULM (or ULM') such as, for example, ILM, VLM, CLM, MLM, ILM', VLM', CLM', and / or MLM'.

In additional embodiments, the present specification comprises mirror isomers, diastereomers, solvates and polymorphs thereof, including pharmaceutically acceptable salt forms thereof, such as acid salt and base salt forms. The compounds described herein are provided.

As used herein, the term "independently" is used to indicate that an independently applied variable changes independently with each application.

The term "alkyl" should, in its context, mean a linear, branched, or cyclic fully saturated hydrocarbon radical or alkyl group, preferably C _1- C ₁₀ , more preferably. Are alkyl radicals of C ₁ -C ₆ or C _{1 -C 3} , which can be optionally substituted. Examples of alkyl groups are especially methyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, 2-methyl-propyl, cyclopropyl, Cyclo-propyl-methyl, cyclobutyl, cyclopentyl, cyclopentylethyl, cyclohexylethyl, and cyclohexyl. In certain embodiments, the alkyl group is end capped with a halogen group (At, Br, Cl, F, or I). In certain preferred embodiments, the compounds according to the present disclosure may be used to covalently bind to the dehalogenase enzyme. These compounds generally contain a side chain (often attached via a polyethylene glycol group), which side chain is an alkyl group having a halogen substituent (often chlorine or bromine) at its distal end. It ends with, which results in a covalent bond between the compound containing the moiety and the protein.

The term "alkenyl" refers to a straight, branched or cyclic C _2- C ₁₀ (preferably C _2- C ₆ ) hydrocarbon radical containing at least one C = C bond.

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.

The term "alkylene", when used, can be optionally substituted-(CH ₂ ) _n- refers to a group (n is generally an integer from 0 to 6). When substituted, the alkylene group is preferably one or more of the methylene groups and _{is preferably substituted with a C 1-} C ₆ alkyl group (including a cyclopropyl group or a t-butyl group), but one or more. Halo group, preferably 1 to 3 halo groups, or one or two hydroxyl groups, O- (C _1- C ₆ alkyl) groups, or substituted with amino acid side chains disclosed elsewhere herein. May be done. In certain embodiments, the alkylene groups may be substituted with urethane or alkoxy groups (or other groups), which are further polyethylene glycol chains (1-10, preferably 1-6, often 1-6). Is substituted with a chain of 1 to 4 ethylene glycol units), to which the alkyl group is substituted (preferably on the distal end of the polyethylene glycol chain), the alkyl chain is a halogen group, It is preferably substituted with a chlorine group. In yet other embodiments, the alkylene (often methylene) group is a natural or unnatural amino acid, such as, for example, alanine, β-alanine, arginine, aspartic acid, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine. , Phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan or tyrosine side chain groups may be substituted with amino acid side chain groups.

The term "unsubstituted" shall mean that it has been substituted only with a hydrogen atom. The range of carbon atoms containing C ₀ means that carbon was absent and was replaced by H. Therefore, _{the range of carbon atoms of C 0} -C ₆ includes 1, 2, 3, 4, 5 and 6 carbon atoms, and for C ₀ there is H instead of carbon.

The term "substituted" or "optionally substituted" refers to one or more substituents (on a moiety in a compound according to the present disclosure) at any carbon (or nitrogen) position on a molecule in the context. Independently up to 5 substituents, preferably up to 3 substituents, often 1 or 2 substituents, which may contain substituents that may be further substituted by themselves). As meant (ie, if there are multiple substituents, each substituent is independent of another), and as substituents, hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (ie). NO ₂ )
Halogen (in particular alkyl, in particular, for example preferably in the methyl group, such as trifluoromethyl, 2 or 3 halogens), alkyl groups (preferably C ₁ -C _10, more preferably C ₁ - _6), Aryl (especially phenyl and substituted phenyls such as benzyl or benzoyl), alkoxy groups (preferably C _1- C ₆ alkyl or aryl, including phenyl and substituted phenyl), thioethers (C _1- C ₆ alkyl or aryl), acyls (preferably C 1-C 6 alkyl or aryl). It is preferably a C _1- C ₆ acyl), ester or thioester (preferably C _1- C ₆ alkyl or aryl) and an alkylene ester (its bond is on an alkylene group rather than an ester functional group, preferably C _1- C ₆ alkyl or aryl group substituted), preferably _{containing C 1-} C ₆ alkyl or aryl, halogen (preferably F or Cl), amine (containing 5 or 6 member cyclic alkylene amines, C _1). It _{further comprises -C 6} alkylamine or C ₁ -C ₆ dialkylamine, the alkyl group being substituted with one or two hydroxyl groups), or optionally substituted -N (C ₀ -C ₆ alkyl). C (O) (OC _1- C ₆ alkyl) groups (which can be optionally substituted with polyethylene glycol chains, to which an alkyl group containing one halogen, preferably a chlorine substituent is further attached), hydrazine, amide, This is preferably one or two C _1- C ₆ alkyl groups (including carboxamides optionally substituted with one or two C _1- C ₆ alkyl groups), alkanols (preferably C _1- C ₆ alkyl or aryl). ), Or those substituted with alkanoic acid (preferably C _1- C ₆ alkyl or aryl). Substituents according to the present disclosure may include, for example, -Si R _{1 R 2} R ₃ groups, where in the formula _{each of R 1} and R ₂ is described elsewhere herein, and R ₃ is H or C _1. -C ₆ alkyl groups, preferably R ₁ , R ₂ , R ₃ in this context are C _1- C ₃ alkyl groups (including isopropyl or t-butyl groups). Each of the above groups may be attached directly to the substituted moiety, or the substituents may be optionally substituted _{via (CH 2} ) _m- or optionally substituted-(OCH ₂ ). _It may be attached to a substituted moiety (preferably in the case of an aryl or heteroaryl moiety) via an m-,-(OCH ₂ CH ₂ ) _m- or-(CH ₂ CH ₂ O) _m-group. , They may be substituted with any one or more of the above-mentioned substituents. _{The-(CH 2} ) _m- or-(CH ₂ ) _n- group of the alkylene group or other chains, such as the ethylene glycol chains identified above, may be substituted with any of those chains. Preferred substituents on the alkylene group include halogens, or C _1- C ₆ (preferably C ₁ -C ₃ ) alkyl groups, which may optionally be one or two hydroxyl groups, one or two. It may be substituted with an ether group (OC _1- C ₆ groups), up to 3 halo groups (preferably F), or the amino acid side chains described elsewhere herein, and optionally substituted amides. (Preferably carboxamide substituted as described above) or a urethane group (often having one or two C _0- C ₆ alkyl substituents, which group can also be further substituted). In certain embodiments, the alkylene group (often a single methylene group) is one or two optionally substituted C _1- C ₆ alkyl groups, preferably C _1- C ₄ alkyl groups, most of which. In some cases, it is replaced with a methyl or O-methyl group, or an amino acid side chain described elsewhere herein. In the present disclosure, the moiety in the molecule may be optionally substituted with up to 5 substituents, preferably up to 3 substituents. In most cases, the moieties substituted in this disclosure are substituted with one or two substituents.

The term "substituted" (each substituent is independent of any other substituent) is used in the context of its use as C _1- C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen. , Amid, carboxamide, sulfone containing sulfonamide, keto, carboxy, C ₁ -C ₆ ester (oxyester 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 amines (especially C _1- C ₆ alkylene-NR ₁ R ₂ , mono or di-C ₁ -C ₆ alkyl substituted amines. It also means (including those which can be optionally substituted with one or two hydroxyl groups). Each of these groups contains 1 to 6 carbon atoms in the context, unless otherwise indicated. In certain embodiments, preferred substituents are, for example, -NH-, -NHC (O)-, -O-, = O,-(CH ₂ ) _m- (, depending on the context of the use of the substituent. Where m and n are, in context, 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 groups), NO ₂ , CN, or halogen (F, Cl, Br, I, preferably F or Cl) will be included. R ₁ and R _{2 are H or C 1-} C ₆ alkyl groups, respectively, in context, each of which may be substituted with one or two hydroxyl groups, or up to three halogen groups, preferably fluorine. The term "substituted" is also optionally substituted or heteroaryl group within the chemical background of the specified compound and the substituent used or optionally described elsewhere herein. It shall mean the heterocyclic group to be substituted. The alkylene group may also be substituted as otherwise disclosed herein, preferably optionally substituted C _1- C ₆ alkyl groups (preferably methyl, ethyl or hydroxymethyl or hydroxyethyl). A chiral center is provided), the side chains of the amino acid groups described elsewhere herein, the above-mentioned amide groups, or urethane groups, OC (O) -NR ₁ R ₂ groups, in the formula, R ₁ and R ₂ may be substituted with groups as described elsewhere herein, but many other groups may also be used as substituents. Various optionally substituted moieties may be substituted with 3 or more substituents, preferably 3 or less substituents, and preferably 1 or 2 substituents. In a compound, a substitution is required at a particular position in the molecule (mainly because of the valence), but if no substitution is indicated, the substituent is H unless otherwise suggested in the context of the substitution. Note that it is considered or understood.

The term "aryl" or "aromatic" has been substituted in the context with a single ring (eg, benzene, phenyl, benzyl) or a fused ring (eg, naphthyl, anthrasenylphenyl, phenanthrenyl, etc.). Refers otherwise) or unsubstituted monovalent aromatic radicals herein, as specified otherwise in accordance with the present disclosure, at any available stable position on the ring or in the chemical structure presented. Can be attached to the compound as such. Other examples of aryl groups include, in the context, one or more in a ring of a heterocyclic aromatic ring system such as imidazole, frill, pyrrol, furanyl, thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole and the like. Examples include "heteroaryl" groups having a nitrogen atom, an oxygen atom or a sulfur atom, or a fused ring system such as, in particular, indole, quinoline, indolizine, azindolizine, benzoflazan, which are optionally substituted as described above. Can be done. Heteroaryl groups that may be mentioned include, for example, pyrrole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole, indole, isoindole, indridin, azindridin, purine, indazole, quinoline. , Dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, quinolysin, phthalazine, naphthylidine, quinoxalin, quinazoline, sinoline, pteridine, imidazolididine, imidazolidine, pyrazinopyridazine, aclysine, phenanthridin, carbazole, carbazoline, pyrimidine. , Fenantroline, phenacene, oxadiazole, benzimidazole, pyroloppyridine, pyrrolopyrimidine, and nitrogen-containing heteroaryl groups such as pyridopyrimidine; for example, sulfur-containing aromatic heterocycles such as thiophene and benzothiophene; for example, furan, pyran. , Cyclopentapirane, benzofurans, and oxygen-containing aromatic heterocycles such as isobenzofurans; as well as, for example, thiazole, thiazisol, isothiazole, benzoxazole, benzothiazole, benzothiasiazol, phenothiazine, isoxazole, flazan, phenoxazine, pyrazoloxa. Aromatic heterocycles containing two or more heteroatoms selected from nitrogen, sulfur, and oxygen, such as sol, imidazole thiazole, thienofuran, flopilol, pyridoxazine, flopyridine, flopyrimidine, thienopyrimidine, and oxazole. All of them can be optionally replaced.

The term "substituted aryl" refers to an aromatic carbocyclic ring composed of at least one aromatic ring, or at least one composed of a plurality of fused rings that are aromatic, in this case one ring. It is substituted with the above substituents. For example, the aryl group may contain a substituent 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 on the amine. The alkyl group is optionally one or two hydroxyl groups or up to three halo (preferably F, Cl) groups, OH, COOH, C _1- C ₆ alkyl, preferably CH ₃ , CF ₃ , OMe, OCF. ₃ , NO ₂ , or CN group (each of which can be substituted at the ortho, meta, and / or para-position, preferably para-position of the phenyl ring), optionally substituted phenyl group (the phenyl group itself itself) , Preferably substituted with a linker group added to a PTM group containing a ULM group) and / or F, Cl, OH, COOH, CH ₃ , CF ₃ , OMe, OCF ₃ , NO ₂ , or CN group (Ortho-position, meta-position and / or para-position, preferably para-position of the phenyl ring) substituted with at least one, optionally substituted naphthyl group, optionally substituted heteroaryl, preferably. Is optionally substituted isoxazole containing methyl-substituted isoxazole, optionally substituted oxazole containing methyl-substituted oxazole, optionally substituted thiazole containing methyl-substituted thiazole, optionally substituted isothiazole including methyl-substituted isothiazole. , Optionally substituted pyrol containing methyl substituted pyrol, optionally substituted imidazole containing methylimidazole, optionally substituted benzimidazole or methoxybenzyl imidazole, optionally substituted oxyimidazole or methyloxyimidazole, methyldi Arbitrarily substituted diazole group including azole group, optionally substituted triazole group including methyl substituted triazole group, optionally substituted pyridine including halo- (preferably F) or methyl substituted pyridine group or oxapyridine group. Group (in the formula, the pyridine group is bonded to the phenyl group by oxygen), Furan substituted at will, benzofuran optionally substituted, dihydrobenzofuran optionally substituted, indole optionally substituted, indolizine or azaindlizine (2,3, or 4-azindolizine), optionally Quinolines to be replaced, and combinations thereof.

"Carboxyl" means --C (O) OR, where R is hydrogen, alkyl, substituted alkyl,
Aryl, substituted aryl, heteroaryl or substituted heteroaryl, while these generic substituents have the same meaning as the corresponding group definitions defined herein.

The terms "heteroaryl" or "hetalyl" are, but are not limited to, optionally substituted quinoline (which can be added to the pharmacophore or substituted on any carbon atom within the quinoline ring), optionally. Indols substituted with (including dihydroindols), indolidines optionally substituted, aziindolidins optionally substituted (2,3, or 4-azindolidins), benzimidazoles optionally substituted, benzo Thiazole, 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 methyl group, triisopropylsilyl group, optionally substituted-(CH ₂ ) _m -OC ₁ -C ₆ alkyl group, or optionally substituted-(CH ₂ ) _m -C (O) -OC _{It can mean a 1-} C ₆ alkyl group substituted 1,2,3-triazole), an optionally substituted pyridine (2,3, or 4-pyridine), or a group with the following chemical structure:

During the ceremony:
S ^c is CHR ^SS , NR ^URE , or O;
R ^HET is H, CN, NO ₂ , halo (preferably Cl or F), optionally substituted C _1- C ₆ alkyl (Preferably Cl or F).
Preferably one or two hydroxyl groups or up to three halo groups (eg CF ₃ )
Substituted with), optionally substituted O (C _1- C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted The acetylene group-C≡CR _a , where R _a in the formula is an acetylene group that is an H or C _1- C ₆ alkyl group (preferably C ₁ -C _{3 alkyl);}
R ^SS is H, CN, NO ₂ , halo (preferably F or Cl), optionally substituted C _1- C ₆ alkyl (preferably F or Cl).
Preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O- (C _1- C ₆ alkyl) (preferably one or two hydroxyl groups or maximum). Substituted with 3 halo groups) or optionally substituted with -C (O) (C ₁ -C ₆ alkyl) (preferably with 1 or 2 hydroxyl groups or up to 3 halo groups) Will be replaced);
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), with each group being optionally one or more. Two hydroxyl groups or up to three halo groups, preferably those substituted with a fluorine group, or optionally substituted heterocycles such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, Piperazine, etc., each of which is optionally substituted, and
Y ^C is N or CR ^YC, wherein, R ^YC is H, OH, CN, NO _2, halo (preferably Cl or F), C ₁ -C ₆ alkyl (preferably substituted with optionally One or two hydroxyl groups or up to three halo groups (eg CF ₃ ) substituted, optionally O (C _1- C ₆ alkyl) (preferably one or two hydroxyl groups) _{Or an acetylene group-C≡CR a} substituted with up to 3 halo groups), or optionally substituted, where R _a is an H or C _1- C ₆ alkyl group (preferably C). It is an acetylene group that is _1- C _{3 alkyl).}

The terms "aralkyl" and "heteroarylalkyl" refer to groups comprising aryls or heteroaryls, respectively, and alkyl and / or heteroalkyl, and / or carbocycles and / or heterocycloalkyl ring systems, as defined above. ..

As used herein, the term "arylalkyl" refers to the above-defined aryl group added to the above-defined alkyl group. Arylalkyl groups are attached to the parent moiety via an alkyl group, in which case the alkyl group is one to six carbon atoms. The aryl group in the arylalkyl group may be substituted as described above.

The term "heterocycle" refers to a cyclic group containing at least one heteroatom, eg, N, O or S, which may be aromatic (heteroaryl) or non-aromatic. Therefore, the heteroaryl moiety is included under the definition of a heterocycle, depending on the circumstances of its use. Exemplary heteroaryl groups are described above herein.

Exemplary heterocycles include azetididinyl, benzimidazolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothienyl, dihydroimidazolyl, dihydropyranyl, dihydro. Furanyl, dioxanyl, dioxolanyl, ethyleneurea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, frills, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, indolinyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl , Isoxazolidinyl, isoxazolyl, morpholinyl, naphthyldinyl, oxazolidinyl, oxazolyl, pyridone, 2-pyrrolidone, pyridine, piperazinyl, N-methylpiperazinyl, piperidinyl, phthalimide, succinimide, pyrazinyl, pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl, Examples thereof include pyrrolinyl, pyrrolyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinoline, thiazolidinyl, thiazolyl, thienyl, tetrahydrothiophene, oxane, oxetanyl, oxathiolanyl and thiane.

The heterocyclic groups are alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl. , Keto, thioketo, carboxy, carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, hetero Cyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SOaryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, oxo ( = O), and may optionally be substituted with one selected from the group consisting of -SO2-heteroaryl. Such a heterocyclic group may have a single ring or a plurality of fused rings. Examples of nitrogen heterocycles and heteroaryls are, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indridin, isoindole, indol, indazole, purine, quinoline, isoquinolin, quinoline, phthalazine, naphthylpyridine. , Kinoxalin, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridin, aclysine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indolin, morpholino, piperidinyl, Examples include tetrahydrofuranyl and the like, as well as N-alkoxy-nitrogen-containing heterocycles. The term "heterocyclic" also refers to a bicyclic group in which one of the heterocycles is fused to a benzene ring or a cyclohexane ring or another heterocycle (eg, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, etc.). Also includes.

The term "cycloalkyl" includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc., such as saturated monocyclic hydrocarbon groups having 3 to 20 carbon atoms in the ring. It means, but is not limited to, a monocyclic or polycyclic alkyl group or a monovalent group derived from a cycloalkane as defined herein. The term "substituted cycloalkyl" is monocyclic or substituted with one or more substituents such as, for example, amino, halogen, alkyl, substituted alkyl, calviroxy, calvir mercapto, aryl, nitro, mercapto or sulfo. It means, but is not limited to, a polycyclic alkyl group, but these generic substituents have the same meaning as the definition of the corresponding group defined in this description.

A "heterocycloalkyl" is a monocyclic or polycyclic alkyl group in which at least one ring carbon atom of its cyclic structure is substituted with a heteroatom selected from the group consisting of N, O, S or P. Point to. A "substituted heterocycloalkyl" is a monocyclic or polycyclic alkyl group in which at least one ring carbon atom of its cyclic structure is substituted with a heteroatom selected from the group consisting of N, O, S or P. The group contains one or more substituents selected from the group consisting of halogen, alkyl, substituted alkyl, calviroxy, calvir mercapto, aryl, nitro, mercapto or sulfo, all of which are generic. Substituents have the same meaning as the definition of the corresponding group defined in this description.

The term "hydrocarbyl" shall mean a compound containing carbon and hydrogen and may be fully saturated, partially unsaturated or aromatic, with aryl, alkyl, alkenyl and alkynyl groups. include.

As used herein, the term "independently" is used to indicate that an independently applied variable changes independently with each application.

The term "lower alkyl" refers to methyl, ethyl, or propyl.
The term "lower alkoxy" refers to methoxy, ethoxy, or propoxy.

In any of the embodiments described herein, W, X, Y, Z, G, G', R, R', R'', Q1 to Q4, and A are independently linkers, and / Or can be covalently attached to a linker attached to one or more PTM, ULM, ILM or ILM'groups.

Illustrative CLM
Neo-imide Compounds In one embodiment, the present specification provides compounds useful for binding and / or inhibiting cereblon. In certain embodiments, the compound is selected from the group consisting of the following chemical structures:

During the ceremony:
Equations (a)-(e) [For example, (a1), (b), (c), (d1), (e), (f), (a2), (d2), (a3), and (a4) )] W is independently CH ₂ , O, CHR, C = O, SO ₂ , NH, optionally substituted cycloalkyl (eg, optionally substituted 3-6 member cycloalkyl, optionally) Substituted cyclopropyl group, or optionally substituted cyclobutyl group), optionally substituted heterocycloalkyl, and
Selected from the group of N-alkyl;
W ₃ is selected from C or N;
X in equations (a) to (e) independently does not exist or is selected from the group of _{O, S and CH 2;}
Y in formulas (a) to (e) is independent of CH ₂ , -C = CR', NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O and Selected from the group of S;
Z in equations (a) to (e) does not exist independently or _{is selected from the group of O, S or CH 2} , but both X and Z do not exist or are CH _2. Must not;
G and G'in equations (a) to (e) are independently H, linear or branched alkyl, OH, R'OCOOR, R'OCONRR ",-(arbitrarily substituted. CH ₂ ) _n , -OP (= O) (OC _1-6 alkyl) (OH),-(CH ₂ ) _n , -OP (= O) (OC _1-6 alkyl) ₂ ,-(CH ₂ ) _n , -OP (= O) (OH) ₂ , -CH ₂ OCOO (CH ₂ CH ₂ O) _{n ”} CH ₃ ,
Selected from the group of CH ₂ -heterocyclyl optionally substituted with R', and benzyl optionally substituted with R';
"n" is an integer from 8 to 35 (for example, 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 or 35);
Q1 to Q4 of formulas (a) to (e) each independently represent carbon C substituted with a group independently selected from H, R, N or N-oxide;
A in formulas (a) to (e) is independently selected from the group of H, optionally substituted linear or branched alkyl, cycloalkyl, Cl and F;
R in equations (a) to (e) is not limited, but includes: H, -CONR'R ", -OR', -NR'R", -SR', -SO ₂ R',- _{SO 2 NR'R ", - CR'R"} -, - CR'NR'R "-, (- CR'O) n 'R", halogen, aryl optionally substituted with (e.g., optionally substituted with C5-C7aryl), optionally substituted alkyl-aryl (eg, optionally substituted C1-C6 alkyl, optionally substituted C5-C7aryl, or alkyl comprising at least one of a combination thereof. -Aryl), optionally substituted heteroaryl (eg, optionally substituted C5-C7 heteroaryl), unsubstituted or substituted linear or branched alkyl (eg, one or more halogens) , Cycloalkyl (eg, C3-C6cycloalkyl), or optionally substituted with aryl (eg, C5-C7aryl), C1-C6 linear or branched alkyl, optionally substituted. An alkoxyl group (eg, methoxy, ethoxy, butoxy, propoxy, pentoxy or hexoxy; where the alkoxyl is one or more halogens, alkyls, haloalkyls, fluoroalkyls, cycloalkyls (eg, C3-C6cycloalkyl) or aryls (eg, C3-C6cycloalkyl). , C5-C7 aryl) can be substituted), optionally substituted

(For example, optionally substituted with one or more halogens, alkyls, haloalkyls, fluoroalkyls, cycloalkyls (eg, C3-C6cycloalkyl) or aryls (eg, C5-C7aryl)), optionally substituted.

(For example, optionally substituted with one or more halogens, alkyls, haloalkyls, fluoroalkyls, cycloalkyls (eg, C3-C6cycloalkyl) or aryls (eg, C5-C7aryl)), optionally substituted. Cycloalkyl (eg, optionally substituted C3-C7)
Cycloalkyl), optionally substituted heterocyclyl (eg, optionally substituted C3-C7)
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 ;
Each of x, y, and z is independently 0, 1, 2, 3, 4, 5, or 6;
R'and R'in formulas (a)-(e) are independently H, optionally substituted linear or branched alkyl, optionally substituted cycloalkyl, optionally substituted. Select from aryl, optionally substituted heteroaryl, optionally substituted heterocycle, -C (= O) R, optionally substituted heterocyclyl;
N and n'in equations (a) to (e) are independently 1 to 10 (eg, 1 to 4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). ) Is an integer;

Illustrative CLM
In any of the compounds described herein, CLM comprises a chemical structure selected from the following groups:

During the ceremony:
Equations (a)-(e) [For example, (a1), (b), (c), (d1), (e), (f), (a2), (d2), (a3), and (a4) )] W is independently CH ₂ , O, CHR, C = O, SO ₂ , NH, optionally substituted cycloalkyl (eg, optionally substituted 3-6 member cycloalkyl, optionally) From the group of cyclopropyl groups substituted, or cyclobutyl groups optionally substituted), heterocycloalkyl optionally substituted (eg, 3- to 6-membered heterocycloalkyl optionally substituted), and N-alkyl. Selected;
W ₃ is selected from C or N;
X in equations (a) to (e) independently does not exist or is selected from the group of _{O, S and CH 2;}
Y in formulas (a) to (e) is independent of CH2, -C = CR', NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O and S. Selected from the group of;
Z in equations (a) to (e) does not exist independently or _{is selected from the group of O, S, and CH 2} , but both X and Z do not exist, or CH ₂ Must not be;
G and G'in equations (a) to (e) are independently H, linear or branched alkyl, OH, R'OCOOR, R'OCONRR ",-(arbitrarily substituted. CH ₂ ) _n , -OP (= O) (OC _1-6 alkyl) (OH),-(CH ₂ ) _n , -OP (= O) (OC _1-6 alkyl) ₂ ,-(CH ₂ ) _{n '} -OP (= O) (OH) ₂ , -CH ₂ OCOO (CH ₂ CH ₂ O) _{n ”} CH ₃ ,
Selected from the group of CH ₂ -heterocyclyl optionally substituted with R', and benzyl optionally substituted with R';
"n" is an integer from 8 to 35 (for example, 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 or 35);
Q1 to Q4 of formulas (a) to (e) each independently represent carbon C substituted with a group independently selected from H, R, N or N-oxide;
A in formulas (a) to (e) is independently selected from the group of H, optionally substituted linear or branched alkyl, cycloalkyl, Cl and F;
R of equations (a) to (e) is not limited, but includes: H, -CONR'R ", -OR', -NR'R", -SR', -SO ₂ R',- _{SO 2 NR'R ", - CR'R"} -, - CR'NR'R "-, (- CR'O) n 'R", halogen, heterocyclyl optionally substituted with (e.g., optionally substituted with C3-C7 heterocyclyl),
Arbitrarily substituted aryl (eg, optionally substituted C5-C7aryl), optionally substituted alkyl-aryl (eg, optionally substituted C1-C6 alkyl, optionally substituted C5-C7aryl) , Or alkyl-aryl comprising at least one of their combinations), optionally substituted heteroaryl (eg, optionally substituted C5-C7 heteroaryl), optionally substituted linear or minute. C1-C6 linear or optionally substituted with branched alkyl (eg, one or more halogens, cycloalkyl (eg, C3-C6cycloalkyl), or aryl (eg, C5-C7aryl)). Branched alkyl), optionally substituted alkoxyl groups (eg, methoxy, ethoxy, butoxy, propoxy, pentoxy or hexoxy; where the alkoxyl is one or more halogens, alkyls, haloalkyls, fluoroalkyls, cycloalkyls. Can be substituted with (eg, C3-C6cycloalkyl) or aryl (eg, C5-C7aryl), optionally substituted

(For example, optionally substituted with one or more halogens, alkyls, haloalkyls, fluoroalkyls, cycloalkyls (eg, C3-C6cycloalkyl) or aryls (eg, C5-C7aryl)), optionally substituted.

(For example, optionally substituted with one or more halogens, alkyls, haloalkyls, fluoroalkyls, cycloalkyls (eg, C3-C6cycloalkyl) or aryls (eg, C5-C7aryl)), optionally substituted. Cycloalkyl (eg, optionally substituted C3-C7 cycloalkyl), optionally substituted cycloalkyl (eg, optionally substituted C3-C7 cycloalkyl), optionally substituted heterocyclyl (eg, optionally) Substituted C3-C7 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 , where at least one R (eg, O, OH, N, NH, NH ₂ , C1-C6 alkyl, C1- C6 alkoxy, optionally substituted cycloalkyl (eg, optionally substituted C3-C7 cycloalkyl), optionally substituted heterocyclyl (eg, optionally substituted C3-C7 heterocyclyl), -alkyl-aryl (eg, optionally substituted C3-C7 heterocyclyl). For example, including at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof-alkyl-aryl), aryl (eg, C5-C7aryl), heteroarylaryl (eg, C5-C7 hetero). (Aryl), amine, amide, or at least one of carboxy) is a PTM, chemical linker group (L), ULM, CLM'(eg, CLM'has the same or different structure as the first CLM. (Additional CLM) or modified to be covalently coupled to a combination thereof.
Each of x, y, and z is independently 0, 1, 2, 3, 4, 5, or 6;
R'and R'in formulas (a)-(e) are independently bonded, H, linear or branched alkyl optionally substituted, cycloalkyl optionally substituted, optionally substituted. Aryl to be substituted, heteroaryl optionally substituted, heterocyclic ring optionally substituted, -C (= O) R, heterocyclyl optionally substituted;
N and n'in equations (a) to (e) are independently 1 to 10 (eg, 1 to 4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). ) Is an integer;
Equations (a) to (e)

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

During the ceremony:
W in formula (g) is _{selected independently from the group of CH 2} , C = O, NH and N-alkyl;
A in formula (g) is selected independently of H, methyl, alkyl (eg C1-C6 alkyl (straight chain, branched chain, optionally substituted)).
R in formula (g) is independently H, OH, NH ₂ , halogen, methyl, optionally substituted linear or branched chain alkyl (eg, optionally substituted linear or minute). Branch-chain C1-C6 alkyl)
, Arbitrarily substituted C1-C6 alkoxy, optionally substituted cycloalkyl (eg, optionally substituted C3-C7 cycloalkyl), optionally substituted heterocyclyl (eg, optionally substituted C3-C7). Heterocyclyl), optionally substituted alkyl-aryls (eg, including at least one of C1-C6 alkyl, C4-C7 aryl or combinations thereof-
Alkyl-aryl), optionally substituted aryl (eg, C5-C7aryl), amines, amides, or carboxys;
N in formula (g) represents an integer from 1 to 4 (eg, 1, 2, 3, or 4) and at least one R (eg, OH, NH ₂ , halogen, C1-C6 alkyl, for example) in the formula. C1-C6 Alkoxy, -alkyl-aryl (eg, including at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof-alkyl-aryl), aryl (eg, C5-C7 aryl), At least one of amines, amides, or carboxys) is modified to be covalently attached to a PTM, chemical linker group (L), ULM, CLM (or CLM') or a combination thereof; and formula (g). )of

In any of the embodiments described herein, equations (a) to (g) [eg, (a1), (b), (c), (d1), (e), (f), (a2), (d2), (a3), (a4), and (g)] W, X, Y, Z, G, G', R, R', R'', Q1 to Q4, and A Can independently be covalently attached to a linker and / or a linker attached to one or more PTM, ULM, CLM or CLM'groups.

In any of the embodiments or embodiments described herein, the CLM comprises ₁ to 4 R groups in Q 1, Q ₂ , Q ₃ , Q ₄ or a combination thereof, where each R is. , For example, OH, halogen, C1-C6 alkyl, C1-C6 alkoxy, optionally substituted cycloalkyl (eg, optionally substituted C3-C7 cycloalkyl), optionally substituted heterocyclyl (eg, optionally). Substituted C3-C7 heterocyclyl), -alkyl-aryl (eg, including at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof-alkyl-aryl), aryl (eg, C5-). Independently selected functional groups or atoms such as C7aryl), amines, amides, cyanos, or carboxys, optionally one of which is a PTM, chemical linker group (L), ULM, CLM ( Or CLM'), or modified to be covalently coupled to a combination thereof.

In some embodiments, the CLM is represented by the following structure, where the dashed line indicates the linker binding point:

More specifically, non-limiting examples of CLMs include those shown below, as well as "hybrid" molecules resulting from one or more combinations of different properties shown in the following molecules.

In any of the compounds described herein, CLM comprises a chemical structure selected from the following groups:

During the ceremony:
W is independently selected from CH ₂ , O, CHR, C = O, SO ₂ , NH, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and N-alkyl;
Q ₁ , Q ₂ , Q ₃ , Q ₄ , and Q ₅ each independently represent carbon C or N substituted with a group independently selected from H, R', N or N-oxides;
R ¹ is absent or selected from H, OH, CN, C1-C3 alkyl, C = O;
R ² is absent or selected from the group of H, OH, CN, C1-C3 alkyl, CHF ₂ , CF ₃ , CHO, C (= O) NH _2;
R ³ is H, alkyl (eg C1-C6 alkyl or C1-C3 alkyl), substituted alkyl (eg substituted C1-C6 alkyl or C1-C3 alkyl), alkoxy (eg C1-C6 alkoxyl or C1-C3 alkoxyl). ), Substituted alkoxy (eg substituted C1-C6 alkoxyl or C1-C3 alkoxyl);
R ⁴ is selected from H, alkyl, substituted alkyl;
R ⁵ and R ⁶ are independently H, halogen, C (= O) R', CN, OH, CF ₃ ;
X is C, CH, C = O or N;
X ₁ is C = O, N, CH or CH ₂ ;
R'is H, OH, halogen, amine, cyano, alkyl (eg C1-C3 alkyl), substituted alkyl (eg substituted C1-C3 alkyl), alkoxy (eg C1-C3 alkoxyl), substituted alkoxy (eg C1-C3 alkoxy). For example, C1-C3 alkoxyl to be substituted), NR ² R ³ , C (= O) OR ² , optionally substituted phenyl;
n is 0-4;

In any embodiment or embodiment described herein, CLM or CLM'is expressed in formula (h).
) ~ R group of equation (ab) (eg R, R ¹ , R ² , R ³ , R ⁴ or R'), W, X, or Q group (eg Q ₁ , Q ₂ , Q 3, Q ₃₎ Covalently attached to PTM, chemical linker group (L), ULM, CLM, CLM', or a combination thereof via ₄ or Q _5).

In any of the embodiments described herein, CLM or CLM'is expressed in formula (h).
) ~ 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 in equation (ab), Covalently attached to PTM, chemical linker group (L), ULM, CLM, CLM', or a combination thereof.

In any of the embodiments described herein, W, X, R ¹ , R ² , R ³ , R ⁴ , R', Q ₁ , Q ₂ , Q of formulas (h) to (ab). ₃ , Q ₄ , and Q ₅ may be independently covalently attached to a linker and / or covalently attached to a linker attached to one or more PTM, ULM, ULM', CLM or CLM' groups. May be.

More specifically, non-limiting examples of CLMs include those listed below, as well as "hybrid" molecules or compounds resulting from a combination of one or more properties of the following compounds:

During the ceremony:
W is independently _{selected from the group of CH 2} , CHR, C = O, SO ₂ , NH and N-alkyl;
R ¹ is absent or selected from the group of H, CH, CN, C1-C3 alkyl;
R ² is H or C1-C3 alkyl;
R ³ is selected from H, alkyl, substituted alkyl, alkoxy, substituted alkoxy;
R ⁴ is methyl or ethyl;
R ⁵ is H or halo;
R ⁶ is H or halo;
R of CLM is H;
R'is H or PTM, PTM', chemical linker group (L), ULM, CLM
, CLM'is the point of connection,
Q ₁ and Q ₂ are C or N, respectively, independently substituted with a group selected independently of H or C1-C3 alkyl;

Is a single or double bond;
n is an integer from 1 to 4 (eg 1, 2, 3, or 4); and
R includes: H, -CONR'R ", -OR', -NR'R", -SR', -SO ₂ R', -SO ₂ NR'R ", -CR'R"-, -CR'NR'R "-, (- CR'O) n 'R", halogen, heterocyclyl optionally substituted with, aryl optionally substituted with (e.g., C5-C7 aryl optionally substituted with), optionally Alkyl-aryl substituted with (eg, optionally substituted C1-C6 alkyl, optionally substituted C5-C7 aryl, or an alkyl-aryl comprising at least one of a combination thereof), optionally substituted. Heteroaryl to be optionally substituted (eg, C5-C7aryl optionally substituted), linear or branched alkyl optionally substituted (eg, one or more halogens, cycloalkyl (eg, C3-C6). Cycloalkyl), or C1-C6 linear or branched alkyl optionally substituted with aryl (eg, C5-C7aryl), alkoxyl groups optionally substituted (eg, methoxy, ethoxy, etc.) Butoxy, propoxy, pentoxy or hexoxy; where the alkoxyl is replaced with one or more halogens, alkyl, haloalkyl, fluoroalkyl, cycloalkyl (eg, C3-C6cycloalkyl) or aryl (eg, C5-C7aryl). Get), optionally replaced

(For example, optionally substituted with one or more halogens, alkyls, haloalkyls, fluoroalkyls, cycloalkyls (eg, C3-C6cycloalkyl) or aryls (eg, C5-C7aryl)), optionally substituted.

(For example, optionally substituted with one or more halogens, alkyls, haloalkyls, fluoroalkyls, cycloalkyls (eg, C3-C6cycloalkyl) or aryls (eg, C5-C7aryl)), optionally substituted. Cycloalkyl, optionally substituted 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 ;
In any of the embodiments or embodiments described herein _{, at least one R of Q 1} , Q ₂ , Q ₃ , Q ₄ , Q ₅ or a combination thereof (eg, OH, NH ₂ , C 1). -C6 alkyl, C1-C6 alkoxy, -alkyl-aryl (eg, including at least one of C1-C6 alkyl, C4-C7 aryl or a combination thereof-alkyl-aryl), aryl (eg, C5-C7). (Aryl), amine, amide, or at least one of carboxy) is a PTM, chemical linker group (L), ULM, CLM'(eg, CLM'has the same or different structure as the first CLM. (Additional CLM), or modified to be covalently coupled to a combination thereof.

In any of the embodiments described herein, W, R ¹ , R ^{2 of equations (ac) to (an).}
, Q ₁ , Q ₂ , Q ₃ , Q ₄ , and R may be independently covalently attached to the linker and / or attached to one or more PTM, ULM, ULM', CLM or CLM' groups. It may be covalently attached to the linker to be used.

In any of the embodiments described ^{herein, R 1, R 2, Q} 1, Q 2, Q 3, Q 4 of Formula (ac) ~ formula (an,), and R is independently a linker It may be covalently attached to and / or it may be covalently attached to a linker attached to one or more PTM, ULM, ULM', CLM or CLM' groups.

In any of the embodiments described _{herein, Q 1, Q 2, Q} 3, Q 4 of Formula (ac) ~ formula (an,), and R is independently be covalently attached to a linker Well and / or may be covalently attached to a linker attached to one or more PTM, ULM, ULM', CLM or CLM' groups.

In any aspect or embodiment described herein, R of formulas (ac) to formula (an) is modified to have the same chemical structure as the linker group (L), PTM, ULM, CLM. Covalently attached to CLM, CLM', a second linker, or any plurality or combination thereof.

In any embodiment or embodiment described herein, the CLM is selected from:

In the formula, R'is a halogen and R ¹ is as described in any of the embodiments or embodiments described herein.

In certain examples, the CLM may be an imide that binds to cereblon E3 ligase.
These imide and linker binding points may have, but are not limited to, the following structures:

Illustrative VLM
In certain embodiments of the compounds described herein, ULM is VLM and the following ULM-a
Including the chemical structure of

During the ceremony:
Dashed lines indicate the binding of at least one PTM, another ULM or VLM or MLM or ILM or CLM (ie ULM'or VLM' or CLM' or ILM' or MLM'), or a chemical linker moiety and at least one PTM. , ULM'or VLM' or CLM'or ILM'
Or MLM'attached to the other end of the linker;
^{X 1} and X ² of the formula ULM-a are independently selected from the group of bonds, O, NR ^Y3 , CR ^Y3 R ^Y4 , C = O, C = S, SO, and SO _2;
^{R Y3} and R ^Y4 of the formula ULM-a are independently substituted with H, a linear or branched C _1-6 alkyl optionally substituted (eg, optionally substituted with one or more halos). , Arbitrarily substituted from the group of C _1-6 alkoxyls (eg, optionally substituted with 0 to 3 R ^P groups);
^{The R P} of the formula ULM-a is 0, 1, 2 or 3 groups, each independently selected from H, halo, -OH, C _1-3 alkyl, C = O;
^{W 3 in the} formula ULM-a is optionally replaced by T, 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-diheteroaryl, optionally substituted-T-heterocycle, optionally substituted-T-diheterocycle , Arbitrarily substituted-NR ¹ -T-aryl, optionally substituted-NR ¹ -T-heteroaryl, or optionally substituted-NR ¹ -T-selected from the group of heterocycles;
^{X 3} of the equation ULM-a is C = O, R ¹ , R ^1a , R ^1b ;
R ¹ , R ^1a , and R ^1b _{are H, linear or branched C 1-} C ₆ alkyl groups optionally substituted by one or more halo or -OH groups, R ^{Y 3} C = O, R, respectively. ^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 ) Selected independently from the group consisting of _{SO 2;}
The T in the formula ULM-a is _{selected from the group of optionally substituted alkyl,-(CH 2} ) _n -group, or -OH group, or optionally substituted amino acid side chains, in which case the methylene group. each optionally alkoxy substituted halogen, methyl, _{optionally, - (CH 2) m '} C (= O) (CH 2) m' C (= O) (OH), (CH 2) m 'OCOCH _{2 (CH 2) m 'OCH} 2 (CH 2) m' CO (CH 2) m 'OH, (CH 2) m' OCOCH 2 (CH 2) m 'CO (CH 2) m' OH, 1 or more _{Linear or branched C 1} -C ₆ optionally substituted with halogen or OH of
Substituted with one or two substituents selected from the group of alkyl groups, C (O) NR ¹ R ^1a , or NR ¹ R ^{1a , or R 1} and R ^1a combined and optionally substituted Form a heterocycle to be
Each m'is an integer from 1 to 4 (eg, 1, 2, 3, or 4);
^{W 4 in the} formula ULM-a is optionally substituted-NR ^1- T-aryl, optionally substituted-NR ^1- T-heteroaryl group, or optionally substituted-NR ^1- T-complex. It is a ring, in which case the aryl group may be optionally substituted with a optionally substituted 5- to 6-membered heteroaryl, an optionally substituted aryl, or an optionally substituted alkoxy. -NR ¹ is covalently attached to ^{X 2 and R 1} is H or CH ³ , preferably H; and
n is 0-6, often 0, 1, 2, or 3, preferably 0 or 1.

In any of the embodiments described herein, T is from a group of optionally substituted alkyl,-(CH ₂ ) _n -group, or -OH group, or optionally substituted amino acid side chains. Selected
In this case, each of the methylene groups is optional, halogen, methyl, optionally substituted alkoxy,-(CH ₂ ) _m'C (= O) (CH ₂ ) _m'C (= O) (OH), ( _{CH 2) m 'OCOCH 2 (} CH 2) m' OCH 2 (CH 2) m 'CO (CH
_{2) m 'OH, (CH} 2) m' OCOCH 2 (CH 2) m 'CO (CH 2) m' OH, 1 or more linear optionally substituted with a halogen or a branched C Substituted with one or two substituents selected from the group of _1- C ₆ alkyl groups, C (O) NR ¹ R ^1a , or NR ¹ R ^{1a , or R 1} and R ^1a combined. Each m'is an integer from 1 to 4 (eg, 1, 2, 3, or 4), where n is 0 to 6, often 0. , 1, 2, or 3, preferably 0 or 1.

In any embodiment or embodiment described herein, W ⁴ of formula ULM-a is:

W ⁵ is optionally substituted phenyl, optionally substituted naphthyl, or optionally substituted 5-10 membered heteroaryl (eg, W ⁵ is optional and is one or more [eg, 1, 2]. , 3, 4,
Or 5] optionally substituted linear or branched chain with one or more (eg, 1, 2, 3, 4 or more) carbon atoms substituted with halo, CN, oxygen atoms C1-C12 alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, hydroxy, or optionally substituted haloalkoxy);
R _{14a and} R _14b are independently H, haloalkyl, optionally substituted alkoxy, optionally substituted hydroxylalkyl,-(CH ₂ ) _m'C (= O) (CH ₂ ) _m'C ( = O) (OH), ( CH 2) m 'OCOCH 2 (CH 2) m' OCH 2 (CH 2) m 'CO (CH 2) m' OH, (CH 2) m 'OCOCH 2 (CH 2) _{m 'CO (CH 2) m} ' OH or selected oxygen one or more carbon atoms which is substituted with from the group of straight or branched alkyl optionally substituted with having optionally;
Each m'is an integer from 1 to 4 (eg, 1, 2, 3, or 4);
R ¹ is H, a linear or branched C _1- C ₆ alkyl group optionally substituted with one or more halos,
Or -OH group;
W ⁶ is an optionally substituted 8--14 member bicyclic heterocycle (eg, for example).

R ₁₅ can be replaced with 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. Alkyl substituted, haloalkyl optionally substituted, alkoxy optionally substituted, haloalkoxy optionally substituted, aryl optionally substituted, heteroaryl optionally substituted, cycloalkyl optionally substituted, or It is selected from the group of cycloheteroalkyls that are optionally substituted.

In any embodiment or embodiment described herein, W ⁵ of formula ULM-a is an optionally substituted phenyl or an optionally substituted 5-10 membered heteroaryl (eg, W). ⁵ is optional and one or more (eg, 1, 2, 3, 4 or more) carbons substituted with one or more [eg, 1, 2, 3, 4, or 5] halos, CNs, oxygen atoms. Arbitrarily substituted linear or branched C1-C12 alkyl having an atom, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted haloalkoxy, or hydroxy substituted _{), The R 15} of the formula ULM-a is 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 alkoxy, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, Select from the group of optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl;
In aspects or embodiments described herein, W ⁴ substituents for use in the present disclosure further specifically includes a W ⁴ substituents present in the particular compound disclosed herein (Not limited to the particular disclosed compound). Each of these W ⁴ substituents may be used in conjunction with any number of W ³ substituents, which are also disclosed herein.

In aspects or embodiments described herein, ULM-a is optionally substituted by 0-3 R ^P groups in the pyrrolidine moiety. Each R ^P is independently H, halo, -OH, C1-3 alkyl, and C = O.

In the embodiments or embodiments described herein, W ³ and W ⁴ of formula ULM-a may be independently covalently attached to a linker attached to one or more PTM groups.
And in the equation, the dashed line indicates the binding site of the chemical linker moiety that binds at least one PTM, another ULM (ULM'), or at least one PTM and / or ULM' to ULM.

In certain embodiments, ULM is VHL and is represented by the following structure:

During the ceremony:
^{W 3 in the} formula ULM-b can be optionally substituted aryl, optionally substituted heteroaryl, or

_{R 9} and R ₁₀ of the 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 atoms to which they are attached form cycloalkyls that are optionally substituted;
_{R 11} of the formula ULM-b is an optionally substituted heterocyclic equation, an optionally substituted alkoxy, an optionally substituted heteroaryl, an optionally substituted aryl,

_{R 12} of the formula ULM-b is selected from the group of H or optionally substituted alkyl;
_{R 13} of the formula ULM-b is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl) alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted. Select from a group of arylcarbonyls, optionally substituted (heterocyclyl) carbonyls, or optionally substituted aralkyl;
Formula ULM-b of R _14a, R _14b are each independently, H, haloalkyl, alkoxy, which is optionally substituted, hydroxyl alkyl substituted with _{optionally, - (CH 2) m '} C (= O) (CH 2 _{) m 'C (= O)} (OH), (CH 2) m' OCOCH 2 (CH 2) m 'OCH 2 (CH 2) m' CO (CH 2) m 'OH, (CH 2) m' OCOCH _{2 (CH 2) m 'CO} (CH 2) m' OH or selected oxygen one or more carbons that is substituted with from the group of straight or branched alkyl optionally substituted with with optionally, ;
R ¹ is H, a linear or branched C _1- C ₆ alkyl group optionally substituted with one or more halos,
Or -OH group;
Each m'is an integer from 1 to 4 (eg, 1, 2, 3, or 4);
^{W 5} of the formula ULM-b is selected from the group of optionally substituted phenyls or optionally substituted 5-10 membered heteroaryls;
_{R 15} of the formula ULM-b is 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, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally. Selected from the group of cycloheteroalkyl to be substituted;
_{Each R 16} of the formula ULM-b independently has an optionally substituted alkyl having one or more carbon atoms substituted with H, CN, halo, oxygen atoms (eg, optionally substituted with CN or OH). Is), optionally substituted from the group of haloalkyl, hydroxy, or optionally substituted haloalkoxy;
The o in the formula ULM-b is 0, 1, 2, 3, or 4;
_{R 18} of formula ULM-b is independently selected from the group of H, halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy or linker; and of formula ULM-b. p is 0, 1, 2, 3, or 4, and in the equation, the dashed line is at least one PTM, another ULM (ULM'), and at least one PTM and / or ULM'.
The binding site of the chemical linker moiety that binds to is shown.

In certain embodiments, the R ₁₅ of the formula ULM-b is

In the equation, R ₁₇ is H, halo, optionally substituted C _3-6 cycloalkyl, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 alkenyl, and C. _{It is 1-6} haloalkyl; and Xa is S or O.

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

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

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

In certain embodiments, ULM has a chemical structure selected from the following groups:

During the ceremony:
_{R 1} of the formulas ULM-c, ULM-d, and ULM-e is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; optionally substituted alkyl, optional. Hydroxyalkyl substituted with, optionally substituted heteroaryl, or haloalkyl;
R _14a of formula ULM-c, ULM-d, and ULM-e is, H, haloalkyl, alkyl substituted with optionally, methyl, fluoromethyl, hydroxymethyl, ethyl, _{isopropyl, (CH 2) m 'OCOCH} 2 ( _{CH 2) m 'OCH 2 (} CH 2) m' CO (CH 2) m 'OH, (CH 2) m' be _{OCOCH 2 (CH 2) m '} CO (CH 2) m' OH or cyclopropyl, ;
Each m'is an integer from 1 to 4 (eg, 1, 2, 3, or 4);
_{R 15} of the formulas ULM-c, ULM-d, and ULM-e is H, halogen, CN, OH, NO ₂ , optionally substituted heteroaryl, optionally substituted aryl; optionally substituted alkyl. , Arbitrarily substituted haloalkyl, optionally substituted haloalkoxy, cycloalkyl, or cycloheteroalkyl;
X in formula ULM-c, formula ULM-d, and formula ULM-e is C, CH ₂ , or C = O and formula ULM-c, formula ULM-d, and formula ULM-e R ₃ It is a 5- or 6-membered heteroaryl that is absent, or bound or optionally substituted; and in the formula, the dashed line is at least one PTM, another ULM (ULM'), or at least one PTM or ULM' or The binding site of the chemical linker moiety that binds both to ULM is shown.

In certain embodiments, ULM comprises groups according to the following chemical structure:

During the ceremony:
R _14a of formula ULM-f may, H, haloalkyl, alkyl substituted with optionally, methyl, fluoromethyl, hydroxymethyl, ethyl, _{isopropyl, (CH 2) m 'OCOCH} 2 (CH 2) m' OCH 2 (CH _{2) m 'CO (CH 2} ) m' OH, be _{(CH 2) m 'OCOCH 2} (CH 2) m' CO (CH 2) m 'OH or cyclopropyl;
Each m'is an integer from 1 to 4 (eg, 1, 2, 3, or 4);
_{R 9 in the} formula ULM-f is H;
_{R 10} of the 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 it is a heteroaryl that is optionally substituted;
P in the formula ULM-f is 0, 1, 2, 3, or 4;
_{Each R 18} of the formula ULM-f is independently halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy or linker;
_{R 12 in the} equation ULM-f is H, C = O;
_{R 13} of the 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 the formula ULM-f is H, halogen, Cl, CN, OH, NO ₂ , optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloheteroalkyl,

Selected from a group of
The dashed line in the formula ULM-f indicates the binding site of the chemical linker moiety that binds at least one PTM, another ULM (ULM'), or at least one PTM and / or ULM' to ULM.

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

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

Here, the phenyl rings of ULM-a1 to ULM-a15, ULM-b1 to ULM-b12, ULM-c1 to ULM-c15, and ULM-d1 to ULM-d9 are optionally fluorine, lower alkyl, and alkoxy groups. Substituted with, where the dashed line indicates the binding site of the chemical linker moiety that binds at least one PTM, another ULM (ULM'), or at least one PTM and / or ULM' to ULM-a.

In one embodiment, ULM-a1 to ULM-a15, ULM-b1 to ULM-b12, ULM-c1 to ULM-c15,
And the phenyl rings of ULM-d1 to ULM-d9 are functionalized as esters, which can be part of the prodrug.

In certain embodiments, ULM-a1 to ULM-a15, ULM-b1 to ULM-b12, ULM-c1 to ULM-c15,
And the hydroxyl groups on the pyrrolidine rings of ULM-d1 to ULM-d9 each contain an ester-bonded prodrug moiety.

In any of the embodiments or embodiments described herein, ULM, and ULM'if present, or pharmaceutically acceptable salts, stereoisomers, solvates or polymorphs thereof, respectively. Independently, it is a group that follows the following chemical structure:

During the ceremony:
R ¹ of ULM-g ^'is, C ₁ -C ₆ alkyl that is optionally substituted, optionally substituted with - (CH _{2) n} OH, optionally substituted with - (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 epoxidized moiety WCOCW Each W is an independently H or 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 , optional Replaced by-(CH ₂ ) _n OC (O) -NR ₁ R ₂ ,-(CH ₂ O) _n H, optionally replaced- (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 ,
Arbitrarily replaced-(CH ₂ O) _n C (O) -NR ₁ R ₂ ,-(CH ₂ CH ₂ O) _n H, optionally replaced-(CH ₂ CH ₂ O) _n COOH, optional Substituted with-(OCH ₂ CH ₂ ) _n O- (C ₁ -C ₆ alkyl), optionally replaced with- _{(CH 2 CH 2} O) _n C (O)-(C ₁ -C ₆ alkyl) , Arbitrarily replaced-(OCH ₂ CH ₂ ) _n NHC (O) -R ₁ , Arbitrarily replaced-(CH ₂ CH ₂ O) _n C (O) -NR ₁ R ₂ , Arbitrarily replaced -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 of ULM-g _{can be independently substituted with H, or a C 1-} C ₆ alkyl group optionally substituted with one or two hydroxyl groups or up to three halogen groups (preferably fluorine). And;
_{The R S of} ULM-g is a C _1- C ₆ alkyl group, an optionally substituted aryl, heteroaryl group or heterocyclic group, _{or-(CH 2} ) _m NR ₁ R ₂ groups;
The X and X'of ULM-g are independently C = O, C = S, -S (O), S (O) ₂ (preferably both X and X'are C = O). );
ULM-g R ^{2 'is} a, optionally substituted with _{- (CH 2) n - (} C = O) u (NR 1) v (SO 2) w alkyl group, optionally substituted with - (CH _{2) n-} (C = O) _u (NR ₁ ) _v (SO ₂ ) _w NR _1N R _2N groups, 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- (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, optional Replaced by -NR ^1- (CH ₂ ) _n -C (O) _u (NR ₁ ) _v (SO ₂ ) _{w --NR 1N} R _2N , optionally replaced by -NR ^1- (CH ₂ ) _n- C (O) _u (NR ₁ ) _v (SO ₂ ) _w -NR ₁ C (O) R _1N , optionally replaced -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) _v NR ₁ (SO ₂ ) _w -Complex ring, optionally substituted -X ^R2'- alkyl group; optionally substituted -X ^R2'- -X ^R2 is optionally substituted; aryl group ^'- a heteroaryl group; -X ^R2 is optionally ^substituted' - heterocycle; optionally substituted with, a and; ULM-g of R ^{3 'is} optionally Alkyl to be substituted, 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 replaced-(CH ₂ ) _n -C (O) _u (NR ₁ ) _v (SO ₂ ) _w -NR ₁ C (O) ) R _1N , optionally replaced-(CH ₂ ) _n -C (O) _u (NR ₁ ) _v (S) O 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 replaced -NR ^1- (CH ₂ ) _n -C (O) _u (NR ₁ )
_v (SO ₂ ) _w -NR ₁ C (O) R _1N , optionally replaced -NR ^1- (CH ₂ ) _n -C (O) _u (NR ₁ ) _v (SO ₂ ) _w -aryl, optional Replaced by -NR ^1- (CH ₂ ) _n -C (O) _u (NR ₁ ) _v (SO ₂ ) _w -Heteroaryl, optionally replaced -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, Arbitrarily replaced -O- (CH ₂ ) n- (C = O) _u (NR ₁ ) _v (SO ₂ ) _w -NR _1N R _2N , optionally replaced -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, optionally substituted- O- (CH ₂ ) _n- (C = O) _u (NR ₁ ) _v (SO ₂ ) _w --Heterocyclic;-(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'- alkyl group; optionally substituted-X ^R3'- aryl group; optionally substituted -X ^R3'- heteroaryl group; Arbitrarily substituted-X ^R3'- complex ring; optionally substituted, and;
ULM-g's R _1N and R _2N are H independently, or one or two hydroxyl groups and up to three halogen groups or optionally substituted-(CH ₂ ) _n -aryl groups. ,-(CH ₂ ) _n -heteroaryl group, or-(CH ₂ ) _{n- C 1} -C ₆ alkyl optionally substituted with a heterocyclic group;
The V of ULM-g is O, S or NR ₁ ;
_{R 1 of} ULM-g is the same as above;
ULM-g of R ¹ and R _{1 'are} each independently H or C ₁ -C ₃ alkyl group;
ULM-g of X ^{R2 'and} X ^R3' are each independently, -CH _{2) n} which is optionally substituted _{-, - 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, where X _v is H, halo, or arbitrary. It is a C _1- C ₃ alkyl group substituted with;
Each m of ULM-g is independently 0, 1, 2, 3, 4, 5, 6;
Each m'of ULM-g is independently 0 or 1;
Each n of ULM-g is independently 0, 1, 2, 3, 4, 5, 6;
Each n'in ULM-g is independently 0 or 1;
Each u of ULM-g is independently 0 or 1;
Each v of ULM-g is independently 0 or 1;
Each w of ULM-g is independently 0 or 1; and
^{If any one or more of R 1'} , R ^2' , R ^3' , X and X'of ULM-g is optionally modified and the PTM is not ULM', the PTM group via the linker group. If the PTM is ULM', any one or more ^{of R 1'} , R ^2' , R ^{3', X and X'of ULM and ULM'are optionally modified.} And are covalently attached to each other either directly or via a linker group.

In any of the embodiments or embodiments described herein, ULM, and ULM'if present, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, solvate or poly. Each polymorph is an independent group that follows the following chemical structure:

During the ceremony:
ULM-h of R ^{1 ',} R ^2' each and R ³ 'are the same as above, X is, C = O, C = S , -S (O) group or S (O) ₂ group, Yes, more preferably the C = O group, and
R ¹ of ^{ULM-h ', R 2'} , and R ^{3 'any} one or more of is modified optionally, PTM is ULM' if it is not, a linker group which is further covalently bonded to the PTM group , Or if the PTM is ULM', ^{one or more of each of ULM and ULM', R 1'} , R ^2' , R ^3' , is optionally modified, either directly or Covalently bonded to each other via a linker group.

In any of the embodiments or embodiments described herein, ULM, and ULM', if present, or a pharmaceutically acceptable salt thereof, enantiomers, diastereomers, solvates or polymorphisms thereof. Each form independently follows the following chemical structure:

During the ceremony:
R ¹ of ^{ULM-I ', R 2'} , and R ^{3 'any} one or more of is modified optionally, PTM is ULM' if it is not, a linker group which is further covalently bonded to the PTM group , Or if the PTM is ULM', ^{one or more of each of ULM and ULM', R 1'} , R ^2' , R ^3' , is optionally modified, either directly or Covalently bonded to each other via a linker group.

In a further aspect of the present disclosure, R ^{1 'is} a ULM-g~ULM-i, professional preferably hydroxyl group or a hydroxyl group or metabolic group capable of being into a carboxylic acid group, whereby the compound active compound It presents a drag type. Examples of preferred R ^1'groups are, for example,-(CH ₂ ) _n OH, (CH ₂ ) _n -O- (C ₁ -C ₆ ) alkyl groups,-(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. In the formula, R ^{1 'is} a carboxylic acid group, or a hydroxyl group or an amine group, or contain it, the hydroxyl group, carboxylic acid group or amine (each they can be optionally substituted) further chemically modified Can provide a covalent bond to a linker group that is attached to a PTM group, including a ULM'group;
The X and X'of ULM-g and ULM-h, if present, are preferably C = O, C = S, -S (O) or _two S (O) groups, more preferably C = O. Is the basis;
ULM-g~ULM-i of R ^{2 'is} substituted preferably -NR ¹ -T- aryl, -NR ¹ -T- heteroaryl group is optionally substituted is optionally substituted, or optionally - NR ¹ -T- is a heterocycle, in which R ¹ is H or CH ₃ , preferably H, and T is optionally substituted-(CH ₂ ) _n -group, in the formula. Each one of the middle and methyl groups is preferably a halogen, one or two substituents selected from the _{amino acid side chains or C 1-} C _{3 alkyl groups described elsewhere herein, preferably optionally.} It may be optionally substituted with one or two methyl groups that can be substituted; and n is 0-6 (eg 0, 1, 2, or 3, eg 0 or 1). Alternatively, T can be-(CH ₂ O) _n -group,-(OCH ₂ ) _n -group,-(CH ₂ CH ₂ O) _n -group,-(OCH ₂ CH ₂ ) _n -group. Well, all of those groups are optionally replaced.

R ² of ULM-g~ULM-i ^'Preferred aryl groups for a phenyl or naphthyl group is optionally substituted, preferably include a phenyl group, the phenyl or naphthyl group, PTM group (ULM' Linker groups to which (including groups) are attached, halogens (preferably F or Cl), amines, monoalkylamines or dialkylamines (preferably dimethylamine).
, 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 is an ortho-, meta-, and phenyl ring ortho-, meta-, and / Or para-position, preferably para-position substituted), optionally substituted phenyl group (the phenyl group itself is optionally attached to the PTM via a linker group (including ULM'group)) , And / or F, Cl, OH, COOH, CH ₃ , CF ₃ , OMe, OCF ₃ , NO ₂ , or CN group (ortho-, meta-, and / or para-position of the phenyl ring, preferably para-position. Includes at least one of (positions), a naphthyl group optionally substituted, a heteroaryl optionally substituted, preferably an optionally substituted isoxazole containing a methyl substituted isoxazole, a methyl substituted oxazole. Optionally substituted oxazole, optionally substituted thiazole containing methyl substituted thiazole, optionally substituted isothiazole containing methyl substituted isothiazole, optionally substituted pyrrol including methyl substituted pyrrole , Optionally substituted imidazole including methylimidazole, optionally substituted benzimidazole or methoxybenzyl imidazole, optionally substituted oxyimidazole or methyloxyimidazole, optionally substituted diazole group including methyldiazol group, Optional including a triazole group optionally substituted, including a methyl substituted triazole group, a halo- (preferably F) or a methyl substituted pyridine group or an oxapyridine group (the pyridine group is attached to the phenyl group by oxygen). A pyridine group substituted with, optionally substituted furan, optionally substituted benzofuran, optionally substituted dihydrobenzofuran, optionally substituted indol, indolidine or azaindridin (2, 3 or 4-aza). Indolidin), optionally substituted quinoline, optionally attached to a PTM group via an optionally substituted group according to the following chemical structure:

During the ceremony:
S ^c of ULM-g~ULM-i is an CHR ^SS, NR ^URE or O;
R ^HET of ULM-g~ULM-i is, H, CN, NO _2, halo (preferably Cl or F), C ₁ -C ₆ alkyl (preferably one or two hydroxyl groups or substituted with optionally Up to 3 halo groups (eg CF ₃ ) substituted), optionally substituted O (C _1- C ₆ alkyl) (preferably one or 2 hydroxyl groups or up to 3 halo groups (Substituted with) or optionally substituted acetylene group -C≡CR _a , in which R _a is an H or C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl). It is an acetylene group;
^{The R SS} of ULM-g to ULM-i are H, CN, NO ₂ , halo (preferably F or Cl), optionally substituted C _1- C ₆ alkyl (preferably one or two hydroxyl groups or Substituted with up to 3 halo groups), optionally substituted with O- (C _1- C ₆ alkyl) (preferably with 1 or 2 hydroxyl groups or up to 3 halo groups) ), Or optionally substituted-C (O) (C _1- C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups);
R ^URE of ULM-g~ULM-i is, H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl), or a _{-C (O) (C 1 -C} 6 alkyl), Each group is optionally substituted with one or two hydroxyl groups or up to three halo groups, preferably a fluorine group, or optionally substituted phenyl group, optionally substituted heteroaryl group, or optionally. The heterocycle to be substituted is, for example, piperidine, morpholine, pyrrolidine, tetrahydrofuran;
^{The R PROs} of ULM-g to ULM-i are groups of H, optionally substituted C _1- C ₆ alkyl, or optionally substituted aryl (phenyl or naphthyl), heteroaryl or heterocycle, and they. The groups are oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazin, morpholin, quinoline ( Each is preferably _{substituted with a C 1-} C ₃ alkyl group, preferably a methyl group or a halo group, preferably F or Cl), selected from the group consisting of benzofurans, indols, indolidines, azindridinines;
ULM-g~ULM-i of R ^PRO1 and R ^PRO2 are each, independently, H, or C ₁ -C ₃ alkyl group optionally substituted with, or together form a keto group; and
Each n of ULM-g to ULM-i is a heterocycle, preferably 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1) or optionally substituted. Tetrahydrofuran, tetrahydrothien, piperidine, piperazine or morpholine (each of which group is preferably substituted with methyl or halo (F, Br, Cl) when substituted), and each of these groups is It can optionally be attached to a PTM group (including a ULM'group) via a linker group.

In certain preferred embodiments

Preferred heteroaryl groups for R ^{2 'of} ULM-g~ULM-i, (may be substituted on any carbon atom in either coupled to the pharmacophore or quinoline ring) optionally quinoline substituted , Arbitrarily substituted indole, optionally substituted indolidine, optionally substituted azaindidine, optionally substituted benzofuran including optionally substituted benzofuran, optionally substituted isoxazole, optionally substituted Thiazole to be optionally substituted isothiazole, optionally substituted thiophene, optionally substituted pyridine (2-, 3- or 4-pyridine), optionally substituted imidazole, optionally substituted pyrrol , Arbitrarily substituted diazole, optionally substituted triazole, tetrazole, optionally substituted oxyimidazole, or groups according to the following chemical structure:

During the ceremony:
S ^c of ULM-g~ULM-i is an CHR ^SS, NR ^URE or O;
R ^HET of ULM-g~ULM-i is, H, CN, NO _2, halo (preferably Cl or F), C ₁ -C ₆ alkyl (preferably one or two hydroxyl groups or substituted with optionally Up to 3 halo groups (eg CF ₃ ) substituted), optionally substituted O (C _1- C ₆ alkyl) (preferably one or 2 hydroxyl groups or up to 3 halo groups _{The acetylene group -C≡CR a} substituted with (replaced with) or optionally substituted, in which _{the R a} of ULM-g to ULM-i is an H or C ₁ -C ₆ alkyl group (preferably C). It is an acetylene group that is _1- C _{3 alkyl);}
^{The R SS} of ULM-g to ULM-i are H, CN, NO ₂ , halo (preferably F or Cl), optionally substituted C _1- C ₆ alkyl (preferably one or two hydroxyl groups or Substituted with up to 3 halo groups), optionally substituted with O- (C _1- C ₆ alkyl) (preferably with 1 or 2 hydroxyl groups or up to 3 halo groups) ), Or optionally substituted-C (O) (C _1- C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups);
R ^URE of ULM-g~ULM-i is, H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl), or a _{-C (O) (C 1 -C} 6 alkyl), Each group is optionally substituted with one or two hydroxyl groups or up to three halogens, preferably a fluorine group, or optionally substituted heterocycles such as piperazine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene. , Piperidine, piperazine, etc., each of which is optionally substituted, and
^{The Y C} of ULM-g to ULM-i is N or CR ^YC , where R ^YC is H, OH, CN, NO ₂ , halo (preferably Cl or F), optionally substituted C. _1- C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to 3 halo groups (eg CF ₃ )), optionally substituted O (C _1- C ₆ alkyl) (preferably) Is substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted acetylene group-C≡CR _a , where R _a is H or C _1- An acetylene group that is a _{C 6} alkyl group (preferably C _1- C _{3 alkyl) and}
Each of the groups can optionally be attached to a PTM group, including a ULM'group, via a linker group.

Preferred heterocyclic groups for R ^{2 'of} ULM-g~ULM-i, tetrahydrofuran, tetrahydrothien-tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, oxane or thiane and the like, each of the groups, It may be optionally substituted or may be a group according to the following chemical structure:

During the ceremony:
^{The R PROs} of ULM-g to ULM-i are groups of H, optionally substituted C _1- C ₆ alkyl, or optionally substituted aryl, heteroaryl or heterocycle;
ULM-g to ULM-i R ^PRO1 and R ^PRO2 are independently H, optionally substituted C _1- C ₃ alkyl groups, or both form keto groups, and
Each n of ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (often 0 or 1), and each of each group is via a linker group. Can optionally be attached to PTM groups (including ULM'groups).

Preferred R ^{2 'substituents} of ULM-g~ULM-i, is found in certain compounds disclosed herein (including the specific compounds disclosed in the drawings accompanying the present specification and the specification) R ^{2 'substituents} can also be mentioned specifically (but not limited to the particular compounds disclosed). These R ^{2 'each} substituent, R ³ any ^number' may be used in conjunction with substituents, also disclosed herein.

ULM-g~ULM-i R ^{3 'is} preferably a substituted -T- aryl is optionally substituted, -T- heteroaryl is optionally substituted, -T- heterocycle is optionally substituted, optionally Is -NR ¹ -T-aryl, optionally substituted -NR ¹ -T-heteroaryl, or optionally substituted -NR ¹ -T- heterocycle. In a preferred embodiment, R ¹ is an H or C _1- C ₃ alkyl group, preferably H or CH ₃ , where T is optionally substituted-(CH ₂ ) _n -group, one of each of the formula, methylene group. Is preferably one or two selected from halogens, C _1- C ₆ alkyl groups (straight, branched, optionally substituted) or side chains of amino acids as described separately herein. It may be optionally substituted with one substituent, preferably methyl; and n is 0-6, eg 0, 1, 2, or 3 (eg 0 or 1). Alternatively, T can be-(CH ₂ O) _n -group,-(OCH ₂ ) _n -group,-(CH ₂ CH ₂ O) _n -group,-(OCH ₂ CH ₂ ) _n -group. Often, each of those groups is optionally substituted.

Preferred aryl groups for R ^{3 'of} ULM-g~ULM-i, a phenyl group or a naphthyl group is optionally substituted, preferably include a phenyl group, the phenyl or naphthyl group in this case, the linker group Via and / or halogen (preferably F)
Or Cl), amines, monoalkylamines or dialkylamines (preferably dimethylamine), amide groups (preferably-(CH ₂ ) _m- NR ₁ C (O) R ₂ groups, m, R ₁ and in the formula. R ₂ is the same as above), halo (often F or Cl), OH, CH ₃ , CF ₃ , OMe, OCF ₃ , NO ₂ , CN or S (O) ₂ R _S groups (R _S) Is a C _1- C ₆ alkyl group, optionally substituted aryl, heteroaryl, or heterocyclic _{group or-(CH 2} ) _m NR ₁ R ₂ group) via PTM group (including ULM'group) Are optionally attached to, each of which can be substituted with a phenyl ring (preferably a para position), or an aryl (preferably phenyl), heteroaryl or heterocyclic ortho-position, meta-position, and / or para-position. Preferred phenyl groups of the substituents are optionally substituted phenyl groups (ie, the phenyl groups of the substituents themselves are preferably F, Cl, OH, SH, COOH, CH ₃ , CF ₃ , OMe, OCF _3). , NO ₂ , CN, or at least one of the linker groups, and those groups are attached to PTM groups (including ULM'groups), in which case the substitution is ortho, meta, and / of the phenyl ring. Or para-positions, preferably occurring at the para-position), optionally substituted naphthyl groups including the above, optionally substituted heteroaryls (preferably optionally substituted isoxazoles, including methyl substituted isoxazoles, methyl substituteds). Arbitrarily substituted oxazole containing a substituted oxazole, optionally substituted thiazole containing a methyl-substituted thiazole, optionally substituted pyrol containing a methyl-substituted pyrrole, methyl imidazole, benzyl imidazole or methoxybenzyl imidazole. Includes optionally substituted imidazole, oxyimidazole or methyloxyimidazole, optionally substituted diazole group including methyldiazol group, optionally substituted triazole group including methyl substituted triazole group, halo (preferably F). ) Or a pyridine group containing a methyl-substituted pyridine group or an oxapyridine group (the pyridine group is bonded to a phenyl group with oxygen), or an optionally substituted heterocycle (tetrahydrothiophene, pyrrolidine, piperidine). , Morphorin, piperazine, tetrahydroquinoline, oxane, or thian). The aryl, heteroaryl or heterocyclic groups can optionally be attached to a PTM group (including the ULM'group) via a linker group.

Preferred heteroaryl groups for R ^{3 'of} ULM-g~ULM-i, quinoline optionally substituted with (or coupled to the pharmacophore can be substituted on any carbon atom in the quinoline ring), Optionally substituted indole (including dihydroindol), optionally substituted indolizine, optionally substituted aziindolidin (2,3, or 4-azindolidine), 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 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 groups (1,2,3-triazole), optionally substituted pyridines (2,3, or 4-pyridines), or groups with the following chemical structure:

During the ceremony:
S ^c of ULM-g~ULM-i is an CHR ^SS, NR ^URE or O;
R ^HET of ULM-g~ULM-i is, H, CN, NO _2, halo (preferably Cl or F), C ₁ -C ₆ alkyl (preferably one or two hydroxyl groups or substituted with optionally Up to 3 halo groups (eg CF ₃ ) substituted), optionally substituted O (C _1- C ₆ alkyl) (preferably one or 2 hydroxyl groups or up to 3 halo groups (Substituted with) or optionally substituted acetylene group -C≡CR _a , in which R _a is an H or C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl). It is an acetylene group;
^{The R SS} of ULM-g to ULM-i are H, CN, NO ₂ , halo (preferably F or Cl), optionally substituted C _1- C ₆ alkyl (preferably one or two hydroxyl groups or Substituted with up to 3 halo groups), optionally substituted with O- (C _1- C ₆ alkyl) (preferably with 1 or 2 hydroxyl groups or up to 3 halo groups) ), Or optionally substituted-C (O) (C _1- C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups);
R ^URE of ULM-g~ULM-i is, H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl), or a _{-C (O) (C 1 -C} 6 alkyl), Each group is optionally substituted with one or two hydroxyl groups or up to three halogens, preferably a fluorine group, or optionally substituted heterocycles such as piperazine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene. , Piperidine, piperazine, etc., each of which is optionally substituted, and
^{The Y C} of ULM-g to ULM-i is N or CR ^YC , where R ^YC is H, OH, CN, NO ₂ , halo (preferably Cl or F), optionally substituted C. _1- C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to 3 halo groups (eg CF ₃ )), optionally substituted O (C _1- C ₆ alkyl) (preferably) Is substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted acetylene group-C≡CR _a , where R _a is H or C _1- It is an acetylene group which is a C ₆ alkyl group (preferably C _1- C _{3 alkyl).} Each of the heteroaryl groups can optionally be attached to a PTM group, including a ULM'group, via a linker group.
Preferred heterocyclic groups for R ^{3 'of} ULM-g~ULM-i, tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, tetrahydrofuran, tetrahydrothiophene, include oxane or Jiang, each of the groups, It may be optionally substituted or may be a group according to the following chemical structure:

During the ceremony:
^{The R PROs} of ULM-g to ULM-i are groups of H, optionally substituted C _1- C ₆ alkyl, or optionally substituted aryl (phenyl or naphthyl), heteroaryl or heterocycle, and they. The groups are oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazin, morpholin, quinoline ( Each is preferably _{substituted with a C 1-} C ₃ alkyl group, preferably a methyl group or a halo group, preferably F or Cl), selected from the group consisting of benzofurans, indols, indolidines, azindridinines;
ULM-g to ULM-i R ^PRO1 and R ^PRO2 are independently H, optionally substituted C _1- C ₃ alkyl groups, or both form keto groups, and
Each n of ULM-g to ULM-i is 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1), and each of the heterocyclic groups is a PTM group via a linker group. It can optionally be attached to (including the ULM'group).

Preferred R ^{3 'substituent} of ULM-g~ULM-i, is found in certain compounds disclosed herein (including the specific compounds disclosed in the drawings accompanying the present specification and the specification) R ^{3 'substituent} may also be mentioned specifically (but not limited to the particular compounds disclosed). These R ^{3 'each} substituent, R ² any ^number' may be used in conjunction with substituents, also disclosed herein.

In certain alternative preferred ^{embodiments, ULM-g~ULM-i R 2} ' are, -NR ₁ -X ^R2 is optionally ^substituted' of - alkyl group, -NR ₁ -X ^{R2 '-} aryl group; X ^{R2 '-HET,} - -NR ₁ being optionally substituted
-NR ₁ -X ^R2 is optionally substituted ^'- X ^R2 - -NR ₁ is substituted aryl -HET or ^optionally,' -HET-
Aryl and
During the ceremony:
_{R 1} of ULM-g to ULM-i is an H or C _1- C ₃ alkyl group (preferably H);
ULM-g~ULM-i of X ^{R2 'is,} -CH _{2) n} which is optionally substituted _{-, - 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
ULM-g to ULM-i X _{v are H, halos, or C 1-} C ₃ alkyl groups optionally substituted with one or two hydroxyl groups or up to three halogen groups;
The alkyl of ULM-g to ULM-i is an optionally substituted C1-C ₁₀ alkyl (preferably C _1- C ₆ alkyl) group (in certain preferred embodiments, the alkyl group is a halo group, many In the case of Cl or Br, the end is closed);
The aryls of ULM-g to ULM-i are optionally substituted phenyl or naphthyl groups (preferably phenyl groups); and
ULM-g to ULM-i HETs are optionally substituted with oxazole, isoxazole, thiazole,
Isothiazole, imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazin, morpholine, benzofuran, indolizine, indolizine, azidolizine, Quinoline (when substituted, each preferably substituted with a C _1- C ₃ alkyl group, preferably a methyl or halo group, preferably F or Cl), or a group according to the following chemical structure:

S ^c of ULM-g~ULM-i is an CHR ^SS, NR ^URE or O;
R ^HET of ULM-g~ULM-i is, H, CN, NO _2, halo (preferably Cl or F), C ₁ -C ₆ alkyl (preferably one or two hydroxyl groups or substituted with optionally Up to 3 halo groups (eg CF ₃ ) substituted), optionally substituted O (C _1- C ₆ alkyl) (preferably one or 2 hydroxyl groups or up to 3 halo groups (Substituted with) or optionally substituted acetylene group -C≡CR _a , in which R _a is an H or C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl). It is an acetylene group;
^{The R SS} of ULM-g to ULM-i are H, CN, NO ₂ , halo (preferably F or Cl), optionally substituted C _1- C ₆ alkyl (preferably one or two hydroxyl groups or Substituted with up to 3 halo groups), optionally substituted with O- (C _1- C ₆ alkyl) (preferably with 1 or 2 hydroxyl groups or up to 3 halo groups) ), Or optionally substituted-C (O) (C _1- C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups);
R ^URE of ULM-g~ULM-i is, H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl), or a _{-C (O) (C 1 -C} 6 alkyl), Each group is optionally substituted with one or two hydroxyl groups or up to three halo groups, preferably a fluorine group, or optionally substituted heterocycles such as piperazine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydro. Thiophen, piperidine, piperazine, etc., each of which is optionally substituted;
^{The Y C} of ULM-g to ULM-i is N or CR ^YC , where R ^YC is H, OH, CN, NO ₂ , halo (preferably Cl or F), optionally substituted C. _1- C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to 3 halo groups (eg CF ₃ )), optionally substituted O (C _1- C ₆ alkyl) (preferably) Is substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted acetylene group-C≡CR _a , where R _a is H or C _1- It is an acetylene group that is a C ₆ alkyl group (preferably C _1- C _{3 alkyl);}
^{The R PROs} of ULM-g to ULM-i are groups of H, optionally substituted C _1- C ₆ alkyl, or optionally substituted aryl (phenyl or naphthyl), heteroaryl or heterocycle, and they. The groups are oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazin, morpholin, quinoline ( Each is preferably _{substituted with a C 1-} C ₃ alkyl group, preferably a methyl group or a halo group, preferably F or Cl), selected from the group consisting of benzofurans, indols, indolidines, azindridinines;
ULM-g to ULM-i R ^PRO1 and R ^PRO2 are independently H, optionally substituted C _1- C ₃ alkyl groups, or both form keto groups, and
Each n of ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1).

Each of the groups can optionally be attached to a PTM group, including a ULM'group, via a linker group.

In certain alternative embodiments of the present disclosure, R ³ of ULM-g~ULM-i ^'is optionally substituted _{- (CH 2) n - (} V) n' - (CH 2) n - (V ) _n'- R ^S3'group , optionally replaced-(CH ₂ ) _n -N (R _1' ) (C = O) _m' -(V) _n
'-R ^S3' group, -X ^R3 is optionally substituted ^'- alkyl group, -X ^R3 is optionally ^substituted' - aryl group; -X ^{R3 '-Het} group optionally substituted, an optionally substituted that -X ^R3 - an -HET- aryl group ^'aryl -HET group or -X ^R3 is optionally ^{substituted,'}
During the ceremony:
R ^S3'is an optionally substituted alkyl group (C _1- C ₁₀ , preferably C ₁ -C ₆ alkyl), an optionally substituted aryl or HET group;
R _{1 'is} H or C ₁ -C ₃ alkyl group (preferably H);
V is O, S or NR _1' ;
X ^R3'is- (CH ₂ ) _n -,-(CH ₂ CH ₂ O) _n- , _{-CH 2} ) _n -CH (X _v ) = CH (X _v )-(cis or trance), -CH ₂ ) _n -CH≡CH-, or C _3- C ₆ cycloalkyl groups, all of which are optionally substituted;
X _{v is an H, halo, or C 1-} C ₃ alkyl group optionally substituted with one or two hydroxyl groups or up to three halogen groups;
The alkyl is an optionally substituted C _1- C ₁₀ alkyl (preferably C 1 -C ₆ alkyl) group _{(preferably a C 1-C 6 alkyl).}
In certain preferred embodiments, the alkyl group is terminated with a halo group, often Cl or Br);
Aryl is an optionally substituted phenyl or naphthyl group (preferably a phenyl group); and
HET can be optionally substituted with oxazole, isothiazole, thiazole, isothiazole, imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine. , Morphorin, benzofuran, indole, indolidine, azindridin, quinoline (preferably C _1- C ₃ alkyl groups, respectively, if substituted).
It is preferably substituted with a methyl or halo group, preferably F or Cl), or a group according to the following chemical structure:

S ^c of ULM-g~ULM-i is an CHR ^SS, NR ^URE or O;
R ^HET of ULM-g~ULM-i is, H, CN, NO _2, halo (preferably Cl or F), C ₁ -C ₆ alkyl (preferably one or two hydroxyl groups or substituted with optionally Up to 3 halo groups (eg CF ₃ ) substituted), optionally substituted O (C _1- C ₆ alkyl) (preferably one or 2 hydroxyl groups or up to 3 halo groups (Substituted with) or optionally substituted acetylene group -C≡CR _a , in which R _a is an H or C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl). It is an acetylene group;
^{The R SS} of ULM-g to ULM-i are H, CN, NO ₂ , halo (preferably F or Cl), optionally substituted C _1- C ₆ alkyl (preferably one or two hydroxyl groups or Substituted with up to 3 halo groups), optionally substituted with O- (C _1- C ₆ alkyl) (preferably with 1 or 2 hydroxyl groups or up to 3 halo groups) ), Or optionally substituted-C (O) (C _1- C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups);
R ^URE of ULM-g~ULM-i is, H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl), or a _{-C (O) (C 0 -C} 6 alkyl), Each group is optionally substituted with one or two hydroxyl groups or up to three halo groups, preferably a fluorine group, or optionally substituted heterocycles such as piperazine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydro. Thiophen, piperidine, piperazine, etc., each of which is optionally substituted;
^{The Y C} of ULM-g to ULM-i is N or CR ^YC , where R ^YC is H, OH, CN, NO ₂ , halo (preferably Cl or F), optionally substituted C. _1- C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to 3 halo groups (eg CF ₃ )), optionally substituted O (C _1- C ₆ alkyl) (preferably) Is substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted acetylene group-C≡CR _a , where R _a is H or C _1- It is an acetylene group that is a C ₆ alkyl group (preferably C _1- C _{3 alkyl);}
^{The R PROs} of ULM-g to ULM-i are groups of H, optionally substituted C _1- C ₆ alkyl, or optionally substituted aryl (phenyl or naphthyl), heteroaryl or heterocycle, and they. The groups are oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazin, morpholin, quinoline ( Each is preferably _{substituted with a C 1-} C ₃ alkyl group, preferably a methyl group or a halo group, preferably F or Cl), selected from the group consisting of benzofurans, indols, indolidines, azindridinines;
ULM-g~ULM-i of R ^PRO1 and R ^PRO2 are each, independently, H, or C ₁ -C ₃ alkyl group optionally substituted with, or together form a keto group;
Each n of ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1);
Each m'of ULM-g to ULM-i is 0 or 1; and
Each n'of ULM-g to ULM-i is 0 or 1;
In the formula, each of the compounds, preferably an alkyl group, an aryl group or a Het group, is optionally attached to a PTM group (including a ULM'group) via a linker group.

In another embodiment, ULM-g~ULM-i of R ^{3 'is,} - (CH _{2) n} - _{aryl, - (CH 2 CH 2 O} ) n - aryl, - (CH _{2) n} -HET or, -(CH ₂ CH ₂ O) _n -HET,
During the ceremony:
The aryl of ULM-g to ULM-i is a phenyl optionally substituted with one or two substituents, where the substituent is preferably-(CH ₂ ) _n OH, itself. CN, halo (up to 3 halo groups), OH,-(CH ₂ ) _n O (C ₁ -C ₆ ) alkyl, amine, mono- or di- (C ₁ -C ₆ alkyl) amine and more optionally Selected from the substituted C _1- C ₆ alkyl, in this case the alkyl group of the amine is optionally substituted with one or two hydroxyl groups or up to three halo (preferably F, Cl) groups, or
The aryl groups of ULM-g to ULM-i are-(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) Alkyl substituted with amine, in this case the alkyl of the amine groups, one or two hydroxyl groups or (preferably F, Cl) three halo up group, CN, NO _2, optionally substituted _{with, - (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 optionally substituted, where V is O, S or NR _1' , R _1'is an H or C _1- C ₃ alkyl group (preferably H), and R ^PEG is an H or optionally substituted C _1- C ₆ alkyl group (preferably H). (Including those optionally substituted with a carboxyl group), or
The aryl groups of ULM-g to ULM-i are oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, Piperidine, piperazine, morpholine, quinoline, benzofuran, indole, indolidine, azindridin (if substituted, each preferably preferably a C _1- C ₃ alkyl group, preferably a methyl or halo group, preferably F or Cl. (Substituted with), or optionally substituted with a heterocyclic ring containing a heteroaryl selected from the group consisting of groups according to the following chemical structure:

S ^c of ULM-g~ULM-i is an CHR ^SS, NR ^URE or O;
R ^HET of ULM-g~ULM-i is, H, CN, NO _2, halo (preferably Cl or F), C ₁ -C ₆ alkyl (preferably one or two hydroxyl groups or substituted with optionally Up to 3 halo groups (eg CF ₃ ) substituted), optionally substituted O (C _1- C ₆ alkyl) (preferably one or 2 hydroxyl groups or up to 3 halo groups (Substituted with) or optionally substituted acetylene group -C≡CR _a , in which R _a is an H or C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl). It is an acetylene group;
^{The R SS} of ULM-g to ULM-i are H, CN, NO ₂ , halo (preferably F or Cl), optionally substituted C _1- C ₆ alkyl (preferably one or two hydroxyl groups or Substituted with up to 3 halo groups), optionally substituted with O- (C _1- C ₆ alkyl) (preferably with 1 or 2 hydroxyl groups or up to 3 halo groups) ), Or optionally substituted-C (O) (C _1- C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups);
R ^URE of ULM-g~ULM-i is, H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl), or a _{-C (O) (C 0 -C} 6 alkyl), Each group is optionally substituted with one or two hydroxyl groups or up to three halo groups, preferably a fluorine group, or optionally substituted heterocycles such as piperazine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydro. Thiophen, piperidine, piperazine, etc., each of which is optionally substituted;
^{The Y C} of ULM-g to ULM-i is N or CR ^YC , where R ^YC is H, OH, CN, NO ₂ , halo (preferably Cl or F), optionally substituted C. _1- C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to 3 halo groups (eg CF ₃ )), optionally substituted O (C _1- C ₆ alkyl) (preferably) Is substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted acetylene group-C≡CR _a , where R _a is H or C _1- It is an acetylene group that is a C ₆ alkyl group (preferably C _1- C _{3 alkyl);}
^{The R PROs} of ULM-g to ULM-i are groups of H, optionally substituted C _1- C ₆ alkyl, or optionally substituted aryl (phenyl or naphthyl), heteroaryl or heterocycle, and they. The groups are oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazin, morpholin, quinoline ( Each is preferably _{substituted with a C 1-} C ₃ alkyl group, preferably a methyl group or a halo group, preferably F or Cl), selected from the group consisting of benzofurans, indols, indolidines, azindridinines;
ULM-g~ULM-i of R ^PRO1 and R ^PRO2 are each, independently, H, or C ₁ -C ₃ alkyl group optionally substituted with, or together form a keto group;
The ULM-g to ULM-i HETs are preferably oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine. , Piperidine, piperazine, morpholine, quinoline (preferably _{substituted with C 1-} C ₃ alkyl groups, preferably methyl or halo groups, preferably F or Cl), benzofurans, indols, indridins, azind. Lysine, or a group that follows the chemical structure below:

S ^c of ULM-g~ULM-i is an CHR ^SS, NR ^URE or O;
R ^HET of ULM-g~ULM-i is, H, CN, NO _2, halo (preferably Cl or F), C ₁ -C ₆ alkyl (preferably one or two hydroxyl groups or substituted with optionally Up to 3 halo groups (eg CF ₃ ) substituted), optionally substituted O (C _1- C ₆ alkyl) (preferably one or 2 hydroxyl groups or up to 3 halo groups (Substituted with) or optionally substituted acetylene group -C≡CR _a , in which R _a is an H or C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl). It is an acetylene group;
^{The R SS} of ULM-g to ULM-i are H, CN, NO ₂ , halo (preferably F or Cl), optionally substituted C _1- C ₆ alkyl (preferably one or two hydroxyl groups or Substituted with up to 3 halo groups), optionally substituted with O- (C _1- C ₆ alkyl) (preferably with 1 or 2 hydroxyl groups or up to 3 halo groups) ), Or optionally substituted-C (O) (C _1- C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups);
R ^URE of ULM-g~ULM-i is, H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl), or a _{-C (O) (C 0 -C} 6 alkyl), Each group is optionally substituted with one or two hydroxyl groups or up to three halo groups, preferably a fluorine group, or optionally substituted heterocycles such as piperazine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydro. Thiophen, piperidine, piperazine, etc., each of which is optionally substituted;
^{The Y C} of ULM-g to ULM-i is N or CR ^YC , where R ^YC is H, OH, CN, NO ₂ , halo (preferably Cl or F), optionally substituted C. _1- C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to 3 halo groups (eg CF ₃ )), optionally substituted O (C _1- C ₆ alkyl) (preferably) Is substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted acetylene group-C≡CR _a , where R _a is H or C _1- It is an acetylene group that is a C ₆ alkyl group (preferably C _1- C _{3 alkyl);}
^{The R PROs} of ULM-g to ULM-i are groups of H, optionally substituted C _1- C ₆ alkyl, or optionally substituted aryl, heteroaryl or heterocycle;
ULM-g~ULM-i of R ^PRO1 and R ^PRO2 are each, independently, H, or C ₁ -C ₃ alkyl group optionally substituted with, or together form a keto group;
Each m'of ULM-g to ULM-i is independently 0 or 1; and
Each n of ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1).
In the formula, each of the compounds is preferably attached to a PTM group (including ULM'group) via a linker group, preferably on the aryl group or HET group.

In a further additional embodiment, preferred compounds follow the following chemical structure or include pharmaceutically acceptable salts thereof, stereoisomers, solvates or polymorphs:

During the ceremony:
ULM-i of R ^{1 'is} a group metabolized OH or in a patient or subject, to OH;
ULM-i R ^{2 'is} a, -NH-CH ₂ - aryl -Het (preferably coupled directly to thiazole which is methyl-substituted phenyl); and
R ³ of ULM-i ^'is, -CHR ^CR3' is -NH-C (O) -R ^3P1 group or -CHR ^{CR3 '-R 3P2} groups;
ULM-i of R ^{CR3 'is,} C ₁ -C ₄ alkyl group, there preferably methyl, isopropyl or tert- butyl;
ULM-i's R ^{3P 1} is C _1- C ₃ alkyl (preferably methyl), an optionally substituted oxetane group (preferably methyl substituted-(CH ₂ ) _n OCH ₃ groups, where n is in the formula. 1 or 2 (preferably 2)), or

The aryl of ULM-i is phenyl;
The ULM-i HET is an optionally substituted thiazole, or isothiazole; and
^{The R HET of} ULM-i is an H or halo group (preferably H);
Each of the compounds is optionally attached to a PTM group (including ULM') via a linker group.

In certain embodiments, a bifunctional compound comprising a ubiquitin E3 ligase binding moiety (ULM),
Or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof, wherein the ULM is a group according to the following chemical structure:

During the ceremony:
_{Each R 5} and R ₆ of ULM-j is an independently substituted OH, SH, or optionally substituted alkyl,
Or R ₅ , R ₆ and the carbon atoms to which they bond form a carbonyl;
_{R 7 of} ULM-j is H or an optionally substituted alkyl;
E in ULM-j is binding, C = O, or C = S;
G in ULM-j is a bond, an optionally substituted alkyl, -COOH, or C = J;
J of ULM-j is O or NR ₈ ;
ULM-j's R ₈ is H, CN, optionally substituted alkyl, or optionally substituted alkoxy;
ULM-j's M is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, or

_{Each R 9} and R ₁₀ of ULM-j is independently H; optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted thioalkyl, disulfide bonded. 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;
ULM-j's R ₁₁ is optionally substituted heterocyclic, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl, or

_{R 12 of} ULM-j is H or an optionally substituted alkyl;
ULM-j's R ₁₃ is H, optionally substituted alkyl, optionally substituted alkylcarbonyl,
Arbitrarily substituted (cycloalkyl) alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl) carbonyl, or optionally substituted aralkyl; optionally It is a substituted (oxoalkyl) carbamate and is
_{Each R 14} of ULM-j is independently H, haloalkyl, optionally substituted cycloalkyl, optionally substituted alkyl, or optionally substituted heterocycloalkyl;
ULM-j R ₁₅ is H, optionally substituted heteroaryl, haloalkyl, optionally substituted aryl, optionally substituted alkoxy, or optionally substituted heterocyclyl;
_{Each R 16} of ULM-j is independently halo, optionally substituted alkyl, optionally substituted haloalkyl, CN, or optionally substituted haloalkoxy;
_{Each R 25} of ULM-j is independently H or an optionally substituted alkyl; or _{both R 25} groups may be combined to form an oxo or optionally substituted cycloalkyl group. ;
_{R 23 of} ULM-j is H or OH;
ULM-j's Z ₁ , Z ₂ , Z ₃ and Z ₄ are independently C or N; and
The o of ULM-j is 0, 1, 2, 3 or 4.

In certain embodiments, G in ULM-j is C = J, J is O, R ₇ is H, each R ₁₄ is H, and o is 0.

In certain embodiments, G in ULM-j is C = J, J is O, R ₇ is H, each R ₁₄ is H, and R ₁₅ is an optionally substituted heteroaryl. And o is 0. In another example, E is C = O and M is

In certain embodiments, E in ULM-j is C = O and R ₁₁ is an optionally substituted heterocyclic or

In certain embodiments, E in ULM-j is C = O and M is

And each R ₁₈ is independently halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, or haloalkoxy; and p is 0, 1, 2, 3, or 4 Is.

In certain embodiments, ULM, and ULM'if present, are independent groups that follow the following chemical structures:

During the ceremony:
G of ULM-k is C = J and J is O;
ULM-k's R ₇ is H;
_{Each R 14} of ULM-k is H;
ULM-k o is 0;
ULM-k R ₁₅

_{R 17 of} ULM-k is H, halo, optionally substituted cycloalkyl, optionally substituted alkyl, optionally substituted alkenyl, and haloalkyl.

In another example, R _{17 of} ULM-k is alkyl (eg, methyl) or cycloalkyl (eg, cyclopropyl).

In other embodiments, ULM, and ULM'if present, are independent groups that follow the following chemical structures:

During the ceremony:
G of ULM-k is C = J and J is O;
ULM-k's R ₇ is H;
_{Each R 14} of ULM-k is H;
ULM-k o is 0; and
ULM-k's R ₁₅ is selected from the following group:

In other embodiments, ULM, and ULM'if present, are independent groups that follow the following chemical structures:

In yet another embodiment, a compound having the following chemical structure,

The q of ULM-k is 1 or 2;
ULM-k's R ₂₀ is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or

_{R 21 of} ULM-k is H or an optionally substituted alkyl; and
ULM-k R ₂₂ is H, optionally substituted alkyl, optionally substituted alkoxy, or haloalkyl.

In any of the embodiments described herein, R ₁₁ of ULM-j or ULM-k is selected from the group consisting of:

_{In certain embodiments, R 11} of ULM-j or ULM-k is selected from the group consisting of:

In certain embodiments, ULM (or ULM'if present) is a group that follows the following chemical structure:

During the ceremony:
ULM-l's X is O or S;
Y of ULM-l is H, methyl or ethyl;
_{R 17 of} ULM-l is H, methyl, ethyl, hydroxymethyl, or cyclopropyl; M of ULM-l is optionally substituted aryl, optionally substituted heteroaryl, or

ULM-l's R ₉ is H;
ULM-l R ₁₀ is H, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted hydroxyalkyl, optionally substituted Is thioalkyl, or cycloalkyl;
ULM-l R ₁₁ can be optionally substituted heteroaromatic, optionally substituted heterocyclic, optionally substituted aryl, or

ULM-l R ₁₂ is H or an optionally substituted alkyl; and
ULM-l R ₁₃ is H, optionally substituted alkyl, optionally substituted alkylcarbonyl,
Arbitrarily substituted (cycloalkyl) alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl) carbonyl, or optionally substituted aralkyl; optionally It is a substituted (oxoalkyl) carbamate.

In some embodiments, ULM, and ULM'if present, are independent groups that follow the following chemical structures:

During the ceremony:
Y of ULM-m is H, methyol or ethyl
ULM-m's R ₉ is H;
R ₁₀ is isopropyl, tert-butyl, sec-butyl, cyclopentyl, or cyclohexyl;
_{R 11 of} ULM-m is an optionally substituted amide, an optionally substituted isoindolinone, an optionally substituted isooxazole, and an optionally substituted heterocycle.

In other embodiments of the present disclosure, ULM and, if present, ULM'are independent groups that follow the following chemical structures.

During the ceremony:
ULM-n R ₁₇ is methyl, ethyl, or cyclopropyl; and
ULM-n's R ₉ , R ₁₀ , and R ₁₁ are as defined above. In another example, R ₉ is H; and
_{R 10 of} ULM-n is H, alkyl, or cycloalkyl (preferably isopropyl, tert-butyl, sec-butyl, cyclopentyl, or cyclohexyl).

In any of the embodiments or embodiments described herein, the ULM (or ULM'if present) described herein is a pharmaceutically acceptable salt, mirror image isomer, diastereomer. It may be ulm, solvate, or polymorph. Further, in any of the embodiments or embodiments described herein, the ULM described herein (or ULM'if present) is attached to the PTM either directly via binding or by a chemical linker. It may be combined.

In certain embodiments of the present disclosure, the ULM moiety is selected from the group consisting of:

In this case, at any suitable location, including, for example, aryl, heteroaryl, phenyl, or phenyl of an indole group, optionally via any suitable functional group such as amine, ester, ether, alkyl, or alkoxy. , VLM may be attached to PTM via a linker as described herein.

Illustrative ILM
AVPI Tetrapeptide Fragment In any of the compounds described herein, the ILM may comprise an alanine-valine-proline-isoleucine (AVPI) tetrapeptide fragment, or an unnatural mimetic thereof. In certain embodiments, the ILM is selected from the group consisting of the following chemical structures represented by formulas (I), (II), (III), (IV) and (V):

During the ceremony:
^{R 1} of formulas (I), (II), (III), (IV), and (V) is selected from H or alkyl;
^{R 2} of formulas (I), (II), (III), (IV), and (V) is selected from H or alkyl;
^{R 3} of formulas (I), (II), (III), (IV), and (V) is selected from H, alkyl, cycloalkyl and heterocycloalkyl;
_{R 5} and R ₆ of formulas (I), (II), (III), (IV), and (V) are independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, or more preferably. Expression (I
), (II), (III), (IV), and (V) R ⁵ and R ⁶ together form a pyrrolidine ring or a piperidine ring, which ring further optionally 1-2 cycloalkyls. , Heterocycloalkyl, aryl or heteroaryl rings, each of which can then be condensed into yet another cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring;
^{Both R 3} and R ⁵ of equations (I), (II), (III), (IV), and (V) can form a 5- to 8-membered ring, which is optionally 1 Condensed into two cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings;
^{R 7} of formulas (I), (II), (III), (IV), and (V) is cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aryl-C (O). -R ⁴ , arylalkyl, heteroaryl, heteroaryl-C (O) -R ⁴ , heteroaryl-R ⁴
, Heteroaryl-naphthalene, heteroarylalkyl, or -C (O) NH-R ⁴ , each of which is further optional, halogen, alkyl, haloalkyl, hydroxyl, alkoxy, cyano, (hetero) cycloalkyl, (hetero). ) Substituted with 1-3 substituents selected from aryl, -C (O) NH-R ⁴ , or -C (O) -R ^{4; and}
R ⁴ is selected from alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and optionally 1 to 3 as described above. It is substituted with a substituent of.

As mentioned above, P1, P2, P3, and P4 of formula (II) correlate with A, V, P, and I of the AVPI tetrapeptide fragment or its unnatural mimetics, respectively. Similarly, each of formulas (I) and (III)-(V) has a moiety that correlates with A, V, P, and I of the AVPI tetrapeptide fragment or its unnatural mimetic.

In any of the compounds described herein, the ILM can have the structure of formula (VI), or a non-natural mimic thereof, which is the IAP antagonist described in WO 2008/014236. A derivative, or a pharmaceutically acceptable salt or hydrate thereof:

During the ceremony:
_{R 1} of formula (VI) is selected independently of H, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkenyl, C ₁ -C ₄ -alkynyl, or C ₃ -C _{10 -cycloalkyl.} , These are unsubstituted or substituted; R _{2 in} formula (VI) is H, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkenyl, C ₁ -C ₄ -alkynyl, or C. _{Selected independently of 3-} C ₁₀ -cycloalkyl, these are unsubstituted or substituted; R _{3 in} equation (VI) is H, -CF ₃ , -C ₂ H ₅ , C _1- Selected independently of C ₄ -alkyl, C ₁ -C ₄ -alkenyl, C ₁ -C ₄ -alkynyl, -CH ₂ -Z, or any R ₂ and R ₃ form a heterocyclic ring. death;
Each Z in equation (VI) is selected independently of H, -OH, F, Cl, -CH ₃ , -CF ₃ , -CH ₂ Cl, -CH ₂ F or -CH _{2 OH;
R 4} of formula (VI) is C ₁ -C ₁₆ linear or branched alkyl, C ₁ -C ₁₆ -alkenyl, C ₁ -C ₁₆ -alkynyl, C ₃ -C ₁₀ -cycloalkyl,- Selected independently of (CH ₂ ) _0-6 -Z ₁ ,-(CH ₂ ) _0-6 -aryl, _{and-(CH 2} ) _0-6 -het, in the formula alkyl, cycloalkyl and phenyl Unreplaced or replaced;
R ₅ of formula (VI), C _1-10 - alkyl, aryl, phenyl, C _3-7 - _{cycloalkyl, - (CH 2) 1 -} 6 -C 3-7 - cycloalkyl, -C _1-10 -Alkyl-aryl,-(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 Selected independently of, or R ₅ is selected from the residues of amino acids, where the substituents of alkyl, cycloalkyl, phenyl, and aryl are unsubstituted or substituted;
_{Z 1 in} equation (VI) is -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 -Cyclo Alkyl, -C (O) -O- (CH ₂ )
_0-6 -Phenyl, -C (O) -O- (CH ₂ ) _1-6 -het, -OC (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 independently selected, where alkyl , Cycloalkyl, and phenyl are unsubstituted or substituted;
The het in formula (VI) is a 5- to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from N, O and S, or one selected from N, O and S. , 2 or 3 heteroatoms contained in at least one 5- to 7-membered heterocyclic ring, independently selected from an 8- to 12-membered fused ring system, the heterocyclic ring or Heterocyclic systems are unsubstituted or substituted on carbon or nitrogen atoms;
_{R 10 in} equation (VI) is selected from H, -CH ₃ , -CF ₃ , -CH ₂ OH, or -CH ₂ Cl;
_{R 11} and R ₁₂ of equation (VI) are H, C _1-4 -alkyl, C _3-7 -cycloalkyl,-(CH ₂ ) _1-6 -C _3-7 -cycloalkyl, (CH ₂ ). _0-6- Selected independently of phenyl, where alkyl, cycloalkyl and phenyl are unsubstituted or substituted; or R ₁₁ and R ₁₂ form het with nitrogen, and formula (VI). U is independently as shown in Eq. (VII) below:

During the ceremony:
Each n in equation (VII) is independently selected from 0-5;
X in formula (VII) is selected from the group of -CH and N;
_{R a} and R _b of formula (VII) are independently selected from the group of O atom, S atom, or N atom or C _0-8 -alkyl, where one of the carbon atoms in the alkyl chain. The above is optionally substituted with a heteroatom selected from O, S or N, where each alkyl is independently unsubstituted or substituted;
_{R d in} Eq. (VII) is selected from the group Re-Q- (R _f ) _p (R _g ) _q and Ar ₁ -D-Ar _{2;
R c in} formula (VII) is selected from the H group, or any R _c and R _d are both cycloalkyl or het.
Where R _c and R _d form a cycloalkyl or het, then R ₅ is attached to the formed ring at the C or N atom;
P and q in equation (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, where each Re is 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 in} equation (VII) are independently H, -C _1-10 -alkyl, C _1-10 -alkylaryl, -OH, -OC _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 (0) -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, - is selected from alkyl, wherein the alkyl, cycloalkyl, -SO het and aryl are unsubstituted or substituted ₂ -C _1-2 - Alkyl, -SO _2- C _1-2- alkylphenyl, -OC _1-4 -alkyl, or any R _g and R _f both form a ring selected from het or aryl;
D in equation (VII) is _{selected from the group of -CO-, -C (O) -C 1-7} -alkylene or arylene, -CF _2- , -O-, -S (O) _r and is in the equation. , R is 0-2, 1,3-dioxalane, or C _1-7 -alkyl-OH;
Alkyl, alkylene, or arylene is unsubstituted or substituted with one or more halogens, OH, -OC _1-6 alkyl, -SC _1-6 alkyl, or -CF ₃ ; or each D is Selected independently of N (R _h);
Rh is 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 -alkyl-aryl, _{-COC 01-10} -alkyl, _{-COC 0-10} -alkyl-aryl, -SO ₂ -C _1-10 -alkyl, or -SO ₂ -Selected from the group of (C _{0-10-alkylaryl);
R 6} , R ₇ , R ₈ and R ₉ of formula (VII) independently form H, -C _1-10 -alkyl, -C _1-10 -alkoxy, aryl-C _1-10 -alkoxy, -OH, -OC _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 -Selected _{from the group of R 14} ; in the formula, each alkyl, cycloalkyl, and aryl is unsubstituted or substituted; and any R ₆ , R ₇ , R ₈ , and R ₉ are optionally together. Form a ring system;
_{R 13} and R _{14 in} equation (VII) are independently H, C _1-10 -alkyl,-(CH ₂ ) _0-6 -C _3-7 -cycloalkyl,-(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 ) _{Selected from the group 1-6} -het, where each alkyl, cycloalkyl, and aryl is unsubstituted or substituted: or any R ₁₃ and R ₁₄ form a het with a nitrogen atom;
_{Here, the alkyl substituents of R 13} and R ₁₄ in formula (VII) are unsubstituted or substituted, and are substituted.
When substituted, substituted with one or more substituents selected from _{C 1-10} -alkyl, halogen, OH, -OC _1-6 -alkyl, -SC _1-6 -alkyl, and -CF ₃ And the substituted phenyls or aryls of _{R 13} and R _{14 are halogens, hydroxyls, C 1-4} alkyl, C _1-4 alkoxy, nitro, -CN, -OC (O) -C _1-4 alkyl, and-. Substituted by one or more substituents selected from C (O) -OC _{1-4 aryls.}

In any of the compounds described herein, the ILM can have the structure of formula (VIII), or an unnatural mimetic thereof, which is Ndubaku, C., et al. Antagonism of c-. Based on the IAP ligands described in 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):

Here each of A1 and A2 of formula (VIII) is independently selected from optionally substituted monocyclic, fused rings, aryls and heteroaryls; and
R in equation (VIII) is selected from H or Me.

In certain embodiments, 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).

In certain embodiments, the ILM is selected from the group consisting of:

In any of the compounds described herein, the ILM can have the structure of formula (IX) below, or a non-natural mimic thereof, which is Mannhold, R., et al. IAP antagonists. : Promising candidates for cancer therapy, Drug Discov. Derived from the chemical species cross-referenced in Today, 15 (5-6), 210-9 (2010):

In the formula, R ¹ is selected from alkyl, cycloalkyl and heterocycloalkyl, most preferably from isopropyl, tert-butyl, cyclohexyl and tetrahydropyranyl, and R ^{2 in} formula (IX) is -OPh. Or selected from H.

In any of the compounds described herein, the ILM can have the structure of formula (X) below, or a non-natural mimic thereof, which is Mannhold, R., et al. IAP antagonists. : promising candidates for cancer therapy, Drug Discov. Today, 15 (5-6), 210-9
Derived from chemical species cross-referenced in (2010):

During the ceremony:
^{R 1 in} equation (X) is selected from H, -CH ₂ OH, --CH ₂ CH ₂ OH, --CH ₂ NH ₂ , --CH ₂ CH ₂ NH ₂ .
X in equation (X) is selected from _{S or CH 2;}
^{R 2 in} equation (X) is selected from:

In any of the compounds described herein, the ILM can have the structure of formula (XI) below, or a non-natural mimic thereof, which is Mannhold, R., et al. IAP antagonists. : Promising candidates for cancer therapy, Drug Discov. Derived from the chemical species cross-referenced in Today, 15 (5-6), 210-9 (2010):

In any of the compounds described herein, the ILM can have the structure of formula (XII) below, or an unnatural mimetic thereof, which is Mannhold, R., et al. IAP antagonists. : Promising candidates for cancer therapy, Drug Discov. Derived from the chemical species cross-referenced in Today, 15 (5-6), 210-9 (2010):

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

In any of the compounds described herein, ILM can have the structure of formula (XIII), or an unnatural mimetic thereof, which is Flygare, JA, et al. Small-molecule pan-IAP. based on IAP ligands summarized in opponents: a patent review, Expert Opin. Ther. Pat., 20 (2), 251-67 (2010):

In any of the compounds described herein, ILM can have a structure of formula (XIV), which is Flygare, JA, et al. Small-molecule pan-IAP antagonists: a patent.
Based on the IAP ligand summarized in review, Expert Opin. Ther. Pat., 20 (2), 251-67 (2010):

During the ceremony:
Z in equation (XIV) does not exist or is O;
^{R 3} and R ⁴ of equation (XIV) are independently selected from H or Me;
^{R 1 in} equation (XIV) is selected from:

In any of the compounds described herein, the ILM is selected from the group consisting of:

It is a derivative of the ligand disclosed in US Patent Publication No. 2008/0269140 and US Pat. No. 7,244,851.

In any of the compounds described herein, the ILM can have the structure of formula (XV), or an unnatural mimetic thereof, which is the IAP ligand described in WO 2008/128171. Derivative:

In certain embodiments, the ILM has the following structure:

In any of the compounds described herein, the ILM can have the structure of formula (XVI), or an unnatural mimetic thereof, to the IAP ligand described in WO 2006/069063. Origin:

During the ceremony:
^{R 2} of formula (XVI) is selected from alkyl, cycloalkyl, and heterocycloalkyl; more preferably from isopropyl, tert-butyl, cyclohexyl, and tetrahydropyranyl, most preferably from cyclohexyl;
Of expression (XVI)

Is a 5- or 6-membered nitrogen-containing heteroaryl; more preferably a 5-membered nitrogen-containing heteroaryl, most preferably a thiazole; and Ar in formula (XVI) is an aryl or heteroaryl. be.

In any of the compounds described herein, the ILM can have the structure of formula (XVII), or an unnatural mimetic thereof, which is Cohen, F. et al., Antogonists of inhibitors of apoptosis. Based on the IAP ligands described in proteins based on thiazole amide isosteres, Bioorg. Med. Chem. Lett., 20 (7), 2229-33 (2010):

In any of the compounds described herein, ILM can have the structure of formula (XVIII), or an unnatural mimetic thereof, which is Cohen, F. et al., Antogonists of inhibitors of apoptosis. Based on the IAP ligands described in proteins based on thiazole amide isosteres, Bioorg. Med. Chem. Lett., 20 (7), 2229-33 (2010):

In the formula, R in formula (XVIII) is selected from alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, or halogen (at variable substitution positions).

In any of the compounds described herein, ILM can have the structure of formula (XIX), or an unnatural mimetic thereof, which is Cohen, F. et al., Antogonists of inhibitors of apoptosis. Based on the IAP ligands described in proteins based on thiazole amide isosteres, Bioorg. Med. Chem. Lett., 20 (7), 2229-33 (2010):

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

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

In any of the compounds described herein, the ILM can have the structure of formula (XX), or an unnatural mimetic thereof, to the IAP ligand described in WO 2007/101347. Based on:

In any of the compounds described herein, the ILM can have the structure of formula (XXI), or a non-natural mimic thereof, which is U.S. Pat. No. 7,345,081 and U.S. Pat. No. 7,419,975. Based on the IAP ligand described in

In certain embodiments, the ILM of the compound is selected from the group consisting of:

In any of the compounds described herein, the ILM comprises a structure of formula (XXII) or formula (XXIV), or a structure of an unnatural mimetic thereof, and a chemical linker for the linker group L shown below. The structure can have WO 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. Derived from the IAP ligand described in (2015):

During the ceremony:
^{R 1} of formula (XXII), formula (XXIII), or formula (XXIV) 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), formula (XXIII) or formula (XXIV) is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, Select from optionally substituted arylalkyl or optionally substituted aryl;
Or, or
^{R 1} and R ² of formula (XXII), formula (XXIII) or formula (XXIV) are independently selected from optionally substituted thioalkyls, where any substituent attached to the S atom of the thioalkyl is optional. Alcyl substituted, branched-chain alkyl optionally substituted, heterocyclyl optionally substituted,-(CH ₂ ) _v COR ²⁰ , -CH ₂ CHR ²¹ COR ²² or -CH ₂ R ²³ ;
During the ceremony:
v is an integer from 1 to 3;
-(CH ₂ ) _v COR ²⁰ and -CH ₂ R ²³ R ²⁰ and R ²² are independently selected from OH, NR ²⁴ R ²⁵ or OR ^26;
-CH ₂ CHR ²¹ COR ² R ²¹ is selected from ^{NR 24} R ^25;
R ²³ of -CH ₂ R ²³ is selected from heterocyclyl which is substituted aryl optionally substituted with or optionally, wherein As the optional substituents include alkyl and halogen;
R ²⁴ of NR ²⁴ R ²⁵ is selected from hydrogen or optionally substituted alkyl;
NR ²⁴ R ²⁵ in R ²⁵ is hydrogen, alkyl which is optionally substituted, branched chain alkyl which is optionally substituted, arylalkyl which is optionally substituted, heterocyclyl which is optionally substituted, -CH ₂ (OCH ₂ CH ₂ O) _m CH _3, or for example selected from a polyamine chain, such as spermine or spermidine,; R ²⁶ of oR ²⁶ is selected from alkyl substituted with optionally, wherein said 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), formula (XXIII) or formula (XXIV) are independently 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. The substituent is alkyl, halogen or OH;
^{R 5} , R ⁶ , R ⁷ and R ⁸ of formula (XXII), formula (XXIII) or formula (XXIV) are independently hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl. ;
In certain embodiments, ILM: according to equations (XXII) to (XXIV):
R ⁷ and R ⁸ are selected from H or Me;
R ⁵ and R ⁶ are selected from the group including:

In any of the compounds described herein, the ILM is a structure of formula (XXV), formula (XXVI), formula (XXVII), or formula (XXVIII), or a structure of an unnatural mimetic thereof. It can have a chemical linker for the linker group L shown below, the structure of which is WO 2014/055461, and Kim, KS, Discovery of tetrahydroisoquinoline-based bivalent heterodimeric IAP antagonists. Bioorg. Med. Chem. Lett. 24 ( 21), Derived from the IAP ligand described in 5022-9 (2014):

During the ceremony:
^{R 2 in} formulas (XXV) to (XXVIII) is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted. Selected from arylalkyl to be substituted, or optionally substituted aryl;
Or, or
^{R 1} and R ² of formula (XXV) and formula (XXVIII) are independently selected from H, optionally substituted thioalkyl-CR ⁶⁰ R ⁶¹ SR ⁷⁰ , in which R ⁶⁰ and R ⁶¹ are H. Or selected from methyl, R ⁷⁰ is optionally substituted alkyl, optionally substituted branched chain alkyl, optionally substituted heterocyclyl,-(CH ₂ ) _v COR ²⁰ , -CH ₂ CHR ²¹ COR ²² Or-CH ₂ R ²³ ;
During the ceremony:
v is an integer from 1 to 3;
-(CH ₂ ) _v COR ²⁰ and -CH ₂ CHR ²¹ COR ²² R ²⁰ and R ²² are independently selected from OH, NR ²⁴ R ²⁵ or OR ^26;
-CH ₂ CHR ²¹ COR ²² R ²¹ is selected from ^{NR 24} R ^25;
R ²³ of -CH ₂ R ²³ is selected from heterocyclyl which is substituted aryl optionally substituted with or optionally, wherein As the optional substituents include alkyl and halogen;
R ²⁴ of NR ²⁴ R ²⁵ is selected from hydrogen or optionally substituted alkyl;
NR ²⁴ R ²⁵ in R ²⁵ is hydrogen, alkyl which is optionally substituted, branched chain alkyl which is optionally substituted, arylalkyl which is optionally substituted, heterocyclyl which is optionally substituted, CH ₂ CH ₂ (OCH ₂ CH ₂ ) _m CH ₃ , or polyamine chains such as spermine or spermidine-[CH ₂ CH ₂ (CH ₂ ) _δ NH] _Ψ CH ₂ CH ₂ (CH ₂ ) _ωr NH ₂ selected from
In the formula, δ = 0 to 2, Ψ = 1 to 3, ω = 0 to 2;
R ²⁶ of OR ²⁶ is an optionally substituted alkyl, where the optional substituent is OH, halogen or NH ₂ ;
m is an integer from 1 to 8;
^{R 6} and R ⁸ of equations (XXV) to (XXVIII) are independently hydrogen, optionally substituted alkyl,
Or optionally substituted from cycloalkyl; and R ³¹ of formulas (XXV) to (XXVIII) is optionally further substituted from alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl. Preferably selected from the group consisting of:

In any of the compounds described herein, the ILM can have the structure of formula (XXIX) or formula (XXX), or an unnatural mimetic thereof, which are described in WO 2013/071039. Derived from the IAP ligand:

During the ceremony:
^{R 43} and R ⁴⁴ of formula (XXIX) and formula (XXX) are independently and optionally substituted from hydrogen, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl. And
^{R 6} and R ⁸ of formula (XXIX) and formula (XXX) are independently selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl.
Each X in equations (XXIX) and (XXX) is independently selected from:

Or selected from any of the above tautomeric types, in the formula:
R ³ of -C (O) R ³ are, OH, is selected from ^{_{NHCN, NHS0 2 R 10, NHOR}} 11 or ^{N (R 12) (R 13} );
NHS0 ₂ R ¹⁰ and R ¹¹ of R ¹⁰ and NHOR ¹¹ are independently, -C ₁ -C ₄ alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl, substituted they either optionally Being selected from, and hydrogen;
Each of R ¹² and R ¹³ of N (R ¹² ) (R ¹³ ) is independent of 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
_{-Selected from} (C 1- C ₄ alkylene) -O- (C _1- C ₄ hydroxyalkyl); or ^{R 12} and R ^{13 of N (R 12} ) (R ¹³ ) are bound in common. Together with the nitrogen atom, it forms a saturated heterocyclyl containing an additional heteroatom optionally selected from N, O and S, where the saturated heterocycle is optionally substituted with methyl.

In any of the compounds described herein, the ILM can have the structure of formula (XXXI) or an unnatural mimetic thereof, which is derived from the IAP ligand described in WO 2013/071039. :

During the ceremony:
^{W 1 in} equation (XLI) is selected from O, S, NR ^A , or C (R ^8a ) (R ^8b );
^{W 2 in the} formula (XLI) is selected from O, S, NR ^A , or C (R ^8c ) (R ^8d ); however, W ¹ and W ² are both O, or both are not S. ;
^{R 1 in} formula (XXXI) is 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 Selected from unsubstituted aryls, substituted or unsubstituted heteroaryls, -C ₁ -C ₆ alkyl- (substituted or unsubstituted aryls), or -C ₁ -C ₆ alkyl- (substituted or unsubstituted heteroaryls);
If X ^{1 is, O, NR A, S,} S (O), or is selected from S (O) ^_2, X ₂ is an C (R ^2a R ^2b);
or:
^{X 1 in} equation (XXXI) is selected from ^{CR 2c} R ^{2d , X 2} is CR ^2a R ^2b , and ^{both R 2c} and R ^2a form a bond;
or:
^{X 1} and X ² of formula (XXXI) are independently selected from C and N, with condensed or unsubstituted saturated or partially saturated 3- to 10-membered cycloalkyl rings, condensed or unsubstituted saturated or partially saturated. Is a component of a 3- to 10-membered heterocycloalkyl ring, a condensed or unsubstituted 5- to 10-membered aryl ring, or a condensed-substituted or unsubstituted 5- to 10-membered heteroaryl ring;
or:
^{X 1 in} equation (XXXI) is _{selected from CH 2} , where X ² is C = 0, C = C (R ^C ) ₂ , or C = NR ^C ; each R ^C is independently 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 NR ^A is H, C ₁ -C ₆ alkyl, -C (= O) C ₁ -C ₂ alkyl, substituted or unsubstituted aryl,
Or selected from substituted or unsubstituted heteroaryl;
CR ^2c R ^2d and CR ^2a R ^2b R ^2a , R ^2b , R ^2c , R ^2d are independently 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 selected from;
-C (= O) R ^B of R ^B is a 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 NR ^D R ^E is independently, H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₅ heteroaryl cycloalkyl, 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 Selected from substituted C ₂ -C ₅ heterocycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted aryl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted heteroaryl);
The m in equation (XXXI) is chosen from 0, 1 or 2;
-U- in equation (XXXI) is -NHC (= O)-, -C (= O) NH-, -NHS (= O) _2- , -S (= O) ₂ NH-, -NHC (=) Selected from O) NH-, -NH (C = O) O-, -O (C = O) NH-, or -NHS (= O) _{2 NH-;}
^{R 3 in} formula (XXXI) is selected from C _1- C ₃ alkyl or C ₁ -C ₃ fluoroalkyl;
^{R 4 in} equation (XXXI) is selected from -NHR ⁵ , -N (R ⁵ ) 2, -N + (R ⁵ ) 3 or -OR ⁵ ;
^{-NHR 5, -N (R 5)} 2, -N + (R 5) 3 and each R ⁵ in the -OR ⁵ is independently, H, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ Selected from -C ₃ heteroalkyl and -C ₁ -C ₃ alkyl- (C ₃ -C ₅ cycloalkyl);
or:
^{R 3} and R ⁵ of formula (XXXI) form a substituted or unsubstituted 5- to 7-membered ring with the atom to which they are attached;
or:
^{R 3} of formula (XXXI) binds to the nitrogen atom of U to form a substituted or unsubstituted 5- to 7-membered ring;
^{R 6} of equation (XXXI) is -NHC (= O) R ⁷ , -C (= O) NHR ⁷ , -NHS (= O) 2R ⁷ , -S (= O) ₂ NHR ⁷ ; 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) 2 NHR ⁷ , substituted or unsubstituted C _2- C ₁₀ heterocycloalkyl, or substituted or unsubstituted heteroaryl;
-NHC (= O) R ⁷ , -C (= O) NHR ⁷ , -NHS (= O) 2R ⁷ , -S (= O) ² NHR ₇ each R 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 is independently 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-C 6 alkyl- (substituted or unsubstituted aryl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted) Heteroaryl),-(CH2) p-CH (substituted or unsubstituted aryl) 2,-(CH ₂ ) _p -CH (substituted or unsubstituted heteroaryl) 2,-(CH ₂ ) _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 aryl) Aryl),-(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted aryl), or-(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted heteroaryl);
P in R ⁷ is selected from 0, 1 or 2;
C (R ^8a ) (R ^8b ) and C (R ^8c ) (R ^8d ) R ^8a , R ^8b , R ^8c and R ^8d are H, C ₁ -C ₆ alkyl, C ₁ -C ₆
Selected from fluoroalkyl, C _1- C ₆ alkoxy, C _1- C ₆ heteroalkyl, and substituted or unsubstituted aryl;
or:
R ^8a and R ^8d are as defined above, and R ^8b and R ^8c both form a bond;
or:
R ^8a and R ^8d are as defined above, and R ^8b and R ^8c are substitutions containing 1-3 heteroatoms selected from S, O and N, along with the atom to which they are attached. Alternatively, an unsubstituted or unsubstituted condensed 5- to 7-membered saturated or partially saturated carbocycle or heterocyclic ring, a substituted or unsubstituted condensed 5- to 10-membered aryl ring, or 1 to 3 selected from S, O and N. Forming substituted or unsubstituted condensed 5- to 10-membered heteroaryl rings containing heteroatoms;
or:
R ^8c and R ^8d are as defined above, and R ^8a and R ^8b are substitutions containing 1-3 heteroatoms selected from S, O and N, along with the atom to which they are attached. Alternatively, an unsubstituted or partially saturated 3- to 7-membered spiro ring or heterospiro ring is formed;
or:
R ^8a and R ^8b are as defined above, and R ^8c and R ^8d are substitutions containing 1-3 heteroatoms selected from S, O and N, along with the atom to which they are attached. Alternatively, an unsubstituted or partially saturated 3- to 7-membered spiro ring or heterospiro ring is formed;
Wherein each substituted alkyl, heteroalkyl, fused, spirocyclic, Heterosupiro ring, cycloalkyl, heterocycloalkyl, aryl or heteroaryl substituted with 1-3 R ^9; and
R ^8a, R ^8b, each R ⁹ in R ^8c and R ^8d are independently halogen, -OH, -SH, (C = O), CN, C 1 -C 4 alkyl, C1-C4 fluoroalkyl alkyl, 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 (= 0) NH ₂ , -C (= O) C ₁ -C ₃ Alkoxy, -S (= O) ₂ CH ₃ , -NH (C ₁ -C ₄ Alkoxy) -OH, -NH (C _1- C ₄ alkyl) -O- (CC _{4 alkyl), - O (C 1 -C} 4 alkyl) --NH2 is selected from; -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, halogen, -OH or C ₁ -C ₃ alkyl Form an substituted or unsubstituted methylenedioxy ring or ethylenedioxy ring.

In any of the compounds described herein, the ILM can have the structure of formula (XXXII) or an unnatural mimetic thereof, which are derived from the IAP ligands described in WO 2013/071039. :

During the ceremony:
^{W 1 in} equation (XXXII) is O, S, NR ^A , or C (R ^8a ) (R ^8b );
^{W 2 in} equation (XXXII) is O, S, NR ^A , or C (R ^8c ) (R ^8d ); however, W ¹ and W ² are both O, or both are not S;
^{R 1 in} formula (XXXII) is 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 Selected from unsubstituted aryls, substituted or unsubstituted heteroaryls, -C ₁ -C ₆ alkyl- (substituted or unsubstituted aryls), or -C ₁ -C ₆ alkyl- (substituted or unsubstituted heteroaryls);
^{If X 1 in} equation (XXXII) is NR ^A , then X ² is C = O or CR ^2c R ^2d , and X ³ is CR ^2a R ^2b ;
or:
^{X 1 in} equation (XXXII) is selected from S, S (O), or S (O) ₂ , where X ² is CR ^2c R ^2d and X ³ is CR ^2a R ^2b ;
or:
^{If X 1 in} equation (XXXII) is O, then X ² is CR ^2c R ^2d , and NR ^A and X ³ are CR ^2a R ^2b ;
or:
When X ¹ of the formula (XXXII) is CH _3, X ² is, O, NR ^A, S, is selected from S (O), or S (O) _2, and X ³ is an CR ^2a R ^2b ;
^{If X 1 in} equation (XXXII) is CR ^2e R ^2f and X ² is CR ^2c R ^2d , then ^{both R 2e} and R ^2c form a bond, and X ^{3 in} equation (XXXII) is CR ^2a R ^2b. And;
or:
^{Both X 1} and X ^{3 in} equation (XXXII) are CH ₂ ^{, and X 2 in} equation (XXXII) is C = 0, C = C (R ^C ) 2, or C = NR ^C ; each R. ^C is independently H, -CN, -OH, alkoxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C _3- C ₆ cycloalkyl, substituted or unsubstituted C _2- C ₅ heterocyclo. Alkoxy, 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 Selected from 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 (XXXII) are independently selected from C and N, with condensed or unsubstituted saturated or partially saturated 3- to 10-membered cycloalkyl rings, condensed or unsubstituted saturated or partially saturated. 3-10 membered heterocycloalkyl ring, condensed or unsubstituted 5-10 membered aryl ring, or condensed substituted or unsubstituted 5-10 membered heteroaryl ring, and X ³ is CR ^2a. R ^2b ;
or:
^{X 2} and X ³ of formula (XXXII) are independently selected from C and N, with condensed or unsubstituted saturated or partially saturated 3- to 10-membered cycloalkyl rings, condensed or unsubstituted saturated or partially saturated. A component of a 3- to 10-membered heterocycloalkyl ring, a condensed or unsubstituted 5- to 10-membered aryl ring, or a condensed-substituted or unsubstituted 5- to 10-membered heteroaryl ring, and X of formula (XXXII). ¹ is CR ^2e R ^2f ;
R ^A of NR ^A is H, C ₁ -C ₆ alkyl, -C (= O) C ₁ -C ₂ alkyl, substituted or unsubstituted aryl,
Or selected from substituted or unsubstituted heteroaryl;
CR ^2c R ^2d , CR ^2a R ^2b and CR ^2e R ^2f R ^2a , R ^2b , R ^2c , R ^2d , R ^2e and R ^2f independently 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 Select from ₁ -C ₆ alkyl- (substituted or unsubstituted aryl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted heteroaryl), and -C (= O) R ^B;
-C (= O) R ^B of R ^B is a substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted Or unsubstituted heteroaryl, -C1-C6 alkyl- (substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl- (substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 alkyl-( Selected from substituted or unsubstituted aryl), -C1-C6 alkyl- (substituted or unsubstituted heteroaryl), or-NR ^D R ^E;
R ^D and R ^E of NR ^D R ^E is independently, H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₅ heteroaryl cycloalkyl, 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 Selected from substituted C ₂ -C ₅ heterocycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted aryl), or -C ₁ -C ₆ alkyl- (substituted or unsubstituted heteroaryl);
The m in equation (XXXII) is chosen from 0, 1 or 2;
-U- in equation (XXXII) is -NHC (= O)-, -C (= O) NH-, -NHS (= O) _2- , -S (= O) ₂ NH-, -NHC (=) Selected from O) NH-, -NH (C = O) O-, -O (C = O) NH-, or -NHS (= O) _{2 NH-;}
^{R 3 in} formula (XXXII) is selected from C _1- C ₃ alkyl or C ₁ -C ₃ fluoroalkyl;
^{R 4 in} equation (XXXII) is selected from -NHR ⁵ , -N (R ⁵ ) ₂ , -N + (R ⁵ ) ₃ or -OR ⁵ ;
-NHR ⁵ , -N (R ⁵ ) ₂ , -N + (R ⁵ ) ₃ and -OR ⁵ R ⁵ are independently H, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ Selected from -C ₃ heteroalkyl and -C ₁ -C ₃ alkyl- (C ₃ -C ₅ cycloalkyl);
or:
^{R 3} and R ⁵ of formula (XXXII) form a substituted or unsubstituted 5- to 7-membered ring with the atom to which they are attached;
or:
^{R 3} of formula (XXXII) binds to the nitrogen atom of U to form a substituted or unsubstituted 5- to 7-membered ring;
^{R 6 in} equation (XXXII) is -NHC (= O) R ⁷ , -C (= O) NHR ⁷ , -NHS (= O) 2R ⁷ , -S (= O) ₂ NHR ⁷ ; 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 selected from substituted or unsubstituted heteroaryl;
-NHC (= O) R ⁷ , -C (= O) NHR ⁷ , -NHS (= O) 2R ⁷ , -S (= O) ² NHR ₇ each R 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) 2 NHR ⁷ independently C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C 3 -C 10 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-C 10 heterocycloalkyl, -C1-C 6 alkyl- (substituted or unsubstituted aryl), -C ₁ -C ₆ alkyl -(Substituted or unsubstituted heteroaryl),-(CH2) p-CH (substituted or unsubstituted aryl) 2,-(CH ₂ ) _p -CH (substituted or unsubstituted heteroaryl) 2,-(CH ₂ ) _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 aryl),-(Substituted or unsubstituted heteroaryl)-(Substituted or unsubstituted aryl), or-(Substituted or unsubstituted heteroaryl)-(Substituted or unsubstituted hetero) Aryl) selected from;
P in R ⁷ is selected from 0, 1 or 2;
C (R ^8a ) (R ^8b ) and C (R ^8c ) (R ^8d ) R ^8a , R ^8b , R ^8c and R ^8d are H, C ₁ -C ₆ alkyl, C ₁ -C ₆
Selected from fluoroalkyl, C _1- C ₆ alkoxy, C _1- C ₆ heteroalkyl, and substituted or unsubstituted aryl;
or:
R ^8a and R ^8d are as defined above, and R ^8b and R ^8c both form a bond;
or:
R ^8a and R ^8d are as defined above, and R ^8b and R ^8c are substitutions containing 1-3 heteroatoms selected from S, O and N, along with the atom to which they are attached. Alternatively, an unsubstituted or unsubstituted condensed 5- to 7-membered saturated or partially saturated carbocycle or heterocyclic ring, a substituted or unsubstituted condensed 5- to 10-membered aryl ring, or 1 to 3 selected from S, O and N. Forming substituted or unsubstituted condensed 5- to 10-membered heteroaryl rings containing heteroatoms;
or:
R ^8c and R ^8d are as defined above, and R ^8a and R ^8b are substitutions containing 1-3 heteroatoms selected from S, O and N, along with the atom to which they are attached. Alternatively, an unsubstituted or partially saturated 3- to 7-membered spiro ring or heterospiro ring is formed;
or:
R ^8a and R ^8b are as defined above, and R ^8c and R ^8d are substitutions containing 1-3 heteroatoms selected from S, O and N, along with the atom to which they are attached. Alternatively, an unsubstituted or partially saturated 3- to 7-membered spiro ring or heterospiro ring is formed;
Wherein each substituted alkyl, heteroalkyl, fused, spirocyclic, Heterosupiro ring, cycloalkyl, heterocycloalkyl, aryl or heteroaryl substituted with 1-3 R ^9; and
R ^8a, R ^8b, each R ⁹ in R ^8c and R ^8d are independently halogen, -OH, -SH, (C = O), CN, C 1 -C 4 alkyl, C1-C4 fluoroalkyl alkyl, 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 (= 0) NH ₂ , -C (= O) C ₁ -C ₃ Alkoxy, -S (= O) ₂ CH ₃ , -NH (C ₁ -C ₄ Alkoxy) -OH, -NH (C _1- C ₄ alkyl) -O- (CC _{4 alkyl), - O (C 1 -C} 4 alkyl) --NH2 is selected from; -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, halogen, -OH or C ₁ -C ₃ alkyl Form an substituted or unsubstituted methylenedioxy ring or ethylenedioxy ring.

In any of the compounds described herein, the ILM can have the structure of formula (XXXIII), or an unnatural mimetic thereof, which is derived from the IAP ligand described in WO 2013/071039. death:

During the ceremony:
W ¹ of formula (XXXIII) is, O, S, is selected from NR ^A or ^{C, (R 8a) (R} 8b);
^{W 2 in} equation (XXXIII) is selected from O, S, NR ^A , or C (R ^8c ) (R ^8d ); however, W ¹ and W ² are both O, or both are not S. ;
^{R 1 in} formula (XXXIII) is 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 Selected from unsubstituted aryls, substituted or unsubstituted heteroaryls, -C ₁ -C ₆ alkyl- (substituted or unsubstituted aryls), or -C ₁ -C ₆ alkyl- (substituted or unsubstituted heteroaryls);
^{If X 1 in} equation (XXXIII) is selected from NR ^A , S, S (O), or S (O) ₂ ^{, then X 2 in} equation (XXXIII) is CR ^2c R ^2d , and equation (XXXIII). ) X ³ is CR ^2a R ^2b ;
or:
When X ¹ of the formula (XXXIII) is O, X ² of formula (XXXIII) is, O, NR ^A, S, is selected from S (O), or S (O) _2, and formula (XXXIII) X ³ is CR ^2a R ^2b ;
or:
^{If X 1 in} equation (XXXIII) is CR ^2e R ^{2f and X 2 in} equation (XXXIII) is CR ^2c R ^2d , then ^{both R 2e} and R ^2c form a bond and X ^{3 in equation (XXXIII).} Is CR ^2a R ^2b ;
or:
^{X 1} and X ² of formula (XXXIII) are independently selected from C and N, with condensed or unsubstituted saturated or partially saturated 3- to 10-membered cycloalkyl rings, condensed or unsubstituted saturated or partially saturated. A component of a 3- to 10-membered heterocycloalkyl ring, a condensed or unsubstituted 5- to 10-membered aryl ring, or a condensed-substituted or unsubstituted 5- to 10-membered heteroaryl ring, and X of formula (XXXIII). ³ is CR ^2a R ^2b ;
or:
^{X 2} and X ³ of formula (XXXIII) are independently selected from C and N, with condensed or unsubstituted saturated or partially saturated 3- to 10-membered cycloalkyl rings, condensed or unsubstituted saturated or partially saturated. A component of a 3- to 10-membered heterocycloalkyl ring, a condensed or unsubstituted 5- to 10-membered aryl ring, or a condensed-substituted or unsubstituted 5- to 10-membered heteroaryl ring, and X of formula (VLII). ¹ is CR ^2e R ^2f ;
R ^A of 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;
CR ^2c R ^2d , CR ^2a R ^2b and CR ^2e R ^2f R ^2a , R ^2b , R ^2c , R ^2d , R ^2e and R ^2f independently 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 ;
-C (= O) R ^B of R ^B is a 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 NR ^D R ^E is independently, H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₅ heteroaryl cycloalkyl, 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 Selected from substituted 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 in equation (XXXIII) is 0, 1 or 2;
-U- in equation (XXXIII) 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 in} formula (XXXIII) is C _1- C ₃ alkyl, or C ₁ -C ₃ fluoroalkyl;
^{R 4 in} equation (XXXIII) is -NHR ⁵ , -N (R ⁵ ) ₂ , -N + (R ⁵ ) ₃ or -OR ⁵ ;
-NHR ⁵ , -N (R ⁵ ) ₂ , -N + (R ⁵ ) ₃ and -OR ⁵ R ⁵ are independently H, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ Selected from -C ₃ heteroalkyl and -C ₁ -C ₃ alkyl- (C ₃ -C ₅ cycloalkyl);
or:
^{R 3} and R ⁵ of formula (XXXIII) form a substituted or unsubstituted 5- to 7-membered ring with the atom to which they are attached;
or:
^{R 3} of formula (XXXIII) binds to the nitrogen atom of U to form a substituted or unsubstituted 5- to 7-membered ring;
^{R 6 in} equation (XXXIII) is -NHC (= O) R ⁷ , -C (= O) NHR ⁷ , -NHS (= O) 2R ⁷ , -S (= O) ₂ NHR ⁷ ; 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 selected from substituted or unsubstituted heteroaryl;
-NHC (= O) R ⁷ , -C (= O) NHR ⁷ , -NHS (= O) 2R ⁷ , -S (= O) ² NHR ₇ each R 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) 2 NHR ⁷ independently C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C 3 -C 10 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-C 10 heterocycloalkyl, -C1-C 6 alkyl- (substituted or unsubstituted aryl), -C ₁ -C ₆ alkyl -(Substituted or unsubstituted heteroaryl),-(CH2) p-CH (substituted or unsubstituted aryl) 2,-(CH ₂ ) _p -CH (substituted or unsubstituted heteroaryl) 2,-(CH ₂ ) _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 aryl),-(Substituted or unsubstituted heteroaryl)-(Substituted or unsubstituted aryl), or-(Substituted or unsubstituted heteroaryl)-(Substituted or unsubstituted hetero) Aryl) selected from;
The p in R ⁷ is 0, 1, or 2;
C (R ^8a ) (R ^8b ) and C (R ^8c ) (R ^8d ) R ^8a , R ^8b , R ^8c and R ^8d are H, C ₁ -C ₆ alkyl, C ₁ -C ₆
Selected from fluoroalkyl, C _1- C ₆ alkoxy, C _1- C ₆ heteroalkyl, and substituted or unsubstituted aryl;
or:
R ^8a and R ^8d are as defined above, and R ^8b and R ^8c both form a bond;
or:
R ^8a and R ^8d are as defined above, and R ^8b and R ^8c are substitutions containing 1-3 heteroatoms selected from S, O and N, along with the atom to which they are attached. Alternatively, an unsubstituted or unsubstituted condensed 5- to 7-membered saturated or partially saturated carbocycle or heterocyclic ring, a substituted or unsubstituted condensed 5- to 10-membered aryl ring, or 1 to 3 selected from S, O and N. Forming substituted or unsubstituted condensed 5- to 10-membered heteroaryl rings containing heteroatoms;
or:
R ^8c and R ^8d are as defined above, and R ^8a and R ^8b are substitutions containing 1-3 heteroatoms selected from S, O and N, along with the atom to which they are attached. Alternatively, an unsubstituted or partially saturated 3- to 7-membered spiro ring or heterospiro ring is formed;
or:
R ^8a and R ^8b are as defined above, and R ^8c and R ^8d are substitutions containing 1-3 heteroatoms selected from S, O and N, along with the atom to which they are attached. Alternatively, an unsubstituted or partially saturated 3- to 7-membered spiro ring or heterospiro ring is formed;
Wherein each substituted alkyl, heteroalkyl, fused, spirocyclic, Heterosupiro ring, cycloalkyl, heterocycloalkyl, aryl or heteroaryl substituted with 1-3 R ^9; and
R ^8a, R ^8b, each R ⁹ in R ^8c and R ^8d are independently halogen, -OH, -SH, (C = O), CN, C 1 -C 4 alkyl, C1-C4 fluoroalkyl alkyl, 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 (= 0) NH ₂ , -C (= O) C ₁ -C ₃ Alkoxy, -S (= O) ₂ CH ₃ , -NH (C ₁ -C ₄ Alkoxy) -OH, -NH (C _1- C ₄ alkyl) -O- (CC _{4 alkyl), - O (C 1 -C} 4 alkyl) --NH2 is selected from; -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, halogen, -OH or C ₁ -C ₃ alkyl Form an substituted or unsubstituted methylenedioxy ring or ethylenedioxy ring.

In any of the compounds described herein, the ILM can have the structure of formula (XXXIV), or an unnatural mimetic thereof, which is derived from the IAP ligand described in WO 2013/071039. death:

During the ceremony:
^{W 1 in} equation (XXXIV) is selected from O, S, NR ^A , or C (R ^8a ) (R ^8b );
^{W 2 in} equation (XXXIV) is selected from O, S, NR ^A , or C (R ^8c ) (R ^8d ); however, W ¹ and W ² are both O, or both are not S. ;
^{W 3 in} equation (XXXIV) is selected from O, S, NR ^A , or C (R ^8e ) (R ^8f ), where ^{the ring containing W 1} , W ² and W ³ has two adjacent oxygens. Contains no atoms or sulfur atoms;
^{R 1 in} formula (XXXIV) is 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 Selected from unsubstituted aryls, substituted or unsubstituted heteroaryls, -C ₁ -C ₆ alkyl- (substituted or unsubstituted aryls), or -C ₁ -C ₆ alkyl- (substituted or unsubstituted heteroaryls);
^{If X 1 in} equation (XXXIV) is O, then X ^{2 in} equation (XXXIV) is ^{selected from CR 2c} R ^2d and NR ^{A, and W 3 in} equation (XXXIV) is CR ^2a R ^2b ;
or:
When X ¹ of the formula (XXXIV) is CH _2, X ² of formula (XXXIV) is, O, NR ^A, S, is selected from S (O), or S (O) _2, wherein the (XXXIV) X ³ is CR ^2a R ^2b ;
or:
^{If X 1 in} equation (XXXIV) is CR ^2e R ^{2f and X 2 in} equation (XXXIV) is CR ^2c R ^2d , then ^{both R 2e} and R ^2c form a bond and X ^{3 in equation (XXXIV).} Is CR ^2a R ^2b ;
or:
^{Both X 1} and X ^{3 in} equation (XXXIV) are CH ₂ ^{, and X 2 in} equation (XXXIV) is C = 0, C = C (R ^C ) 2, or C = NR ^C ; each R. ^C is independently 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 (XXXIV) are independently selected from C and N, with condensed or unsubstituted saturated or partially saturated 3- to 10-membered cycloalkyl rings, condensed or unsubstituted saturated or partially saturated. A component of a 3- to 10-membered heterocycloalkyl ring, a condensed or unsubstituted 5- to 10-membered aryl ring, or a condensed-substituted or unsubstituted 5- to 10-membered heteroaryl ring, and X of formula (XXXIV). ³ is CR ^2a R ^2b ;
or:
^{X 2} and X ³ of formula (XXXIV) are independently selected from C and N, with condensed or unsubstituted saturated or partially saturated 3- to 10-membered cycloalkyl rings, condensed or unsubstituted saturated or partially saturated. A component of a 3- to 10-membered heterocycloalkyl ring, a condensed or unsubstituted 5- to 10-membered aryl ring, or a condensed-substituted or unsubstituted 5- to 10-membered heteroaryl ring, and X of formula (VLIV). ¹ is CR ^2e R ^2f ;
R ^A of NR ^A is H, C ₁ -C ₆ alkyl, -C (= O) C ₁ -C ₂ alkyl, substituted or unsubstituted aryl,
Or selected from substituted or unsubstituted heteroaryl;
CR ^2c R ^2d , CR ^2a R ^2b and CR ^2e R ^2f R ^2a , R ^2b , R ^2c , R ^2d , R ^2e and R ^2f independently 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 ;
-C (= O) R ^B of R ^B is a substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted Or unsubstituted heteroaryl, -C1-C6 alkyl- (substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl- (substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 alkyl-( Selected from substituted or unsubstituted aryl), -C1-C6 alkyl- (substituted or unsubstituted heteroaryl), or-NR ^D R ^E;
R ^D and R ^E of NR ^D R ^E is independently, H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₅ heteroaryl cycloalkyl, 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 Selected from substituted C ₂ -C ₅ heterocycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted aryl), or -C ₁ -C ₆ alkyl- (substituted or unsubstituted heteroaryl);
The m in equation (XXXIV) is selected from 0, 1 or 2;
-U- in equation (XXXIV) is -NHC (= O)-, -C (= O) NH-, -NHS (= O) _2- , -S (= O) ₂ NH-, -NHC (=) Selected from O) NH-, -NH (C = O) O-, -O (C = O) NH-, or -NHS (= O) _{2 NH-;}
^{R 3 in} formula (XXXIV) is selected from C _1- C ₃ alkyl or C ₁ -C ₃ fluoroalkyl;
^{R 4 in} equation (XXXIV) is selected from -NHR ⁵ , -N (R ⁵ ) ₂ , -N + (R ⁵ ) ₃ or -OR ⁵ ;
-NHR ⁵ , -N (R ⁵ ) ₂ , -N + (R ⁵ ) ₃ and -OR ⁵ R ⁵ are independently H, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ Selected from -C ₃ heteroalkyl and -C ₁ -C ₃ alkyl- (C ₃ -C ₅ cycloalkyl);
or:
^{R 3} and R ⁵ of formula (XXXIV) form a substituted or unsubstituted 5- to 7-membered ring with the atom to which they are attached;
or:
^{R 3} of formula (XXXIV) binds to the nitrogen atom of U to form a substituted or unsubstituted 5- to 7-membered ring;
^{R 6 in} equation (XXXIV) is -NHC (= O) R ⁷ , -C (= O) NHR ⁷ , -NHS (= O) 2R ⁷ , -S (= O) ₂ NHR ⁷ ; 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 selected from substituted or unsubstituted heteroaryl;
-NHC (= O) R ⁷ , -C (= O) NHR ⁷ , -NHS (= O) 2R ⁷ , -S (= O) ² NHR ₇ each R 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) 2 NHR ⁷ independently C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C 3 -C 10 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-C 10 heterocycloalkyl, -C1-C 6 alkyl- (substituted or unsubstituted aryl), -C ₁ -C ₆ alkyl -(Substituted or unsubstituted heteroaryl),-(CH2) p-CH (substituted or unsubstituted aryl) 2,-(CH ₂ ) _p -CH (substituted or unsubstituted heteroaryl) 2,-(CH ₂ ) _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 aryl),-(Substituted or unsubstituted heteroaryl)-(Substituted or unsubstituted aryl), or-(Substituted or unsubstituted heteroaryl)-(Substituted or unsubstituted hetero) Aryl) selected from;
P in R ⁷ is selected from 0, 1 or 2;
C (R ^8a ) (R ^8b ), C (R ^8c ) (R ^8d ) and C (R ^8e ) (R ^8f ) R ^8a , R ^8b , R ^8c , R ^8d , R ^8e and R ^8f are independent. , 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:
C (R ^8a ) (R ^8b ), C (R ^8c ) (R ^8d ) and C (R ^8e ) (R ^8f ) R ^8a , R ^8d , R ^8e and R ^8f are as defined above. ^Yes , and R 8b and R ^8c both form a bond;
or:
C (R ^8a ) (R ^8b ), C (R ^8c ) (R ^8d ) and C (R ^8e ) (R ^8f ) R ^8a , R ^8b , R ^8d and R ^8f are as defined above. ^Yes , and R 8c and R ^8e both form a bond;
or:
C (R ^8a ) (R ^8b ), C (R ^8c ) (R ^8d ) and C (R ^8e ) (R ^8f ) R ^8a , R ^8d , R ^8e and R ^8f are as defined above. , And R ^8b and R ^8c are substituted or unsubstituted condensation 5-7 member saturated or partially saturated containing 1-3 heteroatoms selected from S, O and N, along with the atom to which they are attached. Carbocyclic or heterocyclic rings, substituted or unsubstituted condensed 5- to 10-membered aryl rings,
Or to form a substituted or unsubstituted condensed 5- to 10-membered heteroaryl ring containing 1-3 heteroatoms selected from S, O and N;
or:
C (R ^8a ) (R ^8b ), C (R ^8c ) (R ^8d ) and C (R ^8e ) (R ^8f ) R ^8a , R ^8b , R ^8d and R ^8f are as defined above. , And R ^8c and R ^8e are substituted or unsubstituted condensation 5-7 member saturated or partially saturated containing 1-3 heteroatoms selected from S, O and N, along with the atom to which they are attached. Carbocyclic or heterocyclic rings, substituted or unsubstituted condensed 5- to 10-membered aryl rings,
Or to form a substituted or unsubstituted condensed 5- to 10-membered heteroaryl ring containing 1-3 heteroatoms selected from S, O and N;
or:
^{R 8c} , R ^8d , R ^8e and R ^8f of C (R ^8c ) (R ^8d ) and C (R ^8e ) (R ^8f ) are as defined above, and R ^8a and R ^8b are them. Form a substituted or unsubstituted saturated or partially saturated 3- to 7-membered spiro ring or hetero-spiro ring containing 1 to 3 heteroatoms selected from S, O and N with the atom to which it is bonded;
or:
^{R 8a} , R ^8b , R ^8e and R ^8f of C (R ^8a ) (R ^8b ) and C (R ^8e ) (R ^8f ) are as defined above, and R ^8c and R ^8d are them. Form a substituted or unsubstituted saturated or partially saturated 3- to 7-membered spiro ring or hetero-spiro ring containing 1 to 3 heteroatoms selected from S, O and N with the atom to which it is bonded;
or:
^{R 8a} , R ^8b , R ^8c and R ^8d of C (R ^8a ) (R ^8b ) and C (R ^8c ) (R ^8d ) are as defined above, and R ^8e and R ^8f are them. Form a substituted or unsubstituted saturated or partially saturated 3- to 7-membered spiro ring or hetero-spiro ring containing 1 to 3 heteroatoms selected from S, O and N with the atom to which it is bonded;
or:
Wherein each substituted alkyl, heteroalkyl, fused, spirocyclic, Heterosupiro ring, cycloalkyl, heterocycloalkyl, aryl or heteroaryl substituted with 1-3 R ^9; and
^{R 8a, R 8b, R 8c} , each R ⁹ in R ^8d, R ^8e, and R ^8f is independently halogen, -OH, -SH, (C = O), CN, C 1- C 4 alkyl, C1-C4 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 (= 0) 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- (CC _{4 alkyl), - O (C 1 -C} 4 alkyl) --NH2 is selected from; -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, halogen, -OH Alternatively, a C _1- C ₃ alkyl substituted or unsubstituted methylenedioxy ring or ethylenedioxy ring is formed.

In any of the compounds described herein, the ILM can have the structure of formula (XXXV), formula (XXXVI) or formula (XXXVII), or an unnatural mimic thereof, which is Vamos. , M., et al., Expedient synthesis of highly potent antagonists of inhibitor of apoptosis proteins (IAPs) with unique epitopes for ML-IAP, ACS Chem. Biol.,
Derived from the IAP ligand described in 8 (4), 725-32 (2013):

During the ceremony:
^{R 2} of equation (XXXV) and equation (XXXVII) is independently selected from H or ME;
^{R 3} and R ⁴ of equation (XXXV) are independently selected from H or ME;
X in formula (XXXV) and formula (XXXVII) is independently selected from O or S; and R ^{1 in} formula (XXXV) and formula (XXXVII) is selected from:

In certain embodiments, the ILM has a structure according to the following equation (XXXVIII):

In certain embodiments, of formula (XXXVIII)

In certain embodiments, the ILM has a structure as shown below and is attached to the linker group L:

In any of the compounds described herein, the ILM can have the structure of formula (XXXIX) or formula (XL), or an unnatural mimetic thereof, which is Hennessy, EJ, et al. , Discovery of aminopiperidine-based Smac mimetics as IAP antagonists, Bioorg. Med. Chem. Lett., 22 (4), 1960-4 (2012).

^{R 2 in} formula (XXXIX) and formula (XL) is selected from H or Me;
^{R 3} of formula (XXXIX) and formula (XL) is selected from:

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

In any of the compounds described herein, the ILM has the structure of formula (XLI) or formula (XLII) or an unnatural mimic thereof, as set forth in formula (XLI) or formula (XLII). Can have and can be chemically bonded to the linker:

In any of the compounds described herein, the ILM can have the structure of formula (XLIII), or a non-natural mimic thereof, which is 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).

In certain embodiments, the ILM is represented by the following structure:

In certain embodiments, the ILM is selected from the group consisting of the following, indicating its chemical bond between the ILM and the linker group L:

In any of the compounds described herein, the ILM is selected from the group consisting of the following, or structures of its non-natural mimetics, which are 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
Based on the IAP ligand described in (2013):

In certain embodiments, the ILM is selected from the group consisting of the following, indicating its chemical bond between the ILM and the linker group L:

In any of the compounds described herein, the ILM can have the structure of formula (XLIV), or an unnatural mimetic thereof, which is 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): Based on the IAP ligand described in 5725-37 (2013):

In the formula, X in formula (XLIV) is one or two substituents independently selected from H, halogen, or cyano.

In any of the compounds described herein, the ILM has the structure of formula (XLV) or formula (XLVI) or an unnatural mimic thereof, as set forth in formula (XLV) or formula (XLVI). Can have and can be chemically bonded to the linker group L:

In the formula, X in formula (XLV) and formula (XLVI) is one or two substituents independently selected from H, halogen, or cyano, and; formula (XLV) and formula (XLVI). ) L is the linker group described herein.

In any of the compounds described herein, the ILM can have the structure of formula (XLVII), or a non-natural mimic thereof, which is 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)
Based on the IAP ligand described in:

In any of the compounds described herein, the ILM has the structure of formula (XLVIII) or formula (XLIX) or an unnatural mimic thereof, as set forth in formula (XLVIII) or formula (XLIX). Can have and can be chemically bonded to the linker group L:

Is a natural or unnatural amino acid; and L of formula (XLVIII) and formula (XLIX) is the linker group described herein.

In any of the compounds described herein, the ILM can have a structure selected from the group consisting of the following, or a structure of an unnatural mitochondria thereof, which 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): Derived from the IAP ligand described in 319-29 (2014):

In any of the compounds described herein, the ILM has a structure according to formula (L), or an unnatural mimetic thereof, which is Hird, AW, et al., Structure-based design. and synthesis of tricyclic IAP (Inhibitors of Apoptosis Proteins) inhibitors, Bioorg. Med. Chem. Lett., 24 (7): Based on the IAP ligand described in 1820-4 (2014):

HETs are monocyclic heteroaryls or condensed bicyclic heteroaryls; and
--- in equation (L) is an arbitrary double bond.

In certain embodiments, the ILM of the compound has a chemical structure selected from the group consisting of:

Illustrative MLM
In certain additional embodiments, the MLM of the bifunctional compound may be, for example, substituted imidazoline, substituted spiro-indolinone, substituted pyrrolidine, substituted piperidinone, substituted substituted morpholinone, substituted pyrolopyrimidine, substituted imidazolopyridine, substituted thiazolomidazoline, substituted. Includes chemical moieties such as pyrrolopyrolidinones and substituted isoquinolinones.

In additional embodiments, the MLM comprises the core structure described above with adjacent bis-aryl substitutions positioned as cis or trans configurations.

In a further additional embodiment, MLM is structural as in RG7112, RG7388, SAR405838, AMG-232, AM-7209, DS-5272, MK-8242, and NVP-CGM-097, and analogs or derivatives thereof. Includes feature parts.

In certain preferred embodiments, the MLM is a derivative of the substituted imidazoline represented by formula (A-1), or a derivative of thiazolomidazoline represented by formula (A-2), or represented by formula (A-3). Derivatives of spiroidlinone, or derivatives of pyrrolidine represented by the formula (A-4), or derivatives of piperidinone / morphrinone represented by the formula (A-5), or represented by the formula (A-6). It is a derivative of isoquinolinone, a derivative of pyrrolopyrimidine / imidazolopyridine represented by the formula (A-7), or a derivative of pyrolopyrolidinone / imidazolopyrolidinone represented by the formula (A-8).

In the above equations (A-1) to (A-8),
X in formulas (A-1) to (A-8) are carbon, oxygen, sulfur, sulfoxide, sulfone, and NR ^a.
Selected from the group consisting of;
R ^a is independently an H, or an alkyl group with 1 to 6 carbon atoms;
Y and Z in formulas (A-1) to (A-8) are independently carbon or nitrogen;
A, A'and A "of formulas (A-1) to (A-8) are selected independently of C, N, O or S, or form a fused bicyclic ring. Alternatively, it may be one or two atoms forming the 6,5- and 5,5-fused aromatic bicyclic groups;
_{R 1} and R ₂ of the formulas (A-1) to (A-8) are independently selected from the group consisting of an aryl group or a heteroaryl group, and the heteroaryl group is independent of sulfur or nitrogen. It has one or two heteroatoms to be selected, and the aryl group or heteroaryl group may be monocyclic or bicyclic, or one to three selected independently from the group consisting of the following. May be substituted or unsubstituted with a substituent of:
Halogen, -CN, C1-C6 alkyl group, C3-C6 cycloalkyl, -OH, alkoxy containing 1-6 carbons, sulfoxide alkoxy containing 1-6 carbons, containing 1-6 carbons Sulfoxides, sulfones containing 1 to 6 carbons, ketones containing 2 to 6 carbons, amides containing 2 to 6 carbons, and dialkylamines containing 2 to 6 carbons;
_{R 3} and R ₄ of formulas (A-1) to (A-8) are independently selected from the group consisting of H, methyl and C1 to C6 alkyl;
_{R 5} of formula (A-1) to formula (A-8) is selected from the group consisting of aryl groups or heteroaryl groups, and the heteroaryl group is selected one or two independently of sulfur or nitrogen. It has a heteroatom, and the aryl group or heteroaryl group may be monocyclic or bicyclic, or is substituted with 1 to 3 substituents independently selected from the group consisting of the following. Or may be unsubstituted:
Halogen, -CN, C1-C6 alkyl group, C3-C6 cycloalkyl, -OH, alkoxy containing 1-6 carbons, sulfoxide alkoxy containing 1-6 carbons, containing 1-6 carbons Sulfoxide, sulfone containing 1-6 carbons, ketones containing 2-6 carbons, amides containing 2-6 carbons, dialkylamines containing 2-6 carbons, alkyl ethers (C2-C6) , Alkyl Ketones (C3 to C6), Morphorinyl, Alkyl Esters (C3 to C6), Alkyl Cyanides (C3 to C6);
_{R 6 in} equations (A-1) to (A-8) is H, or -C (= O) R ^b , and in the equation,
^{R b} of formulas (A-1) to (A-8) are alkyl, cycloalkyl, mono-substituted, di-substituted or tri-substituted aryl or heteroaryl, 4-morpholinyl, 1- (3-oxopiperaznyl). , 1-piperidinyl, 4-NR ^c -morpholinyl, 4-R ^c -1-piperidinyl, and 3-R ^c -1-piperidinyl.
^{R c} of the formulas (A-1) to (A-8) are alkyl, fluorine-substituted alkyl, cyanoalkyl, hydroxyl-substituted alkyl, cycloalkyl, alkoxyalkyl, amide alkyl, alkyl sulfone, alkyl sulfoxide, alkyl amide, aryl. , Heteroaryl, mono-substituted, di- and tri-substituted aryl or heteroaryl, CH2CH2R ^d , and CH2CH2CH2R ^d .
^{R d} of formulas (A-1) to (A-8) are alkoxy, alkyl sulfone, alkyl sulfoxide, N-substituted carboxamide, -NHC (O) -alkyl, -NH-SO ₂ -alkyl, aryl, substituted. Selected from the group consisting of aryl, heteroaryl, substituted heteroaryl;
_{R 7} of formulas (A-1) to (A-8) is H, C1-C6 alkyl, cyclic alkyl, fluorine-substituted alkyl, cyano-substituted alkyl, 5- or 6-membered heteroaryl or aryl, 5-membered or Selected from the group consisting of 6-membered substituted heteroaryls or aryls;
_{R 8} of formulas (A-1) to (A-8) is -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 selected from the group consisting of ^{g, in the formula:
R e} of formulas (A-1) to (A-8) is an alkylene or bond containing 1 to 6 carbons;
^{R f in} equations (A-1) to (A-8) is a 4- to 7-membered substituted heterocycle;
^{R g} of formulas (A-1) to (A-8) is selected from the group consisting of aryls, heteroaryls, substituted aryls or heteroaryls, and 4- to 7-membered heterocycles;
^{R 9} of the formulas (A-1) to (A-8) is selected from the group consisting of a mono-substituted group, a di-substituted group or a tri-substituted group on the fused bicyclic aromatic ring in the formula (A-3). Here, the substituent is independently selected from the group consisting of Cl or F substituted or unsubstituted halogen, alkene, alkyne, alkyl;
_{R 10} of formulas (A-1) to (A-8) is selected from the group consisting of aryl or heteroaryl groups, wherein the heteroaryl group is one or two, such as sulfur or nitrogen. Heteroatoms may be contained and the aryl group or heteroaryl group may be monocyclic or bicyclic, and the aryl group or heteroaryl group may be halogen, F, Cl, -CN, alkene, alkyne, etc. C1-C6 alkyl groups, C1-C6 cycloalkyls, -OH, alkoxys containing 1-6 carbons, fluorine-substituted alkoxys containing 1-6 carbons, sulfoxides containing 1-6 carbons, 1
It may be substituted or unsubstituted with 1 to 3 substituents, including sulfones containing up to 6 carbons, ketones containing 2 to 6 carbons;
^{R 11} of equations (A-1) to (A-8) is -C (O) -N (R ^h ) (R ⁱ ), and in the equations, R ^h and R ⁱ are a group consisting of the following. Selected from:
H; Arbitrarily substituted linear or branched C1-C6 alkyl; alkoxy substituted alkyl; mono-hydroxy substituted alkyl and di-hydroxy substituted alkyl (eg C3-C6), sulfon substituted alkyl; optionally Aryl substituted; optionally substituted heteroaryl; mono-substituted, bis-substituted, or tri-substituted aryl or heteroaryl; phenyl-4-carboxylic acid; substituted phenyl-4-carboxylic acid, alkylcarboxylic acid; optionally substituted Heteroarylcarboxylic acid; alkylcarboxylic acid; fluorine-substituted alkylcarboxylic acid; optionally substituted cycloalkyl, 3-hydroxycyclobutane, 4-hydroxycyclohehexane, aryl-substituted cycloalkyl; heteroaryl-substituted cycloalkyl; or Rh And Ri together form a ring;
_{R 12} and R ₁₃ of formulas (A-1) to (A-8) are independently H, lower alkyl (C1 to C6), lower alkenyl (C2 to C6), lower alkynyl (C2 to C6), Selected from cycloalkyl (4-membered, 5-membered and 6-membered rings), substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, 5- and 6-membered aryls and heteroaryls, R12 and R13 combine to form a ring. May form 5- and 6-membered rings with or without substitutions in;
_{R 14} of the formulas (A-1) to (A-8) is alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, Selected from the group consisting of substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl;
_{R 15 in} equations (A-1) to (A-8) is CN;
_{R 16} of the formulas (A-1) to (A-8) is C1-C6 alkyl, C1-6 cycloalkyl, C2-6 alkenyl, C1-6 alkyl in which one or more hydrogens are substituted with fluorine, or C3-6 cycloalkyl, one CH ₂ is S (= O), -S or -S (= O) ₂ substituted alkyl or cycloalkyl, terminal CH ₃ is S (= O) ₂ N (alkyl) With (alkyl), -C (= O) N (alkyl) (alkyl), -N (alkyl) S (= O) ₂ (alkyl), -C (= O) 2 (alkyl), -O (alkyl) Substituted alkyl or cycloalkyl, C1-6 alkyl or alkyl-cycloalkyl in which hydrogen is substituted with a hydroxyl group, optionally 3- to 7 member cycloalkyl or heterocycloalkyl containing a-(C = O) -group. , Or a group consisting of a 5- to 6-membered aryl group or a heteroaryl group, the heterocycloalkyl or heteroaryl group is one to three heteroatoms selected independently of O, N or S. And the cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group may contain halogen, C1-6 alkyl group, hydroxylated C1-6 alkyl, thioether containing C1-6 alkyl, ether, sulfone. , Sulfoxide, fluorine substituted ether or optionally substituted with 1 to 3 substituents independently selected from the cyano group;
_{R 17 in} equations (A-1) to (A-8) is selected from the group consisting of (CH ₂ ) nC (O) NR ^k R ^{l , in which R k} and R ^l are independent. H, C1-6 alkyl, hydroxylated C1-6 alkyl, C1-6 alkoxyalkyl, one or more hydrogens substituted with fluorine C1-6 alkyl, one carbon substituted with S (O) C1- 6-alkyl, S (O) (O), C1-6 alkoxyalkyl in which one or more hydrogens are substituted with fluorine, C1-6alkyl in which hydrogen is substituted with cyano groups, 5- and 6-membered aryls or heteros. It is selected from aryls, alkylaryls having an alkyl group containing 1 to 6 carbons, and alkyl heteroaryls having an alkyl group containing 1 to 6 carbons, wherein the aryl group or heteroaryl group is further substituted. obtain;
_{R 18} of formulas (A-1) to (A-8) is selected from the group consisting of substituted aryls, heteroaryls, alkyls and cycloalkyls, the substitutions preferably being -N (C1-4 alkyl) ( Cycloalkyl), -N (C1-4alkyl) alkyl-cycloalkyl, and -N (C1-4alkyl) [(alkyl)-(heterocyclic substitution) -cycloalkyl];
_{R 19} of formulas (A-1) to (A-8) is selected from the group consisting of aryls, heteroaryls, bicyclic heteroaryls, and these aryl and heteroaryl groups are halogen, C1-. It may be substituted with 6 alkyl, C1-6 cycloalkyl, CF ₃ , F, CN, alkyne, alkyl sulfone, and the halogen substitution may be mono-, bi- or tri-substituted;
_{R 20} and R ₂₁ of formulas (A-1) to (A-8) are independently C1-6 alkyl, C1-6 cycloalkyl, C1-6 alkoxy, hydroxylated C1-6 alkoxy, and fluorine substitutions. Selected from C1-6 alkoxy, in the formula, R ₂₀ and R ₂₁ may be further coupled to form a 5, 6, and 7-membered ring or heterocycle, which may be further substituted;
_{R 22} of the formulas (A-1) to (A-8) is H, C1-6alkyl, C1-6cycloalkyl, carboxylic acid, carboxylic acid ester, amide, reverse amide, sulfonamide, Selected from the group consisting of reverse sulfonamide, N-acylurea, nitrogen-containing 5-membered heterocycles, the 5-membered heterocycle is further substituted with C1-6 alkyl, alkoxy, fluorine-substituted alkyl, CN, and alkylsulfones. May be;
_{R 23} of formulas (A-1) to (A-8) is aryl, heteroaryl, -O-aryl, -O-heteroaryl, -O-alkyl, -O-alkyl-cycloalkyl, -NH- Aryl groups selected from alkyl, -NH-alkyl-cycloalkyl, -N (H) -aryl, -N (H) -heteroaryl, -N (alkyl) -aryl, -N (alkyl) -heteroaryl. Alternatively, the heteroaryl group may be substituted with halogen, C1-C6 alkyl, hydroxylated C1-6 alkyl, cycloalkyl, fluorine substituted C1-6 alkyl, CN, alkoxy, alkylsulfone, amide, and sulfonamide;
_{R 24} of formulas (A-1) to (A-8) is selected from the group consisting of -CH2- (C1-6alkyl), -CH2-cycloalkyl, -CH2-aryl, CH2-heteroaryl. The alkyl, cycloalkyl, aryl and heteroaryl may be substituted with halogen, alkoxy, hydroxylated alkyl, cyano-substituted alkyl, cycloalkyl, and substituted cycloalkyl;
_{R 25} of formulas (A-1) to (A-8) is C1-6 alkyl, C1-6 alkyl-cycloalkyl, alkoxy substituted alkyl, hydroxylated alkyl, aryl, heteroaryl, substituted aryl or heteroaryl, Selected from the group consisting of 5, 6 and 7-membered nitrogen-containing saturated heterocycles, 5,6-condensed and 6,6-condensed nitrogen-containing saturated heterocycles, and these saturated heterocycles are C1-6 alkyl, fluorine-substituted C1. -6 Alkoxy, alkoxy, aryl and heteroaryl groups may be substituted;
_{R 26} of the formulas (A-1) to (A-8) is selected from the group consisting of C1-6alkyl and C3-6cycloalkyl, and the alkyl or cycloalkyl is -OH, alkoxy, or fluorine-substituted alkoxy. , Fluorine Substituted Alkoxy, -NH ₂ , -NH-alkyl, NH-C (O) Alkoxy, -NH-S (O) ₂ -alkyl,
And may be substituted with -S (O) _{2-alkyl;
R 27} of the formulas (A-1) to (A-8) is selected from the group consisting of aryl, heteroaryl, and bicyclic heteroaryl, and the aryl group or heteroaryl group is C1-6 alkyl, alkoxy. , NH2, NH-alkyl, halogen or -CN, and the substitutions may be independently mono-, di- and tri-substituted;
_{R 28} of formulas (A-1) to (A-8) is aryl, 5- and 6-membered heteroaryl, bicyclic heteroaryl, cycloalkyl, saturated heterocycles such as piperidin, piperidinone, Selected from the group consisting of tetrahydropyran, N-acyl-piperidin, the cycloalkyl, saturated heterocycle, aryl or heteroaryl may be mono-, di- or tri-substituted, -CN, alkyl containing -OH, alkoxy, halogen. It may be further substituted with a sulfone, and a fluorine-substituted alkyl group; and R _{1 "in} formulas (A-1) to (A-8) is H, alkyl, aryl substituted alkyl, alkoxy substituted alkyl, cycloalkyl, It is selected from the group consisting of aryl-substituted cycloalkyls and alkoxy-substituted cycloalkyls.

^{In certain embodiments, the heterocycles in R f} and R ^g of formulas (A-1) to (A-8) are substituted pyrrolidine, substituted piperidine, substituted piperizine.

More specifically, non-limiting examples of MLMs include those listed below, as well as "hybrid" molecules resulting from one or more combinations of different properties shown in the following molecules.

Using the MLMs of formulas A-1 to A-8, the following PROTACs can be made to target for the degradation of specific proteins, where "L" is the connector (ie, linker group). )
And "PTM" is a ligand that binds to the target protein.

In certain embodiments, the present specification provides bifunctional molecules comprising structures selected from the group consisting of:

In the formula, 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 ^l , 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 equations (A-1) to (A-8). As it is done.

In certain embodiments, the present specification provides a bifunctional or chimeric molecule having the structure of PTM-L-MLM, wherein in the formula PTM is a protein target binding moiety linked to MLM by L. , In the formula, L is a bound (ie, 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:

During the ceremony:
R1'and R2'of equations A-1-1 to A-1-4 (ie, A-1-1, A-1-2, A-1-3, and A-1-4) are independent. And selected from the 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 equations A-1-1 to A-1-4 are 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) _{Selected from the group consisting of 2} CH ₃ , -S (O ₂ ) CH ₂ CH ₃ , -NHC (CH ₃ ) ₃ , -N (CH ₃ ) ₂ , pyrrolidinyl, and 4-morpholinyl;
R5'in formulas A-1-1 to A-1-4 are halogen, -cyclopropyl, -S (O) ₂ CH ₃ , -S (O) ₂ CH ₂ CH ₃ , 1-pyrrolidinyl, -NH. Selected from the group consisting of ₂ , -N (CH ₃ ) ₂ , and -NHC (CH ₃ ) _{3; and}
R6'in formulas A-1-1 to A-1-4 are selected from the structures represented below, in which the linker binding point is indicated as "*".
Apart from R6'as a linker binding point, R4'can also serve as a linker binding position. If R4'is the linker binding site, the linker will be attached to the terminal atom of the R4'group as shown above.

In certain embodiments, the linker binding points of formulas A-1-1 to A-1-4 are at least one of R4'and / or R6'.

In certain embodiments, R6'in formulas A-1-1 to A-1-4 are independently H,

In certain embodiments, the linker of formulas A-4-1 to A-4-6 is at least one of R1', R2', R3', R4', R5', R6', or a combination thereof. Combined with.

In certain embodiments, the present specification provides a bifunctional or chimeric molecule having the structure of PTM-L-MLM, wherein in the formula PTM is a protein target binding moiety linked to MLM by L. , In the formula, L is a bound (ie, absent) or chemical linker. In certain embodiments, the MLM consists of the following groups A-4-1, A-4-2, A-4-3, A-4-4, A-4-5, and A-4-6: Has a structure selected from:

During the ceremony:
R7'from formulas A-4-1 to A-4-6 (ie, A-4-1, A-4-2, A-4-3, A-4-4, A-4-5, and A-4-6) is one or more (eg, 1, 2, 3, or 4) halogens;
R8'in formulas A-4-1 to A-4-6 are H, -F, -Cl, -Br, -I, -CN, -NO ₂ , ethylnyl, cyclopropyl, methyl, ethyl, isopropyl, vinyl. , Methoxy, ethoxy, isopropoxy, -OH, other C1-6 alkyl, other C1-6 alkenyl and C1-6 alkynyl, one or more groups selected from the group (eg, 1, 2, 3, Or 4 groups), which are mono-, di- or tri-substituted;
R9'in formulas A-4-1 to A-4-6 are alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl. , Alkenyl and substituted cycloalkenyl;
Z in formulas A-4-1 to A-4-6 is selected from the group consisting of _{H, -OCH 3} , -OCH ₂ CH _{3, and halogen;}
R10'and R11' of equations A-4-1 to A-4-6 are independent 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- (CH2) _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- (CH ₂ ) _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', (CH2) _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 Select from the group consisting of NR'R'', aryl- (CH ₂ ) _n- COOH, and heteroaryl-alkyl-CO-alkyl-NR'R''m, and heteroaryl- (CH ₂ ) _{n-heterocycle.} In this case, the alkyl may be substituted with OR', in which case the heterocycle may optionally be substituted with alkyl, hydroxyl, COOR'and COR'; in the equation, R'and R'are , H, alkyl, halogen substituted alkyl, hydroxyl, NH2, NH (alkyl), N (alkyl) ₂ , oxo, carboxy, clocroalkyl and heteroaryl;
m, n, and p are 0-6 independently;
R12'in formulas A-4-1 to A-4-6 are -O- (alkyl), -O- (alkyl) -alkoxy, -C (O)-(alkyl), -C (OH)- Alkoxy-alkoxy, -C (O) -NH- (alkyl), -C (O) -N- (alkyl) ₂ , -S (O)-(alkyl), S (O) _2- (alkyl),- Selected from the group consisting of C (O)-(cyclic amines) and -O-aryl- (alkyl), -O-aryl- (alkoxy);
R1 "in formulas A-4-1 to A-4-6 is selected from the group consisting of H, alkyl, aryl substituted alkyl, alkoxy substituted alkyl, cycloalkyl, aryl substituted cycloalkyl, and alkoxy substituted cycloalkyl. ..

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

In certain embodiments, the linker binding point of formulas A-4-1 to A-4-6 is at least one of Z, R8', R9', R10', R11 ", R12", or R1 ". It is one.

The methods used in the design of the chimeric molecules presented in A-1-1 to A-1-4 and A-4-1 to A-4-6 are Formula A-2, Formula A-3, Formula A. -5, Formula A-6, Formula A-7 and Formula A-8 can be applied to MLM, where the solvent exposure region of MLM may be attached to the linker "L", which may be this. The linker will bind to the target protein ligand "PTM" and build PROTAC.

Examples of MDM2 binding moieties include, but are not limited to:
1. 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
The compounds described below, Natrin-3, Natrin-2, and Natrin-1 (derivatized), as identified in route to chemical proteomics, Bioorg. Med. Chem. Lett. 18 (2008) 5904-5908, and HDM2 / MDM2 inhibitors, including (or additionally) all of their derivatives and analogs:

2. Trans-4-iodine-4'-boranil-chalcone

Exemplary Linkers In certain embodiments, the compounds described herein are via a chemical linker (L) at least one of one or more ULMs (eg, CLM, VLM, MLM, ILM, or a combination thereof). )
Includes one or more PTMs that are chemically linked or bound to. In certain embodiments,
The linker group L is a group containing one or more covalently bonded structural units (eg, -A ^L _{1 ...} (A ^L ) _q-or- (A ^L ) _q- ), where A ₁ is. a group bonded to PTM, (a ^L) _q is a group bonded through a ULM.

In any aspect or embodiment described herein, the connection or binding from the linker (L) to ULM (eg, VLM, ILM, CLM, or MLM) is a stable L-ULM connection. For example, in any aspect or embodiment described herein, when the linker (L) and ULM are connected via a heteroatom, any subsequent heteroatom, if present, eg, an acetal group. Alternatively, it is separated by at least one single carbon atom (eg, -CH _{2-), such as an aminal group.} As a further example, in any embodiment or embodiment described herein, when the linker (L) and ULM are linked via a heteroatom, the heteroatom is not part of the ester.

In any embodiment or embodiment described herein, the linker group L is _{a chemical linker group that is a bond or is represented by the formula-} ^(AL ) q-, where A is a chemical. Part, q is an integer from 1 to 100 (eg 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, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100), and in the formula, L is covalently bound to PTM and ULM, sufficient to cause ubiquitination of the target protein, of the PTM to the target protein. Provides binding and binding of ULM to E3 ubiquitin ligase.

In any of the embodiments or embodiments described herein, the linker group L is-( ^AL ) _q- and in the formula,
(A ^L) _q is, ULM moiety, PTM moiety (e.g., CLM or VLM) be, or at least one coupled to the group of those combinations;
The linker q is an integer greater than or equal to 1 (eg 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, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100);
Each A ^L is independently coupled, 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 (= N)
CN) NR ^L4 , NR ^L3 C (= NCN), NR ^L3 C (= CNO ₂ ) NR ^L4 , optionally 0-6 R ^L1 and / or _{C 3-11} cycloalkyl substituted with ^{R L2 groups,} _{C 5-13} spirocycloalkyl optionally substituted with 0-9 R ^L1 and / or R ^L2 groups, C _3-11 optionally substituted with 0-6 R ^L1 and / or R ^{L2 groups} _{Heterocyclyl, C 5-13} spiroheterocycloalkyl optionally substituted with 0-8 R ^L1 and / or R ^L2 groups, aryl substituted with optionally 0-6 R ^L1 and / or R ^L2 groups , Optionally selected from the group consisting of 0-6 R ^L1 and / or ^{heteroaryls substituted with R L2} groups, in which case R ^L1 or R ^{L 2} is optionally attached to each other independently. And optionally form cycloalkyl and / or heterocyclyl moieties substituted with 0-4 R ^{L5 groups; and}
R ^L1 , R ^L2 , R ^L3 , R ^L4 and R ^L5 are independent, H, halo, 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, OC _3-8 cycloalkyl, SC _3-8 cycloalkyl, NHC _3-8 cycloalkyl, N ( C _3-8 cycloalkyl) ₂ , N (C _3-8 cycloalkyl) (C _1-8 alkyl), OH, NH ₂ , SH, SO ₂ C _1-8 alkyl, P (O) (OC _1-8) Alkyl) (C _1-8 alkyl), P (O) (OC _1-8 alkyl) ₂ , CC-C _1-8 alkyl, CCH, CH = CH (C _1-8 alkyl), C (C _{1-8 alkyl)} 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 , COC _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 (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 , NH SO ₂ NH ₂ .

In any aspect or embodiment described herein, q in the linker is an integer greater than or equal to 0. In certain embodiments, q is an integer greater than or equal to 1.

In any embodiment or embodiment described herein, for example, where q of the linker is greater than 2, ( ^AL ) _q is ^{a group that is A L} ₁ and (A ^L ) _q , and is a unit. A ^L is a combination of PTM and ULM.

In any aspect or embodiment described herein, for example, if q linker is 2, (A ^L) _q is a group connected to A ^L ₁ and ULM.

In any embodiment or embodiment described herein, for example, where q of the linker is 1, the structure of the linker group L is -A ^L _1- , and A ^L ₁ is the ULM moiety and PTM. It is the basis connected to the part.

In any embodiment or embodiment described herein, the linker (L) comprises a group represented by a general structure selected from the group consisting of:
-NR (CH ₂ ) _n- (Lower Alkyl)-, -NR (CH ₂ ) _n- (Lower Aryl)-, -NR (CH ₂ ) _n- (Lower Aryl) -OCH _2- , -NR (CH ₂₎ ) _n- (Lower Aryl)-(Lower Alkyl) -OCH _2- , -NR (CH ₂ ) _n- (Cycloalkyl)-(Lower Alkyl) -OCH _2- , -NR (CH ₂ ) _n- (Heterocyclo) Alkyl)-,-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) -CH ₂ , -N (R1R2)-(heterocycle) -CH ₂ ; :
The linker n may be 0 to 10;
R of the linker may be H, low alkyl;
R1 and R2 of the linker may form a ring having an N bond.

In any embodiment or embodiment described herein, the linker (L) comprises 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-;

During the ceremony
The linkers m, n, o, p, q, and r are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, respectively. 15, 16, 17, 18, 19, 20;
If the number is zero, there are no NO or OO bonds.
The R of the linker is H, methyl and ethyl;
The Xs in the linker are H and F,

In any of the embodiments or embodiments described herein, the linker (L) is selected from the group consisting of:

In any of the embodiments or embodiments described herein, the linker (L) is selected from the group consisting of:

In any of the embodiments or embodiments described herein, the linker (L) is selected from the group consisting of:

In any of the embodiments or embodiments described herein, the linker (L) is selected from the group consisting of:

In any of the embodiments or embodiments described herein, the linker (L) is selected from the group consisting of:

In any aspect or embodiment described herein, the linker (L) comprises, but is not limited to, a structure selected from, but not limited to, the structure shown below, where the dashed line goes to the PTM or ULM moiety. Indicates the connection point of.

During the ceremony:
W ^L1 and W ^L2 are each independently absent, or is optionally substituted with R ^Q, a 4-8 membered ring with 0-4 heteroatoms, each R ^Q is independently , H, halo, OH, CN, CF ₃ , optionally substituted linear or branched C _1- C ₆ alkyl, optionally substituted linear or branched C _1- C ₆ alkoxy, or two R ^Q groups, together with the atoms to which they are attached, form a 4- to 8-membered ring system containing 0-4 heteroatoms;
Each Y ^L1 is a linear or branched C _1- C ₆ alkyl that is independently bonded or optionally substituted, and optionally one or more C atoms are substituted with O. Or a linear or branched C _1- C ₆ alkoxy optionally substituted;
n is 0 to 10; and

In any aspect or embodiment described herein, the linker (L) comprises, but is not limited to, a structure selected from, but not limited to, the structure shown below, where the dashed line goes to the PTM or ULM moiety. Indicates the connection point of.

During the ceremony:
W ^L1 and W ^L2 are independent and absent, or aryl, heteroaryl, cyclic, heterocyclic, optionally one or more C atoms substituted with O, C _1-6 alkyl, optionally one. one or more of C _1-6 alkyne C _1-6 alkene C atoms are replaced by O, is one or more C atoms optionally substituted by O, bicyclic, two aryl, two heteroaryl or two, It is a heterocyclic, each of which is optionally ^{substituted with R Q} , and each R ^Q is independently H, halo, OH, CN, CF ₃ , hydroxyl, nitro, C.
≡CH, C _2-6 alkenyl, C _2-6 alkynyl, the optionally substituted linear or branched C ₁ -C ₆ alkyl, straight or branched optionally substituted with C ₁ -C ₆ alkoxy, optionally substituted OC _1-3 alkyl (eg, optionally substituted with one or more -F), OH, NH ₂ , NR ^Y1 R ^Y2 , CN or Two R ^Q groups, together with the atom to which they are attached, form a 4- to 8-membered ring system containing 0-4 heteroatoms;
Y ^L1 is independently coupled, NR ^YL1 , O, S, NR ^YL2 , C ^YL1 R ^YL2 , C = O, C = S, SO, SO ₂ , optionally substituted linear or branched chain C _1- C ₆ alkyl in the form, optionally one or more C atoms substituted with O; optionally substituted linear or branched C _1- C ₆ alkoxy;
Q ^L is a 3- to 6-membered alicyclic or aromatic ring with 0 to 4 heteroatoms, optionally crosslinked, optionally ^{replaced with 0 to 6 R Q} , and each R ^Q. Is an independently H, a linear or branched C _1-6 alkyl optionally substituted (eg, optionally substituted with one or more halos, or a C _1-6 alkoxyl)? , Or two R ^Q groups form a 3- to 8-membered ring system containing 0 to 2 heteroatoms with the atom to which they are attached;
R ^YL1 and R ^YL2 are independently H, OH, and optionally substituted linear or branched C _1-6.
Alkyl (eg, optionally substituted with one or more halos, or C _1-6 alkoxyls), or R ¹ , R ² contains 0 to 2 heteroatoms along with the atom to which they are attached. 3
Forming a ring system of ~ 8 members;
n is 0 to 10; and

In additional embodiments, the linker group is about 1 to about 100 ethylene glycol units (eg, 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, 44, 45, 46, 47, 48, 49, 50 ethylene glycol units), about 1 to about 50 ethylene glycol units, about 1 to about 25 ethylene glycol units , Approximately 1 to 10 ethylene glycol units, 1 to approximately 8 ethylene glycol units, and 1 to 6 ethylene glycol units, optionally substituted with approximately 2 to 4 ethylene glycol units (poly) Ethylene glycol or an optionally substituted alkyl group interspersed with O, N, S, P or Si atoms that are optionally substituted. 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.

In any of the embodiments of the compounds described herein, the linker group may be any suitable moiety described herein. In one embodiment, the linker is about 1 to about 12 ethylene glycol units, 1 to about 10 ethylene glycol units, about 2 to 6 ethylene glycol units, about 2 to 5 ethylene glycol units, about 2 to 4 ethylene glycol units. A size range of substituted or unsubstituted polyethylene glycol groups.

In any embodiment or embodiment described herein, the linker (L) is optionally substituted with a C _1- C ₁₀₀ alkyl (eg, C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ , C ₁₂ , C ₁₃ , C ₁₄ , C ₁₅ , C ₁₆ , C ₁₇ , C ₁₈ , C ₁₉ , C ₂₀ , C ₂₁ , C ₂₂ , C ₂₃ , C ₂₄ , C ₂₅ , C ₂₆ , C ₂₇ , C ₂₈ , C ₂₉ , C ₃₀ , C ₃₁ , C ₃₂ , C ₃₃ , C ₃₄ , C ₃₅ , C ₃₆ , C ₃₇ , C ₃₈ , C ₃₉ , C ₄₀ , C ₄₁ , C ₄₂ , C ₄₃ , C ₄₄ , C ₄₅ , C ₄₆ , C ₄₇ , C ₄₈ , C ₄₉ , C ₅₀ , C ₅₁ , C ₅₂ , C ₅₃ , C ₅₄ , C ₅₅ , C ₅₆ , C ₅₇ , C ₅₈ , C ₅₉ , C ₆₀ , C ₆₁ , C ₆₂ , C ₆₃ , C ₆₄ , C ₆₅ , C ₆₆ , C ₆₇ , C ₆₈ , C ₆₉ , C ₇₀ , C ₇₁ , C ₇₂ , C ₇₃ , C ₇₄ , C ₇₅ , C ₇₆ , C ₇₇ , C ₇₈ , C ₇₉ , C ₈₀ , C ₈₁ , C ₈₂ , C ₈₃ , C ₈₄ , C ₈₅ , C ₈₆ , C ₈₇ , C ₈₈ , C ₈₉ , C ₉₀ , C ₉₁ , C ₉₂ , C ₉₃ , C ₉₄ , C ₉₅ , C ₉₆ , C ₉₇ , C ₉₈ , C ₉₉ , or C ₁₀₀ alkyl), in which case each carbon is optional ( 1) Heteroatomic selected from N, S, P or Si atoms with the appropriate number of hydrogens, substitutions or both for the full valence, (2) optionally substituted cycloalkyl or bicyclic cyclo Alkyl, (3) optionally substituted heterocycloalkyl, or bicyclic heterocycloalkyl, (4) optionally substituted aryl or bicyclic aryl, or (5) optionally substituted heteroaryl or bi! It is replaced with a cyclic heteroaryl. In any aspect or embodiment described herein, the linker (L) has no heteroatom-heteroatom bond (eg, the heteroatom is not a covalently bonded linker or is placed adjacently. It has not been).

In any of the embodiments or embodiments described herein, the linker (L) is optionally substituted with a C _1- C ₁₀₀ alkyl (eg, C ₁ , C ₂ , C ₃ , C ₄ , C 5, _{C 5).} C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ , C ₁₂ , C ₁₃ , C ₁₄ , C ₁₅ , C ₁₆ , C ₁₇ , C ₁₈ , C ₁₉ , C ₂₀ , C ₂₁ , C ₂₂ , C ₂₃ , C ₂₄ , C ₂₅ , C ₂₆ , C ₂₇ , C ₂₈ , C ₂₉ , C ₃₀ , C ₃₁ , C ₃₂ , C ₃₃ , C ₃₄ , C ₃₅ , C ₃₆ , C ₃₇ , C ₃₈ , C ₃₉ , C ₄₀ , C ₄₁ , C ₄₂ , C ₄₃ , C ₄₄ , C ₄₅ , C ₄₆ , C ₄₇ , C ₄₈ , C ₄₉ , C ₅₀ , C ₅₁ , C ₅₂ , C ₅₃ , C ₅₄ , C ₅₅ , C ₅₆ , C ₅₇ , C ₅₈ , C ₅₉ , C _6
0 , C ₆₁ , C ₆₂ , C ₆₃ , C ₆₄ , C ₆₅ , C ₆₆ , C ₆₇ , C ₆₈ , C ₆₉ , C ₇₀ , C ₇₁ , C ₇₂ , C ₇₃ , C ₇₄ , C ₇₅ , C ₇₆ , C ₇₇ , C ₇₈ , C ₇₉ , C ₈₀ , C ₈₁ , C ₈₂ , C ₈₃ , C ₈₄ , C ₈₅ , C ₈₆ , C ₈₇ , C ₈₈ , C ₈₉ , C ₉₀ , C ₉₁ , C ₉₂ , C ₉₃ , C ₉₄ , C ₉₅ , C ₉₆ , C ₉₇ , C ₉₈ , C ₉₉ , or C ₁₀₀ alkyl), in the formula,
Each carbon is optional, 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 , optionally substituted with 0-6 R ^L1 and / or R ^L2 _{groups, C 3-11} cycloalkyl, optionally substituted with 0-9 R ^L1 and / or R ^L2 groups C _5-13 spirocycloalkyl, optionally substituted with 0-6 R ^L1 and / or R ^L2 _{groups, C 3-11} heterocyclyl, ^{optionally with 0-8 R L1} and / or R ^L2 groups C _5-13 spiro heterocyclyl substituted, is substituted optionally with 0-6 aryl optionally substituted with at R ^L1 and / or R ^L2 groups, 0-6 R ^L1 and / or R ^L2 group Substituted with heteroaryl, in the formula, R ^L1 or R ^{L 2}
Each independently binds to another group 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 independent, H, halo, 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, OC _3-8 cycloalkyl, SC _3-8 cycloalkyl, NHC _3-8 cycloalkyl, N ( C _3-8 cycloalkyl) ₂ , N (C _3-8 cycloalkyl) (C _1-8 alkyl), OH, NH ₂ , SH, SO ₂ C _1-8 alkyl, P (O) (OC _1-8) Alkyl) (C _1-8 alkyl), P (O) (OC _1-8 alkyl) ₂ , CC-C _1-8 alkyl, CCH, CH = CH (C _1-8 alkyl), C (C _{1-8 alkyl)} 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 , COC _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 (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 , NH SO ₂ NH ₂ .

In any embodiment or embodiment described herein, the linker (L) has no heteroatom-heteroatom bond (eg, the heteroatom is not a covalently bonded linker or is placed adjacently. It has not been).

In any of the embodiments or embodiments described herein, about 1 to about 50 linkers (L) are optionally substituted (eg, 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, 44, 45, 46, 47, 48, 49, or 50) Containing alkylene glycol units, in which case carbon or oxygen , With an appropriate number of hydrogens for the full valence, may be replaced with a heteroatom selected from N, S, P or Si atoms. For example, in any of the embodiments or embodiments described herein, the linker (L) has a chemical structure selected from:

, In the equation, carbon or oxygen may be replaced with a heteroatom selected from N, S, P, or Si atoms with an appropriate number of hydrogens for the full valence, m, n, o. , P, q, r, and s are independent, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, Choose from 18, 19, and 20.

In any aspect or embodiment described herein, the present disclosure is directed to a compound containing a PTM group as described above, wherein the group binds to a target protein or polypeptide (eg, RAF). It is ubiquitinated by ubiquitin ligase and is chemically attached directly to the ULM group or through the linker moiety L. Alternatively, the PTM is an alternative ULM'group, and the ULM' group is also a ubiquitin ligase binding moiety, which may be the same as or different from the ULM group described above, through the linker moiety or directly from the ULM group. Combined with. And L is the linker moiety described above, which may or may not be present, ULM and PTM, or pharmaceutically acceptable salts thereof, mirror isomers, stereoisomers, solvates, or polymorphisms. Chemically bond (covalently bond) polymorphs.

In any embodiment or embodiment described herein, the linker group L is a group comprising one or more covalently bonded 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 is hydrogen or alkyl,

Is a monocyclic or bicyclic aryl or heteroaryl optionally substituted with 1 to 3 substituents selected from alkyl, halogen, haloalkyl, hydroxy, alkoxy, or cyano;

Is a monocyclic or bicyclic cycloalkyl or heterocycloalkyl optionally substituted with 1 to 3 substituents selected from alkyl, halogen, haloalkyl, hydroxy, alkoxy, or cyano; and phenyl. The ring fragment may be optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, and cyano. In certain embodiments, the linker group L comprises up to 10 covalently bonded structural units as described above.

The ULM and PTM groups are suitable for the chemical properties of the linker and may be covalently attached to the linker group via any stable group, and in the preferred embodiment of the present disclosure, the linker is independent. Covalently attached to ULM and PTM groups via amides, esters, thioesters, keto groups, carbamates (urethanes), carbons or ethers, each of which is on either a ULM group or a PTM group. It may provide the maximum binding of ULM groups to the inserted and ubiquitin ligase and the maximum binding of the PTM group to the targeted protein to be degraded. (Note that in certain embodiments where the PTM group is an ULM group, the targeted protein to be degraded can also be the ubiquitin ligase itself). In certain preferred embodiments, the linker may be attached to an optionally substituted alkyl, alkylene, alkene or alkyne group, aryl group or heterocyclic group on ULM and / or PTM groups.

Illustrative PTM
In a preferred embodiment of the present disclosure, the PTM group is a group that binds to the target protein. The target of a PTM group is diverse, and the target is selected from proteins expressed in the cell such that at least a part of the sequence is present in the cell and can bind to the PTM group. The term "protein" includes oligonucleotide and polypeptide sequences of sufficient length to be able to bind to a PTM group in accordance with the present disclosure. As described elsewhere herein, any protein in the eukaryotic cell line or microbial line including viruses, bacteria or fungi is the target of ubiquitination regulated by the disclosed compounds. The target protein is preferably a eukaryotic cell protein.

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 non-limiting examples of the following small molecule target protein binding moieties: RAF. Inhibitors, Hsp90 inhibitors, kinase inhibitors, HDM2 and MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, nuclear hormone acceptance Body compounds, immunosuppressive compounds, and compounds that specifically target the aryl hydrocarbon receptor (AHR). The compositions described below exemplify some of the small molecule target protein binding moieties. Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, mirror isomers, solvates, and polymorphs of these compositions, as well as other small molecules capable of targeting the protein of interest. .. These binding moieties bind to the ubiquitin ligase binding moiety, preferably through a linker, to present the target protein (where the protein target moiety is attached) for the purpose of ubiquitination and degradation in close proximity to the ubiquitin ligase. Will be done.

Any protein that can bind to a protein target moiety or PTM group, can act by ubiquitin ligase, or can be degraded by ubiquitin ligase (eg, RAF) is a target protein according to the present disclosure. In general, target proteins include, for example, structural proteins, receptors, enzymes, cell surface proteins, as well as catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (assimilation and catabolic activity), antioxidant activity, etc. Protein solubility, biosynthesis, protein with kinase activity, oxidation-reduction activity, transferase activity, hydrolysis activity, lyase activity, isomerase activity, ligase activity, enzyme control activity, signal transduction activity, structural molecule activity, binding activity (protein, Lipid carbohydrates), receptor activity, cell motility, membrane fusion, cell transmission, control of biological processes, development, cell differentiation, stimulus response, behavioral proteins, cell attachment proteins, proteins involved in cell death, proteins involved in transport (Including protein transport activity, nuclear transport, ion transport activity, channel transport activity, carrier activity, permeation activity, secretory activity, electron transfer activity), phagocytosis, chaperon control activity, nucleic acid binding activity, transcription control activity, extracellular integration and Examples thereof include proteins involved in the integrated function of cells, including proteins involved in biosynthetic activity and translation control activity. Target proteins include eukaryotic (eg, c-RAF, A-RAF, and / or B-RAF) and prokaryotic-derived proteins, including humans and other animals as targets for drug treatment. These include, among so many, microorganisms for determining the target of livestock animals, antibiotics and other antimicrobial agents, as well as plants, and especially viruses (eg, v-RAF and / or v-Mil). Can be mentioned.

Many conditions and / or conditions may be treated using the present disclosure, where the condition and / or condition is any condition in which the protein is in a deregulated state and the patient will benefit from protein degradation. Includes pathology and / or condition of.

In additional embodiments, the present specification comprises an effective amount of a compound described herein or a salt form thereof, and a pharmaceutically acceptable carrier, additive or excipient, and optionally an additional bioactive agent. Provided is a therapeutic composition. Therapeutic compositions can be used in a patient or subject, eg, an animal such as a human, to regulate the degradation of a protein and to treat or ameliorate a medical condition or condition regulated via the degraded protein. In certain embodiments, the therapeutic compositions described herein are used to treat diseases such as cancer, heart / face / skin syndrome, neurofibromatosis type 1, Costello syndrome, Noonan syndrome, LEOPARD syndrome. Alternatively, it may cause degradation of the target protein for the purpose of improvement. In certain additional embodiments, the disease is renal cell carcinoma, pancreatic cancer, colorectal cancer, lung cancer, ovarian cancer, thyroid cancer, hairy cell astrocytoma, prostate cancer, gastric cancer, hepatocellular carcinoma, and black color. It is a tumor.

In another aspect, the disclosure relates to a method of treating a subject's condition in need thereof, or ameliorating the symptoms of a disease or condition by degrading a protein or polypeptide, wherein said protein. Alternatively, the pathology or condition is regulated via a polypeptide, the method comprising providing the patient or subject with an effective amount, eg, a therapeutically effective amount, of at least one of the above-mentioned compounds, optionally a pharmaceutically acceptable carrier. , Additives or excipients, and optionally in combination with additional bioactive agents, wherein the composition is effective in treating or ameliorating the disease or disorder of the subject or its symptoms. .. Cancer, Cardiofacio-Skin Syndrome, Neurofibromatosis Type 1, Costello Syndrome, Noonan by administering an effective amount of at least one of the compounds described herein using the methods according to the present disclosure. Many conditions or conditions can be treated, including syndrome, LEOPARD syndrome. The condition or condition is a disease caused by a microbial entity, or an extrinsic factor such as a virus (eg, mouse retrovirus or triretrovirus, eg triretrovirus MH2), bacteria, fungi, protozoans or other microbial factors. It may be, or it may be a condition caused by the overexpression of the protein that causes the condition and / or the condition and / or the presence of a constitutively activated protein.

In another aspect, the present specification provides a method of identifying the degrading effect of a protein of interest in a biological system using the compounds according to the present disclosure.

The term "target protein" is used herein to describe the target protein or polypeptide to which the disclosed compounds bind and are degraded by ubiquitin ligase. Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, mirror isomers, solvates, and polymorphs of these compositions, as well as other small molecules capable of targeting the protein of interest. .. These binding moieties are attached to at least one ULM group (eg, VLM, CLM, ILM, and / or MLM) via at least one linker group L.

Target proteins that can be bound to a protein target moiety and that can be degraded by a ligase to which a ubiquitin ligase binding moiety is attached include any protein or peptide, including fragments thereof, analogs thereof, and / or homologs thereof. Is done. Target proteins include proteins and peptides having any biological function or activity, including structural, regulatory, hormonal, enzymatic, genetic, immune, contractile, conservative, transport, and signal transduction. .. More specifically, many of the drug targets for human therapy can be protein targets, to which the protein target moieties can be bound and incorporated into compounds according to the present disclosure. These proteins include proteins that can be used for functional recovery in many polygenic diseases, such as B7.1 and B7, TINFRlm, TNFR2, NADPH oxidase, BclIBax and other partner factors of the apoptosis pathway, C5a receptor. Body, HMG-CoA Protease ,, PDE V Phosphodiesterase Type, PDE IV Phosphodiesterase Type 4, PDE I, PDEII, PDEIII, Squalancyclase Inhibitors, CXCR1, CXCR2, Nitrogen Monoxide (NO) Synthase, Cyclo-oxygenase 1, Cyclo -Oxygenase 2, 5HT receptor, dopamine receptor, G protein, ie Gq, histamine receptor, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purinucleoside phosphorylase, GAPDH tripanosomal, glycogen phosphorylase, carbonate dehydration enzyme, chemokine Receptors, JAW STAT, RXR and similar, HIV 1 protease, HIV 1 integrase, influenza neurominidase, hepatitis B virus reverse transcript, sodium channel, multidrug resistance (MDR), protein P-sugar protein (and MRP) , Tyrosine kinase, CD23, CD124, Tyrosine kinase p56 lck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-αR, ICAM1, Cat + channel, VCAM, VLA-4 integrin, selectin, CD40 / CD40L , Neurokinin and receptor, inosinic acid dehydrogenase, p38 MAP kinase, Ras / Raf / MEK-ERK pathway, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3 RNA helicase, glycinamide ribonucleotide formyl Transtransferase, Rhinovirus 3C Protease, Simple Herpesvirus-1 (HSV-I), Protease, Cytomegalovirus (CMV) Protease, Poly (ADP-Ribose) polymerase, Cyclin-Dependent Kinase,
Vascular endothelial growth factor, oxytocin receptor, microsome transport protein inhibitor, bile acid transport inhibitor, 5α reductase inhibitor, angiotensin 11, glycine receptor, noradrenaline reuptake receptor, endoserin receptor, neuropeptide Y and receptor , Estrogen receptor, androgen receptor, adenosine receptor, adenosine kinase and AMP deaminase, purinergic receptor (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyl transferase, geranylgeranyl transferase, TrkA NGF receptor, Included are beta-amyloid, tyrosine kinase Flk-IIKDR, bitronectin receptor, integulin receptor, Her-21 neu, telomerase inhibition, cytoplasmic phosphoripase A2, and EGF receptor tyrosine kinase. Additional protein targets include, for example, ecdysone 20-monooxygenase, GABAergic chlorine channel ion channels, acetylcholine esterase, potential sensitive sodium channel proteins, calcium release channels, and chlorine channels. Further target proteins include acetyl-Coacarboxylase, adenylosuccinate synthase, protoporphyrinogen oxidase, and enolpyrvirsikimic acid-phosphate synthase.

These various protein targets may be used in screening to identify a compound moiety that binds to the protein, and by incorporating the moiety within the disclosed compounds, the activity of the protein with respect to the end result of treatment. You can change the level.

The term "protein target portion" or "PTM" refers to a protein or polypeptide that binds to the target protein or other protein or polypeptide of interest and allows ubiquitin ligase to degrade the protein or polypeptide. Used to describe small molecules placed / presented in close proximity to ubiquitin ligase. Non-limiting examples of small molecule target protein binding moieties include RAF inhibitors, Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, and human lysine methyl. Examples include transferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds specifically targeting aryl hydrocarbon receptors (AHRs). The compositions described below exemplify some of the constituents of small molecule target proteins.

Exemplary protein targeting moieties according to the present disclosure include RAF inhibitors, haloalkane halide enzyme inhibitors, Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors. , Human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds that target the aryl hydrocarbon receptor (AHR).

The compositions below exemplify some of the constituents of these types of small molecule target protein binding moieties. Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, mirror isomers, solvates, and polymorphs of these compositions, as well as other small molecules capable of targeting the protein of interest. .. References cited herein in their entirety are incorporated herein by reference in their entirety.

.. In any of the embodiments or embodiments described herein, PTM is a small molecule comprising a B-RAF protein targeting moiety.

In any of the embodiments or embodiments described herein, PTM targets RAF and /
Or combine. For example, in any of the embodiments or embodiments described herein, the PTM may comprise a chemical group selected from the following chemical structures consisting of PTM-Ia or PTM-Ib.

During the ceremony:
The double dashed line bond is an aromatic bond,
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; C, O, C, CH, C; 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 selected independently of CH and N;
R _PTM1 is ULM, 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 heterocyclic;
R _PTM2a and R _PTM2b are hydrogen, OH, halogen;
R _PTM3 is absent or hydrogen, aryl, methyl, ethyl, other alkyl, cyclic alkyl, OCH _3, NHCH ₃ or M1-CH ₂ -CH ₂ -M2,, wherein, M1 is CH ₂ , O and NH, 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 is selected from the following group:

In any of the embodiments or embodiments described herein, the PTM may comprise a chemical group selected from the following chemical structures consisting of PTM-IIa or PTM-IIb.

During the ceremony:
X _PTM1 , X _PTM2 , X _PTM3 , X _PTM4 , X _PTM5 and X _PTM6 are selected independently of CH or N;
R _PTM5a is selected from the group consisting of: bonds, optionally substituted amines, optionally substituted amides (eg, optionally substituted with an alkyl group, methyl group, ethyl group, propyl group, or butyl group). ), H,

R _PTM5b is hydrogen, or linear or branched C1-C4 alkyl (eg, methyl or ethyl);
R _PTM6a and R _PTM6b are independently selected from hydrogen, halogen, or optionally substituted linear or branched C _1- C ₆ alkyl;
R _PTM6 is absent or hydrogen, halogen, aryl, methyl, ethyl, OCH _3, NHCH ₃ or _{M1-CH 2 -CH 2 -M2,} , wherein, M1 is CH _2, O and NH Yes, M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle;
R _PTM6c is hydrogen, or linear or branched C1-C4 alkyl (eg, methyl or ethyl);
R _PTM7 is absent or hydrogen, halogen, aryl, methyl, ethyl, OCH _3, NHCH ₃ or _{M1-CH 2 -CH 2 -M2,} , wherein, M1 is CH _2, O or NH Yes, M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle;
R _PTM8 , R _PTM9 or R _PTM10 are independently absent or hydrogen, halogen, aryl, heteroaryl, alkyl, cycloalkyl, heterocycle, methyl, ethyl, OCH ₃ , NHCH ₃ or M1-CH _2- Selected from the group consisting of CH _2- M2, in the formula M1 is CH ₂ , O and NH, M2 is 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. , M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle; and
At _{least one of R PTM8} , R _PTM9 , or R _PTM10 is ULM, chemical linker group (L), CLM.
, ILM, VLM, MLM, ULM', CLM', ILM', VLM', MLM', or a combination thereof modified to be covalently bonded, or two of R _PTM8 , R _PTM9 , and R _PTM10. It is modified to form a polycyclic (eg, bicyclic) fused ring with a chemical linker group.

In certain embodiments, the PTM may contain a chemical group selected from the group of chemical structures consisting of:

In the formula, R _PTM5 , R _PTM6a , R _PTM6b , R _PTM6 , R _PTM7 , R _PTM8 , R _PTM9 , R _PTM10 , and R _PTM11 are as described herein.

In some embodiments, when R _PTM9 is a covalent bond position, R _PTM7 and R _PTM8 form a covalent bond in such a way that they form a bicyclic group with a ring to which R _PTM7 and R _{PTM8 attach.} Can be coupled to each other through.

In other embodiments, when R _PTM8 is a covalent bond position, R _PTM9 and R _PTM10 are in such a way as to form a bicyclic group having a ring that R _PTM9 and R _PTM10 are attached, via a covalent bond Can be combined with each other.

In a further embodiment, when R _PTM10 is a covalent bond position, R _PTM8 and R _PTM9 are in such a way as to form a bicyclic group having a ring that R _PTM8 and R _PTM9 are attached, via a covalent bond Can be combined with each other.

In any of the embodiments or embodiments described herein, the PTM may comprise a chemical group selected from the group of chemical structures consisting of PTM-III below.

During the ceremony:
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 in CH or N can be;
R _PTM12 , R _PTM13 , R _PTM14 , R _PTM15 , R _PTM16 , R _PTM17 , R _PTM18 , R _PTM19 are independent or absent, or hydrogen, halogen, aryl, heteroaryl, cycloalkyl, heterocycle, methyl, ethyl, other alkyl, selected from the group consisting of OCH _3, NHCH ₃ or M1-CH ₂ -CH ₂ -M2, wherein, M1 is CH _2, O and NH, M2 is hydrogen, alkyl, cycloalkyl , Aryl or heterocycle;
R _PTM20 is a small group containing less than four non-hydrogen atoms.
R _PTM21 is trifluoromethyl, chloro, bromo, fluoro, methyl, ethyl, propyl, isopropyl, tert-butyl, butyl, iso-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, OCH ₃ , NHCH ₃ , dimethylamino or is selected from the group consisting of M1-CH ₂ -CH ₂ -M2, wherein, M1 is CH _2, O or NH, M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocyclic; and
At _{least one of R PTM12} , R _PTM13 and R _PTM16 is ULM, chemical linker group (L), CLM, ILM, VLM, MLM, ULM', CLM', ILM', VLM', MLM', or a combination thereof. It is modified to be covalently bonded to.

In some embodiments, when R _PTM12 is in a covalent bond position, R _PTM13 and R _PTM14 form a covalent bond in such a way that they form a bicyclic group with a ring to which R _PTM13 and R _{PTM14 attach.} through it can be coupled to one another; and / or R _PTM15 and R _PTM16 are coupled in such a way as to form a bicyclic group having a ring that R _PTM15 and R _PTM16 are attached, to one another via a covalent bond Can be done.

In other embodiments, when R _PTM13 is a covalent bond position, R _PTM12 and R _PTM16 are in such a way as to form a bicyclic group having a ring that R _PTM12 and R _PTM16 are attached, via a covalent bond Can be combined with each other. And / or R _PTM15 and R _PTM16 can be attached to each other via a covalent bond in such a way as to form a bicyclic group with a ring to which _{R PTM15} and R _{PTM16 attach.}

In a further embodiment, when R _PTM16 is a covalent bond position, R _PTM12 and R _PTM13 are in such a way as to form a bicyclic group having a ring that R _PTM12 and R _PTM13 are attached, via a covalent bond Can be combined with each other. And / or R _PTM13 and R _PTM14 can be attached to each other via a covalent bond in such a way as to form a bicyclic group with a ring to which _{R PTM13} and R _{PTM14 attach.}

In any of the embodiments or embodiments described herein, the PTM may comprise a chemical group selected from the following chemical structures consisting of PTM-IVa or PTM-IVb.

During the ceremony:
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 independently in CH or N can be;
R _PTM22 is selected from the following group:

R _PTM25a and R _PTM25b are 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 bonded, hydrogen, halogen, aryl (optionally substituted), heteroaryl (optionally). Substituted), cycloalkyl (optionally substituted), heterocycle (optionally substituted), methyl,
Ethyl (optionally substituted with), other alkyl (straight chain, branched chain, optionally substituted with), is selected from the group consisting of OCH _3, NHCH ₃ or M1-CH ₂ -CH ₂ -M2, wherein Among them, M1 is CH ₂ , O and NH, and M2 is hydrogen, alkyl (straight chain, branched chain, optionally substituted), cyclic alkyl (optionally substituted), aryl (optionally substituted). ) Or a heterocycle (optionally substituted); and
R _PTM25 is absent or hydrogen, halogen, C _1- C ₆ alkyl (straight chain, branched chain, optionally substituted), OCH ₃ , NHCH 3 or SCH ₃ ;
R _PTM26 is absent or hydrogen, halogen, C _1- C ₆ alkyl (straight chain, branched chain, optionally substituted), OCH ₃ , NHCH 3 or SCH ₃ ;
R _PTM27 is absent or selected from the group consisting of hydrogen, halogen, C _1- C ₆ alkyl (straight chain, branched chain, optionally substituted), OCH ₃ , NHCH 3 or SCH _{3; and}
At _{least one of R PTM24} , R _PTM29 and R _PTM32 is ULM, chemical linker group (L), CLM, ILM, VLM, MLM, ULM', CLM', ILM', VLM', MLM', or a combination thereof. It is modified to be covalently bonded to.

In some embodiments, when R _PTM24 is a covalent bond, R _PTM31 and R _PTM32 are
R _PTM31 and R _PTM32 can be attached to each other via covalent bonds in such a way as to form a bicyclic group with a ring to which _{R PTM31 and R PTM32 attach; or R PTM29} and R _PTM30 can be combined with R _PTM29 and R _PTM30. They can be attached to each other via covalent bonds in such a way as to form bicyclic groups with attached rings.

In other embodiments, when R _PTM29 is a covalent bond position, R _PTM24 and R _PTM32 are in such a way as to form a bicyclic group having a ring that R _PTM24 and R _PTM32 are attached, via a covalent bond Can be combined with each other. And / or R _PTM31 and R _PTM32 can be attached to each other via a covalent bond in such a way as to form a bicyclic group with a ring to which _{R PTM31} and R _{PTM32 attach.}

In a further embodiment, when R _PTM32 is a covalent bond position, R _PTM24 and R _PTM29 are in such a way as to form a bicyclic group having a ring that R _PTM24 and R _PTM29 are attached, via a covalent bond Can be combined with each other. And / or R _PTM29 and R _PTM30 can be attached to each other via a covalent bond in such a way as to form a bicyclic group with a ring to which _{R PTM29} and R _{PTM30 attach.}

In any embodiment or embodiment described herein, the PTM may comprise a chemical group selected from the following chemical structures consisting of PTM-Va or PTM-Vb:

During the ceremony:
X _PTM35 , X _PTM36 , X _PTM37 , X _PTM38 , and X _PTM39 are independently CH or N;
R _PTM33 is a halogen or linear or branched C1-C4 haloalkyl;
R _PTM34 , R _PTM35 , R _PTM36 , R _PTM37 , and R _PTM38 are independently hydrogen, halogen, or linear or branched C _1- C ₄ alkyl (eg, methyl, ethyl, propyl, etc.). Or butyl);
R _PTM39 is an optionally substituted C4-C7 heterocycloalkyl (eg, optionally substituted C5 or C6 heterocycloalkyl); and

In any embodiment or embodiment described herein, the PTM is a chemical structure PTM-1, PTM-2, PTM-3, PTM-4, PTM-5, PTM-6, PTM-7, PTM- Select from the group consisting of 8, PTM-9, PTM-10, PTM-11, PTM-12 and PTM-13:

In any embodiment or embodiment described herein, ULM is selected from the group consisting of:

In the formula, R _14a is H, methyl or hydroxymethyl.
In any of the embodiments or embodiments described herein, (i) PTM is a compound of the present disclosure.
Selected from PTMs 1-873 or 307-873; (ii) Chemical linker groups (L) selected from the linkers of compound 1-873 or 307-873 of the present disclosure; (ii) ULMs of the present disclosure. Selected from ULMs of compound 1-873 or 307-873; (iv) the compound further comprises a prodrug chemical moiety selected from the PTM of compound 796-873, or (v) at least a combination thereof. One.

In any embodiment or embodiment described herein, ULM is selected from the group consisting of:

In any aspect or embodiment described herein, the bifunctional compounds or prodrugs thereof of the present disclosure further comprise a plurality of ethylene glycol units. In any aspect or embodiment described herein, the bifunctional compounds of the present disclosure or prodrugs thereof are at least one (eg, 1, 2, 3, 4, 5, 6, 7, 8, Or more) further contains polyethylene glycol (PEG) chains. In any aspect or embodiment described herein, the bifunctional compounds or prodrugs thereof of the present disclosure have a uniform chain length or a plurality of mixed chain lengths (eg, 2, 3, 4). , 5, 6, 7, 8, or more) further comprises polyethylene glycol (PEG) chains. In any of the embodiments or embodiments described herein, the bifunctional compound or prodrug thereof further comprises a prodrug moiety selected from the exemplary compound 796-873.

In any aspect or embodiment described herein, the bifunctional compounds of the present disclosure or prodrugs thereof are at least one described herein (eg, 1, 2, 3, 4, 5). , 6, 7, 8, or more) further comprising polyethylene glycol chains, in which case each polyethylene glycol chain is at the same point as the PEG chain bond in the compound selected from the exemplary compound 796-873. Covalently attached to a bifunctional compound. In any embodiment or embodiment described herein, each PEG chain is added directly or indirectly via the variable sites described herein (eg, via a methyl group or O). Or the variable sites of VLM described herein (eg, R ^P , R ^14a , R ^14b , W4, W5, R ^1' , R ^2' , R ^3' ), described herein. It is indirectly added in place of the variable site of CLM (eg, G or G'), or the variable site of PTM described herein (eg, R _PTM6c). For example, in any aspect or embodiment described herein with VLM, R ^P , R ^14A , R ^14b , or a combination thereof, covalently or indirectly to a moiety containing a PEG chain. (For example, the hydroxyl group of ^{R P} or R ^{1' , the methyl group of R 14a} , R ^14b , or W 5 is modified to be covalently bonded) or contains a PEG chain. Replaced with a part. Further in any aspect or embodiment described herein with CLM, G, G', or a combination thereof is modified to be covalently attached directly or indirectly to a moiety containing a PEG chain. (Eg, the methyl of G or G'is modified to be covalently bonded) or replaced with a moiety containing a PEG chain.

In any aspect or embodiment described herein, the bifunctional compounds of the present disclosure or prodrugs thereof are at least one (eg, 1, 2, 3, 4, 5, 6, 7, 8, Or more)

In the formula, r is an integer from 8 to 35 (eg, 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 or 35). For example, in any aspect or embodiment described herein with VLM, R ^P , R ^14A , R ^14b , or a combination thereof, may be directly or directly to one of the structures listed above. Indirectly covalently modified (eg, the hydroxyl group of ^{R P , R 14a} , R ^14b , or the methyl group of W5 is modified to be covalently bonded) or listed above. It is replaced with one of the created structures. Further in any aspect or embodiment described herein with CLM, G, G', or a combination thereof, shares directly or indirectly with one of the structures listed above. Modified to be combined (eg G or G'
Methyl is covalently modified) or replaced with one of the structures listed above. For example, in any of the embodiments or embodiments described herein, each PEG chain may be attached to VLM, CLM, or PTM via a chemical group selected from:

In any embodiment or embodiment described herein, the polyethylene glycol chain of the bifunctional compound or prodrug thereof is from about 8 ethylene glycol units to about 35 ethylene glycol units (eg, 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, or 35), about 10 ethylene glycol units to about 35 ethylene glycol units (eg, about 10 to about 35) Ethylene glycol units, about 10 to about 30 ethylene glycol units, about 10 to about 25 ethylene glycol units, about 10 to about 20 ethylene glycol units, about 10 to about 15 ethylene glycol units, about 15 to about 35 ethylene glycol units, about 15 to about 30 ethylene glycol units, about 15 to about 25 ethylene glycol units, about 15 to about 20 ethylene glycol units, about 20 to about 35 ethylene glycol units, about 20 to about 30
Ethylene glycol units, about 20 to about 25 ethylene glycol units, about 25 to about 35 ethylene glycol units, about 25 to about 30 ethylene glycol units, or about 30 to about 35 ethylene glycol units) or contains.

In any embodiment or embodiment described herein, the present invention uses methoxypolyethylene glycol, or polyethylene glycol having an average molecular weight of 1000 (eg, mPEG-1000, etc.) and capped at one end with a methyl group. The disclosed prodrug bifunctional compounds may be prepared. For example, in any embodiment or embodiment, the pros of the present disclosure are made using methoxypolyethylene glycol, or polyethylene glycol end-capped with a methyl group having an average chain length of 22 units (eg, mPEG-1000). Drug bifunctional compounds may be prepared. The methods described herein can be used to make longer or shorter PEG chains with uniform or varying chain lengths.

In any of the embodiments or embodiments described herein, the prodrug bifunctional compounds of the present disclosure have a release percentage of at least about 10%. For example, in any aspect or embodiment described herein, the prodrug bifunctional compounds of the present disclosure are about 30 minutes, about 60 minutes, about 1.5 hours, about 2 hours, about 2.5 hours. So, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 4.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours. So, in about 8 hours, about 8.5 hours, about 9 hours, about 9.5 hours, or about 10 hours, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about about 80%, at least about 85%, at least about 90%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 10% to about 30%, about 20% to about 90%
, About 20% ~ about 80%, about 20% ~ about 70%, about 20% ~ about 60%, about 20% ~ about 50%, about 20% ~ about 40%, about 30% ~
About 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, about 30% to about 50%, about 40% to about 90%, about 40% to about 80 %, About 40% to about 70%, About 40% to about 60%, About 50% to about 90%, About 50% to about 80%, About 50% to about 70%
Has about 60% to about 90%, or about 60% to about 80%, about 70% to about 90% release percent.

In any of the embodiments or embodiments described herein, the prodrug bifunctional compounds of the present disclosure have a half-life of at least about 60 minutes. For example, in any aspect of the embodiments described herein, the prodrug bifunctional compounds of the present disclosure are serums (eg, human serum, monkey serum, dog serum, cat serum, pig serum, horse serum, etc.). Inside, about 1 minute or less,
About 5 minutes or less, 10 minutes or less, about 15 minutes or less, about 30 minutes or less, about 45 minutes or less, about 1 hour or less, 1.5 hours or less, about 2 hours or less, about 2.5 hours or less, about 3 hours or less, about 3.5 Hours or less, about 4 hours or less, 4.5 hours or less, about 5 hours or less, about 5.5 hours or less, about 6 hours or less, about 6.5 hours or less, about 7 hours or less, about 7.5 hours or less, about 8 hours or less, 8.5 hours or less , About 9 hours or less, 9.5 hours or less, about 10 hours or less, about 11 hours or less, about 12 hours or less, about 14 hours or less, about 16 hours or less, about 18 hours or less, about 20 hours or less, about 22 hours or less, About 24 hours or less, about 26 hours or less, about 28 hours or less, about 30 hours or less, about 32 hours or less, about 34 hours or less, about 36 hours or less, about 38 hours or less, about 40 hours or less, about 42 hours or less, About 44 hours or less, about 46 hours or less, about 48 hours or less, about 50 hours or less, about 15 seconds to about 50 hours, about 15 seconds to about 45 hours, about 15 seconds to about 40 hours, about 15 seconds to about 35 Time, about 15 seconds to about 30 hours, about 15 seconds to about 25 hours, about 15 seconds to about 20 hours, about 15 seconds to about 15 hours, about 15 seconds to about 10 hours, about 15 seconds to about 5 hours, About 30 seconds to about 50 hours, about 30 seconds to about 45 hours, about 30 seconds to about 40 hours, about 30 seconds to about 35 hours, about 30 seconds to about 30 hours,
About 30 seconds to about 25 hours, about 30 seconds to about 20 hours, about 30 seconds to about 15 hours, about 30 seconds to about 10 hours, about 30 seconds to about 5 hours, about 1 minute to about 50 hours, about 1 Minutes to about 45 hours, about 1 minute to about 40 hours, about 1 minute to about 35 hours, about 1 minute to about 30 hours, about 1 minute to about 25 hours, about 1 minute to about 20 hours, about 1 minute ~ About 15 hours, about 1 minute to about 10 hours, about 1 minute to about 5 hours, about 1 to about 50 hours, about 1 to about 45 hours, about 1 to about 40 hours, about 1 to about 35 hours, about 1 ~ About 30 hours, about 1 ~ about 25 hours, about 1 ~ about 20 hours, about 1 ~ about 15 hours, about 1 ~ about 10 hours, about 1 ~ about 5 hours, about 5 ~ about 50 hours, about 5 ~ About 45 hours, about 5 to about 40 hours, about 5 to about 35 hours, about 5 to about 30 hours, about 5 to about 25 hours, about 5 to about 20 hours, about 5 to about 15 hours, about 5 to about 10 hours, about 10 to about 50 hours, about 10 to about 45 hours, about 10 to about 40 hours, about 10 to about 35 hours, about 10 to about 30 hours, about 10 to about 25 hours, about 10 to about 20 Time, about 15 to about 50 hours, about 15 to about 45 hours, about 15 to about 40 hours, about 15 to about 35 hours, about 15 to about 30 hours, about 15 to about 25 hours, about 20 to about 50 hours , About 20 to about 45 hours, about 20 to about 40 hours, about 20 to about 35 hours, about 20 to about 30 hours, about 25 to about 50 hours, about 25 to about 45 hours, about 25 to about 40 hours, About 25 to about 35 hours, about 30 to about 50 hours, about 30 to about 45 hours, about 30 to about 40 hours, about 35 to about 50 hours, about 35 to about 45 hours, about 40 to about 50 hours of serum Has a half-life or plasma half-life (eg, serum or plasma from humans, crab monkeys, rats, mice, pigs, dogs, cats, etc.).

Therapeutic Compositions A combination of an effective amount of at least one bifunctional compound described herein and one or more of the compounds separately described herein is pharmaceutically effective. Pharmaceutical compositions comprising in combination with a large amount of carrier, additive, or excipient represent a further aspect of the present disclosure.

The present disclosure, where applicable, includes compositions comprising pharmaceutically acceptable salts of the compounds described herein, in particular acid or base addition salts. The acid used to prepare a pharmaceutically acceptable acid addition salt of the above-mentioned basic compound useful in accordance with this embodiment is a non-toxic acid addition salt, that is, a salt containing a pharmacologically acceptable anion. For example, among many other acids, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, heavy sulfate, phosphate, perphosphate, acetate, lactate, etc. Citrate, percitrate, tartrate, heavy tartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfon Acids that form acid salts, p-toluenesulfonates, and pamoates [ie, 1,1'-methylene-bis- (2-hydroxy-3 naphthoic acid)].

A pharmaceutically acceptable base addition salt can also be used to produce a pharmaceutically acceptable salt form of a compound or derivative according to the present disclosure. A chemical base that can be used as a reagent for preparing a pharmaceutically acceptable base salt of this compound, which is acidic in nature, is a base that forms a non-toxic base salt with such a compound. Such non-toxic base salts are in particular derived from pharmaceutically acceptable cations such as alkali metal cations (eg, potassium and sodium) and alkaline earth metal cations (eg, calcium, zinc and magnesium). Examples thereof include the base salts obtained, ammonium or water-soluble amine-added salts such as N-methylglucamine- (meglumin), and lower alkanolammonium, as well as other pharmaceutically acceptable organic amine base salts.

The compounds described herein may be administered in single doses or in divided doses by oral, parenteral or topical routes in accordance with the present disclosure. Administration of the active compound may range from continuous (intravenous drip) to several oral doses per day (eg QID), oral, topical, parenteral, intramuscular, intravenous, among other routes of administration. It may include intra-, subcutaneous, transdermal (which may include permeation enhancers), intraoral, sublingual, and suppository administration. Enteric coated oral tablets may be used to enhance bioavailability of the compound from the route of administration. The most effective dosage form will depend on the pharmacokinetics of the particular drug selected, as well as the severity of the patient's disease. Administration of the compounds according to the present disclosure as a spray, mist, or aerosol for intranasal, intratracheal or pulmonary administration may be used. Accordingly, the present disclosure is further intended to be a pharmaceutical composition comprising an effective amount of a compound described herein in an optional combination of a pharmaceutically acceptable carrier, additive or excipient. Compounds according to the present disclosure may be administered in immediate release, intermediate release, sustained release or controlled release. Sustained-release or controlled-release forms are preferably given orally, but suppositories and transdermal or other topical forms are also given. Intramuscular injection in the liposome form may be used to control or maintain the release of the compound at the injection site.

The compositions described herein may be formulated by conventional methods using one or more pharmaceutically acceptable carriers, and may be administered as a controlled release formulation. Pharmaceutically acceptable carriers that can be used in these pharmaceutical compositions are, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffers such as phosphoric acid. Salt, glycine, sorbic acid, potassium sorbate, partial glyceride mixture of saturated vegetable fatty acids, water, salt or electrolytes such as prolamin sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica , Magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylic acid salt, wax, polyethylene-polyoxypropylene block polymer, polyethylene glycol, and wool fat.

The compositions described herein are administered orally, parenterally by inhalation spray, topically, intrarectally, intranasally, intraorally, intravaginally, or via a transplant container. You may. As used herein, the term "parenteral" refers to subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrasubarachnoid, intrahepatic, intralesional, and intracranial injections or. Includes drip technology. The composition is preferably administered orally, intraperitoneally, or intravenously.

The sterile injection form of the compositions described herein may be an aqueous suspension or an oily suspension. These suspensions may be formulated by techniques known in the art using suitable dispersants or wetting agents and suspending agents. The sterile injectable preparation may be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a 1,3-butanediol solution. Among the acceptable vehicles and solvents that can be adopted are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oil is customarily used as a solvent or suspension medium. Any brand of fixed oil may be employed for this purpose, including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as there are naturally pharmaceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethylated forms. be. These oily solutions or suspensions may contain long chain alcohol diluents or dispersants such as Ph. Helv or similar alcohols.

The pharmaceutical compositions described herein may be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or aqueous solutions. For tablets for oral use, commonly used carriers include lactose and cornstarch. Typically, a lubricant such as magnesium stearate is also added. For oral administration in capsule form, useful diluents include lactose and dried cornstarch. If an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifier and suspending agent. If desired, certain sweeteners, flavors, or colorants may also be added.

Alternatively, the pharmaceutical compositions described herein may be administered in the form of suppositories for rectal administration. They can be prepared by mixing with suitable non-irritating excipients that are solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such substances include cocoa butter, beeswax and polyethylene glycol.

The pharmaceutical compositions described herein may also be administered topically. Suitable topical formulations are readily prepared for each of these regions or organs. Topical application to the lower intestinal tract can be effective with a rectal suppository formulation (see above) or a suitable enema. Locally acceptable transdermal patches may be used.

For topical application, the pharmaceutical composition may be formulated with a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the disclosed compounds include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsified wax and water. In certain preferred embodiments of the present disclosure, the compound may be coated onto a stent that is surgically implanted in the patient, thereby reducing or reducing the likelihood of occlusion in the stent within the patient.

Alternatively, the pharmaceutical composition may be formulated with a suitable lotion or cream containing the active ingredient 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 ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic applications, the pharmaceutical composition is an isotonic, pH adjusted sterile saline solution as a micronized suspension, or preferably an isotonic, pH adjusted sterile saline solution. It may be formulated, and the presence or absence of a preservative such as benzylalconium chloride may or may not be present. Alternatively, for ophthalmic applications, the pharmaceutical composition may be formulated with an ointment such as petrolatum.

The pharmaceutical compositions described herein may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques known in the field of pharmaceutical formulations, and as a solution of saline, benzyl alcohol or other suitable preservatives, absorption promoters to improve bioavailability, fluorocarbons, and / Or may be prepared by adopting other conventional solubilizers or dispersants.

The amount of a compound in a pharmaceutical composition described herein that can be combined with a carrier material to produce a single dosage form will vary depending on the recipient and disease being treated, the particular mode of administration. Let's go. Preferably, the composition, alone or in combination with at least one other compound according to the present disclosure, is about 0.05 milligrams to about 750 milligrams or more, more preferably about 1 milligram to about 600 milligrams, even more preferably about. It should be formulated containing 10 milligrams to about 500 milligrams of active ingredient.

Specific dosage and treatment regimens for any particular patient include activity, age, weight, general health, gender, diet, dosing time, rate of excretion, drug combination, and treatment of the specific compound used. It should also be understood that it depends on the judgment of the physician doing the treatment and various factors including the severity of the particular disease or condition being treated.

Patients or subjects in need of treatment with a compound according to the methods described herein are optionally provided with an effective amount of the compound according to the present disclosure, including its pharmaceutically acceptable salt, solvate or polymorph. Treated by administration to a patient (subject) alone in a pharmaceutically acceptable carrier or diluent, or in combination with other known erythropoiesis agents specified separately herein. Can be done.

These compounds can be administered by any suitable route, such as oral, parenteral, intravenous, intradermal, subcutaneous, or topical, and transdermally, for example, in liquid, cream, gel, or solid form. , Or can be administered in aerosol form.

The active compound in a pharmaceutically acceptable carrier or diluent is sufficient to deliver a therapeutically effective amount to the patient for the desired indication and does not cause a serious toxic effect on the patient being treated. Is contained. Preferred doses of the active compound for all of the conditions referred to herein are in the range of about 10 ng / kg to 300 mg / kg, preferably in the range of 0.1-100 mg / kg per day, more generally the recipient. / The range is 0.5 to about 25 mg per kg of patient body weight per day. Typical topical doses can range from 0.01 to 5% wt / wt in a suitable carrier.

The compound is conveniently administered in any suitable unit dosage form containing less than 1 mg, 1 mg to 3000 mg, preferably 5 to 500 mg of active ingredient per unit dosage form, but is not limited thereto. About 25-250 mg
Oral doses of are often convenient.

The active ingredient is preferably administered to achieve a peak plasma concentration of the active compound of about 0.00001 to 30 mM, preferably about 0.1 to 30 μM. This can be achieved, for example, by intravenous injection of the active ingredient solution or formulation, optionally in aqueous saline solution or in an aqueous medium, or by bolus administration of the active ingredient. Oral administration is also suitable for producing effective plasma concentrations of the active agent.

The concentration of active compound in the drug composition will depend on the rate of absorption, distribution, inactivation, and excretion of the drug, as well as other factors known to those of skill in the art. Note that dosage values will also vary depending on the severity of the alleviated condition. Furthermore, a particular dosing regimen should be adjusted over time according to the individual's request and the professional judgment of the person who administers or controls the administration of the composition to any particular subject. It should be understood that the concentration ranges described herein are merely exemplary and are not intended to limit the scope or practice of the claimed composition. The active ingredient may be administered at one time, or may be divided into a number of smaller doses and administered at various time intervals.

Oral compositions will generally include an inert diluent or edible carrier. It may be encapsulated in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound or a prodrug derivative thereof can be combined with an excipient and used in the form of tablets, troches, or capsules. A pharmaceutically compatible binder and / or adjuvant substance can be included as part of the composition.

Tablets, pills, capsules, troches, etc. are the following ingredients, or compounds of similar nature, such as binders such as microcrystalline cellulose, tragacant gum, or gelatin; excipients such as starch or lactose, eg, Dispersants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or Sterotes; flow promoters such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; eg peppermint, It can contain either methyl salicylate or a flavoring agent such as an orange flavoring agent. When the dosage unit dosage form is a capsule, it can include, for example, a liquid carrier such as a fatty acid in addition to the above-mentioned types of substances. In addition, the dosage unit dosage form can contain a variety of other substances that modify the physical shape of the physical dosage unit, such as, for example, sugar coatings, shellac, or enteric solvents.

The active compound or a pharmaceutically acceptable salt thereof can be administered as a component such as elixir, suspension, syrup, wafer, chewing gum and the like. In addition to the active compound, the syrup may contain sucrose as a sweetening agent, or certain preservatives, dyes and colorants, as well as flavoring agents.

In addition, active compounds, or pharmaceutically acceptable salts thereof, have the desired effect with other active substances that do not impair the desired effect, or in particular such as erythropoiesis promoters such as EPO and dalvapoetin alfa. Can be mixed with complementary substances. In certain preferred embodiments of the present disclosure, one or more compounds according to the present disclosure may be combined with another bioactive agent such as, for example, an erythropoiesis agent, or a wound healing agent containing an antibiotic, which is described elsewhere herein. Co-administered.

Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include the following components: for example, water for injection, saline, fixed oils, polyethylene glycol, glycerin, Sterilized diluents such as propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium chloride; chelating agents such as ethylenediamine tetraacetic acid; eg Buffers such as acetates, citrates, or phosphates, and tonicity modifiers such as, for example, sodium chloride or dextrose. Parenteral preparations may be encapsulated in ampoules, disposable syringes, or multi-dose vials made of glass or plastic.

When administered intravenously, the preferred carrier is saline or phosphate buffered saline (PBS).
).

In one embodiment, the active compound is prepared with a carrier that protects the compound from rapid excretion from the body, such as release controlled formulations such as implants and microencapsulated delivery systems. Biodegradable and biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods of preparation of such formulations will be apparent to those skilled in the art.

Liposomal suspensions can also be pharmaceutically acceptable carriers. These may be prepared according to methods known to those of skill 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, a liposome formulation comprises dissolving suitable lipids (eg, stearoylphosphatidylethanolamine, stearoylphosphatidylcholine, arachadoylphosphatidylcholine, and cholesterol) in an inorganic solvent and then evaporating to allow the dried lipids on the container surface. It may be prepared by leaving a thin film. Then an aqueous solution of the active compound is placed in a container. The container is then rotated by hand to remove the lipid material from the sides of the container, disperse the lipid mass and form a liposome suspension.

Therapeutic method In an additional aspect, the present specification provides a therapeutic composition comprising an effective amount of a compound described herein or a salt form thereof, and a pharmaceutically acceptable carrier. Therapeutic compositions can be used in a patient or subject, eg, an animal such as a human, to regulate the degradation of a protein and to treat or ameliorate a medical condition or condition regulated via the degraded protein.

As used herein, the terms "treat,""treat," and "treatment" refer to any action that benefits the patient and is regulated via the protein to which the compound binds. The compound may be administered for its benefit, including treatment of any condition or condition. Cancer, heart / face / skin syndrome, neurofibromatosis type 1, Costello syndrome, Noonan syndrome, LEOPARD (hokuro, electrocardiogram abnormality, hypertelorism, or pulmonary valve stenosis, which can be treated using the compounds according to the present disclosure, Pathophysiology or conditions such as genital abnormalities, growth retardation, hearing loss) syndrome are described herein.

The present specification describes, for example, cancer, heart / face / skin syndrome, neurofibromatosis type 1, Costello syndrome, Noonan syndrome, or LEOPARD (mole, electrocardiogram abnormality, hypertelorism, pulmonary valve stenosis, genital abnormality, growth retardation). , A therapeutic composition as described herein for performing degradation of a subject protein to treat or ameliorate a disease such as (hearing loss) syndrome. In certain additional embodiments, the disease is multiple myeloma. Therefore, in another embodiment, the present specification provides a method for ubiquitinating / degrading a target protein in a cell. In certain embodiments, the method comprises administering a bifunctional compound described separately herein, which is preferably attached via a linker moiety, eg, ULM and PTM, wherein the ULM is attached to the PTM. Linked, ULM recognizes ubiquitin pathway proteins such as ubiquitin ligases such as celebrone, VHL, IAP, and / or E3 ubiquitin ligase containing MDM2, and PTM recognizes the target protein so that the target protein Degradation of the target protein occurs when placed in close proximity to the ubiquitin ligase, thus reducing / inhibiting the effect of the target protein and resulting in control of the protein level. The regulation of protein levels provided by the present disclosure provides treatment for a pathological condition or condition, which is regulated via a target protein by reducing the level of that protein in cells, such as patient cells. In certain embodiments, the method comprises an effective amount of a compound described herein, optionally, a pharmaceutically acceptable excipient, carrier, adjuvant, another bioactive agent, or a combination thereof. , Including administration.

In an additional embodiment, the specification provides a method of treating or ameliorating a disease, disorder or symptom thereof in a subject or patient, such as an animal such as a human, which is described herein. A composition comprising an effective amount, such as a therapeutically effective amount of a compound or salt thereof thereof, and a pharmaceutically acceptable excipient, carrier, adjuvant, another bioactive agent, or a combination thereof. In this case, the composition is effective in treating or ameliorating a disease or disorder or symptoms thereof in a subject.

In another aspect, the present specification provides a method of identifying the degrading effect of a protein of interest in a biological system using the compounds according to the present disclosure.

In another embodiment, the present disclosure is directed to a method of treating a human patient in need for a protein-mediated pathology or condition, wherein degradation of the protein produces a therapeutic effect in that patient. The method comprises administering an effective amount of the disclosed compound to a patient in need, optionally in combination with another bioactive agent. The condition or condition can be a disease caused by a microbial organism, or an extrinsic factor such as, for example, a virus, bacterium, fungus, protozoan or other microorganism, or overexpression of a protein that causes the condition and / or condition. / Or it may be a condition caused by overactivation (eg, constitutive activity).

The term "pathology or condition" refers to the occurrence of protein dysregulation (ie, an increased amount of protein expressed in a patient) that requires the degradation of one or more proteins in the patient. It is used to describe any condition or condition that results in beneficial treatment or relief for the patient. In certain cases, the condition or condition can be treated.

Pathophysiology or conditions that can be treated with the compounds according to the present disclosure include, for example, autoimmune diseases such as asthma, polysclerosis, various cancers, ciliary-related diseases, palatal fissures, diabetes, heart disease, hypertension, inflammation. Sexual colitis, mental retardation, mood disorders, obesity, refractive abnormalities, infertility, Angelman's syndrome, canavanism, celiac disease, Charcomary Tooth's disease, cystic fibrosis, Duchenne's muscle dystrophy, hemochromatosis, hemophilia, Kleinfelder Syndrome, neurofibromatosis, phenylketonuria, polycystic kidney disease, (PKD1) or 4 (PDK2) Prada-Willi syndrome,
Examples include sickle cell disease, Tay-Sachs disease, and Turner syndrome.

Throughout this specification, the term "neoplasm" or "cancer" is used throughout the specification to grow and initiate a cancerous or malignant neoplasm, that is, cells that often grow and initiate much faster than normal. It is used to refer to the pathological process that results in the formation and growth of abnormal tissue that continues to grow after a growth-stopping stimulus. Malignant neoplasms exhibit partial or complete lack of structural organization and lack of functional coordination with normal tissue, and most invade surrounding tissues, metastasize to several sites and are eliminated. Will recur after an attempt and there is a high probability that the patient will die unless properly treated. As used herein, the term neoplasm is used to describe all cancerous pathologies and includes pathological processes associated with malignant hematopoietic cells, ascites and solid tumors. Examples of cancers that can be treated with the disclosed compounds 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, colon cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, renal cancer, liver cancer, lung cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, and gastric cancer; leukemia; benign and malignant Lymphomas, especially Berkit lymphoma and non-Hodgkin lymphoma; benign and malignant melanoma; myeloid proliferative disorders; Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, fatty sarcoma, myoma, peripheral neuroepitheloma, synovial sarcoma, glioma Tumor, stellate cell tumor, oligodendroglioma, lining tumor, glial blastoma, neuroblastoma, ganglion cell tumor, ganglion glioma, medullary blastoma, pine fruit cell tumor-like, medulla tumor, spinal cord Membranous sarcoma, sarcoma including neurofibromas and nerve sheath tumors; colon cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testis cancer, thyroid cancer, stellate cell tumor, esophageal cancer, pancreatic cancer , Gastric cancer, liver cancer, colon cancer, melanoma; cancer sarcoma, Hodgkin's disease, Wilms tumor, and malformed cancer. Further cancers that can be treated using compounds according to the present disclosure include, for example, T-cell lineage acute lymphoblastic leukemia (T-ALL), T-cell lineage lymphoblastic lymphoma (T-LL), peripheral T cells. Included are lymphoma, adult T-cell lymphoma, precursor B-cell ALL, precursor B-cell lymphoma, large-cell B-cell lymphoma, Berkit lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, and Philadelphia chromosome-positive CML.

The term "biologically active agent" is used to describe agents other than the compounds according to the present disclosure, in order to aid in the therapeutic, inhibitory, and / or control / preventive effects of the intended use of the compounds. It is used in combination with this compound as a biologically active agent. Preferred bioactive agents for use herein include agents having pharmacological activity similar to the activity in which the compound is used or administered, such as anticancer agents, antiviral agents, especially antiHIV agents, antiretro. Examples include viral agents, anti-HCV agents, antimicrobial agents, antifungal agents and the like.

The term "additional anti-cancer agent" is used to describe an anti-cancer agent that can be used in combination with a compound according to the present disclosure to treat cancer. Examples of these agents include 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, enzastaurin, bandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitor, VEGFR inhibitor, EGFR TK Inhibitors, Aurora Kinase Inhibitors, PIK-1 Modulators, Bcl-2 Inhibitors, HDAC Inhibitors, c-MET Inhibitors, PARP Inhibitors, Cdk Inhibitors, EGFR TK Inhibitors, IGFR-TK Inhibitors, Anti HGF antibody, PI3 kinase inhibitor, AKT inhibitor, mTORC1 / 2
Inhibitor, JAK / STAT inhibitor, Checkpoint-1 or 2 inhibitor, focal adhesion kinase inhibitor, Map kinase kinase (mek) inhibitor, VEGF trap antibody, pemetrexed, erlotinib, dasatanib d ( rubitecan , Gosipole, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR1 KRX-0402, lucanthone , LY317615, neuradiab, vitalespan, Rta 744, Sdx 102, talampanel,
Atrasentan, Xr 311, lomidepsin, ADS-100380, snitinib, 5-fluorouracil, bolinostat, etopocid, gemcitabine, doxorbisin, doxorubicin liposomes, 5'-deoxy-5-fluorouridine, bincristine, temozolomid, ZK-304709 , Celiciclib; PD0325901, AZD-6244, capecitabin, L-glutamic acid, N- [4- [2- (2-amino-4,7-dihydro-4-oxo-1H-pyrrolo [2,3-d] ] Pyrimidin-5-yl) ethyl] Benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxyphene, tremiphencitrate, anastrazole, exemethan, retrozole, DES ( Diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevasizumab, IMC-1C11, CHIR-258); 3- [5- (methylsulfonylpiperazinmethyl) -indrill-quinolone, vatalanib, AG-013736, AVE -0005, goseleline acetate, leuprolide acetate, tryptrelymphmoate, medroxyprogesterone acetate, hydroxyprogesterone capronate, megestrol acetate, laroxyphene, bicalutamide, flutamide, niltamide, megestrol acetate, CP-724714; TAK-165, HKI-272, ellotinib, lapatanib, canertinib, ABX-EGF antibody, arbitux, EKB-569, PKI-166, GW-572016, Ionafarnib, BMS- 214662, tipifarnib; amifostine, NVP-LAQ824, suberoyl analide hydroxamic acid, valproic acid, tricostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutetimid, arnsacrine. ), Anagrelide, L-asparaginase, Bacillus Calmette-Guerin: BCG) Vaccines, Adriamycin, Breomycin, Buserelin, Busulfan, Carboplatin, Carmustine, Chlorambusyl, Cisplatin, Cladribine, Clodronate, Ciproteron, Cytarabine, Dacarbazine, Dactinomycin, Daunorubicin, diethylstilvestrol, Epirubicin, Fludalabine, Fludrocortisone , Fluoxymesterone, Flutamide, Gleevec, Gemcytarabine, Hydroxyurea, Idalbisin, Iphosphamide, Imatinib, Leuprolide, Revamizol, Romustine, Mechloretamine, Melfaran, 6-mercaptopurine, Mesna, Metotrexate, Mitomycin, Mitotan, Mitoxanthron , Octreotide, oxaliplatin, paclitaxel, pentostatin, plicamycin, porphymer, procarbazine, valrubicin, rituximab, streptozosine, teniposide, testosterone, salidamide, thioguanine, thiotepa, tretinoin, bindesin, 13-cis-retinoinic acid, phenyl Mustard, Estramstin, Altretamine, Floxuridine, 5-Deoxyuridine, Cytocin arabinoside, 6-mecaptopurine, Deoxycoformycin, Carmustine, Valrubicin, Mitramycin, Vinblastine, Vinorelbin , Topotecan, razoxin, marimastat, COL-3, neovasstat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angio Statins, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimitidine, trussumab, deniroykin difftitox, gefitinib, vortezimib, paclitaxel, paclitaxel, paclitaxel (Cremophor-free paclitaxel), docetaxel, epitylone B, BMS-24 7550, BMS-310705, droloxifene, 4-hydroxytamoxifene, pipendoxifene, ERA-923, asparaginase, fullbestland, acorbiphen, lasofoxyphene, idoxyphene, TSE-424 , HMR-3339, ZK186619, Topotecan, PTK787 / ZK 222584, VX-745, PD 184352, Rapamycin, 40-O- (2-Hydroxyethyl) -Rapamycin, Temcilolimus, AP-23573, RAD001, ABT-578, BC- 210, LY294002, LY292223, LY292696, LY293684, LY293646, Waltmannin, ZM336372, L-779,450, PEG-filgrastim, dalbepoetin, erythropoetin, granulocyte colony stimulator, zolendronate, prednisolone, setuximab, granulocyte macrophages Colony stimulant, histreline, PEGylated interferon alpha-2a, interferon alpha-2a, PEGylated interferon alpha-2b, interferon alpha-2b, azacitidine, PEG-L-asparaginase, lenalidomido, gemtuzumab, hydrocortisone, interleukin-11, dexamethasone , Alemtuzumab, total trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibritgumomab tyuxetane, androgen, decitabin, hexamethylmelamine, bexarotene, tositumomab, trioxidation Arsenic, cortisone, editronate, mitotan, cyclosporin, downorbisin liposomes, Edwina-asparaginase, strontium 89, cassopitant, netupitant, NK-1 receptor antagonist, paronosetron, aprepitant, diphenhydramine, hydroxydine, Lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondancetron, dracetron, topotetron, peg Examples include filgrastim, erythropoietin, epoetin alfa, darbepoetin alfa and mixtures thereof.

The terms "anti-HIV agent", "anti-retrovirus" or "additional anti-HIV agent" are particularly referred to, in particular, for example, nucleotide reverse transcriptase inhibitors (NRTIs), other non-nucleoside reverse transcription inhibitors (ie, the present disclosure). (Non-representative agents), protease inhibitors, fusion inhibitors, and exemplary compounds thereof include, for example, 3TC (Lamivudine), AZT (Zidovudine), (- )-FTC, ddI (Didanosine), ddC (zalcitabine), abacavir (ABC), tenofovir (PMPA), D-D4FC (Reverset), D4T (stubzine) (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 fusion inhibitors such as T20, fusions and mixtures thereof (including anti-HIV compounds currently under clinical trial or development).

Other anti-HIV / anti-retroviral agents that may be used in co-administration with compounds according to the present disclosure include, for example, other NNRTIs (ie, other than NNRTIs according to the present disclosure), in particular 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-Francarbotiamide), etravirine (TMC125), Trovirdine (Ly300046.HCl), MKC-442 (emivirine, coactinon), HI-236, HI-240 , HI-280, HI-281, rilpivirine (TMC-278), MSC-127, HBY 097, DMP266, Baicalin (TJN-151) ADAM-II (3', 3'-dichloro-4) ', 4 ”-dimethoxy-5', 5” -bis (methoxycarbonyl) -6,6-diphenylhexanate methyl), 3-bromo-5- (1-5-bromo-4-methoxy-3- (methoxy) Methyl benzoate (alkenyldiarylmethane analog, Adam analog), (5-chloro-3- (phenylsulfinyl) -2'-indolecarboxamide), AAP -BHAP (U-104489 or PNU-104489), Capravirine (AG-1549, S-1153), atevirdine (U-87201E), aurin tricarboxylic acid (SD-095345), 1-[(6-cyano-2-indrill) 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-indrill) carbonyl] piperazine, 1-[(6-formyl-2-indrill) carbonyl] -4- [3- (isopropylamino) -2- Pyridinyl] piperazine, 1-[[5- (methylsulfonyloxy) -2-indoli) 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) pyrimidine-4-one (DABO-546), DPC 961, E -EBU, E-EBU-dm, E-EPSeU, E-EPU, Foscarnet (Foscavir), HEPT (1-[(2-hydroxyethoxy) methyl] -6- (phenylthio) timine ), HEPT-M (1-[(2-hydroxyethoxy) methyl] -6- (3-methylphenyl) thio) timine), HEPT-S (1-[(2-hydroxyethoxy) methyl] -6-( Phenylthio) -2-thiothymine), Inophyllum P, L-737,126, Michelamine A (NSC650898), Michelamine B (NSC649324), Michelamine 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 (PETT Cl, F derivative), N- {2- (2,6-difluorophenethyl] -N'-[2- (5-bromopyridyl)] Aurea {PETT derivative), N- {2- (2,6-difluorophenethyl] -N'-[2- (5-methylpyridyl)] thiourea {PETT pyridyl derivative), N- [2- (3-fluorofura) Nyl) 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-difluorobenzoxa) Zol-2-yl) ethyl} -5-ethyl-6-methyl (pyridine-2 (1H) -thione (2-pyridinone derivative), 3-[[(2-methoxy-5,6-dimethyl-3-pyridyl) ) Methyl] Amine] -5-Ethyl-6-Methyl (pyridine-2 (1H) -thione, R82150, R82913, R87232, R88703, R89439 (Loviride), R90385, S-2720, Suramin Sodium ), TBZ (thiazolobenzimidazole, NSC 625487), thiazoloisoindole-5-one, (+) (R) -9b- (3,5-dimethylphenyl-2,3-dihydrothiazolo [2,3) -a] Isoindole-5 (9bH) -on, may be selected from the group consisting of Tivirapine (R86183), UC-38 and UC-84.

The term "pharmaceutically acceptable salt" is used throughout the specification to describe the salt form of one or more of the compounds described herein where appropriate. , Shows increased solubility of the compound in the gastric juice of the patient's gastrointestinal tract, promoting dissolution and bioavailability of the compound. Pharmaceutically acceptable salts include, where appropriate, those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals such as potassium and sodium, such as alkaline earth metals such as calcium and magnesium, and ammonium salts, among many other acids and bases known, especially in the pharmaceutical field. Can be mentioned. Salts of sodium and potassium are particularly preferred as neutralizing salts of the phosphate according to the present disclosure.

The term "pharmaceutically acceptable derivative" is used throughout the specification to describe any pharmaceutically acceptable prodrug form (eg, esters, amides, other prodrug groups, etc.). When administered to a patient, they give rise to the compound directly or indirectly, or give rise to an active metabolite of the compound.

General Synthetic Methods The realization and optimization of the synthesis of the bifunctional molecules described herein may be tackled in a stepwise or modular manner. For example, identification of a compound that binds to a target molecule may include a high-throughput or medium-throughput screening campaign if the appropriate ligand is not readily available. It is not uncommon for initial ligands to require iterative design and cycle optimization to improve the suboptimal aspects identified by appropriate in vitro pharmacological and / or ADMET assay data. Part of the optimization / SAR campaign is to probe ligand positions that are tolerated for substitution and may be suitable positions for binding the linker chemicals referred to above herein. If crystallographic or NMR structural data are available, use them to
We can focus on such synthetic efforts.

In a very similar manner, the ligand for E3 ligase, ie ULM / ILM / VLM.
/ CLM / ILM can be identified and optimized.

Those skilled in the art can use the PTMs and ULMs at hand (eg, ILM, VLM, CLM, and / or ILM) to use known synthetic methods for the combination with or without a linker moiety. can. Linker moieties can be synthesized and functionalized with a range of compositions, lengths, and flexibility so that PTM and ULM groups can be continuously attached to the distal end of the linker. Thus, a library of bifunctional molecules can be realized and profiled in in vitro and in vivo pharmacological and ADMET / PK tests. Similar to the PTM and ULM groups, the final bifunctional molecule can be iteratively designed and optimized to identify the molecule with the desired properties.

In some examples, protecting group strategies and / or functional group interconversion (FGI) may be required to facilitate the preparation of the desired material. Such chemical processes are well known to synthetic organic chemists, many of whom are “Greene's Protective Groups in Organic Synthesis” Peter GM Wuts and Theodora W. Greene (Wiley) and “Organic Synthesis: The”. It can be found in books such as the Disconnection Approach ”Stuart Warren and Paul Wyatt (Wiley).

List of abbreviations
AcOH, acetic acid
aq., aqueous solution
BINAP, 2,2'-bis (diphenylphosphino) -1,1'-binaphthalene
Boc, tert-butoxycarbonyl
Boc ₂ O, di-tert-butyl dicarbonate
BOP, (benzotriazole-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphart
CDCl ₃ , Deuterated chloroform
CD3OD, Deuterio Methanol
CH ₃ CN, acetonitrile
CH ₃ OH, methanol
CsF, cesium fluoride
Cs ₂ CO ₃ , cesium carbonate
Cu (OAc) ₂ , copper acetate (II)
Cy ₂ NMe, dicyclohexylmethylamine
DCM, dichloromethane
DIAD, diisopropyl azodicarboxylate
DIEA or DIPEA, diisopropylethylamine
DMAP, N, N-dimethylaminopyridine
DMF, N, N-dimethylformamide
DMSO, dimethyl sulfoxide
DMSO-d ₆ , hexajuuterodimethyl sulfoxide
Et ₂ NH, Diethylamine
EtOAc or EA, ethyl acetate
HCl, hydrochloric acid
H ₂ O, water
HPLC, high performance liquid chromatography
IBX, 2-iodoxybenzoic acid
KOAc, potassium acetate
LCMS, Liquid Chromatography / Mass Spectrometry
LiOH, lithium hydroxide
MeOH, methanol
MsCl, Methane Sulfonyl Chloride
N ₂ , nitrogen
NaH, sodium hydride
NaBH ₃ CN, sodium cyanoborohydride
NaBH (OAc) ₃ , sodium triacetoxyborohydride
NaCl, sodium chloride
י ₃ , sodium bicarbonate
NaI, sodium iodide
Na ₂ SO ₄ , sodium sulfate
n-BuLi, n-butyllithium
NH ₃ , ammonia
NH ₄ Cl, Ammonium Chloride
NH ₂ OH ^. HCl, Hydroxylamine Hydrochloride
NMP, N-methylpyrrolidone
NMR, nuclear magnetic resonance
O ₂ , oxygen
Pd (aMPhos) Cl ₂ , Bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) Dichloropalladium (II)
Pd ₂ (dba) ₃ , Tris (dibenzylideneacetone) dipallad (0)
Pd (dppf) Cl ₂ , [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II)
Pd (OH) ₂ , palladium hydroxide
Pd (PPh ₃ ) ₄ , Tetrakis (Triphenylphosphine) Palladium (0)
PE, petroleum ether
Ph ₃ P, triphenylphosphine
Py, pyridine
PyBOP, (benzotriazole-1-yloxy) tripyrolidinophosphonium hexafluorophosphate
rt, room temperature
TBAF, Tetra-n-Butyl Ammonium Fluoride
TBDPSCl, tert-butyldiphenylsilyl chloride
TBS, tert-butyldimethylsilyl
tBuOK, potassium tert-butoxide
[tBu ₃ PH] BF ₄ , tri-tert-butylphosphonium tetrafluoroborate
TEA, triethylamine
THF, tetrahydrofuran
TLC, thin layer chromatography
TMSOTf, trimethylsilyl trifluoromethanesulfonate
TsCl, p-toluenesulfonyl chloride sulfonyl chloride
TsOH, p-toluenesulfonic acid
Scheme 1A

The compounds of formula I are suitable palladium catalysts such as bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II), suitable bases such as cesium fluoride, under palladium catalyst cross-linking conditions. Reagent II (commercially available or to those skilled in the art) using 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. Can be easily prepared using known standard reaction techniques) to produce compounds of formula III. One of M or M'represents a functional group capable of undergoing palladium-catalyzed transmetallation, such as boronic acid, boron ester, or trialkylstannan; the other of M or M'is Represents a functional group capable of undergoing palladium-catalyzed oxidative addition, such as iodide, bromide, chloride, or trifluoromethanesulfonate; Ar represents an aromatic or heteroaromatic ring system; L represents an aromatic or heteroaromatic ring system.
Represents any linker or linker portion

Represents a primary or secondary amine optionally cyclized to a 4- to 8-membered heterocycle, where PG represents a suitable protecting group, such as, but not limited to, t-butoxycarbonyl or benzyl. Equation III
The compound of formula IV can be converted to the compound of formula IV when the PG is t-butoxycarbonyl by treatment with a reagent suitable for removing the PG, for example hydrogen chloride in 1,4-dioxane. Compound IV may then be reacted with compound V to form compound VI, where L'represents any linker or linker moiety, Y is CH ₂ or C = O, and X. Is a suitable leaving group (eg, OMs, OTs, Cl, etc.) or aldehyde (CHO). When X is a leaving group, n
Is 0, and suitable reaction conditions are conditions for the alkylation reaction, such as diisopropylethylamine, potassium iodide, DMSO or acetonitrile, 80 ° C. When X is an aldehyde, n is 1, and suitable reaction conditions are conditions for the reductive amination reaction, such as sodium cyanoborohydride, methanol, dichloromethane, acetic acid, room temperature.

Scheme 1B

The compounds of formula I are suitable palladium catalysts such as bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II), suitable bases such as cesium fluoride, under palladium catalyst cross-linking conditions. Reagent II (commercially available or to those skilled in the art) using 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. Can be easily prepared using known standard reaction techniques) to produce compounds of formula III. One of M or M'represents a functional group capable of undergoing palladium-catalyzed transmetallation, such as boronic acid, boron ester, or trialkylstannan; the other of M or M'is Represents a functional group capable of undergoing a palladium-catalyzed oxidative addition, such as iodide, bromide, chloride, or trifluoromethanesulfonate; Z and Z'are independent of each other, H, or, for example, t-butoxycarbonyl. A suitable protecting group, such as; Ar represents an aromatic or heteroaromatic ring system; L represents any linker or linker moiety.

Represents a primary or secondary amine, optionally cyclized to a 4- to 8-membered heterocycle and / or condensed to Ar, where PG is a suitable protecting group, eg, but not limited to, t. -Represents butoxycarbonyl or benzyl. The compound of formula III is converted to the compound of formula IV when the PG is t-butoxycarbonyl by treatment with a reagent suitable for removing PG, for example hydrogen chloride in 1,4-dioxane. sell. Compound IV then reacts with compound V and compound VI
In the equation, L'represents any linker or linker moiety, Y is CH ₂ or C = O, and X is the appropriate leaving group (eg OMs, OTs, Cl, etc.) or aldehyde (CHO). ), R is any substituent (eg F or OCH ₃ ), and W is

When X is a leaving group, n is 0 and suitable reaction conditions are conditions for the alkylation reaction, such as diisopropylethylamine, potassium iodide, DMSO or acetonitrile, 80 ° C. When X is an aldehyde, n is 1, and suitable reaction conditions are conditions for the reductive amination reaction, such as sodium cyanoborohydride, methanol, dichloromethane, acetic acid, room temperature. If desired, enantiomers or mixtures of diastereomers of any compound IV, V, or VI may be techniques known to those of skill in the art, such as, but not limited to, preparative high performance liquid chromatography or preparative supercritical fluids. Techniques such as chromatography may be used to divide them into constitutive enantiomers or constitutive diastereomers.

W is

If compound VI is treated with conditions suitable for imide cyclization, such as 100 ° C. with an acetonitrile solution of benzenesulfonic acid or a solution of N-methylpyrrolidone, compounds of different formula VI may be obtained. Well, during the ceremony, W is

If one or both of Z or Z'are protecting groups, the protecting group is removed from compound VI, for example, by treatment with trifluoroacetic acid when Z and / or Z'is t-butoxycarbonyl. In the formula, Z and Z'are H.
Is.

II

It will be apparent to those skilled in the art that the position of is reversed in compound VI. In such cases, X may also be CH ₂ OH, for example as its acetal, or protected with an aldehyde, and before reacting with V, for example, Dess-Martin peryodinan. Oxidation of the alcohol with, or deprotection of the acetal with, for example, an aqueous acetone solution of Amberlyst 15 in perfusion may convert the X to a compound of CHO.

Scheme 2

A compound of formula IV may be reacted with a compound of formula VII to produce a compound of formula VIII, where X is a suitable leaving group such as fluorine or chlorine and Y is C =. O, R represents any one or more substituents, W is H or CH ₃ , and the reaction conditions are nucleophilic aromatic substitution conditions such as triethylamine, DMSO, 70 ° C.

Scheme 3A

The compounds of formula I can be readily prepared using reagent IX (commercially available or standard reaction methods known to those of skill in the art) under palladium-catalyzed cross-coupling conditions, eg, as shown in Scheme 1A or 1B. It may react with (prepared) to produce a compound of formula X. One of M or M'represents, for example, a functional group capable of undergoing palladium-catalyzed transmetallation, such as boronic acid, boron ester, or trialkylstannan; M.
Or the other of M'represents a functional group capable of undergoing palladium-catalyzed oxidative addition, such as iodide, bromide, chloride, or trifluoromethanesulfonate; Ar is aromatic or heteroaromatic. Represents a ring system; L represents any linker or linker moiety and PG represents a suitable ester protecting group, such as methyl, ethyl, or t-butyl. When the PG is t-butyl, the compound of formula X can be converted to the compound of formula XI by treatment with a reagent suitable for removing PG, such as hydrogen chloride in 1,4-dioxane. Compound XI is then subjected to compound XII (where Z is optional in the formula) under amide-forming conditions, such as (benzotriazole-1-yloxy) tripyrolidinophosphonium hexafluorophosphate, diisopropylethylamine, DMF, room temperature. Can be reacted with a substituent of (eg, H, methyl, or hydroxymethyl) to form a compound of formula XIII.

Scheme 3B

The compounds of formula I'are simple, for example, under palladium-catalyzed cross-coupling conditions as set forth in Scheme 1A or 1B, using reagent IX (commercially available or standard reaction methods known to those of skill in the art). Can be reacted with (prepared in) to produce a compound of formula X. One of M or M'represents, for example, a functional group capable of undergoing palladium-catalyzed transmetallation, such as boronic acid, boron ester, or trialkylstannan; the other of M or M'. Represents a functional group capable of undergoing palladium-catalyzed oxidative addition, such as iodide, bromide, chloride, or trifluoromethanesulfonate; Ar represents an aromatic or heteroaromatic ring system; L represents an aromatic or heteroaromatic ring system. , Represents any linker or linker moiety; PG represents a suitable ester protecting group, such as methyl, ethyl, or t-butyl; and W represents any protecting group, such as 2- (trimethylsilyl) ethoxymethyl. show. If necessary, for example, when L contains a primary or secondary amine or alcohol, the functional group may optionally be protected with a suitable protecting group, eg t-when the functional group is an amine. Butoxycarbonyl, optionally protected with t-butyldimethylsilyl when the functional group is alcohol. The compound of formula X can be treated with a reagent suitable for the removal of any W, for example, when W is 2- (trimethylsilyl) ethoxymethyl, in 1,4-dioxane and methanol, or in ethylenediamine and tetra. By treatment with hydrogen chloride in -n-butylammonium fluoride; then, for example, when the PG is t-butyl, with a suitable reagent for removing PG, eg hydrogen chloride in 1,4-dioxane. By treatment, it may be converted to a compound of formula XI. Compound XI may then react with compound XII, where Z is an optionally substituted carbon such as CH ₂ , CD ₂ , CH (Me), CH (CH ₂ OH), C ( CH ₃ ) ₂ where R is any substituent, eg F or CH ₂ OH, and Y is any substituent, eg halogen, CN, or optionally substituted aryl or heterocyclyl. There, thereby producing a compound of formula XIII under amide-forming conditions, such as (benzotriazole-1-yloxy) tripyrolidinophosphonium hexafluorophosphate, diisopropylethylamine, DMF, room temperature and the like. To those skilled in the art, when L contains a protected amine or alcohol, the protecting group is optionally at the stage of compound X, XI, or XIII, eg, the protecting group is t-butoxycarbonyl. It will be apparent that it can sometimes be removed by treatment with trifluoroacetic acid, or with hydrochloric acid in methanol when the protecting group is t-butyldimethylsilyl.

Scheme 4A

Alternatively, a compound of formula IX can be converted to a compound of formula XIV using conditions similar to the conditions for conversion from X to XI in Scheme 3A or 3B. Compounds of formula XIV can be converted to compounds of formula XV using conditions similar to the conditions for conversion from XI to XIII in Scheme 3A or 3B. The compound of formula XV is then converted to the compound of formula XIII by reaction with the compound of formula I using conditions similar to those for the conversion of I and IX to X in Scheme 3A or 3B. sell.

Scheme 4B

Alternatively, a compound of formula IX can be converted to a compound of formula XIV using conditions similar to the conditions for conversion from X to XI in Scheme 3A or 3B. Compounds of formula XIV can be converted to compounds of formula XV using conditions similar to the conditions for conversion from XI to XIII in Scheme 3A or 3B. The compound of formula XV is then reacted with the compound of formula I using conditions similar to those for I'and IX to X conversion in Scheme 3B, followed by optionally deprotection of W. Thereby, it can be converted into a compound of the formula XIII.

Scheme 5

Compounds of formula XVI are subjected to standard reaction techniques such as copper acetate (II), pyridine or diethylamine or triethylamine, 100 ° C., Reagent II'(commercially available or known to those of skill in the art) under Changlam cross-linking conditions. Can be reacted with (easily prepared using) to produce a compound of formula XVII. M'represents a boronic acid or boron ester; Ar represents an aromatic or heteroaromatic ring system; L represents any linker.

Represents a primary or secondary amine optionally cyclized to a 4- to 8-membered heterocycle, where PG represents a suitable protecting group, such as, but not limited to, t-butoxycarbonyl or benzyl. Compounds of formula XVII can be subjected to palladium-catalyzed cross-coupling conditions, such as [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium, tri-tert-butylphosphine tetrafluoroborate, cesium fluoride, 1,4-dioxane. , 90 ° C. may be reacted with reagent XVIII to produce a compound of formula XIX. M represents a functional group capable of undergoing a palladium-catalyzed metal exchange reaction, such as boronic acid, boronic acid ester, or trialkylstannan, and Ar'is an aromatic or optionally a heterocyclic aromatic with a substituent. Represents a family ring system. The compound of formula XIX is then converted to the compound of formula XX when the PG is t-butyl by treatment with a suitable reagent for removing PG, such as 1,4-dioxane or hydrogen chloride in methanol. sell. Alternatively, the compound of formula XX may be reacted with the compound of formula VII to produce the compound of formula XXI, where X is a suitable leaving group such as fluorine or chlorine and Y is C. = O, the aromatic ring of VII may have any additional substituents, and the reaction conditions are conditions for nucleophilic aromatic substitution, such as triethylamine, DMSO, 80 ° C. If the Ar'group contains any substituents, such as ketones, the group undergoes further functionalization, for example by treatment with hydroxylamine hydrochloride and pyridine at room temperature, and is further compound of formula XXI. Can be generated.

Scheme 6

Alternatively, a compound of formula XVII can be converted to a compound of formula XXII using conditions similar to the conditions for conversion from XIX to XX in Scheme 5. The compound of formula XXII can then be treated with the compound of formula VII as defined in Scheme 5 to produce the compound of formula XXIII. The compound of formula XXIII can then be treated with reagent XVIII as defined in Scheme 5 to produce the compound of formula XXI. If the group Ar'contains any substituents such as ketones, they are further functionalized, for example by treating hydroxylamine hydrochloride and pyridine at room temperature to provide additional compounds of formula XXI.

Scheme 7

Reductive amination of compounds of formula XXIV (prepared in a manner similar to the preparation of XVI and XVII from II'in Scheme 5 and optionally subjected to additional functional group conversions known to those of skill in the art). Compounds of formula XXVI can be prepared by reacting with compounds of formula XXV under conditions such as sodium cyanoborohydride, acetic acid, methanol, room temperature. As used herein, Ar represents an aromatic or heteroaromatic ring system; L and L'represent any linker or linker moiety.

Represents a primary or secondary amine optionally cyclized to a 4- or 8-membered heterocycle, where Y is CH ₂ or C = O. The compound of formula XXVI may then be treated with reagent XVIII as defined in Scheme 5 to produce the compound of formula XXVII. If the group Ar'contains optionally substituents such as ketones, they may be further functionalized and treated with, for example, hydroxylamine hydrochloride and pyridine at room temperature to provide additional compounds of formula XVII. ..

Scheme 8

Alternatively, the compound of formula XXII may be treated with the compound of formula XXVIII under reductive amination conditions, eg, under the same conditions as in Scheme 7, to provide the compound of formula XXVI'. In the present specification, Ar, L, L',

And Y are defined as in Scheme 7. The compound of formula XXVI'can then be treated with reagent XVIII as defined in Scheme 5 to produce the compound of formula XXVII'. If the group Ar'contains optionally substituents such as ketones, they undergo further functionalization and are treated with, for example, hydroxylamine hydrochloride and pyridine at room temperature to provide additional compounds of formula XVII'. sell.

Scheme 9

A compound of formula XIX may be reacted with a compound of formula VII to provide a compound of formula XXX, where X is a suitable leaving group such as fluorine or chlorine and Y is C = O. Yes, the aromatic ring of VII may have any additional substituents, and the reaction conditions are conditions for nucleophilic aromatic substitution, such as diisopropylethylamine, NMP, 130 ° C., with microwave irradiation. Or none.

Scheme 10

Alternatively, the compound of formula XIX is treated with the compound of formula XXVIII under reductive amination conditions such as sodium triacetoxyborohydride, ethanol, dichloromethane, room temperature to provide the compound of formula XXXI. Can be done.

Scheme 11

Alternatively, a compound of formula XXXII prepared from a compound of formula XIX through a simple conversion known by those of skill in the art, such as alkylation or reductive amination, can be prepared under amide forming conditions, eg (benzotriazole-1-. Iloxy) Tripyrolidinophosphonium Hexafluorophosphate, diisopropylethylamine, DMF, compounds of formula XXXIII can be reacted with compounds of formula XII under conditions such as DMF, room temperature to provide compounds of formula XXXIII.

Scheme 12A

Compounds of formula XXXIV are subjected to nucleophilic substitution conditions, such as potassium carbonate, potassium iodide, DMSO, 60 ° C., with reagent XXXV (commercially available or using standard reaction techniques known to those of skill in the art). Can be reacted with (easily prepared) to produce a compound of formula XXXVI. Alternatively, the reaction conditions may be conditions for the Mitsunobu reaction, such as triphenylphosphine, diethyl azodicarboxylate, THF. As used herein, Y is CH ₂ or C = O; one of M or M'is a functional group capable of undergoing palladium-catalyzed transmetallation, such as boronic acid, boron ester, or. Represents trialkylstannan, etc .; the other of M or M'represents a functional group capable of undergoing palladium-catalyzed oxidative addition, such as iodide, bromide, chloride, or trifluoromethanesulfonate; Ar. Represents an aromatic or heteroaromatic ring system; and L represents a linker. When the reaction is a nucleophilic substitution reaction, X represents a suitable leaving group, such as p-toluenesulfonic acid, methanesulphonate, iodide, bromide, or chloride; the reaction is a Mitsunobu reaction, X is OH. The compound of formula XXXVI is then subjected to palladium-catalyzed cross-linking conditions, such as a suitable palladium catalyst such as bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II), a suitable base such as cesium fluoride. Further conversion by reaction with compound I at a suitable temperature, such as 100 ° C., with or without microwave irradiation, using a suitable solvent such as a mixture of 1,4-dioxane and water. , Can produce compounds of formula XXXVII.

Scheme 12B

Compounds of formula XXXIV may be reacted with reagent XXXV (commercially available or readily prepared using standard reaction techniques known to those of skill in the art) to prepare compounds of formula XXXVI. In all cases, M represents a functional group capable of undergoing palladium-catalyzed transmetallation, such as boronic acid, boron ester, or trialkylstannan; or M.
Represents a functional group capable of undergoing a palladium-catalyzed oxidative addition, such as iodide, bromide, chloride, or trifluoromethanesulfonate; Ar represents an aromatic or heteroaromatic ring system; L represents an aromatic or heteroaromatic ring system. Represents a linker; R represents any one or more substituents; and R'
And R "are both carboxylic acid esters such as CO ₂ CH ₂ CH ₃ , R is a carboxylic acid ester such as CO ₂ CH ₃ , and R'is CN, or R and R'are both. Form one of the following:

In the equation, Y is _{either CH 2} or C = O.
In some examples, X is a primary or secondary amine optionally cyclized to a 4- to 8-membered heterocycle, Y is a suitable leaving group, such as fluorine or chlorine, and The reaction conditions are nucleophilic aromatic substitution conditions, such as triethylamine, DMSO, 70 ° C. In these cases, Z is the corresponding secondary or tertiary amine derived from X.
In another example, X is a suitable leaving group, eg, p-toluenesulfonate, methanesulfonate, iodide, bromide, or chloride, Y is OH, and the reaction conditions are sought. Conditions for nuclear substitution, such as potassium carbonate, potassium iodide, DMSO, 60 ° C. In these cases, Z is O.
In another example, X is OH, Y is OH, and the reaction conditions may be Mitsunobu reaction conditions such as triphenylphosphine, diethyl azodicarboxylate, THF. In these cases, Z is O.
Compounds of formula XXXVI may be further converted to compounds of formula XXXVI. When R'is a carboxylic acid ester and R'is CN, the reduction from R'to CHO is, for example, pyridine,
It can be realized by performing treatment with sodium hypophosphate and Raney nickel in a mixed solution of acetic acid and water. Both R'and R'

In the case of forming, for example, by performing solvolysis using sodium hydroxide in an alcoholic solvent and tetrahydrofuran, R'is a carboxylic acid ester and R "is CH ₂ OH.
You may obtain the compound which is. This compound is further oxidized with, for example, manganese dioxide to form R.
You may obtain XXXVI of an equivalent compound in which'is a carboxylic acid ester and R'is CHO. Then, the compound in which R'is a carboxylic acid ester and R'is CHO can be obtained, for example, methanol and dichloromethane. A novel compound of formula XXXVI may be obtained by reacting with 3-aminoglutalimide in the presence of sodium triacetoxyborohydride, diisopropylethylamine, and acetic acid in the formula, where both R'and R'are.

And Y is CH ₂ .
The compound of formula XXXVI is then subjected to palladium-catalyzed cross-linking conditions such as bis (di-tert-butyl (4-tert-butyl) (4-).
Suitable such as 100 ° C with a suitable palladium catalyst such as dimethylaminophenyl) phosphine) dichloropalladium (II), a suitable base such as cesium fluoride, and a suitable solvent such as a mixture of 1,4-dioxane and water. At various temperatures, with or without microwave irradiation
Further conversion by reaction with compound I can result in the compound of formula XXXVII. As used herein, M', Z, and Z'are as specified in Scheme 1B.
If one or both of Z or Z'are protecting groups, the protecting group is removed from compound XXXVII, for example, by treatment with trifluoroacetic acid when Z and / or Z'is t-butoxycarbonyl. Thus, different compounds of formula XXXVII may be obtained, where Z and Z'are H.

If both R'and R'are carboxylic acid esters in compound XXXVII, different compounds XXXVII may be obtained, for example, by hydrolysis with aqueous methanol solution of sodium hydroxide, in the formula R'and R ”is CO ₂ H. The compound is then reacted with 3-aminoglutarimide, (benzotriazole-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate, and diisopropylamine, for example in N, N-dimethylformamide, to formula XXXVII. New compounds of may be obtained, in which both R'and R'are in the formula.

Scheme 13A

The compound of formula I is subjected to palladium-catalyzed cross-linking conditions, for example in a suitable solvent such as [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II), sodium carbonate, 1,4-dioxane / water mixture. The compound of formula XXXIX is reacted with reagent XXXVIII (easily prepared using standard reaction techniques known to those of skill in the art) at appropriate temperatures, such as 100 ° C., with or without microwave heating. Can be generated. One of M or M'represents a functional group capable of undergoing palladium-catalyzed transmetallation, such as boronic acid, boron ester, or trialkylstannan; the other of M or M'is , Palladium-catalyzed, represents a functional group capable of undergoing oxidative addition, such as iodide, bromide, chloride, or trifluoromethanesulfonate; Ar represents an aromatic or heteroaromatic ring system; L represents an aromatic or heteroaromatic ring system. Represents any linker or linker moiety, where PG represents a suitable ester protecting group, such as methyl, ethyl, or t-butyl. The compound of formula XXXIX is a suitable reagent for the removal of PG, for example, when PG is methyl or ethyl, it can be converted to the compound of formula XL by treatment with methanol and sodium hydroxide in water, 40 ° C. .. Compound XL is then subjected to, for example, N-[(dimethylamino) -1H-1,2,3-triazolo- [4,5-b] pyridin-1-ylmethylene] -N-hexafluorophosphorus under amide forming conditions. Methylmethane aminium acid N-oxide, diisopropylethylamine, DMF, room temperature, etc., are reacted with compound XLI (where Z is any substituent, eg H, methyl, or hydroxymethyl), formula XLII. Can produce the compound of.

Scheme 13B

The compound of formula I'is in a suitable solvent such as palladium-catalyzed cross-linking conditions such as [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II), sodium carbonate, 1,4-dioxane / water mixture. , 100 ° C., with or without microwave heating, and reaction with reagent XXXVIII (easily prepared using standard reaction techniques known to those of skill in the art) of formula XXXIX. Can produce compounds. One of M or M'represents a functional group capable of undergoing palladium-catalyzed transmetallation, such as boronic acid, boron ester, or trialkylstannan; the other of M or M'is Represents a functional group capable of undergoing palladium-catalyzed oxidative addition, such as iodide, bromide, chloride, or trifluoromethanesulfonate; Ar represents an aromatic or heteroaromatic ring system; L represents an aromatic or heteroaromatic ring system. Represents any linker or linker moiety; PG represents a suitable ester protecting group, such as methyl, ethyl, or t-butyl; W represents any protecting group, such as 2- (trimethylsilyl) ethoxymethyl; And the isoxazole of compound XXXVIII and the following structures can have any substituents. The compounds of formula XXXIX can be treated with reagents suitable for the removal of any W, for example, when W is 2- (trimethylsilyl) ethoxymethyl, in 1,4-dioxane and methanol, or in ethylenediamine and tetra. By treatment with hydrogen chloride in -n-butylammonium fluoride; then a suitable reagent for the removal of PG, eg, when PG is methyl or ethyl, in an aqueous methanol solution of sodium hydroxide at 40 ° C. By processing, it may be converted to a compound of formula XL. Compound XL is then subjected to, for example, N-[(dimethylamino) -1H-1,2,3-triazolo- [4,5-b] pyridin-1-ylmethylene] -N-hexafluorophosphorus under amide forming conditions. Methylmethane aminium acid N-oxide, diisopropylethylamine, DMF, room temperature, etc., are reacted with compound XLI (where Z is any substituent, eg H, methyl, or hydroxymethyl), formula XLII. Can produce the compound of. Optionally, as will be apparent to those of skill in the art, the order of the amide coupling and palladium-catalyzed cross-coupling steps may be reversed in the reaction sequence via proper manipulation of M, M'and PG. good.

Scheme 14

Compounds of formula XLIII with reagent XLIV (commercially available or readily prepared using standard reaction techniques known to those of skill in the art) and nucleophilic substitution conditions (eg, cesium carbonate, DMF, 75 ° C.). Can be reacted with to produce compounds of formula XLV. Ar represents an aromatic or heteroaromatic ring system; X represents a suitable leaving group, such as p-toluenesulfonic acid, methanesulphonate, iodide, bromide, or chloride; L is optional. Represents a linker of; and PG represents a suitable ester-protecting group, such as methyl, ethyl, or t-butyl. When the PG is t-butyl, the compound of formula XLV is converted to the compound of formula XLVI by treatment at room temperature with a reagent suitable for removing PG, for example, 3N hydrochloric acid in 1,4-dioxane. sell. Compound XLVI is then added to the compound defined in Scheme 3A or 3B under amide-forming conditions, such as (benzotriazole-1-yloxy) tripyrolidinophosphonium hexafluorophosphate, diisopropylethylamine, DMF, room temperature. It may be reacted with XII to produce a compound of formula XLVII. The compound of formula XLVII can then be treated with the compound of reagent XVIII as defined in Scheme 5 to produce the compound of formula XLVIII. If the group Ar'contains optionally substituents such as ketones, they may be further functionalized and treated with, for example, hydroxylamine hydrochloride and pyridine at room temperature to provide additional compounds of formula XLVIII. ..

Intermediate 1: (3R) -N- [3-([5-bromo-1H-pyrrolo [2,3-b] pyridin-3-yl] carbonyl) -2,4-difluorophenyl] -3-fluoropyrrolidine -1-sulfonamide

Step A: 2,6-difluoro-3-nitrobenzoyl chloride

A 150-mL round bottom flask was charged with 2,6-difluoro-3-nitrobenzoic acid (15.0 g, 73.8 mmol, 1.0 eq), toluene (80 mL) and thionyl chloride (80 mL). The resulting mixture was stirred at 80 ° C. overnight and concentrated under reduced pressure. As a result, 14.1 g (86%) of 2,6-difluoro-3-nitrobenzoyl chloride was obtained as a brown oil.

Step B: 5-bromo-3- [(2,6-difluoro-3-nitrophenyl) carbonyl] -1H-pyrrolo [2,3-b] pyridine

5-Bromo-1H-pyrrolo [2,3-b] pyridine (11.0 g, 55.8 mmol, 1.1 eq) is mixed with 200 mL of chloromethane to give aluminum trichloride (42.0 g, 318.2 mmol, 6.4 eq). Added little by little. The reaction was stirred at room temperature for 1 hour and 2,6-difluoro-3-nitrobenzoyl chloride (11.0 g, 49.6 mmol, 1.0 eq) was added. The reaction was heated overnight at 50 ° C., 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 mixed organic layer was washed with brine (500 mL x 2) and dried over anhydrous sodium sulfate. Concentration of the solvent gives (5-bromo-1H-pyrrolo [2,3-b] pyridin-3-yl) (2,6-difluoro-3-nitrophenyl) methanone (12.2 g) as a yellow solid. It was used directly in the next step without further purification. LCMS (ES ⁺ ): m / z 381.30 [M + H] ⁺ .

Step C: 3-([5-bromo-1H-pyrrolo [2,3-b] pyridin-3-yl] carbonyl) -2,4-difluoroaniline

(5-Bromo-1H-pyrrolo [2,3-b] pyridine-3-yl) (2,6-difluoro-3-nitrophenyl) methanone (7.8 g, 20.4 mmol, 1.0 eq), iron (5.6 g, A mixture of 100.2 mmol (4.9 eq), ammonium chloride (3.6 g, 68 mmol), hydrochloric acid (25.0 mL) in ethanol (40 mL) and tetrahydrofuran (40 mL) was refluxed overnight. After cooling to room temperature, the mixture was filtered through a pad of Celite. The filtrate is concentrated in vacuo and the residue is purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1/2) (3-amino-2,6-difluorophenyl) (5-bromo). -1H-Pyrrolo [2,3-b] pyridine-3-yl) metanone (4.3 g, 60% yield) was obtained as a yellow solid. LCMS (ES ⁺ ): m / z 351.80 [M + H] ⁺ .

Step D: (R) -3-fluoropyrrolidine-1-sulfonyl chloride

The oven-dried flask was filled with (R) -3-fluoropyrrolidine hydrochloride (3.0 g, 24 mmol), triethylamine (7.2 g, 72 mmol) and dichloromethane (150 mL). The mixture was stirred at room temperature for 15 minutes and then cooled in a dry ice / acetonitrile bath to about -30 ° C for 10 minutes. Sulfuryl chloride (6.0 g, 48 mmol) was added dropwise over 10 minutes. Approximately -30 reaction mixture
After stirring at ° C. for 1 hour, the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with aqueous HCl (1 N, 70 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (50 mL x 3). Aqueous mixed organic layer
Washed with HCl (1 N, 50 mL) and brine (50 mL) and dried over anhydrous sodium sulfate. Concentration of the solvent gave (R) -3-fluoropyrrolidine-1-sulfonyl chloride (4.5 g) as a white solid, which was used directly in the next step without further purification.

Step E: (3R) -N- [3-([5-bromo-1H-pyrrolo [2,3-b] pyridin-3-yl] carbonyl) -2,4-difluorophenyl] -3-fluoropyrrolidine- 1-Sulfonamide

Pyridine (25.0 g) 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 equivalent) To the solution was added (R) -3-fluoropyrrolidin-1-sulfonyl chloride (4.6 g, 24.60 mmol, 1.08 equivalent) and 4-dimethylaminopyridine (560.0 mg, 4.59 mmol, 0.2 equivalent). The reaction mixture was stirred at 40 ° C. for 12 hours.
The solvent was removed, water (20 mL) was added, the pH was adjusted to pH = 7-8 with aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate (100 mL × 2). The mixed organic layer was washed with brine (50 mL x 2) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel with ethyl acetate / petroleum ether (3: 1) and then (R) -N- (3- (5-bromo-1H-). Pyrrolo [2,3-b] pyridine-3-carbonyl) -2,4-difluorophenyl) -3-fluoropyrrolidin-1-sulfonamide (6.4 g) was obtained as a yellow solid. LCMS (ES ⁺ ): m / z 505.05 [M + H] ⁺ .

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

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
(R) -N- (3- (5-bromo-1H-pyrrolo [2,3-b] pyridin-3-carbonyl) -2,4-difluorophenyl) -3-fluoropyrrolidin-1-sulfonamide (1.0) KOAc (392.0 mg, 4.0 mmol), Pd (dppf) Cl ₂ (163.0 mg, 0.2 mmol), and 4,4,4', 4', 5, in a 1,4-dioxane solution of g, 2.0 mmol). 5,5', 5'-octamethyl-2,2'-bi (1,3,2-dioxaborolane) (1.02 g, 4.0 mmol) was added in succession. The resulting solution was _{heated under N 2} at 90 ° C. overnight. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was eluted on silica gel with ethyl acetate / petroleum ether (1: 1) and purified by column chromatography. As a result, 551.0 mg (50%) (R) -N- (2,4-difluoro-3- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)) ) -1H-pyrrolo [2,3-b] pyridin-3-carbonyl) phenyl) -3-fluoropyrrolidine-1-sulfonamide was obtained as a light brown solid. LCMS (ES ⁺ ): m / z 551.15 [M + H] ⁺ .

Intermediate 3: N- (3- [5-bromo-1H-pyrrolo [2,3-b] pyridin-3-carbonyl] -2,4-difluoro
Phenyl) -2- (dimethylamino) ethane-1-sulfonamide

Step A: N- (3- [5-bromo-1H-pyrrolo [2,3-b] pyridin-3-carbonyl] -2,4-difluorof
Enil) Ethane-1-sulfonamide

In a 100 mL round bottom flask, 3- [5-bromo-1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoroaniline (500 mg, 1.42 mmol, 1 eq), pyridine (20 mL, 248.47 mmol, 174.99 eq), DMAP (35 mg, 0.29 mmol, 0.20 eq), ethenesulfonyl chloride (360 mg, 2.84 mmol, 2.00 eq), dichloromethane (20 mL) were added. The resulting solution was stirred at room temperature for 0.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was applied on a silica gel column and eluted with ethyl acetate / petroleum ether (1: 1). As a result, 300 mg (48%) of N- (3- [5-bromo-1H-pyrrolo [2,3-b] pyridin-3-carbonyl] -2,4-difluorophenyl) ethen-1-sulfonamide Was obtained as a white solid. LCMS (ES ⁺ ): m / z 443.80 [M + H] ⁺ .

Step B: N- (3- [5-bromo-1H-pyrrolo [2,3-b] pyridin-3-carbonyl] -2,4-difluorof
Enyl) -2- (dimethylamino) ethane-1-sulfonamide

In a 100 mL round bottom flask, N- (3- [5-bromo-1H-pyrrolo [2,3-b] pyridin-3-carbonyl] -2,4-difluorophenyl) ethen-1-sulfonamide (300) mg, 0.68 mmol, 1 equivalent), dichloromethane (20 mL), dimethylamine (2.0 mL) were added. The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. As a result, 360 mg (crude) N- (3- [5-bromo-1H-pyrrolo [2,3-b] pyridin-3-carbonyl] -2,4-difluorophenyl) -2- (dimethylamino) Ethane-1-sulfonamide was obtained as a white solid. LCMS (ES ⁺ ): m / z 488.85 [M + H] ⁺ .

Intermediate 4: N- (3- [5-bromo-1H-pyrrolo [2,3-b] pyridin-3-carbonyl] -2,4-difluoro
Phenyl) -2,3-dihydroxypropane-1-sulfonamide

Step A: N- (3- [5-bromo-1H-pyrrolo [2,3-b] pyridin-3-carbonyl] -2,4-difluorof
Enil) Propal-2-en-1-sulfonamide

In a 25 mL round bottom flask, 3- [5-bromo-1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoroaniline (500 mg, 1.42 mmol, 1 eq), pyridine (2 mL, 15 eq), prop-2-en-1-sulfonyl chloride (399.2 mg, 2.84 mmol, 2 eq), DMAP (52.0 mg, 0.43 mmol, 0.3 eq) were added. The resulting solution was stirred in an oil bath at 45 ° C. overnight. The resulting mixture was concentrated. The residue was applied on a silica gel column and eluted with ethyl acetate / petroleum ether (1/1). As a result, 480 mg (74%) of N- (3- [5-bromo-1H-pyrrolo [2,3-b] pyridin-3-carbonyl] -2,4-difluorophenyl) prop-2-ene- 1-Sulfonamide was obtained as a yellow solid.

Step B: N- (3- [5-bromo-1H-pyrrolo [2,3-b] pyridin-3-carbonyl] -2,4-difluorof
Enyl) -2,3-dihydroxypropane-1-sulfonamide

In a 50 mL round bottom flask, N- (3- [5-bromo-1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluorophenyl) prop-2-en-1- Sulfonamide (430 mg, 0.94 mmol, 1 equivalent), acetone (20 mL), N-methylmorpholine N-oxide (226 mg), water (5 mL), tetraoxoosmium (4 mL) were added. The resulting solution was stirred at room temperature overnight. The reaction was then stopped by the addition of water (20 mL). The resulting solution was extracted with ethyl acetate (30 mL x 3). The resulting mixture was washed with brine (20 mL x 1), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied on a silica gel column and eluted with ethyl acetate / petroleum ether (1/1). As a result, 377 mg (82%) of N- (3- [5-bromo-1H-pyrrolo [2,3-b] pyridin-3-carbonyl] -2,4-difluorophenyl) -2,3-dihydroxy Propane-1-sulfonamide was obtained as a white solid.

Intermediate 5: (R) -N- (3- (5-bromo-1H-pyrrolo [2,3-b] pyridin-3-carbonyl) -2,4-diflu
Orophenyl) -3-fluoropyrrolidine-1-carboxamide

(3-Amino-2,6-difluorophenyl) (5-bromo-1H-pyrrolo [2,3-b] pyridine-3-yl) methanone (2.0 g, 5.70 mmol, 1.00 eq), triethylamine (8.6 g, To a solution of 85.5 mmol, 15.00 eq) in dichloromethane (80 mL), gradually add a solution of bis (trichloromethyl) carbonate (2.5 g, 8.55 mmol, 1.50 eq) in dichloromethane (40 mL), followed by (R)-. A solution of 3-fluoropyrrolidin (761.0 mg, 8.55 mmol, 1.50 eq) in dichloromethane (40 mL) was added dropwise at 0 ° C. The resulting solution was stirred at 0 ° C. for 30 minutes in a water / ice bath. The resulting solution was quenched with an aqueous solution of ammonium chloride (40 mL) and extracted with dichloromethane (40 mL x 2). Then, the organic layers were combined and concentrated. The residue was applied on a silica gel column with chloroform / methanol (10: 1). As a result, 541.0 mg (20%) of (R) -N- (3- (5-bromo-1H-pyrrolo [2,3-b] pyridin-3-carbonyl) -2,4-difluorophenyl) -3 -Fluoropyrrolidine-1-carboxamide was obtained as a tan solid. LCMS (ES ⁺ ): m / z 467.10 [M + H] ⁺ .

Scheme 15

A compound of formula XLIX (which is readily prepared using standard reaction methods known to those of skill in the art) may be reacted with the compound of formula.

The compound of formula XLIX may be reacted with reagent XLIV under nucleophilic substitution conditions such as diisopropylethylamine, potassium iodide, acetonitrile and 100 ° C. to produce the compound of formula L. L'represents any linker or linker moiety; Nu-H, for example,
Represents a suitable leaving group such as an alcohol or a secondary amine; X represents a suitable leaving group, such as p-toluenesulfonic acid, methanesulphonate, iodide, bromide, or chloride; L is optional. Represents a linker of; and PG represents a suitable ester protecting group, such as methyl, ethyl, or t-butyl. When the PG is t-butyl, the compound of formula L may be converted to the compound of formula LI by treating with a reagent suitable for removing PG, for example, trifluoroacetic acid, dichloromethane, 30 ° C., etc. .. Compound LI is then reacted with compound XII as defined in Scheme 3A or 3B under amide-forming conditions such as 1-ethyl-3 (3-dimethylaminopropyl) carbodiimide, 1-hydroxybenzotriazole, triethylamine, DMF. , 30 ° C. may produce compounds of formula LII.

Scheme 16

The compound of formula XLIX specified in Scheme 15 may be reacted with compound V to form compound LIII, where L represents any linker or linker moiety and Y represents CH ₂ or C =. O, where X is either a suitable leaving group (eg, OMs, OTs, Cl, etc.) or an aldehyde (CHO); R is any substituent (eg, F or OCH ₃ ); And W are:
If Y is C = O

When X is a leaving group, n is 0, Nu-H is a primary or secondary amine or alcohol, and suitable reaction conditions are conditions for the alkylation reaction, such as potassium carbonate, etc.
DMF, 70 ° C. When X is an aldehyde, n is 1, Nu-H is a primary or secondary amine, and suitable reaction conditions are conditions for a reductive amination reaction, such as sodium cyanoborohydride, methanol, dichloromethane, etc. Acetic acid, room temperature. Nu-H and V in XLIX
'The position of X in'may also be reversed, thereby it will be apparent to those skilled in the art that the positions of _{Nu and (CH 2} ) _{n are reversed in compound LIII.} Compounds of formula LIII in which W is in the open form are those of formula LIII.
W may be further converted to another compound of the formula, where W is glutarimide by cyclization under suitable conditions such as benzenesulfonic acid, acetonitrile, 100 ° C. and the like.

Scheme 17

Compounds of formula LIV (prepared using standard conditions known to those of skill in the art, similar to the synthesis of compound III of scheme 1A or 1B) were added to the compound of formula LV (compound XV of scheme 2). (Prepared using similar standard conditions known to those of skill in the art) and under reductive amination conditions, such as sodium triacetoxyborohydride, triethylamine, dichloroethane, 30 ° C. The compound of the formula LVI may be produced. As used herein, Ar is an aromatic or heteroaromatic ring system; L and L'are any linker or linker moiety; X is H or any substituent, which are optional. May be cyclized to L to form a ring;

Scheme 18

Compounds of formula LIV (prepared using standard conditions known to those of skill in the art, similar to the synthesis of compound III of scheme 1A or 1B) were combined with compounds of formula LVII (standards known to those of skill in the art). (Prepared using conditions) and under reductive amination conditions, such as sodium triacetoxyborohydride, acetic acid, dichloroethane, methanol, 30 ° C. to produce the compound of formula LVIII. You may. As used herein, Ar is an aromatic or heteroaromatic ring system; L and L'are any linker or linker moiety; X is H or any substituent, which are optional. May be cyclized to L to form a ring;

Synthesis example of compound 86

Step A: (R) -tert-butyl 4-(4- (3- (2,6-difluoro-3- (3-fluoropyrrolidin-1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] ] Pyridine-5-yl) phenyl) piperazine-1-cal
Bonate

(R) -N- (3- (5-bromo-1H-pyrrolo [2,3-b] pyridine-3-carbonyl) -2,4-difluorophenyl) -3-fluoropyrrolidin-1-sulfonamide (0.50) In a 1,4-dioxane / H ₂ O (20 mL / 2 mL) solution of g, 1.0 mmol), 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) in an argon atmosphere. Added below. 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 x 3) and the mixed organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification of the crude product with silica gel (sulfone / methanol = 12: 1) results in compound (R) -tert-butyl 4-(4- (3- (2,6-difluoro-3- (3-fluoropyrrolidin-1)). -Sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-carboxylate (0.39 g, 57%) was obtained 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, brs.), 8.66 (1H, d, J = 2.4 Hz), 9.87 (1H, 1H, s), 12.93 (1H, s).
Step B: (R) -N- (2,4-difluoro-3- (5- (4- (piperazine-1-yl) phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl) Phenyl) -3-fluoropyrrolidine-1-sulfonamide

(R) -tert-butyl 4-(4- (3- (2,6-difluoro-3- (3-fluoropyrrolidin-1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridine- A solution of 5-yl) phenyl) piperazine-1-carboxylate (0.39 g, 0.57 mmol) in hydrochloric acid / 1,4-dioxane (5 mL, 4.0 N) was stirred at room temperature for 3 hours. The solvent was then removed directly, then water (10 mL) was added and the pH of the mixture was adjusted to 8-9 with saturated sodium bicarbonate. The aqueous phase was extracted with ethyl acetate (10 mL x 3), the mixed organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give (R) -N- (2,4-difluoro-3). -(5- (4- (Piperazine-1-yl) phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl) phenyl) -3-fluoropyrrolidin-1-sulfonamide (0.30 g, 91) %) Was obtained as a yellow solid.

Step C: 2- (2-Chloroethoxy) ethyl 4-methylbenzenesulfonate

Stir 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) overnight at room temperature. did. Pour the mixture into saturated sodium bicarbonate solution (20 mL) and dichloromethane (20).
Extracted with mL × 3). When the mixed organic phase is concentrated in vacuum and the residue is purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10/1), 2- (2-chloroethoxy) ethyl 4-methylbenzenesulfonic acid Salt (0.9 g, 80% yield) was obtained as a colorless oil. LCMS: m / z 279.1 [M + H] ⁺ .

Step D: 5- (2- (2-chloroethoxy) ethoxy) -2- (2,6-dioxopiperidine-3-yl) iso
Indoline-1,3-Zeon

2- (2-Chloroethoxy) ethyl 4-methylbenzenesulfonate (100 mg, 0.36 mmol), 2- (2,6-dioxopiperidine-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) of the mixture in dimethyl sulfoxide (5 mL) was heated at 45 ° C. for 2 hours and cooled to room temperature. The reaction mixture was poured into water (10 mL) and extracted with dichloromethane (15 mL x 3). The mixed organic phase is concentrated in vacuo and the residue is silica gel (dichloromethane / methanol =
When purified by column chromatography on 20/1), 5- (2- (2-chloroethoxy) ethoxy)
-2- (2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione (48 mg, 35% yield) was obtained as a white solid. LCMS: m / z 381.2 [M + H] ⁺ .

Step E: (3R) -N- (3- (5- (4- (4- (2- (2- (2- (2- (2,6-dioxopiperidine-3-yl))-1,3-dioki)
Soisoindoline-5-yloxy) ethoxy) ethyl) piperazine-1-yl) phenyl) -1H-pi
Lolo [2,3-b] Pyridine-3-carbonyl) -2,4-difluorophenyl) -3-fluoropyrrolidine-1-sulfonamide

5- (2- (2-Chloroethoxy) ethoxy) -2- (2,6-dioxopiperidine-3-yl) isoindrin-1,3-dione (40 mg, 0.11 mmol), (R) -N -(2,4-difluoro-3-(5-(4- (piperazine-1-yl) phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl) phenyl) -3-fluoropyrrolidine- A mixture of 1-sulfonamide (61 mg, 0.11 mmol), ethyldiisopropylamine (28 mg, 0.22 mmol) and potassium iodide (18 mg, 0.11 mmol) in dimethylsulfoxide (5 mL) overnight at 80 ° C. Heated. Pour the mixture into water (10 ml) and dichloromethane (10 mL x 3)
Extracted with. When the organic phase is concentrated in vacuum and the residue is purified by pre-HPLC, (3R) -N- (3- (5- (4- (4- (2- (2- (2- (2,6) 2- (2,6) -Dioxopiperidine-3-yl) -1,3-dioxoisoindoline-5-yloxy) ethoxy) ethyl) piperazine-1-yl) phenyl) -1H-pyrrolo [2,3-b] pyridine-3- Carbonyl) -2,4-difluorophenyl) -3-fluoropyrrolidine-1-sulfonamide (31 mg, 30% yield) was obtained as a yellow solid. LCMS: m / z 929.3 [M + H] +; 1H NMR (400 MHz, DMSO-d6) 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, brs), 11.1 (1H) , s), 12.9 (1H, s).
Compounds 87-90 can be prepared in a similar fashion.

Synthesis example of compound 91

Step A: 2- (2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy) ethoxy) ethanol

4- (4,4,5,5-Tetramethyl-1,3,2-) in a solution of 2- (2-chloroethoxy) ethanol (2.0 g, 16.1 mmol) in N, N-dimethylformamide (15.0 mL). 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) were added. The reaction mixture was stirred at 60 ° C. overnight. Water (50 mL) was then added, extracted with ethyl acetate (50 mL x 3) and washed with brine (5 mL x 4). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Residue on silica gel (
Purification with petroleum ether / ethyl acetate = 2: 1), 2- (2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy) ethoxy) Ethanol (2.1 g, 42%) was obtained as a yellow oil. 1H NMR (400 MHz, DMSO-d6) 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).
Step B: 2- (2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy) ethoxy) ethylmethane sulfonate

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) Triethylamine (231 mg, 2.28 mmol) and methanesulfonyl chloride (157 mg, 1.37 mmol) were added to the solution under nitrogen. The resulting reaction mixture was stirred at room temperature for 1 hour. Then add an aqueous solution of sodium hydrogen carbonate (20.0 mL), extract with dichloromethane (20 mL x 3), wash with brine, dry and concentrate in vacuum to give a crude 2- (2- (4- (4,,,) 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy) ethoxy) ethyl methanesulfonate is obtained as a yellow oil, which can be used in the next step without further purification. did. LCMS: m / z 404.2 [M + 18] ⁺
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

2- (2- (4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy) ethoxy) ethylmethane sulfonate (1.14 mmol) acetonitrile (20 mL) ) Solution was added potassium carbonate (315 mg, 2.28 mmol) and tert-butyl piperazine-1-carboxylate (234 mg, 1.25 mmol). The resulting reaction mixture was stirred at 80 ° C. overnight. The solvent was concentrated in vacuo. The residue was extracted with ethyl acetate (20 mL x 3) and water (20 mL). Dry the organic layer and
Concentrated in vacuum. Purification of the residue with preparative TLC (petroleum ether / ethyl acetate = 1: 2) results in tert-butyl 4-(2- (2- (4- (4,4,5,5-tetramethyl-1,3)). , 2-Dioxaborolan-2-yl) phenoxy) ethoxy) ethyl) piperazin-1-carboxylate (280 mg, 52% for two steps) was obtained as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) 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).
Step D: (R) -tert-butyl 4-(2- (2- (4- (3- (2,6-difluoro-3- (3-fluoropyrrolidin-1-sulfonamide) benzoyl))-1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenoxy) ethoxy) Ethyl) Piperazine-1-carboxylate

tert-butyl 4-(2- (2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy) ethoxy) ethyl) piperazine-1-carboxylic acid In a 1,4-dioxane / water (10 mL / 1 mL) solution of salt (114 mg, 0.238 mmol), (R) -N- (3- (5-bromo-1H-pyrrolo [2,3-b]] Ppyridine-3-carbonyl) -2,4-difluorophenyl) -3-fluoropyrrolidin-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) was added. 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 x 3). The organic layer was dried and concentrated in vacuo. Purification of the residue with preparative TLC (dichloromethane / methanol = 20: 1) results in (R) -tert-butyl 4-(2- (2- (4- (3- (2,6-difluoro-3-)). 3-Fluoropyrrolidine-1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenoxy) ethoxy) ethyl) piperazine-1-carboxylate (60 mg, 33%) Obtained as a pale yellow solid. LCMS: m / z 773.3 [M + H] ⁺ .

Step E: (R) -N- (2,4-difluoro-3- (5- (4- (2- (2- (piperazine-1-yl) ethoxy) ethoki)
Phenyl) -1H-pyrrolo [2,3-b] pyridin-3-carbonyl) phenyl) -3-fluoropyrrolid
N-1-sulfonamide hydrochloride

(R) -tert-butyl 4-(2- (2- (4- (3- (2,6-difluoro-3- (3-fluoropyrrolidin-1-sulfonamide) benzoyl))-1H-pyrrolo [2, 3-b] Pylidyl-5-yl) phenoxy) ethoxy) ethyl) piperazine-1-carboxylate (60 mg, 0.0517 mmol) in hydrochloric acid / 1,4-dioxane (5 mL, 4 M) at room temperature 1 Stirred for hours. When the solvent is concentrated in vacuo, compound (R) -N- (2,4-difluoro-3-(5-(4-(2-(2- (piperazin-1-yl) ethoxy) ethoxy) phenyl)- 1H-Pyrrolidine [2,3-b] Pyridine-3-carbonyl) Phenyl) -3-fluoropyrrolidine-1-sulfonamide hydrochloride is obtained as a pale yellow solid, which is the next step without further purification. Used in. LCMS: m / z 673.2 [M + H] ⁺ .

Step F: (3R) -N- (3- (5- (4- (2- (2- (2- (2- (2- (2- (2,6-dioxopiperidine-3-yl))-1,3-dioki)
Soisoindoline-5-yl) piperazine-1-yl) ethoxy) ethoxy) phenyl) -1H-pyrrolo [2,3-b] pyridin-3-carbonyl) -2,4-difluorophenyl) -3-fluoropyrrolidine- 1-Sulfonamide

(R) -N- (2,4-difluoro-3- (5-(4- (2- (2- (piperazine-1-yl) ethoxy) ethoxy) phenyl) -1H-pyrrolo [2,3-b ] Pyridine-3-carbonyl) Phenyl) -3-fluoropyrrolidine-1-sulfonamide In a solution of hydrochloride (0.0517 mmol) in dimethyl sulfoxide (3 mL), 2- (2,6-dioxopiperidine-3-yl) -5-Fluoroisoindrin-1,3-dione (14.3 mg, 0.0517 mmol) and triethylamine (10.5 mg, 0.104 mmol) were added. The reaction mixture was stirred at 70 ° C. for 24 hours. After cooling to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10.0 mL × 3).
The mixed organic phase was washed with brine (2.0 mL x 4), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. When the residue was purified twice by preparative TLC (dichloromethane / methanol = 20: 1), (3R) -N- (3- (5- (4- (2- (2- (4- (2- (2- (2)) , 6-dioxopiperidine-3-yl) -1,3-dioxoisoindoline-5-yl) piperazine-1-yl) ethoxy) ethoxy) phenyl) -1H-pyrrolo [2,3-b] pyridin- 3-carbonyl) -2,4-difluorophenyl) -3-fluoropyrrolidine-1-
Sulfonamide (6.7 mg, 14%) was obtained as a yellow solid. LCMS: m / z 929.3 [M + H] +.
1H NMR (400 MHz, DMSO-d6) 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, brs), 8.66 (1H, d, J = 2.4 Hz), 9.88 (1H, s), 11.09 (1H, s), 12.95 (1H, s).
Compounds 92-97 can be prepared in a similar fashion.

Synthesis example of compound 99

Step A: tert-butyl 4- (4-bromophenyl) piperazine-1-carboxylate

Toluene (100 mL) solution of 1,4-dibromobenzene (5.0 g, 21.2 mmol), tert-butyl piperazine-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 BINAP (485 mg, 0.53 mmol) were added. The resulting solution was stirred at 90 ° C. for 3 hours in _{an N 2 atmosphere.} After cooling to room temperature, the reaction was _{quenched with H 2} O (50 mL) and the mixture was extracted with EA. The mixed organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue on silica gel gave the desired product (1.2 g, 17% yield) as a white solid. 1H NMR (400 MHz, CDCl3): 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).
Step B: tert-butyl 4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-1-carboxylate

4,4,4', 4', 5, in a 1,4-dioxane (24 mL) solution of tert-butyl 4- (4-bromophenyl) piperazine-1-carboxylate (1.2 g, 3.53 mmol) 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) was added. The resulting solution was _{stirred under N 2} atmosphere at 90 ° C. overnight. TLC
Indicates that the reaction is complete. After cooling to room temperature, the reaction was diluted with 50 mL EA and the mixture was washed with water and brine. The organic phase was dried over anhydrous sodium sulfate. Purification of the residue on a chromatographic column gave the desired product (1.0 g, 73% yield). LCMS (ES ⁺ ): m / z 48 2.0.

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

DCM 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) TFA (1.5 mL, 20.2 mmol) was added to the (5 mL) solution. The resulting solution was stirred at 5 ° C. for 2 hours. Removal of the solvent under vacuum gave a residue (547 mg, calculated), which was used directly in the next step. Residue (547
In a dehydrated DMF (5 mL) solution of mg, 1.42 mmol), K ₂ CO ₃ (977 mg, 7.08 mmol), KI (470 mg, 2.83 mmol) and tert-butyl 2- (2-chloroethoxy) acetate (2-chloroethoxy) acetate ( 550 mg (2.83 mmol) was added. The resulting solution was stirred at 90 ° C. for 3 hours. After cooling to room temperature, the reaction was quenched with 20 mL of saturated NaCl solution and the mixture was extracted twice with EA. The mixed organic layer was concentrated in vacuo and the residue was purified on silica gel to give the desired product (300 mg, 47% yield in 2 steps) as an oil. 1H NMR (400 MHz, CDCl3): 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).
Step D: (R) -tert-butyl 2- (2- (4- (4- (3- (2,6-difluoro-3- (3-fluoropyrrolidin-1-sulfonamide) benzoyl))-1H-pyrrolo [2,3-b] Pyridine-5-yl) phenyl) piperazine-1-yl) ethoxy) acetate

tert-Butyl 2- (2- (4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-1-yl) ethoxy) acetate (100 mg, 0.20 mmol) 1,4-dioxane / H ₂ O
In a (10 ml / 1 mL) solution, (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) were added.
The resulting solution was _{stirred under N 2} atmosphere at 95 ° C. for 3 hours. TLC showed that the reaction was complete. After cooling to room temperature, the reaction was diluted with 50 mL EA and the mixture was washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue on a chromatographic column gave the desired product (100 mg, 66% yield). LCMS (ES ⁺ ): m / z 743.2 [M + H-16] ⁺ .

Step E: (2S, 4R) -1-((S) -2- (2- (2- (4- (4- (4- (3- (2,6-difluoro-3- ((R) -3-fluoro) Pyrrolidine-1-sulfonamide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Pipe
Radin-1-yl) ethoxy) acetamide) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide

(R) -tert-butyl 2- (2- (4- (4- (3- (2,6-difluoro-3- (3-fluoropyrrolidin-1-sulfonamide) benzoyl))-1H-pyrrolo [2, 3-b] pyridine-5-yl) phenyl) piperazine-1-yl) ethoxy) acetate compound and methanol (100 mg, 0.13 mmol) in a 1,4-dioxane (2 mL) solution in HCl (g) , 1,4-Dioxane (1 mL, 8 M) was added. The resulting solution was stirred at 50 ° C. for 3 hours. TLC showed that the reaction was complete. After cooling to room temperature, the reaction mixture was concentrated to give a crude product (93 mg, 100% yield, calculated), which was used in the next reaction. In a dehydrated NMP (5 mL) solution of crude product (93 mg, 0.13 mmol), (2S, 4R) -N- (4- (4-methylthiazole-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 PyBOP (203 mg, 0.39 mmol) Continued to add. The resulting solution was stirred at 10 ° C. for 1 hour. The reaction was then quenched with brine (20 mL) and the mixture was extracted twice with EA. The organic layer was concentrated and the residue was purified by silica gel and preparative HPLC to give the desired product (39 mg, 27% yield in two steps) as a yellow solid. 1H NMR (400 MHz, CD3OD): 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] +.
Compounds 98, 100 to 101, 102, 103 to 106, and 223 to 252 can be prepared in a similar manner.

Synthesis example of compound 114

Step A: 1- (azetidine-3-yl) -4- (4-bromophenyl) piperazine hydrochloride

_{KOAc (1.4 g, 14.4 mmol) and catalytic amount in CH 3} OH / DCM (v / v = 1/1, 30 mL) solution of 1- (4-bromophenyl) piperazine hydrochloride (2.0 g, 7.21 mmol). AcOH (0.1 mL) was added at room temperature. 30
After stirring for minutes, NabH (OAc) ₃ (7.6 g, 36.1 mmol). The mixture was stirred at 30 ° C. overnight. The reaction was _{quenched with 3} aqueous NaHCO 3 (50 mL) and the mixture was extracted with DCM (100 mL x 2). The mixed organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to give the desired crude product (2.5 g) as a light brown solid, which was obtained. Used in the next step without further purification. _{HCl (g) / CH 3} OH (10 mL) was added to a solution of the above intermediate in methanol (20 mL). The resulting solution was stirred at room temperature for 2 hours. The solvent was removed under vacuum. The residue was pulverized with DCM and filtered to give the desired product 1- (azetidine-3-yl) -4- (4-bromophenyl) piperazine hydrochloride (2.0 g) as a brown solid. rice field.

Step B: Ethyl 2- (3- (4- (4-bromophenyl) piperazine-1-yl) azetidine-1-yl) vinegar
Acid salt

_{KOAc in CH 3} OH / DCM (v / v = 1/1, 10 mL) solution of 1- (azetidine-3-yl) -4- (4-bromophenyl) piperazine hydrochloride (2.0 g, 6.01 mmol) (1.2 g, 12.1 mmol) and a catalytic amount of AcOH (0.1 mL) were added at room temperature. After stirring for 30 minutes, NaBH (OAc) ₃ (6.3 g, 30.1 mmol). Mixture at 30 ° C
Stird overnight. The reaction was _{quenched with NaHCO 3} (30 mL) aqueous solution and then the mixture was extracted with DCM (50 mLx3). The mixed organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give the desired product, ethyl 2- (3- (4- (4-bromophenyl) piperazine-). 1-Il) Azetidine-1-yl) acetate (1.0 g, crude) was obtained 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] ⁺ .
Step C: Methyl 2- (3- (4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-1-yl) azetidine-1 -Il) Acetate

Ethyl 2- (3- (4- (4-bromophenyl) piperazine-1-yl) azetidine-1-yl) acetate (1.0 g, crude) in methanol (20 mL) solution in HCl (g) / CH ₃ OH (10 mL) was added. The resulting solution was stirred at 60 ° C. for 2 hours. The solvent was removed under vacuum. The residue was dissolved in DCM (100 mL) and the mixture was washed with NaHCO ₃ (30 mL x 3). The organic phase was concentrated under vacuum. The residue (500 mg) was used in the next reaction without further purification. _{KOAc (267 mg, 2.8 mmol), Pd (dppf) Cl 2} (190 mg, 0.14 mmol), 4,4, in a 1,4-dioxane (20 mL) solution of the above intermediate (500 mg, 1.4 mmol). Add 5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolan (700 mg, 2.8 mmol) rice field. 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 was dissolved in EtOAc. The organic phase was concentrated under vacuum. Purification of the residue on silica gel with PE / EA (10 to 1/1) yields the desired product methyl 2- (3- (4- (4- (4,4,5,5-tetramethyl-1)). , 3,2-Dioxaborolan-2-yl) phenyl) piperazine-1-yl) azetidine-1-yl) acetate (300 mg) was obtained as a brown solid. LCMS (ES ⁺ ): m / z 416.3 [M + H] ⁺ .

Step D: (2S, 4R) -N- (4- (4-Methylthiazole-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) piperazine-1-yl) azetidine-1-yl) acetamide) butanoyl) -4-hydroxy Pyrrolidine-2-carboxamide

Methyl 2- (3- (4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-1-yl) azetidine-1-yl) LiOH (34 mg, 1.5 mmol) was added to a solution of acetate (300 mg, 0.72 mmol) in H _{2 O / THF (v / v = 1/5, 5 mL).} The resulting solution was stirred at room temperature for 1 hour. The solvent was then removed under vacuum. The residue was used in the next reaction without further purification. DIEA (300 mg, 2.2 mmol), (2S, 4R) -N- (4- (4-methylthiazole-5-yl) benzyl) -1-((S) in a DMF (5.0 mL) solution of the above intermediate. ) -2-Amino-3,3-dimethylbutanoyl) -4-hydroxypyrrolidine-2-carboxamide hydrochloride (338 mg, 0.72 mmol) and PyBOP (564 mg, 1.1 mmol) were added at room temperature. The resulting solution was stirred at 20 ° C. for 2 hours. The reaction was _{quenched with H 2} O (10 mL) and the mixture was extracted with EtOAc (20 mL × 3). The mixed organic layer was concentrated under vacuum. Preparative TLC purification of the residue with DCM / CH ₃ OH (20/1) yields the desired product (2S, 4R) -1-((S) -3,3-dimethyl-2- (2-). (3- (4- (4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-1-yl) azetidine-1-yl) acetamide) butanoyl ) -4-Hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide (80 mg) was obtained as a light brown solid. LCMS (ES ⁺ ): m / z 814.4 [M + H] ⁺ .

Step E: (2S, 4R) -N- (4- (4-Methylthiazole-5-yl) benzyl) -1-((S) -2- (2- (3- (4- (4- (3) -(2,6-difluoro-3-((R) -3-fluoropyrrolidin-1-sulfonamide) benzoyl) -1H-
Pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperazine-1-yl) Azetidine-1-yl) Acetamide) -3,3-dimethylbutanoyl) -4-Hydroxypyrrolidine-2-carboxamide

(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) azetidine-1-yl) acetamide) butanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2 _{-CsF (45 mg, 0.29 mmol), Pd (amphos) Cl 2} (in a solution of carbonylxamide (80 mg, 0.098 mmol) in H ₂ O / 1,4-dioxane (v / v = 1/5, 5.0 mL). 8 mg, 0.01 mmol), (R) -N- (3- (5-bromo-1H-pyrrolo [2,3-b] pyridin-3-carbonyl) -2,4-difluorophenyl) -3-fluoropyrrolidin -1-sulfonamide (70 mg, 0.14 mmol) was added at room temperature. 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 was dissolved in EtOAc. The mixed organic layer was concentrated under vacuum. Purification of the residue by preparative TLC with DCM / CH ₃ OH (20/1) yields the desired product (2S, 4R) -1-((S) -2- (2- (3- (4) -(4- (3- (2,6-difluoro-3-(((R) -3-fluoro-pyrrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridine-5 -Il) Phenyl) Piperazin-1-yl) Azetidine-1-yl) Acetamide) -3,3-Dimethylbutanoyl) -4-Hydroxy-N- (4- (4-Methylthiazole-5-yl) benzyl) Pyrrolidine-2-carboxamide (35 mg) was obtained as a pale 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 H) , 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 (br, 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 [MH] +.
Compounds 107-113, 115, 116, and 253-269 can be prepared in a similar manner.

Synthesis example of compound 117

Step A: tert-Butyl 4- (4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazole-1-yl)
Enil) piperazine-1-carboxylate

4- (4-Bromo-1H-pyrazole-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 pyridine (30 mL) of cupric acetate (4.0 g, 22.3 mmol) was stirred at 100 ° C. overnight. The medium mixture is concentrated in vacuo and the residue is purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 5/1) with tert-butyl 4- (4- (4-bromo-3- (pyridine)). -4-yl) -1H-pyrazol-1-yl) phenyl) piperazine-1-carboxylate (10.8 g, 70% yield) was obtained as a brown solid.

Step B: tert-Butyl 4- (4- (4- (1-oxo-2,3-dihydro-1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazol-1-) Il) phenyl) piperazine-1-carboxylate

tert-Butyl 4- (4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenyl)
Piperazin-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 m)
A mixture of mol) 1,4-dioxane / water (20 mL, 10/1) was stirred overnight at 90 ° C. The mixture was poured into water (30 ml) and extracted with dichloromethane (30 mL x 3). The mixed organic phase is concentrated in vacuo and the residue is purified by column chromatography on silica gel (dichloromethane / methanol = 20/1) with tert-butyl 4- (4- (1-oxo-2,,). 3-Dihydro-1H-Inden-5-
Ill) -3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenyl) piperazine-1-carboxylate (1.6 g, 60% yield) was obtained as a yellow solid. LCMS: m / z 536.3 [M + H] ⁺ .

Step C: 5- (1- (4- (Piperazine-1-yl) Phenyl) -3- (Pyrazole-4-yl) -1H-Pyrazole-4-yl) -2,3-Dihydro-1H-Inden- 1-on hydrochloride

tert-Butyl 4- (4- (4- (1-oxo-2,3-dihydro-1H-indene-5-yl) -3- (pyridin-4-yl)
A dehydrated hydrochloric acid / methanol (30 mL, 1.0 M.) solution of -1H-pyrazole-1-yl) phenyl) piperazine-1-carboxylate (1.6 g, 3.0 mmol) was stirred overnight at room temperature. When the reaction mixture is concentrated in vacuo, 5- (1- (4- (piperazine-1-yl) phenyl) -3- (pyridin-4-yl) -1H-pyrazole-4-yl) -2,3- Dihydro-1H-inden-1-one hydrochloride (1.0 g, 80% yield) was obtained as a white solid, which was used directly in the next step without further purification.

Step D: 2- (2,6-dioxopiperidine-3-yl) -5-(4- (4- (4- (1-oxo-2,3-dihydro-1H-inden-5-yl))- 3- (Pyridine-4-yl) -1H-pyrazole-1-yl) phenyl) piperazine-1-yl) isoindoline-1,3-dione

5- (1- (4- (Piperazine-1-yl) phenyl) -3- (pyridin-4-yl) -1H-pyrazol-4-yl) -2,3-dihydro-1H-inden-1-one Hydrochloride (1.0 g, 2.3 mmol), 2- (2,6-dioxopiperidine-3-yl) -5-fluoroisoindoline-1,3-dione (635 mg, 2.3 mmol) and triethylamine (697 mg, The mixture of 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 x 3). When the mixed organic phase is concentrated in vacuo and the residue is purified by column chromatography on silica gel (dichloromethane / methanol = 20/1), 2- (2,6-dioxopiperidine-3-yl) -5- (4- (4- (4- (
1-oxo-2,3-dihydro-1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenyl) piperazine-1-yl) isoindoline-1, 3-Dione (1.1 g, 70% yield) was obtained as a yellow solid. LCMS: m / z 692.3 [M + H] ⁺ .

Step E: (E) -2- (2,6-dioxopiperidine-3-yl) -5-(4- (4- (4- (1- (hydroxyimino) -2,3-dihydro-1H-) Inden-5-yl) -3- (Pyridine-4-yl) -1H-Pyrazole-1-yl) Phenyl) Piperazine-1-yl) Isoindoline-1,3-dione

2- (2,6-dioxopiperidine-3-yl) -5-(4- (4- (4- (1-oxo-2,3-dihydro-1H-inden-5-yl) -3- ( Pyridine-4-yl) -1H-pyrazole-1-yl) phenyl) piperazine-1-yl)
A mixture of isoindoline-1,3-dione (300 mg, 0.43 mmol) and hydroxylamine hydrochloride (300 mg, 4.3 mmol) in pyridine (10 mL) was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo. When the residue is purified by preparative HPLC, (E) -2- (2,6-dioxopiperidine-3-yl) -5-(4- (4- (4- (1- (hydroxyimino) -2) , 3-Dihydro-1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenyl) piperazine-1-yl) isoindoline-1,3-dione (182) mg, yield 60%) was obtained as a yellow solid. LCMS: m / z 707.3 [M + H] +; 1H NMR (400 MHz, DMSO-d6) 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, brs), 3.66 (4H, brs), 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).
Compounds 118-132 and 271 can be prepared in a similar fashion.

Example of synthesis of compound 137

Step A: tert-butyl (2- (4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazole-1-yl))
Enoxy) Ethyl) (Methyl) Carbamic Acid

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- _{Et 2} NH (6.91 g, 94.72 mmol), Cu (OAc) ₂ (1.72 g, 9.47) in a DCM (20 mL) solution of (4-bromo-1H-pyrazol-3-yl) pyridine (2.12 g, 9.47 mmol). mmol) was added. The resulting mixture is cooled to 30 ° C in _{an O 2 atmosphere.}
Was stirred for 16 hours. The mixture was diluted with DCM (30 mL) and then washed 3 times _{with NH 3} · H _{2 O.} The organic phase is evaporated under reduced pressure and the residue is purified by silica gel column chromatography on silica gel (DCM / MeOH = 80/1) with tert-butyl (2- (4- (4-bromo-3- (4- (4-bromo-3- (). Pyridine-4-
Il) -1H-pyrazole-1-yl) phenoxy) ethyl) (methyl) carbamic acid salt (3.0 g, yield 66.9%) was obtained as a brown oil.

Step B: 2- (4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenoxy) -N-
Methylethane-1-amine

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) HCl / dioxane (6 N, 10 mL) was added slowly to the MeOH (6 mL) solution at room temperature. The mixture was stirred at room temperature for 2 hours. When the mixture is evaporated under reduced pressure, 2- (4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenoxy) -N-methylethan-1-amine is colorless. Obtained as a solid (1.23 g, 100% yield).

Step C: 5-((2- (4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenoxy) ethyl) (methyl) amino) -2- (2, 6-dioxopiperidine-3-yl) isoindoline-1,3-geo
Hmm

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-dioxopiperidine-3-yl) -5-fluoroisoindoline-1,3-dione (591.9 mg, 2.14 mmol) in NMP (2 mL) solution, DIPEA (1.38 g).
, 10.7 mmol) was added. The resulting mixture was stirred at 130 ° C. for 12 hours in _{an N 2 atmosphere.} The mixture was diluted with EA (30 mL) and then the mixture was washed twice with brine. The organic phase is evaporated under reduced pressure and the residue is purified on silica gel (PE / EtOAc = 1/3) by column chromatography to 5-((2- (4- (4-bromo-3- (pyridine)). -4-yl) -1H-pyrazol-1-yl) phenoxy) ethyl) (methyl) amino) -2- (2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione (500 mg) , Yield 74.1%) was obtained.

Step D: 2- (2,6-dioxopiperidine-3-yl) -5- (methyl (2- (4- (4- (1-oxo-2,3-dihi))
Doro-1H-Inden-5-yl) -3- (Pyridine-4-yl) -1H-Pyrazole-1-yl) Phenoxy) D
Chill) Amino) Isoindoline-1,3-dione

5-((2- (4- (4-Bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenoxy) ethyl) (methyl) amino) -2- (2,6-di) Oxopiperidin-3-yl) Isoindrin-1,3-dione (500 mg, 0.79 mmol) and 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- _{T-Bu 3} PHBF ₄ (92.2 mg _{) in a 1,4-dioxane / H 2} O (9 mL, 8: 1) solution of 2,3-dihydro-1H-inden-1-one (307.6 mg, 1.19 mmol). , 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 in _{an N 2 atmosphere.} The solvent was evaporated under reduced pressure. The residue was diluted with EA (30 mL) and then the mixture was washed twice with brine. When the organic phase is evaporated under reduced pressure and the residue is purified by column chromatography on silica gel (PE / DCM / MeOH = 800/200/25), 2- (2,6-dioxopiperidine-3-yl) ) -5- (Methyl (2- (4- (4- (1-oxo-2,3-dihydro-1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazole-1) -Il) Phenoxy) Ethyl) Amino) Isoindoline-1,3-dione (500 mg, yield 92.4%) was obtained.

Step E: (E) -2- (2,6-dioxopiperidine-3-yl) -5-((2- (4- (4- (1- (hydroxyimino) -2,3-dihydro-1H) -Inden-5-yl) -3- (Pyridine-4-yl) -1H-Pyrazole-1-yl) Fe
Noxy) Ethyl) (Methyl) Amino) Isoindoline-1,3-dione

2- (2,6-dioxopiperidine-3-yl) -5-(methyl (2- (4- (4- (1-oxo-2,3-dihydro-1H-inden-5-yl) -3) -3 -(Pyridine-4-yl) -1H-pyrazol-1-yl) phenoxy) ethyl) amino) isoindoline-1,3-dione (200 mg, 0.294 mmol) CH ₃ CN / Py (3 mL / 3 mL) ) NH ₂ OH · HCl (200 mg, 2.877 mmol) was added to the solution, and the mixture was stirred at 40 ° C. for 0.5 hours. The mixture was diluted with DCM (30 mL) and washed twice with brine. The organic layer was evaporated under reduced pressure. Purification of the residue with TLC (DCM / EA / MeOH = 50/100/15) reveals (E) -2- (2,6-dioxopiperidine-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 was obtained as a yellow-green solid (103 mg, yield 49.9%). 1H NMR (400 MHz, CDCl3): 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, 4H), 2.12 --2.15 (d, J = 8.4 Hz, 1H); LCMS (ES +): m / z 696.2 [M + H] +.
Compounds 133-136, 138-149, and 273-281 can be prepared in a similar manner.

Synthesis example of compound 150

Step A: 4- (4-bromo-1- (4- (2- (3-((tert-butyldimethylsilyl) oxy) propoxy) ethoxy) phenyl) -1H-pyrazole-3-yl) pyridine

_{K 2} CO ₃ (299 mg) in a dehydrated DMF (10 mL) solution of 2- (3-((tert-butyldimethylsilyl) oxy) propoxy) ethyl 4-methylbenzene-sulfonic acid salt (420 mg, 1.08 mmol). , 2.16 mmol) and 4- (4-bromo-1H-pyrazol-3-yl) pyridine (342 mg, 1.08 mmol) were added in succession. The resulting solution was stirred at 80 ° C. for 3 hours. The reaction mixture was diluted with EA (30 mL) and washed with brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. Purification of the residue yields the desired product 4-(4-bromo-1- (4-(2-(3-((tert-butyldimethylsilyl) oxy) propoxy) ethoxy) phenyl) -1H-pyrazole-3. -Il) Pyridine (DCM: MeOH = 20: 1) (430 mg) was obtained as a colorless solid. 1H NMR (400 MHz, CDCl3): 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).
Step B: 3- (2- (4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenoxy)
Ethoxy) Propanol-1-ol

4- (4-bromo-1- (4- (2- (3-((tert-butyldimethylsilyl) oxy) propoxy) ethoxy) phenyl) -1H-pyrazole-3-yl) pyridine (430 mg, 0.808 mmol) 6 M Hydrochloric acid (in 1,4-dioxane) (4 mL) was added to the 1,4-dioxane (2 mL) solution of). The resulting solution is 25 ° C
Stir for 1 hour. When the solvent is removed under reduced pressure, the desired crude product 3- (2-(4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenoxy) ethoxy) propane -1-Ol (270 mg crude) was obtained, which was used in the next step without further purification. LCMS (ES ⁺ ): m / z 420.0 [M + H] ⁺ .

Step C: 3- (2- (4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenoxy)
Ethoxy) Propionaldehyde

3- (2- (4- (4-Bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenoxy) ethoxy) propanol-1-ol (135 mg, 0.32 mmol), IBX ( _{It was added to a solution of CH 3} CN (4 mL) at 136 mg, 0.48 mmol) at room temperature. The mixture was stirred at 80 ° C. for 2 hours. After the reaction was complete, the mixture was filtered. When the filtrate is concentrated under vacuum, the desired crude product 3- (2- (4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenoxy) ethoxy) Propanal (140 mg crude) was obtained and used in the next step without further purification. LCMS (ES ⁺ ): m / z 416.0 [M + H] ⁺
..

Step D: tert-Butyl 4- (2- (2,6-dioxopiperidine-3-yl) -1,3-dioxoisoindoline-4-yl) piperazine-1-carboxylate

2- (2,6-dioxopiperidine-3-yl) -4-fluoroisoindoline-1, in NMP (10 mL) solution of tert-butyl piperazine-1-carboxylate (1.35 g, 7.25 mmol) 3-Dione (1 g, 3.62 mmol) and DIEA (1.87 g, 14.5 mmol) were added. The resulting solution was _{stirred under N 2} at 90 ° C. for 4 hours. The reaction mixture was diluted with EA (30 mL) and washed with brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. Purification of the residue yields the desired product tert-
Butyl 4- (2- (2,6-dioxopiperidine-3-yl) -1,3-dioxoisoindoline-4-yl) piperazine-1-carboxylate (DCM: EA = 1: 1) ( 1.4 g) was obtained as a yellow solid. 1H NMR
(400 MHz, DMSO-d6): 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).
Step E: 2- (2,6-dioxopiperidine-3-yl) -4- (piperazine-1-yl) isoindoline-1,3-dione hydrochloride

Of tert-butyl 4- (2- (2,6-dioxopiperidine-3-yl) -1,3-dioxoisoindoline-4-yl) piperazine-1-carboxylate (1.4 g, 3.16 mmol) To a solution of 1,4-dioxane (4 mL) was added 6 M hydrochloric acid (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 yields the desired product 2- (2,6-dioxopiperidine-3-yl) -4- (piperazine-1-yl) isoindoline-1,3-dione hydrochloride (1.4 g crude). It was used in the next step without further purification. LCMS (ES ⁺ ): m / z 343.1 [M + H] ⁺ .
Step F: 4- (4- (3- (3- (4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenoxy) ethoxy) propyl) piperazine-1- Il) -2- (2,6-dioxopiperidine-3-yl) iso
Indoline-1,3-Zeon

3- (2- (4- (4-Bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenoxy) ethoxy) propanol (140 mg crude, 0.32 mmol), 2- (2) , 6-dioxopiperidine-3-yl) -4- (piperazine-1-yl) isoindoline-1,3-dione (123 mg, 0.32 mmol), NaBH ₃ CN (41 mg, 0.64 mmol), acetic acid ( 3.8 mg, 0.062 mmol) in MeOH solution. The resulting solution was stirred at room temperature overnight. The mixture was diluted with EA and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. Purification of the residue yields the desired product 4-(4-(3-(4- (4-(4-bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenoxy) ethoxy). ) Propyl) piperazine-1-yl) -2- (2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione (DCM: MeOH = 15: 1) (70 mg) is a yellow solid Obtained as a thing. LCMS (ES ⁺ ): m / z 742.1 [M + H
] ⁺ .

Step G: 2- (2,6-dioxopiperidine-3-yl) -4- (4- (3- (2- (4- (4- (1-oxo-2,3-dihi))
Doro-1H-Inden-5-yl) -3- (Pyridine-4-yl) -1H-Pyrazole-1-yl) Phenoxy) D
Toxi) Propyl) Piperazine-1-yl) Isoindoline-1,3-dione

4- (4- (3- (2- (4- (4-Bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenoxy) ethoxy) propyl) piperazine-1-yl)- 2- (2,6-dioxopiperidine-3-yl) isoindrin-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- 1,4-Dioxane / H2O (6 mL, 10/1) solution of tert-butylphosphin tetrafluoroborate (115 mg, 0.39 mmol), N, N-dicyclohexylmethylamine (9 mg, 0.047 mmol). The resulting solution was irradiated with microwaves at 100 ° C. under _{N 2 for 2 hours.} After cooling to room temperature, the mixture was diluted with EA and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. Purification of the residue reveals the desired product 2- (2,6-dioxopiperidine-3-yl) -4- (4- (3- (2- (4- (4- (1-oxo-2,,) 3-Dihydro-1H-Inden-5-yl) -3- (Pyridine-4-yl) -1H-Pyrazole-1-yl) Phenoxy) ethoxy) propyl) Piperazine-1-yl) Isoindoline-1,3- Zeon (DCM: MeOH = 20: 1) (33 mg) was obtained as a yellow solid. LCMS (ES ⁺ ): m / z 795.3 [M + H] ⁺ .

Step H: (E) -2- (2,6-dioxopiperidine-3-yl) -4- (4- (3- (2- (4- (4- (1- (hydroxyimino) -2,) 3-Dihydro-1H-Inden-5-yl) -3- (Pyridine-4-yl) -1H-Pyrazole-1-yl) Phenoxy) ethoxy) Propyl) Piperazine-1-yl) Isoindoline-1,3- Zeon

2- (2,6-dioxopiperidine-3-yl) -4- (4- (3- (2- (4- (4- (1-oxo-2,3-dihydro-1H-)-
Inden-5-yl) -3- (Pyridine-4-yl) -1H-Pyrazole-1-yl) Phenoxy) ethoxy) propyl) Piperazine-1-yl) Isoindoline-1,3-dione (33 mg, 0.042) Hydroxylamine hydrochloride (27 mg, 0.42 m) in acetonitrile (2 mL) and pyridine (1.5 mL) solution of mmol)
mol) was added. The mixture was stirred at 40 ° C. for 20 minutes, diluted with 20 mL of DCM and washed with brine (10 mL). When the organic layer is concentrated and purified by preparative TLC, (E) -2- (2,6-dioxopiperidine-3-yl) -4- (4- (3- (2- (4- (4- (4- (4- (4-) 4-) (1- (Hydroxyimino) -2,3-dihydro-1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenoxy) ethoxy) propyl) piperazine-1 -Il) Isoindoline-1,3-dione (22 mg, 66.6% yield) was obtained as a yellow solid. 1H NMR (400 MHz, CDCl3): 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] +.
Compounds 151-172 and 282-284 can be prepared in a similar manner.

Synthesis example of compound 174

Step A: 4- (benzyloxy) butyl 4-methylbenzenesulfonate

TsCl (50 mL) in DCM (50 mL) 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). 7.94 g, 41.64 mmol) was added in batches. The resulting solution was stirred at 15 ° C. for 2 hours. The reaction was _{quenched by the addition of saturated NH 4} Cl (50 mL). The mixture was extracted with DCM (50 mL x 2). The mixed organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. Purification of the residue on silica gel gave the desired product 4- (benzyloxy) butyl 4-methylbenzenesulfonate (5.6 g, 60% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3): 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).
Step B: (S) -tert-butyl 5-amino-4-(4- (4- (benzyloxy) butoxy) -1,3-dioxoisoindoline-2-yl) -5-oxovalerate

_{K 2} CO ₃ (0.4 g, 2.88 mmol), tert-butyl (S)-in a dehydrated DMF (8.0 mL) solution of 4- (benzyloxy) butyl 4-methylbenzene sulfonate (0.63 g, 1.87 mmol). 5-Amino-4- (4-hydroxy-1,3-dioxoisoindrin-2-yl) -5-oxovalerate (0.5 g, 1.44 mmol) was added in succession. The resulting solution was stirred at 70 ° C. for 2 hours. After cooling to room temperature, the reaction was quenched with water (30 mL) and the mixture was extracted with EA (40 mL x 2). The mixed organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. Purification of the residue on a silica gel column reveals (S) -tert-butyl 5-amino-4-(4- (4- (benzyloxy) butoxy) -1,3-dioxoisoindoline-2-yl) -5. -Oxovalerate (0.4 g, 55% yield) was obtained. 1H NMR (400 MHz, CDCl3): 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).
Step C: (S) -2- (2,6-dioxopiperidine-3-yl) -4- (4-hydroxybutoxy) isoin
Drin-1,3-Zeon

(S) -Tert-Butyl 5-amino-4- (4- (4- (benzyloxy) butoxy) -1,3-dioxoisoindoline-2-yl) -5-oxovalerate (400 mg, ^TsOH. H ₂ O (1.48 g, 7.84 mmol) was added to a solution of acetonitrile (5 mL) of 0.784 mmol). The resulting solution was stirred at 80 ° C. for 2 hours. The reaction was _{quenched with saturated NaHCO 3} and extracted with EA. When the organic layer is dried over anhydrous sodium sulfate, concentrated and purified on a column, (S) -4- (4- (benzyloxy) butoxy) -2- (2,6-dioxopiperidine-3-yl) Isoindoline-1,3-dione (370 mg) was obtained. THF / MeOH of (S) -4- (4- (benzyloxy) butoxy) -2- (2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione (370 mg, 0.85 mmol) To the (4 mL / 1 mL) solution was _{added Pd (OH) 2} (185 mg) and two drops of concentrated HCl. The resulting mixture was _{stirred under 1 atmosphere H 2} at 20 ° C. for 1 hour. The resulting solution was filtered and evaporated. Purification of the residue by preparative TLC yields the desired product (S) -2- (2,6-dioxopiperidine-3-yl) -4- (4-hydroxybutoxy) isoindoline-1,3-dione. (250 mg, yield 92% in two steps) was obtained. LCMS (ES ⁺ , Neg): m / z 345.0 [MH]
⁺ .

Step D: (S) -4-((2- (2,6-dioxopiperidine-3-yl) -1,3-dioxoisoindoline-4-yl) oxy) butanal

_{CH 3} CN (5 mL) of (S) -2- (2,6-dioxopiperidine-3-yl) -4- (4-hydroxybutoxy) isoindoline-1,3-dione (0.25 g, 0.72 mmol) ) IBX (607 mg, 2.16 mmol) was added to the solution. The resulting solution was stirred at 75 ° C. for 1 hour. After cooling to room temperature, the reaction mixture was filtered and concentrated under vacuum to give the desired crude product (240 mg crude, calculated, 100% yield), which was used directly in the next step. ..

Step E: (S) -4- (4- (4- (4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazole-1-yl)) Fe
Nil) piperazine-1-yl) butoxy) -2- (2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione

(S) -4-((2- (2,6-dioxopiperidine-3-yl) -1,3-dioxoisoindoline-4-yl) oxy) butanol (240 mg crude, 0.72 mmol) MeOH 1- (4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenyl) piperazine (276 mg, 0.72 mmol) and 2 in solution (6 mL)
Drops of AcOH were added. Then NaBH ₃ CN (134 mg, 2.16 mmol) was added. The resulting solution was stirred at 18 ° C for 2 hours. After quenching with water (30 mL), the mixture was extracted with EA (40 mL x 2). The mixed organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. When the residue is applied on a silica gel column, the desired product (S) -4- (4- (4- (4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazole-1-)-1H-pyrazole-1-) Il) phenyl) piperazine-1-yl) butoxy) -2- (2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione (350 mg, yield 68% in two steps) Was done. LCMS (ES ⁺ ): m / z 713.1 [M + H] ⁺ .

Step F: (S) -2- (2,6-dioxopiperidine-3-yl) -4- (4- (4- (4- (1-oxo-2,3-dihi)
Doro-1H-Inden-5-yl) -3- (Pyridine-4-yl) -1H-Pyrazole-1-yl) Phenyl) Pipe
Radin-1-yl) Butoxy) Isoindoline-1,3-dione

(S) -4- (4- (4- (4- (4-Bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenyl) piperazine-1-yl) butoxy) -2 -(2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione (0.35 g, 0.52 mmol) and 5- (4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-
Il) -2,3-dihydro-1H-inden-1-one (147 mg, 0.57 mmol) in a 1,4-dioxane (15 mL) / H ₂ O (1.5 mL) solution with CsF (316 mg, 2.08). Consecutive with mmol), Pd ₂ (dba) ₃ (190 mg, 0.21 mmol), tri-tert-butylphosphin tetrafluoroborate (121 mg, 0.42 mmol) and two drops of N-cyclohexyl-N-methylcyclohexaneamine. And added. The reaction was heated to 100 ° C. for 2 hours in _{an N 2 atmosphere.} After cooling to room temperature, the reaction was quenched with water (20 mL) and the mixture was extracted with ethyl acetate (30 mL x 2). The mixed organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. When the residue is applied on a silica gel column, the desired product (S) -2- (2,6-dioxopiperidine-3-yl) -4- (4- (4- (4- (4- (1) -Oxo-2,3-dihydro-1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenyl) piperazine-1-yl) butoxy) isoindoline-1 , 3-Dione (0.3 g, 80% yield) was obtained as a yellow solid. LCMS (ES +): m / z 382.8 [(M + H) / 2] ⁺ .

Step G: (S, E) -2- (2,6-dioxopiperidine-3-yl) -4- (4- (4- (4- (1- (hydroxyi))
Mino) -2,3-dihydro-1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenyl) piperazine-1-yl) butoxy) isoindoline-1 , 3-Zeon

(S) -2- (2,6-dioxopiperidine-3-yl) -4- (4- (4- (4- (4- (1-oxo-2,3-dihydro-1H-inden-5) -Il) -3- (Pyridine-4-yl) -1H-Pyrazole-1-yl) Phenyl) Piperazine-1-yl) Butoxy) Isoindoline-1,3-dione (165 mg, 0.22 mmol) acetonitrile / To a solution of 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 is removed under vacuum and the residue is purified by preparative TLC using DCM / MeOH (20/1) to produce the desired product (S, E) -2- (2,6-dioxopiperidine-). 3-Il) -4- (4- (4- (4- (4- (1- (Hydroxyimino) -2,3-dihydro-1H-Inden-5-Il))-3- (Pyridine-4-yl) ) -1H-pyrazol-1-yl) phenyl) piperazine-1-yl) butoxy) isoindoline-1,3-dione (60 mg, 38% yield) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6): 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] +.
Compounds 173 and 175-181 can be prepared in a similar fashion.

Synthesis example of compound 182

Step A: N- (3- (5-((1- (2- (2,6-dioxopiperidine-3-yl) -1,3-dioxoisoindoline-4-yl) piperidine-4-yl) ) (Methyl) amino) -3- (pyrimidine-5-yl) -1H-pyrrolo [3,2-b] pyridin-1-yl) -2,4-difluorophenyl) propan-1-sulfonamide

N- (2,4-difluoro-3- (5- (methyl (piperidine-4-yl) amino) -3- (pyrimidine-5-yl) -1H-pyrrolo [3,2-b] pyridine-1- Il) Phenyl) Propane-1-sulfonamide (100.0 mg, 0.18 mmol) (previously described in International Patent Application Publication No. 2012/104388), 2- (2,6-dioxopiperidine-3-yl)- A mixture of 4-fluoroisoindrin-1,3-dione (102 mg, 0.36 mmol) and DIEA (239 mg, 1.80 mmol) in anhydrous NMP (2.0 mL) was irradiated with microwaves at 130 ° C. for 1 hour. .. After cooling to room temperature, the reaction was quenched with water and the mixture was extracted with EA (10 mL x 3). The mixed organic layer was washed with water (10 mL x 3), brine (20 mL) and dried over anhydrous sodium sulfate.
Concentrated under vacuum. Purification of the residue by preparative TLC yields the desired product N- (3-(5-((1- (2- (2,6-) 6-).
Dioxopiperidine-3-yl) -1,3-dioxoisoindoline-4-yl) piperidin-4-yl) (methyl) amino) -3- (pyrimidine-5-yl) -1H-pyrrolo [3, 2-b] Pyridine-1-yl) -2,4-difluorophenyl) Propane-1-sulfonamide (DCM: MeOH = 10: 1) (45 mg, yield = 30.6%) is obtained as a white solid. rice field. 1H NMR (400 MHz, CDCl3): 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, 2 H), 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] +.
Compound 183 can be prepared in a similar manner.

Synthesis example of compound 184

Step A: tert-butyl (S) -5-amino-4- (4- (2- (benzyloxy) ethoxy) -1,3-dioxo
Isoindoline-2-yl) -5-oxovalerate

tert-butyl (S) -5-amino-4- (4-hydroxy-1,3-dioxoisoindoline-2-yl) -5-
Add oxovalerate (1.22 g, 3.51 mmol), 2- (benzyloxy) ethyl methanesulfonate (900 mg, 3.91 mmol) and K ₂ CO ₃ (1.08 g, 7.83 mmol) to DMF (10 mL). The mixture was stirred at 70 ° C. for 6 hours. After quenching with water, the mixture was extracted with EA. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. Purification of the residue yields the desired product tert-butyl (S) -5-amino-4- (4- (2- (benzyloxy) ethoxy) -1,3-dioxoisoindoline-2-yl)- Five-
Oxovalerate (PE: EtOAc = 1: 5) (907 mg) was obtained.

Step B: (S) -4- (2- (benzyloxy) ethoxy) -2- (2,6-dioxopiperidine-3-yl) a
Sindrin-1,3-Zeon

tert-butyl (S) -5-amino-4- (4- (2- (benzyloxy) ethoxy) -1,3-dioxoisoindoline-2-yl) -5-oxovalerate (907 mg, A solution of 1.88 mmol), p-TsOH (1.5 g, 7.89 mmol) in MeCN (10 mL) was stirred at 80 ° C. for 8 hours. After quenching with water, the mixture was diluted with EA and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. Purification of the residue reveals the desired product (S) -4- (2- (benzyloxy) ethoxy) -2- (2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione ( PE: EtOAc = 1: 1) (1.23 g, crude) was obtained.

Step C: (S) -2- (2,6-dioxopiperidine-3-yl) -4- (2-hydroxyethoxy) isoin
Drin-1,3-Zeon

(S) -4- (2- (benzyloxy) ethoxy) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione (1.23 g, 3.01 mmol), Pd (OH) ) A _{solution of 2} / C (0.7 g), HCl / dioxane (6N, 6 drops) in MeOH / EtOAc (1: 1, 40 mL) was stirred at _{room temperature for 12 hours under 1 atmosphere H 2.} The mixture is filtered through Celite and the filtrate is concentrated under vacuum to give the desired product (S) -2- (2,6-dioxopiperidine-3-yl) -4- (2-hydroxyethoxy) isoindoline. -1,3-dione (700 mg, crude) was obtained.

Step D: (S) -2-((2- (2,6-dioxopiperidine-3-yl) -1,3-dioxoisoindoline-4-yl) oxy) acetaldehyde

_{CH 3} CN (10 mL) of (S) -2- (2,6-dioxopiperidine-3-yl) -4- (2-hydroxyethoxy) isoindoline-1,3-dione (200 mg, 0.63 mmol) ) IBX (352 mg, 1.26 mmol) was added to the solution. The resulting solution was stirred at 80 ° C. for 2 hours. After cooling to room temperature, the mixture is filtered and the filtrate is concentrated under vacuum to give the desired crude product (S) -2-((2- (2,6-dioxopiperidine-3-yl)-)-. 1,3-Dioxoisoindoline-4-yl) oxy) acetaldehyde (200 mg crude) was obtained as a yellow solid, which was used in the next reaction without further purification.

Step E: N-(3-(5-((1- (2-((2- (2,6-dioxopiperidine-3-yl) -1,3-dioxoisoindoline-4-yl) oxy) ) Ethyl) piperidine-4-yl) (methyl) amino) -3- (pyrimidine-5-yl) -1H-pyrrolo [3,2-b] pyridin-1-yl) -2,4-difluorophenyl) propane -1-sulfone
Amide

(S) -2-((2- (2,6-dioxopiperidine-3-yl) -1,3-dioxoisoindoline-4-yl))
Oxy) Acetaldehyde (200 mg crude, 0.631 mmol), N- (2,4-difluoro-3- (5- (methyl (piperidine-4-yl) amino) -3- (pyrimidine-5-yl) -1H- EtOH / DCM (v / v) of pyrolo [3,2-b] pyridin-1-yl) phenyl) propan-1-sulfonamide hydrochloride (80 mg, 0.148 mmol), CH _{3 COOH (3.8 mg, 0.062 mmol)} NaBH (OAc) 3 (400 mg, 1.88 mmol) was added to the = 1/1, 20 mL) solution. The resulting solution was stirred at room temperature overnight. After quenching with water, the mixture was extracted with EtOAc. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. Purification of the residue with preparative TLC (DCM / EtOAc / MeOH = 10/1/1) yields the desired product (S) -N- (3- (5-((1- (2-((2-2-)-). (2,6-dioxopiperidine-3-yl) -1,3-dioxoisoindoline-4-yl) -oxy) ethyl) piperidine-4-yl) (methyl) amino) -3- (pyrimidine-5) -Il) -1H-pyrrolo [3,2-b] pyridin-1-yl) -2,4-difluorophenyl) propan-1-sulfonamide (20.1 mg) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.80 --0.02 (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); LC-MS: (ES +): m / z 842.3 [M + H] +.
Compounds 185-189 can be prepared in a similar fashion.

Synthesis example of compound 191

Step A: tert-butyl 2- (2- (2-oxoethoxy) ethoxy) acetate

IBX (3.8 g, 13.64 mmol) was added to a solution of tert-butyl 2- (2- (2-hydroxyethoxy) ethoxy) acetate (1 g, 4.55 mmol) in CH _{3 CN (15 mL).} The resulting solution was stirred at 75 ° C. for 1 hour. After cooling to room temperature, the mixture is filtered and the filtrate is concentrated under vacuum to give the desired crude product tert-butyl 2- (2- (2-oxoethoxy) ethoxy) acetate (1 g crude, yield). A rate of 100%) was obtained, which was used directly in the next step. 1H NMR (400 MHz, CDCl3): δ 9.75 (s,
1H), 4.18 (s, 2H), 4.03 (s, 2H), 3.77 (s, 4H), 1.48 (s, 9H).
Step B: tert-butyl-2-(2-(2-(4-((1- (2,6-difluoro-3- (propylsulfonamide) phenyl) -3- (pyrimidine-5-yl) -1H) -Pyrrolo [3,2-b] Pyridine-5-yl) (Methyl) Amino) Piperidine-1-yl) ethoxy) ethoxy) Acetate

N- (2,4-difluoro-3- (2,4-difluoro-3- (1/1)) in EtOH / DCM (1/1) solution of tert-butyl 2- (2- (2-oxoethoxy) ethoxy) acetate (181 mg crude, 0.83 mmol) 5- (Methyl (piperidin-4-yl) amino) -3- (pyrimidine-5-yl) -1H-pyrrolo [3,2-b] pyridin-1-yl) phenyl) propan-1-sulfonamide hydrochloride (150 mg, 0.28 mmol) and a catalytic amount of AcOH were added. If the pH 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 with water (20 mL), the mixture was extracted with DCM (30 mL x 2). The mixed organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. When the residue is applied on a silica gel column, the desired product 2- (2-(2-(((1- (2,6-difluoro-3- (propylsulfonamide) phenyl) -3- (pyrimidine) -5-yl) -1H-pyrrolo [3,2-b] pyridin-5-yl) (methyl) amino) piperidine-1-yl) ethoxy) ethoxy) acetate (120 mg, 58% yield) obtained Was done. LCMS: (ES ⁺ ): m / z 744.3 [M + H] ⁺ .
Step C: 2- (2- (2- (4-((1- (2,6-difluoro-3- (propyl sulfonamide) phenyl) -3- (
Pyrimidine-5-yl) -1H-pyrrolo [3,2-b] pyridin-5-yl) (methyl) amino) piperidine-1-
Il) ethoxy) ethoxy) acetic acid

tert-butyl 2- (2- (2- (4-((1- (2,6-difluoro-3- (propylsulfonamide) phenyl) -3- (pyrimidine-5-yl) -1H-pyrrolo [3 , 2-b] Pyridine-5-yl) (methyl) amino) piperidine-1-yl) ethoxy) ethoxy) acetate (0.12 g, 0.16 mmol) in DCM (3 mL) solution in TFA (1 mL)
Was added. The resulting solution was stirred at 30 ° C. for 1 hour. When the solvent is removed under vacuum,
Desired product 2- (2-(2-(4-((1- (2,6-difluoro-3- (propylsulfonamide) phenyl) -3- (pyrimidine-5-yl) -1H-pyrrolo [ 3,2-b] Pyridine-5-yl) (Methyl) Amino) Piperidine-1-yl) ethoxy) ethoxy) Acetic acid (111 mg crude, calculated) was obtained and the following reaction was performed without further purification. Used for. LCMS: (ES ⁺ ): m / z 688.2 [M + H] ⁺ .
Step D: (2S, 4R) -1-((S) -2- (2- (2- (2- (4-((1- (2,6-difluoro-3- (propyl sulfone))
Mido) Phenyl) -3- (pyrimidine-5-yl) -1H-pyrrolo [3,2-b] pyridin-5-yl) (methyl) a
Mino) piperidine-1-yl) ethoxy) ethoxy) acetamide) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide

2- (2- (2- (4-((1- (2,6-difluoro-3- (propylsulfonamide) phenyl) -3- (pyrimidine-5-yl) -1H-pyrrolo [3,2- b] Pyridine-5-yl) (methyl) amino) piperidine-1-yl) ethoxy) ethoxy) acetic acid (111 mg crude, 0.16 mmol) in a DCM (10 mL) solution to (2S, 4R) -1- (2S, 4R) -1- ( (S) -2-
Amino-3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide hydrochloride (150 mg, 0.32 mmol), DIPEA (209) mg, 1.62 mmol) and PyBOP (250 mg, 0.48 mmol) were added in succession. After stirring at 30 ° C. for 1 hour, the reaction mixture was diluted with DCM (30 mL) and washed with water (10 mL × 2) and brine (10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was first purified on a column (DCM / MeOH 19/1) and then purified by preparative HPLC to produce the desired product (2S, 4R) -1-((S) -2- (2- (2). -(2-(4-((1- (2,6-difluoro-3- (propylsulfonamide) phenyl) -3- (pyrimidine-5-yl) -1H-pyrrolo [3,2-b] pyridine- 5-yl) (methyl) amino) piperidin-1-yl) ethoxy) ethoxy) acetamide) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) Benzyl) Pyrimidine-2-carboxamide (55 mg, 31% yield in two steps) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6): 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] +.
Compounds 190 and 192 can be prepared in a similar manner.

Compound 195 [(3R) -N-(3-(5-(4- (2- (2- (2,6-dioxopiperidine-3-yl) -1,3-dioxo)
Isoindoline-5-yloxy) ethoxy) phenyl) -1H-pyrrolo [2,3-b] pyridin-3-carbonyl) -2,4-difluorophenyl) -3-fluoropyrrolidine-1-sulfonamide]

Step A: Ethyl 2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pheno
Kishi) Acetate

4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (5 g, 22.7 mmol) in N, N-dimethylformamide (50 mL) solution with ethyl 2 -Bromoacetic acid salt (4.52 g, 27.2 mmol) and potassium carbonate (6.27 g, 45.4 mmol) were added. The mixture was stirred under nitrogen gas overnight. The reaction mixture was added to water (200 mL) and extracted with ethyl acetate (150 mL x 3). The organic layer was washed with brine (100 mL x 3). The mixed organic phase is dried over anhydrous sodium sulfate, filtered and
And when concentrated in vacuo, ethyl 2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy) acetate (5.2 g, 75%) is colorless. Obtained as oil.

Step B: Methyl 2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pheno
Kishi) Ethanol

Tetrahydrofuran / ethanol (10 mL / 10) of ethyl 2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy) acetate (1 g, 3.27 mmol) To the mL) solution was added sodium borohydride (124 mg, 3.27 mmol) under an ice water bath. The mixture was warmed to room temperature and stirred for 2 hours. The mixture was partitioned between ethyl acetate (100 mL) and water (50 mL). Separate the organic layer and
Washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo with methyl 2- (4- (4,4,5,5-tetramethyl-1,3). , 2-Dioxaborolan-2-yl) phenoxy) Ethanol (0.8 g, 93%) was obtained as a colorless oil.

Step C: 2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy) d
Chill methanesulfonate

2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy) ethanol (200 mg, 0.76 mmol) and ethyldiisopropylamine (293 mg,) Methyl methanesulfonyl chloride (105 mg, 0.91 mmol) was added under cooling to a solution of 2.27 mol) in dichloromethane (10.0 mL) and the mixture was stirred at 0 ° C. for 30 minutes. The mixture is quenched with cold water (10.0 mL), the organic layer is washed with sodium hydrogen carbonate solution (10.0 mL x 3) and brine (10.0 mL x 3), dried over anhydrous saturated sodium sulfate, filtered and in vacuo. Concentration with (2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy) ethyl methanesulfonate is obtained in the next step. Used directly in.

Step D: 2- (2,6-dioxopiperidine-3-yl) -5-(2- (4- (4,4,5,5-tetramethyl-1,3,2-)
Dioxaborolan-2-yl) Phenoxy) ethoxy) Isoindoline-1,3-dione

(2- (4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy) ethyl methanesulfonate (260 mg, 0.76 mmol), potassium carbonate (210 mg) , 1.52 mol), potassium iodide (126 mg, 0.76 mmol) and 2- (2,6-dioxopiperidine-3-yl) -5-hydroxyisoindrin-1,3-dione (208 mg, 0.76 mmol) The mixture in dimethylsulfoxide (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 a crude product, which is preparative TLC (dioxide / methanol = 20: 1). ), 2- (2,6-dioxopiperidine-3-yl) -5-(2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2) -Il) Phenoxy) ethoxy) Isoindrin-1,3-dione (140 mg, 36% in two steps) was obtained as a white solid. ^{LCMS (ES +} ): m / z 521.2 [M + H] ⁺ , 538.2 [M + 18] ⁺ .

Step E: (3R) -N- (3- (5- (4- (2- (2- (2,6-dioxopiperidine-3-yl) -1,3-dioxoiso)
Indoline-5-yloxy) ethoxy) phenyl) -1H-pyrrolo [2,3-b] pyridin-3-carbonyl) -2,4-difluorophenyl) -3-fluoropyrrolidine-1-sulfonamide

2- (2,6-dioxopiperidine-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] pyridin-3-carbonyl) -2 , 4-Difluorophenyl) -3-fluoropyrrolidin-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 to the mixture under an argon atmosphere, and the mixture was stirred at 100 ° C. for 6 hours. When cooled to room temperature, add water (20 mL), extract the resulting mixture with EA (20 mL x 3), wash with brine (10 mL x 3), dry over anhydrous sodium sulfate and filter. And concentrated. Purification of the residue by preparative HPLC reveals (3R) -N- (3-(5-(4- (2- (2- (2,6-dioxopiperidine-3-yl) -1,3-di). Oxoisoindoline-5-yloxy) ethoxy) phenyl) -1H-pyrrolo [2,3-b] pyridin-3-carbonyl) -2,4-difluorophenyl) -3-fluoropyrrolidine-1-sulfonamide (8.1 mg) , Yield 4%) was obtained as a white solid. LCMS (ES +): m / z 817.2 [M + H] +; 1H NMR (400 MHz, DMSO-d6) 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, brs.), 11.14 (1H, s), 12.96 (1H, brs.).
Compounds 194 and 195 can be prepared in a similar manner.

Compound 285 [(2S, 4R) -1-((S) -2- (3- (2- (4- (4- (3- (2,6-difluoro-3- (((R) -3-) Fluoropyrrolidine) -1-sulfonamide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperazin-1-yl) ethoxy) Isoxazole-5-yl) -3-Methylbuta Noyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide] and compound 286 [(2S, 4R) -1-((R) -2-( 3- (2- (4- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3 -b] Pyridine-5-yl) Phenyl) Piperazin-1-yl) ethoxy) Isoxazole-5-yl) -3-Methylbutanoyl) -4-Hydroxy-N- (4- (4-Methylthiazole-5-) Il) benzyl) pyrrolidine-2-carboxamide] synthesis example

Step A: 2- (3-Hydroxy-1,2-oxazol-5-yl) -3-methylbutanoic acid

In a 100 mL round bottom flask, 2- (3-methoxy-1,2-oxazol-5-yl) -3-methylbutanoic acid (1.0 g, 5.02 mmol, 1.0 eq) and hydrobromic acid (11.9 g, A solution of 147.07 mmol (29.30 eq) in acetic acid (20 mL) was added. The resulting solution was stirred overnight at 60 ° C. in an oil bath. The reaction mixture was concentrated under reduced pressure. As a result, 650.0 mg (crude) 2- (3-hydroxy-1,2-oxazol-5-yl) -3-methylbutanoic acid was obtained as a white solid.

LCMS (ES ⁺ ): m / z 186.05 [M + H] ⁺ .
Step B: Ethyl 2- (3-hydroxy-1,2-oxazol-5-yl) -3-methylbutanoate

2- (3-Hydroxy-1,2-oxazol-5-yl) -3-methylbutanoic acid (650.0 mg, 3.51 mmol, 1.00 eq) in a 50 mL round-bottom flask purged and maintained in an inert nitrogen atmosphere. Ethanol (30 mL) solution and sulfuric acid (1 mL) were added. The resulting solution was stirred at 70 ° C. overnight. The reaction mixture was then quenched by adding 20 mL of water and extracted with ethyl acetate (20 mL x 2).
The mixed organic layer was dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure. As a result, 720.0 mg (96%) of ethyl 2- (3-hydroxy-1,2-oxazol-5-yl) -3-methylbutanoate was obtained as a yellow oil.

Step C: Ethyl 2- [3- (2-bromoethoxy) -1,2-oxazol-5-yl] -3-methylbutanoate

In a 50 mL round bottom flask purged and maintained in an inert nitrogen atmosphere, ethyl 2- (3-hydroxy-1,2-oxazol-5-yl) -3-methylbutanoate (380.0 mg, 1.78 mmol, A solution of 1.00 equivalent) in acetone (15 mL), 1,2-dibromoethane (994.8 mg, 5.30 mmol, 3.00 equivalent) and Cs ₂ CO ₃ (1.17 g, 3.59 mmol, 2.00 equivalent) were added. The resulting mixture was stirred at room temperature overnight. The reaction mixture was then quenched by adding water (15 mL) and extracted with ethyl acetate (20 mL x 3). The mixed organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied on a silica gel column and eluted with ethyl acetate / petroleum ether (1: 5). As a result, 450.0 mg (79%) of ethyl 2- [3- (2-bromoethoxy) -1,2-oxazol-5-yl] -3-methylbutanoate was obtained as a colorless solid.

Step D: 1- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] pipe
Radin

In a 100 mL round bottom flask purged and maintained in an inert nitrogen atmosphere, tert-butyl 4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) After adding a solution of phenyl] piperazine-1-carboxylate (1.6 g, 4.12 mmol, 1.00 eq) in dichloromethane (40 mL), TMSOTf (1.5 g, 6.75 mmol, 1.60 eq) was added dropwise at 0 ° C. with stirring. did. 6-Dimethylpyridine (132.5 mg, 1.00 mmol, 0.30 eq) was added to the above solution. The resulting solution was stirred at room temperature for 3 hours. The reaction was quenched by the addition of 50 mL saturated aqueous sodium hydrogen carbonate solution. The resulting solution was extracted with ethyl acetate (30 mL x 3). The mixed organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied on a silica gel column and eluted with dichloromethane / methanol (10: 1). As a result, 854.0 mg (72%) of 1- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine was used as an off-white solid. Obtained. LCMS (ES ⁺ ): m / z 289.15 [M + H] ⁺ .

Step E: Ethyl 3-Methyl-2- [3- (2- [4- [4- (Tetramethyl-1,3,2-Dioxaborolan-2-)
Ill) phenyl] piperazine-1-yl] ethoxy) -1,2-oxazol-5-yl] butaneate

Ethyl 2- [3- (2-bromoethoxy) -1,2-oxazol-5-yl] -3-methylbutanoate (576.0) in a 30 mL sealed tube purged and maintained in an inert nitrogen atmosphere. N, N-dimethylformamide (6 mL) solution in mg, 1.80 mmol, 1.00 eq), 1- [4- (tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine (624.0 mg, 2.17) Ethyl, 1.20 eq), DIEA (17 mL), NaI (20 mg) were added. The resulting solution was stirred at 130 ° C. for 16 hours. 30 mL of reaction mixture
Water was added and quenched. The resulting solution was extracted with ethyl acetate (30 mL x 3). The mixed organic layer was washed with brine (30 mL x 3), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied on a silica gel column and eluted with ethyl acetate / petroleum ether (1: 2). As a result, 720.0 mg (76%) of ethyl 3-methyl-2- [3- (2- [4- [4- (tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine-1) -Il] ethoxy) -1,2-oxazol-5-yl] butaneate was obtained as a pale yellow solid. LCMS (ES ⁺ ): m / z 528.25 [M + H] ⁺ .

Step F: Ethyl 2- (3- [2- [4- (4- [3-[(2,6-difluoro-3-[[(3R) -3-fluoropyrrolidines)
Luhonyl] amino] phenyl) carbonyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazine-1-yl] ethoxy] -1,2-oxazol-5-yl) -3-methylbutane Acid salt

In a 30 mL sealed tube purged and maintained in an inert nitrogen atmosphere, ethyl 3-methyl-2- [3- [2- [4- [4- (tetramethyl-1,3,2-dioxaborolan-2) -Il) phenyl] piperazine-1-yl] ethoxy) -1,2-oxazol-5-yl] butanoate (527.0 mg, 1.00 mmol, 1.00 eq) 20 mL of 1,4-dioxane / water (4) 1) Solution in, (3R) -N- [3- (5-bromo-1H-pyrrolo [2,3-b] pyridine-3-ylcarbonyl) -2,4-difluorophenyl] -3-fluoro Pyrrolidine-1-sulfonamide (503.0 mg, 1.00 mmol, 1.00 eq), sodium carbonate (318.0 mg, 3.00 mmol, 3.00 eq) and Pd (dppf) Cl ₂ (82.0 mg, 0.10 mmol, 0.10 eq) were added. The reaction mixture was reacted at 100 ° C. for 2 hours under microwave irradiation. The reaction mixture was then quenched by adding 20 mL of water. The resulting solution was extracted with ethyl acetate (30 mL x 3). The mixed organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied on a silica gel column and eluted with dichloromethane / methanol (10: 1). As a result, 460.0 mg (56%) of 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) piperazine-1-yl] ethoxy] -1,2-oxazole-5-yl) -3- Methylbutanoate was obtained as a pale yellow solid. LC
MS (ES ⁺ ): m / z 824.15 [M + H] ⁺ .

Step G: 2- (3- [2- [4- (4- [3- [(2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1-sul)
Honyl] amino] phenyl) carbonyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazine-1-yl] ethoxy] -1,2-oxazol-5-yl) -3-methylbutane acid

In a 50 mL round bottom flask purged and maintained in an inert nitrogen atmosphere, ethyl 2- (3- [2- [4- (4- [3- [(2,6-difluoro-3-[[(3R) ) -3-Fluoropyrrolidin-1-sulfonyl] amino] phenyl) carbonyl] -1H-pyrrolo [2,3-b] pyridine-5-yl] phenyl) piperazine-1-yl] ethoxy] -1,2-oxazol -5-yl) -3-Methylbutanoate (420.0 mg, 0.51 mmol, 1.00 equivalent) in methanol (10 mL) followed by sodium hydroxide (102.0 mg, 2.55 mmol, 5.00 equivalent) in water (2 mL). ) The solution was added. The resulting solution was stirred at 40 ° C. for 5 hours. The pH value of the solution was adjusted to pH 6 with hydrogen chloride (1 mol / L). The solids were collected by filtration. The solid was dried in an oven under reduced pressure. As a result, 366.0 mg (90%) 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) piperazine-1-yl] ethoxy] -1,2-oxazole-5-yl) -3-methylbutane The acid was obtained as a solid. LCMS (ES ⁺ ): m / z 796.10 [M + H] ⁺ .

Step H: (2S, 4R) -1- [2- (3- [2- [4- (4- [3- [(2,6-difluoro-3- [[(3R) -3-fluoropyrroli)
Din-1-sulfonyl] amino] phenyl) carbonyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazine-1-yl] ethoxy] -1,2-oxazol-5-yl) -3-Methylbutanoyl] -4-Hydroxy-N-[[4- (4-Methyl-1,3-thiazole-5-yl) Phenyl-Methyl] Pyrrolidine-2-carboxamide

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 eq) and (2S, 4R) -4-hydroxy-N- [4- (4-methyl-1,3-thiazole-5-yl) phenyl] methylpyrrolidin-2-carboxamide hydrochloride (199.9 mg, 0.56 mmol, 1.50 eq) N, N-
DIEA (3.0 mL) and BOP (200.3 mg, 0.45 mmol, 1.20 eq) were added to a solution of dimethylformamide (10 mL). The obtained mixture was stirred at room temperature for 1 hour. The reaction was then stopped by the addition of 20 mL of water. The resulting solution was extracted with ethyl acetate (30 mL x 3). The mixed organic layer was washed with brine (30 mL x 3), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied on a silica gel column and eluted with dichloromethane / methanol (10: 1). As a result, 265.0 mg (64%) of (2S, 4R) -1- [2- (3- [2- [4- (4- [3- [(2,6-difluoro-3- [[(3R) ) -3-Fluoropyrrolidine-1-sulfonyl] amino] phenyl) carbonyl] -1H-
Pyrrolidine [2,3-b] Pyridine-5-yl] Phenyl) Piperazine-1-yl] ethoxy] -1,2-Oxazole-5-yl) -3-Methylbutanoyl] -4-hydroxy-N- [ [4- (4-Methyl-1,3-thiazole-5-yl) phenyl] methyl] Pyrrolidine-2-carboxamide was obtained as a solid. LCMS (ES ⁺ ): m / z 1095.30 [M + H] ⁺ .

Step I: (2S, 4R) -4-hydroxy-N-[[4- (4-methyl-1,3-thiazole-5-yl) phenyl]
Chill] -1- (2- [3- [2- (methylamino) ethoxy] -1,2-oxazol-5-yl] butanoyl) pyrrolidine-2-carboxamide

(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-methyl Separation of butanoyl] -4-hydroxy-N-[[4- (4-methyl-1,3-thiazole-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide by chiral HPLC yielded: ..

25.7 mg (10%) of (2S, 4R) -1-((S) -2- (3- (2- (4- (4- (3- (2,6-difluoro-3-) (((R) ) -3-Fluoropyrrolidine) -1-sulfonamide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperazine-1-yl) ethoxy) Isoxazole-5-yl)- 3-Methylbutanoyl) -4-
Hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide. 1H NMR (300 MHz, DMSO-d6): δ9.10-8.97 (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, 5H), 7.18-7.07 (m, 2H), 6.18-6.12 (m, 1H), 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] +.
57.5 mg (22%) of (2S, 4R) -1-((R) -2- (3- (2- (4- (4- (3- (2,6-difluoro-3- (((R) ) -3-Fluoropyrrolidin) -1-sulfonamide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperazine-1-yl) ethoxy) Isoxazole-5-yl) -3 -Methylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide. 1H NMR (300 MHz, DMSO-d6): δ12.90 (brs, 1H), 9.84 (brs, 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] +.
Exemplary compounds 287 and 288 can be prepared in a similar fashion.

Compound 291 [(2S, 4R) -4-hydroxy-1-((S) -2-(2-(2-(4-(4-((E) -1- (hydroxyimino) -2,3-) Dihydro-1H-Inden-5-yl) -3- (Pyridine-4-yl) -1H-Pyrazole-1-yl) Fe
Noxy) ethoxy) acetamide) -3,3-dimethylbutanoyl) -N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide]

Step A: tert-butyl 2- (2- (4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazole-1-)
Il) Phenoxy) ethoxy) Acetateethoxy (acetatethoxy)) Acetate

In a solution of tert-butyl 2- (2-chloroethoxy) acetate (400 mg, 2.06 mmol) and Cs ₂ CO ₃ in DMF (15 mL), tert-butyl 4- (4-bromo-3- (pyridine-4) -Il) -1H-pyrazole-1-yl) phenol (525 mg, 1.66 mmol) was added. The mixture was stirred at 75 ° C. for 3 hours. The solution was diluted with EA (100 mL). The mixture was washed with water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. When the residue is purified by silica gel column chromatography, 2- (2- (4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenoxy) ethoxy) acetate ethoxy) acetic acid A salt (290 mg, 0.62 mmol) was obtained. LCMS (ES ⁺ ): m / z 475
.21 [M + H] ⁺ , 476.1 [M + 2H] ⁺ .

Step B: (2S, 4R) -1-((S) -2- (2- (2- (4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazole-1-yl)) Phenoxy) ethoxy) acetamide) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide

2- (2- (4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenoxy) ethoxy) acetate ethoxy) acetate (290 mg, 0.61 mmol) 1, HCl (g) (3 M, 5 mL) in 1,4-dioxane was added to the 4-dioxane (5 mL) solution. The reaction 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-methylthiazole-5-yl) benzyl) pyrrolidine-2 -Carboxamide hydrochloride (394 mg, 0.92 mmol), DIPEA (394 mg, 3.05 mmol) and PyBOP (954 g, 1.83 mmol) were added subsequently to the solution. After stirring for 30 minutes, it was diluted with DCM (50 mL). The mixture was washed with water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by silica gel column chromatography reveals that (2S, 4R) -1-((S) -2- (2- (2- (4- (4-bromo-3- (pyridin-4-yl))- 1H-pyrazole-1-yl) phenoxy) ethoxy) acetamide) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide (390 mg, 0.46 mmol) was obtained. LCMS (ES ⁺ ): m / z 830.2 [M + H] ⁺ .

Step C: (2S, 4R) -1-((S) -3,3-dimethyl-2- (2- (2- (4- (4- (1-oxo-2,3-dihydro-1H-a) -a)
Benzyl-5-yl) -3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenoxy) ethoxy) acetamide) butanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5) -Il) Benzyl) Pyrazole
Lysine-2-carboxamide

(2S, 4R) -1-((S) -2-(2-(4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazole-1-yl))
Phenoxy) ethoxy) acetamide) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4- (4- (4-)
Methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide (390 mg, 0.46 mmol) and 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2 _{Pd (aMPhos) Cl 2} (36 mg, 0.046 mmol) in a 1,4-dioxane / water (20 mL / 1 mL) solution of 3-dihydro-1H-inden-1-one (248 mg, 0.92 mmol). , CsF (360 mg, 2.30 mmol) were added in succession. The reaction mixture was stirred at 90 ° C. overnight under a nitrogen atmosphere. After cooling to room temperature, it was diluted with ethyl acetate (100 mL). The mixture was washed with brine (50 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. When the residue is purified by silica gel column chromatography (DCM / MeOH), (2S, 4R) -1-((S) -3,3-dimethyl-2- (2- (2- (4- (4- (4- (4- (4- (4- (4- (4- (4- (4- (4- (4- (4- (4- (4- (4- (4- (4- (4-) 1-oxo-2,3-dihydro-1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenoxy) ethoxy) acetamide) butanoyl) -4-hydroxy- N- (4- (4-Methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide (230 mg, 0.26 mmol) was obtained. LCMS (ES ⁺ ): m / z 882.3 [M + H] ⁺ .

Step D: (2S, 4R) -4-Hydroxy-1-((S) -2-(2-(2-(4-(4-((E) -1- (Hydroxyimino) -2,3-) Dihydro-1H-Inden-5-yl) -3- (Pyridine-4-yl) -1H-Pyrazole-1-yl) Phenoki
F) ethoxy) acetamide) -3,3-dimethylbutanoyl) -N- (4- (4-methylthiazole-5-a)
Le) Benzyl) pyrrolidine-2-carboxamide

(2S, 4R) -1-((S) -3,3-dimethyl-2- (2- (2- (4- (4- (1-oxo-2,3-dihydro-1H-inden-5-) Ill) -3- (Pyridine-4-yl) -1H-Pyrazole-1-yl) Phenoxy) ethoxy) Acetamide) Butanoyl) -4-Hydroxy-N- (4- (4-Methylthiazole-5-yl) benzyl _{) NH 2} OH · HCl (179 mg, 2.6 mmol) was added to a solution of pyrrolidine-2-carboxamide (230 mg, 0.26 mmol) in CH ₃ CN and pyridine (v / v = 1/1, 5 mL). The solution was stirred at 20 ° C. for 3 hours. The mixture was filtered through Celite. The filtrate was concentrated under vacuum. Purification of the residue by silica gel column chromatography (DCM / MeOH) reveals (2S, 4R) -4-hydroxy-1-((S) -2- (2- (2- (4- (4- (4- ((E)). ) -1- (Hydroxyimino) -2,3-dihydro-1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenoxy) ethoxy) acetamide) -3 , 3-Dimethylbutanoyl) -N- (4- (4-Methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide (21 mg, 0.023 mmol) was obtained. 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] +.
Exemplary compounds 289, 290, 292, and 293 can be prepared in a similar manner.

Example 15-Synthetic Scheme A: Compounds 305, 298, 299, 300, 301, 302, 514, and 303

tert-ブチル4-(4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェノキシ)ブタン酸塩(1)。4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェノール(209.12 mg、0.95 mmol)およびtert-ブチル4-ブロモブタン酸塩(212 mg、0.95 mmol)のN,N-ジメチルホルムアミド(2 mL)中の混合物にCs₂CO₃(402.47 mg、1.24 mmol)を加えた。反応混合物を65℃で12時間加熱した(一晩)。TLCによる、少量の開始物質(Hex:AcOEt、7:3)。粗製生成物をフラッシュCC(SiO₂-25g、Hex:AcOEt、勾配9:1〜4:6)で精製すると、198 mg(収率57%)の生成物が油として得られた。1H NMR (500 MHz, DMSO-d6) 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 (p, J = 6.7 Hz, 2H), 1.39 (s, 9H), 1.27 (s, 12H).13C 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. LC-MS（ESI）：m/z [M+Na]⁺: C₂₀H₃₁BO₅Naに対する計算値,385.2162. 実
測値：385.2194。

tert-Butyl 4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy) butaneate (1). 4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (209.12 mg, 0.95 mmol) and tert-butyl 4-bromobutaneate (212 mg, 0.95 mmol) _{Cs 2} CO ₃ (402.47 mg, 1.24 mmol) was added to the mixture in N, N-dimethylformamide (2 mL). The reaction mixture was heated at 65 ° C. for 12 hours (overnight). A small amount of starting material by TLC (Hex: AcOEt, 7: 3). The crude product was purified by flash _{CC (SiO 2 -25g, Hex:} AcOEt, gradient 9: 1 to 4: 6) to furnish, 198 product mg (57% yield) as an oil. 1H NMR (500 MHz, DMSO-d6) 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 (p, J = 6.7 Hz, 2H), 1.39 (s, 9H), 1.27 (s, 12H) .13C 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. LC-MS (ESI): m / z [M + Na] ⁺ : C ₂₀ H ₃₁ BO ₅ Calculated value for Na, 385.2162. Measured value: 385.2194 ..

tert-Butyl 4- (4- (3-benzoyl-1H-pyrrolo [2,3-b] pyridin-5-yl) phenoxy) pig
Phosphate (2). tert-Butyl 4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)
Phenoxy] -butaneate (72 mg, 0.2 mmol) and (5-bromo-1H-pyrrolo [2,3-b] pyridin-3-yl) -phenyl--methanone (59.85 mg, 0.2 mmol) dioxane ( 6 mL) The solution was degassed under vacuum and purged with argon. K ₂ CO ₃ (82.4 mg, 0.6 mmol) was then added, then water (2 mL) was added, the reaction mixture was degassed under vacuum and purged again with argon. Tricyclohexylphosphin (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 purged again with argon. The reaction mixture was then stirred at 90 ° C. for 2 hours. By TLC, with some SM (Hex: AcOEt, 3: 7), additional amounts of tricyclohexylphosphin (5.57 mg, 0.02 mmol) and Pd (dba) ₂ (5.71 mg, 0.01 mmol) were added twice. The reaction mixture was stirred for an additional 2 hours. The reaction mixture was diluted with AcOEt (20 mL) and
It was dried (Na ₂ SO ₄ ), filtered in vacuo on a Celite pad, 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 -40g, gradient Hex: AcOEt, gradient relative to 100% AcOEt 9: 1) to furnish the product off-white 69 mg (68%) Obtained as a solid substance. ¹ H NMR (500 MHz, DMSO-d6) 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.LC-MS (ESI); m / z: [M + H] ⁺ C ₂₈ H ₂₉ N ₂ O ₄ Calculated value, 457.2127. Measured value: 457.2156.

4- (4- (3-Benzoyl-1H-pyrrolo [2,3-b] pyridin-5-yl) phenoxy) butanoic acid (3). Of tert-butyl 4- (4- (3- (2,6-difluorobenzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) -phenoxy) butaneate (30 mg, 0.06 mmol) A solution of 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 further purification (26.5 mg, quantitative yield). LC-MS (ESI); m / z: [M + H] ⁺ C ₂₄ H ₂₁ N ₂ O ₄ calculated value, 401.1501. Measured value: 401.1420.

(2S, 4R) -1-((S) -2- (4- (4- (3-benzoyl-1H-pyrrolo [2,3-b] pyridin-5-yl) phenoki)
B) Butanamide) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide (Compound 305) 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-dimethyl-butanoyl] -4-hydroxy-N-[[4- (4-methylthiazole-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide; DMF of hydrochloride (30.91 mg, 0.07 mmol) TEA (0.2 ml, 1.43 mmol) and PyBOP (37.88 mg, 0.07 mmol) were added to the (2 ml) solution at room temperature. The reaction mixture was stirred at the same temperature for 12 hours (overnight). TLC (DCM: MeOH: NH ₄ OH, 90: 9: 1) indicates that there is no initiator. DMF was removed under high vacuum. The crude product was filtered on a silica carbonate cartridge (1 g) using DCM: MeOH (9: 1) as an eluent. The filtrate was evaporated under vacuum and the crude product was purified by PTLC (MeOH: DCM, 9: 1) to give 31 mg of product (58% yield). 1H NMR (400 MHz, DMSO-d6) 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) .13C 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. .LC-MS (ESI); m / z [M + H] ⁺ : C ₄₆ H ₄₉ N ₆ O ₆ S calculated value, 813.3434.
Measured value: 813.3478.

(2S, 4S) -1-((S) -2- (4- (4- (3- (2,6-difluoro-3- (propylsulfonamide) benzoyl) -1H-pyrrolo [2,3-b] ] -Pyridine-5-yl) Phenoxy) Butanamide) -3,3-Dimethylbutanoyl) -4-Hydroxy-N- (4- (4-Methylthiazole-5-yl) -benzyl) Pyrrolidine-2-carboxamide ( Compound 514)

4- [4- [3- [2,6-difluoro-3- (propyl-sulfonylamino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenoxy] butanoic acid (4.08 mg, 0.00732 mmol) and (2S, 4S) -1-((S) -2-amino-3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl )-To a solution of pyrrolidine-2-carboxamide (3.76 mg, 0.00873 mmol) in DMF (1.5 ml) was added TEA (0.200 mL, 1.43 mmol) and PyBOP (4.19 mg, 0.00805 mmol) at room temperature. The reaction mixture was stirred at the same temperature for 4 hours. TLC (DCM: MB, 1: 1) indicates that there is no initiator. DMF was removed under high vacuum (the product is partially water soluble). The crude product was filtered on a silica carbonate cartridge using DCM: MeOH (9: 1) as an eluent. The filtrate was evaporated under vacuum and the crude product was purified by PTLC (DCM: MeOH: NH ₄ OH, 90: 9: 1) to give 3.1 mg of product (43% yield). 1H (500 MHz, DMSO-d6) δ 12.83 (bs, 1H), 9.64 (bs, 1H), 8.96 (s, 1H), 8.77 --8.41 (m, 3H), 8.18 (s, 1H), 7.97 (d) , J = 8.6 Hz, 1H), 7.65 (d, J = 8.5 Hz, 2H), 7.61 --7.78 (m, 1H), 7.38 (q, J = 8.2 Hz, 4H), 7.26 (t, J = 8.7 Hz) , 1H), 7.04 (d, J = 8.7 Hz, 2H), 5.43 (d, J = 7.2 Hz, 1H), 4.54 --4.31 (m, 3H), 4.30 --4.15 (m, 2H), 4.08 --3.88 ( m, 3H), 3.50 --3.40 (m, 1H), 3.16 --3.02 (m, 2H), 2.44 --2.26 (m, 3H), 2.42 (s, 3H), 2.04 --1.84 (m, 2H), 1.79- 1.63 (m, 3H), 0.95 (s, 9H), 0.94 (t, 3H). 13C NMR (151 MHz, DMSO-d6) δ 181.03, 172.89, 172.34, 170.35, 158.75, 156.44 (dd, J = 246.1, 6.7 Hz), 152.78 (dd, J = 249.5, 8.6 Hz), 151.89, 148.94, 148.15, 144.15, 139.63, 139.07, 131.74, 131.55, 130.82, 130.14, 129.36 --129.11 (m), 129.08, 128.68, 127.86, 126.85 , 122.35 (dd, J = 13.6, 3.4 Hz), 117.94, 116.03, 115.59, 69.53, 67.52, 58.95, 57.24, 56.04, 53.86, 42.21, 37.36, 35.11, 31.62, 26.82, 25.42, 17.26, 16.37, 13.04.LC -MS (ESI); m / z [M + H] ⁺ : C ₄₉ H ₅₄ F ₂ N ₇ O ₈ Calculated value of S ₂ , 970.3443. Measured value, 970.3422
Example 16-Synthesis Scheme B: 217, 220, 510, and 221

tert-butyl (4- (3- (2,6-difluoro-3- (propylsulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) carbamate (5a) .. tert-butyl (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) -carbamate salt (50.99 mg, 0.16)
In a dioxane (3 ml) solution of mmol), N- [3- (5-bromo-1-H-pyrrolo [2,3-b] pyridine-3-carbonyl) -2,4-difluoro-phenyl] 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) were added. The reaction mixture was then degassed under vacuum, purged with argon, Pd (dba) ₂ (3.83 mg, 0.01 mmol) was added and the reaction mixture was heated to 80 ° C. for 3 hours. TLC A small amount of SM (Hex: AcOEt, 3: 7) filtered the reaction mixture under vacuum on a Celite bed and poured the filtrate into saturated aqueous NaCl solution (20 mL). The product was extracted with EtOAc (2x20 mL). The EtOAc layers were combined, dried (Na ₂ SO ₄ ) and concentrated under vacuum. The crude material was diluted with DCM, and purified by flash chromatography (SiO ₂ -12 g, hexane: AcOEt, gradient 8: 2~100% AcOEt) to afford a solid off-white product of 47 mg (56%) I got it as a thing. ¹ H NMR (400 MHz, DMSO-d6) δ 12.96 (bs, 1H), 9.77 (bs, 1H), 9.49 (s, 1H), 8.68 (d, J = 2.1 Hz, 1H), 8.57 (bs, 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 (dq, 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. LC-MS (ESI); m / z: [ M + H] ⁺ C ₂₈ H ₂₉ F ₂ N ₄ O ₅ S calculated value, 571.1826. Measured value: 571.1917.

N- (3- (5- (4-Aminophenyl) -1H-pyrrolo [2,3-b] Pyridine-3-carbonyl) -2,4-difluorophenyl) Propyl-1-sulfonamide (6) tert- Butyl (4- (3- (2,6-difluoro-3- (propylsulfonamide) benzoyl) -1H-pyrrolo- [2,3-b] pyridin-5-yl) phenyl) carbamate (30 mg, A solution of TFE (2 mL) of 0.05 mmol) was heated at 140 ° C. for 3 hours under microwave supplemented conditions. The reaction mixture was evaporated to dryness under vacuum to give a product with a quantitative yield of 23 mg. The crude product was used in the next step without further purification. LC-MS (ESI); m / z: [M + H] ⁺ C ₂₃ H ₂₁ F ₂ N ₄ O ₃ S calculated value, 471.1302. Measured value: 471.1351.

tert-butyl-5-((4- (3- (2,6-difluoro-3- (propyl sulfoneamide) benzoyl) -1H-pyrrolo [2,3-b] pyridine-5-yl) phenyl) amino) -5-oxovalerate (7) tert-butyl 5-chloro-5-oxopentanate (21.96 mg, 0.11 mmol) in THF (2 mL) solution to N- (3- (5- (4- (4- (4-) 4-) Aminophenyl) -1H-pyrrolo [2,3-b] -pyridine-3-carbonyl) -2,4-difluorophenyl) propan-1-sulfonamide (10 mg, 0.02 mmol) was added. The resulting suspension was heated to reflux for 12 hours (overnight). The reaction mixture was evaporated in vacuo and the crude product was purified by PTLC (MB: DCM, 4: 6) to give 10.7 mg (79% yield) of white powder. ¹ H NMR (500 MHz, DMSO-d6) 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 (p) , J = 7.4 Hz, 2H), 1.75 (h, 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.LC-MS (ESI); m / z: [M + H] ⁺ C ₃₂ H ₃₅ F ₂ N ₄ O ₆ S calculated value, 641.2245. Measured value: 641.2473.

5-((4- (3- (2,6-difluoro-3- (propylsulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridine-5-yl) phenyl) amino) -5-oxo Valkic acid (8) tert-butyl 5-((4- (3- (2,6-difluoro-3- (propylsulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridine-5-yl)) A mixed solution of TFA (1 ml, 13.46 mmol) and dichloromethane (2 ml) of phenyl) amino) -5-oxopentanate (10.7 mg, 0.02 mmol) 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 further purification (9.7 mg, quantitative yield). LC-MS (ESI); m / z: [M + H] ⁺ C ₂₈ H ₂₇ F ₂ N ₄ O ₆ S calculated value, 585.1619. Measured value: 585.1636.

N1- (4- (3- (2,6-difluoro-3- (propyl sulfoneamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) -N5-((S) -1-((2S, 4R) -4-hydroxy-2-((4- (4-methylthiazole-5-yl) benzyl) carbamoyl) pyrrolidine-1-yl) -3,3-dimethyl-1-oxobutane -2-yl) Glutalamide (Compound 217). 5-((4- (3- (2,6-difluoro-3- (propylsulfonamide) -benzoyl) -1H-pyrrolo [2,3-b] pyridine-5-yl) phenyl) amino) -5- Oxopentanoic acid (9.7 mg, 0.02 mmol) and (2S, 4R) -1-[(2S) -2-amino-3,3-dimethyl-butanoyl] -4-hydroxy-N-[[4- (4- (4- (4- (4-) Methylthiazole-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide; TEA (0.1 ml, 0.72 mmol) and PyBOP (9.5 mg, 0.02) in a DMF (1 ml) solution of hydrochloride (8.52 mg, 0.02 mmol). mmol) was added at room temperature. The reaction mixture was stirred at the same temperature for 4 hours. TLC (DCM: MeOH: NH ₄ OH, 90: 9: 1) indicates that there is no initiator. The reaction mixture was diluted with EtOAc (10 mL), washed with brine (5 mL, 4x), the organic phase was dried (Na ₂ SO ₄ ) and evaporated under vacuum. Purification of the crude product with PTLC (DCM: MeOH: NH ₄ OH, 90: 9: 1) yielded 4.8 mg of product (29% yield). ¹ H 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 (dq, 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 H)
z), 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. LC-MS (ESI); m / z [M + H] ⁺ : C ₅₀ H ₅₅ F ₂ N ₈ O ₈ S ₂ calculated value, 997.3552. Measured value: 997.3524.

N1- (4- (3- (2,6-difluoro-3- (propylsulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) -N4-((S) -1-((2S, 4R) -4-hydroxy-2-((4- (4-methylthiazole-5-yl) benzyl) carbamoyl) pyrrolidine-1-yl) -3,3-dimethyl-1-oxo -Bu
Tan-2-yl) -N1-methylsuccinamide (Compound 510)

4- [4- [3- [2,6-difluoro-3- (propylsulfonylamino) -benzoyl] -1H-pyrrolo [2,3-b] pyridine-5-yl] -N-methyl-anilino]- 4-oxo-butanoic acid (33.7 mg, 0.06 mmol) and (2S, 4R) -1-[(2S) -2-amino-3,3-dimethyl-butanoyl] -4-hydroxy-N-[[4- (4-Methylthiazol-5-yl) phenyl] Methyl] pyrrolidine-2-carboxamide; TEA (0.2 mL, 1.43 mmol) and PyBOP in a DMF (2 ml) solution of hydrochloride (4) (32.31 mg, 0.07 mmol). (36 mg, 0.07 mmol) was added. The reaction mixture was stirred at the same temperature for 4 hours. TLC (DCM: MeOH: NH ₄ OH, 90: 9: 1) indicates that some starting material (acid) remains. The reaction mixture was evaporated to dryness under high vacuum. The crude product was purified by PTLC (DCM: MeOH: NH ₄ OH, 90: 9: 1) to give 4.6 mg of product (8% yield). ¹ H NMR (400 MHz, DMSO-d6) δ 13.01 (bs, 1H), 9.70 (bs, 1H), 8.95 (s, 1H), 8.73 (d, J = 2.3 Hz, 1H), 8.66 (bs, 1H) ), 8.54 (t, J = 5.9 Hz, 1H), 8.22 (s, 1H), 7.84 (dd, J = 19.4, 8.6 Hz, 2H), 7.57 (td, J = 9.0, 6.1 Hz, 1H), 7.52 --7.30 (m, 6H), 7.26 (t, J = 8.5 Hz, 1H), 5.08 (d, J = 3.2 Hz, 1H), 4.47 (d, J = 9.2 Hz, 1H), 4.44 --4.25 (m, 3H), 4.19 (dd, J = 16.0, 5.4 Hz, 1H), 3.66 --3.54 (m, 2H), 3.19 (s, 3H), 3.16 --3.00 (m, 2H), 2.75 --2.16 (m, 4H) , 2.42 (s, 3H), 2.06 - 1.96 (m, 1H), 1.93 - 1.80 (m, 1H), 1.79 -. 1.64 (m, 2H), 0.94 (t, 3H), 0.90 (s, 9H) 13 C NMR (151 MHz, DMSO-d6) δ 181.08, 172.37, 171.90, 171.57, 170.00, 156.45 (dd, J = 246.4, 7.0 Hz), 152.76 (dd, J = 249.3, 8.9 Hz), 151.88, 149.37, 148.13 , 144.49, 143.73, 139.91, 139.34, 137.64, 131.59, 131.11, 130.04, 129.53 -129.16 (m), 129.06, 127.84, 127.55, 122.35 (d, J = 15.0 Hz), 119.06 --118.23 (m), 117.93, 116.13 , 112.77 (d, J = 22.0 Hz), 69.31, 59.13, 56.87, 56.75, 53.86, 42.07, 38.32, 35.76, 30.61, 29.66, 26.77, 22.93, 17.26, 16.37, 13.04. LC-MS (ESI); m / z [M + H] ⁺ : C ₅₀ H ₅₅ F ₂ N ₈ O ₈ S ₂ calculated value, 997.3552. 997.3572.
Example 17-Synthesis Scheme C: Compounds 218, 219 and 222

tert-Butyl 4- (3- (2,6-difluoro-3- (propylsulfonamide) benzoyl) -1H-pyro
B [2,3-b] Pyridine-5-yl) Piperazine-1-carboxylate (9a). N- [3- (5-bromo-1H-pyrrolo [2,3-b] pyridine-3-carbonyl) -2,4-difluoro-phenyl] propan-1-sulfonamide (61 mg, 0.13 mmol) and tert -A solution of butylpiperazin-1-carboxylate (37.19 mg, 0.2 mmol) in THF (3 mL) was purged with argon (5x). RuPhos (18.63 mg, 0.04 mmol) and Pd (OAc) ₂ (2.99 mg, 0.01 mmol) were added, followed by 1 M LHMDS in THF (0.53 ml). The reaction mixture was heated to 60 ° C. and stirred for 6 hours. The reaction was cooled and poured into an aqueous solution of oxalic acid (5%, 2 ml), then a saturated aqueous solution of NaHCO3 (5 ml) was added and the product was extracted with DCM (3x10 ml). The organic extracts were mixed, dried (Na2SO4) and evaporated under vacuum. The crude product was purified by PTLC (DCM: MeOH: NH ₄ OH, 90: 9: 1) (20 mg, 26%). ¹ H NMR (400 MHz, DMSO-d6) δ 12.61 (bs, 1H), 9.73 (bs, 1H), 8.27 (d, J = 2.6 Hz, 1H), 8.03 (s, 1H), 7.94 (bs, 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 (dq, 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 = 7.8 Hz) 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. LC-MS (ESI); m / z: [M + H] ⁺ C ₂₆ H ₃₂ F ₂ N ₅ O ₅ S calculated value, 564.2092. Measured value: 564.2
N- (2,4-difluoro-3- (5- (piperazine-1-yl) -1H-pyrrolo [2,3-b] pyridin-3-carbonyl) phenyl) propan-1-sulfonamide (9b) tert -Butyl 4- (3- (2,6-difluoro-3- (propylsulfonamide) benzoyl) -1H-pyrrolo- [2,3-b] pyridin-5-yl) piperazine-1-
A solution of the mixture of carboxylate (20 mg, 0.04 mmol) in DCM: TFA (3 mL: 1 mL) was stirred at room temperature for 1 hour. TLC showed that no starting material (DCM: MeOH: NH ₄ OH, 90: 9: 1) remained. 16.4 mg of product (quantitative yield), the crude product was used in the next step without further purification. LC-MS (ESI); m / z [M + H] ⁺ : C ₂₁ H ₂₄ F ₂ N ₅ O ₃ S calculated value, 464.1567. Measured value: 464.17122.

tert-Butyl 5- (4- (3- (2,6-difluoro-3- (propylsulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) piperazine-1-yl) -5-oxopentanate (10). N- (2,4-
Difluoro-3- (5- (piperazin-1-yl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl) -phenyl) propan-1-sulfonamide (16.4 mg, 0.04 mmol) and 5- TEA (0.1 ml, 0.72 mmol) and PyBOP (20.25 mg, 0.04 mmol) were added to a solution of (tert-butoxy) -5-oxopentanoic acid (7.99 mg, 0.04 mmol) in DMF (2 ml) at room temperature. The reaction mixture was stirred at the same temperature for 3 hours. TLC (DCM: MeOH: NH ₄ OH, 90: 9: 1) indicates that there is no initiator. The reaction mixture was dissolved in EtOAc (10 mL) and washed with brine / water (3x5 mL). The organic extract was concentrated under vacuum and the crude product was purified by PTLC (DCM: MeOH: NH ₄ OH, 90: 9: 1) to give 15.4 mg of product (69% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.67 (bs, 1H), 9.71 (bs, 1H), 8.29
(s, 1H), 8.03 (s, 1H), 7.95 (s, 1H), 7.56 (q, 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). 13C 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. LC-MS (ESI); m / z [M + H] ⁺ : C ₃₀ H ₃₈ F ₂ N ₅ O ₆ S
Calculated value, 634.2510. Measured value: 634.2621.

5-((4- (3- (2,6-difluoro-3- (propylsulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) amino) -5-oxo Valeric acid (11). tert-butyl 5-((4- (3- (2,6-difluoro-3- (propylsulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridine-5-yl) phenyl) amino)- A mixed solution of 5-oxopentanate (10.7 mg, 0.02 mmol) with TFA (1 ml, 13.46 mmol) and dichloromethane (2 ml) was stirred at room temperature 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 further purification (9.7 mg, quantitative yield). LC-MS (ESI); m / z: [M + H] ⁺ C ₂₈ H ₂₇ F ₂ N ₄ O ₆ S calculated value, 585.1619. Measured value: 585.1636.

(2S, 4R) -1-((S) -2- (5- (4- (3- (2,6-difluoro-3- (propylsulfonamide) benzoyl) -1H-pyrrolo [2,3-b] ] Pyridine-5-yl) Piperazine-1-yl) -5-oxopentanamide) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl ) Pillow
Lysine-2-carboxamide (Compound 218). 5- (4- (3- (2,6-difluoro-3- (propylsulfonamide) -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-dimethyl-butanoyl] -4-hydroxy-N-[[4- (4) -Methylthiazole-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide; in a DMF (1 ml) solution of hydrochloride (8.27 mg, 0.018 mmol), TEA (0.1 ml, 0.72 mmol) and PyBOP (9.22 mg, 0.018 mmol) was added at room temperature. The reaction mixture was stirred at the same temperature for 4 hours. TLC (DCM: MeOH: NH ₄ OH, 90: 9: 1) indicates that there is no initiator. The reaction mixture was diluted with EtOAc (10 mL), washed with brine (5 mL, 4x), the organic phase was dried (Na ₂ SO ₄ ) and evaporated under vacuum. On TLC, no product was found in the crude mixture and there was only some VHL initiator (4) (the product is water soluble). The water extract was lyophilized overnight and the solid residue _{was filtered using a mixture of DCM: MeOH: NH 4} OH (90: 9: 1, 30 mL). The filtrate was evaporated to dryness and the crude product was purified by PTLC (DCM: MeOH: NH ₄ OH, 90: 9: 1) to give 13 mg of product (81% yield). 1H NMR (500 MHz, DMSO-d6) 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 (bs, 1H), 7.90 (d, J = 9.2 Hz, 1H), 7.59 --7.74 (m, 1H), 7.47 --7.27 (m, 4H), 7.20 (t) , J = 8.7 Hz, 1H), 5.13 (bs, 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 --1.61 (m, 4H), 0.95 (s, 9H), 0.94 (t, 3H). 13C 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.LC-MS (ESI); m / z [M + H] ⁺ : C ₄₈ H ₅₈ F ₂ N ₉ O ₈ S ₂
Calculated value, 990.3817. Measured value: 990.3889.

Example 18-Synthesis Scheme C: Compounds 304, and 306

tert-Butyl 4- [4- [3- [2,6-difluoro-3- (propylsulfonylamino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] piperazine-1-yl] Butanate (12). Methyl N- [2,4-difluoro-3- (5-piperazin-1-yl-1H-pyrrolo [2,3-b] -pyridin-3-carbonyl) phenyl] propan-1-sulfonamide; 2,2 , 2-Trifluoroacetic acid (17.4 mg, 0.03 mmol) and tert-
TEA (0.03 ml, 0.15 mmol) was added to a DMF (1 ml) solution of butyl 4-iodobutaneate (8.95 mg, 0.03 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 on a silica carbonate cartridge (1 g) using DCM: MeOH (9: 1) as an eluent. The filtrate was evaporated under vacuum and the crude product was purified by PTLC (DCM: MeOH: NH ₄ OH, 90: 9: 1) to give 8.8 mg of product (48% yield). ¹ H NMR (400 MHz, DMSO-d6) δ 12.63 (bs, 1H), 9.73 (bs, 1H), 8.25 (d, J = 2.7 Hz, 1H), 8.00 (s, 1H), 7.89 (bs, 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-d6)
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. LC-MS (ESI); m / z: [M + H] ⁺ C ₂₉ H ₃₈ F ₂ N ₅ O ₅ S calculated value, 606.2561. Measured value: 606.2504.

4- [4- [3- [2,6-difluoro-3- (propylsulfonylamino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] piperazine-1-yl] butanoic acid ( 13). tert-butyl 4- [4- [3- [2,6-difluoro-3- (propylsulfonylamino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] piperazine-1-yl] A mixed solution of butaneate (8.8 mg, 0.01 mmol) 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 further purification (7.9 mg, quantitative yield). LC-MS (ESI); m / z: [M + H] + C ₂₅ H ₃₀ F ₂ N ₅ O ₅ S calculated value, 550.1936. Measured value: 550.1865.

(2S, 4R) -1-((S) -2- (4- (4- (3- (2,6-difluoro-3- (propylsulfonamide) benzoyl) -1H-pyrrolo [2,3-b ] Pyridine-5-yl) piperazine-1-yl) butaneamide) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2- Carboxamide (Compound 304). 4- [4- [3- [2,6-difluoro-3- (propylsulfonyl-amino))
Benzoyl] -1H-pyrrolidine [2,3-b] pyridin-5-yl] piperazine-1-yl] butanoic acid (7.9 mg, 0.01 mmol) and (2S, 4R) -1-[(2S) -2- Amino-3,3-dimethyl-butanoyl] -4-hydroxy-N-[[4- (4-methylthiazo-l-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide; hydrochloride (7.38 mg, 0.02 mmol) ) In DMF (1 ml) solution, TEA (0.1 ml, 0.72 mmol) and PyBOP (8.23 mg).
, 0.02 mmol) was added at room temperature. The reaction mixture was stirred at the same temperature for 12 hours (overnight). TLC (DCM: MeOH: NH ₄ OH, 90: 9: 1) indicates that there is no initiator. The reaction mixture was evaporated and dried. The crude product was filtered on a silica carbonate cartridge (1 g) using DCM: MeOH (9: 1) as an eluent (washed a few times, the product has a high affinity for the stationary phase). The filtrate was evaporated under vacuum and the crude product was purified by PTLC (DCM: MeOH, 9: 1) to give 7.2 mg of product (52% yield). ¹ H NMR (500 MHz, DMSO-d6) 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 (bs, 1H), 7.88 (d, J = 9.1) Hz, 1H), 7.63 --7.74 (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 (dq, 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-d6) 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. LC-MS (ESI); m / z
[M + H] ⁺ : C ₄₇ H ₅₈ F ₂ N ₉ O ₇ S ₂ calculated value, 962.3868. Measured value: 962.3986.

Example 19-Synthesis Scheme E: Compounds 511, and 513

tert-Butyl 3- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide) propanoate (14).

4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid (538 mg, 2.17 mmol) and tert-butyl 3-aminopropanoate (315 mg, 2.17 mmol) N, N-diisopropylethylamine (1.13 mL, 6.51 mmol) and O- (7-azabenzotriazole-1-yl) -N, N, N', N'in a solution of N, N-dimethylformamide (10 ml). -Tetramethyluronium hexafluorophosphate (825 mg, 2.17 mmol) was added at room temperature. The reaction mixture was stirred at the same temperature for 4 hours. TLC (DCM: MeOH: NH ₄ OH, 90: 9: 1) indicates that there is no initiator. The reaction mixture was diluted with EtOAc (50 mL), washed with water / brine (4 x 30 mL), dried (Na ₂ SO ₄ ) and evaporated under vacuum. The crude product was purified by flash chromatography (SiO ₂ -25g, gradient Hex: EtOAc, 1 for 15 minutes: 9 to 100% EtOAc) to afford the product 471 mg (90% pure by NMR, yield 52%) was obtained. This product was used in the next step without further purification. ¹ H NMR (500 MHz, chloroform-d) δ 7.86 (d, J = 7.9 Hz, 2H), 7.74 (d, J = 7.9 Hz, 2H), 6.87 (t, 1H) z 3.69 (q, J = 5.9) Hz, 2H), 2.56 (t, J = 5.8 Hz, 2H), 1.45 (s, 9H), 1.35 (s, 12H). LC-MS (ESI); m / z [M + H] ⁺ : C ₂₀ Calculated value of H ₃₁ BNO ₅ , 376.2295. Measured value, 376.2259.
tert-butyl 3-(4- (3- (2,6-difluoro-3- (propylsulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) benzamide) -propanoate (15).

N- [3- (5-bromo-1H-pyrrolo [2,3-b] pyridine-3-carbonyl) -2,4-difluoro-phenyl] propan-1-sulfonamide (5) (87.3 mg, 0.191 mmol) ) In a dioxane (6 ml) solution, tert-butyl 2- [2- [2- [2- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)) Phenoxy] ethoxy] ethoxy] ethoxy] acetate (14) (65.0 mg, 0.173 mmol), K ₂ CO ₃ (71.8 mg, 0.520 mmol), lycyclohexylphosphine (4.86 mg, 0.017 mmol) and water (2 mL). added. The reaction mixture was then degassed under vacuum, purged with argon (5x) and Pd (dba) ₂ (4.98 mg).
, 0.080 mmol) was added and the reaction mixture was heated at 90 ° C. for 3 hours. With a small amount of SM (Hex: EtOAc, 3: 7) TLC, the reaction mixture is filtered in vacuo on a Celite pad, the filtrate is poured into saturated NaCl aqueous solution (20 mL) and the product is EtOAc (2x20). It was extracted with mL). The EtOAc layers were mixed, dried (Na ₂ SO ₄ ) and concentrated under vacuum. The crude material was diluted with CH ₂ Cl _2, flash chromatography (SiO ₂ -12 g, hexane: EtOAc, 15 minutes 9: 1~100% EtOAc) to afford product obtained 75 mg (71%) rice field. ¹³ C NMR (101 MHz, DMSO-d6) δ 181.08, 171.05, 166.24, 156.44 (dd, J = 246.3, 6.9 Hz), 152.76 (dd, J = 249.7, 8.2 Hz), 149.55, 144.57, 141.15, 139.40, 133.71, 130.98, 129.65 --128.79 (m), 128.43, 127.64, 127.55 --126.10 (m), 122.66 --122.12 (m), 119.00 --118.20 (m), 117.93, 116.15, 112.78 (dd, J = 22.9, 3.5 Hz) ), 80.28, 53.88, 36.10, 35.45, 28.17, 17.25, 13.03. ¹ H NMR (500 MHz, DMSO-d6) δ 13.03 (bs, 1H), 9.76 (bs, 1H), 8.78 (s, 1H), 8.69 (s, 1H), 8.61 (t, J = 4.6 Hz, 1H), 8.26 (s, 1H), 7.98 (d, J = 7.1 Hz, 2H), 7.87 (d, J = 7.2 Hz, 2H), 7.59 (q, J = 7.6 Hz, 1H), 7.29 (t, J = 8.7 Hz, 1H), 3.50 (q, J = 5.7 Hz, 2H), 3.13 (t, 2H), 2.64 --2.44 (m, 2H) , 1.74 (dq, J = 13.9, 7.3 Hz, 2H), 1.40 (s, 9H), 0.96 (t, J = 7.4 Hz, 3H). LC-MS (ESI); m / z [M + H] ⁺ : C ₃₁ H ₃₃ F ₂ N ₄ O ₆ S calculated value, 627.2088. Measured value, 627.2485.
(2S, 4R) -1-((S) -2-(3-(4- (3- (2,6-difluoro-3- (propylsulfonamide) benzoyl))-1H-pyrrolo [2,3-b ] Pyridine-5-yl) -Benzamide) Propylamide) -3,3-dimethylbutanoyl) -4-hydroxy-N-(4- (4-methylthiazole-5-yl) benzyl) pyrrole-dyne-2- Carboxamide (Compound 511).

TFA (1 mL, 13.46) of tert-butyl 4- [4- (3-benzoyl-1H-pyrrolo [2,3-b] pyridin-5-yl) phenoxy] butaneate (15) (26.0 mg, 0.0415 mmol) A mixed solution of mmol) and dichloromethane (3 ml) was stirred for 1.5 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 further purification (23.5 m).
g, quantitative yield). LS-MS (ESI); m / z: [M + H] ⁺ C ₂₇ H ₂₅ F ₂ N ₄ O ₆ S calculated value, 571.1462. Measured value, 571.1812. [3- [2,6-difluoro-3- (propylsulfonylamino) benzoyl] -1H-pyrrolo [2,3-b] pyridine-5-yl] -N-methyl-anilino] -4-oxo-butanoic acid (23.5 mg, 0.0402 mmol) and (2S, 4R) -1-[(2S) -2-amino-3,3-dimethyl-butanoyl] -4-hydroxy-N-[[4- (4-methylthiazole-) 5-Il) phenyl] methyl] pyrrolidine-2-carboxamide; in a solution of hydrochloride (4) (21.0 mg, 0.0450 mmol) in DMF (1 ml) at room temperature with TEA (0.139 mL, 1.00 mmol) and PyBOP (23.4 mg, 23.4 mg, 0.0450 mmol) was added. The reaction mixture was stirred at the same temperature for 4 hours. TLC (DCM: MB, 1: 1) indicates that there is no initiator (acid). The reaction mixture was evaporated to dryness under high vacuum (the product may be soluble in water). The crude product was filtered on a silica carbonate cartridge (100 mg) using DCM: MeOH (9: 1) as an eluent. The filtrate was evaporated under vacuum and the crude product was purified by PTLC (MBLDCM, 1: 1). A second purification was performed by PTLC (DCM: MeOH: NH ₄ OH, 90: 9: 1) to give 27 mg of product (73% yield). ¹ H NMR (500 MHz, DMSO-d6) δ 13.03 (bs, 1H), 9.77 (bs, 1H), 8.96 (s, 1H), 8.77 (s, 1H), 8.69 (s, 1H), 8.57 (t, J) = 5.7 Hz, 1H), 8.53 (t, J = 4.9 Hz, 1H), 8.26 (s, 1H), 8.03 (d, J = 9.1 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.59 (q, J = 8.8 Hz, 1H), 7.40 (dd, 4H), 7.28 (t, J = 8.6 Hz, 1H), 5.16 (d, J = 2.8) Hz, 1H), 4.58 (d, J = 9.1 Hz, 1H), 4.50 --4.34 (m, 3H), 4.22 (dd, J = 15.8, 5.1 Hz, 1H), 3.80 --3.61 (m, 2H), 3.58 --3.40 (m, 2H), 3.15 --3.06 (m, 2H), 2.69 2.49 (m, 2H), 2.43 (s, 3H), 2.11 --1.99 (m, 1H), 1.96 --1.86 (m, 1H), 1.83 --1.66 (m, 2H), 0.95 (t, 3H), 0.94 (s, 9H). ¹³ C NMR (151 MHz, DMSO-d6) δ 180.69, 171.95, 170.40, 169.62, 165.76, 156.00 (dd, J) = 246.6, 6.9 Hz), 152.34 (dd, J = 249.4, 8.3 Hz), 151.42, 149.13, 147.71, 144.14, 140.67, 139.50, 138.99, 133.39, 131.16, 130.58, 129.64, 128.81 (d, J = 9.8 Hz) , 128.64, 128.03, 127.42, 127.23, 126.91, 122.26 --121.63 (m), 118.52 --117.80 (m), 117.52, 115.75, 112.77 --111.89 (m), 68.92, 58 .75, 56.53, 56.40, 53.47, 41.67, 37.97, 36.32, 35.26, 34.89, 26.40, 16.85, 15.95, 12.63.LC-MS (ESI); m / z [M + H] ⁺ : C ₄₉ H ₅₃ F ₂ Calculated value of N ₈ O ₈ S ₂ , 983.3395. Measured value, 983.3963.
Example 20-Synthesis Scheme F: Compounds 512, 513 and 516

tert-butyl 4-(4- (3- (2,6-difluoro-3- (propylsulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) -piperazine-1 -Carboxylate (16).

N- [3- (5-bromo-1H-pyrrolo [2,3-b] pyridine-3-carbonyl) -2,4-difluoro-phenyl] propan-1-sulfonamide (5) (70.8 mg, 0.155 mmol) ) In a dioxane (6 ml) solution, tert-butyl 4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazin-1-carboxylate. (60.0 mg, 0.155 mmol), K ₂ CO ₃ (64.2 mg, 0.465 mmol), tricyclohexylphosphine (4.33 mg, 0.0155 mmol) and water (2 mL) were added. The reaction mixture was then degassed under vacuum, purged with argon (5x), Pd (dba) ₂ (4.44 mg, 0.00773 mmol) was added and the reaction mixture was heated at 90 ° C. for 3 hours. With a small amount of SM (Hex: AcOEt, 3: 7) TLC, the reaction mixture is filtered in vacuo on a Celite pad, the filtrate is poured into saturated NaCl aqueous solution (20 mL) and the product is EtOAc (2x20 mL). ). The EtOAc layers were mixed, dried (Na ₂ SO ₄ ) and concentrated under vacuum. The crude material was diluted with CH ₂ Cl _2, flash chromatography (SiO ₂ -12 g, hexane: EtOAc, 15 minutes 9: 1~100% EtOAc) to afford product obtained 82 mg (83%) rice field. ¹³ C NMR (151
MHz, DMSO-d6) δ 180.61, 156.04 (dd, J = 246.5, 6.9 Hz), 153.88, 152.34 (dd, J = 249.4, 8.6 Hz), 150.35, 148.44, 143.61, 138.60, 131.47, 128.92 --128.75
(m), 128.19 (d, J = 161.3 Hz), 126.05, 121.94 (dd, J = 13.6, 3.6 Hz), 118.96-
117.87 (m), 117.60, 116.33, 115.61, 112.36 (dd, J = 22.6, 3.2 Hz), 79.03, 53.42, 48.08, 43.72, 42.58, 28.09, 16.87, 12.64. ¹ H NMR (500 MHz, DMSO-d6)
δ 12.92 (bs, 1H), 9.76 (bs, 1H), 8.66 (d, J = 2.2 Hz, 1H), 8.55 (s, 1H), 8.19 (s, 1H), 7.75 --7.46 (m, 3H), 7.28 (t, J = 8.7 Hz, 1H), 7.10 (d, J = 8.7 Hz, 2H), 3.49 (t, 4H), 3.19 (t, J = 5.2 Hz, 4H), 3.16 --3.05 (m, 2H) ), 1.74 (h, J = 7.5 Hz, 2H), 1.43 (s, 9H), 0.96 (t, J = 7.4 Hz, 3H). LC-MS (ESI); m / z [M + H] ⁺ : C ₃₂ H ₃₆ F ₂ N ₅ O ₅ S calculated value, 640.2405. Measured value, 640.2541.
N- (2,4-difluoro-3- (5- (4- (piperazine-1-yl) phenyl) -1H-pyrrolo [2,3-b] pyridin-3-carbonyl) phenyl) propan-1-sulfone Amide (17).

tert-Butyl 4- [4- [3- [2,6-difluoro-3- (propylsulfonylamino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl] piperazin-1- A mixed solution of DCM / TFA (3: 1, 4 mL) of carboxylate (16) (28.0 mg, 0.0438 mmol) was stirred at room temperature for 1 hour (without SM "A" according to TLC). The solvent was removed under vacuum and the residue was dried under high vacuum for 2 hours (product 23 mg, quantitative yield). The crude product was used in the next step without further purification. LC-MS (ESI); m / z [M + H] ⁺ : C ₂₇ H ₂₈ F ₂ N ₅ O ₃ S calculated value, 540.1880. Measured value, 540.1949.
tert-Butyl 2- (4- (4- (3- (2,6-difluoro-3- (propylsulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) -phenyl) Piperazine-1-yl) acetate (18).

N- [2,4-difluoro-3- [5- (4-piperazin-1-ylphenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -phenyl] propan-1-sulfonamide (17) Add tert-butyl 2-bromoacetate (9.15 mg, 0.0469 mmol) to a DMF (1 ml) solution of (23.0 mg, 0.0426 mmol) and TEA (0.0594 mL, 0.426 mmol), and add the resulting solution. The mixture was stirred at room temperature for 3 hours. The reaction mixture was evaporated under vacuum. The crude product was purified by PTLC (DCM: MeOH: NH ₄ OH, 90: 9: 1, 2x) to give 19 mg of pure product (69% yield). 1H NMR (500 MHz, DMSO-d6) δ 12.92 (bs, 1H), 9.76 (bs, 1H), 8.65 (t, J = 2.6 Hz, 1H), 8.55 (s, 1H), 8.18 (s, 1H) , 7.76 --7.42 (m, 3H), 7.28 (t, J = 8.3 Hz, 1H), 7.07 (d, J = 6.5 Hz, 2H), 3.33 (s, 2H), 3.30 --3.16 (m, 4H), 3.16 --3.04 (m, 2H), 2.81 --2.55 (m, 4H), 1.84 --1.67 (m, 2H), 1.43 (s, 9H), 0.96 (t, J = 7.2 Hz, 3H). 13C NMR (151) MHz, DMSO-d6) δ 180.57, 169.22, 156.02 (dd, J = 246.3, 7.0 Hz), 152.33 (dd, J = 249.4, 8.6 Hz), 150.42, 148.37, 143.55, 138.50, 131.53, 128.75 (d, J) = 9.6 Hz), 128.17, 127.58, 125.93, 121.92 (dd, J = 13.6, 3.6 Hz), 118.25 (t, J = 23.6 Hz), 117.58, 115.80, 115.58, 112.33 (dd, J = 21.9, 3.0 Hz) , 80.23, 59.21, 53.44, 51.81, 47.93, 27.82, 16.84, 12.62. LC-MS (ESI); m / z [M + H] ⁺ : C ₃₃ H ₃₈ F ₂ N ₅ O ₅ S calculated value, 654.2561 Measured value, 654.2675.
(2S, 4R) -1-((S) -2- (2- (4- (4- (4- (3- (2,6-difluoro-3- (propyl sulfonamide)) benzo
Ill) -1H-pyrrolidine [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) acetamide) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4) -Methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide (Compound 512).

tert-butyl 2- (4- (4- (3- (2,6-difluoro-3- (propylsulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridine-5-yl) phenyl) piperazine A mixed solution of TFA (2 mL, 13.46 mmol) and dichloromethane (2 ml) of -1-yl) acetate (18) (20.0 mg, 0.0306 mmol) was stirred for 5 hours. The solvent was then removed under vacuum and the crude product was dried under high vacuum for 1 hour. The crude product was used in the next step without further purification (18.3 mg, quantitative yield). LC-MS (ESI); m / z: [M + H] ⁺ C ₂₉ H ₃₀ F ₂ N ₅ O ₅ S calculated value, 598.1935. Measured value, 598.1953. (4- (3- (2,6-difluoro-3- (propylsulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridine-5-yl) phenyl) -piperazin-1-yl) acetic acid ( 18.3 mg, 0.0306 mmol) and (2S, 4R) -1-[(2S) -2-amino-3,3-dimethyl-butanoyl] -4-hydroxy-N-[[4- (4-methylthiazole-5) -Il) phenyl] methyl] pyrrolidine-2-carboxamide; hydrochloride (4) (17.2 mg, 0.0367)
TEA (0.106 mL, 0.762 mmol) and PyBOP (19.1 mg, 0.0367 mmol) were added to a solution of DMF (1 ml) in mmol) at room temperature. The reaction mixture was stirred at the same temperature for 4 hours. TLC (DCM: MeOH: NH ₄ OH, 90: 9: 1) indicates the absence of an initiator (acid). The reaction mixture was evaporated to dryness under high vacuum. The crude product was diluted with EtOAc (10 mL), _{washed with saturated aqueous solution of NaHCO 3} (2x5 mL), and the organic extract was dried (Na ₂ SO ₄₎ and evaporated under vacuum. The crude product was purified by PTLC (DCM: MeOH: NH ₄ OH, 90: 9: 1, 2x) to give 20 mg of pure product (65% yield).
.. 1H NMR (500 MHz, DMSO-d6) δ 12.92 (bs, 1H), 9.76 (bs, 1H), 8.91 (s, 1H), 8.66
(s, 1H), 8.65 --8.45 (m, 2H), 7.85 (d, J = 9.1 Hz, 1H), 7.74 --7.52 (m, 3H), 7.49 --7.32 (m, 4H), 7.28 (t, J) = 8.6 Hz, 1H), 7.09 (d, J = 8.5 Hz, 2H), 5.16 (d, J = 3.0 Hz, 1H), 4.54 (d, J = 9.6 Hz, 1H), 4.52 --4.32 (m, 3H) ), 4.26 (dd, J = 15.7, 5.4 Hz, 1H), 3.76 --3.58 (m, 2H), 3.27 (s, 4H), 3.21 --2.95 (m, 4H), 2.68 (s, 4H), 2.40 ( s, 3H), 2.07 (dd, J = 12.9, 7.7 Hz, 1H), 1.92 (ddd, J = 13.1, 9.0, 4.6 Hz, 1H), 1.75 (h, J = 7.5 Hz, 2H), 0.97 (s) , 9H), 0.96 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, DMSO-d6) δ 180.56, 171.77, 169.28, 168.48, 156.02 (dd, J =
246.6, 7.0 Hz), 152.37 (dd, J = 240.8, 8.8 Hz), 151.30, 150.27, 148.38, 147.68, 143.55, 139.42, 138.47, 131.48, 131.12, 129.68, 129.10 --128.66 (m), 128.63, 128.33, 127.57 , 127.51, 125.96, 121.92 (dd, J = 13.7, 3.6 Hz), 118.60 --117.95 (m), 117.57, 115.84, 115.59, 112.32 (dd, J = 23.0, 2.7 Hz), 68.91
, 60.59, 58.81, 56.56, 55.86, 48.16, 41.67, 37.87, 35.80, 26.26, 16.83
, 15.90, 12.61.LC-MS (ESI); m / z [M + H] ⁺ : C ₅₁ H ₅₈ F ₂ N ₉ O ₇ S ₂ calculated value, 1010.3868. Measured value, 1010.4036
(2S, 4R) -1-((S) -2- (4- (4- (3- (2,6-difluoro-3- (propylsulfonamide) benzoyl) -1H-pyrrolo [2,3-b] ] -Pyridine-5-yl) benzamide) butaneamide) -3,3-dimethylbutanoyl) -4-hydroxy-N-(4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-cal
Boxamide (Compound 513).

Crude product from SJF-0633: 4- (4- (3- (2,6-difluoro-3- (propylsulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) Benzamide) Butanoic acid (29.0 mg, 0.0496 mmol) and (2S, 4R) -1-[(2S) -2-amino-3,3-dimethyl-butanoyl] -4-hydroxy-N-[[4- (4) -Methylthiazole-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide; TEA (0.172 mL, 1.23 mmol) and PyBOP (31.0 mg, 0.0595 mmol) in a DMF (2 ml) solution of hydrochloride (27.8 mg, 0.0595 mmol). mmol) was added at room temperature. The reaction mixture was stirred at the same temperature for 4 hours. TLC (DCM: MeOH: NH ₄ OH, 90: 9: 1) indicates the absence of an initiator (acid). The reaction mixture was evaporated to dryness under high vacuum. The crude product was filtered on a silica carbonate cartridge (1 g) using DCM: MeOH (9: 1) as an eluent. The filtrate was evaporated under vacuum and the crude product was purified by PTLC (DCM: MeOH: NH ₄ OH, 85: 14: 1) to give 35 mg of product (71% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.96 (bs, 1H), 9.70 (bs, 1H), 8.97 (s, 1H), 8.77 (d, J = 2.0 Hz, 1H), 8.69 (bs, 1H) , 8.56 (t, J = 5.6 Hz, 2H), 8.26 (s, 1H), 8.08 --7.92 (m, 3H), 7.86 (d, J = 8.2 Hz, 2H), 7.65 --7.53 (m, 1H), 7.40 (dd, J = 8.2 Hz, 4H), 7.29 (t, J = 8.7 Hz, 1H), 5.14 (d, J = 3.5 Hz, 1H), 4.57 (d, J = 9.3 Hz, 1H), 4.51- 4.31 (m, 3H), 4.22 (dd, J = 15.9, 5.4 Hz, 1H), 3.77 --3.59 (m, 2H), 3.32- 3.21 (m, 2H), 3.17 --3.05 (m, 2H), 2.44 ( s, 3H), 2.42 --2.14 (m, 2H), 2.08 --1.98 (m, 1H), 1.97 --1.84 (m, 1H), 1.88 --1.61 (m, 4H), 0.96 (s, 9H), 0.95 ( t, 3H). 13C NMR (151 MHz, DMSO-d6) δ 181.11, 172.38, 172.30, 170.10, 166.19, 156.45 (dd, J = 246.3, 7.1 Hz), 152.78 (dd, J = 249.6, 8.2 Hz), 151.86, 149.54, 148.13, 144.57, 141.04, 139.92, 139.43, 133.94, 131.59, 131.04, 130.05, 129.46 --129.15 (m), 129.06, 128.49, 127.84, 127.63, 127.32, 122.35 (dd, J = 13.4, 3.8 Hz) , 118.94 --118.30 (m), 117.94, 116.15, 112.79 (d, J = 22.6 Hz), 69.32, 59.14, 56.87, 56.82, 5 3.87, 42.08, 40.46, 38.39, 35.69, 33.08, 26.84, 26.10, 17.26, 16.38, 13.04.LC-MS (ESI); m / z [M + H] ⁺ : C ₅₀ H ₅₅ F ₂ N ₈ O ₈ S _{Calculated value of 2} , 997.3552. Measured value, 997.2761.
(2S, 4S) -1-((S) -2- (2- (4- (4- (4- (3- (2,6-difluoro-3- (propyl sulfonamide)) benzo
Ill) -1H-pyrrolidine [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) acetamide) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4) -Methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide (Compound 516).

Crude product of SJF-0660; 2- (4- (4- (3- (2,6-difluoro-3- (propylsulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridine-5- Il) phenyl) -piperazin-1-yl) acetic acid (5.70 mg, 0.00954 mmol) and (2S, 4S) -1-((S) -2-amino-3,3-dimethylbutanoyl) -4-hydroxy- TEA (0.1 mL, 0.762 mmol) and PyBOP (5.96) in a DMF (1 ml) solution of N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide (5.35 mg, 0.0124 mmol). mg, 0.0114 mmol) was added at room temperature. The reaction mixture was stirred at the same temperature for 4 hours. TLC (DCM: MeOH: NH ₄ OH, 85: 14: 1) indicates the absence of an initiator (acid). The reaction mixture was evaporated to dryness under high vacuum (the product may be soluble in water). The crude product was filtered on a silica carbonate cartridge (100 mg) using DCM: MeOH (9: 1) as an eluent and evaporated under vacuum. The crude product was purified by PTLC (DCM: MeOH: NH ₄ OH, 85: 14: 1) to give 6.1 mg of product (63% yield). 1H NMR (500 MHz, DMSO-d6) δ 12.93 (bs, 1H), 9.76 (bs, 1H), 8.93 (s, 1H), 8.69 (t, J = 5.8 Hz, 1H), 8.66 (s, 1H) , 8.56 (bs, 1H), 8.18 (s, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.65 --7.50 (m, 3H), 7.51 --7.32 (m, 4H), 7.28 (t, J) = 8.7 Hz, 1H), 7.09 (d, J = 8.2 Hz, 2H), 5.48 (d, J = 7.2 Hz, 1H), 4.49 (d
, J = 9.2 Hz, 1H), 4.46 --4.33 (m, 2H), 4.32 --4.18 (m, 2H), 3.96 --3.88 (m, 1H), 3.54 --3.42 (m, 1H), 3.30 --3.19 (m) , 4H), 3.17 --3.00 (m, 4H), 2.78 --2.56 (m, 4H), 2.41 (s, 3H), 2.39 --2.30 (m, 1H), 1.82 --1.68 (m, 3H), 0.98 (s) , 9H), 0.95 (t, 3H). 13C NMR (151 MHz, DMSO-d6) δ 180.60, 172.29, 169.55, 168.84, 156.04 (dd, J = 246.5, 6.9 Hz), 152.38 (dd, J = 249.4, 8.3 Hz), 151.40, 150.29, 148.40, 147.75, 143.57, 139.16, 138.53, 131.50, 131.12, 129.79, 128.78 (d, J = 7.4 Hz), 128.70, 128.36, 127.54, 125.99, 121.93 (dd, J = 13.4, 3.6 Hz), 118.52 --117.94 (m), 117.59, 115.87, 115.60, 112.35 (dd, J = 23.0, 3.9 Hz), 69.09, 60.50, 58.62, 56.01, 55.63, 53.46, 52.70, 48.17, 41.83, 36.90, 35.21 , 26.25, 16.85, 15.93, 12.63.LC-MS (ESI); m / z [M + H] ⁺ : C ₅₁ H ₅₈ F ₂ N ₉ O ₇ S ₂ calculated value, 1010.3868. Measured value, 1010.3542.
Example 21-Synthesis Scheme G: Compound 515

tert-Butyl 5- (4-bromophenyl) -5-oxovalerate (19).

In a flask equipped with a magnetic stirring bar, t-butanol (1.00 mL, 10.5) of 5- (4-bromophenyl) -5-oxovaleric acid (0.460 g, 1.70 mmol) and Boc anhydride (0.481 g, 2.21 mmol) It was dissolved in mmol) and then magnesium chloride (0.0162 g, 0.170 mmol) was added. The mixture was stirred at 40 ° C. for 16 hours (overnight). The crude reaction mixture is diluted with EtOAc (100 mL), water (2x100 mL), י ₃
It was washed with an aqueous solution (2x100 mL), dried (Na ₂ SO ₄ ), and evaporated by the rotary evaporation method. The crude product was purified by flash chromatography (SiO ₂ -25g, gradient Hex 100% in 15 minutes ~Hex: EtOAc, 1: 1) to afford product 198mg (35% yield). ¹ H NMR (500 MHz, chloroform-d) δ 7.82 (d, J = 8.3 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 2.99 (t, J = 7.2 Hz, 2H), 2.33 ( t, J = 7.1 Hz, 2H), 2.01 (p, J = 7.2 Hz, 2H), 1.44 (s, 9H). ¹³ C NMR (101 MHz, cdcl3) δ 198.68, 172.67, 135.69, 132.04, 129.72, 128.33 , 80.54, 37.64,
34.68, 28.27, 19.68. LC-MS (ESI); m / z [M + Na] ⁺ : C ₁₅ H ₁₉ BrO ₃ Na calculated value, 349.0415. Measured value, 349.0676 and 351.0609.
tert-Butyl 5- (4- (3- (2,6-difluoro-3- (propylsulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) -5-oxo Valerate (20).

4,4,5,5-Tetramethyl-2- in a dioxane (5 mL) solution of tert-butyl 5- (4-bromophenyl) -5-oxo-valerate (19) (74.0 mg, 0.226 mmol) (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-Dioxaborolan (63.2 mg, 0.249 mmol), CH ₃ CO ₂ K (66.6 mg, 0.678) Methyl) was added and the reaction mixture was degassed under argon. X-PHOS (16.2 mg, 0.0339 mmol) and palladium (II) acetate (2.54 mg, 0.0113 mmol) were added and the reaction mixture was stirred at 100 ° C. (external temperature) for 1 hour under an argon atmosphere. After 1 hour, the temperature of the heating bath was lowered to 90 ° C. and the flask was pulled out of the heating bath, but stirring was continued. N- [3- (5-bromo-1H-pyrrolo [2,3-b] pyridin-3-carbonyl) -2,4-difluoro-phenyl] propan-1-sulfonamide (5) (104 mg, 0.226 mmol) And potassium carbonate (93.8 mg, 0.678 mmol) were added. Water (2.00 ml), tricyclohexylphosphin (6.34 mg, 0.0226 mmol, 2x) and Pd (dba) ₂ (6.50 mg, 0.0113 mmol) were then added and the reaction mixture was heated at 90 ° C. with firm stirring. After stirring for 3 hours, the reaction mixture was cooled to atmospheric temperature. The reaction mixture was diluted with EtOAc (30 mL) and poured into brine (20 mL) to dry the organic extract (Na ₂ SO ₄ ) and evaporated under vacuum. The crude product was purified by flash chromatography (SiO ₂ -40g, gradient Hex: EtOAc, 20 minutes 1: 9~100% EtOAc) was purified by. The product was approximately 85% pure and was purified _{again by PTLC (DCM: MeOH: NH 4} OH, 90: 9: 1) to give 45 mg of product (32% yield). ¹ H NMR (500 MHz, DMSO-d6) δ 12.98 (bs, 1H), 9.68 (bs, 1H), 8.78 (s, 1H), 8.69 (s, 1H), 8.26 (s, 1H), 8.07 (d , J = 8.3 Hz, 2H), 7.92 (d, J = 8.3 Hz, 2H), 7.65 --7.74 (m, 1H), 7.27 (t, J = 8.7 Hz, 1H), 3.10 (q, J = 7.8, 7.3 Hz, 4H), 2.29 (t, J = 7.4 Hz, 2H), 1.85 (p, J = 7.3, 6.8 Hz, 2H), 1.79 --1.62 (m, 2H), 1.39 (s, 9H), 0.95 ( t, J = 7.4 Hz, 3H). ¹³ C NMR (151 MHz, DMSO-d6) δ 199.09, 180.72, 172.08, 156.04 (dd, J = 246.5, 6.9 Hz), 152.37 (dd, J = 249.6, 8.5 Hz) ), 149.29, 144.21, 142.60, 139.11, 135.42, 130.30, 128.97 --128.74 (m), 128.78, 127.40, 127.35, 122.00 (dd, J = 13.6, 3.7 Hz), 118.66 --117.86 (m), 117.55, 115.79, 112.38 (dd, J = 22.7, 3.8 Hz), 79.61, 53.48, 37.08, 34.03, 27.80, 19.46, 16.86, 12.64. LC-MS (ESI); m / z: [M + H] ⁺ C ₃₂ H ₃₄ F ₂ N ₃ O ₆ S calculated value, 626.2136. Measured value, 626.2191.
(2S, 4R) -1-((S) -2- (5- (4- (3- (2,6-difluoro-3- (propylsulfonamide) benzoyl) -1H-pyrrolo [2,3-b] ] Pyridine-5-yl) -phenyl) -5-oxopentanamide) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) -pyrrolidin -2-Carboxamide (Compound 515).

tert-butyl 5-(4- (3- (2,6-difluoro-3- (propyl-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) -5- A mixture of TFA (1.50 mL, 20.2 mmol) and dichloromethane (3 ml) of oxovalerate (20) (22.0 mg, 0.0352 mmol) 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 further purification (19.9 mg, quantitative yield). LC-MS (ESI); m / z: [M + H] ⁺ C ₂₈ H ₂₆ F ₂ N ₃ O ₆ S calculated value, 570.1510. Measured value, 570.1553. The crude product described above; 5-(4- (3- (2,6-difluoro-3- (propylsulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl)- 5-oxovaleric acid (22.0 mg, 0.0386 mmol) and (2S, 4R) -1-((S) -2-amino-3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4) -Methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide hydrochloride (4) (19.8 mg, 0.0425 mmol) in DMF (2 ml) solution with TEA (0.200 mL, 1.43 mmol) and PyBOP (22.1 mg, 0.0425 mmol). mmol) was added at room temperature. The reaction mixture was stirred at the same temperature for 4 hours. TLC (DCM: MeOH: NH ₄ OH, 90: 9: 1) indicates that there is no initiator. DMF was removed under high vacuum. The crude product was filtered on a silica carbonate cartridge using DCM: MeOH (9: 1) as an eluent. When the filtrate is evaporated under vacuum and the crude product is purified by PTLC (DCM: MeOH: NH ₄ OH, 85: 14: 1), 25 mg of product (yield 64%, about 97% according to NMR). Purity) was obtained. 1H NMR (600 MHz, DMSO-d6) δ 13.03 (bs, 1H), 9.73
(bs, 1H), 8.94 (s, 1H), 8.76 (d, J = 2.1 Hz, 1H), 8.69 (bs, 1H), 8.55 (t, J = 6.0 Hz, 1H), 8.25 (s, 1H) , 8.06 (d, J = 8.3 Hz, 2H), 7.93 (d, J = 9.3 Hz, 1H), 7.90 (d, J = 8.2 Hz, 2H), 7.63 --7.50 (m, 1H), 7.37 (dd, 4H), 7.26 (t, J = 8.6 Hz,
1H), 5.11 (d, J = 3.5 Hz, 1H), 4.54 (d, J = 9.3 Hz, 1H), 4.46 --4.36 (m, 2H), 4.36 --4.30 (m, 1H), 4.19 (dd, J) = 15.8, 5.5 Hz, 1H), 3.78 -3.55 (m, 2H), 3.13 --3.07 (m, 2H), 3.04 (t, J = 7.4 Hz, 2H), 2.40 (s, 3H), 2.37 -2.21 ( m, 2H), 2.08-
1.95 (m, 1H), 1.96 -1.79 (m, 3H), 1.71 (h, J = 7.5 Hz, 2H), 0.93 (s, 9H), 0.92 (t, 3H). 13C 51 MHz, DMSO-d6) δ 199.32, 180.72, 171.98, 171.86, 169.74, 156.03 (dd, J = 246.6, 6.9 Hz), 152.36 (dd, J = 249.4, 8.4 Hz), 151.43, 149.28, 147.71, 144.21, 142.52, 139.52, 139.12, 135.48 , 131.17, 130.32, 129.63, 129.00 -128.81 (m), 128.79, 128.64, 127.43, 127.36, 127.36, 121.98 (dd, J = 13.6, 3.6 Hz), 118.75 -117.76 (m), 117.54, 115.78, 112.37 (dd) , J = 22.4, 3.6 Hz), 68.92, 58.74, 53.46, 41.67, 37.99, 37.47, 35.20, 34.11, 26.43, 20.38, 16.86, 15.95, 12.63.LC-MS (ESI); m / z [M + H] ⁺ : C ₅₀ H ₅₄ F ₂ N ₇ O ₈ S ₂ calculated value, 982.3443. Measured value, 982.3535.
Example of Synthesis of Compound 196: (Z) -2- (2,6-dioxopiperidine-3-yl) -5-(3- (4- (4- (4- (1- (H)
Droxyimino) -2,3-dihydro-1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenoxy) butoxy) phenyl) isoindoline-1,3-dione ..

Step A: 5- (1- (4- (4-Hydroxybutoxy) phenyl) -3- (pyridin-4-yl) -1H-pyrazole-4-yl) -2,3-dihydro-1H-inden-1 -on.

4- (4- (4-Bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenoxy) butane-1-ol (150 mg, 0.39 mmol) and 5- (4,4, _{1,4-Dioxane / H 2} O (10 mL) of 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2,3-dihydroinden-1-one (120 mg, 0.46 mmol) , V / v = 10/1) solution to 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) was added. The obtained solution was _{stirred under N 2} at 100 ° C. for 2 hours. The solvent was evaporated under reduced pressure. The residue was diluted with EA (30 mL) and the mixture was washed with brine. When the organic phase is evaporated under reduced pressure and the residue is purified on silica gel (DCM / MeOH = 80/1) by silica gel column chromatography, the desired product (140 mg, 82.4% yield) is colorless. Obtained as oil.

Step B: tert-Butyl 5- (3- (pyridin-4-yl) -1- (4- (4- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-) 2-Il) Phenoxy) Butoxy) Phenyl) -1H-Pyrazole-4-yl) -2,3-Dihydro-1H-Inden-1-one.

5- (1- (4- (4-Hydroxybutoxy) phenyl) -3- (pyridin-4-yl) -1H-pyrazole-4-yl) -2,3-dihydro-1H-inden-1-one ( MsCl (43.8 mg, 0.38 mmol) was added to a solution of 140 mg, 0.32 mmol) and triethylamine (96.8 mg, 0.96 mmol) in DCM (10 mL) at 0 ° C. 30 ℃
After stirring in 1 hour, the solvent was removed under vacuum. The residue was diluted with EA (30 mL) and the mixture was washed with brine. Concentration of the organic phase gave the intermediate mesylate (180 mg, 0.34 mmol, 109%). 3- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (449.7 mg) in a dehydrated DMF (10 mL) solution of mesylate (90 mg, 0.17 mmol) , 0.22 mmol) and K ₂ CO ₃ (47.9 mg, 0.34 mmol) were added. The resulting mixture was stirred at 68 ° C. for 4 hours. The mixture was diluted with EtOAc (40 mL), the mixture was 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 give the desired product (80 mg, 71.7% yield). 1H NMR (400 MHz, CDCl3): 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 --3.37 (m, 1H), 3.13 (s, 2H), 2.74 (s, 2H), 2.01 (s, 2H), 1.34 (s, 12H).
Step C: tert-butyl 2- (2,6-dioxopiperidine-3-yl) -5-(4- (4- (4- (1-oxo-2,3-dihydro-1H- indene) -5-yl) -3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenoxy) butoxy) phenyl) isoindoline-1,3-dione.

tert-butyl 5- (3- (pyridin-4-yl) -1- (4- (4- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -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) solution, 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) were added. The resulting mixture was _{stirred under N 2} at 100 ° C. for 2 hours. The solvent was evaporated under reduced pressure. The residue was diluted with EA (30 mL) and the mixture was washed with brine. The organic phase was evaporated under reduced pressure. Purification of the residue with TLC (PE / EtOAc = 1/8) gave the desired product (40 mg, 41.5% yield).

Step D: (Z) -2- (2,6-dioxopiperidine-3-yl) -5-(3- (4- (4- (4- (1- (Hydroxyimi))
No) -2,3-dihydro-1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenoxy) butoxy) phenyl) isoindoline-1,3-dione ..

tert-butyl 2- (2,6-dioxopiperidine-3-yl) -5-(3- (4- (4- (4- (1-oxo-2,3-dihydro-1H-inden-5-) _{CH 3} CN / Py (5) of isoindoline-1,3-dione (40 mg, 0052 mmol) _{NH 2} OH · HCl (40 mg, 0.57 mmol) was added to the mL / 2 mL) solution. The reaction was stirred at 40 ° C. for 0.5 hours. The mixture was diluted with EtOAc (30 mL) and washed twice with brine. The organic layer was evaporated under reduced pressure. Purification of the residue by preparative HPLC gave the desired product as a white solid (13.5 mg, 8.6% yield). 1H NMR (400 MHz, CDCl3): 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 --7.74 (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] +.
Example of synthesis of compound 197: (E) -2- (2,6-dioxopiperidine-3-yl) -5-(4- (2- (2- (4- (4- (1- (hydroxyimino)) -2,3-Dihydro-1H-Inden-5-yl) -3- (Pyridine-4-yl) -1H-Pyrazole-1-yl) Phenoxy) ethoxy) Ethyl) Piperazine-1-yl) Isoindoline-1 , 3-Zeon.

Step A: 2- (2- (4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenoxy)
Ethoxy) ethanol.

_{Cs 2} CO ₃ (1.55 g) in a dehydrated DMF (5 mL) solution of 4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenol (500 mg, 1.58 mmol). , 4.75 mmol) and 2- (2-hydroxyethoxy) ethyl 4-methylbenzenesulfonate (1.23 g, 4.75 mmol) were added in succession. The resulting solution was stirred at 70 ° C. for 3 hours. After cooling to room temperature, the reaction was quenched with water (20 mL) and the mixture was extracted with EtOAc (20 mL x 3). The mixed organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. Purification of the residue on a silica gel column gave the desired product (500 mg, 78% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3): 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).
Step B: 2- (2- (4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenoxy)
Ethoxy) Ethyl methanesulfonate.

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) MsCl (169 mg, 1.48 mmol) was added dropwise at 0 ° C. to a solution of mmol) in DCM (5 mL). The resulting solution was stirred at 5 ° C for 0.5 hours. After quenching with saturated NaHCO ₃ (20 mL), the mixture was extracted with DCM (20 mL x 2). The mixed organic layer was dried over anhydrous sodium sulfate and concentrated to give the desired product (550 mg crude, calculated) as an oil, which was used directly in the next step. LCMS (ES +): m / z 482.0 [M + H] ⁺ .

Step C: tert-butyl 4-(2- (2- (4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenoxy) ethoxy) ethyl) piperazine-1- Carboxylate.

2- (2- (4- (4-Bromo-3- (pyridine-4-yl) -1H-pyrazol-1-yl) phenoxy) ethoxy) ethyl methanesulfonate (0.5 g, 1.04 mmol) and tert- _{K 2} CO ₃ (715 mg, 5.20 mmol) and KI (860 mg, 5.20 mmol) were subsequently added to a solution of butylpiperazin-1-carboxylate (385 mg, 2.08 mmol) in DMF (5 mL). The resulting solution was stirred at 75 ° C. for 3 hours. After cooling to room temperature, the reaction was quenched with water (20 mL) and the mixture was extracted with ethyl acetate (30 mL x 2). The mixed organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. When the residue was applied on a silica gel column, the desired product (0.4 g, 56% yield in two steps) was obtained as a brown oil. 1H NMR (400 MHz, CDCl3): 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).
Step D: tert-Butyl 4- (2- (2- (4- (4- (1-oxo-2,3-dihydro-1H-inden-5-yl) -3-)
(Pyridine-4-yl) -1H-pyrazole-1-yl) Phenoxy) ethoxy) Ethyl) Piperazine-1-
Carboxylate.

tert-Butyl 4- (2- (2- (4- (4-bromo-3- (pyridine-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) CsF (425 mg, 2.80 mmol), Pd ₂ (dba) ₃ (256 mg, 0.28 mmol), tori in a 1,4-dioxane (15 mL) / H _{2 O (1.5 mL) solution of mg, 1.05 mmol).} -tert-Butylphosphin tetrafluoroborate (162 mg, 0.56 mmol) and a catalytic amount of N-cyclohexyl-N-methylcyclohexaneamine were subsequently added. The reaction was heated to 100 ° C. for 2 hours in _{an N 2 atmosphere.} After cooling to room temperature, the reaction was quenched with water (20 mL) and the mixture was extracted with ethyl acetate (30 mL x 2). The mixed organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. When the residue was applied on a silica gel column, the desired product (0.4 g crude) was obtained as a brown oil. LCMS (ES ⁺ ): m / z 624.7 [M + H] +.

Step E: 2- (2,6-dioxopiperidine-3-yl) -5-(4- (2- (2- (4- (4- (1-oxo-2,3-dihydro-1H-inden)) -5-yl) -3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenoxy) et
Xi) Ethyl) Piperazine-1-yl) Isoindoline-1,3-dione.

tert-butyl 4-(2- (2- (4- (4- (1-oxo-2,3-dihydro-1H-inden-5-yl) -3- (pyridine-4-yl) -1H-pyrazole) -1-yl) phenoxy) ethoxy) ethyl) piperazine-1-carboxylate (400 mg, 0.64 mmol) in MeOH (5 mL) solution with hydrochloric acid (5 mL, 8 mol / L) in 1,4-dioxane. ) Was added. The resulting solution was stirred at 10 ° C. for 1 hour. When the solvent is removed under vacuum,
The desired product (359 mg, calculated) was obtained and used directly in the next step. DIEA (825 mg, 6.40 mmol) and 2- (2,6-dioxopiperidine-3-yl) -5-fluoroisoindoline-in a solution of crude product (359 mg, 0.64 mmol) in NMP (5 mL). 1,3-Dione (530 mg, 1.92 mmol) was added in succession. The reaction was irradiated with microwaves for 60 minutes to 150 ° C. After cooling to room temperature
The reaction was quenched with water (20 mL) and the mixture was extracted with ethyl acetate (30 mL x 2). The mixed organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. When the residue was applied on a silica gel column, the desired product (3 g crude, containing NMP) was obtained as a brown oil. LCMS (ES +):
m / z 780.8 [M + H] ⁺ .

Step F: (E) -2- (2,6-dioxopiperidine-3-yl) -5-(2-(2- (4- (4- (1- (hydroxyimino) -2,) 3-Dihydro-1H-Inden-5-yl) -3- (Pyridine-4-yl) -1H-Pyrazole-1-yl) Phenoxy) ethoxy) Ethyl) Piperazine-1-yl) Isoindoline-1,3- Zeon.

2- (2,6-dioxopiperidine-3-yl) -5-(4- (2- (2- (4- (4- (1-oxo-2,3-dihydro-1H-)-
Inden-5-yl) -3- (Pyridine-4-yl) -1H-Pyrazole-1-yl) Phenoxy) ethoxy) Ethyl) Piperazine-1-yl) Isoindoline-1,3-dione (625 mg, 0.64) To a solution of MeOH / DCM (4 mL / 1 mL) of mmol (mmol) and hydroxylamine hydrochloride (667 mg, 9.60 mmol) _{was added NaHCO 3} (1.21 g, 14.4 mmol) at 50 ° C. The mixture was stirred at 50 ° C. for 10 minutes. The residue was purified by preparative TLC using DCM / MeOH = 20/1 and then further purified by preparative HPLC to give the desired 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] + ..
Example of synthesis of compound 198: (E) -2- (2,6-dioxopiperidine-3-yl) -5-(2- (2- (4- (4- (4- (1- (hydroxyimino)) -2,3-Dihydro-1H-Inden-5-yl) -3- (Pyridine-4-yl) -1H-Pyrazole-1-yl) Phenyl) Piperazine-1-yl) ethoxy) ethoxy) Isoindoline-1 , 3-Zeon.

Step A: 5- (1- (4- (4- (2- (2-Hydroxyethoxy) ethyl) piperazine-1-yl) phenyl) -3- (pyridin-4-yl) -1H-pyrazole-4- Ill) -2,3-dihydro-1H-inden-1-one.

tert-Butyl 4- (4- (4- (1-oxo-2,3-dihydro-1H-inden-5-yl) -3- (pyridine-4-yl) -1H-pyrazol-1-yl) phenyl ) A solution of 6 M HCl (g) in 1,4-dioxane (1 mL) was added to a solution of piperazine-1-carboxylate (200 mg, 0.37 mmol) in MeOH (3 mL). The resulting solution was stirred at 25 ° C. for 1 hour. The solvent was removed under vacuum. The pH was adjusted to about 9 by diluting the residue with 20 mL DCM _{and adding NaHCO 3 aqueous solution incrementally.} The mixture was extracted with DCM. The mixed organic layer was _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give the desired product, which was used directly in the next step. _{2- (2-Hydroxyethoxy) ethyl 4-methylbenzenesulfonate (194 mg, 0.75 mmol) and K 2} CO ₃ (153.2) in a DMF (3 mL) solution of the above intermediate (180 mg crude, 0.37 mmol). mg, 1.11 mmol) was added. The resulting solution was stirred at 70 ° C. for 2 hours. After cooling to room temperature, the reaction 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. Purification of the residue by preparative TLC gave the desired product (53 mg, 27.2% yield) as a yellow solid. LCMS (ES ⁺ ): m / z 524.2 [M + H] ⁺ .

Step B: tert-butyl 2- (2,6-dioxopiperidine-3-yl) -5-(2- (2- (4- (4- (4- (1-Oki))
So-2,3-dihydro-1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazole-1-yl)
Enil) Piperazine-1-yl) ethoxy) ethoxy) Isoindoline-1,3-dione .

5- (1- (4- (4- (2- (2-Hydroxyethoxy) ethyl) piperazine-1-yl) phenyl) -3- (pyridin-4-yl) -1H-pyrazole-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-3-yl) -5- DIAD (60.7 mg, 0.3 mmol) was added dropwise under _{N 2} to a dehydrated THF (3.0 mL) solution of fluoroisoindoline-1,3-dione (41.1 mg, 0.15 mmol). The mixture was stirred at 20 ° C. for 1.5 hours. After quenching with H ₂ O (20 mL), the mixture was extracted with DCM (20 mL x 3). The mixed organic layer was washed with brine, dried over Na ₂ SO ₄ , and concentrated under vacuum. Purification of the residue by preparative TLC yields the desired product (
Crude, 45 mg, yield 34.7%) was obtained as a yellow solid. LCMS (ES ⁺ ): m / z 780.3 [M + H] ⁺ .

Step C: (E) -2- (2,6-dioxopiperidine-3-yl) -5-(2- (2- (4- (4- (4- (1- (hydroxyimino) -2,) 3-Dihydro-1H-Inden-5-yl) -3- (Pyridine-4-yl) -1H-Pyrazole-1-yl) Phenyl) Piperazine-1-yl) ethoxy) ethoxy) Isoindoline-1,3- Zeon.

tert-Butyl 2- (2,6-dioxopiperidine-3-yl) -5-(2- (2- (4- (4- (4- (1-oxo-2,3-) 3-yl)
Dihydro-1H-Inden-5-yl) -3- (Pyridine-4-yl) -1H-Pyrazole-1-yl) Phenyl)
Piperazine-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) solution with hydroxylamine hydrochloride (40.1 mg, 0.58 mmol) was added. The mixture was stirred at 40 ° C. for 20 minutes. The reaction was then diluted with DCM (20 mL) and the mixture was washed with brine (10 mL x 3). The mixed organic layer was removed under vacuum and the residue was purified by preparative TLC and preparative HPLC to give the desired product (5.5 mg, 12% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3): 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 (br, 1H). LCMS (ES +): m / z 795.3 [M + H] +.
Example of Synthesis of Compound 199: (E) -2- (2,6-dioxopiperidine-3-yl) -4- (4- (4- (4- (1- (1- (H))
Droxyimimino) -2,3-dihydro-1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenyl) piperazine-1-yl) propoxy) isoindoline-1 , 3-Zeon.

Step A: 5- (1- (4- (4- (3-Hydroxypropyl) piperazine-1-yl) phenyl) -3- (pyridi)
N-4-yl) -1H-pyrazole-4-yl) -2,3-dihydro-1H-indene-1-one.

tert-Butyl 4- (4- (4- (1-oxo-2,3-dihydro-1H-inden-5-yl) -3- (pyridine-4-yl) -1H-pyrazol-1-yl) phenyl ) To a solution of piperazine-1-carboxylate (270 mg, 0.50 mmol) in MeOH (5 mL) was added 6 M hydrochloric acid (1 mL) in 1,4-dioxane. The resulting solution was stirred at 25 ° C. for 1 hour. The solvent was removed in vacuo. Dilute the residue with 20 mL DCM and י
_The pH was adjusted to about 9 by adding 3 aqueous solutions. The mixture was extracted with DCM. The mixed 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.

_{3-Hydroxypropyl 4-methylbenzenesulfonate (230 mg, 1 mmol) and K 2} CO ₃ (207 mg, 1.5 mmol) in a DMF (5 mL) solution of the above intermediate (240 mg crude, 0.50 mmol). Was added.
The resulting solution was stirred at 70 ° C. for 2 hours. After cooling to room temperature, the reaction was diluted with DCM (20 mL). The mixture was washed with brine and dried over Na ₂ SO ₄ . The solution was filtered and concentrated under reduced pressure. Purification of the residue by preparative TLC gave the desired product (100 mg, 30.5% yield) as a yellow solid. LCMS (ES ⁺ ): m / z 494.3 [M + H] ⁺ .
Step B: tert-butyl 5-amino-4-(1,3-dioxo-4- (3- (4- (4- (4- (1-oxo-2,3-dihydro-1H-inden-5-) Il) -3- (Pyridine-4-yl) -1H-Pyrazole-1-yl) Phenyl) Pipera
Gin-1-yl) Propoxy) Isoindoline-2-yl) -5-oxovalerate.

5- (1- (4- (4- (3-Hydroxypropyl) piperazin-1-yl) phenyl) -3- (pyridine-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-dioxoisoindoline) -2-yl) -DIAD (121.2 mg, 0.60 mmol) was added dropwise under _{N 2} to a dehydrated THF (5.0 mL) solution of 5-oxopentanate (104.4 mg, 0.30 mmol). The mixture was stirred at 20 ° C. for 1.5 hours. The reaction is quenched with DCM (20 mL) and the mixture is brine (10 mL).
It was washed with × 3). The organic phase was concentrated under vacuum. Purification of the residue by preparative TLC gave the desired product (120 mg, 43.1% yield) as a yellow solid. LCMS (ES ⁺ ): m / z 824.3 [M + H] ⁺ .

Step C: 2- (2,6-dioxopiperidine-3-yl) -4- (3- (4- (4- (4- (1-oxo-2,3-dihydro-1H-inden-5-) Ill) -3- (Pyridine-4-yl) -1H-Pyrazole-1-yl) Phenyl) Piperazine-1-yl) Propoxy) Isoindoline-1,3-dione .

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-pyrazole-1-yl) phenyl) piperazine-1-yl) propoxy) isoindoline-2-yl) -5-oxopentanoate ( Crude 120 mg, 0.087 m
To a solution of mol) 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, dilute the reaction with DCM (30 mL) and
The mixture was washed with brine (10 mL x 2). The organic phase was _{dried over Na 2} SO ₄ and concentrated under vacuum. Purification of the residue by preparative TLC gave the desired product (40 mg, 61.1% yield) as a yellow solid. LCMS (ES ⁺ ): m / z 750.3 [M + H] ⁺ .

Step D: (E) -2- (2,6-dioxopiperidine-3-yl) -4- (3- (4- (4- (1- (hydroxyimi))
C) -2,3-dihydro-1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenyl) piperazine-1-yl) propoxy) isoindoline-1 , 3-Zeon.

2- (2,6-dioxopiperidine-3-yl) -4- (4- (4- (4- (4- (1-oxo-2,3-dihydro-1H-inden-5-yl))- 3- (Pyridine-4-yl) -1H-pyrazol-1-yl) phenyl) piperazine-1-yl) propoxy) Isoindoline-1,3-dione (40 mg, 0.053 mmol) acetonitrile / pyridine (v / To a solution (v = 3/1, 4 mL) was added hydroxylamine hydrochloride (36.8 mg, 0.53 mmol). The mixture was stirred at 40 ° C. for 20 minutes and then diluted with DCM (20 mL). The mixture was washed with brine (10 mL x 2). The organic phase was _{dried over Na 2} SO ₄ and concentrated under vacuum. The residue was purified by preparative TLC and preparative HPLC to give the desired 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] +.
Example of Synthesis of Compound 200: (E) -2- (2,6-dioxopiperidine-3-yl) -4- (3- (3- (4- (4- (1- (H))
Droxyimino) -2,3-dihydro-1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenoxy) propoxy) phenyl) isoindoline-1,3-dione ..

Step A: 3- (4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenoxy) propan-1-ol.

_{K 2} CO ₃ (434 mg, 3.16 mmol) and 3-hydroxypropyl 4 in a dehydrated DMF (10.0 mL) solution of 4- (4-bromo-1H-pyrazol-3-yl) pyridine (500 mg, 1.58 mmol). -Methylbenzene sulfonate (400 mg, 1.74 mmol) was added in succession. The resulting solution was stirred at 80 ° C. for 3 hours. The reaction mixture was diluted with EA (30 mL) and washed with brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. Purification of the residue reveals the desired product 3- (4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenoxy) propanol-1-ol (PE: EA).
= 1: 1) (400 mg, 67% yield) was obtained as a pale yellow oil. LCMS (ES ⁺ ): m / z 376.0 [M + H] ⁺ .

Step B: 3- (4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenoxy) propan-1-ol.

3- (4- (4-Bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenoxy) Propane-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), N, N-dicyclohexylmethylamine (9.0 mg, 0.047 mmol), 10% of 1,4-dioxane The mixed aqueous solution (10 ml) was irradiated with microwaves at 100 ° C. under _{N 2 for 2 hours.} The mixture was cooled to room temperature and quenched with water. The mixture was diluted with EA and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. Purification of the residue reveals the desired product 3- (4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenoxy) propan-1-ol (DCM: MeOH =). 50: 1) (450 mg, 87% yield) was obtained as a yellow solid. LCMS (ES ⁺ ): m / z 426.1 [M + H] ⁺ .

Step C: 5- (3- (pyridin-4-yl) -1- (4- (3- (3- (4,4,5,5-tetramethyl-1,3,2-dioxa)
Bororan-2-yl) Phenoxy) Propoxy) Phenyl) -1H-Pyrazole-4-yl) -2,3-Dihydro-1H-Inden-1-one.

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) ) MsCl (145 mg, 1.27 mmol) was added dropwise at 0 ° C. to the DCM (10.0 mL) solution. The resulting solution was stirred at 25 ° C. for 1 hour. The solvent was evaporated and the residue was diluted with EA (50 mL). The solution was washed with saturated NaHCO ₃ and brine. The organic layer was dried over anhydrous sodium sulfate. Removal of the solvent under vacuum gave the desired crude product (520 mg crude), which was used directly in the next step. _{K 2} CO ₃ (285 mg, 2.07 mmol) and 3- (4,4,5,5-tetramethyl-1) in a dehydrated DMF (10 mL) solution of the above desired product (520 mg, 1.03 mmol). , 3,2-Dioxaborolan-2-yl) Phenol (341 mg, 1.55 mmol) was added. The resulting solution was stirred at 70 ° C. overnight. After cooling to room temperature, the reaction mixture was diluted with EA (50 mL) and the mixture was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate. Purification of the residue on a chromatographic column reveals 5- (3- (pyridin-4-yl) -1- (4- (3- (3- (4,4,5,5-tetramethyl-1,3,)). 2-Dioxaborolan-2-yl) Phenoxy) Propoxy) Phenyl) -1H-Pyrazole-4-yl) -2,3-Dihydro-1H-Inden-1-one (200 g, 32% yield in two steps) was gotten. 1H NMR (400 MHz, CDCl3): 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).
Step D: 2- (2,6-dioxopiperidine-3-yl) -4- (3- (3- (4- (4- (1-oxo-2,3-dihydro-1H-inden-5-) Ill) -3- (Pyridine-4-yl) -1H-Pyrazole-1-yl) Phenoxy) Propoxy) Phenyl) Isoindoline-1,3-dione.

4-Chloro-2- (2,6-dioxopiperidine-3-yl) isoindoline-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-pyrazole-4-yl) -2 , 3-Dihydro-1H-inden-1-one (47 mg, 0.159 mmol) in a dioxane (5 mL) / H ₂ O (0.5 mL) solution, CsF (97 mg, 0.64 mmol), Pd (aMphos) Cl ₂ (12 mg, 0.016 mmol) was added. After stirring at 100 ° C. for 2 hours under a nitrogen atmosphere, 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 under vacuum. Purification of the residue by preparative TLC (DCM / MeOH = 20/1) gives the desired product 2- (2,6-dioxopiperidine-3-yl) -4- (3- (3- (4- (4-) (4- (1-oxo-2,3-dihydro-1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenoxy) propoxy) phenyl) isoindoline- 1,3-dione (50 mg, 40% yield) was obtained as a yellow solid. LCMS (ES ⁺ ): m / z 758.2 [M + H] ⁺ .

Step E: (E) -2- (2,6-dioxopiperidine-3-yl) -4- (3- (3- (4- (4- (1- (Hydroxyimi))
No) -2,3-dihydro-1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenoxy) propoxy) phenyl) isoindoline-1,3-dione ..

2- (2,6-dioxopiperidin-3-yl) -4-(3-(3-(4-(4-(1-oxo-2,3-dihydro-1H-inden-5-yl))- 3- (Pyridine-4-yl) -1H-pyrazole-1-yl) phenoxy) propoxy) phenyl) isoindoline-1,3-dione (50 mg, 0.053 mmol) acetonitrile (2 mL) and pyridine (1 mL) ) To the solution of hydroxylamine hydrochloride (34 mg, 0.53 mmol). After stirring at 40 ° C. for 20 minutes, the reaction was diluted with DCM (20 mL) and the mixture was washed with brine (10 mL x 2). The organic phase was _{dried on Na 2} SO ₄ , concentrated under vacuum and the residue was purified by preparative TLC to (E) -2- (2,6-dioxopiperidine-3-yl) -4-. (3- (3- (4- (4- (1- (Hydroxyimino) -2,3-dihydro-1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazole-1 -Il) Phenoxy) Propoxy) Phenyl) Isoindoline-e-1,3-dione (26 mg, 51% yield) was obtained 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] +.
Synthesis example of compound 201:

Step A: 5-Fluoro-2- (1-methyl-2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione.

NaH (145 mg, 3.62) in a dehydrated DMF (10.0 mL) solution of 2- (2,6-dioxopiperidine-3-yl) -5-fluoroisoindoline-1,3-dione (500 mg, 1.81 mmol). mmol) was added at 0 ° C. After stirring for 0.5 hours, CH ₃ I (513.7 mg, 3.62 mmol) was added at 0 ° C. The resulting solution was stirred for 2 hours. After quenching with NH ₄ Cl aqueous solution, dilute the mixture with 30 mL A and brine (20 mL).
It was washed with × 3). When the organic phase is _{dried over Na 2} SO ₄ and concentrated, 5-fluoro-2- (1-methyl-2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione (500 mg, Yield 95.2%) was obtained as a brown solid, which was used directly in the next step. LCMS (ES ⁺ ): m / z 291.1 [M + H] ⁺ .

Step B: 2- (1-Methyl-2,6-dioxopiperidine-3-yl) -5-(4- (4- (1-oxo-2,3-di)
Hydro-1H-Inden-5-yl) -3- (Pyridine-4-yl) -1H-Pyrazole-1-yl) Phenyl) Pi
Perazine-1-yl) Isoindoline-1,3-dione .

tert-Butyl 4- (4- (4- (1-oxo-2,3-dihydro-1H-inden-5-yl) -3- (pyridine-4-yl) -1H-pyrazol-1-yl) phenyl ) To a solution of piperazine-1-carboxylate (100 mg, 0.19 mmol) in MeOH (3 mL) was added 6M hydrochloric acid (1 mL) in 1,4-dioxane. The resulting solution was stirred at 25 ° C. for 1 hour. The solution was concentrated, diluted with 20 mL DCM and _{aqueous NaHCO 3} was added to adjust 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. 5-Fluoro-2- (1-methyl-2,6-dioxopiperidine-3-yl) isoindoline-1,3-yl in NMP (5 mL) solution of the above intermediate (90 mg crude, 0.19 mmol) Dione (100 mg, 0.29 mmol) and DIEA (245.1 mg, 1.9 mmol) were added. The resulting solution was irradiated with microwaves at 150 ° C. for 2 hours. After cooling to room temperature, it 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. Purification of the residue on a silica gel column reveals 2- (1-methyl-2,6-dioxopiperidine-3-yl) -5-(4- (4- (4- (1-oxo-2,3-dihydro) -1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenyl) piperazine-1-yl) isoindoline-1,3-dione (43 mg, yield) 26.5%) was obtained. LCMS (ES ⁺ ): m / z 706.3 [M + H] ⁺ .

Step C: (E) -2- (2,6-dioxopiperidine-3-yl) -5-(4- (4- (4- (1- (hydroxyimino) -2,3-dihydro-1H-) Inden-5-yl) -3- (Pyridine-4-yl) -1H-Pyrazole-1-yl) Phenyl) Piperazine-1-yl) Isoindoline-1,3-dione.

2- (1-Methyl-2,6-dioxopiperidine-3-yl) -5-(4- (4- (4- (1-oxo-2,3-dihydro-1H-inden-5-yl)) -3- (Pyridine-4-yl) -1H-pyrazol-1-yl) phenyl) piperazine-1-yl) isoindoline-1,3-dione (43 mg, 0.061 mmol) acetonitrile / pyridine (3 mL, 3 mL, v / v = 2/1) Hydroxylamine hydrochloride (42.4 mg, 0.61 mmol) was added to the solution at room temperature. The mixture was heated at 40 ° C. for 40 minutes. After cooling to room temperature, it was diluted with DCM (20 mL) and washed with brine (10 mL). The organic phase was concentrated under vacuum. By purifying the residue by preparative TLC, (E) -2- (2,6-dioxopiperidine-3-yl) -5-(4- (4- (4- (1- (hydroxyimino)) -2,3-dihydro-1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenyl) piperazine-1-yl) isoindoline-1,3-dione (23 mg, yield 52.3%) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6): 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 (br, 1H). LCMS (ES +) : m / z 721.3 [M + H] +.
Example of Synthesis of Compound 202: (3R) -N- (3- (5-(4- (4- (2- (4- (2- (2,6-dioxopiperidine-3-yl) -1,3) -Dioxoisoindoline-5-yl) piperazine-1-yl) ethyl) piperazine-1-yl) phenyl) -1H-pyrrolidine [2,3-b] pyridine-3-carbonyl) -2,4-difluorophenyl ) -3-Fluoropyrrolidine-1-sulfonamide.

Step A: 1- (4-bromophenyl) -4- (2,2-diethoxyethyl) piperazine.

_{2-bromo-1,1-diethoxyethane (4.1 g, 20.8 mmol) and K 2} CO ₃ (4 g, 20.8 mmol) in a dehydrated DMF (50 ml) solution of 1- (4-bromophenyl) piperazine (5 g, 20.8 mmol). 8.6 g, 62.4 mmol) was added. The resulting solution was stirred at 90 ° C. for 16 hours. The reaction was diluted with EA (50 mL) and the mixture was washed (20 mL x 2). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied on a silica gel column to give the desired product (6 g, 81% yield) as an oil.

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).
Step B: 1- (2,2-diethoxyethyl) -4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaboro)
Ran-2-yl) phenyl) piperazine.

4,4,4', 4 in a 1,4-dioxane (70 mL) solution of 1- (4-bromophenyl) -4- (2,2-diethoxyethyl) piperazine (7.8 g crude, 21.9 mmol) ', 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) was added. The resulting solution was _{stirred under N 2} atmosphere at 90 ° C. overnight. TLC
Indicates that the reaction is complete. After cooling to room temperature, the reaction mixture was concentrated and purified on a chromatography column. 1- (2,2-diethoxyethyl) -4- (4- (4,4,5,5-tetramethyl-1,4) 3,2-Dioxaborolan-2-yl) phenyl) piperazine (5 g, 74% yield) was obtained. 1H
NMR (400 MHz, CDCl3): 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).
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 .

(R) -N- (3- (5-bromo-1H-pyrrolo [2,3-b] pyridin-3-carbonyl) -2,4-difluorophenyl) -3-fluoropyrrolidine-1-sulfonamide (300) mg, 0.60 mmol) 1,4-dioxane / H ₂ O
In (10 mL / 2 mL) solution, 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) were added. The resulting solution was _{stirred under N 2} atmosphere at 95 ° C. for 3 hours. TLC showed that the reaction was complete. After cooling to room temperature, the reaction mixture was diluted with EA (50 mL) and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate. Purification of the residue on a chromatographic column reveals (R) -N- (3-(5-(4- (4- (2,2-diethoxyethyl) piperazine-1-yl) phenyl) -1H-pyrrolo [ 2,3-b] pyridine-3-carbonyl) -2,4-difluorophenyl) -3-fluoropyrrolidine-1-sulfonamide (350 mg, 70% yield) was obtained. LCMS (ES ⁺ ): m / z 701.3 [M + H] ⁺ .

Step D: (R) -N- (2,4-difluoro-3- (5- (4- (4- (2-oxoethyl) piperazine-1-yl) phenyl) -1H-pyrrolo [2,3-b ] Pyridine-3-carbonyl) Phenyl) -3-fluoropyrrolidine-1-s
Luhonamide.

(R) -N- (3- (5- (4- (4- (2-,2-diethoxyethyl) piperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b] pyridine-3- Concentrated HCl (3 mL, 9 mL H ₂ O _{) in CH 3} CN (10 mL) solution of carbonyl) -2,4-difluorophenyl) -3-fluoropyrrolidine-1-sulfonamide (350 mg, 0.50 mmol). Dilution) was added. The resulting solution was stirred at 55 ° C. for 16 hours. After cooling to room temperature, saturated NaHCO ₃ was added to the reaction mixture to adjust the pH to 7-8. A large amount of solid matter was observed. The suspension was extracted with DCM. The organic phase is dried over anhydrous sodium sulfate and concentrated to give (R) -N- (2,4-difluoro-3-(5-(4- (4- (2-oxoethyl) piperazine-1-yl) phenyl). ) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl) phenyl) -3-fluoropyrrolidine-1-sulfonamide (490 mg, crude) was obtained. LCMS (ES ⁺ ): m / z 645.2 [M + H + 18] ⁺ .

Step E: (3R) -N- (3- (5- (4- (4- (2- (2- (2- (2- (2,6-dioxopiperidine-3-yl))-1,3-dioki)
Soisoindoline-5-yl) piperazine-1-yl) ethyl) piperazine-1-yl) phenyl) -1H-pyrrolidine [2,3-b] pyridin-3-carbonyl) -2,4-difluorophenyl) -3 -Fluoropyrrolidine-1-sulfonamide.

(R) -N- (2,4-difluoro-3- (5- (4- (4- (2-oxoethyl) piperazine-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) solution in 2- (2,6-) Dioxopiperidine-3-yl) -5- (piperazine-1-yl) isoindoline-1,3-dione hydrochloride (364 mg)
, 0.96 mmol) and two drops of AcOH were added. Then NaBH ₃ CN (248 mg, 4.00 mmol) was added. The resulting solution was stirred at 20 ° C. for 2 hours. The reaction mixture was diluted with 20 mL of saturated NaCl solution and extracted with DCM. The organic phase was dried over anhydrous sodium sulfate and concentrated. When the crude is applied first on a silica gel column and then on a preparative HPLC, the desired product (3R) -N- (3- (5- (4- (4- (2- (4- (2- (2) 2- (2) , 6-dioxopiperidine-3-yl) -1,3-dioxoisoindoline-5-yl) piperazin-1-yl) ethyl) piperazine-1-yl) phenyl) -1H-pyrrolo [2,3- b] Pyridine-3-carbonyl) -2,4-difluorophenyl) -3-fluoropyrrolidine-1-sulfonamide (75 mg, 16% yield in two steps) was obtained 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] +.
Example of synthesis of compound 203: (E) -2- (2,6-dioxopiperidine-3-yl) -5-(2- (3- (4- (1- (hydroxyimino) -2,3-dihydro) -1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenoxy) ethoxy) isoindoline-1,3-dione.

Step A: 4- (1- (3- (2- (benzyloxy) ethoxy) phenyl) -4-bromo-1H-pyrazole-3-yl) pyridine.

2- (3- (2- (benzyloxy) ethoxy) phenyl) -4,4,5,5-tetramethyl-1,3,2-
In a DCM (50 mL) solution of dioxaborolane (1.2 g, 3.39 mmol), 4- (4-bromo-1H-pyrazole-3-yl) pyridine (831.53 mg, 3.73 mmol), Cu (OAc) ₂ (615.6 mg, 3.39 mmol), Et ₂ NH (2.47 g, 33.9 mmol) were added in succession. The resulting solution was stirred at 30 ° C overnight. The mixture was washed with ammonium hydroxide (30 mL x 3). The organic phase was dried and concentrated under vacuum. Purification of the residue on a silica gel column with PE / EA results in the desired product 4-(1- (3- (2- (benzyloxy) ethoxy) phenyl) -4-bromo-1H-pyrazole-3-yl. ) Pyridine (900 mg, 59% yield) was obtained as a purple solid. LCMS (ES ⁺ ): m / z 450.1 [M + H] ⁺ .

Step B: 5- (1- (3- (2- (benzyloxy) ethoxy) phenyl) -3- (pyridin-4-yl) -1H-pyrazole-4-yl) -2,3-dihydro-1H- Inden-1-on.

4- (1- (3- (2- (benzyloxy) ethoxy) phenyl) -4-bromo-1H-pyrazole-3-yl) pyridine (900 mg, 2.0 mmol) 1,4-dioxane / H ₂ O In (20mL, v / v = 10/1) solution, 5- (4,4,5,5-
Tetramethyl-1,3,2-dioxaborolan-2-yl) -2,3-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), N, N-dicyclohexylmethylamine (503 mg, 2.58 mmol) were added in succession. The resulting solution was _{stirred under N 2} at 100 ° C. for 2 hours. After cooling to room temperature, the reaction was diluted with EA (50 mL) and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. Purification of the residue on a silica gel column reveals 5- (1- (3- (2- (benzyloxy) ethoxy) phenyl) -3- (pyridin-4-yl) -1H-pyrazole-4-yl) -2, 3-Dihydro-1H-inden-1-one (750 mg, 74.9% yield) was obtained as a yellow solid. LCMS (ES ⁺ ): m / z 502.2 [M + H] ⁺ .

Step C: 5- (1- (3- (2-Hydroxyethoxy) phenyl) -3- (pyridin-4-yl) -1H-pyrazole-4-yl) -2,3-dihydro-1H-inden-1 -on.

5- (1- (3- (2- (benzyloxy) ethoxy) phenyl) -3- (pyridin-4-yl) -1H-pyrazole-4-yl) -2,3-dihydro-1H-inden-1 _{-BBr 3 (} 1.13 g, 4.50 mmol) in DCM (5 mL) was added dropwise to a solution of on (750 mg, 1.50 mmol) in DCM (10 mL) _{under N 2 at -60 ° C.} After stirring for 1 hour, the mixture was diluted with DCM (20 mL) and washed with brine (10 ml x 2). When the organic phase is concentrated and purified on a silica gel column, 5- (1- (3- (2-hydroxyethoxy) phenyl) -3- (pyridin-4-yl) -1H-pyrazole-4-yl) -2, 3-Dihydro-1H-inden-1-one (150 mg, 24.4% yield) was obtained as a yellow solid. LCMS (ES ⁺ ): m / z 412.1 [M + H] ⁺ .

Step D: 2- (2,6-dioxopiperidine-3-yl) -5-(2- (3- (4- (1-oxo-2,3-dihydro-1H-inden-5-yl))- 3- (Pyridine-4-yl) -1H-pyrazole-1-yl) Phenoxy) ethoxy) Isoindoline-1,3-dione .

5- (1- (3- (2-Hydroxyethoxy) phenyl) -3- (pyridin-4-yl) -1H-pyrazole-4-yl) -2,3-dihydro-1H-inden-1-one ( MsCl (61.56 mg, 0.54 mmol) was added dropwise at 0 ° C. to a solution of DCM (10 mL) and TEA (109.08 mg, 1.08 mmol) at 150 mg, 0.36 mmol). The resulting solution was stirred at 25 ° C. for 0.5 hours. Water was then added and extracted by DCM. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated to give the desired crude product (170 mg crude, 95.5% yield) as a yellow oil, which is the next step. Used directly in. _{K 2} CO ₃ (144.9 mg, 1.05 mmol), 2- (2,6-dioxopiperidine-3-yl)-in a DMF (10 ml) solution of the desired product (170 mg, 0.35 mmol) above. 5-Hydroxyisoindoline-1,3-dione (191.8 mg, 0.70 mmol) was added. The resulting solution was stirred at 70 ° C. for 2 hours. After quenching with water, the mixture was extracted with EA (30 mL) and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to remove 2- (2,6-dioxopiperidine-3-yl) -5- (2- (3- (4- (1- (1- (1- (1- (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) , Yield 25.9%) was obtained as a white solid. LCMS (ES ⁺ ): m / z
668.2 [M + H] ⁺ .

Step E: (E) -2- (2,6-dioxopiperidine-3-yl) -5-(2- (3- (4- (1- (hydroxyimino) -2,3-dihydro-1H-) Inden-5-yl) -3- (Pyridine-4-yl) -1H-Pyrazole-1-yl) Phenoxy) ethoxy) Isoindoline-1,3-dione .

S2- (2,6-dioxopiperidin-3-yl) -5-(2-(3-(4-(1-oxo-2,3-dihydro-1H-inden-5-yl) -3-( Pyridine-4-yl) -1H-pyrazole-1-yl) Phenoxy) ethoxy) Isoindoline-1,3-dione (60 mg, 0.090 mmol) acetonitrile / pyridine (3.0 mL, v / v = 2/1) To the solution was added hydroxylamine hydrochloride (58.41 mg, 0.90 mmol). 40 of the mixture
The mixture was stirred at ° C for 20 minutes. It was then diluted with DCM (20 mL) and washed with brine (10 mL). When the organic phase is concentrated and purified by preparative HPLC, (E) -2- (2,6-dioxopiperidine-3-yl) -5-(2- (3- (4- (1- (hydroxyimino)) ) -2,3-Dihydro-1H-Inden-5-yl) -3- (Pyridine-4-yl) -1H-Pyrazole-1-yl) Phenoxy) ethoxy) Isoindoline-1,3-dione (8 mg) , Yield 65.6%) was obtained as a white solid. 1H NMR (400 MHz, CDCl3): 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] +.
Compounds 204 and 205 can be prepared in a manner similar to compound 203.

Example of Synthesis of Compound 206: (E) -2- (2,6-dioxopiperidine-3-yl) -5-(2- (4- (4- (1- (hydroxyimino) -2,3-dihydro) -1H-Inden-5-yl) -3- (Pyridine-4-yl) -1H-Pyrazole-1-yl) Piperidine-1-yl) ethoxy) Isoindoline-1,3-dione.

Step A: tert-butyl 4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate.

4- (4-Bromo-1H-pyrazole-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 ( A 11.0 g, 33.6 mmol) DMF (50 mL) solution was stirred at 55 ° C. overnight. When cooled to room temperature, water (50 mL) was added. The resulting mixture was extracted with ethyl acetate (20 mL x 3), the mixed organic layer was washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated. When the residue is purified by column chromatography on silica (petroleum ether / ethyl acetate = 1/1), it is tert-butyl.
4- (4-Bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate (3.7 g, 41% yield) is obtained as a brown oil. rice field. LCMS: m / z 407.1 [M + H] ⁺ .

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.

tert-Butyl 4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) piperidine-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 mmo
_{Pd (PPh 3} ) ₄ (200 mg) was added to a solution of l) in 1,4-dioxane (40 mL) and water (8 mL) under an Ar atmosphere, and the mixture was stirred at 80 ° C. for 2 hours. When cooled to room temperature, the mixture is ethyl acetate (20 mL).
Extracted in × 3), the mixed 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) and 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, 84% yield) is yellow Obtained as oil. LCMS: m / z 459.3 [M + H] ⁺
..

Step C: 5- (1- (piperidine-4-yl) -3- (pyridin-4-yl) -1H-pyrazole-4-yl) -2,3-dihydro-1H-inden-1-one.

tert-butyl 4- (4- (1-oxo-2,3-dihydro-1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazole-1-yl) piperidine- The mixture of 1-carboxylate (1.9 g, 4.1 mmol) in HCl / 1,4-dioxane (20 mL) was stirred at room temperature for 2 hours. The solvent was then removed directly in vacuo to give the crude product (1.6 g, 100% yield) as hydrochloride, which was used directly in the next step without further purification.

Step D: 2- (2,6-dioxopiperidine-3-yl) -5-(2- (4- (4- (1-oxo-2,3-dihydro-1H-inden-5-yl))- 3- (Pyridine-4-yl) -1H-pyrazole-1-yl) piperidine-1-yl) ethoxy) isoindoline-1,3-dione.

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-dioxopiperidine-3-yl) isoindoline-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. When cooled to room temperature, add water (10 mL), extract the mixture with ethyl acetate (5 mL x 3), wash the mixed organic layer with brine (5 mL x 3) and dry over anhydrous sodium sulfate. , Filtered and concentrated. When the residue is purified by preparative TLC (DCM / MeOH = 10/1), 2- (2,6-dioxopiperidine-3-yl) -5- (2- (4- (4- (1-oxo)) -2,3-dihydro-1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazol-1-yl) piperidine-1-yl) ethoxy) isoindoline-1,3-dione (180 mg, 22% yield) was obtained as a white solid. LCMS: m / z 659.3 [M + H] ⁺ .

Step E: (E) -2- (2,6-dioxopiperidine-3-yl) -5-(2- (4- (4- (1- (hydroxyimino) -2,3-dihydro-1H-) Inden-5-yl) -3- (Pyridine-4-yl) -1H-Pyrazole-1-yl) Piperidine-1-yl) ethoxy) Isoindoline-1,3-dione.

2- (2,6-dioxopiperidine-3-yl) -5-(2- (4- (4- (1-oxo-2,3-dihydro-1H-inden-5-yl) -3- ( Pyridine-4-yl) -1H-pyrazole-1-yl) piperidine-1-yl) ethoxy)
To a solution of isoindoline-1,3-dione (120 mg, 0.2 mmol) in pyridine (2 mL) was added hydroxylamine hydrochloride (126 mg, 1.8 mmol) and the mixture was stirred at room temperature for 2 hours. The solvent was then removed in vacuo and the residue was purified by preparative HPLC to (E) -2- (2,6-dioxopiperidine-3-yl) -5- (2- (4- (4-). (4- (1- (Hydroxyimino) -2,3-dihydro-1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazol-1-yl) piperidine-1-yl) Ethoxy) Isoindoline-1,3-dione (52 mg, 42% yield) was obtained. LCMS: m / z 674.2 [M + H] +; 1H NMR (400 MHz, DMSO-d6) 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).
Example of synthesis of compound 207: (E) -2- (2,6-dioxopiperidine-3-yl) -5-(4- (4- (1- (hydroki))
Siimino) -2,3-dihydro-1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazole-1-
Il) -1,4'-bi piperidine-1'-il) Isoindoline-1,3-dione.

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.

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) DMF (20 mL) of 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). The solution was stirred at 110 ° C. overnight. When cooled to room temperature, water (30 mL) was added. The resulting mixture was extracted with ethyl acetate (20 mL x 3), the mixed organic layer was washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated. Purification of the residue on silica (DCM / MeOH = 20/1) by column chromatography reveals tert-butyl 4-(4- (1-oxo-2,3-dihydro-1H-inden-5-yl)- 3- (Pyridine-4-yl) -1H-pyrazole-1-yl) -1,4'-bipiperidin-1'-carboxylate (360 mg, 10% yield) was obtained as a brown oil. LCMS: m / z 542.3 [M + H] ⁺ .

Step B: 5- (1- (1,4'-bipiperidin-4-yl) -3- (pyridin-4-yl) -1H-pyrazole-4-yl)
Le) -2,3-dihydro-1H-inden-1-one.

tert-butyl 4- (4- (1-oxo-2,3-dihydro-1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazole-1-yl) -1,4 A mixture of'-bipiperidine-1'-carboxylate (360 mg, 0.7 mmol) in HCl / 1,4-dioxane (10 mL) was stirred at room temperature for 30 minutes. The solvent was then removed directly in vacuo to give the crude product (300 mg, 100% yield) as hydrochloride, which was used directly in the next step without further purification.

Step C: 2- (2,6-dioxopiperidine-3-yl) -5-(4- (4- (1-oxo-2,3-dihydro-1H-b)
Nden-5-yl) -3- (pyridin-4-yl) -1H-pyrazole-1-yl) -1,4'-bipiperidin-1'-yl) isoindoline-1,3-dione.

5- (1- (1,4'-bipyridine-4-yl) -3- (pyridin-4-yl) -1H-pyrazole-4-yl) -2,3-dihydro-1H-inden-1-one (290 mg, 0.7 mmol), 2- (2,6-dioxopiperidine-3-yl) -5-fluoroisoindoline-1,3-dione (183 mg, 0.7 mmol), and Et ₃ N (336 mg). , 3.3 mmol) DMSO (5 mL) solution was stirred at 80 ° C. overnight. When cooled to room temperature, add water (10 mL), extract the mixture with ethyl acetate (5 mL x 3), wash the mixed organic layer with brine (5 mL x 3) and dry over anhydrous sodium sulfate. , Filtered and concentrated. When the residue is purified by preparative TLC (DCM / MeOH = 20/1), 2- (2,6-dioxopiperidine-3-yl) -5-(4- (4- (1-oxo-2,,) 3-Dihydro-1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazol-1-yl) -1,4'-bipyridine-1'-yl) isoindoline-1,3 -Dione (195 mg, 42% yield) was obtained as a white solid. LCMS:
m / z 698.3 [M + H] ⁺ .

Step D: (E) -2- (2,6-dioxopiperidine-3-yl) -5-(4- (4- (1- (hydroxyimino) -2,3-dihydro-1H-inden-5) -Il) -3- (Pyridine-4-yl) -1H-Pyrazole-1-yl) -1,4'-bi
Piperidine-1'-yl) isoindoline-1,3-dione.

2- (2,6-dioxopiperidine-3-yl) -5-(4- (4- (1-oxo-2,3-dihydro-1H-inden-5-yl) -3- (pyridine-4) -Il) -1H-pyrazol-1-yl) -1,4'-bipyridine-1'-yl) Isoindoline-1,3-dione (95 mg, 0.1 mmol) in a pyridine (2 mL) solution with hydroxyl Amine hydrochloride (94 mg, 1.3 mmol) was added and the mixture was stirred at room temperature for 2 hours. The solvent was then removed in vacuo and the residue was purified by preparative HPLC to give (E) -2- (2,6-dioxopiperidine-3-yl) -5- (4- (4- (4- ( 1- (Hydroxyimino) -2,3-dihydro-1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazole-1-yl) -1,4'-bipyridine-1' -Il) Isoindoline-1,3-dione (53 mg, 55% yield) was obtained. LCMS: m / z 713.4 [M + H] +; 1H NMR (400 MHz, DMSO-d6) 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, m) 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).
Example of synthesis of compound 208: (3R) -N- (3- (5- (4- (2- (2- (2- (2- (4- (2- (2,6-dioxopiperidine-3-) Ill) -1,3-dioxoisoindoline-5-yl) piperazine-1-yl) ethoxy) ethoxy) d
Toxi) ethoxy) phenyl) -1H-pyrrolo [2,3-b] pyridin-3-carbonyl) -2,4-difluoro
Phenyl) -3-fluoropyrrolidine-1-sulfonamide.

Step A: 2- (2- (2- (2- (4-Bromophenoxy) ethoxy) ethoxy) ethoxy) acetaldehyde
Hid.

IBX (3.7 g, 13.40) in a solution of 2- (2- (2- (2- (4-bromophenoxy) ethoxy) ethoxy) ethoxy) ethane-1-ol (3.1 g, 8.90 mmol) in acetonitrile (30 mL). mmol) was added. The mixture was heated at 80 ° C. for 1 hour. After cooling to room temperature, the mixture is filtered through Celite and concentrated to give the desired crude product 2- (2- (2- (2- (4-bromophenoxy) ethoxy) ethoxy) ethoxy) acetaldehyde (3.2 g, Crude) was obtained as oil.

Step B: 5- (4- (2- (2- (2- (2- (4-bromophenoxy) ethoxy) ethoxy) ethoxy) ethyl) piperazine-1-yl) -2- (2,6-dioxo) Piperidine-3-yl) Isoindoline-1,3-dione.

2- (2- (2- (2- (4-Bromophenoxy) ethoxy) ethoxy) ethoxy) acetaldehyde (3.2)
g, 9.20 mmol) and 2- (2,6-dioxopiperidine-3-yl) -5- (piperazine-1-yl) isoindoline-1,3-dione hydrochloride (3.1 g, 9.20 mmol) in methanol _{NaBH 3} CN (0.58 g, 9.20 mmol) was added to the solution of (100 mL) and 2 drops of AcOH. The mixture was stirred at room temperature overnight. Water (50
After quenching with mL), the mixture was extracted with DCM (100 mL x 2). Brine mixed organic layer (200)
It was washed with mL), dried over Na ₂ SO ₄ , and filtered. The solvent was evaporated under reduced pressure. Purification of the residue by column chromatography (DCM: MeOH = 20: 1) reveals the desired compound 5-(2- (2- (2- (2- (2- (4-bromophenoxy) ethoxy) ethoxy) ethoxy) ethoxy). ) Ethyl) piperazine-1-yl) -2- (2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione (1.1 g, 18%) was obtained as a yellow solid. LC-MS: (ES ⁺ ): m / z 675.1 [M + H] ⁺ .
Step C: 2- (2,6-dioxopiperidine-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) piperazine-1-yl) isoindoline-1,3-dione.

5- (4- (2- (2- (2- (2- (4-Bromophenoxy) ethoxy) ethoxy) ethoxy) ethyl) piperazine-1-yl) -2- (2,6-dioxopiperidine-3) -Il) Isoindoline-1,3-dione (400 mg, 0.60 mmol), 4,4,4', 4', 5,5,5', 5'-octamethyl-2,2'-bi (1, 3,2-Dioxaborolan) (227
A solution of dioxane (10 mL) of mg, 0.89 mmol), Pd (dppf) Cl ₂ (88 mg, 0.12 mmol) and KOAc (118 mg, 1.20 mmol) was heated overnight at 90 ° C. under an _{N 2 atmosphere.} The reaction was quenched with water (15 mL) and the mixture was extracted with DCM (50 mL x 2). The mixed layer was washed with water and brine. The mixed organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Purification of the residue by silica gel chromatography reveals 2- (2,6-dioxopiperidine-3-yl) -5-(2- (2- (2- (2- (4- (4,4)) , 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) Phenoxy) ethoxy) ethoxy) ethoxy) Ethyl) Piperazine-1-yl) Isoindoline-1,3-dione (200 mg, 47%) ) Was obtained as a yellow solid. LCMS (ES ⁺ ): m / z 721.3 [M + H] ⁺ .

Step D: (3R) -N- (3-(5-(4- (2- (2- (2- (2- (4- (2- (2,6-dioxopiperidine-3-yl))- 1,3-
Dioxoisoindoline-5-yl) piperazine-1-yl) ethoxy) ethoxy) ethoxy) eth
Xi) Phenyl) -1H-pyrrolo [2,3-b] Pyridine-3-carbonyl) -2,4-difluorophenyl) -3-fluoropyrrolidine-1-sulfonamide.

2- (2,6-dioxopiperidine-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) piperazine-1-yl) isoindrin-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-fluoropyrrolidin-1-sulfonamide (116 mg, 0.23 mmol), Pd ( _{A dioxane / H 2} O (5 mL / 1 mL) solution of aMPhos) Cl ₂ (66 mg, 0.09 mmol) and CsF (141 mg, 0.93 mmol) was heated at 100 ° C. for 4 hours under _{N 2 atmosphere.} The reaction was quenched with water (15 mL) and the mixture was extracted with DCM (50 mL x 2). The mixed layer was washed with water and brine. The mixed organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Purification of the residue by silica gel chromatography reveals that (3R) -N- (3- (5- (4- (2- (2- (2- (2- (2- (2- (2,6-dioxo)) Piperidine-3-yl) -1,3-dioxoisoindoline-5-
Il) Piperazine-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%) was obtained as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 11.23 (bs, 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] +.
Example of synthesis of compound 209:
Step A: 3- (tert-butyldimethylsilyloxy) cyclohexanol.

Tert-butyldimethylsilyl in a mixed solution of 1,3-cyclohexanediol (cis and trans mixture, 25 g, 0.216 mmol) and imidazole (8.8 g, 0.129 mmol) in dichloromethane (150 mL) and tetrahydrofuran (150 mL). A mixed solution of chloride (16.2 g, 0.107 mmol) in dichloromethane (40 mL) and tetrahydrofuran (40 mL) was added dropwise at 0 ° C.
The reaction mixture was warmed to ambient temperature and stirred overnight. The insoluble material is removed by filtration and the mother liquor is concentrated under reduced pressure to give a residue, which is dissolved in ethyl acetate (300 mL), 1 N aqueous hydrochloric acid (100 mL), brine (100 mL), saturated. It was washed successively with aqueous sodium hydrogen carbonate solution (100 mL) and saturated sodium chloride (100 mL), and dried over anhydrous sodium sulfate. Evaporation of the solvent yields a residue, which is chromatographed on silica gel (ethyl acetate / n-hexane = 1: 5) to 3- (tert-butyldimethylsilyloxy) cyclohexanol (cis and cis and). Transmixture) (12.5 g, 51% yield) was obtained as a colorless oil.

Step B: 3- (Pyridine-4-yloxy) cyclohexanol.

THF (40 mL, anhydrous) mixture of 3- (tert-butyldimethylsilyloxy) cyclohexanol (10 g, 43.4 mmol), pyridin-4-ol (3.9 g, 41.2 mmol), triphenylphosphine (14.8 g, 56.42 mmol) Diisopropylazodicarboxylate (10.5 g, 52.1 mmol) was added dropwise to the solution under a nitrogen atmosphere at room temperature for 0.5 hours. The mixture was stirred at room temperature for 3 hours under a nitrogen atmosphere. Aqueous HCl (70 mL, 1N) was added, and the mixture was stirred for 0.5 hours. The mixture was extracted with DCM (60 mL x 3). The liquid layer was basicized with KOH and extracted with ethyl acetate (60 mL × 4). The mixed 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] ⁺ .

Step C: 3- (piperidine-4-yloxy) cyclohexanol.

To a mixture of 3- (pyridine-4-yloxy) cyclohexanol (3.3 g, 17 mmol) in ethanol (30 mL), platinum dioxide (660 mg, 2.9 mmol) and sulfuric acid (2.5 g, 26 mmol) are added. The reaction mixture was stirred under 2.0 MPa of hydrogen at 50 ° C. for 2 days. The mixture was filtered and concentrated, brine (30 mL x 3) was added, and the mixture was extracted with DCM / MeOH (10/1, 30 mL x 3). The mixed organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification of the residue on silica (dichloromethane / methanol = 10/1) by column chromatography yields 3- (piperidine-4-yloxy) cyclohexanol (330 mg, 10% yield) as a pale yellow oil. rice field.

Step C: tert-butyl 4- (3-hydroxycyclohexyloxy) piperidine-1-carboxylate.

3- (Piperidin-4-yloxy) cyclohexanol (330 mg, 1.66 mmol) and DIEA (642)
To a solution of mg, 4.9 mmol) in dichloromethane (15 mL _{) was added Boc 2} O (436 mg, 2.0 mmol), which was stirred overnight at room temperature. The solvent is removed in vacuum at room temperature and the residue is purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1/1) with tert-butyl 4- (3-hydroxycyclohexyloxy) piperidine. -1-carboxylate (352 mg, 71% yield) was obtained as a yellow oil.

Step D: tert-Butyl 4- (3- (Methylsulfonyloxy) Cyclohexyloxy) Piperidi
N-1-Carboxylate.

MsCl (162 mg) in a solution of tert-butyl 4- (3-hydroxycyclohexyloxy) piperidin-1-carboxylate (352 mg, 1.18 mmol) and DIEA (457 mg, 3.5 mmol) in dichloromethane (15 mL).
mg, 1.4 mmol) was added and the mixture was stirred at 0 ° C. for 1 hour. It was washed _{continuously with 3} aqueous NaHCO 3 (15 mL x 2) and brine (10 mL x 2). The organic phase is _{dried over anhydrous Na 2} SO ₄ , filtered and concentrated in vacuo to give crude tert-butyl 4- (3- (methylsulfonyloxy) cyclohexyloxy) piperidin-1-carboxylate (351). mg, yield 79%) was obtained as a pale yellow oil.

Step E: Sith-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.

tert-butyl 4- (3- (Methylsulfonyloxy) cyclohexyloxy) piperidine-1-carboxylate (450 mg, 1.19 mmol), 4- (4-bromo-1H-pyrazole-3-yl) pyridine ( 252 mg
, 1.13 mmol), Cs ₂ CO ₃ (1.16 g, 3.57 mmol) in N, N-dimethylformamide (5 mL) was stirred at 80 ° C. for 2 days. It was diluted with brine (15 mL) and extracted with ethyl acetate (15 mL x 3). The mixed organic layer was washed with brine (15 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification of the residue on silica gel (ethyl acetate / petroleum ether = 1/1) by column chromatography reveals cis-tert-butyl-3- (4-bromo-3- (pyridin-4-yl) -1H-pyrazole). -1-yl) cyclohexyloxy) piperidine-1-carboxylate (140 mg) and trans-tert-butyl-3- (4-bromo-3- (pyridin-4-yl) -1H-pyrazol-1 -Il) cyclohexyloxy) piperidin-1-carboxylate (130 mg) was obtained as a pale yellow solid. Sis-tert-butyl-3- (4-bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) cyclohexyloxy) piperidine-1-carboxylate: LCMS: m / z 505.3 [M + H] +; 1H NMR (400 MHz, CDCl3) 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, brs), 4.09-4.15 (1H, m), 7.52 (1H, s), 7.84 (2H, d, J = 6.0 Hz) , 8.59 (2H, s). 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] +; 1H NMR (400 MHz, CDCl3) 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, brs), 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).
Step F: tert-Butyl 4-((1S, 3R) -3- (4- (1-oxo-2,3-dihydro-1H-inden-5-yl) -3- (pyridin-4-yl)- 1H-pyrazole-1-yl) cyclohexyloxy) piperidine-1-carboxylate.

tert-butyl 4-((1S, 3R) -3- (4-bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) cyclohexyloxy) piperidin-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), tetrakis (triphenylphosphine) palladium (10 mg, 10 M%), 1,4-dioxane / water (6 mL, 5/1). The mixture was stirred at 80 ° C. for 2 hours under a medium and nitrogen atmosphere. After cooling the mixture, it was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The mixed organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate.
Filtered and concentrated in vacuo. Purification of the residue by column chromatography (petroleum ether / ethyl acetate = 45/55) reveals tert-butyl 4-((1S, 3R) -3- (4- (1-oxo-2,3-dihydro-1H)). -Inden-5-yl) -3- (pyridine-4-yl) -1H-pyrazol-1-yl) cyclohexyloxy) piperidine-1-carboxylate (20 mg, 44% yield) is yellow Obtained as a solid. LCMS: m / z 557.3 [M + H] ⁺ .

Step G: 5- (1-((1R, 3S) -3- (piperidine-4-yloxy) cyclohexyl) -3- (pyridin-4-yl) -1H-pyrazole-4-yl) -2,3- Dihydro-1H-inden-1-one.

tert-Butyl 4-((1S, 3R) -3- (4- (1-oxo-2,3-dihydro-1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazole A solution of 4N hydrochloric acid solution in 1,4-dioxane (3 mL) of -1-yl) cyclohexyloxy) piperidin-1-carboxylate (40 mg, 0.08 mmol) was stirred at 0 ° C. for 5 hours. .. Then, when the solvent is directly removed, 5-(1-((1R, 3S) -3- (piperidine-4-yloxy) cyclohexyl) -3- (pyridin-4-yl) -1H-pyrazole-4-yl) -2,3-Dihydro-1H-inden-1-one (38 mg, crude, 100% yield) was obtained, which was used directly in the next step without further purification.

Step H: 2- (2,6-dioxopiperidine-3-yl) -5-(4-((1S, 3R) -3- (4- (1-oxo-2,3-dihydro-1H-inden) -5-yl) -3- (pyridin-4-yl) -1H-pyrazole-1-yl) cyclohexyloxy) piperidine-1-yl) isoindoline-1,3-dione.

5- (1-((1R, 3S) -3- (piperidine-4-yloxy) cyclohexyl) -3- (pyridin-4-yl) -1H-pyrazole-4-yl) -2,3-dihydro-1H -Inden-1-one (20 mg, 0.044 mmol), 2- (2,6-)
Dioxopiperidine-3-yl) -5-fluoroisoindoline-1,3-dione (18 mg, 0.066 mmol), DIEA (17 mg, 0.13 mmol) in DMSO (3 mL) at 80 ° C. Stirred in the evening. It was diluted with brine (15 mL) and extracted with ethyl acetate (15 mL x 3). The mixed organic layer was washed with brine (15 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. When the residue is purified by preparative TLC (DCM / MeOH = 20/1), 2- (2,6-dioxopiperidine-3-yl) -5-(4-((1S, 3R) -3- ( 4- (1-oxo-2,3-dihydro-1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazole-1-yl) cyclohexyloxy) piperidine-1-yl) iso Indoline-1,3-dione (15 mg, 50% yield) was obtained as a yellow solid. LCMS: m / z 713.3 [M + H] ⁺ .

Step I: 2- (2,6-dioxopiperidine-3-yl) -5-(4-((1S, 3R) -3- (4-((E) -1- (hydroxyimino) -2, 3-Dihydro-1H-Inden-5-yl) -3- (Pyridine-4-yl) -1H-Pyrazole-1-a
Le) Cyclohexyloxy) Piperidine-1-yl) Isoindoline-1,3-dione.

2- (2,6-dioxopiperidine-3-yl) -5-(4-((1S, 3R) -3-(4- (1-oxo-2,3-dihydro-1H-inden-5-) Ill) -3- (Pyridine-4-yl) -1H-Pyrazole-1-yl) Cyclohexyloxy) Piperidine-1-yl) Isoindoline-1,3-dione (15 mg, 0.021 mmol), hydroxylamine hydrochloride The mixture in (15 mg, 0.21 mmol) pyridine (3 mL) was stirred overnight at room temperature. The solvent was removed directly in vacuum at room temperature and the residue was purified by preparative HPLC to 2- (2,6-dioxopiperidine-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) piperidine-1-yl) isoindoline-1,3-dione (2.8 mg, 18% yield) was obtained as a yellow solid. LCMS: m / z 728.3 [M + H] +; 1H NMR (400 MHz, CDCl3) 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) 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).
Compound 210 can be prepared in a manner similar to compound 209.

Example of synthesis of compound 211: (E) -2- (2,6-dioxopiperidine-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) piperidine-4-yl) azetidine-1-yl) Isoindoline-1,3-dione.

Step A: tert-Butyl-3- (1- (2- (4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenoxy) ethyl) piperidine-4-yl ) Azetidine-1-carboxylate.

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) To tert-butyl-3- (piperidine-4-yl) azetidine-1-carboxylate (272 mg, 1.14 mmol) and a catalytic amount of AcOH were added. If the pH was below 5-6, AcOK was added. Then NaBH (OAc) ₃ (810 mg, 3.80 mmol) was added. The resulting solution was stirred at 30 ° C. for 1 hour. The reaction was _{quenched with 3} aqueous NaHCO 3 (20 mL) and the mixture was extracted with DCM (30 ml x 2). The mixed organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. When the residue is applied on a silica gel column, the desired product tert-butyl-3- (1- (2- (4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazole-1-)-1H-pyrazole-1-) Il) phenoxy) ethyl) piperidine-4-yl) azetidine-1-carboxylate (270 mg) was obtained. LCMS: (ES ⁺ ): m / z 583.3 [M + H] ⁺ .
Step B: 4- (1- (4- (2- (4- (Azetidine-3-yl) piperidine-1-yl) ethoxy) phenyl) -4-bromo-1H-pyrazole-3-yl) pyridine.

tert-butyl 3-(1- (2- (4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) -phenoxy) ethyl) piperidine-4-yl) azetidine- TFA (2 ml) was added to a solution of 1-carboxylate (0.27 g, 0.46 mmol) in DCM (6 ml). The resulting mixture was stirred at 30 ° C. for 1 hour. When the solvent is removed under vacuum and the residue is co-evaporated twice with DCM, the desired product 4-(1- (4- (2- (4- (azetidine-3-yl) piperidine-1-) Il) ethoxy) -phenyl) -4-bromo-1H-pyrazol-3-yl) pyridine (224 mg crude, calculated value, 0.46 mmol) was obtained and used in the next reaction without further purification. LCMS: (ES ⁺ ): m / z 482.0 [M + H] ⁺ .
Step C: 5- (3- (1- (2- (4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenoxy) ethyl) piperidine-4-yl) Azetidine-1-yl) -2- (2,6-dioxopiperidine-3-a)
Le) Isoindoline-1,3-dione.

4- (1- (4- (2- (4- (Azetidine-3-yl) piperidine-1-yl) ethoxy) phenyl) -4-bromo-1H-pyrazole-3-yl) pyridine (224 mg crude, 2- (2,6-dioxopiperidine-3-yl) -5-fluoroisoindoline-1,3-dione (254 mg, 0.92 mmol) and DIEA (0.6) in a solution of 0.46 mmol) in NMP (5 mL). g, 4.6 mmol) was added. The resulting solution was exposed to microwaves at 150 ° C. for 2 hours. After cooling to room temperature, the mixture was diluted with EA (50 mL). The mixture was washed with brine (10 mL x 3). The organic phase was _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure. When the residue is purified by preparative TLC, 5-(3-(1-(2-(4-(4-bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenoxy) ethyl) ) Piperidine-4-yl) Azetidine-1-yl) -2- (2,6-dioxopiperidine-3-yl) Isoindoline-1,3-dione (60 mg) was obtained. LCMS: (ES ⁺ ): m / z 739.3 [M + H] ⁺ .
Step D: 2- (2,6-dioxopiperidine-3-yl) -5-(3- (1- (2- (4- (4- (1-oxo-2,3-dihydro-1H-inden)) -5-yl) -3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenoxy) ethi
Le) Piperidine-4-yl) Azetidine-1-yl) Isoindoline-1,3-dione.

5- (3- (1- (2- (4- (4-Bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenoxy) ethyl) piperidine-4-yl) azetidine-1 -Il) -2- (2,6-dioxopiperidine-3-yl) isoindoline-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) solution, CsF (49 mg, 0.325 mmol), Pd ₂ (dba) ₃ (30 mg, 0.033 mmol), tri-tert-butylphosphin tetrafluoroborate (20 mg, 0.066 mmol) and two drops of Cy ₂ NCH ₃ in succession. added. The resulting solution was heated at 100 ° C. for 16 hours in an _{N 2 atmosphere.} After cooling to room temperature, the reaction was quenched with water (20 mL) and the mixture was extracted with ethyl acetate (30 mL x 2). The mixed organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. Purification of the residue by preparative TLC yields the desired product 2- (2,6-dioxopiperidine-3-yl) -5- (3- (1- (2- (4- (4- (1-) 1-). Oxo-2,3-dihydro-1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenoxy) ethyl) piperidine-4-yl) azetidine-1-yl ) Isoindoline-1,3-dione (30 mg, 47% yield) was obtained as a yellow solid. LCMS: (ES +): m / z 790.3 [M + H] ⁺ .
Step E: (E) -2- (2,6-dioxopiperidine-3-yl) -5-(1- (2- (4- (4- (1- (hydroxyimino) -2,) 3-Dihydro-1H-Inden-5-yl) -3- (Pyridine-4-yl) -1H-Pyrazole-1-yl) Phenoxy) Ethyl) Piperidine-4-yl) Azetidine-1-yl) Isoindoline- 1,3-Zeon
..

2- (2,6-dioxopiperidine-3-yl) -5-(3- (1- (2- (4- (4- (1-oxo-2,3-dihydro-1H-inden-5-) Ill) -3- (Pyridine-4-yl) -1H-pyrazol-1-yl) Phenoxy) Ethyl) Piperidine-4-yl) Azetidine-1-yl) Isoindoline-1,3-dione (30 mg, 0.038 mmol) ) To a _{solution of 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 is removed under vacuum and the residue is purified by preparative TLC using DCM / MeOH (15/1) to give the desired product (E) -2- (2,6-dioxo). Piperidine-3-yl) -5-(3- (1- (2- (4- (4- (1- (hydroxyimino) -2,3-dihydro-1H-inden-5-yl) -3- ( Pyridine-4-yl) -1H-pyrazole-1-yl) phenoxy) ethyl) piperidine-4-yl) azetidine-1-yl) isoindoline-1,3-dione (15 mg, 50% yield) was obtained. .. 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] +.
Example of synthesis of compound 213: (E) -2- (2,6-dioxopiperidine-3-yl) -4- (2- (2-((4- (4- (1- (hydroxyimino)) ) -2,3-Dihydro-1H-Inden-5-yl) -3- (Pyridine-4-yl) -1H-Pira
Zol-1-yl) Phenoxy) Methyl) Phenoxy) ethoxy) Propoxy) Isoindoline-1,3-dione.

Step A: (2- (2- (3-((tert-butyldimethylsilyl) oxy) propoxy) ethoxy) pheni
Le) Methanol.

2- (3-((tert-butyldimethylsilyl) oxy) propoxy) ethyl 4-methylbenzenesulfonate (1 g, 2.58 mmol) in DMF (10 mL) solution with 2- (hydroxymethyl) phenol (0.38) g, 3.09 mol) and K ₂ CO ₃ (1.07 g, 2.74 mmol) were added. The resulting solution is 70 ° C.
Was stirred for 3 hours. After cooling to room temperature, the reaction was _{quenched with aqueous NH 4} Cl and the mixture was extracted with EtOAc. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. Purification of the residue on a chromatographic column reveals that (2- (2- (3-((tert-butyldimethylsilyl) oxy) -propoxy) ethoxy) phenyl) methanol (400 mg, 45.6% yield) is a colorless oil. Obtained as. 1H NMR (400 MHz, CDCl3): 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).
Step B: 4- (4-bromo-1- (4-((2- (2- (3-((tert-butyldimethylsilyl) oxy) propoki)
S) ethoxy) benzyl) oxy) phenyl) -1H-pyrazole-3-yl) pyridine.

(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) solution MsCl (268 mg, 2.36 mmol) was added at 0 ° C. The resulting solution was stirred at room temperature for 1 hour. The reaction was diluted with DCM (100 mL) and washed with water and brine. The organic phase is dried over anhydrous sodium sulfate and
Concentration in vacuo gave the desired crude product (320 mg, 100% yield), which was used directly in the next step. _{K 2} CO ₃ (368.5 mg, 2.67 mmol) and 4- (4-bromo-3- (pyridin-4-yl)) in a dehydrated DMF (20 ml) solution of the above desired product (320 mg, 0.89 mmol). ) -1H-pyrazole-1-yl) phenol (309.7 mg, 0.98 mmol) was added. 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) and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate. Purification of the residue on a chromatographic column reveals 4-(4-bromo-1- (4-((2- (2- (3-((tert-butyldimethylsilyl) oxy) propoxy) ethoxy) benzyl) oxy). Phenyl) -1H-pyrazole-3-yl) -pyridine (300 mg, 2-step yield 40.1%) was obtained as the red oil. . 1H NMR (400 MHz, CDCl3): 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).
Step C: 3- (2-(((4- (4-Bromo-3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenoxy) methyl) phenoxy) ethoxy) propan-1- All.

4- (4-bromo-1- (4-((2- (2- (3-((tert-butyldimethylsilyl) oxy) -propoxy) ethoxy) benzyl) oxy) phenyl) -1H-pyrazole-3- Il) Pyridine (300 mg, 0.47 mmol)
HCl (1 mL, 6 M / L, 6 mmol) in 1,4-dioxane was added to a solution of MeOH (10 mL) 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 under vacuum. Purification of the residue by preparative TLC yields the desired product 3-(2-((4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenoxy). ) Methyl) Phenoxy) ethoxy) Propane-1-
All (160 mg, 65% yield) was obtained as a white solid. LCMS (ES ⁺ ): m / z 524.1 [M + H]
⁺ .

Step D: tert-butyl 5-amino-4- (4- (3- (2-(((4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazole-1-yl) -1H-pyrazole-1-yl) ) Phenoxy) Methyl) Phenoxy) ethoxy) Propoxy) -1,3-Dioqui
Soisoindoline-2-yl) -5-oxovalerate .

3- (2-(((4- (4-Bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenoxy) methyl) phenoxy) ethoxy) propan-1-ol (160) mg, 0.31 mmol) PPh ₃ (244 mg, 0.93 mmol) and tert-butyl 5-amino-4- (4-hydroxy-1,3-dioxoisoindoline-2-yl) -5-oxopentanate ( DIAD (188 mg, 0.93 mmol) was added under _{N 2} to a dehydrated THF (10 mL) solution of 159.4 mg, 0.46 mmol). The resulting solution was stirred at room temperature for 2 hours. After quenching with water, the mixture was extracted with DCM. The mixed organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated. Purification of the residue by preparative TLC yields the desired product tert-butyl 5-amino-4-(4-(2-(((4- (4-bromo-3- (pyridine-4) -4). -Il) -1H-pyrazole-1-yl) phenoxy) methyl) phenoxy) ethoxy) -propoxy) -1,3-dioxoisoindoline-2-yl) -5-oxopentaate (110 mg, yield 42.2%) was obtained as a white solid. LCMS (ES ⁺ ): m / z 854.2 [M + H] ⁺ .

Step D: 4- (3- (2-(((4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazole-1-yl)) Fe
Noxy) Methyl) Phenoxy) ethoxy) Propoxy) -2- (2,6-dioxopiperidine-3-yl) Isoindoline-1,3-dione .

tert-butyl 5-amino-4- (4-(3-(2-((4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenoxy)) Methyl) phenoxy) ethoxy) propoxy) -1,3-dioxoisoindoline-2-yl) -5-oxopentanate (80 mg, 0.094 mmol) in acetonitrile (15 mL) solution, 4-methylbenzenesulfon Acid (32.3 mg, 0.28 mmol) was added. The solution was stirred at 60 ° C. for 48 hours. After cooling to room temperature, the reaction was _{quenched with NaHCO 3} aqueous solution (pH> 7) and the mixture was extracted with DCM (20 mLx3). The mixed organic layer was _{dried over Na 2} SO ₄ and concentrated under vacuum. Purification of the residue by preparative TLC yields the desired product 4-(3- (2-(((4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazole-1-)-1H-pyrazole-1-). Il) Phenoxy) Methyl) Phenoxy) ethoxy) Propoxy) -2- (2,6-dioxopiperidine-3-yl) -isoindoline-1,3-dione (40 mg, yield 54.8%) is a white solid Obtained as a thing. LCMS (ES ⁺ ): m / z 781.1 [M + H] ⁺ .

Step E: 2- (2,6-dioxopiperidine-3-yl) -4- (3- (2-((4- (4- (1-oxo-2,3-dihi)
Doro-1H-Inden-5-yl) -3- (Pyridine-4-yl) -1H-Pyrazole-1-yl) Phenoxy)
Chill) Phenoxy) ethoxy) Propoxy) Isoindoline-1,3-dione.

4- (3- (2-(((4- (4-Bromo-3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenoxy))
Methyl) phenoxy) ethoxy) propoxy) -2- (2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione (40 mg, 0.051 mmol) 1,4-dioxane / H ₂ O ( 5 mL, v / v = 10/1)
In solution, 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), N, N-dicyclohexylmethylamine (0.50 mg, 0.0026 mmol) was added. The resulting solution was _{stirred under N 2} at 100 ° C. for 2 hours. After cooling to room temperature, the reaction was diluted with DCM (50 mL) and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. Purification of the residue by preparative TLC yields the desired product 2- (2,6-dioxopiperidine-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, 70.3% yield) was obtained as a white solid. LCMS (ES ⁺ ): m / z 832.3 [M + H] ⁺ .

Step F: (E) -2- (2,6-dioxopiperidine-3-yl) -4- (2- (2-((4- (4- (1- (hydroxy)
Imino) -2,3-dihydro-1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazole-1-i
Le) Phenoxy) Methyl) Phenoxy) ethoxy) Propoxy) Isoindoline-1,3-dione.

2- (2,6-dioxopiperidine-3-yl) -4- (3- (2-(((4- (4- (1-oxo-2,3-dihydro-1H-inden-5) -Il) -3- (Pyridine-4-yl) -1H-Pyrazole-1-yl) Phenoxy) Methyl) Phenoxy) ethoxy) -Propoxy) Isoindoline-1,3-dione (30 mg, 0.036 mmol) acetonitrile / In a pyridine (3 mL, v / v = 2/1) solution, hydroxylamine hydrochloride (25.1 mg)
, 0.36 mmol) was added. The mixture was stirred at 40 ° C. for 20 minutes, then diluted with DCM (20 mL) and washed with brine (10 mL). The organic phase was concentrated under vacuum. Purification of the residue by preparative TLC reveals that (E) -2- (2,6-dioxopiperidine-3-yl) -4-(3- (2- (2-((4- (4- (1) -(Hydroxyimino) -2,3-dihydro-1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenoxy) methyl) phenoxy) ethoxy) propoxy) iso Indoline-1,3-dione (6.2 mg, yield 20.3%) was obtained as a white solid. 1H NMR (400 MHz, CDCl3): 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 = 7.2Hz, 1H), 7.28 (s, 2H), 7.23 (s, 2H), 7.15-7.13 (d, J = 7.6Hz, 1H) ), 7.08-7.06 (m, 2H), 7.00-6.97 (m, 1H), 6.91-6.89 (d, J = 7.6Hz, 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 = 4.4Hz, 2H), 3.86-3.84 (t, J = 4.8Hz, 2H), 3.79-3.76 (t, J = 6.0Hz, 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] +.
Compound 212 can be prepared in a manner similar to compound 213.

Example of Synthesis of Compound 215: (E) -2- (2,6-dioxopiperidine-3-yl) -4-(3-((4'-(4- (1- (1- (1- (
Hydroxyimino) -2,3-dihydro-1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazole-1-yl)-[1,1'-biphenyl] -4-yl ) Oxy) Propoxy) Propoxy) Isoindoline-1,3-dione.

Step A: 4-bromo-4'-methoxy-1,1'-biphenyl.

_{1,4-Dibromobenzene (11.6 g, 49.4 mmol), Pd (PPh 3} ) ₄ (1.9) in toluene / MeOH (200 mL / 100 mL) solution of (4-methoxyphenyl) boronic acid (5 g, 32.9 mmol) g, 1.65 mmol) and Cs ₂ CO ₃ (21.4 g, 65.8 mmol) were added. The resulting solution was stirred at 100 ° C. for 16 hours under _{N 2 atmosphere.} TLC showed that the reaction was complete. After cooling to room temperature, the reaction mixture was diluted with 50 mL EA and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue on a chromatographic column gave 4-bromo-4'-methoxy-1,1'-biphenyl (7.0 g, 80% yield). LCMS (ES +): m / z 263.1 [M + H] ⁺ .

Step B: (4'-methoxy- [1,1'-biphenyl] -4-yl) boronic acid.

N-BuLi (9.2 ml, 22.9 mmol, in 2.5 M hexanes) -78 in a dehydrated THF (30 mL) solution of 4-bromo-4'-methoxy-1,1'-biphenyl (2 g, 7.63 mmol). It was added dropwise at N _{2 atmosphere at ° C.} 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 at -78 ° C for 1 hour and at 5 ° C overnight. After quenching with saturated NH ₄ Cl solution, the mixture was extracted with EA (30 mL x 2). The mixed organic layer was dried over anhydrous sodium sulfate. Purification of the residue on a chromatographic column gave (4'-methoxy- [1,1'-biphenyl] -4-yl) boronic acid (1.0 g, 58% yield). 1H NMR (400 MHz, DMSO-d6): 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).
Step C: 4- (4-bromo-1- (4'-methoxy- [1,1'-biphenyl] -4-yl) -1H-pyrazole-3-yl) pyridine .

_{Cu (OAc) 2} (0.8 g, 0.8 g) in DCM / pyridine (40 ml / 4 ml) solution of (4'-methoxy- [1,1'-biphenyl] -4-yl) boronic acid (1 g, 4.39 mmol) 4.39 mmol) and 4- (4-bromo-1H-pyrazole-3-)
Il) Pyridine (1.5 g, 6.58 mmol) was added. 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 x 2). The organic phase was _{dried over Na 2} SO ₄ and concentrated under vacuum. When the residue is applied on a silica gel column, the desired product 4- (4-bromo-1- (4'-methoxy- [1,1'-biphenyl] -4-yl) -1H-pyrazole-3-yl) ) Pyridine (1 g crude, 56% yield) was obtained. LCMS (ES ⁺ ): m / z 407.4 [M + H] +.

Step D: 4- (1- (4'-(3- (3- (benzyloxy) propoxy) propoxy)-[1,1'-biphenyl] -4-yl) -4-bromo-1H-pyrazole-3 -Il) Pyridine.

4- (4-bromo-1- (4'-methoxy- [1,1'-biphenyl] -4-yl) -1H-pyrazole-3-yl)
_{BBr 3} (1.85 g, 7.38 mmol) was added dropwise to a solution of pyridine (1 g, 2.46 mmol) in DCM (40 mL). The resulting solution was stirred at 10 ° C. for 2 hours. After quenching with MeOH, it is concentrated and the crude product is applied on a silica gel column to give the desired product 4'-(4-bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl)-. [1,1'-biphenyl] -4-ol (0.6 g, yield 62%) was obtained. 4'-(4-Bromo-3- (pyridin-4-yl) -1H-pyrazole-1-yl)-[1,1'-biphenyl] -4-
_{Cs 2} CO ₃ (1.56 g, 4.80 mmol) and 3- (3- (benzyloxy) propoxy) propyl methanesulfonate (0.58 g,) in a solution of all (375 mg, 0.96 mmol) dehydrated DMF (5 mL). 1.92 mmol) was added. The resulting solution was stirred at 75 ° C. for 2 hours. After cooling to room temperature, the reaction mixture was diluted with EA (50 mL) and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate. Purification of the residue on a chromatographic column reveals 4-(1-(4'-(3-(3- (benzyloxy) propoxy) propoxy)-[1,1'-biphenyl] -4-yl) -4- Bromo-1H-pyrazole-3-yl) pyridine (400 mg, 70% yield) was obtained. 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).
Step E: 5- (1- (4'-(3- (3-Hydroxypropoxy) propoxy)-[1,1'-biphenyl] -4-a
Le) -3- (Pyridine-4-yl) -1H-pyrazole-4-yl) -2,3-dihydro-1H-inden-1-one.

4- (1- (4'-(3- (3- (benzyloxy) propoxy) propoxy)-[1,1'-biphenyl] -4-yl) -4-bromo-1H-pyrazole-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 ( CsF (328 mg, 2.16 mmol) and Pd ₂ (dba) ₃ (196 mg, 0.216 mmol) were added to a 1,4-dioxane (15 ml) / H _{2 O (1.5 ml) solution of 260 mg, 1.01 mmol).} Tri-tert-butylphosphine tetrafluoroborate (124 mg, 0.43 mmol) and two drops of N-cyclohexyl-N-methylcyclohexaneamine were added sequentially. The reaction was heated at 100 ° C. for 2 hours in an _{N 2 atmosphere.} After cooling to room temperature, the reaction was quenched with water (20 mL) and the mixture was extracted with ethyl acetate (30 mL x 2). The mixed organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. When the residue is applied on a silica gel column, the desired product 5-(1-(4'-(3-(3- (benzyloxy) propoxy) propoxy)-[1,1'-biphenyl] -4-yl) ) -3- (Pyridine-4-yl) -1H-pyrazole-4-yl) -2,3-dihydro-1H-indene-1-one (0.4 g, 92% yield) is obtained as a brown oil. rice field. 5- (1- (4'-(3- (3- (benzyloxy) propoxy) propoxy)-[1,1'-biphenyl] -4-yl) -3- (pyridin-4-yl) -1H- Pd (OH) in a solution of pyrazole-4-yl) -2,3-dihydro-1H-inden-1-one (400 mg, 0.16 mmol) in THF / MeOH (10 mL / 1 mL and 2 drops of concentrated HCl). ) ₂ was added on carbon (200 mg). The mixture was stirred at 1 ATM H ₂ for 1 hour at 5 ° C. The mixture was filtered and the solid was washed with THF. The organic layer was concentrated and the column. Purified with 5- (1- (4'-(3- (3-hydroxypropoxy) propoxy)-[1,1'-biphenyl] -4-yl) -3- (pyridin-4-yl) -1H -Pyrazole-4-yl) -2,3-dihydro-1H-inden-1-one (250 mg, 72% yield) was obtained. 1H NMR (400 MHz, CDCl3): 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)
Step F: tert-butyl 5-amino-4-(1,3-dioxo-4- (3-(((4'-(4- (1-oxo-2,3-dihydro-1H-inden-) 5-Il) -3- (Pyridine-4-yl) -1H-Pyrazole-1-yl)-[1,1'-Bife
Nil] -4-yl) oxy) propoxy) propoxy) isoindoline-2-yl) -5-oxovaleric acid
Salt .

5- (1- (4'-(3- (3-Hydroxypropoxy) propoxy)-[1,1'-biphenyl] -4-yl) -3- (
Pyridine-4-yl) -1H-pyrazole-4-yl) -2,3-dihydro-1H-inden-1-one (250 mg, 0.45 mmol), Ph ₃ P (351 mg, 1.35 mmol) and tert- Dehydrated THF of butyl 5-amino-4- (4-hydroxy-1,3-dioxoisoindoline-2-yl) -5-oxopentanate (233 mg, 0.67 mmol)
A solution of DIAD (266 mg, 1.35 mmol) in THF (3 mL) was added dropwise to the (20 mL) solution at 0 ° C. The resulting solution was stirred at 0-10 ° C. for 2 hours. The reaction was diluted with EA (50 mL) and washed with water and brine. When the organic layer is dried over anhydrous sodium sulfate, concentrated and applied on a silica gel column, 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-pyrazole-1-yl)-[1,1'-biphenyl] -4-yl) Oxy) Propoxy) Propoxy) Isoindoline-2-yl) -5-oxopentanate (150 mg, 38% yield) was obtained as an oil. LCMS (ES +): m / z 890.4 [M + H] ⁺ .

Step G: 2- (2,6-dioxopiperidine-3-yl) -4- (3- (3-((4'-(4- (1-oxo-2,3-dihydro)
B-1H-Inden-5-yl) -3- (Pyridine-4-yl) -1H-Pyrazole-1-yl)-[1,1'-Bifeni
Le] -4-yl) oxy) propoxy) propoxy) isoindoline-1,3-dione.

tert-butyl 5-amino-4-(1,3-dioxo-4-(3-((4'-(4- (1-oxo-2,3-dihydro-1H-inden-5-yl) ) -3- (Pyridine-4-yl) -1H-pyrazole-1-yl)-[1,1'-biphenyl] -4-yl) oxy) propoxy) propoxy) isoindoline-2-yl) -5- TsOH (289 mg, 1.68 mmol) was added to a _{CH 3} CN (5 mL) solution of oxopentanate (150 mg, 0.168 mmol). The resulting solution was stirred at 80 ° C. for 3 hours. The reaction was _{quenched with saturated NaHCO 3} and extracted with EA. The organic layer was dried over anhydrous sodium sulfate, concentrated and purified by preparative TLC to remove 2- (2,6-dioxopiperidine-3-yl) -4-(3- (3-((4'-). (4- (1-oxo-2,3-dihydro-1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazole-1-yl)-[1,1'-biphenyl] -4-yl) Oxy) Propoxy) Propoxy) Isoindoline-1,3-dione (100 mg, 73% yield) was obtained. LCMS (ES +): m / z 816.3 [M + H] ⁺
Step H: (E) -2- (2,6-dioxopiperidine-3-yl) -4-(3-((4'-(4- (1- (hydroxyi)
Mino) -2,3-dihydro-1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazole-1-yl)-[1,1'-biphenyl] -4-yl) Oxy) Propoxy) Propoxy) Isoindoline-1,3-dione.

2- (2,6-dioxopiperidin-3-yl) -4-(3-(3-((4'-(4-(1-oxo-2,3-dihydro-1H-inden-5-yl)-yl) ) -3- (Pyridine-4-yl) -1H-pyrazol-1-yl)-[1,1'-biphenyl] -4-yl) oxy) propoxy) propoxy) isoindoline-1,3-dione (100) To a solution of MeOH / DCM (4 mL / 1 mL) of mg, 0.123 mmol) and hydroxylamine hydrochloride (256 mg, 3.681 mmol) _{was added NaHCO 3} (464 mg, 5.521 mmol) at 50 ° C. The mixture was stirred at 50 ° C. for 1 hour. Purification of the residue by preparative TLC with DCM / MeOH (20: 1) gives the desired product (E) -2- (2,6-dioxopiperidine-3-yl) -4- (3-). (3-((4'-(4- (1- (Hydroxyimino) -2,3-dihydro-1H-indene-5-yl) -3- (pyridin-4-yl) -1H-pyrazole-1-yl) Il)-[1,1'-biphenyl] -4-yl) oxy) propoxy) propoxy) Isoindoline-1,3-dione (24 mg, 24% yield) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6): 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] +.
Compound 214 can be prepared in a manner similar to compound 215.

Example of synthesis of compound 100: (2S, 4R) -1-((S) -2- (2- (3- (4- (4- (3- (2,6-difluoro-3- ((R)-)- 3-Fluoropyrrolidine-1-sulfonamide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperazine-1-yl) Propoxy) Acetamide) -3,3-dimethylbutanoyl) -4-Hydroxy-N- (4- (4-Methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide.

Step A: tert-butyl 2- (3-chloropropoxy) acetate .

0 NaOH (1.2 g, 31 mmol) in a dehydrated DMF (15 mL) solution of tert-butyl 2-bromoacetate (5.0 g, 26 mmol) and 3-chloropropane-1-ol (2.9 g, 31 mmol). Added at ° C. After stirring at 0 ° C. for 2 hours, the mixture was warmed to room temperature overnight. The reaction was quenched at H ₂ O (20 mL) 0 ° C. and the mixture was extracted with PE (20 mL × 2). The mixed organic layer was washed with water and brine. When the organic phase was concentrated in vacuo, the desired product tert-butyl 2- (3-chloropropoxy) -acetate (2.8 g, 52% yield) was used directly as an oil 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).

Step B: tert-butyl 2- (3- (4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-)
Ill) phenyl) piperazine-1-yl) propoxy) acetate.

1-(4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine 2,2,2-trifluoroacetate (530 mg, 1.32 mmol) _{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) in dehydrated DMF (5 mL) solution. Continued to add. The resulting solution was stirred at 90 ° C. for 3 hours. After cooling to room temperature, the reaction was diluted with EA (50 mL) and the mixture was washed with water and brine. The organic phase was concentrated under vacuum. Purification of the residue by preparative TLC yields the desired product tert-butyl 2-(3-(4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-) Ill) phenyl) piperazine-1-yl) propoxy) acetate (300 mg, crude) was obtained. 1H NMR (400 MHz, CDCl3): δ 7.70 (d, J = 8.0 Hz, 2H), 6.89 (d, J = 8.0 Hz, 2H), 3.96 (br, 2H), 3.27 (br, 4H), 3.21 ( br, 2H), 2.60 (br, 4H), 2.51-2.53 (m, 2H), 1.82-1.85 (m, 2H), 1.42 (s, 9H), 1.24 (s, 12H).
Step C: (R) -tert-butyl 2- (3-(4- (4- (3- (2,6-difluoro-3- (3-fluoropyrrolidin-1-sulfonamide) benzoyl))-1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperazine-1-yl) Propoxy) Acetate.

(R) -N- (3- (5-bromo-1H-pyrrolo [2,3-b] pyridine-3-carbonyl) -2,4-difluorophenyl) -3-fluoropyrrolidine-1-sulfonamide (100) tert-Butyl 2- (3- (4- (4- (4,4,5,5-tetramethyl-1,3,3,)] in a dioxane / H _{2 O (10 mL / 1 mL) solution of mg, 0.20 mmol)} 2-Dioxaborolan-2-yl) phenyl) piperazine-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) Was added. The resulting solution was _{stirred under N 2} atmosphere at 95 ° C. for 16 hours. TLC showed that the reaction was complete.
After cooling to room temperature, the reaction mixture was diluted with 50 mL EA and washed with water and brine.
The organic layer was dried over anhydrous sodium sulfate. Purification of the residue with a conditioning TLC yields the desired product (R) -tert-butyl 2- (3-(4- (4- (3- (2,6-difluoro-3- (3-fluoropyrrolidine-)). 1-Sulfonamide) Benzoyl) -1H-Pyrrolidine [2,3-b] Pyridine-5-yl) Phenyl) Piperazine-1-
Ill) propoxy) acetate (80 mg, 53% yield) was obtained. 1H NMR (400 MHz, CDCl3): 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).
Step D: (2S, 4R) -1-((S) -2- (2- (3- (4- (4- (4- (3- (2,6-difluoro-3- ((R) -3-fluoro) Pyrrolidine-1-sulfonamide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Pipe
Radin-1-yl) propoxy) acetamide) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4)
-(4-Methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide.

(R) -tert-butyl 2- (3- (4- (4- (3- (2,6-difluoro-3- (3-fluoropyrrolidin-1-sulfonamide) benzoyl))-1H-pyrrolo [2, 3-b] pyridine-5-yl) phenyl) piperazine-1-yl) propoxy) Acetate (80 mg, 0.13 mmol) in dioxane (2 mL) solution with HCl (2 mL, 8 M) solution in dioxane added. The resulting solution was stirred at 50 ° C. for 5 hours. After cooling to room temperature, when the solvent is removed under vacuum, (R) -2- (3- (4- (4- (3- (2,6-difluoro-3- (3-fluoropyrrolidin-1-sulfon) Amide) Benzoyl) -1H-Pyrrolidine [2,3-b] Pyridine-5-yl) Phenyl)
Piperazine-1-yl) propoxy) acetic acid (74 mg, 100% yield, calculated value) was obtained. (R) -2- (3- (4- (4- (3- (2,6-difluoro-3- (3-fluoropyrrolidin-1-sulfonamide) -benzoyl) -benzoyl) -1H-pyrrolo [2,3- b] Pyridine-5-yl) phenyl) piperazin-1-yl) propoxy) acetic acid (74 mg, 0.11 mmol), (2S, 4R) -1-((S) -2-amino-3,3-dimethylbuta Dehydrated NMP of noyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide hydrochloride (91 mg, 0.19 mmol) and DIEA (142 mg, 1.10 mmol) PyBOP (172 mg, 0.33 mmol) was added to the (5.0 mL) solution at room temperature. After stirring at 10 ° C. for 1 hour, the reaction was quenched with brine (20 mL) and the mixture was dissolved in EA. The organic phase is concentrated under vacuum and the residue is purified by preparative TLC and preparative HPLC to produce the desired product (2S, 4R) -1-((S) -2- (2- (3- (4). -(4- (3- (2,6-difluoro-3-((R) -3-fluoropyrrolidine-1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) Phenyl) piperazine-1-yl) propoxy) acetamide) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide (20) mg, yield of 2 steps 17%) was obtained as a white solid. 1H NMR (400 MHz, CD3OD): 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] +.
Example of Synthesis of Compound 152: (E) -2- (2,6-dioxopiperidine-3-yl) -5-(2- (4- (4- (1- (1- (H))
Droxyimino) -2,3-dihydro-1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenoxy) ethyl) piperazine-1-yl) isoindoline-1 , 3-Zeon.

Step A: 2- (4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenoxy) acetaldehyde.

4- (4-bromo-1- (4- (2,2-diethoxyethoxy) phenyl) -1H-pyrazole-3-yl) pyridine (1 g, 2.32 mmol) in CH ₃ CN (10 mL) solution , Concentrated HCl (2 mL, _{diluted with 6 mL H 2} O) was added. The resulting solution was stirred at 55 ° C. for 1 hour. After cooling to 0 ° C., a saturated aqueous solution of NaHCO3 was gradually added to adjust the pH to about 9. When the solid is filtered and _{co-evaporated with CH 3} CN, 2- (4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenoxy) acetaldehyde (0.3 g, Yield 66.9%) was obtained as a white solid. LCMS (ES ⁺ ): m / z 358.0, 376.0 / 378.0 [M + H] ⁺ , [M + 18] ⁺ .

Step B: 5- (4- (2- (4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenoki)
Si) Ethyl) piperazine-1-yl) -2- (2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione.

2- (4- (4-Bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenoxy) Acetaldehyde (0.1 g, 0.28 mmol) in MeOH (10 mL) solution in 2- ( 2,6-Dioxopiperidine-3-yl) -5- (piperazine-1-yl) isoindoline-1,3-dione hydrochloride (127 mg, 0.34 mmol) and a catalytic amount of HOAc were added. If the pH was below 5-6, AcOK was added. Then NaBH ₃ CN (87 mg, 1.40 mmol) was added. The resulting solution was stirred at 20 ° C. for 1 hour. After quenching with saturated NH ₄ Cl (20 mL), the mixture was extracted with DCM (30 mL × 2). The mixed organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. Purification of the residue by preparative TLC yields the desired product 5-(4-(4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) -phenoxy). ) Ethyl) piperazine-1-yl) -2- (2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione (90 mg,
Yield 35%) was obtained. LCMS (ES ⁺ ): m / z 684.1 / 686.1 [M + H] ⁺ .

Step C: 2- (2,6-dioxopiperidine-3-yl) -5-(4- (2- (4- (4- (1-oxo-2,3-dihydro-1H-inden-5-) Ill) -3- (Pyridine-4-yl) -1H-Pyrazole-1-yl) Phenoxy) Ethyl)
Piperazine-1-yl) Isoindoline-1,3-dione.

5- (4- (2- (4- (4-Bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenoxy) ethyl) piperazine-1-yl) -2- (2, 6-Dioxopiperidine-3-yl) Isoindoline-1,3-dione (90 mg, 0.13 mmol) and 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- Il) -2,3-dihydro-1H-inden-1-one (37 mg, 0.15 mmol) in a dioxane / H ₂ O (10 mL / 1 mL) solution with t-Bu ₃ PHBF ₄ (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) were added in succession. The resulting mixture was _{stirred under N 2} at 90 ° C. for 2 hours. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was diluted with EA (30 mL) and then the mixture was washed with brine. The organic phase was evaporated under vacuum. Purification of the residue by preparative TLC and preparative HPLC yields the desired product 2- (2,6-dioxopiperidine-3-yl) -5-(4- (2- (4- (4- (1) -Oxo-2,3-dihydro-1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenoxy) ethyl) piperazine-1-yl) isoindoline-1 , 3-Dione (60 mg, 69% yield) was obtained. LCMS (ES ⁺ ): m / z 736.3 [M + H] ⁺ .

Step D: (E) -2- (2,6-dioxopiperidine-3-yl) -5- (2- (4- (4- (1- (Hydroxyimi))
No) -2,3-dihydro-1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenoxy) ethyl) piperazine-1-yl) isoindoline-1 , 3-Zeon.

2- (2,6-dioxopiperidine-3-yl) -5-(4- (4- (4- (4- (1-oxo-2,3-dihydro-1H-inden-5-yl))- 3- (Pyridine-4-yl) -1H-pyrazole-1-yl) Phenoxy) Ethyl) Piperazine-1-yl) Isoindoline-1,3-dione (60 mg, 0.08 mmol) CH ₃ CN / Pyridine ( 6 mL / 3
To the mL) solution was _{added NH 2} OH · HCl (57 mg, 0.82 mmol). The mixture was stirred at 45 ° C. for 0.5 hours. The mixture was diluted with DCM (30 mL) and washed with brine. The organic phase was concentrated under reduced pressure. Purification of the residue by preparative TLC (DCM / MeOH 15/1) yields the desired product (E) -2- (2,6-dioxopiperidine-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 ) Piperazine-1-yl) Isoindoline-1,3-dione was obtained 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] +.
Example of synthesis of compound 216: (2S, 4R) -1-((S) -2- (3- (2- (3- (3- (2,6-difluoro-3- (propyls))
Luhonamide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenoxy) ethoxy)
Lopanamide) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide.

3- [2- [3- [3- [2,6-difluoro-3- (propylsulfonyl-amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenoxy] ethoxy]- Propylanoic acid (22.8 mg, 0.04 mmol) and (2S, 4R) -1-[(2S) -2-amino-3,3-dimethyl-butanoyl] -4-hydroxy-N-[[4- (4- (4- (4- (4-) Methylthiazole-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide; TEA (0.1 ml, 0.72 mmol) and PyBOP (22.21 mg, 0.043) in a DMF (2 ml) solution of hydrochloride (19.93 mg, 0.043 mmol). mmol) was added at room temperature. The reaction mixture was stirred at the same temperature for 12 hours (overnight). TLC (DCM: MEOH: NH ₄ OH, 90: 9: 1) indicates that there is no starting material. DMF was removed under high vacuum. The crude product was filtered on a silica carbonate cartridge using DCM: MeOH (9: 1) as an eluent. The filtrate was evaporated under vacuum and the crude product was purified by PTLC (MeOH: DCM, 1: 9, 2x) to give 20 mg of product (52% yield). 1H NMR (500 MHz, DMSO-d6) 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 (q, 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).
13C 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.LC-MS (ESI); m / z [M + H] +: Calculated value of C50H56F2N7O9S2, 1000.3548. Measured value: 1000.3536 ..

Example of Synthesis of Compound 217: N1- (4- (3- (2,6-difluoro-3- (propylsulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl)- N5-((S) -1-((2S, 4R) -4-hydroxy-2- ((4- (4-methylthiazole-5-yl) benzyl) carbamoyl) pyrrolidine-1-yl) -3,3 -Dimethyl-1-oxobutane-2-yl) Glutalamide.

5-((4- (3- (2,6-difluoro-3- (propylsulfonamide) -benzoyl) -1H-pyrrolo [2,3-b] pyridine-5-yl) phenyl) amino) -5- Oxopentanoic acid (9.7 mg, 0.02 mmol) and (2S, 4R) -1-[(2S) -2-amino-3,3-dimethyl-butanoyl] -4-hydroxy-N-[[4- (4- (4- (4- (4- (4-) Methylthiazole-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide; TEA (0.1 ml, 0.72 mmol) and PyBOP (9.5 mg, 0.02) in a DMF (1 ml) solution of hydrochloride (8.52 mg, 0.02 mmol). mmol) was added at room temperature. The reaction mixture was stirred at the same temperature for 4 hours. TLC (DCM: MEOH: NH ₄ OH, 90: 9: 1) indicates that there is no starting material. The reaction mixture was diluted with EtOAc (10 mL), washed with brine (5 mL, 4x), the organic phase was dried (Na2SO4) and evaporated under vacuum. Purification of the crude product with PTLC (DCM: MEOH: NH ₄ OH, 90: 9: 1, 2x) yielded 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 (dq, J = 14.9, 7.4 Hz, 2H), 0.96 (s, 9H), 0.95 (t, 3H) .13C 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. LC-MS (ESI); m / z [M + H] +: Calculated value of C50H55F2N8O8S2, 997.3552. Measured value: 997.3524.

Example of Synthesis of Compound 218: (2S, 4R) -1-((S) -2- (5- (4- (3- (2,6-difluoro-3- (propylsulfonamide) benzoyl) -1H-pyrrolo) [2,3-b] Pyridine-5-yl) Piperazin-1-yl) -5-oxopentanamide) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole) -5-yl) benzyl) pyrrolidine-2-carboxamide.

5- (4- (3- (2,6-difluoro-3- (propylsulfonamide) -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-dimethyl-butanoyl] -4-hydroxy-N-[[4- (4) -Methylthiazole-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide; in a DMF (1 ml) solution of hydrochloride (8.27 mg, 0.018 mmol), TEA (0.1 ml, 0.72 mmol) and PyBOP (9.22 mg, 0.018 mmol) was added at room temperature. The reaction mixture was stirred at the same temperature for 4 hours. TLC (DCM: MEOH: NH ₄ OH, 90: 9: 1) indicates that there is no starting material. The reaction mixture was diluted with EtOAc (10 mL), washed with brine (5 mL, 4x), the organic phase was dried (Na2SO4) and evaporated under vacuum. According to the TLC, no product was found in the crude mixture and there was only some starting material (the product was water soluble). The water extract was lyophilized overnight and the solid residue 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 PTLC (DCM: MEOH: NH4OH, 90: 9: 1, 2x) to give 13 mg of product (81% yield). 1H NMR (500 MHz, DMSO-d6) 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 (bs, 1H), 7.90 (d, J = 9.2 Hz, 1H), 7.59 --7.74 (m, 1H), 7.47 --7.27 (m, 4H), 7.20 (t) , J = 8.7 Hz, 1H), 5.13 (bs, 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 --1.61 (m, 4H), 0.95 (s, 9H), 0.94 (t, 3H) .13C 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.LC-MS (ESI); m / z [M + H] +:
Calculated value of C48H58F2N9O8S2, 990.3817. Measured value: 990.3889.

Example of Synthesis of Compound 219: (2S, 4R) -1-((S) -2- (4- (4- (3- (2,6-difluoro-3- (propylsulfonamide) benzoyl) -1H-pyrrolo) [2,3-b] Pyridine-5-yl) piperazin-1-yl) -4-oxobutaneamide) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole) -5-yl) benzyl) pyrrolidine-2-carboxamide.

4- (4- (3- (2,6-difluoro-3- (propylsulfonamide) -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-dimethyl-butanoyl] -4-hydroxy-N-[[4- (4- (4- (4- (4- (4-) Methylthiazole-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide; TEA (0.1 ml, 0.72 mmol) and PyBOP (9.14 mg, 0.018) in a DMF (1 ml) solution of hydrochloride (8.2 mg, 0.018 mmol). mmol) was added at room temperature. The reaction mixture was stirred at the same temperature for 12 hours (overnight). TLC (DCM: MEOH: NH ₄ OH, 90: 9: 1) indicates that there is no starting material. The reaction mixture was evaporated and dried. The crude product was filtered on a silica carbonate cartridge (100 mg) using DCM: MeOH (9: 1) as an eluent. Evaporation of the filtrate under vacuum to purify the crude product with PTLC (DCM: MEOH: NH ₄ OH, 90: 9: 1, 2x) yields 11 mg of product (75% yield). Obtained. 1H NMR (500 MHz, DMSO-d6) δ 12.66 (bs, 1H), 9.45 (bs, 1H), 8.98 (s, 1H), 8.60 (bs, 1H), 8.29 (s, 1H), 8.04 (s, 1H), 8.01 --7.81 (m, 2H), 7.62 --7.49 (m, 1H), 7.40 (q, 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 (q, J = 7.5 Hz, 2H), 0.96 (t, 3H), 0.94 (s, 9H). 13C 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.m / z [M + H] +: C47H56F2N9 Calculated value of O8S2, 976.3661. Measured value: 976.3712.

Example of Synthesis of Compound 220: N1- (4- (3- (2,6-difluoro-3- (propylsulfonamide) 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) pyrrolidine-1-yl) -3,3 -Dimethyl-1-oxobutane-2-yl) -Sulfinamide. 4-((4- (3- (2,6-difluoro-3- (propylsulfonamide) -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-dimethyl-butanoyl] -4-hydroxy-N-[[4- (4-methyl) Thiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide; TEA (0.1 ml, 0.72 mmol) and PyBOP (15.05 mg, 0.03 mmol) in DMF (1 ml) solution of hydrochloride (13.51 mg, 0.03 mmol). ) Was added at room temperature. The reaction mixture was stirred at the same temperature for 4 hours. TLC (DCM: MEOH: NH4OH, 90: 9: 1) indicates that there is no initiator. The reaction mixture was evaporated to dryness under high vacuum. The crude product was filtered on a silica carbonate cartridge (100 mg) using DCM: MeOH (9: 1) as an eluent. The filtrate was evaporated under vacuum and the crude product was purified by PTLC (DCM: MEOH: NH4OH, 90: 9: 1, 2x) to give 12 mg of product (purity of about 85%). The product was repurified with PTLC (DCM: MeOH, 9: 1) to give 8 mg of product (31% yield). 1H NMR (500 MHz, DMSO-d6) 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 --7.74 (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 (q, 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 (dq, J = 13.2, 8.3, 7.3 Hz, 2H), 0.96 (t, 3H), 0.95 (s, 9H). 13C 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, 5
6.41, 53.51, 41.71, 37.98, 35.45, 31.98, 30.14, 26.43, 16.88, 15.99, 12.65.LC-MS
(ESI); m / z [M + H] +: Calculated value of C49H53F2N8O8S2, 983.3395. Measured value: 983.3569.

Example of Synthesis of Compound 221: N1- (4- (3- (2,6-difluoro-3- (propylsulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl)- N3-((S) -1-((2S, 4R) -4-hydroxy-2- ((4- (4-methylthiazole-5-yl) benzyl) carbamoyl) pyrrolidine-1-yl) -3,3 -Dimethyl-1-oxobutan-2-yl) -malonamide. 3-((4- (3- (2,6-difluoro-3- (propylsulfonamide) -benzoyl) -1H-pyrrolo [2,3-b] pyridine-5-yl) phenyl) amino) -3- Oxopropanoic acid (16.8 mg, 0.03 mmol) and (2S, 4R) -1-[(2S) -2-amino-3,3-dimethyl-butanoyl] -4-hydroxy-N-[[4- (4- (4- (4- (4- (4-) Methylthiazole-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide; TEA (0.1 ml, 0.72 mmol) and PyBOP (17.28 mg, 0.033) in a DMF (1 ml) solution of hydrochloride (15.5 mg, 0.033 mmol). mmol) was added at room temperature. 12 of the reaction mixture at the same temperature
Stir for hours (overnight). TLC (DCM: MEOH: NH ₄ OH, 90: 9: 1) indicates that there is no starting material. The reaction mixture was evaporated to dryness under high vacuum. The crude product was filtered on a silica carbonate cartridge (100 mg) using DCM: MeOH (9: 1) as an eluent. Evaporate the filtrate under vacuum
The crude product was purified with PTLC (DCM: MEOH: NH ₄ OH, 90: 9: 1, 2x) and the product was purified again with PTLC (DCM: MeOH, 9: 1) to give 19.5 mg of product (19.5 mg). Yield 67%) was obtained. 1H NMR (400 MHz, DMSO-d6) 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 (q, 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 (q, J = 10.6 Hz, 2H), 3.44 (q, 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 (dq, J = 14.8, 7.3 Hz, 2H), 0.98 (s, 9H), 0.97 (t, J = 8.3 Hz, 3H). 13C 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, 1 5.96, 12.62. LC-MS (ESI); m / z [M + H] +: Calculated value of C48H51F2N8O8S2, 969.3239. Measured value: 969.3272.

Example of Synthesis of Compound 222: (2S, 4R) -1-((S) -2- (3- (4- (3- (2,6-difluoro-3- (propylsulfonamide) benzoyl) -1H-pyrrolo) [2,3-b] Pyridine-5-yl) piperazin-1-yl) -3-oxopropanamide) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole) -5-yl) benzyl) pyrrolidine-2-carboxamide. 3- (4- (3- (2,6-difluoro-3- (propylsulfonamide) -benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) piperazine-1-yl) -3 ---
Oxopropanoic acid (12.5 mg, 0.02 mmol) and (2S, 4R) -1-[(2S) -2-amino-3,3-dimethyl-butanoyl] -4-hydroxy-N-[[4- (4- (4- (4- (4- (4-) Methylthiazole-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide; TEA (0.1 ml, 0.72 mmol) and PyBOP (13.02 mg, 0.03) in DMF (1 ml) solution of hydrochloride (11.69 mg, 0.03 mmol). mmol) was added at room temperature. The reaction mixture was stirred at the same temperature for 12 hours (overnight). TLC (DCM: MEOH: NH ₄ OH, 90: 9: 1) indicates that there is no starting material. The reaction mixture was evaporated and dried. The crude product was filtered on a silica carbonate cartridge (100 mg) using DCM: MeOH (9: 1) as an eluent. The filtrate was evaporated under vacuum and the crude product was purified by PTLC (MeOH: DCM, 1: 9, 2x) to give 14.1 mg of product (64% yield). 1H NMR (500 MHz, DMSO-d6) 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 (bs, 1H), 7.57 (q, 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 (q, 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 (h, J = 7.3 Hz, 2H), 0.97 (s, 9H)., 0.96 (t, 3H). 13C 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.LC-MS (ESI); m / z [M + H] +: Calculated value of C46H54F2N9O8S2, 962.3504. Measured value: 962.3694.

Example of synthesis of compound 294: (E) -2- (2,6-dioxopiperidine-3-yl) -5-(3- (4- (4- (1- (hydroxyimino) -2,3-dihydro) -1H-Inden-5-yl) -3- (Pyridine-4-yl) -1H-Pyrazole-1-yl) Phenoxy)-[1,3'-Biazetidine] -1'-Il) Isoindoline-1, 3-Zeon.

Step A: tert-butyl-3- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy) azetidine-1-carboxylate.

tert-butyl-3-iodoazetidine-1-carboxylate (2.8 g, 12.6 mmol), 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (3.9) The mixture in dehydrated DMF (20 mL) of g, 13.8 mmol) and K ₂ CO ₃ (3.5 g, 25.2 mmol) was 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 under vacuum. Purification of the residue on silica gel (PE: EA = 9: 1) via a flash column gave the desired product (2.4 g, 65% yield).

Step B: tert-butyl 3- (4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenoxy) azetidine-1-carboxylate.

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-Pyrazole-3-)
To a solution of 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 under O 2} at 30 ° C. for 16 hours. The mixture was diluted with DCM (30 mL) and the mixture was washed with aqueous ammonia (10 mL x 3). When the organic phase is evaporated under reduced pressure and the residue is purified on silica gel (DCM / MeOH = 20/1) by silica gel column chromatography, tert-butyl 3- (4- (4-bromo-3- (4- (4-bromo-3-)). Pyridine-4-
Ill) -1H-pyrazole-1-yl) phenoxy) azetidine-1-carboxylate (1.5 g, 50% yield)
Was obtained as a brown oil. LCMS (ES ⁺ ): m / z 471 [M + H] ⁺ .

Step C: 4- (1- (4- (Azetidine-3-yloxy) phenyl) -4-bromo-1H-pyrazole-3-a
Le) Pyridine.

DCM (3 mL) of tert-butyl 3- (4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenoxy) azetidine-1-carboxylate (700 mg) To the solution was added 3 m hydrochloric acid (3 mL) in 1,4-dioxane. The resulting solution was stirred at room temperature for 2 hours. Removal of the solvent under reduced pressure gave the desired crude product (600 mg, crude). LCMS (ES ⁺ ): m / z 371 [M + H] ⁺ .

Step D: tert-Butyl-3- (4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazole-1-yl)
Enoxy)-[1,3'-Biazetidine] -1'-Carboxylate.

4- (1- (4- (Azetidine-3-yloxy) phenyl) -4-bromo-1H-pyrazole-3-yl) pyrididine (50 mg, 0.14 mmol) and tert-butyl 3-oxoazetidine-1-carboxylic acid Salt (48 mg)
, 0.28 mmol) to a solution of DCE (1.0 mL _{) was added AcOH (1 drop), NaBH (OAc) 3} (74 mg, 0.35 mmol). The resulting solution was stirred at 30 ° C. overnight. The mixture was diluted with EA (5 mL) and the mixture was washed ₃ times with NaHCO 3 aqueous solution. When the organic phase is evaporated under reduced pressure and the residue is purified on silica gel (PE / EA = 1/1) by silica gel column chromatography, tert-butyl 3- (4- (4-bromo-3- (pyridine)) -4-yl) -1H-pyrazole-1-yl) -phenoxy)-[1,3'-biazetidine] -1'-carboxylate (30 mg, 42% yield) was obtained as a brown oil. .. LCMS (ES ⁺ ): m / z 526 [M + H] ⁺ .

Step E: 5-(3- (4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenoxy)-[1,3'-biazetidin] -1'-yl ) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,
3-Zeon.

tert-Butyl 3- (4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenoxy)-[1,3'-biazetidine] -1'-carboxylate ( To a solution of 160 mg) DCM (2 mL) was added 3M hydrochloric acid (1 mL) in 1,4-dioxane. The resulting solution was stirred at room temperature for 2 hours. Removal of the solvent under reduced pressure gave the desired product (150 mg, crude). 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, DIPEA (1 drop) was added to a solution of 6-dioxopiperidine-3-yl) -5-fluoroisoindoline-1,3-dione (9.0 mg, 0.033 mmol) in NMP (1.0 mL). The resulting solution was _{stirred under N 2} at 130 ° C. for 1 hour. After cooling to room temperature, the mixture was diluted with EA (3 mL) and the mixture was washed twice with brine. The organic phase is evaporated under reduced pressure and the residue is purified by column chromatography on silica gel (DCM / MeOH = 15/1) and then 5- (3- (4- (4-bromo-3- (pyridine-). 4-yl) -1H-pyrazole-1-yl) phenoxy)-[1,3'-biazetidine] -1'-yl) -2- (2,6-dioxopiperidine-3-yl) isoindoline-1 , 3-Dione (4 mg, 36% yield) was obtained. LCMS (ES ⁺ ): m / z 682 [M + H] ⁺ .

Step F: 2- (2,6-dioxopiperidine-3-yl) -5-(3- (4- (4- (1-oxo-2,3-dihydro-1H-inden-5-yl))- 3- (Pyridine-4-yl) -1H-pyrazole-1-yl) Phenoxy)-[1,3'-biazetidine] -1'-yl) Isoindoline-1,3-dione.

5- (3- (4- (4-Bromo-3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenoxy)-[1,3'-
Biazetidin] -1'-yl) -2- (2,6-dioxopiperidine-3-yl) isoindoline-1,3-dione (200 mg, 0.29 mmol) 1,4-dioxane / H ₂ O ( v / v = 10/1, 5 mL) In a solution, 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) were added in succession. The resulting solution was heated to 100 ° C. for 2 hours under _{N 2.} After cooling to room temperature, the reaction was diluted with EA (10 mL) and the mixture was washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. When the residue is purified by preparative HPLC, 2- (2,6-dioxopiperidine-3-yl) -5-(3- (4- (4- (1-oxo-2,3-dihydro-1H-)- Inden-5-yl) -3- (Pyridine-4-yl) -1H-Pyrazole-1-yl) Phenoxy)-[1,3'-Biazetidine] -1'-Il) Isoindoline-1,3-dione (90 mg, 41.9% yield) was obtained as a yellow solid. LCMS
(ES ⁺ ): m / z 733 [M + H] ⁺ .

Step G: (E) -2- (2,6-dioxopiperidine-3-yl) -5-(3- (4- (4- (1- (hydroxyimino) -2,3-dihydro-1H-) Inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenoxy)-[1,3'-biazetidine] -1'-il) isoindoline-1,3-dione ..

2- (2,6-dioxopiperidine-3-yl) -5-(3- (4- (4- (1-oxo-2,3-dihydro-1H-inden-5-yl) -3- ( Pyridine-4-yl) -1H-pyrazole-1-yl) Phenoxy)-[1,3'-biazetidine] -1'-yl) Isoindoline-1,3-dione (90 mg, 0.12 mmol) acetonitrile / To a solution of 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 with DCM (20 mL), the mixture was washed with brine (10 mL x 2). When the organic phase is concentrated under vacuum and the residue is purified by preparative TLC, (E) -2- (2,6-dioxopiperidine-3-yl) -5- (3- (4- (4- (4- (4- (4- (4- (4-) (1- (Hydroxyimino) -2,3-dihydro-1H-inden-5-yl) -3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenoxy)-[1,3'- Biazetidine] -1'-yl) isoindoline-1,3-dione (25 mg, 27% yield) was obtained as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ): δ11.06 (s, 1H), 10.89 (s, 1H), 8.73 (s, 1H), 8.57 (d, J = 4.8Hz, 2H), 7.87 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.0 Hz, 1H), 7.56 (d, J
= 8.0Hz, 1H), 7.48 (d, J = 4.8Hz, 2H), 7.40 (s, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 8.8Hz, 2H), 6.80 (s, 1H), 6.68 (d, J = 8.4Hz, 1H), 5.02-5.07 (m, 1H), 4.96 (t, J = 2.4Hz, 1H), 4.09 (t, J = 8.4Hz, 2H) ), 3.80-3.87 (m, 4H), 3.73 (s, 1H), 3.22 (s, 4H), 3.01 (d, J = 5.2Hz, 2H), 2.84 (d, J = 5.6Hz, 2H), 2.01 (d, J = 9.2Hz, 2H); LCMS (ES ⁺ ): m / z 748.79 [M + H] ⁺ .
Example of synthesis of compound 226: (2S, 4R) -1-((S) -2- (2- (4-((4- (4- (3- (2,6-difluoro-3- ((R))) -3-
Fluoropyrrolidine-1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) methyl) piperidine-1-yl) acetamide) -3,3- Dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-ca
Luboxamide.

Step A: tert-butyl 2- (4-formylpiperidine-1-yl) acetate.

tert-Butyl 2- (4- (hydroxymethyl) piperidine-1-yl) acetate (1.5 g, 6.55 mmol)
IBX (2.7 g, 9.85 mmol) was added to a solution of CH _{3 CN (10 mL).} The resulting solution is 80 ° C
Was stirred for 5 hours. After cooling to room temperature, the reaction mixture was diluted with EA (30 mL) and the solution was washed with sodium sulfite and sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate. The organic phase was concentrated under vacuum. Purification of the residue by silica gel chromatography (PE: EA = 5: 1) gives the desired product tert-butyl 2- (4-formylpiperidine-1-yl) acetate (350 mg, 25% yield). Was obtained as yellow oil. 1H NMR (400 MHz, CDCl3): 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).
Step B: tert-butyl-2-(4-((4- (4-bromophenyl) piperazine-1-yl) methyl) piperi
Gin-1-yl) acetate.

_{CH 3} OH / DCM (v /) of tert-butyl 2- (4-formylpiperidine-1-yl) acetate (370 mg, 1.54 mmol) and 1- (4-bromophenyl) piperazine (350 mg, 1.54 mmol) v = 1/11, 10 mL) of the catalyst AcOH (0.1 mL) was added at room temperature. 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 with 3} aqueous NaHCO 3 (20 mL), the mixture was extracted with DCM (10 mL × 3). The mixed organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. Purification of the residue on silica gel (DCM: MeOH = 50: 1) results in tert-butyl 2-(4-((4- (4-bromophenyl) piperazine-1-yl) methyl) piperidin-1-yl) acetic acid. Salt (330 mg, 47% yield) was obtained as a yellow oil. LCMS (ES ⁺ ): m / z 454.2 [M + H] ⁺ .

Step C: tert-butyl 2- (4-((4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-1-yl)) Methyl) piperidine-1-yl) acetate.

4,4,4', 4', 5,5,5', 5'-octamethyl-2,2'-bi (1,3,2-dioxaborolane) (242 mg, 0.951)
1,4- of tert-butyl 2- (4-((4- (4-bromophenyl) piperazin-1-yl) methyl) -piperidine-1-yl) acetate (330 mg, 0.732 mmol) KOAc (145 m) in dioxane (5 mL) solution
g, 1.46 mmol) and Pd (dppf) ClCl ₂ (54 mg, 0.0732 mmol) were added. After stirring overnight at 90 ° C. under a nitrogen atmosphere, the reaction mixture is diluted with 30 mL ethyl acetate and the solution is brine (10).
Washed with mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. Purification of the residue with silica gel (DCM: MeOH = 100: 3) yields the desired product tert-butyl 2-(4-((4- (4- (4,4,5,5-tetramethyl-1,)). 3,2-Dioxaborolan-2-yl) phenyl) piperazine-1-yl) methyl) piperidine-1-yl) acetate (100 mg, 27% yield) was obtained as a yellow solid. LCMS (ES ⁺ ): m / z 499.4 [M + H] ⁺ .

Step D: (R) -tert-butyl-2-(4-((4- (4- (3- (2,6-difluoro-3- (3-fluoropyrrolidin-1-sulfonamide) benzoyl))-1H) -Pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperazine-1-yl) Methyl) Piperidine-1-yl) Acetate.

tert-butyl 2-(4-((4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-1-yl) methyl) piperidine _{CsF (121 mg, 0.796 mmol), Pd (aMPhos) Cl 2 in H 2} O / dioxane (v / v = 1/5, 5.0 mL) solution of -1-yl) acetate (100 mg, 0.199 mmol). (14 mg, 0.0199 mmol) and (R) -N- (3- (5-bromo-1H-pyrrolo [2,3-b] pyridine-3-carbonyl) -2,4-difluorophenyl) -3-fluoro Piperidine-1-sulfonamide (100 mg, 0.199 mmol) was added at room temperature. 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 was dissolved in EtOAc. The mixed organic layer was concentrated under vacuum. Purification of the residue with preparative TLC (DCM: CH ₃ OH = 20: 1) yields the desired product (R) -tert-butyl 2- (4-((4- (4- (3- (2,,)). 6-Difluoro-3- (3-fluoropyrrolidin-1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) methyl) piperidine-1- Il) Acetate (50 mg, 32% yield) was obtained as a pale yellow solid. LCMS (ES ⁺ ): m / z 797.6 [M + H] ⁺ .

Step E: (R) -2- (4-((4- (4- (3- (2,6-difluoro-3- (3-fluoropyrrolidin-1-sulfonamide) benzoyl))-1H-pyrrolo [2 , 3-b] Pyridine-5-yl) Phenyl) Piperazine-1-yl) Methyl) Piperidine-1-yl) Acetic acid.

(R) -tert-butyl 2-(4-((4- (4- (3- (2,6-difluoro-3- (3-fluoropyrrolidin-1-sulfonamide) benzoyl))-1H-pyrrolo [2 , 3-b] Pyridine-5-yl) Phenyl) Piperazine-1-yl) Methyl) Piperidine-1-yl) Acetate (50 mg, 0.0629 mmol) in DCM (1 mL) solution to TFA (0.5)
mL) was added. The resulting solution was stirred at room temperature for 2 hours. The solvent was removed under vacuum. As a residue, the desired product (R) -2- (4-((4- (4- (3- (2-,6-difluoro-3- (3-fluoropyrrolidin-1-sulfonamide) benzoyl))- 1H-Pyrrolidine [2,3-b] Pyridine-5-yl) Phenyl) Piperazine-1-yl) Methyl) Piperidine-1-yl) Acetic acid (80 mg, crude) was obtained as a yellow solid. LCMS
(ES ⁺ ): m / z 740.2 [M + H] ⁺ .

Step G: (2S, 4R) -1-((S) -2- (2-(4-((4- (4- (3- (2,6-difluoro-3- ((R) -3-) -3-) Fluoropiro
Lysine-1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) pi
Perazine-1-yl) Methyl) Piperidine-1-yl) Acetamide) -3,3-dimethylbutanoyl) -4-Hydroxy-N- (4- (4-Methylthiazole-5-yl) benzyl) Pyrrolidine-2 -Carboxamide.

(R) -2- (4-((4- (4- (3- (2,6-difluoro-3- (3-fluoropyrrolidin-1-sulfonamide))
Benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) methyl)
DIEA (25 mg, 0.189) in a DCM (5.0 mL) solution of piperidine-1-yl) acetic acid (47 mg, 0.0629 mmol).
mmol), (2S, 4R) -1-((S) -2-((l3-chloranil) diazenyl) -3,3-dimethylbutanoyl) -4-
Hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide (30 mg, 0.0691 mmol) and PyBOP (40 mg, 0.0755 mmol) were added at room temperature. The resulting solution was stirred at 20 ° C. for 1 hour. The reaction was _{quenched with H 2} O (10 mL) and the mixture was extracted with DCM (20 mL x 3). The mixed organic layer was concentrated under vacuum. Purification of the residue with preparative TLC (DCM: CH ₃ OH = 10: 1) yields the desired product (2S, 4R) -1-((S) -2- (2- (4-((). 4- (4- (3- (2,6-difluoro-3-((R) -3-fluoropyrrolidin-1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridine-5-yl) ) Phenyl) piperazine-1-yl) methyl) piperidine-1-yl) acetamide) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) Piperidine-2-carboxamide (33 mg) was obtained as a white solid. 1H NMR (400 MHz, CD3OD): 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 (br, 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] +.
Example of synthesis of compound 227: (2S, 4R) -1-((S) -2- (2- (4-((1- (4- (3- (2,6-difluoro-3- ((R))) -3-
Fluoropyrrolidine-1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperidine-4-yl) methyl) piperazin-1-yl) acetamide) -3,3- Dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-ca
Luboxamide.

Step A: 1- (4-Bromophenyl) piperidine-4-carbaldehyde.

Hydrochloric acid (3 N) was added to a solution of 1- (4-bromophenyl) -4- (dimethoxymethyl) piperidine (1 g, 3.18 mmol) in MeCN (10 mL). The resulting solution was stirred at 50 ° C. for 4 hours. After cooling to room temperature, the pH of the mixture was adjusted to 8-9 _{with NaHCO 3 aqueous solution.} The reaction mixture was diluted with 30 mL of EA and the mixture was washed with sodium sulfite and sodium hydrogen carbonate. The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under vacuum. The residue is 1- (4-bromophenyl) piperidine-4-carbaldehyde (1 g, crude), which is the desired product as a yellow solid. LCMS (ES ⁺ ): m / z 268.0 [M + H] ⁺ .

Step B: tert-butyl 4-((1- (4-bromophenyl) piperidine-4-yl) methyl) piperazine-1-carboxylate.

_{CH 3} OH / DCM (v / v =) of 1- (4-bromophenyl) piperidine-4-carbaldehyde (1 g, crude) and tert-butyl piperazine-1-carboxylate (590 mg, 3.18 mmol) A catalytic amount of AcOH (0.1 mL) was added to the 1/1, 10 mL) solution at room temperature. 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 with 3} aqueous NaHCO 3 (20 mL), the mixture was extracted with DCM (10 mLx3). The mixed organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. Purification of the residue on silica gel with PE / EA (8/1) reveals tert-butyl 4-((1- (4-bromophenyl) piperidine-4-yl) methyl) piperazine-1-carboxylate ( 800 mg) was obtained as a yellow oil. LCMS (ES ⁺ ): m / z 440.2 [M + H] ⁺ .

Step C: tert-Butyl 2- (4-((1- (4-bromophenyl) piperidine-4-yl) methyl) pipera
Gin-1-yl) acetate.

TFA (2 mL) in a DCM (4 mL) solution of tert-butyl 4-((1- (4-bromophenyl) piperidine-4-yl) methyl) piperazine-1-carboxylate (800 mg, 1.83 mmol) ) Was added. The resulting solution was stirred at room temperature for 2 hours. Removal of the solvent under vacuum gave the desired crude product (1 g, crude), which was used directly in the next step. _{K 2} CO ₃ (190 mg, 1.37 mmol) is added to a dehydrated DMF (5 mL) solution of the above crude product (500 g, crude) and tert-butyl 2-bromoacetate (176 mg, 0.913 mmol). rice field. The resulting solution was stirred at room temperature overnight. The reaction mixture was diluted with 40 mL EA and the mixture was washed with water and brine. The organic phase was dried over anhydrous sodium sulfate. As a residue, the desired product tert-butyl-2-(4-((1- (4-bromophenyl) piperidine-4-yl) methyl) piperazine-1-yl) acetate (410 mg, crude) Obtained as yellow oil. LCMS (ES ⁺ ): m / z 453.2 [M + H] ⁺ .

Step D: tert-butyl 2- (4-((1- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperidine-4-yl)) Methyl) piperazine-1-yl) acetate.

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- In a solution of (4-((1- (4-bromophenyl) piperidine-4-yl) methyl) -piperazine-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 overnight at 90 ° C. under a nitrogen atmosphere, 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 under vacuum. Purification of the residue on silica gel with DCM / MeOH (100/3) gives the desired product tert-butyl 2-(4-((1- (4- (4,4,5,5-tetramethyl-)- 1,3,2-dioxaborolan-2-yl) phenyl) -piperidine-4-yl) methyl) piperazine-1-yl) acetate (200 mg, crude) was obtained as a yellow solid. LCMS (ES ⁺ ): m / z 500.4 [M + H] ⁺ .

Step E: (R) -tert-butyl 2-(4-((1- (4- (3- (2,6-difluoro-3- (3-fluoropyrrolidin-1-sulfonamide) benzoyl))-1H- Pyrrolidine [2,3-b] Pyridine-5-yl) Phenyl) Piperidine-4-yl) Methyl) Piperazine-1-yl) Acetate.

tert-butyl 2-(4-((1- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl))
Phenyl) piperidine-4-yl) methyl) piperazine-1-yl) acetate (200 mg, crude) in H ₂ O / dioxane (v / v = 1/5, 5.0 mL) solution to CsF (121 mg, 0.796 mmol), Pd (aMPhos) Cl ₂ (14 mg, 0.0199 mmol), (R) -N- (3- (5-bromo-1H-pyrrolo [2,3-b] pyridine-3-carbonyl) -2 , 4-Difluorophenyl) -3-fluoropyrrolidin-1-sulfonamide (100 mg, 0.199 mmol) was added at room temperature. 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 was dissolved in EtOAc. The mixed organic layer was concentrated under vacuum. Purification of the residue with preparative TLC _{using DCM / CH 3} OH (20/1) yields the desired product (R) -tert-butyl 2- (4-((1- (4- (3- (3-(). 2,6-difluoro-3- (3-fluoropyrrolidin-1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperidine-4-yl) methyl) piperazine- 1-Il) acetate (110 mg, 69% yield) was obtained as a pale yellow solid. LCMS (ES ⁺ ): m / z 796.3 [M + H] ⁺ .

Step F: (2S, 4R) -1-((S) -2- (2-(4-((1- (4- (3- (2,6-difluoro-3- ((R) -3-) -3-) Fluoropiro
Lysine-1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) pi
Peridine-4-yl) methyl) piperazine-1-yl) acetamide) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2 -Carboxamide.

(R) -tert-butyl 2-(4-((1- (4- (3- (2,6-difluoro-3- (3-fluoropyrrolidin-1-sulfonamide) benzoyl))-1H-pyrrolo [2 , 3-b] Pyridine-5-yl) Phenyl) Piperidine-4-yl) Methyl) Piperazine-1-yl) Acetate (110 mg, 0.139 mmol) in DCM (3 mL) solution in TFA (1.5)
mL) was added. The resulting solution was stirred at room temperature for 2 hours. Removal of the solvent under vacuum gave the desired crude product (180 mg, crude), which was used directly in the next step. DIEA (54 mg, 0.418 mmol), (2S, 4R) -1-((S) -2-((l3-chloranil) diazenyl) in DMF (5.0 mL) solution of the above acid (180 mg, crude) -3,3-dimethyl-butanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide (66 mg, 0.153 mmol) and PyBOP (87 mg, 0.167) mmol) was added at room temperature. The resulting solution was stirred at 20 ° C. for 1 hour. After quenching with H ₂ O (10 mL), the mixture was extracted with EA (20 mL x 3). The mixed organic layer was concentrated under vacuum. Purification of the residue by preparative HPLC gave the desired product the desired 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] +.
Example of synthesis of compound 295: (2S, 4R) -1-((S) -2- (2- (4-((4- (4- (3- (2,6-difluoro-3- (((3S) , 4S) -3-fluoro-4-hydroxypyrrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) methyl) piperidine- 1-yl) acetamide) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide.

Step A: (3S, 4S) -3-[(tert-butyldiphenylsilyl) oxy] -4-fluoropyrrolidine.

In a 50 mL round bottom flask, (3S, 4S) -4-fluoropyrrolidine-3-ol (500 mg, 4.76 mmol, 1 eq), dichloromethane (10 mL), imidazole (323.8 mg, 4.76 mmol, 1 eq), TBDPSCl (1307.5 mg, 4.76 mmol, 1 eq) was added. The resulting solution was stirred at room temperature overnight. The resulting mixture was concentrated. The residue is applied on a silica gel column and dichloromethane /
It was eluted with methanol (10/1). As a result, 470 mg (29%) of (3S, 4S) -3-[(tert-butyldiphenylsilyl) oxy] -4-fluoropyrrolidine was obtained as a yellow oil.

Step B: (3S, 4S) -3-[(tert-butyldiphenylsilyl) oxy] -4-fluoropyrrolidine-1-sulfonyl chloride.

In a 50 mL round bottom flask, (3S, 4S) -3-[(tert-butyldiphenylsilyl) oxy] -4-fluoropyrrolidine (370 mg, 1 eq), dichloromethane (5 mL), diisopropylethylamine (279 mg, 2 equivalents) and dichlorosulfoxide (290 mg, 2 equivalents) were added. The resulting solution was stirred at -30 ° C for 4 hours. The reaction was then stopped by the addition of water (20 mL). The resulting solution was extracted with dichloromethane (20 mL x 3). The resulting mixture was washed with brine (20 mL x 1), dried over anhydrous sodium sulfate and concentrated. As a result, 450 mg of (3S, 4S) -3-[(tert-butyldiphenylsilyl) oxy] -4-fluoropyrrolidine-1-sulfonyl chloride was obtained as a yellow oil.

Step C: (3S, 4S) -N- (3- [5-bromo-1H-pyrrolo [2,3-b] pyridin-3-carbonyl] -2,4-diph
Luolophenyl) -3-[(tert-butyldiphenylsilyl) oxy] -4-fluoropyrrolidine-1-
Sulfonamide.

In a 25 mL round bottom flask, (3S, 4S) -3-[(tert-butyldiphenylsilyl) oxy] -4-fluoropyrrolidin-1-sulfonyl chloride (449.4 mg, 1.02 mmol, 2.00 equivalents), pyridine (0.7 mL) ), 3- [5-bromo-1H-pyrrolo [2,3-b] pyridin-3-carbonyl] -2,4-difluoroaniline (179 mg, 0.51 mmol, 1 equivalent), dimethylaminopyridine (18.6 mg,) 0.15 mmol (0.30 equivalent) was added. The resulting solution was stirred in an oil bath at 45 ° C. for 3 hours. The resulting mixture was concentrated. The residue was applied on a silica gel column and eluted with ethyl acetate / petroleum ether (1/1). As a result, 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 was obtained as a yellow oil.

Step D: tert-Butyl 2- (4-[[4- [3- [3-([[(3S, 4S) -3-[(tert-butyldiphenylsilyl) oxy] -4-fluoropyrrolidine -1-yl] sulfonyl] amino) -2,6-difluorobenzoyl] -1H-pyrrolidine [2,3-b] pyridin-5-yl] phenyl) piperazine-1-yl] methyl] piperidine.

In a 50 mL round bottom flask, (3S, 4S) -N- (3- [5-bromo-1H-pyrrolo [2,3-b] pyridin-3-carbonyl] -2,4-difluorophenyl) -3- [(tert-Butyldiphenylsilyl) oxy] -4-fluoropyrrolidin-1-sulfonamide (120 mg, 0.16 mmol, 1 eq), 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] piperazine-1-yl] methyl) piperidine-1-yl] acetate (79.1 mg, 0.16 mmol, 1 equivalent), Na ₂ CO ₃ (50.4 mg, 0.48 mmol, 3 equivalents), Pd (dppf) Cl ₂ (39 mg) was added. The resulting solution was stirred in an oil bath at 110 ° C. for 2 hours. The resulting mixture was concentrated. The residue was applied on a silica gel column and eluted with dichloromethane / methanol (10/1). As a result, 90 mg (54%) of tert-butyl 2-(4-[[4- (4- [3- [3-([[(3S, 4S) -3-[(tert-butyldiphenylsilyl)) Oxy] -4-fluoropyrrolidine-1-yl] sulfonyl] amino) -2,6-difluorobenzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazine-1-yl] methyl ] Piperidine was obtained as a yellow oil.

Step E: 2- (4-[[4- (4- [3- [3-([[(3S, 4S) -3-[(tert-butyldiphenylsilyl) oxy] -4-fluoropyrrolidine-1- Il] sulfonyl] amino) -2,6-difluorobenzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazine-1-yl] methyl] piperidine-1-yl) acetic acid
Synthesis of.

In a 25 mL round bottom flask, 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) piperazine-1-yl] methyl] piperido (90 mg, 0.09 mmol, 1 equivalent), dichloromethane (5 mL), trifluoroacetic acid (2)
mL, 0.02 mmol) was added. The resulting solution was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. As a result, 60 mg (70.43%) of 2- (4-[[4- [3- [3-([[(3S, 4S) -3-[(tert-butyldiphenylsilyl) oxy]- 4-Fluoropyrrolidine-1-yl] sulfonyl] amino) -2,6-difluorobenzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazine-1-yl] methyl] piperidine- 1-Il) Acetic acid was obtained as a yellow solid.

Step F: 2- (4-[[4- (4- [3- [2,6-difluoro-3-([[(3S, 4S) -3-fluoro-4-hydroxypyrrolidine-1-yl] sulfonyl] sulfonyl) ] Amino) Benzoyl] -1H-Pyrrolidine [2,3-b] Pyridine-5-yl] Phenyl) Piperazin-1-yl] Methyl] Piperidine-1-yl) Synthesis of acetic acid.

In a 25 mL round bottom flask, 2- (4-[[4- (4- [3- [3-([[(3S, 4S) -3-[(tert-butyldiphenylsilyl) oxy] -4-] Fluoropyrrolidine-1-yl] sulfonyl] amino) -2,6-difluorobenzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazine-1-yl] methyl] piperidine-1- Il) Acetic acid (60 mg, 0.06 mmol, 1 equivalent), tetrahydrofuran (3 mL), TBAF (1 mL, 0.06 equivalent) were added. The resulting solution was stirred at 40 ° C. for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was applied on a silica gel column and eluted with dichloromethane / methanol (10/1). The result was 50 mg (109.62%) of 2- (4-[[4- (4- [3- [2,6-difluoro-3-([[(3S, 4S) -3-fluoro-4-hydroxy). Pyrrolidine-1-yl] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazine-1-yl] methyl] piperidine-1-yl) acetic acid yellow oil Obtained as.

Step G: (2S, 4R) -1-((S) -2- (2-(4-((4- (4- (3- (2,6-difluoro-3- (((3S, 4S)) -3-Fluoro-4-hydroxypyrrolidin) -1-sulfonamide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperazine-1-yl) Methyl) Piperidine-1-yl ) Acetamide) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide.

In a 25 mL round bottom flask, 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] pyridine-5-yl] phenyl) piperazine-1-yl] methyl] piperidine-1-yl) acetic acid (50 mg, 0.066 mmol) , 1 equivalent), DMF (5 mL), (2S, 4R) -1-[(2S) -2-amino-3,3-dimethylbutanoyl] -4-hydroxy-N-[[4- (4- (4- (4-) Methyl-1,3-thiazole-5-yl) phenyl] methyl] piperidine-2-carboxamide (30.8 mg, 0.066 mmol, 1 equivalent), diisopropylethylamine (34.1 mg, 0.264 mmol, 4.00 equivalent), BOP (35 mg, 35 mg, 1 equivalent) 0.079 mmol (1.2 equivalent) was added. The resulting solution was stirred at room temperature for 3 hours. The reaction was then quenched with 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. As a result, 32.6 mg (42%) of (2S, 4R) -1-((S) -2- (2- (4-((4- (4- (3- (2,6-difluoro-3-) (((3S, 4S) -3-fluoro-4-hydroxypyrrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) Methyl) piperidine-1-yl) acetamide) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide is a yellow solid Obtained as a thing. 1H NMR (400 MHz, CD3OD): 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] +.
Example of Synthesis of Compound 298: (2S, 4R) -1-((S) -2- (2- (4- (3- (2,6-difluoro-3- (propylsulfonamide) benzoyl) -1H-pyrrolo) [2,3-b] Pyridine-5-yl) Phenoxy) Acetamide) -3,3-dimethylbutanoyl) -4-Hydroxy-N- (4- (4-Methylthiazole-5-yl) benzyl) -Pi
Loridine-2-carboxamide.

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-dimethyl-butanoyl] -4-hydroxy-N-[[4- (4-methylthiazole-5-yl)- Phenyl] methyl] pyrrolidine-2-carboxamide; TEA (0.1 ml, 0.717 mmol) and PyBOP (11 mg, 0.021 mmol) were added to a solution of hydrochloride (9.5 mg, 0.02 mmol) in DMF (1 ml) at room temperature. .. The reaction mixture was stirred at the same temperature for 4 hours. TLC (DCM: MeOH: NH4OH, 90: 9: 1) indicates that there is no initiator. DMF was removed under high vacuum. The crude product was filtered on a silica carbonate cartridge (100 mg) using a mixture of DCM: MeOH (90:10) as an eluent.
The filtrate was evaporated under vacuum and the crude product was purified by PTLC (DCM: MeOH: NH4OH, 90: 9: 1) to give 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 --8.30 (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). 13C 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. LC-MS (ESI); m / z [M + H] +: Calculated value of C47H50F2N7O8S2, 942.3130. Measured value: 942.3134.

Example of Synthesis of Compound 299 (2S, 4R) -1-((S) -2- (4- (3- (3- (2,6-difluoro-3- (propylsulfonamide) benzoyl))-1H-pyrrolo [ 2,3-b] Pyridine-5-yl) phenoxy) butaneamide) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2 -Carboxamide.

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-dimethyl-butanoyl] -4-hydroxy-N-[[4- (4-methylthiazole-5-yl)) ---
Phenyl] methyl] pyrrolidine-2-carboxamide; TEA (0.1 ml, 0.72 mmol) and PyBOP (18.48 mg, 0.04 mmol) were added to a solution of hydrochloride (16.8 mg, 0.036 mmol) in DMF (2 ml) at room temperature. .. The reaction mixture was stirred at the same temperature for 4 hours. TLC (DCM: MeOH: NH ₄ OH, 90: 9: 1) indicates that there is no initiator. DMF was removed under high vacuum (the product may be partially water soluble). The crude product was filtered on a silica carbonate cartridge using DCM: MeOH (9: 1) as an eluent. The filtrate is evaporated under vacuum and the crude product is PTLC (DCM: MeOH: NH ₄ OH).
, 90: 9: 1) and a second purification with PTLC (DCM: MeOH, 9: 1) yielded 8 mg of product (25% yield). 1H NMR (500 MHz, DMSO-d6) δ 12.97 (bs, 1H), 9.72 (bs, 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 --1.77 (m, 2H), 0.97 ( t, 3H), 0.94 (s, 9H). 13C 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, 42.0 8, 38.38, 35.67, 31.76, 26.80, 25.52, 17.26, 16.37, 13.04.LC-MS (ESI); m / z [M + H] ⁺ : C ₄₉ H ₅₄ F ₂ N ₇ O ₈ S ₂ calculated value , 970.3443. Measured value: 970.3787.

Example of synthesis of compound 300: (2S, 4R) -1-((S) -2- (2- (2- (3- (3- (2,6-difluoro-3- (propyls))
Luhonamide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenoxy) ethoxy) a
Setoamide) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide.

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) -1-[(2S) -2-amino-3,3-dimethyl-butanoyl] -4-hydroxy-N-[[4- (4-methylthiazole-5) -Il) phenyl] methyl] pyrrolidine-2-carboxamide; TEA (0.1 ml, 0.72 mmol) and PyBOP (19.06 mg, 0.04 mmol) in a DMF (2 ml) solution of hydrochloride (17.11 mg, 0.04 mmol) at room temperature. The reaction mixture was stirred at the same temperature for 2 hours. TLC (DCM: MeOH: NH ₄ OH, 90: 9: 1) indicates the absence of starting material. DMF under high vacuum. Removed (product may be partially water soluble). Crude product was filtered using DCM: MeOH (9: 1) as an eluent on a silica carbonate cartridge. Evaporation under vacuum and purification of the crude product with PTLC (DCM: MeOH: NH ₄ OH, 90: 9: 1) gave 13 mg product (40% yield). ¹ H NMR ( 400 MHz, DMSO-d6) δ 12.95 (bs, 1H), 9.74 (bs, 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 --1.74 (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. LC-MS (ESI); m / z [M + H] ⁺ : C ₄₉ H ₅₄ F ₂ N ₇ O ₉ Calculated value of S ₂ , 986.3392. Measured value: 986.3679.

Example of Synthesis of Compound 217: N1- (4- (3- (2,6-difluoro-3- (propylsulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl)- N5-((S) -1-((2S, 4R) -4-hydroxy-2- ((4- (4-methylthiazole-5-yl) benzyl) carbamoyl) pyrrolidine-1-yl) -3,3 -Dimethyl-1-oxobutane-2-yl) Glutalamide.

5-((4- (3- (2,6-difluoro-3- (propylsulfonamide) -benzoyl) -1H-pyrrolo [2,3-b] pyridine-5-yl) phenyl) amino) -5- Oxopentanoic acid (9.7 mg, 0.02 mmol) and (2S, 4R) -1-[(2S) -2-amino-3,3-dimethyl-butanoyl] -4-hydroxy-N-[[4- (4- (4- (4- (4- (4-) Methylthiazole-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide; TEA (0.1 ml, 0.72 mmol) and PyBOP (9.5 mg, 0.02) in a DMF (1 ml) solution of hydrochloride (8.52 mg, 0.02 mmol). mmol) was added at room temperature. The reaction mixture was stirred at the same temperature for 4 hours. TLC (DCM: MeOH: NH ₄ OH, 90: 9: 1) indicates that there is no initiator. The reaction mixture was diluted with EtOAc (10 mL), washed with brine (5 mL, 4x), the organic phase was dried (Na ₂ SO ₄ ) and evaporated under vacuum. Purification of the crude product with PTLC (DCM: MeOH: NH ₄ OH, 90: 9: 1) yielded 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 (dq, J = 14.9, 7.4 Hz, 2H), 0.96 (s, 9H), 0.95 (t, 3H) .13C 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 .LC-MS (ESI); m / z [M + H] ⁺ : C ₅₀ H ₅₅ F ₂ N ₈ O ₈ S ₂ calculated value, 997.3552. Measured value: 997.3524.

Example of Synthesis of Compound 218: (2S, 4R) -1-((S) -2- (5- (4- (3- (2,6-difluoro-3- (propylsulfonamide) benzoyl) -1H-pyrrolo) [2,3-b] Pyridine-5-yl) Piperazin-1-yl) -5-oxopentanamide) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole) -5-yl) benzyl) pyrrolidine-2-carboxamide.

5- (4- (3- (2,6-difluoro-3- (propylsulfonamide) -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-dimethyl-butanoyl] -4-hydroxy-N-[[4- (4) -Methylthiazole-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide; in a DMF (1 ml) solution of hydrochloride (8.27 mg, 0.018 mmol), TEA (0.1 ml, 0.72 mmol) and PyBOP (9.22 mg, 0.018 mmol) was added at room temperature. The reaction mixture was stirred at the same temperature for 4 hours. TLC (DCM: MeOH: NH ₄ OH, 90: 9: 1) indicates that there is no initiator. The reaction mixture was diluted with EtOAc (10 mL), washed with brine (5 mL, 4x), the organic phase was dried (Na ₂ SO ₄ ) and evaporated under vacuum. On TLC, no product was found in the crude mixture and there was only some VHL initiator (4) (the product is water soluble). The water extract was lyophilized overnight and the solid residue _{was filtered using a mixture of DCM: MeOH: NH 4} OH (90: 9: 1, 30 mL). The filtrate was evaporated to dryness and the crude product was purified by PTLC (DCM: MeOH: NH ₄ OH, 90: 9: 1) to give 13 mg of product (81% yield). ¹ H NMR (500 MHz, DMSO-d6) 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 (bs, 1H), 7.90 (d, J = 9.2 Hz, 1H), 7.59 --7.74 (m, 1H), 7.47 --7.27 (m, 4H), 7.20 ( t, J = 8.7 Hz, 1H), 5.13 (bs, 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 --1.61 (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.LC-MS (ESI); m / z [M + H] ⁺ : C ₄₈ H ₅₈ F ₂ N ₉ O ₈ S ₂ calculated value, 990.3817. Measured value: 990.3889.

Example of Synthesis of Compound 219: (2S, 4R) -1-((S) -2- (4- (4- (3- (2,6-difluoro-3- (propylsulfonamide) benzoyl) -1H-pyrrolo) [2,3-b] Pyridine-5-yl) piperazin-1-yl) -4-oxobutaneamide) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole) -5-yl) benzyl) pyrrolidine-2-carboxamide.

4- (4- (3- (2,6-difluoro-3- (propylsulfonamide) -benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) piperazine in DMF (1 ml) -1-yl) -4-oxobutanoic acid (9 mg, 0.016 mmol) and (2S, 4R) -1- [(2S) -2-amino-3,3-dimethyl-butanoyl] -4-hydroxy-N- [[4- (4-Methylthiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide; TEA (0.1 ml, 0.72 mmol) and PyBOP (9.14 mg, 0.018 mmol) to hydrochloride (8.2 mg, 0.018 mmol). ) Was added at room temperature. The reaction mixture was stirred at the same temperature for 12 hours (overnight). TLC (DCM: MeOH: NH ₄ OH, 90: 9: 1) indicates that there is no initiator. The reaction mixture was evaporated and dried. The crude product was filtered on a silica carbonate cartridge (100 mg) using DCM: MeOH (9: 1) as an eluent. The filtrate was evaporated under vacuum and the crude product was purified by PTLC (DCM: MeOH: NH ₄ OH, 90: 9: 1) to give 11 mg of product (75% yield). 1H NMR (500 MHz, DMSO-d6) δ 12.66 (bs, 1H), 9.45 (bs, 1H), 8.98 (s, 1H), 8.60 (bs, 1H), 8.29 (s, 1H), 8.04 (s, 1H), 8.01 --7.81 (m, 2H), 7.62 --7.49 (m, 1H), 7.40 (q, 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 (q, J = 7.5 Hz, 2H), 0.96 (t, 3H), 0.94 (s, 9H). 13C 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. LC-MS (ESI); m / z [M + H ] ⁺ : C ₄₇ H ₅₆ F ₂ N ₉ O ₈ S ₂ calculated value, 976.3661. Measured value: 976.3712.

Example of synthesis of compound 220: N ¹ -(4- (3- (2,6-difluoro-3- (propylsulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) -N ^Four -((S) -1-((2S, 4R) -4-hydroxy-2- ((4- (4-methylthiazole-5-yl) benzyl) carbamoyl) pyrrolidine-1-yl) -3,3- Dimethyl-1-oxobutane-2-yl) succinamide.

Product obtained from the synthesis of compound 218 [(2S, 4R) -1-((S) -2- (5-(4- (3- (2,6-difluoro-3- (propylsulfonamide) benzoyl)) -1H-pyrrolo [2,3-b] pyridin-5-yl) piperazine-1-yl) -5-oxopentanamide) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4-( 4-Methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide]; 4-((4- (3- (2,6-difluoro-3- (propylsulfonamide) -benzoyl) -benzoyl) -1H-pyrrolo [2 , 3-b] Pyridine-5-yl) phenyl) amino) -4-oxobutanoic acid (15 mg, 0.03 mmol) and (2S, 4R) -1- [(2S) -2-amino-3,3-dimethyl -Butanoyl] -4-hydroxy-N-[[4- (4-methylthiazole-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide; DMF (1 ml) solution of hydrochloride (13.51 mg, 0.03 mmol) TEA (0.1 ml, 0.72 mmol) and PyBOP (15.05 mg, 0.03 mmol) were added to the mixture at room temperature. The reaction mixture was stirred at the same temperature for 4 hours. TLC (DCM: MeOH: NH ₄ OH, 90: 9: 1) indicates that there is no initiator. The reaction mixture was evaporated to dryness under high vacuum. The crude product was filtered on a silica carbonate cartridge (100 mg) using DCM: MeOH (9: 1) as an eluent. The filtrate was evaporated under vacuum and the crude product was purified with PTLC (DCM: MeOH: NH4OH, 90: 9: 1) to give 8 mg of product (31% yield). 1H NMR (500 MHz, DMSO-d6) δ 12.97 (bs, 1H), 1
0.11 (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 --7.74 (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 (q, 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 (dq, J = 13.2, 8.3, 7.3 Hz, 2H), 0.96 (t, 3H), 0.95 (s, 9H) .13C 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.LC-MS (ESI); m / z [M + H] ⁺ : C ₄₉ H ₅₃ F ₂ N ₈ O ₈ S ₂ calculated value, 983.3395. Measured value: 983.3569.

Example of Synthesis of Compound 221: N1- (4- (3- (2,6-difluoro-3- (propylsulfonamide) 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) pyrrolidine-1-yl) -3,3 -Dimethyl-1-oxobutan-2-yl) malonamide.

3-((4- (3- (2,6-difluoro-3- (propylsulfonamide) -benzoyl) -1H-pyrrolo [2,3-b] pyridine-5-yl) phenyl) amino) -3- Oxopropanoic acid (16.8 mg, 0.03 mmol) and (2S, 4R) -1-[(2S) -2-amino-3,3-dimethyl-butanoyl] -4-hydroxy-N-[[4- (4- (4- (4- (4- (4-) Methylthiazole-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide; TEA (0.1 ml, 0.72 mmol) and PyBOP (17.28 mg, 0.033) in a DMF (1 ml) solution of hydrochloride (15.5 mg, 0.033 mmol). mmol) was added at room temperature. The reaction mixture was stirred at the same temperature for 12 hours (overnight). TLC (DCM: MeOH: NH ₄ OH, 90: 9: 1) indicates that there is no initiator. The reaction mixture was evaporated to dryness under high vacuum. The crude product was filtered on a silica carbonate cartridge (100 mg) using DCM: MeOH (9: 1) as an eluent. The filtrate was evaporated under vacuum and the crude product was purified by PTLC (DCM: MeOH: NH ₄ OH, 90: 9: 1) to give 19.5 mg of product (67% yield). ¹ H NMR (400 MHz, DMSO-d6) 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 (q, 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 (q, J = 10.6 Hz, 2H), 3.44 (q, 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 (dq, 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. LC-MS (ESI); m / z [M + H] ⁺ : Calculated value of C ₄₈ H ₅₁ F ₂ N ₈ O ₈ S ₂ , 969.3239. Measured value: 969.3272.

Example of Synthesis of Compound 222: (2S, 4R) -1-((S) -2- (3- (4- (3- (2,6-difluoro-3- (propylsulfonamide) benzoyl) -1H-pyrrolo) [2,3-b] Pyridine-5-yl) piperazin-1-yl) -3-oxopropanamide) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole) -5-yl) benzyl) pyrrolidine-2-carboxamide.

3- (4- (3- (2,6-difluoro-3- (propylsulfonamide) -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-dimethyl-butanoyl] -4-hydroxy-N-[[4- (4) -Methylthiazole-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide; in DMF (1 ml) solution of hydrochloride (11.69 mg, 0.03 mmol), TEA (0.1 ml, 0.72 mmol) and PyBOP (13.02 mg, 0.03 mmol) was added at room temperature. The reaction mixture was stirred at the same temperature for 12 hours (overnight). TLC (DCM: MeOH: NH ₄ OH, 90: 9: 1) indicates that there is no initiator. The reaction mixture was evaporated and dried. The crude product was filtered on a silica carbonate cartridge (100 mg) using DCM: MeOH (9: 1) as an eluent. The filtrate was evaporated under vacuum and the crude product was purified by PTLC (DCM: MeOH: NH ₄ OH, 90: 9: 1) to give 14.1 mg of product (64% yield). ¹ H NMR (500 MHz, DMSO-d6) 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 (bs, 1H), 7.57 (q, 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 (q, 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 (h, 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. LC-MS (ESI); m / z [M + H] ⁺ : C ₄₆ H ₅₄ F ₂ N ₉ O ₈ S ₂ calculated value, 962.3504. Measured value: 962.3694.

Example of synthesis of compound 301: (2S, 4R) -1-((S) -2- (4- (4- (3- (3-Butylamide-2,6-difluorobe)
Nzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenoxy) butaneamide) -3,3-dimethyl
Butanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-
Carboxamide.

4- (4- (3- (3-Buyramide-2,6-difluorobenzoyl) -1H-pyrrolo [2,3-b] pyridin-5-
Il) Phenoxy) Butanoic acid (27 mg, 0.05 mmol) and (2S, 4R) -1-[(2S) -2-amino-3,3-dimethyl-butanoyl] -4-hydroxy-N-[[4- (4-Methylthiazole-5-yl) Phenyl] Methyl] Pyrrolidine-2-carboxamide; TEA (0.1 ml, 0.72 mmol) and PyBOP (29.64) in a DMF (2 ml) solution of hydrochloride (26.6 mg, 0.06 mmol). mg, 0.06 mmol) was added at room temperature. The reaction mixture was stirred at the same temperature for 4 hours. TLC (DCM: MeOH: NH ₄ OH, 90: 9: 1) indicates that there is no initiator. DMF was removed under high vacuum. The crude product was filtered on a silica carbonate cartridge using DCM: MeOH (9: 1) as an eluent. The filtrate was evaporated under vacuum and the crude product was purified with PTLC (DCM: MeOH: NH4OH, 90: 9: 1) to give 37 mg of product (76% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.91 (bs, 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 --7.99 (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 (bs, 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 (h, J = 7.4 Hz, 2H), 0.96 (s, 9H), 0.92 (t, J = 7.4 Hz, 3H). 13C 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.LC-MS (ESI); m / z [M + H] ⁺ : C ₅₀ H ₅₄ F ₂ N ₇ O ₇ S calculated value, 934.3773. Measured value: 934.2690.

Example of synthesis of compound 302: (2S, 4R) -1-((S) -2- (4- (4- (3- (3-amino-2,6-difluorobenzoy))
Le) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenoxy) butaneamide) -3,3-dimethylbutano
Il) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carbo
Kisamide.

4- (4- (3- (3-Amino-2,6-difluorobenzoyl) -1 H-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-dimethyl-butanoyl] -4-hydroxy-N-[[4- (4) -Methylthiazole-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide; in a DMF (2 ml) solution of hydrochloride (23.79 mg, 0.05 mmol), TEA (0.1 ml, 0.72 mmol) and PyBOP (14.58 mg, 0.03 mmol) was added at room temperature. The reaction mixture was stirred at the same temperature for 4 hours. TLC (DCM: MeOH: NH ₄ OH, 90: 9: 1) indicates that there is no initiator. DMF was removed under high vacuum. The crude product was filtered on a silica carbonate cartridge (1 g) using DCM: MeOH (9: 1) as an eluent. The filtrate was evaporated under vacuum and the crude product was purified by PTLC (MeOH: DCM, 9: 1) to give 17.5 mg of product (80% yield). 1H
NMR (500 MHz, DMSO-d6) δ 12.68 (bs, 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 (bs, 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). 13C 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. LC-MS (ESI); m / z [M + H] ⁺ : C ₄₆ H ₄₈ F ₂ N ₇ O ₆ S calculated value, 864.3354. Measured value: 864.3437.

Example of synthesis of compound 303: (2S, 4R) -1-((S) -2- (4- (4- (3- (2,6-difluorobenzoyl) -1H-pi
Lolo [2,3-b] Pyridine-5-yl) Phenoxy) Butanamide) -3,3-Dimethylbutanoyl) -4-Hydroxy-N- (4- (4-Methylthiazole-5-yl) benzyl) Pyrrolidine -2-Carboxamide.

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-dimethyl-butanoyl] -4-hydroxy-N-[[4- (4-methylthiazole-5-yl) phenyl] methyl] pyrrolidine-2- Carboxamide; TEA (0.1 ml, 0.72 mmol) and PyBOP (25.45 mg, 0.05 mmol) were added to a solution of hydrochloride (20.76 mg, 0.04 mmol) in DMF (2 ml) at room temperature. The reaction mixture was stirred at the same temperature for 4 hours. TLC (DCM: MeOH: NH ₄ OH, 90: 9: 1) indicates that there is no initiator. DMF was removed under high vacuum. The crude product was filtered on a silica carbonate cartridge (1 g) using DCM: MeOH (9: 1) as an eluent. The filtrate was evaporated under vacuum and the crude product was purified with PTLC (DCM: MeOH: NH4OH, 90: 9: 1) to give 29 mg of product (77% yield). 1H NMR (500 MHz, DMSO-d6) δ 12.89 (bs, 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), 1H 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). 13C 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.LC-MS (ESI); m / z [M + H] ⁺ : C ₄₆ H ₄₇ F ₂ N ₆ O ₆ S calculated value, 849.3245. Actual Measured value: 849.3378.

Example of Synthesis of Compound 304: (2S, 4R) -1-((S) -2- (4- (4- (3- (2,6-difluoro-3- (propylsulfonamide) benzoyl) -1H-pyrrolo) [2,3-b] Pyridine-5-yl) Piperazine-1-yl) Butana
Mido) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) ben
Jill) Pyrrolidine-2-carboxamide.

4- [4- [3- [2,6-difluoro-3- (propylsulfonyl-amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] piperazine-1-yl] butanoic acid (7.9 mg, 0.01 mmol) and (2S, 4R) -1-[(2S) -2-amino-3,3-dimethyl-butanoyl] -4-hydroxy-N-[[4- (4-methylthiazo-l) -Five-
Il) phenyl] methyl] pyrrolidine-2-carboxamide; TEA (0.1 ml, 0.72 mmol) and PyBOP (8.23 mg, 0.02 mmol) in a DMF (1 ml) solution of hydrochloride (7.38 mg, 0.02 mmol) at room temperature. added. The reaction mixture was stirred at the same temperature for 12 hours (overnight). TLC (DCM: MeOH: NH ₄ OH, 90: 9: 1
) Indicates that there is no starting substance. The reaction mixture was evaporated and dried. The crude product was filtered on a silica carbonate cartridge (1 g) using DCM: MeOH (9: 1) as an eluent (washed a few times, the product has a high affinity for the stationary phase). The filtrate was evaporated under vacuum and the crude product was purified by PTLC (DCM: MeOH, 9: 1) to give 7.2 mg of product (52% yield). 1H NMR (500 MHz, DMSO-d6) δ 12.66 (bs, 1H), 9.73 (bs, 1H), 8.96 (s, 1H), 8.61 --8.30 (m, 1H), 8.25 (s, 1H), 8.00 ( s, 1H), 7.93 (bs, 1H), 7.88 (d, J = 9.1 Hz, 1H), 7.63 --7.74 (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 (dq, J = 16.3, 10.5, 8.9 Hz,
4H), 0.95 (t, J = 5.3 Hz, 3H), 0.95 (s, 9H). 13C NMR (151 MHz, DMSO-d6) 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. LC-MS (ESI); m / z [M + H] ⁺ : C ₄₇ H ₅₈ F ₂ N ₉ O ₇ S ₂ calculated value, 962.3868. Measured value: 962.3986.

Example of synthesis of compound 305: (2S, 4R) -1-((S) -2- (4- (4- (3-benzoyl-1H-pyrrolo [2,3-b] pyridine-5-yl) phenoxy)) Butanamide) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide.

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-dimethyl-butanoyl] -4-hydroxy-N-[[4- (4-methylthiazole-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide; hydrochloride (30.91 mg) , 0.07 mmol) to a solution of DMF (2 ml) was added TEA (0.2 ml, 1.43 mmol) and PyBOP (37.88 mg, 0.07 mmol) at room temperature. The reaction mixture was stirred at the same temperature for 12 hours (overnight). TLC (DCM: MeOH: NH ₄ OH, 90: 9: 1) indicates that there is no initiator. DMF was removed under high vacuum. The crude product was filtered on a silica carbonate cartridge (1 g) using DCM: MeOH (9: 1) as an eluent. The filtrate was evaporated under vacuum and the crude product was purified by PTLC (MeOH: DCM, 9: 1) to give 31 mg of product (58% yield). ¹ H NMR (400 MHz, DMSO-d6) 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. , 15.99. LC-MS (ESI); m / z [M + H] ⁺ : C ₄₆ H ₄₉ N ₆ O ₆ S calculated value, 813.3434. Measured value: 813.3478.

Example of synthesis of compound 306: (2S, 4R) -1-((S) -2- (2- (2- (4- (3- (2,6-difluoro-3- (propyls))
Luhonamide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Piperazine-1-yl) Eto
Xi) acetamide) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide.

2- [2- [4- [3- [2,6-difluoro-3- (propyl-sulfonylamino) benzoyl] -1H-pyrrolidine [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-dimethyl-butanoyl] -4-hydroxy-N-[[4- (4) -Methylthiazole-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide; TEA (0.1 ml, 0.72 mmol) and PyBOP (8 mg, 8 mg, in 1 ml) solution of hydrochloride (7.18 mg, 0.02 mmol) in DMF (1 ml). 0.02 mmol) was added at room temperature. The reaction mixture was stirred at the same temperature for 12 hours (overnight). TLC (DCM: MeOH: NH ₄ OH, 90
: 9: 1) indicates that there is no initiator. The reaction mixture was evaporated to dryness under high vacuum. Evaporation of the crude product under vacuum and purification of the crude product with PTLC (DCM: MeOH: NH ₄ OH, 90: 9: 1) yields 8.1 mg of product (59% yield). Was done. 1H NMR (500 MHz, DMSO-d6) δ 12.66 (bs, 1H), 9.72 (bs, 1H), 8.93 (s, 1H), 8.59 (bs, 1H), 8.22 (s,
1H), 7.99 (s, 1H), 7.89 (bs, 1H), 7.56 (dh, 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 (s / t
Duplicate, 12H). ¹³ C NMR (151 MHz, DMSO-d6) 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. LC-MS (ESI) ; m / z [M + H] ⁺ : C ₄₇ H ₅₈ F ₂ N ₉ O ₈ S ₂ calculated value, 978.3817.
Measured value: 978.3933.

(R) -N- (2,4-difluoro-3- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-((2-( Trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b] pyridin-3-carbonyl) phenyl) -3-fluoro-N-((2- (trimethylsilyl) ethoxy) methyl) pyrrolidine-1-sulfonamide ( Synthesis of intermediate 6).

Step 1: Preparation of 2,6-difluoro-3-nitrobenzoyl chloride.

A 500 mL round-bottom flask was charged with 2,6-difluoro-3-nitrobenzoic acid (30.0 g, 147.6 mmol, 1.0 eq), toluene (160 mL) and thionyl chloride (160 mL). The resulting mixture is 80 ° C
The mixture was stirred overnight and concentrated under reduced pressure. As a result, 28.2 g (86%) of 2,6-difluoro-3-nitrobenzoyl chloride was obtained as a brown oil.

Step 2: (5-bromo-1H-pyrrolo [2,3-b] pyridin-3-yl) (2,6-difluoro-3-nitrophenyl) methanone.

Aluminum trichloride (84.0 g, 0.64 mol, 6.4 eq) in a 300 mL chloromethane mixture of 5-bromo-1H-pyrrolo [2,3-b] pyridine (22.0 g, 111.6 mmol, 1.1 eq) several times. Added separately. The reaction was stirred at room temperature for 1 hour and 2,6-difluoro-3-nitrobenzoyl chloride (22.0 g, 100.0 mmol, 1.0 eq) was added. The reaction was heated overnight at 50 ° C., 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 layers were washed with brine (500 mLx2) and dried over anhydrous sodium sulfate. Concentrate the solvent to give (5-bromo-1H-pyrrolo [2,3-b] pyridin-3-yl) (2,6-difluoro-3-nitrophenyl) methanone (24.4g) as a yellow solid. Obtained. LC / MS (ESI) m / z: 381.30 [M + 1] ⁺ .
Step 3: (3-Amino-2,6-difluorophenyl) (5-bromo-1H-pyrrolo [2,3-b] Pyridine-3-
Il) Preparation of metanone.

(5-bromo-1H-pyrrolo [2,3-b] pyridine-3-yl) (2,6-difluoro-3-nitrophenyl) methanone (15.8 g, 40.8 mmol, 1.0 eq), (12.0 g, 200.2) A mixed solution of ethanol (80 ml) and tetrahydrofuran (80 ml) of ammonium chloride (7.2 g, 140.0 mmol), hydrochloric acid (50.0 ml) was perfused overnight. After cooling to room temperature, the mixture was filtered through a pad of Celite. The filtrate is concentrated in vacuum and the residue is silica gel (petroleum ether / ethyl acetate = 1/2).
Purified by column chromatography above, (3-amino-2,6-difluorophenyl) (5-bromo-1H-pyrrolo [2,3-b] pyridin-3-yl) methanone (8.6 g, yield) 60%) was obtained as a yellow solid. LC / MS (ESI) m / z: 351.80 [M + 1] ⁺ .
Step 4: Preparation of (R) -3-fluoropyrrolidine-1-sulfonyl chloride.

The oven-dried flask was filled with (R) -3-fluoropyrrolidine hydrochloride (3.0 g, 24 mmol), triethylamine (7.2 g, 72 mmol) and dichloromethane (150 mL). The mixture was stirred at room temperature for 15 minutes and then cooled to about -30 ° C in a dry ice / acetonitrile tank for 10 minutes. Sulfuryl chloride (6.0 g, 48 mmol) was added dropwise over 10 minutes. The reaction mixture was stirred for 1 hour at about -30 ° C and then at room temperature for 5 hours. The reaction mixture was diluted with aqueous HCl (1 N, 70 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (50 mL x 3). The combined organic layers were 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.

Step 5: (R) -N- (3- (5-bromo-1H-pyrrolo [2,3-b] pyridin-3-carbonyl) -2,4-difluorophenyl) -3-fluoropyrrolidine-1-sulfone Preparation of amide.

(3-Amino-2,6-difluorophenyl) (5-bromo-1H-pyrrolo [2,3-b] pyridin-3-yl) Pyridine (8.0 g, 22.79 mmol, 1.0 equivalent) pyridine (25.0 g) To the solution was added (R) -3-fluoropyrrolidin-1-sulfonyl chloride (4.6 g, 24.60 mmol, 1.08 equivalent) and 4-dimethylaminopyridine (560.0 mg, 4.59 mmol, 0.2 equivalent). The reaction mixture was stirred at 40 ° C. for 12 hours. The solvent was removed and water (20 mL) was added. Aqueous sodium bicarbonate solution was added to adjust the pH to 7-8, followed by extraction with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (50 mLx2) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel with ethyl acetate / petroleum ether (3: 1) to (R) -N- (3- (5-bromo-1H). -Pyrrolo [2,3-b] pyridine-3-carbonyl) -2,4-difluorophenyl) -3-fluoropyrrolidin-1-sulfonamide (6.4 g) was obtained as a yellow solid. LC / MS (ESI) m / z: 505.05 [M + 1] ⁺ .
Step 6: (R) -N- (3- (5-bromo-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolidine [2,3-b] pyridin-3-carbonyl) -2, Preparation of 4-difluorophenyl) -3-fluoro-N-((2- (trimethylsilyl) ethoxy) methyl) pyrrolidine-1-sulfonamide.

(3R) -N- [3- (5-bromo-1H-pyrrolo [2,3-b] pyridin-3-carbonyl) -2,4-difluoro-phenyl] -3-fluoro-pyrrolidin-1-sulfonamide Sodium hydride (925 mg, 23.13 mmol, in mineral oil, purity 60%, 2 eq) in a mixture of (5.82 g, 11.56 mmol, 1 eq) dimethylformamide (70 ml) in several batches at 0 ° C. added. The mixture was then stirred for 0.5 hours at 0-20 ° C. Then 2- (trimethylsilyl) ethoxymethyl chloride (4.24 g, 25.44 mmol, 4.5 mL, 2.2 eq) was added dropwise to the mixture at 20 ° C. The mixture was stirred for 1.5 hours at 50 ° C. Water (150 mL) was poured into the mixture and stirred for 1 minute. The aqueous layer was extracted with ethyl acetate (100 mLx3). The combined organic layers were washed with brine (100 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Residues, silica gel column chromatography (petroleum ether:
Purified by ethyl acetate = 100/1 to 10/1). Product (3R) -N- [3- [5-bromo-1- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl]- 3-Fluoro-N- (2-trimethylsilylethoxymethyl) pyrrolidine-1-sulfonamide (5.01 g, 6.51 mmol, yield 56%, purity 99%) was obtained as a bright yellow oil. LC / MS (ESI) m / z:
765.0 [M + 1] ⁺ .
Step 7: (R) -N- (2,4-difluoro-3- (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-(( 2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b] pyridin-3-carbonyl) phenyl) -3-fluoro-N-((2- (trimethylsilyl) ethoxy) methyl) pyrrolidine-1- Preparation of sulfonamides.

4,4,5,5-Tetramethyl-2- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-Dioxaborolan (349mg, 1.37 mmol) , 1.05 equivalent) and (3R) -N- [3- [5-bromo-1- (2-)
Trimethylsilylethoxymethyl) pyrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl] -3-fluoro-N- (2-trimethylsilylethoxymethyl) pyrrolidine-1-sulfonamide (1g, To a mixture of dioxane (7 ml) of 1.31 mmol (1 eq), potassium acetate (256.97 mg, 2.62 mmol, 2 eq) and [1,1'-bis (diphenylphosphino)] ferrocene dichloropalladium (II) (96 mg). , 0.13 mmol, 0.1 eq) at a time at 15 ° C. under a nitrogen atmosphere. The mixture was stirred at 85 ° C. for 12 hours. Water (50 mL) was poured into the mixture and stirred for 1 minute. The aqueous layer was extracted with ethyl acetate (50 mLx3). The combined organic layers were washed with brine (50 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20/1 to 3/1). Product (3R) -N- [2,4-difluoro-3- [5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-)
Il) -1- (2-trimethylsilylethoxymethyl) pyrrolidine [2,3-b] pyridin-3-carbonyl] phenyl] -3-fluoro-N- (2-trimethylsilylethoxymethyl) pyrrolidine-1-sulfonamide (1.02) g, 1.22 mmol, yield 93%, purity 96%) was obtained as a colorless oil. LC / MS (ESI) m / z: 811.1 [M + 1] ⁺ .
(2S, 4R) -1-((S) -2-amino-3,3-dimethylbutanoyl) -4-hydroxy-N-((S) -1- (4- (4-methylthiazole-5-) Il) Phenyl) Ethyl) Pyrrolidine-2-carboxamide Exemplary Synthesis Step 1: Preparation of tert-butyl (S)-(1- (4-bromophenyl) ethyl) carbamate.

In a 250 mL round bottom flask, (1S) -1- (4-bromophenyl) ethane-1-amine (10.0 g, 49.98 m)
Mol, 1.00 eq) dichloromethane (100 ml), triethylamine (10.0 g, 99.01 mmol, 2.00 eq) and di-tert-butyl bicarbonate (13.0 g, 59.63 mmol, 1.20 eq) were added. The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:10). This gave 15.0 g of tert-butyl N-[(1S) -1- (4-bromophenyl) ethyl] carbamate as a white solid.

Step 2: Preparation of tert-butyl (S)-(1- (4- (4-methylthiazole-5-yl) phenyl) ethyl) carbamate.

In a 250 mL round bottom flask purged and maintained in an inert nitrogen atmosphere, tert-butyl N-[(1S) -1- (4-bromophenyl) ethyl] carbamate (15.0 g, 49.97 mmol, 1.00 eq). ) N, N-dimethylacetamide (100 ml), 4-methyl-1,3-thiazole (9.9 g, 99.84 mmol, 2.00 eq), potassium acetate (9.8 g, 99.86 mmol, 2.00 eq), palladium (II) acetate A solution of salt (112.5 mg, 0.50 mmol, 0.01 eq) was added. The resulting solution was stirred at 120 ° C. for 2 hours. The reaction mixture was quenched by the addition of water (500 mL). The resulting solution was extracted with ethyl acetate (200 mLx3), the organic layers were combined and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1: 5). This results in 7.5 g (47%) of tert-butyl N-[(1S) -1- [4- (4-methyl-1,3-thiazole-5-yl) phenyl] ethyl] carbamate as a white solid. I got it as a thing. LC / MS (ESI) m / z: 319.13 [M + Na] ⁺ .
Step 3: Preparation of (S) -1- (4- (4-methylthiazole-5-yl) phenyl) ethane-1-amine hydrochloride.

In a 100 mL round-bottom flask, tert-butyl N-[(1S) -1- [4- (4-methyl-1,3-thiazole-5-yl) phenyl] ethyl] carbamic acid salt (7.5 g, 23.55 mmol) , 1.00 equivalent) of methanol (20 ml)
The solution was added and hydrogen chloride (gas) was whipped at room temperature. The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum. This gave 4.4 g (86%) of (1S) -1- [4- (4-methyl-1,3-thiazole-5-yl) phenyl] ethane-1-amine as a white solid.

Step 4: tert-butyl (2S, 4R) -4-hydroxy-2-(((S) -1- (4- (4-methylthiazole-5-yl) phenyl) ethyl) carbamoyl) pyrrolidine-1-carboxylic acid Preparation of acid salt.

N, N-dimethylformamide of (2S, 4R) -1-[(tert-butoxy) carbonyl] -4-hydroxypyrrolidine-2-carboxylic acid (4.7 g, 20.32 mmol, 1.00 eq) in a 100 mL round bottom flask. (20 ml) solution, N-ethyl-N-isopropylpropan-2-amine (7.8 g, 60.35 mmol, 3.00 eq), o- (7-)
Azabenzotriazole-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate (11.5 g, 30.26 mmol, 1.50 equivalent), (1S) -1- [4- (4) -Methyl-1,3-thiazole-5-yl) phenyl] ethane-1-amine (4.4 g, 20.15 mmol, 1.00 eq) was added. The resulting solution was stirred at room temperature for 12 hours. The reaction mixture was quenched by adding water (20 mL). The resulting solution was extracted with ethyl acetate (100 mLx3), the organic layers were combined, dried in an oven under reduced pressure and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1: 1). This resulted in 5.0 g (57%) of tert-butyl (2S, 4R) -4-hydroxy-2-[[(1S) -1- [4- (4-methyl-1,3-thiazole-5-yl). ) Phenyl] ethyl] carbamoyl] pyrrolidine-1-carboxylate was obtained as a yellow solid. LC / MS (ESI) m / z: 432.15 [M + 1] ⁺ .
Step 5: Preparation of (2S, 4R) -4-hydroxy-N-((S) -1-(4- (4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide hydrochloride.

In a 500 mL round bottom flask, tert-butyl (2S, 4R) -4-hydroxy-2-[[(1S) -1- [4- (4-methyl-1,3-thiazole-5-yl) phenyl] A solution of ethyl] carbamoyl] pyrrolidine-1-carboxylate (5.0 g, 11.59 mmol, 1.00 eq) in methanol (200 ml) was added and then hydrogen chloride (gas) was whipped into the reaction mixture at room temperature for 2 hours. The resulting mixture was concentrated under vacuum. This resulted in 3.2 g (83%) of (2S, 4R) -4-hydroxy-N-[(1S) -1- [4- (4-methyl-1,3-thiazole-5-yl) phenyl] ethyl. ] Pyrrolidine-2-carboxamide was obtained as a red solid.

Step 6: tert-butyl ((S) -1-((2S, 4R) -4-hydroxy-2-(((S) -1-(4- (4-methylthiazole-5-yl) phenyl) ethyl) ) Carbamoyl) Pyrrolidine-1-yl) -3,3-Dimethyl-1-oxobutan-2-yl) Preparation of carbamate.

In a 25 mL round bottom flask, N, N-dimethylformamide (30 ml) of (2S) -2-[(tert-butoxy) carbonyl] amino-3,3-dimethylbutanoic acid (2.0 g, 8.65 mmol, 0.99 eq) Solution, N-ethyl-N-isopropylpropan-2-amine (3.4 g, 3.00 eq), o- (7-azabenzotriazole-1-)
Il) -N, N, N', N'-tetramethyluronium hexafluorophosphate (5.0 g, 1.50 eq), (2S, 4R) -4-hydroxy-N-[(1S) -1- [ 4- (4-Methyl-1,3-thiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide hydrochloride (3.2 g, 8.70 mmol, 1.00 eq) was added. The resulting solution was stirred at room temperature for 12 hours. The resulting solution was extracted with ethyl acetate (60 mLx3) and washed with water (100 mLx2). The organic layers were combined, dried and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1: 3). This resulted in 4.0 g (84%) of tert-butyl N-[(2S) -1-[(2S, 4R) -4-hydroxy-2-[[(1S) -1- [4- (4-methyl). -1,3-thiazole-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-yl] -3,3-dimethyl-1-oxobutan-2-yl] carbamate was obtained as a yellow solid. LC / MS (ESI) m / z: 545.30 [M + 1] ⁺ .
Step 7: (2S, 4R) -1-((S) -2-amino-3,3-dimethylbutanoyl) -4-hydroxy-N-((S) -1- (4- (4-methylthiazole) -Preparation of 5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide hydrochloride.

In a 100 mL round bottom flask, tert-butyl N-[(2S) -1-[(2S, 4R) -4-hydroxy-2-[[(1S) -1- [4- (4-methyl-1,4) 3-Thiazol-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-yl] -3,3-dimethyl-1-oxobutan-2-yl] carbamate (4.0 g, 7.34 mmol, 1.00 eq)
A solution of methanol (30 ml) was added, and then hydrogen chloride (gas) was whipped into the reaction mixture at room temperature for 2 hours. The resulting mixture was concentrated under vacuum. This resulted in 3.5 g of (2S, 4R) -1-[(2S) -2-amino-3,3-dimethylbutanoyl] -4-hydroxy-N-[(1S) -1- [4- (4). -Methyl-1,3-thiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide hydrochloride was obtained as a yellow solid. LC / MS (ESI) m / z: 445.05 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 8.99 (s, 1 H), 8.57-8.55 (d, J = 7.8 Hz, 1 H) ), 8.01 (b, 3 H), 7.46-7.43 (d, J = 8.4 Hz, 2 H), 7.39-7.37 (d, J = 8.4 Hz, 2 H), 4.98-4.90 (m, 1 H), 4.57-4.51 (m, 1 H), 4.34 (b, 1 H), 3.94-3.92 (m, 1 H), 3.69-3.66 (m, 1 H), 3.53-3.49 (m, 1 H), 2.52 ( s, 3 H),
2.10-2.07 (m, 1 H), 1.83-1.81 (m, 1 H), 1.40-1.30 (m, 3 H), 1.03 (s, 9 H).
N- (2-Methyl-5'-morpholino-6'-(piperidine-4-yloxy)-[3,3'-bipyridine] -5-a
Example of Synthesis of -3- (Trifluoromethyl) Benzamide Hydrochloride (Intermediate 8) Step 1: Preparation of 4- (5-bromo-2-fluoropyridine-3-yl) morpholine.

Sodium hydride (2.51 g, 62.83 mmol, 60% in mineral oil, 3 equivalents) in a dimethylformamide (40 ml) mixture of 5-bromo-2-fluoro-pyridine-3-amine (4 g, 20.94 mmol, 1 equivalent). ) To 0 ° C
Added in. The mixture was stirred for 0.5 hours at 25 ° C. 1-Bromo-2- (2-bromoethoxy) ethane (7.29 g, 31.41 mmol, 3.94 mL, 1.5 eq) was then added to the mixture. The mixture was stirred at 80 ° C. for 1.5 hours. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (70 mLx2). The combined organic layer was washed with water (100 mLx2) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 15: 1-8: 1). Compound 4- (5-bromo-2-fluoro-3-pyridyl) morpholine (3.4 g, 13.02 mmol, yield 62%) was obtained as a light green solid. ¹ H-NMR (400MHz, CDCl ₃ ) δ 7.80-7.79 (m, 1H), 7.33-7.30 (m, 1H), 3.87-3.82 (m, 4H), 3.13-3.08 (m, 4H).
Step 2: Preparation of 4- (2-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-3-yl) morpholine.

4- (5-Bromo-2-fluoro-3-pyridyl) morpholine (2.0 g, 7.66 mmol, 1 eq) and 4,4,5,5-tetramethyl-2- (4,4,5,5-tetra) Methyl-1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolan (2.92 g, 11.49 mmol, 1.5 eq) in a mixed solution of dioxane (25 ml) with potassium acetate (2.26 g, 22.98 mmol, 3 eq) and 1,1'-bis (diphenylphosphino) ferrocene-palladium (ii) dichloride dichloromethane complex (625 mg, 0.76 mmol, 0.1 eq) were added. The mixture was degassed, filled with nitrogen 3 times and stirred at 100 ° C. for 2 hours under a nitrogen atmosphere. The mixture was filtered and concentrated under reduced pressure to give the crude product. The crude product was used in the next step without further purification. Crude product 4- [2-Fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3-pyridyl] morpholine (5.0 g, crude) Obtained as a yellow oil. LC / MS (ESI) m / z: 309.1 [M + 1] ⁺ .
Step 3: Preparation of N- (6'-fluoro-2-methyl-5'-morpholino- [3,3'-bipyridine] -5-yl) -3- (trifluoromethyl) benzamide.

N- (5-bromo-6-methyl-3-pyridyl) -3- (trifluoromethyl) benzamide (1.5 g, 4.18 mmol, 1 eq) and 4- [2-fluoro-5- (4,4,5) , 5-Tetramethyl-1,3,2-dioxaborolan-2-yl) -3-pyridyl] Morpholine (2.70 g, 8.77 mmol, 2.1 eq) in a mixture of dioxane (15 ml) and potassium carbonate (1.73 g, 12.53). mmol, 3 eq), 1,1'-bis (diphenylphosphino) ferrocene-palladium (ii) dichloride dichloromethane complex (341 mg, 0.41 mmol, 0.1 eq) and water (3 ml) were added. The mixture was degassed and filled with nitrogen three times. The mixture was then stirred at 100 ° C. for 4 hours under a nitrogen atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3: 2 to 1: 4). Compound N- [5- (6-fluoro-5-morpholino-3-pyridyl) -6-methyl-3-pyridyl] -3- (trifluoromethyl) benzamide (1.3 g, 2.82 mmol, 67% yield) Obtained as a yellow solid. ¹ H-NMR (400MHz, CDCl ₃ ) δ 8.63 (d, J = 2.4 Hz, 1H), 8.32 (s, 1H), 8.20 (d, J = 3.2 Hz, 1H), 8.15 (s, 1H), 7.85 -7.83 (m, 1H), 7.76-7.74 (m, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.24-7.20 (m, 1H), 3.91-3.89 (m, 4H), 3.18-3.16 (m, 4H), 2.49 (s, 3H).
Step 4: tert-butyl 4-((2'-methyl-5-morpholino-5'-(3- (trifluoromethyl) benzamide)-[3,3'-bipyridine] -6-yl) oxy) piperidine- Preparation of 1-carboxylate.

tert-butyl 4-hydroxypiperidine-1-carboxylate (2.62 g, 13.03 mmol, 1.5 eq)
Sodium hydride (764 mg, 19.11 mmol, purity 60%, 2.2 eq) was added to the dimethylformamide (100 ml) mixture at 15 ° C. The mixture was stirred for 0.5 hours at 15 ° C. and N- [5- (6-fluoro-5-morpholino-3-pyridyl) -6-methyl-3-pyridyl] -3- (trifluoromethyl) benzamide (4 g).
, 8.69 mmol, 1 eq) was added to the reaction mixture and stirred for 2 hours at 80 ° C. The mixture is quenched by adding water (200 mL), diluted with ethyl acetate (20 mL), extracted with ethyl acetate (40 mLx4), the combined organic layers washed with brine (50 mL) and anhydrous. It was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was pulverized with petroleum ether / ethyl acetate (V / V = 5: 1, 30 mL) and collected by filtration. Compound tert-butyl 4-[[5- [2-methyl-5-[[3- (trifluoromethyl) benzoyl] amino] -3-pyridyl] -3-morpholino-2-pyridyl] oxy] piperidine-1- Carboxylate (4.5 g, 7.01 mmol, 80% yield) was obtained as a brown solid. LC / MS (ESI) m / z: 642.2 [M + 1] +; 1H-NMR (400MHz, CDCl3) δ 8.64 (d, J = 2.4 Hz, 1H), 8.23
--8.09 (m, 4H), 7.86 (d, J = 7.6 Hz, 1H), 7.78 (d, J = 1.8 Hz, 1H), 7.72 --7.63 (m,
1H), 7.07 (d, J = 1.7 Hz, 1H), 5.48 --5.34 (m, 1H), 3.96 --3.86 (m, 4H), 3.78 --3.66 (m, 2H), 3.52 --3.39 (m, 2H) , 3.16 (s, 4H), 2.54 (s, 3H), 2.12 --2.03 (m, 2H), 1.86 (m, 2H), 1.51 (s, 9H).
Step 5: N- (2-Methyl-5'-morpholino-6'-(piperidine-4-yloxy)-[3,3'-bipyridine] -5-yl) -3- (trifluoromethyl) benzamide hydrochloride Preparation.

tert-butyl 4-[[5- [2-methyl-5-[[3- (trifluoromethyl) benzoyl] amino] -3-pyridyl] -3-morpholino-2-pyridyl] oxy] piperidine-1-carboxylic acid Hydrochloride (4.5 g, 7.01 mmol)
, 1 eq) of dichloromethane (100 ml) mixed with hydrogen chloride / dioxane (4M, 17 mL, 10 eq). The mixture was stirred at 15 ° C. for 1 hour. The mixture was concentrated under reduced pressure. Compound N- [6-Methyl-5- [5-morpholino-6- (4-piperidyloxy) -3-pyridyl] -3-pyridyl] -3- (trifluoromethyl) benzamide (4.5 g, crude, hydrochloride) ) Was obtained as a brown solid. LC / MS (ESI) m / z: 542.2 [M + 1] ⁺ .
(2S, 4R) -1-((S) -2-amino-3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthi)
Exemplary Synthesis of Azole-5-yl) benzyl) Pyrrolidine-2-carboxamide Hydrochloride (Intermediate 9) Example 1: Preparation of 4- (4-Methylthiazole-5-yl) benzonitrile.

In a 1 L round bottom flask purged and maintained in an inert nitrogen atmosphere, a solution of 4-bromobenzonitrile (20 g, 109.88 mmol, 1.00 eq) in DMA (250 ml), 4-methyl-1,3-thiazole (20 g, 109.88 mmol, 1.00 eq). 21.88 g, 220.67 mmol, 2.00 eq), Pd (OAc) ₂ (743 mg, 3.31 mmol, 0.03 eq) and KOAc (21.66 g, 220.71 mmol, 2.00 eq) were added. The resulting solution was stirred at 150 ° C. for 5 hours. The reaction mixture was cooled in a water / ice bath and diluted with 1 L of water. The resulting solution was extracted with 3x300 mL of ethyl acetate. The combined organic layers were washed with 3x300 mL of water and 1x300 mL of brine, then dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by combiflash with ethyl acetate / petroleum ether (1: 100-1: 5). This gave 20 g (91%) of 4- (4-methyl-1,3-thiazole-5-yl) benzonitrile as a beige solid.

Step 2: Preparation of (4- (4-methylthiazole-5-yl) phenyl) methaneamine.

4- (4-Methyl-1,3-thiazole-5-yl) benzonitrile (35 g, 174.77 mmol, 1.00 eq) in a 3 L triple-necked round-bottom flask purged and maintained in an inert nitrogen atmosphere. Nitrogen (1000 ml) solution was added. Subsequently, LiAlH ₄ (20 g, 526.32 mmol, 3.00 eq) was added in several portions at 0 ° C. for 10 minutes. The obtained solution was stirred at 60 ° C. for 3 hours in an oil bath. The reaction was cooled to 0 ° C. using a water / ice bath and then quenched by the addition of 20 mL of water, 20 mL of NaOH (15%), and 60 mL of water. The resulting solution was diluted with 200 mL ethyl acetate. The solids were filtered off. The filtrate was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded into a silica gel column with dichloromethane / methanol (10: 1).
This gave 20 g (56%) of [4- (4-methyl-1,3-thiazole-5-yl) phenyl] methaneamine as a yellow oil.

Step 3: Preparation of tert-butyl (2S, 4R) -4-hydroxy-2-((4- (4-methylthiazole-5-yl) benzyl) carbamoyl) pyrrolidine-1-carboxylate.

N, N-dimethylformamide of (2S, 4R) -1-[(tert-butoxy) carbonyl] -4-hydroxypyrrolidin-2-carboxylic acid (2.7 g, 11.68 mmol, 1.20 eq) in a 50 mL round bottom flask. (30 ml) solution, DIEA (2.52 g, 19.50 mmol, 1.20 eq), HATU (4.47 g, 11.76 mmol, 1.20 eq), [4- (4-methyl-1,3-thiazole-5-yl) phenyl] methaneamine (2 g, 9.79 mmol, 1.00 eq) was added. The resulting solution was stirred at 25 ° C. overnight. The reaction was then quenched by the addition of 20 mL of water and extracted with 3x20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded into a silica gel column with dichloromethane / methanol (20: 1). This resulted in 1 g (24%) of tert-butyl (2S, 4R) -4-hydroxy-2-([[4- (4-methyl-1,3-thiazole-5-yl) phenyl] methyl] carbamoyl). Pyrrolidine-1-carboxylate was obtained as a yellow solid.

Step 4: Preparation of (2S, 4R) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide hydrochloride.

In a 1000 mL round bottom flask, tert-butyl (2S, 4R) -4-hydroxy-2-([[4- (4-methyl-1,3-thiazole-5-yl) phenyl] methyl] carbamoyl) pyrrolidine- A solution of 1-carboxylate (45 g, 107.78 mmol, 1.00 equivalent) and hydrogen chloride (13.44 L) in dioxane (300 ml) was added. The resulting solution was stirred at 20 ° C. for 2 hours. The solids were collected by filtration. This resulted in 37.3 g (98%) of (2S, 4R) -4-hydroxy-N-[[4- (4-methyl-1,3-thiazole-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide. Hydrochloride was obtained as a yellow solid.

Step 5: tert-butyl ((S) -1-((2S, 4R) -4-hydroxy-2- ((4- (4-methylthiazole-5-yl) benzyl) carbamoyl) pyrrolidine-1-yl) -3,3-dimethyl-1-oxobutan-2-yl)
Preparation of carbamate.

In a 1000 mL round bottom flask, N, N-dimethylformamide (15.73 g, 68.01 mmol, 1.20 eq) of (2S) -2-[[(tert-butoxy) carbonyl] amino] -3,3-dimethylbutanoic acid (15.73 g, 68.01 mmol, 1.20 eq) 500 ml) solution, DIEA (29.2 g, 225.94 mmol, 4.00 eq), HATU (25.9 g, 68.12 mmol, 1.20 eq) and (2S, 4R) -2-amino-5-chloro-4-hydroxy-N-[[ 4- (4-Methyl-1,3-thiazole-5-yl) phenyl]
Methyl] pentane amide (20 g, 56.52 mmol, 1.00 eq) was added. The resulting solution was stirred at 20 ° C. for 16 hours. The reaction was then quenched by the addition of 200 mL of water and extracted with 3x100 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (2: 1). This resulted in 15.2 g (51%) of tert-butyl N-[(2S) -1-[(2S, 4R) -4-hydroxy-2-([[4- (4-methyl-1,3-thiazole). -5-Il) phenyl] methyl] carbamoyl) pyrrolidine-1-yl] -3,3-dimethyl-1-oxobutan-2-yl] carbamate was obtained as a yellow solid.

Step 6: (2S, 4R) -1-((S) -2-amino-3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) Preparation of pyrrolidine-2-carboxamide hydrochloride.

In a 500 mL round bottom flask, tert-butyl N-[(2S) -1-[(2S, 4R) -4-hydroxy-2-([[4- (4- (4- (4- (4- (4-)
Methyl-1,3-thiazole-5-yl) phenyl] methyl] carbamoyl) pyrrolidine-1-yl] -3,3-dimethyl-1-oxobutan-2-yl] carbamate (12 g, 22.61 mmol, 1.00 equivalent) ) Dioxane (20 ml) solution and hydrogen chloride (3.584 L) dioxane (80 ml) solution were added. The resulting solution was stirred at 25 ° C. for 2 hours. The solids were collected by filtration. This resulted in 5.1 g (48%) of (2S, 4R) -1-[(2S) -2-amino-3,3-dimethylbutanoyl] -4-hydroxy-N-[[4- (4-methyl). -1,3-Thiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide hydrochloride was obtained as a yellow solid. LC / MS (ESI) m / z: 431 [M + 1] +; 1H-NMR (400MHz, CD3OD) δ 9.84-9.82 (s)
, 1H), 7.58-7.54 (m, 4H), 4.71-4.41 (m, 4H), 4.13-4.08 (m, 1H), 3.86-3.71 (m, 2H), 3.36 (s, 1H), 2.60-2.58 (s, 3H), 2.35-2.07 (m, 2H), 1.19-1.12 (m, 9H).
tert-butyl 2-(4-((4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-1-yl) methyl) piperidine Illustrative Synthesis of -1-yl) Acetate (Intermediate 10) Step 1: Of tert-butyl 4-((4- (4-bromophenyl) piperazine-1-yl) methyl) piperidine-1-carboxylate Preparation.

1- (4-Bromophenyl) piperazine hydrochloride (900.0 mg, 3.26 mmol) in a 100 mL round bottom flask
, 1.00 eq) in a solution of dichloromethane (20 ml). DIEA (841.0 mg, 6.52 mmol, 2.00 eq) and tert-butyl 4-formylpiperidine-1-carboxylate (694.4 mg, 3.26 mmol, 1.00 eq) were added. After a few minutes, sodium triacetoxyborohydride (2.1 g, 9.78 mmol, 3.00 eq) was added. The resulting solution was stirred at room temperature for 1 hour. The reaction was quenched with water (30 mL) and extracted with dichloromethane (30 mLx2). The organic layer was evaporated under reduced pressure and concentrated, and the residue was placed on a silica gel column with ethyl acetate / petroleum ether (1: 4). This gave 1.3 g (91%) of tert-butyl 4-((4- (4-bromophenyl) piperazin-1-yl) methyl) piperidine-1-carboxylate. LC / MS (ESI) m / z: 438.30 [M + 1] ⁺ .
Step 2: Preparation of 1- (4-bromophenyl) -4- (piperidine-4-ylmethyl) piperazine.

In a 100 mL round bottom flask, tert-butyl 4-((4- (4-bromophenyl) piperazine-1-yl))
A solution of methyl) piperidine-1-carboxylate (1.3 g, 0.64 mmol, 1.00 eq) and 2,2,2-trifluoroacetaldehyde (5 ml) in dichloromethane (10 ml) was added. The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. This will result in 1.3 g (97%) of 1- (4-bromophenyl) -4- (piperidine-4-ylmethyl) containing 2,2,2-trifluoroacetic acid (1: 1).
The piperazine compound was obtained as a white solid. LC / MS (ESI) m / z: 338.05 [M + 1] ⁺ .
Step 3: Preparation of tert-butyl 2- (4-((4- (4-bromophenyl) piperazin-1-yl) methyl) piperidine-1-yl) acetate.

1- (4-Bromophenyl) -4- (piperidine-4-ylmethyl) piperazine compound containing 2,2,2-trifluoroacetic acid (1: 1) in a 100 mL round bottom flask (1.3 g, 2.88 mmol, A solution of 1.00 equivalent) of THF (20 ml) was added. Sodium hydroxide (1M, 10 ml) and tert-butyl 2-bromoacetate (782.2 mg, 4.03 mmol, 1.40 eq) were added. The resulting solution was stirred at 0 ° C. for 30 minutes in an ice bath. The resulting solution was diluted with water (40 mL) and extracted with ethyl acetate (40 mLx2). The organic layer was evaporated under reduced pressure and concentrated, and the residue was placed on a silica gel column using ethyl acetate / petroleum ether (2: 3). This yields 983.4 mg (76%) of tert-butyl 2- (4-((4- (4-bromophenyl) piperazin-1-yl) methyl) piperidine-1-yl) acetate as a white solid. rice field. LC / MS (ESI) m / z: 452.15 [M + 1] ⁺ .
Step 4: tert-Butyl 2- (4-((4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-1-yl)) Preparation of methyl) piperidine-1-yl) acetate.

In a 100-mL round bottom flask, tert-butyl 2- (4-((4- (4-bromophenyl) piperazin-1-yl) methyl) piperidin-1-yl) acetate (983.4 mg, 2.18 mmol, 1.00 equivalent), 4,4,4', 4', 5,5,5', 5'-octamethyl-2,2'-bi (1,3,2-dioxaborolane) (1.1 g, 4.36 mmol, 2.00 equivalent) ), Pd (dppf) Cl ₂ (358.1 mg, 0.44 mmol, 0.20 eq), potassium acetate (641.0 g, 6.54 mmol, 3.00 eq) in a 1,4-dioxane (30 ml) solution. The solution obtained under nitrogen was stirred overnight in an oil bath at 85 ° C. The solids were filtered off. The filtrate was evaporated under reduced pressure and concentrated, and the residue was placed on a silica gel column with ethyl acetate / petroleum ether (1: 1). This resulted in 783.4 mg (72%) of tert-butyl 2-(4-((4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl). ) Piperazine-1-yl) Methyl) Piperidine-1-yl) Acetate was obtained as a yellow solid. LC / MS (ESI) m / z: 500.30 [M + 1] ⁺ .
(2S, 4R) -1-((S) -2-(2-(4-(4-(4-(3-(2,6-difluoro-3-(((R) -3-fluoropyrrolidine)) -1-Sulfonamide) Benzoyl) -1H-Pyrrolidine [2,3-b] Pyridine-5-yl) Phenyl) Piperadi
N-1-yl) piperidine-1-yl) acetamide) -3,3-dimethylbutanoyl) -4-hydroxy-N-((S) -1- (4- (4-methylthiazole-5-yl)) Exemplary Synthesis of Phenyl) Ethyl) Pyrrolidine-2-carboxamide (Example 320) 1: Preparation of tert-butyl 4- (4- (4-bromophenyl) piperazine-1-yl) piperidine-1-carboxylate.

In a 250 mL round bottom flask, a solution of 1- (4-bromophenyl) piperazine hydrochloride (5.0 g, 18.0 mmol, 1.0 eq) in dichloromethane (10 ml), tert-butyl 4-oxopiperidine-1-carboxylate (4.9). g, 24.9 mmol, 1.4 eq), acetyl ethaneper oxyate; sodioboranyl acetate (13.2 g, 62.3 mmol, 3.5 eq) was added. The resulting solution was stirred at room temperature overnight.
The reaction was then stopped by adding 1 mL of water / ice. The resulting solution was extracted with dichloromethane (20 mLx2), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1: 0). This gave 4.2 g (54%) of tert-butyl 4- [4- (4-bromophenyl) piperazin-1-yl] piperidine-1-carboxylate as a white solid. LC / MS (ESI) m / z: 426.10 [M + 1] ⁺ .
Step 2: Preparation of 1- (4-bromophenyl) -4- (piperidine-4-yl) piperazine hydrochloride.

A solution of tert-butyl 4- [4- (4-bromophenyl) piperazine-1-yl] piperidine-1-carboxylate (4.2 g, 9.8 mmol, 1.0 equivalent) in dichloromethane (10 ml) in a 100 mL round bottom flask. , Hydrogen chloride (5 ml) was added. The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum. This gave 3.0 g (85%) of 1- (4-bromophenyl) -4- (piperidine-4-yl) piperazine hydrochloride as a white solid. LC / MS (ESI) m / z: 325.95 [M + 1] ⁺ .
Step 3: Preparation of tert-butyl 2- (4- (4- (4-bromophenyl) piperazine-1-yl) piperidine-1-yl) acetate.

In a 100 mL round bottom flask, a solution of 1- (4-bromophenyl) -4- (piperidine-4-yl) piperazine hydrochloride (3.0 g, 8.3 mmol, 1.0 eq) in dichloromethane (10 ml), triethylamine (2.0 g, 19.8 mmol (2.4 eq), tert-butyl 2-bromoacetate (2.3 g, 11.8 mmol, 1.4 eq) were added. The resulting solution was stirred at room temperature overnight. The reaction was then stopped by adding 1 mL of water / ice. The resulting solution was extracted with dichloromethane (20 mLx2), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1: 0). This gave 2.0 g (53%) of tert-butyl 2- [4- [4- (4-bromophenyl) piperazin-1-yl] piperidine-1-yl] acetate as a white solid. LC / MS (ESI) m / z: 440.30 [M + 1] ⁺ .
Step 4: tert-butyl 2- (4- (4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-)
Preparation of yl) phenyl) piperazine-1-yl) piperidine-1-yl) acetate.

In a 20-30 mL airtight tube, tert-butyl 2- [4- [4- (4-bromophenyl) piperazin-1-yl] piperidine-1-yl] acetate (2.0 g, 4.5 mmol, 1.0 eq) Dioxane (10 ml) solution, 4,4,5,5-
Tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolan (2.3 g, 9.1 mmol, 2.0 eq), KOAc ( 874.6 mg, 8.9 mmol, 2.0 eq) and Pd (dppf) Cl ₂ (700.6 mg, 0.9 mmol, 0.2 eq) were added. The resulting solution was stirred overnight in an oil bath at 85 ° C. The reaction was then stopped by adding 1 mL of water / ice. The resulting solution was extracted with ethyl acetate (20 mlx2), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1: 0). This resulted in 630.0 mg (29%) of tert-butyl 2- (4- [4- [4- (4, 4, 5, 5-)
Tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl] piperazine-1-yl] piperidine-1-yl) Acetate was obtained as a black solid. LC / MS (ESI) m / z: 486.25 [M + 1] ⁺ .
Step 5: tert--butyl (R) -2- (4- (4- (4- (3- (2,6-difluoro-3-((3-fluoropyrrolidin) -1-sulfonamide) benzoyl)-)- Preparation of 1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) piperidine-1-yl) acetate.

In a 20-30 mL closed tube, tert-butyl 2- (4- [4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine- 1-Il] piperidine-1-yl) acetate (630.0 mg, 1.3 mmol, 1.0 eq) in dioxane / H2O (4: 1 ml) solution, (3R) -N- (3-5-bromo-1H-pyrrolo [ 2,3-b]
Pyridine-3-carbonyl-2,4-difluorophenyl) -3-fluoropyrrolidin-1-sulfonamide (300.0 mg, 0.6 mmol, 0.5 eq), Pd (dppf) Cl ₂ (46.9 mg), sodium carbonate (99.2 mg) , 0.9 mmol, 0.7 eq). The resulting solution was stirred at 105 ° C. for 2 hours. The reaction was then quenched by the addition of 1 mL of water / ice. The resulting solution was extracted with ethyl acetate (20 mLx2), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded into a silica gel column with dichloromethane / methanol (10: 1). This resulted in 256.0 mg (25%) of tert-butyl 2- [4- [4- (4- [3- [2,6-difluoro-3- ([[(3R) -3-fluoropyrrolidine-1-). Ill] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazine-1-yl] piperidine-1-yl] acetate was obtained as a yellow solid. LC / MS (ESI) m / z: 782.05 [M + 1] ⁺ .
Step 6: (R) -2- (4- (4- (4- (3- (2,6-difluoro-3-((3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [ 2,3-b] Pyridine-5-yl) Phenyl) Piperazine-1-yl) Piperidine-1-yl) Preparation of acetic acid.

In a 100 mL round bottom flask, tert-butyl 2- [4- [4- (4- [3- [2,6-difluoro-3- ([[(3R) -3-)
Fluoropyrrolidine-1-yl] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazine-1-yl] piperidine-1-yl] acetate (256.0 mg, A solution of 0.3 mmol (1.0 eq) in dichloromethane (10 ml) and trifluoroacetic acid (2 ml) were added. The resulting solution was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum. This resulted in 120.0 mg (50%) of 2- [4- [4- (4- [3- [2,6-difluoro-3- ([[(3R) -3-fluoropyrrolidine-1-yl] sulfonyl] sulfonyl). ] Amino) Benzoyl] -1H-pyrrolo [2,3-b] Pyridine-5-yl] Phenyl) Piperazine-1-yl] Piperidine-1-yl] Acetic acid was obtained as a yellow solid. LC / MS (ESI) m / z: 726.15 [M + 1] ⁺ .
Step 7: (2S, 4R) -1-((S) -2- (2- (4- (4- (4- (3- (2,6-difluoro-3- (((R) -3-) -3-) Fluoropyrrolidine) -1-sulfonamide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperazine-1-yl) Piperidine-1-yl) Acetamide) -3,3-dimethyl Preparation of butanoyl) -4-hydroxy-N-((S) -1-(4- (4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide.

2- [4- [4- (4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) in a 100 mL round bottom flask) Benzoyl] -1H-pyrrolidine [2,3-b] pyridine-5-yl] phenyl) piperazine-1-yl] piperidine-1-yl] N, N-dimethyl of acetic acid (120.0 mg, 0.3 mmol, 1.0 equivalent) Formamide (5 ml) solution, (2S, 4R) -1-[(2S) -2-amino-3,3-dimethylbutanoyl] -4-hydroxy-N-[(1S) -1- [4- (4) -Methyl-1,3-thiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (88.2 mg, 0.4 mmol, 1.2 equivalent), N, N-diisopropylethylamine (64.1 mg, 1.0 mmol, 3.0 equivalent), (Benzotriazole-1-yloxy) Tris (dimethylamino) phosphonium hexafluorophosphate (87.8 mg) was added. The resulting solution was stirred at room temperature for 1 hour. The reaction was then stopped by adding 1 mL of water / ice. The resulting solution was extracted with ethyl acetate (20 mLx2), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by preparative HPLC and 42.9 mg (23%) of (2S, 4R) -1-[(2S) -2- (2- [4- [4- (4- [3- [). 2,6-difluoro-3-([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazine -1-yl] piperidine-1-yl] acetamide) -3,3-dimethylbutanoyl] -4-hydroxy-N-[(1S) -1- [4- (4-methyl-1,3-thiazole-) 5-Il) Phenyl] ethyl] pyrrolidine-2-carboxamide was obtained as an off-white solid. LC / MS (ESI) m / z: 1152.20 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 12.87 (brs, 1H), 9.96 (brs, 1H), 8.96 (d, J = 2.1) Hz, 1H), 8.63 (d, J = 2.3 Hz, 1H), 8.51 (s, 1H), 8.40 (d, J = 7.6 Hz, 1H), 8.04 (s, 1H), 7.74 (d, J = 9.6) Hz, 1H), 7.70-7.60 (m, 3H), 7.47-7.42 (m, 2H), 7.40-7.31 (m, 2H), 7.23 (t, J = 8.9 Hz, 1H), 7.05 (d, J = 8.5 Hz, 2H), 5.36-5.15 (m, 1H), 5.19 (s, 1H), 4.88 (t, J = 7.1 Hz, 1H), 4.54-4.38 (m, 2H), 4.27-4.21 (m, 1H) ), 3.60-3.52 (m, 2H), 3.47-3.41 (m, 1H), 3.37-3.31 (m, 2H), 3.30-3.24 (m, 5H), 3.03 (d, J = 16.1 Hz, 1H), 2.89-2.80 (m, 3H), 2.70-2.55 (m, 5H), 2.34-2.03 (m, 7H), 1.87-1.72 (m, 3H), 1.47-1.37 (m, 6H), 0.93 (s, 9H) ).
(2S, 4R) -1-((S) -2- (2- (4-(((3R, 5S) -4- (4- (3- (2,6-difluoro-3- (((R) ) -3-Fluoropi
Loridine) -1-sulfonamide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) -3,5-dimethylpiperazine-1-yl) Methyl) Piperidine-1-yl) Acetamide )-3,3-Dimethylbutanoyl) -4-Hydroxy-N-((S) -1- (4- (4-Methylthiazole-5-yl) Phenyl) Echi
E. Illustrative synthesis of pyrrolidine-2-carboxamide (eg 360) Step 1: Preparation of tert-butyl bis (2-hydroxypropyl) carbamate.

Boc anhydride (17.2 g, 78.84 mmol, 18 mL, 1.05 eq) and triethylamine in a solution of 1- (2-hydroxypropylamino) propane-2-ol (10 g, 75.08 mmol, 10 mL, 1 eq) in tetrahydrofuran (200 ml). (22.8 g, 225.25 mmol, 31.3 mL, 3 eq) was added. The mixture was stirred at 15 ° C. for 12 hours. Water (400 mL) was poured into the mixture and stirred for 1 minute. The aqueous layer was extracted with ethyl acetate (200 mLx3). The combined organic layers were washed with brine (100 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 10: 1 to 2: 1) and tert-butyl N, N-bis (2-).
Hydroxypropyl) carbamate (14.7 g, 63.01 mmol, 83% yield) was obtained as a white solid. LC / MS (ESI) m / z: 256.1 [M + 23] ⁺ .
Step 2: Preparation of tert-butyl bis (2-oxopropyl) carbamate.

A solution of dimethyl sulfoxide (13.4 g, 171.45 mmol, 4 eq) in dichloromethane (100 ml) was added dropwise to a solution of oxalyl chloride (16.3 g, 128.5 mmol, 3 eq) in dichloromethane (100 ml) at −70 ° C. The mixture was stirred for 0.5 hours at -70 ° C. A solution of tert-butyl N, N-bis (2-hydroxypropyl) carbamate (10 g, 42.86 mmol, 1 eq) in dichloromethane (100 ml) was added dropwise to this mixture and the mixture was added for an additional 0.5 hour. Stir at -70 ° C. Triethylamine (21.7 g, 214.31 mmol, 5 eq) was then added to the reaction mixture at -70 ° C. The mixture was heated to 15 ° C and stirred for 2 hours at 15 ° C. The reaction mixture was diluted with water (500 mL) and extracted with dichloromethane (300 mLx2). The combined organic layers were washed with saturated brine (300 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 10: 1 to 2: 1) to tert-butyl N, N-diacetenylcarbamate (6.4 g, 27.91 mmol, yield 65%). ) Was obtained as a colorless oil.

Step 3: Preparation of tert-butyl 4- (4-bromophenyl) -3,5-dimethylpiperazine-1-carboxylate.

Acetic acid (7 ml) in a methanol (70 ml) solution of tert-butyl N, N-diacetenylcarbamate (6.4 g, 27.91 mmol, 1.2 eq) and 4-bromoaniline (4 g, 23.26 mmol, 1 eq). added. The mixture was stirred at 15 ° C. for 0.5 hours. Borane; 2-methylpyridine (4.98 g, 46.52 mmol, 2 eq) was added and then the mixture was stirred for 12 hours at 15 ° C. The reaction mixture was diluted with water (120 mL) and extracted with ethyl acetate (80 mLx3). Saturated brine (100mLx2) of organic layers combined into one
Washed with, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20: 1-5: 1) and tert-butyl 4- (4-bromophenyl) -3,5-dimethyl-piperazin-1-carboxylic. The acid salt (8 g, 21.66 mmol, 93% yield) was obtained as a colorless oil. LC / MS (ESI) m / z: 369.0 [M + 1] +; 1H-NMR (400MHz, CDCl3) δ 7.44 --7.74 (m, 2H), 7.00 --6.94 (m, 2H), 3.88 (s, 1H) ), 3.49 (s, 1H), 3.11 --2.97 (m, 2H), 2.93 --2.77 (m, 2H), 1.50 (s, 9H), 0.79 (d,
J = 6.0 Hz, 6H).
Step 4: Preparation of 1- (4-bromophenyl) -2,6-dimethylpiperazine.

Dioxane (90 ml) solution of 4M hydrochloric acid in dichloromethane (100 ml) solution of tert-butyl 4- (4-bromophenyl) -3,5-dimethyl-piperazine-1-carboxylate (8 g, 21.66 mmol, 1 eq). Was added. The mixture was stirred at 15 ° C. for 2 hours. The reaction mixture is concentrated under reduced pressure to give the crude product 1- (4-bromophenyl) -2,6-dimethyl-piperazine (6.6 g, 21.59 mmol, 99% yield, hydrochloride) as a white solid. It was obtained and used in the next step without further purification.

Step 5: Preparation of tert-butyl 4-((4- (4-bromophenyl) -3,5-dimethylpiperazine-1-yl) methyl) piperidine-1-carboxylate.

Sodium acetate (5.31 g, 64.78 mmol, 3 eq) in a solution of 1- (4-bromophenyl) -2,6-dimethyl-piperazine (6.6 g, 21.59 mmol, 1 eq, hydrochloride) in methanol (100 ml). added. The mixture was stirred at 15 ° C. for 10 minutes. Tert-butyl 4-formylpiperidine-1-carboxylate (5.99 g, 28.07 mmol, 1.3 eq) was added and the mixture was stirred at 15 ° C. for 20 minutes. Sodium cyanoborohydride (2.71 g, 43.19 mmol, 2 eq) was added, then the mixture was stirred for an additional 12 hours at 15 ° C. The reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (300 mLx2). The combined organic layers were washed with saturated brine (300 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Residues silica gel column chromatography (petroleum ether /
Purified with ethyl acetate = 10: 1 to 3: 1), tert-butyl 4-[[4- (4-bromophenyl) -3,5-dimethyl-piperazine-1-yl] methyl] piperidine-1- Carboxylate (6.6 g, 14.01 mmol, yield 64%, purity 99%) was obtained as a white solid. LC / MS (ESI) m / z: 466.1 [M + 1] +; 1H-NMR
(400MHz, CDCl3) δ 7.38 (d, J = 8.0 Hz, 2H), 6.89 (d, J = 8.0 Hz, 2H), 4.32 (d, J = 6.0 Hz, 1H), 4.21 (s, 1H), 3.58 --3.45 (m, 2H), 2.72 (s, 3H), 2.63 (d, J = 8.8 Hz, 2H), 2.29 (dd, J = 6.4, 10.4 Hz, 2H), 1.95 --1.82 (m, 2H), 1.80 --1.71 (m, 2H), 1.70 --1.57 (m, 1H), 1.47 (s, 9H), 1.17 --1.02 (m, 2H), 0.94 (d, J = 6.0 Hz, 6H).
Step 6: Preparation of 1- (4-bromophenyl) -2,6-dimethyl-4- (piperidine-4-ylmethyl) piperazine.

Dichloromethane (6.6 g, 14.15 mmol, 1 equivalent) of tert-butyl 4-[[4- (4-bromophenyl) -3,5-dimethyl-piperazine-1-yl] methyl] piperidine-1-carboxylate (6.6 g, 14.15 mmol, 1 equivalent) 50 ml) in solution, 4M
A solution of dioxane (50 mL, 14.13 eq) in hydrochloric acid was added. The mixture was stirred at 15 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure. The crude product is pulverized with ethyl acetate (100 mL) to add 1- (4-bromophenyl) -2,6-dimethyl-4- (4-piperidylmethyl) piperazine (6 g, crude, hydrochloride) to a white solid. Got as.

Step 7: Of tert-butyl 2-(4-(((3R, 5S) -4- (4-bromophenyl) -3,5-dimethylpiperazine-1-yl) methyl) piperidine-1-yl) acetate Preparation.

1- (4-Bromophenyl) -2,6-dimethyl-4- (4-piperidylmethyl) piperazine (6 g, 14.90 mmol, 1 eq, hydrochloride) in an acetonitrile (100 ml) solution to diisopropylethylamine (9.63 g, 74.48 mmol, 12.9 mL, 5 eq) and tert-butyl 2-bromoacetate (2.91 g, 14.9 mmol, 2.2 mL, 1 eq) were added. The mixture was stirred at 80 ° C. for 1.5 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mLx2). The combined organic layers were washed with saturated brine (100 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petrazine ether: ethyl acetate = 10: 1 to 2: 1) and tert-butyl 2- [4-[[(3S, 5S) -4- (4-bromophenyl)). -3,5-dimethyl-piperazin-1-yl] methyl] -1-piperidyl] acetate (580 mg, 1.21 mmol, 16% yield) is obtained as a white solid, and 2- [4-[(((). 3R, 5S) -4- (4-bromophenyl) -3,5-dimethyl-piperazine-1-yl] methyl] -1-piperidyl] acetate (2.7 g, 5.62 mmol, 75% yield) as a white solid I got it as a thing. 1H-NMR (400MHz, CDCl3) δ 7.39 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 3.22 (s, 2H), 3.12 (s, 2H), 2.95 (d , J = 11.2 Hz, 2H), 2.67 (d, J = 10.4 Hz, 2H), 2.25 --2.14 (m, 4H), 2.09 (t, J = 9.6 Hz, 2H), 1.77 (d, J = 12.0 Hz) , 2H), 1.55 --1.44 (m, 10H), 1.40 --1.27 (m, 2H), 0.84 (d, J = 6.0 Hz, 6H).
Step 8: tert-butyl 2-(4-(((3R, 5S) -4-(4-(3-(2,6-difluoro-3-(((R) -3-fluoro-N-((() 2- (trimethylsilyl) ethoxy) methyl) piperidine) -1-sulfonamide) benzoyl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) Preparation of phenyl) -3,5-dimethylpiperazin-1-yl) methyl) piperidine-1-yl) acetate.

tert-Butyl 2- [4-[[(3R, 5S) -4- (4-bromophenyl) -3,5-dimethyl-piperazin-1- l] methyl] -1-piperidyl] acetate (150 mg, 0.31) mmol equivalent), (3R) -N- [2,4-difluoro-3- [5- (4)
, 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) -1- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b] Pyridine-3-carbonyl] phenyl] -3 -Fluoro-N- (2-trimethylsilylethoxymethyl) pyrrolidine-1-sulfonamide (253 mg, 0.31 mmol, 1 equivalent), cesium fluoride (190 mg, 1.25 mmol, 4 equivalents) and 4-ditert-butylphosphanyl- N, N-dimethyl-aniline; dichloropalladium (22 mg, 0.03 mmol, 0.1 equivalent) dioxane (4 ml) and water (0.4 ml) mixed solution degassed, purged with nitrogen (3x), then mixed solution Was stirred for 3 hours in a nitrogen atmosphere at 95 ° C. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (10 mLx2). The combined organic layers were washed with brine (10 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by silica gel chromatography (dimethane: methanol = 100: 1-50: 1) and tert-butyl 2- [4-[[(3S, 5S) -4- [4- [3- [2). , 6-Difluoro-3- [[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl- (2-trimethylsilylethoxymethyl) amino] benzoyl] -1- (2-trimethylsilylethoxymethyl) pyrolo [2,3 -b] pyridine-5-yl] phenyl] -3,5-dimethyl-piperazin-1-yl] methyl] -1-piperidyl] acetate (170 mg, 0.15 mmol, yield 50%) as a bright yellow solid Obtained. LC / MS (ESI) m / z: 543.0 [M / 2 + 1] ⁺ .
Step 9: Methyl 2-(4-(((3R, 5S) -4-(4-(3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) ) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) -3,5-dimethylpiperazine-1-yl) Methyl) Piperidine-1-yl) Preparation of acetate.

tert-butyl 2- [4-[[(3R, 5S) -4- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1-yl] sulfonyl- (2-trimethylsilylethoxymethyl) amino] benzoyl] -1- (2-trimethylsilylethoxymethyl) pyrolo [2,3-b] pyridine-5-yl] phenyl] -3,5-dimethyl-piperazine-1-yl] A solution of 4M hydrochloric acid in dioxane (8 ml) was added to a solution of methyl] -1-piperidyl] acetate (170 mg, 0.15 mmol, 1 equivalent) in methanol (4 ml). The mixture was stirred at 40 ° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to remove dioxane, methanol and hydrochloric acid, and the crude product methyl 2- [4-[[(3R, 5S) -4- [4- [3- [2,6-difluoro- 3-[[(3R) -3-fluoropyrrolidine-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl] -3,5-dimethyl-piperazine- 1-Il] methyl] -1-piperidyl] acetate (120 mg, 0.15 mmol, 97% yield) was obtained as a bright yellow solid and used in the next step without further purification. LC / MS (ESI) m / z: 782.5 [M + 1] ⁺ .
Step 10: 2-(4-(((3R, 5S) -4- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide))) Preparation of benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) -3,5-dimethylpiperazine-1-yl) methyl) piperidine-1-yl) acetic acid.

Methyl 2- [4-[[(3R, 5S) -4- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1-yl] sulfonylamino] benzoyl] ] -1H-pyrrolidine [2,3-b] pyridin-5-yl] phenyl] -3,5-dimethyl-piperazine-1-yl] methyl] -1-piperidyl] acetate (120 mg, 0.15 mmol, 1 equivalent) )
Lithium hydroxide monohydrate (32 mg, 0.76 mmol, 5 eq) was added to a solution of methanol (3 ml) and water (1 ml). The mixture was stirred at 40 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to remove methanol. The mixture was adjusted to pH 4-5 with hydrochloric acid (2M) and concentrated under reduced pressure to remove water. The residue was purified by half-reverse phase HPLC and 2- [4-[[(3R, 5S) -4- [4- [3- [2,6-difluoro-3-[[(3R) -3). -Fluoropyrrolidine-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl] -3,5-dimethyl-piperazine-1-yl] methyl] -1- Piperidine] acetic acid (90 mg, 0.11 mmol, yield 76%) was obtained as a yellow solid. LC / MS (ESI) m / z: 768.4 [M + 1] ⁺ .
Step 11: (2S, 4R) -1-((S) -2- (2-(4-(((3R, 5S) -4- (4- (3- (2,6-difluoro-3- (" ((R) -3-fluoropyrrolidine) -1-sulfonamide) Benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl)
Phenyl) -3,5-dimethylpiperazine-1-yl) methyl) piperidine-1-yl) acetamide) -3,3-dimethylbutanoyl) -4-hydroxy-N-((S) -1- (4- (4-) Preparation of (4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide.

2- [4-[[(3R, 5S) -4- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl]] -1H-pyrrolidine [2,3-b] pyridin-5-yl] phenyl] -3,5-dimethyl-piperazin-1-yl] methyl] -1-piperidyl] acetic acid (90 mg, 0.11 mmol, 1 equivalent), (2S, 4R) -1-[(2S) -2-amino-3,3-dimethyl-butanoyl] -4-hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-) Il) phenyl] ethyl] pyrrolidine-2-carboxamide (56 mg, 0.11 mmol, 1 equivalent, hydrochloride), triethylamine (23 mg, 0.23 mmol, 2 equivalents) and hydroxybenzotriazole (19 mg, 0.14 mmol, 1.2 equivalents) dimethyl Holmamide (2 ml) mixture for 0.5 hours at 40 ° C.
Was stirred with. 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (33 mg, 0.17 mmol, 1.5 eq) was added, then the mixture was stirred for 2.5 hours at 40 ° C. The solution was purified by half-taken reverse phase HPLC and (2S, 4R) -1-[(2S) -2-[[2- [4-[[(3R, 5S)-4- [4- [3- [2,6-difluoro-3- [
[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b]
Pyridine-5-yl] phenyl] -3,5-dimethyl-piperazin-1-yl] methyl] -1-piperidyl] acetyl] amino] -3,3-dimethyl-butanoyl] -4-hydroxy-N-[(( 1S) -1- [4- (4-Methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (66.1 mg, 0.05 mmol, yield 44%, purity 97%, formate) as a white solid Got as. LC / MS (ESI) m / z: 597.8 [M / 2 + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 12.92 (s, 1H), 8.99 (s, 1H), 8.68 (d, J) = 2.0 Hz, 1H),
8.57 (s, 1H), 8.44 (d, J = 7.6 Hz, 1H), 8.19 (s, 1H), 8.07 (s, 1H), 7.78 (d, J = 10.0 Hz, 1H), 7.67 --7.59 (m) , 3H), 7.49 --7.42 (m, 2H), 7.40 --7.35 (m, 2H), 7.26 (t, J = 8.0 Hz, 1H), 7.08 (d, J = 8.4 Hz, 2H), 5.39 --5.21 ( m, 1H), 4.91 (q, J = 7.2 Hz, 1H), 4.52 (d, J = 10.0 Hz, 1H), 4.46 (t, J = 8.4 Hz, 1H), 4.30 (s, 1H), 3.69- 3.56 (m, 3H), 3.33 --3.25 (m, 6H), 3.08 --3.00 (m, 2H), 2.94 --2.79 (m, 3H), 2.46 (s, 3H), 2.44 --2.37 (m, 2H), 2.21 (d, J = 6.4 Hz, 3H), 2.17 --1.94 (m, 6H), 1.88 --1.72 (m, 3H), 1.68 --1.51 (m, 1H), 1.40 (d, J = 7.2 Hz, 3H) , 1.31 --1.16 (m, 2H), 1.03 (br d, J = 6.0 Hz, 6H), 0.96 (s, 10H).
(2S, 4R) -4-Hydroxy-1-((2- (2- (2- (2- (4-((2'-Methyl-5-morpholino-5'-(3- (truffle)
Luolomethyl) benzamide)-[3,3'-bipyridine] -6-yl) oxy) piperidine-1-yl) d
Toxi) ethoxy) ethoxy) acetyl) -L-valyl) -N-((S) -1- (4- (4-methylthiazole-5-)
Il) Phenyl) Ethyl) Pyrrolidine-2-carboxamide (Example 346) Exemplary Synthesis Step 1: Preparation of tert-butyl 2- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) acetate.

Sodium hydride (2.46 g, 61.52 mmol, purity 60%, 1.2 eq) in a solution of 2- [2- (2-hydroxyethoxy) ethoxy] ethanol (38 g, 256.34 mmol, 34 mL, 5 eq) in tetrahydrofuran (200 ml). Was added under nitrogen at 0 ° C. for 1 hour. The reaction mixture was stirred for 1 hour. Then, a solution of tert-butyl 2-bromoacetate (10 g, 51.27 mmol, 7.58 mL, 1 equivalent) in tetrahydrofuran (100 ml) was added dropwise to the solution at 0 ° C., and the reaction mixture was added at 20 ° C. for another 12 hours. Was stirred with. The mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mLx3). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 10: 1 to 1: 1). Tert-butyl 2- [2- [2- (2-hydroxyethoxy) ethoxy] ethoxy] acetate (3 g, 11.35 mmol, 22% yield) was obtained as a yellow oil. 1H-NMR (400MHz, CDCl3) δ 4.02 (s, 2H), 3.81 --3.57 (m, 12H), 2.61 (br s, 1H), 1.47
(s, 9H).
Step 2: Preparation of tert-butyl 2- (2- (2- (2- (tosyloxy) ethoxy) ethoxy) ethoxy) acetate.

tert-butyl 2- [2- [2- (2-Hydroxyethoxy) ethoxy] ethoxy] ethoxy] acetate (1 g, 3.78 mmol, 1 eq) in dichloromethane (20 ml) solution with paratoluene chloride sulfonyl (2.1 g, 11.35 mmol). , 3 eq) and triethylamine (1.9 g, 18.92 mmol, 5 eq), 4-dimethylaminopyridine (462 mg, 3.78 mmol, 1 eq) were added. The mixture was stirred at 30 ° C. for 12 hours. The mixture was quenched with water (30 mL) and extracted with dichloromethane (30 mLx3). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 10: 1 to 1: 1). Tert-butyl 2- [2- [2- [2- [2- (p-tolylsulfonyloxy) ethoxy] ethoxy] ethoxy] acetate (500 mg, 1.19 mmol, 31% yield) was obtained as a yellow oil. LC / MS (ESI) m / z: 441.1 [M + 23] ⁺ .
Step 3: tert-Butyl 2- (2-(2-(4-((2'-Methyl-5-morpholino-5'-(3- (trifluoromethyl) benzamide))-[3,3' -Bipyridine] -6-yl) Oxy) Piperidine-1-yl) ethoxy) ethoxy) ethoxy) Preparation of acetate.

N, N- in a solution of tert-butyl 2- [2- [2- [2- (p-tolylsulfonyloxy) ethoxy] ethoxy] ethoxy] acetate (200 mg, 0.477 mmol, 1 eq) in acetonitrile (5 ml). Diisopropylethylamine (370 mg, 2.87 mmol, 6 eq), N- [6-methyl-5- [5-morpholino-6- (4-piperidyloxy) -3-pyridyl] -3-pyridyl] -3- (trifluoro) Methyl) benzamide; hydrochloride and potassium iodide (79 mg, 0.477 mmol, 1 eq) were added. The mixture was stirred at 100 ° C. for 12 hours.
The mixture was quenched with water (30 ml) and extracted with ethyl acetate (30 mlx3). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by preparative-TLC (dichloromethane: methanol = 10: 1). tert-butyl 2- [2- [2- [2- [4-[[5- [2-methyl-5-[[3- (trifluoromethyl) benzoyl] amino] -3-pyridyl] -3-morpholino -2-Pyridyl] oxy] -1-piperidyl] ethoxy] ethoxy] ethoxy] acetate (200 mg, 0.253 mmol, 53% yield) was obtained as a yellow oil. LC / MS (ESI) m / z: 788.2 [M + 1] ⁺ .
Step 4: 2- (2- (2- (2- (4-((2'-Methyl-5-morpholino-5'-(3- (trifluoromethyl) benzamide))-[3,3'-bipyridine]] -6-Il) Oxy) Piperidine-1-Il) ethoxy) ethoxy) ethoxy) Preparation of acetic acid.

tert-butyl 2- [2- [2- [2- [4-[[5- [2-methyl-5-[[3- (trifluoromethyl) benzoyl]]
Amino] -3-pyridyl] -3-morpholino-2-pyridyl] oxy] -1-piperidyl] ethoxy] ethoxy] ethoxy] acetate (200 mg, 0.253 mmol, 1 eq) in dichloromethane (2 ml) solution, trifluoro Acetate (578 mg, 5.08 mmol, 20 eq) was added. The mixture was stirred at 20 ° C. for 12 hours. The mixture was concentrated. The residue was used in the next step without further purification. 2- [2- [2- [2- [4- [[5- [2-Methyl-5-[[3- (trifluoromethyl) benzoyl] amino] -3-pyridyl] -3-morpholino-2- Pyridyl] oxy] -1-piperidyl] ethoxy] ethoxy] ethoxy] acetic acid (200 mg)
, Crude, trifluoroacetic acid) was obtained as a yellow oil. LC / MS (ESI) m / z: 732.2 [M + 1] ⁺ .
Step 5: (2S, 4R) -4-hydroxy-1-((2- (2- (2- (2- (4-((2'-methyl-5-morpholino-5'-(3- (tri) Fluoromethyl) benzamide)-[3,3'-bipyridine] -6-yl) oxy) piperidine-1-yl) ethoxy) ethoxy) ethoxy) acetyl) -L-valyl) -N-((S) -1- Preparation of (4- (4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide.

2- [2- [2- [2- [4- [[5- [2-Methyl-5-[[3- (trifluoromethyl) benzoyl] amino] -3-pyridyl] -3-morpholino-2- Pyridyl] oxy] -1-piperidyl] ethoxy] ethoxy] ethoxy] acetic acid (200 mg, 0.236 mmol, 1 equivalent, trifluoroacetic acid) and (2S, 4R) -1- [(2S) -2-amino-3,3 -Dimethyl-butanoyl] -4-hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (170 mg, 0.354 mmol, 1.5 equivalents, Hydroxybenzotriazole (38 mg, 0.283 mmol, 1.2 equivalents), triethylamine (119 mg, 1.18 mmol, 5 equivalents) and 1- (3-dimethylaminopropyl)-in an N, N-dimethylformamide (2 ml) solution of hydrochloride). 3-Ethylcarbodiimide hydrochloride (68 mg, 0.354 mmol, 1.5 equivalents) was added. The mixture was stirred at 20 ° C. for 12 hours. The mixture was quenched with water (30 mLx3) and extracted with dichloromethane / methanol (10: 1, 30 mLx3). The organic layer was dried over sodium sulfate and concentrated.
The residue was purified by preparative HPLC. (2S, 4R) -1-[(2S) -3,3-dimethyl-2-[[2- [2- [2- [2- [4-[[5- [2-Methyl-5-[[] 3- (Trifluoromethyl) benzoyl] amino] -3-pyridyl] -3-morpholino-2-pyridyl] oxy] -1-piperidyl] ethoxy] ethoxy] ethoxy] acetyl] amino] butanoyl] -4-hydroxy-N -[(1S) -1- [4- (4-Methylthiazole-5-yl) phenyl] ethyl]
Pyrrolidine-2-carboxamide (136.7 mg, 0.107 mmol, yield 45%, purity 98%, formic acid di) was obtained as a yellow solid. LC / MS (ESI) m / z: 1144.5 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 10.66 (s, 1H), 8.97 (s, 1H), 8.84 (d, J = 2.4) Hz, 1H), 8.43 (d, J = 7.6 Hz, 1H), 8.32 (s, 1H), 8.28 (d, J = 8.0 Hz, 1H), 8.16 (s, 2H), 8.03 (d, J = 2.4) Hz, 1H), 7.99 (d, J = 7.6 Hz, 1H), 7.84 --7.74 (m, 2H), 7.46 --7.32 (m, 5H), 7.20 (d, J =
2.0 Hz, 1H), 5.19 (br s, 1H), 4.95 --4.85 (m, 1H), 4.55 (d, J = 9.6 Hz, 1H), 4.44 (t, J = 8.0 Hz, 1H), 4.28 (br s, 1H), 3.96 (s, 2H), 3.75 (br s, 4H), 3.67 --3.49 (m, 12H), 3.09 (br s, 4H), 2.75 --2.74 (m, 2H), 2.55 (br t) , J = 5.6 Hz, 1H),
2.44 (d, J = 4.4 Hz, 9H), 2.09 --1.94 (m, 3H), 1.82 --1.70 (m, 3H), 1.37 (d, J = 7.2 Hz, 3H), 0.94 (s, 9H).
N- (6'-((1- (2- (2-(((2- (2,6-dioxopiperidine-3-yl) -1-oxoisoindoline-5-yl) oxy) ethoxy) ) Ethoxy) ethyl) piperidine-4-yl) oxy) -2-methyl-5'-mo
Luphorino- [3,3'-Bipyridine] -5-yl) -3- (Trifluoromethyl) Benzamide (Example 356) Illustrative Synthesis Step 1: 2- (2- (2-Hydroxyethoxy) ethoxy) ethyl 4 -Preparation of methylbenzene sulfonate.

In a mixture of 2- [2- (2-hydroxyethoxy) ethoxy] ethanol (5.00 g, 33.29 mmol, 1.00 eq) and 4-methylbenzenesulfonyl chloride (1.59 g, 8.32 mmol, 0.25 eq) in dichloromethane (50 ml). , Triethylamine (1.68 g, 16.65 mmol, 2.3 mL, 0.5 eq) was added all at once under nitrogen at 25 ° C. The mixture was stirred at 25 ° C. for 12 hours. The mixture was washed with brine (30 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 1/1 to 0: 1) to 2- [2- (2-hydroxyethoxy) ethoxy] ethyl 4-methylbenzenesulfonate (1.72 g). , 5.65 mmol, yield 17%) was obtained as a colorless oil. 1H-NMR (400MHz, CDCl3) δ 7.81 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 4.22 --4.15 (m, 2H), 3.79 --3.67 (m, 4H) , 3.67 --3.56 (m, 6H), 2.46 (s, 3H).
Step 2: Preparation of tert-butyl 5-amino-4-(((benzyloxy) carbonyl) amino) -5-oxovalerate.

2- (benzyloxycarbonylamino) -5-tert-butoxy-5-oxo-valerate (40 g, 118.56 mmol, 1 eq), pyridine (18.76 g, 237.13 mmol, 2 eq) and di-tert-butyl bicarbonate A mixture of dioxane (400 ml) of salt (41.40 g, 189.70 mmol, 1.6 eq) was stirred for 0.5 hours at 0 ° C. Ammonium bicarbonate (28.12 g, 355.69 mmol, 3 eq) was then added to the reaction mixture at 0 ° C. The mixture was stirred for 12 hours at 15 ° C. The mixture was quenched by the addition of water (1000 mL), diluted with ethyl acetate (200 mLx4), the combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and filtered. Concentrated under reduced pressure. The residue was pulverized with petroleum ether: ethyl acetate (V / V = 3: 1, 100 mL) and then recovered by filtration. The compound tert-butyl 5-amino-4- (benzyloxycarbonylamino) -5-oxo-valerate (35 g, 104.05 mmol, 87% yield) was obtained as a white solid. 1H-NMR (400MHz, CDCl3) δ 7.44 --7.31 (m, 5H), 6.34 (d, J = 2.8 Hz, 1H), 5.83 --5.63 (m, 1H), 5.45 (s, 1H), 5.13 (s, 2H), 4.50 --4.17 (m, 1H), 2.57 --2.45 (m, 1H), 2.41 --2.31 (m, 1H), 2.19 --2.06 (m, 1H), 1.96 (d, J = 7.2, 14.4 Hz, 1H), 1.49 --1.43 (m, 9H).
Step 3: Preparation of tert-butyl 4,5-diamino-5-oxovalerate.

tert-butyl 5-amino-4- (benzyloxycarbonylamino) -5-oxo-valerate (30 g)
, 89.18 mmol, 1 eq) in methanol (300 ml) was added with palladium carbon (8 g, 10% pure) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred at 40 ° C. for 12 hours under hydrogen (45Psi). The mixture was filtered and concentrated under reduced pressure. The residue was used in the next step without further purification. The compound tert-butyl 4,5-diamino-5-oxo-valerate (17 g, 84.05 mmol, 94% yield) was obtained as a gray solid. 1H-NMR (400MHz, DMSO-d6) δ 7.32 (s, 1H), 6.98 (s, 1H), 3.10 (m, 1H), 3.04 --2.58 (m, 2H), 2.24 (m, 2H), 1.84- 1.70 (m, 1H), 1.65 --1.50 (m, 1H), 1.40 (s, 9H).
Step 4: Preparation of methyl 4-((tert-butyldimethylsilyl) oxy) -2-methylbenzoate.

Imidazole (6.15 g, 90.27 mmol, 3.00 eq) was added to a solution of methyl 4-hydroxy-2-methyl-benzoate (5.00 g, 30.09 mmol, 1.00 eq) in dimethylformamide (100 ml). The mixture was stirred for 0.5 hours at 15 ° C., then chlorotrimethylsilane (6.80 g, 45.14 mmol, 5.5 mL, 1.50 eq) was added. The resulting mixture was further stirred for 14.5 hours at 15 ° C. The mixture was poured into saturated brine (300 mL) and then extracted with ethyl acetate (300 mLx2). The combined organic layer was washed with 1M hydrochloric acid (300mLx2), brine (300mLx3), dried over sodium sulfate, filtered and concentrated under vacuum, and methyl 4- [tert-butyl (dimethyl) silyl] oxo. -2-Methyl-benzoate (8.00 g, 28.53 mmol, 95% yield) was obtained as a colorless oil which was used in the next step without further purification. LC / MS (ESI) m / z: 281.2 [M + 1] ⁺ .
Step 5: Preparation of methyl 2- (bromomethyl) -4-((tert-butyldimethylsilyl) oxy) benzoate.

N-Bromosuccinimide (2.29 g, 12.84) in a carbon tetrachloride (40 ml) solution of methyl 4- [tert-butyl (dimethyl) silyl] oxy-2-methyl-benzoate (3.00 g, 10.70 mmol, 1.00 eq). mmol (1.20 eq) and 2,2-azobisisobutyronitrile (88 mg, 0.54 mmol, 0.05 eq) were added. The mixture was stirred at 15 ° C. for 0.5 hours, then heated to 80 ° C. and further stirred at 80 ° C. for 2.5 hours. The mixture was poured into water (300 mL) and the organic layer was separated. The aqueous layer was extracted with dichloromethane (200 mLx2). The combined organic layers were washed with saturated brine (300 mLx3), dried over sodium sulfate, filtered and concentrated under vacuum to methyl 2- (bromomethyl) -4- [tert-butyl (dimethyl) silyl]. Oxy-benzoate (4.00 g, 8.39 mmol, 78% yield, 75% purity) was obtained as a bright yellow oil, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 359.0 / 361.0 [M + 1] ⁺ .
Step 6: tert-butyl 5-amino-4- (5-hydroxy-1-oxoisoindoline-2-yl) -5-
Preparation of oxovalerate.

Methyl 2- (bromomethyl) -4- [tert-butyl (dimethyl) silyl] oxy-benzoate (10 g)
, 27.83 mmol, 1 eq) and tert-butyl 4,5-diamino-5-oxo-valerate (5.63 g, 27.83 mmol, 1 eq) in acetonitrile (150 ml) solution with diisopropylethylamine (14.39 g, 111.32 mmol). , 4 equivalents) was added. The mixture was stirred at 80 ° C. for 12 hours. The mixture was quenched by the addition of water (200 mL), extracted with ethyl acetate (40 mLx6), the combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and filtered. Concentrated under reduced pressure. The residue was purified by preparative HPLC and tert-butyl 5-amino-4- [5- [tert-butyl (dimethyl) silyl] oxy-1-oxo-isoindoline-2-yl] -5-oxo- Obtain tert-butyl 5-amino-4- (5-hydroxy-1-oxo-isoindoline-2-yl) -5-yl as a yellow oil with valerate (3 g, 6.69 mmol, 24% yield). Oxo-valerate (4 g, 11.96 mmol, 42% yield) was obtained as a yellow solid.

Step 7: Of tert-butyl 5-amino-4-(5-(2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) -1-oxoisoindoline-2-yl) -5-oxovalerate Preparation.

2- [2- (2-Hydroxyethoxy) ethoxy] ethyl 4-methylbenzenesulfonate (251 mg, 0.82 mmol, 1.2 eq) in N, N-dimethylformamide (4 ml) solution with potassium carbonate (285 mg, 2.06 mmol). , 3 eq), potassium iodide (114 mg, 0.68 mmol, 1 eq) and tert-butyl 5-amino-4- (5-hydroxy-1-oxo-isoindrin-2-yl) -5-oxo-valeric acid Salt (230 mg, 0.68 mmol, 1 eq) was added. The mixture was stirred at 80 ° C. for 1 hour. The solution was quenched with water (20 mL) and extracted with dichloromethane / methanol (10: 1, 20 mLx8). The organic layer was washed with saturated brine (20 mLx1), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative thin layer chromatography (dichloromethane: methanol = 10: 1) and tert-butyl 5-amino-4- [5- [2- [2- (2-hydroxyethoxy) ethoxy] ethoxy] ethoxy. ] -1-oxo-isoindoline-2-yl] -5-oxo-valerate (275 mg, 0.58 mmol, 85% yield) was obtained as a yellow oil. LC / MS (ESI) m / z: 467.4 [M + 1] ⁺ .
Step 8: tert-butyl 5-amino-5-oxo-4-(1-oxo-5-(2-(2-(2- (tosyloxy) ethoxy) ethoxy) ethoxy) isoindoline-2-yl) valeric acid Preparation of salt.

Triethylamine (178 mg, 1.77 mmol, 3 eq) and dimethylaminopyridine (14 mg, 0.11 mmol, 0.2 eq) and tert in a solution of methanesulfonyl chloride (224 mg, 1.18 mmol, 2 eq) in N, N-dimethylformamide (4 ml). -Butyl 5-amino-4- [5- [2- [2- (2-hydroxyethoxy) ethoxy] ethoxy] -1-oxo-isoindrin-2-yl] -5-oxo-valerate (275 mg, 0.58 mmol (1 eq) was added. The mixture was stirred at 20 ° C. for 1 hour. The solution was quenched with water (10 mL) and extracted with dichloromethane / methanol (10: 1, 10 mLx4). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative thin layer chromatography (dichloromethane: methanol = 10: 1) and tert-butyl 5-.
Amino-5-oxo-4- [1-oxo-5- [2- [2- [2- (p-tolylsulfonyloxy) ethoxy] ethoxy] ethoxy] isoindoline-2-yl] valerate (220 mg, 0.35 mmol (60% yield) was obtained as a yellow oil. LC / MS (ESI) m / z: 621.4 [M + 1] ⁺ .
Step 9: tert-butyl 5-amino-4-(5-(2-(2-(4-(((2'-methyl-5-morpholino-5'-(3- (trifluoromethyl) benzamide) benzamide) )-[3,3'-Bipyridine] -6-yl) Oxy) Piperidine-1-yl) ethoxy) ethoxy) ethoxy) -1-oxoisoindoline-2-yl) -5-oxovalerate preparation.

N- [6-methyl-5- [5-morpholino-6- (4-piperidyloxy) -3-pyridyl] -3-pyridyl] -3- (trifluoromethyl) benzamide (204 mg, 0.35 mmol, 1 equivalent, 1 equivalent, N, N-diisopropylethylamine (137 mg, 1.06 mmol, 3 eq) and potassium iodide (58 mg, 0.35 mmol, 1 eq) and tert-butyl 5-amino-5-oxo in an acetonitrile (5 ml) solution of hydrogen chloride). -4- [1-oxo-5- [2- [2- [2- (p-trylsulfonyloxy) ethoxy] ethoxy] ethoxy] isoindrin-2-yl] valerate (220 mg, 0.35 mmol, 1 equivalent) ) Was added. The mixture was stirred at 100 ° C. for 1 hour. The solution was quenched with water (10 mL) and extracted with dichloromethane / methanol (10: 1, 10 mLx3). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative thin layer chromatography (dichloromethane: methanol = 10: 1) and tert-butyl 5-amino-4- [5- [2- [2- [2- [4- [[5]. -[2-Methyl-5-[[3- (Trifluoromethyl) benzoyl] amino] -3-pyridyl] -3-morpholino-2-pyridyl] oxy] -1-piperidyl] ethoxy] ethoxy] ethoxy] -1 -Oxo-isoindoline-2-yl] -5-oxo-valerate (141 mg, 0.13 mmol, 37% yield, 93% purity) was obtained as a yellow oil. LC / MS (ESI) m / z:
991.5 [M + 1] ⁺ .
Step 10: N-(6'-((1-(2-(2-((2- (2,6-dioxopiperidine-3-yl) -1-oxoisoindoline-5-yl)) Preparation of oxy) ethoxy) ethoxy) ethyl) piperidine-4-yl) oxy) -2-methyl-5'-morpholino- [3,3'-bipyridine] -5-yl) -3- (trifluoromethyl) benzamide ..

tert-butyl 5-amino-4- [5- [2- [2- [2- [4-[[5- [2-methyl-5-[[3- (trifluoromethyl))
Benzene] amino] -3-pyridyl] -3-morpholino-2-pyridyl] oxy] -1-piperidyl] ethoxy] ethoxy] ethoxy] -1-oxo-isoindoline-2-yl] -5-oxo-sylate Benzenesulfonic acid (80 mg, 0.42 mmol, 3 eq) was added to a solution of salt (141 mg, 0.14 mmol, 1 eq) in acetonitrile (1 ml). The mixture was stirred at 100 ° C. for 1 hour. The solution was quenched with water (10 mL) and extracted with dichloromethane / methanol (10: 1, 10 mLx3). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative thin layer chromatography (dichloromethane: methanol = 10: 1) and N- [5- [6- [[1- [2- [2- [2- [2- (2,,) 6-Dioxo-3-piperidyl) -1-oxo-isoindoline-5-yl] oxyethoxy] ethoxy] ethyl] -4-piperidyl] oxy] -5-morpholino-3-pyridyl] -6-methyl-3- Pyridyl] -3- (trifluoromethyl) benzamide (54.1 mg, 0.057 mmol, yield 40%, purity 97%) was obtained as a white solid. LC / MS (ESI) m / z: 916.3 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 10.94 (s, 1H), 10.65 (s, 1H), 8.84 (s, 1H), 8.36 --8.23 (m, 2H), 8.08 --7.94 (m, 2H), 7.87 --7.74 (m, 2H), 7.61 (d, J = 8.8 Hz, 1H), 7.24 --7.14 (m, 2H), 7.06 ( d, J = 8.4 Hz, 1H), 5.20 (s, 1H), 5.06 (dd, J = 5.2, 13.2 Hz, 1H), 4.39 --4.17 (m, 4H), 3.84 --3.73 (m, 6H), 3.66 --3.50 (m, 6H), 3.09 (s, 5H), 2.59 (s, 4H), 2.45 --2.36 (m, 7H), 1.99 (s, 3H), 1.75 (s, 2H), 1.82 --1.62 (m) , 1H)
N- (6'-(4-(2-(2-(((2- (2,6-dioxopiperidine-3-yl) -1,3-dioxoisoindoline-5-yl) oxy) ) Ethoxy) ethoxy) ethoxy) phenoxy) -2-methyl-5'-morpholino- [3,3'-bipyridine] -5-yl) -3- (trifluoromethyl) benzamide (Example 468) Synthesis Example Step 1 : N- (2-methyl-5'-morpholino-6'-(4-((tetrahydro-2H-pyran-2-yl) oxy) phenoxy)-[3,3'-bipyridine] -5-yl)- Preparation of 3- (trifluoromethyl) benzamide.

4-Tetrahydropyran-2-yloxyphenol (949 mg, 4.89 mmol, 1.5 eq) in a mixture of 1-methyl-2-pyrrolidinone (15 ml) with tert-butoxide potassium (731 mg, 6.52 mmol, 2 eq) and N. -[5- (6-Fluoro-5-morpholino-3-pyridyl) -6-methyl-3-pyridyl] -3- (trifluoromethyl) benzamide (1.5 g, 3.26 mmol, 1 eq) once at 15 ° C. Added to. The mixture was stirred at 140 ° C. for 2 hours while being irradiated with microwaves. The mixture was washed with water (50 mL). The aqueous layer was extracted with ethyl acetate (30 mLx7). All of the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative high performance liquid chromatography to obtain a brown solid. N- [6-methyl-5- [5-morpholino-6- (4-tetrahydropyran-2-yloxyphenoxy) -3-pyridyl] -3-pyridyl] -3- (trifluoromethyl) benzamide (600 mg, 0.94 mmol (29% yield) was obtained as a brown solid. LC / MS (ESI) m / z: 635.1 [M + 1] ⁺ .
Step 2: Preparation of N- (6'-(4-hydroxyphenoxy) -2-methyl-5'-morpholino- [3,3'-bipyridine] -5-yl) -3- (trifluoromethyl) benzamide.

N- [6-methyl-5- [5-morpholino-6- (4-tetrahydropyran-2-yloxyphenoxy) -3-
Hydrochloric acid / dioxane (4 M, 2 mL, 20 eq) was added to a mixture of dichloromethane (5 ml) of pyridyl] -3-pyridyl] -3- (trifluoromethyl) benzamide (200 mg, 0.31 mmol, 1 eq). The mixture was stirred at 15 ° C. for 30 minutes. The mixture was concentrated under reduced pressure. The residue was used in the next step without further purification. Compound N- [5- [6- (4-Hydroxyphenoxy) -5-morpholino-3-pyridyl] -6-methyl-3-pyridyl] -3- (trifluoromethyl) benzamide (200 mg, crude,
Hydrochloride) was obtained as a brown solid.

Step 3: N- (6'-(4- (2- (2- (2-bromoethoxy) ethoxy) ethoxy) phenoxy) -2-methyl-5'-morpholino- [3,3'-bipyridine] -5 -Preparation of yl) -3- (trifluoromethyl) benzamide.

N- [5- [6- (4-Hydroxyphenoxy) -5-morpholino-3-pyridyl] -6-methyl-3-pyridyl] -3- (trifluoromethyl) benzamide (200 mg, 0.36 mmol, 1 equivalent) To a solution of acetonitrile (5 ml) was added potassium carbonate (151 mg, 1.09 mmol, 3 eq) and 1,2-bis (2-bromoethoxy) ethane (250.64 mg, 908.22 umol, 2.5 eq). The mixture was stirred at 60 ° C. for 2 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by preparative TLC (dichloromethane: methanol = 10: 1). Compound N- [5- [6- [4- [2- [2- (2-bromoethoxy) ethoxy] ethoxy] phenoxy] -5-morpholino-3-pyridyl] -6-methyl-3-pyridyl] -3 -(Trifluoromethyl) benzamide (160 mg, 0.21 mmol, 59% yield) was obtained as a yellow solid. LC / MS (ESI) m / z: 747.0 [M + 1] ⁺ .
Step 4: Preparation of 2- (2,6-dioxopiperidine-3-yl) -5-hydroxyisoindoline-1,3-dione.

Sodium acetate (4.1 g, 49.4 mmol, 3.00 eq) is added to a solution of 3-aminopiperidin-2,6-dione (4.1 g, 24.7 mmol, 1.50 eq, HCl salt) in acetic acid (45 ml), followed by the mixture. The mixture was stirred at 25 ° C. for 1 hour. Then, 4-hydroxyphthalic acid (3.0 g, 16.5 mmol, 1.00 eq) was added to the mixture, heated to 120 ° C., and stirred for another 11 hours. The mixture was concentrated and then poured into water (20 mL) and filtered. The crude product is purified by column chromatography (dichloromethane: methanol = 50: 1-10: 1) to 2- (2,6-dioxo-3-piperidyl) -5-hydroxy-isoindoline-1,3. ---
Zeon (3.9 g, 14.3 mmol, 86% yield) was obtained as a colorless solid. LC / MS (ESI) m / z: 275 [M + 1] ⁺ ; ¹ H-NMR (400MHz, CDCl ₃ ) δ 11.19 --10.94 (m, 2H), 7.75 (d, J = 8.0 Hz, 1H), 7.20 --7.08 (m, 2H), 5.08 (dd, J = 5.2, 12.8 Hz, 1H), 3.34 (br s, 1H), 2.95 --2.81
(m, 1H), 2.64 --2.55 (m, 1H), 2.08 --1.98 (m, 1H).
Step 5: N- (6'-(4-(2-(2-(((2- (2,6-dioxopiperidine-3-yl) -1,3-dioxoisoindoline-5-) Preparation of yl) oxy) ethoxy) ethoxy) ethoxy) phenoxy) -2-methyl-5'-morpholino- [3,3'-bipyridine] -5-yl) -3- (trifluoromethyl) benzamide.

N- [5- [6- [4- [2- [2- [2- (2-bromoethoxy) ethoxy] ethoxy] phenoxy] -5-morpholino-3-pyridyl] -6-methyl-3-pyridyl] -3- Potassium carbonate (44 mg, 0.32 mmol, 3 eq) and 2- (2,6-dioxo-3-piperidyl)-in a dimethylformamide (2 ml) solution of (trifluoromethyl) benzamide (80 mg, 0.11 mmol, 1 eq). 5-Hydroxy-isoindoline-1,3-dione (44 mg, 0.16 mmol, 1.5 eq) was added. The mixture was stirred at 60 ° C. for 2 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by preparative HPLC. Compound N- [5- [6- [4- [2- [2- [2- [2- [2- (2,6-dioxo-3-piperidyl) -1,3-dioxo-isoindoline-5-yl] oxy] Ethoxy] ethoxy] ethoxy] phenoxy] -5-morpholino-3-pyridyl] -6-methyl-3-pyridyl] -3- (trifluoromethyl) benzamide (25.8 mg, 0.02 mmol, yield 25%, purity 97%) ) Was obtained as a gray solid. LC / MS (ESI) m / z: 939.2 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 11.10 (d, J = 1.0 Hz, 1H), 10.73 ―― 10.60 (m, 1H), 8.85 (d, J = 2.4 Hz, 1H), 8.32 (s, 1H), 8.28 (d, J = 7.7 Hz, 1H), 8.05 (d, J = 2.3 Hz, 1H), 7.99 (d, J = 8.0) Hz, 1H), 7.86 --7.77 (m, 2H), 7.71 (d, J = 2.1 Hz, 1H), 7.46 (d, J = 2.2 Hz, 1H), 7.41 --7.33 (m, 2H), 7.13 --7.05 (m, 2H), 7.00 --6.93 (m, 2H), 5.11 (dd, J = 5.6, 12.9 Hz, 1H), 4.32 (dd, J = 3.6, 5.2 Hz, 2H), 4.16 --4.02 (m, 2H) ), 3.84 --3.79 (m, 2H), 3.78 --3.73 (m, 6H), 3.64 (s, 4H), 3.56 (d, J = 8.8 Hz, 1H), 3.48 --3.37 (m, 1H), 3.21 - 3.17 (m, 3H), 2.94 --2.81 (m, 1H), 2.60 (d, J = 2.4 Hz, 1H), 2.44 (s, 3H), 2.08 --1.98 (m,
1H)
(2S, 4R) -1-((S) -2- (2- (4-((1- (4- (3- (2,6-difluoro-3- (((R) -3-fluoropyrrolidine) )-1-Sulfonamide) Benzoyl) -1H-Pyrrolidine [2,3-b] Pyridine-5-yl) Phenyl) Piperidi
N-4-yl) Methyl) Piperazine-1-yl) Acetamide) -3,3-Dimethylbutanoyl) -4-Hide
Illustrative Synthesis Step 1: (1- ) of Roxy-N-((S) -1- (4- (4- (Hydroxymethyl) Thiazole-5-yl) Phenyl) Ethyl) Pyrrolidine-2-Carboxamide (Example 498) Preparation of (4-bromophenyl) piperidine-4-yl) methanol.

A solution of 4-piperidylmethanol (100 g, 868 mmol, 1 eq), 1-bromo-4-iodo-benzene (245 g, 868 mmol, 1 eq), L-proline (40 g, 347 mmol, 0.4 eq) in dimethylsulfoxide (1.8 L). Copper (I) iodide (33 g, 173 mmol, 0.2 eq) and potassium carbonate (240 g, 1.74 mol, 2 eq) were added. The mixture was degassed in vacuo and purged with nitrogen 3 times. The mixture was then heated to 90 ° C. under nitrogen for 12 hours. The reaction mixture was poured into water (1.0 L) and stirred for 1 hour. The mixture was then extracted with ethyl acetate (1000 mLx3). The combined organic layers were washed with brine (1Lx3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1 to 3: 1). [1- (4-Bromophenyl) -4-piperidyl] methanol (120 g, 444 mmol, 51% yield) was obtained as a white solid. 1H-NMR (400MHz, DMSO-d6) δ 7.46 --7.28 (m, 2H), 6.88 --6.75 (m, 2H), 4.49 (t, J = 5.2 Hz, 1H), 3.69 --3.66 (m, 2H), 3.28 (t, J = 6.0 Hz, 2H), 2.66 ―― 2.60 (m, 2H), 1.75 ―― 1.70 (m, 2H), 1.52 ―― 1.51 (m, 1H), 1.24 ―― 1.18 (m, 2H).
Step 2: Preparation of 1- (4-bromophenyl) piperidine-4-carbaldehyde.

Oxalyl chloride (140.94 g, 1.11 mol, 3 eq) in dichloromethane (550 ml) with dimethyl sulfoxide (115.68 g, 1.48 mol, 4 eq) in dichloromethane (550 ml) at -68 ° C for 0.5 hours under nitrogen. It was added by dropping. The mixture is stirred for 30 minutes at -68 ° C, then [1- (4- (4-)
Bromophenyl) -4-piperidyl] A solution of methanol (100 g, 370.14 mmol, 1 eq) in dichloromethane (1000 ml) was added dropwise at -68 ° C. The mixture was stirred for an additional 0.5 hours at -68 ° C. Triethylamine (299.64 g, 2.96 mol, 8 eq) was added dropwise to the reaction mixture at −68 ° C. The resulting mixture was stirred for 2 hours at -68 ° C. The reaction mixture was quenched with 500 mL of ammonium chloride at 25 ° C. and extracted with ethyl acetate (600 mlx3). The combined organic layers were washed with brine (400 mLx3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was pulverized with petroleum ether (300 mL). 1- (4-Bromophenyl) piperidine-4-carbaldehyde (93 g, 346.82 mmol, 93% yield) was obtained as a yellow solid. 1H-NMR (400MHz,
CDCl3) δ 9.72 (s, 1H), 7.54 --7.34 (m, 2.0 H), 6.85 --6.74 (m, 2.0 H), 3.61 --3.56 (m, 2H), 2.91 --2.86 (m, 2H), 2.48- 2.33 (m, 1H), 2.07 --2.04 (m, 2H), 1.82 --1.80 (m, 2H).
Step 3: Preparation of 1- (4-bromophenyl) -4- (dimethoxymethyl) piperidine.

Trimethoxymethane (732.14 g, 6.90 mol, 5 eq) and 4-methylbenzene in a methyl alcohol (1200 ml) solution of 1- (4-bromophenyl) piperidin-4-carbaldehyde (370 g, 1.38 mol, 1 eq). Sulfonic acid; hydrate (52.49 g, 275.97 mmol, 0.2 eq) was added. The mixture was stirred at 25 ° C. for 12 hours. Quench the reaction mixture with 500 mL of sodium bicarbonate at 25 ° C.
Extracted with dichloromethane (500 mLx3). The combined organic layers were washed with brine (300 mLx3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was pulverized with petroleum ether and ethyl acetate (1.5 L petroleum ether: ethyl acetate = 20: 1). 1- (4- (4-
Bromophenyl) -4- (dimethoxymethyl) piperidine (366 g, 1.16 mol, 84% yield) was obtained as a red solid. The mother liquor (45 g) was further purified by flash chromatography. 1H-NMR (400MHz, CDCl3) δ 7.52 --7.33 (m, 2 H), 6.83 --6.70 (m, 2 H), 4.10 (dd, J = 2.4 Hz, J = 7.2 Hz, 1H), 3.69 --3.66 ( m, 2H), 3.40 (s, 6H), 2.71 --2.65 (m, 2H),
1.88 --1.87 (m, 2H), 1.85 --1.84 (m, 1H), 1.48 --1.44 (m, 2H).
Step 4: Preparation of 4- (dimethoxymethyl) -1- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperidine.

1- (4-bromophenyl) -4- (dimethoxymethyl) piperidine (1 g, 3.18 mmol, 1 equivalent), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl) -1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolan (969 mg, 3.82 mmol, 1.2 eq), ditert-butyl (cyclopentyl) phosphan; dichloropalladium; iron (207 mg, 0.31 mmol, A solution of dioxane (10 eq) and potassium acetate (624 mg, 6.37 mmol, 2 eq) was degassed and then heated to 100 ° C. under nitrogen for 12 hours. The reaction mixture was filtered, diluted with ethyl acetate (50 mL), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50/1 to 10/1). 4- (Dimethoxymethyl) -1- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperidine (500 mg, 1.38 mmol, 43% yield) Was obtained as a white solid. LC / MS (ESI) m / z: 362.2 [M + 1] +; 1H-NMR (400MHz, CDCl3) δ 7.71 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H) , 4.08 (d, J = 6.9 Hz, 1H), 3.85 (d, J = 12.5 Hz, 2H), 3.39 (s, 6H), 2.75 (dt, J = 2.2, 12.5 Hz, 2H), 1.91 --1.75 ( m, 3H), 1.49 --1.38 (m, 2H), 1.35 (s, 12H).
Step 5: (R) -N- (3- (5- (4- (4- (dimethoxymethyl) piperidine-1-yl) phenyl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H- Preparation of pyrrolin [2,3-b] pyridin-3-carbonyl) -2,4-difluorophenyl) -3-fluoro-N-((2- (trimethylsilyl) ethoxy) methyl) pyrrolidine-1-sulfonamide.

4- (Dimethoxymethyl) -1- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperidine (800 mg, 2.21 mmol, 1 equivalent), ( 3R) -N- [3- [5-bromo-1- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl] -3-fluoro- N- (2-trimethylsilylethoxymethyl) pyrrolidine-1-sulfonamide
(1.69 g, 2.21 mmol, 1 eq), cesium fluoride (1.35 g, 8.86 mmol, 4 eq) and 4-ditert-butylphosphanyl-N, N-dimethyl-aniline; dichloropalladium (156 mg, 0.22 mmol, 0.1) A solution of (equivalent) dioxane (15 ml) and water (1.5 ml) was degassed and heated to 85 ° C. under nitrogen for 12 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mLx3). The combined organic layers were washed with brine (50 mLx3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50/1 to 5/1). (3R) -N- [3- [5- [4- [4- (dimethoxymethyl) -1-piperidyl] phenyl] -1- (2-trimethylsilylethoxymethyl) pyrolo [2,3-b] pyridine-3 -Carbonyl] -2,4-difluoro-phenyl] -3-fluoro-N- (2-trimethylsilylethoxymethyl) pyrrolidine-1-sulfonamide (1.5 g, 1.63 mmol, 73% yield) as a yellow solid rice field. LC / MS (ESI) m / z: 918.1 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 8.72 (d, J = 2.0 Hz,
1H), 8.55 (s, 1H), 8.34 (s, 1H), 7.77 (dt, J = 6.0, 8.8 Hz, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.43 --7.36 (m, 1H) ), 7.06 (d, J = 8.8 Hz, 2H), 5.68 (s, 2H), 5.43 --5.21 (m, 1H), 5.01- 4.89 (m, 2H), 4.12 --4.07 (m, 1H), 3.81 ( d, J = 12.4 Hz, 2H), 3.68 --3.61 (m, 2H), 3.57 (t, J = 8.0 Hz, 2H), 3.50 (s, 1H), 3.45 --3.38 (m, 2H), 3.30 --3.25 (m, 7H), 2.20 --2.00 (m, 2H), 1.78 --1.66 (m, 3H), 1.42 --1.27 (m, 2H), 1.21 --1.13 (m, 1H), 0.91 --0.77 (m, 4H) , -0.02 (s, 9H), -0.09 --- 0.14 (m, 9H).
Step 6: (R) -N- (3- (5- (4- (4- (dimethoxymethyl) piperidine-1-yl) phenyl) -1H-pyrrolo [2,3-b] pyridin-3-carbonyl) -2,4-difluorophenyl) -3-fluoropyrrolidine-1-
Preparation of sulfonamides.

(3S) -N- [3- [5- [4- [4- (dimethoxymethyl) -1-piperidyl] phenyl] -1- (2-trimethylsilylethoxymethyl) pyrolo [2,3-b] pyridine-3 -Carbonyl] -2,4-difluoro-phenyl] -3-fluoro-N- (2-trimethylsilylethoxymethyl) pyrrolidine-1-sulfonamide (1.4 g, 1.52 mmol, 1 equivalent) in a methanol (10 ml) solution. Hydrochloride (4M dioxane solution, 20 ml) was added. The reaction mixture was stirred at 50 ° C. for 24 hours. The reaction mixture was concentrated under reduced pressure. (3R) -N- [3- [5- [4- [4- (dimethoxymethyl) -1-piperidyl] phenyl] -1H-pyrrolo [2,3-b] pyridine-3-
Carbonyl] -2,4-difluoro-phenyl] -3-fluoro-pyrrolidin-1-sulfonamide (900 mg, 1.37 mmol, 89% yield) was obtained as a yellow solid. LC / MS (ESI) m / z: 658.1 [M + 1] ⁺ .
Step 7: (R) -N- (2,4-difluoro-3- (5- (4- (4-formylpiperidine-1-yl) phenyl) -1H-pyrrolo [2,3-b] pyridine-3 -Preparation of carbonyl) phenyl) -3-fluoropyrrolidine-1-sulfonamide.

(3R) -N- [3- [5- [4- [4- (dimethoxymethyl) -1-piperidyl] phenyl] -1H-pyrrolidine [2,3-b] pyridin-3-carbonyl] -2,4 -Difluoro-Phenyl] -3-fluoro-pyrrolidine-1-sulfonamide (900 mg, 1.37 mmol, 1 eq) was added to a solution of sulfate (3 M, 18 mL, 40 eq) in tetrahydrofuran (18 ml). The reaction mixture was stirred at 50 ° C. for 0.5 hours. The pH was adjusted to 8 with sodium hydroxide (1 M aqueous solution) and then extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (100 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was pulverized with ethyl acetate (15 mL). (3R) -N- [2,4-difluoro-3- [5- [4- (4-formyl-1-piperidyl) phenyl] -1H-pyrrolidine [2,3-b] pyridine-3-carbonyl] phenyl ] -3-Fluoro-pyrrolidin-1-sulfonamide (710 mg, 1.16 mmol, 84% yield) was obtained as a yellow solid. LC / MS (ESI) m / z: 630.1 [M + 19] +; 1H-NMR (400MHz, DMSO-d6) δ 12.91 (s, 1H), 9.87 (s, 1H), 9.65 (s, 1H), 8.76 --8.64 (m, 2H), 8.23 --8.01 (m, 1H), 7.72 --7.51 (m, 3H), 7.35 --7.22 (m, 1H), 7.15 --6.97 (m, 2H), 5.48 --5.13 (m) , 1H), 3.70 (d, J = 12.8 Hz, 2H), 3.60 (t, J = 6.0 Hz, 1H), 3.48 (s, 1H), 3.36 --3.24 (m, 2H), 2.98 --2.83 (m, 2H), 2.09 (dd, J = 7.6, 12.8 Hz, 1H), 1.99 --1.97 (m, 3H), 1.75 (t, J = 6.4 Hz, 1H), 1.67 --1.51 (m, 2H), 0.91 --0.75 (m, 2H).
Step 8: Preparation of tert-butyl (S)-(1- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) ethyl) carbamate.

tert-butyl N-[(1S) -1- (4-bromophenyl) ethyl] carbamate (5 g, 16.66 mmol, 1 equivalent) and 4,4,5,5-tetramethyl-2- (4,4) , 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolan (5.08 g, 19.99 mmol, 1.2 eq) in a dioxane (100 ml) solution, [1,1 '-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) (974.98 mg)
, 1.33 mmol, 0.08 eq) and potassium acetate (3.27 g, 33.31 mmol, 2 eq). The mixture was stirred at 90 ° C. for 2 hours. The reaction mixture was concentrated to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate = 1: 0 to 10: 1). Compound tert-butyl N-[(1S) -1- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] ethyl] carbamate (8.2 g) , 16.44 mmol, yield 98.7%, purity 69.6%) was obtained as a yellow oil. LC / MS (ESI) m / z: 370.26 [M + 23] ⁺ .
Step 9: Preparation of ethyl (S) -5- (4- (1-((tert-butoxycarbonyl) amino) ethyl) phenyl) thiazole-4-carboxylate.

Ethyl 5-bromothiazole-4-carboxylate (3.49 g, 14.77 mmol, 0.9 eq), tert-butyl N-[(1S) -1- [4- (4,4,5,5-tetramethyl-1) , 3,2-Dioxaborolan-2-yl) phenyl] ethyl] carbamate (5.70 g, 16.41 mmol, 1 eq), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (120 mg) , 0.16 mmol, 0.01 eq), potassium carbonate (4.54 g, 32.83 mmol, 2 eq) dioxane (130 ml) and water (22 ml) degassed, purged with nitrogen three times, 10 The mixture was stirred at 80 ° C. for a period of time in a nitrogen atmosphere. The reaction mixture was concentrated, quenched with water (50 ml) and extracted twice with ethyl acetate (60 mL). The combined organic layer was washed twice with a saturated aqueous solution of sodium chloride (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate = 1: 0 to 1: 1). Compound Ethyl 5- [4-[(1S) -1- (tert-butoxycarbonylamino) ethyl] phenyl] thiazole-4-carboxylate (5.07 g, 13.48 mmol, yield 82.1%) was obtained as a yellow solid. rice field. LC / MS (ESI) m / z: 377.1 [M + 1] +; 1H-NMR (400MHz, CDCl3) δ 8.76 (s, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 4.85 (s, 2H), 4.35-- 4.29 (m, 2H), 1.44 (s, 9H), 1.28 (t, J = 7.2 Hz, 3H), 1.24 (s, 3H).
Step 10: Preparation of tert-butyl (S)-(1- (4- (4- (hydroxymethyl) thiazole-5-yl) phenyl) ethyl) carbamate.

Ethyl 5- [4-[(1S) -1- (tert-butoxycarbonylamino) ethyl] phenyl] thiazole-4-carboxylate (900 mg, 2.39 mmol, 1 equivalent) and calcium chloride (796 mg, 7.17 mmol, 3) Sodium borohydride (181 mg) in a mixed solution of water (40 ml) and tetrahydrofuran (20 ml) (equivalent amount)
, 4.78 mmol, 2 eq) was added under nitrogen at 0 ° C. The mixture was heated to 5 ° C. and stirred for 2 hours. Hydrochloric acid (5M, 4.50 mL) and acetone (4.95 mL) were then added at 0 ° C. and the reaction mixture was stirred at 5 ° C. for an additional 0.5 hour. The pH was adjusted to 5 with 5M sodium hydroxide. The aqueous layer was extracted with ethyl acetate (20 mLx4). The combined organic layers were washed with brine (20 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by half-reverse phase HPLC. Compound tert-butyl N-[(1S) -1- [4- [4- (hydroxymethyl) thiazole-5-yl] phenyl] ethyl] carbamate (400 mg, 1.20 mmol, yield 50.0%) as a white solid I got it as a thing. LC / MS (ESI) m / z: 335.2 [M + 1] ⁺ .
Step 11: Preparation of (S)-(5- (4- (1-aminoethyl) phenyl) thiazole-4-yl) methanol.

tert-butyl N-[(1S) -1- [4- [4- (hydroxymethyl) thiazole-5-yl] phenyl] ethyl] carbamate (0.4 g, 1.20 mmol, 1 eq) dichloromethane (1.5 ml) ) Hydrochloric acid / dichloromethane (4M, 10 ml) was added to the mixture at 15 ° C. The mixture was stirred at 15 ° C. for 2 hours. The mixture was concentrated at 45 ° C. under reduced pressure. Compound [5- [4- [(1S) -1-aminoethyl] phenyl] thiazole-4-yl] methanol (380 mg, crude, hydrochloride) was obtained as a white solid.

Step 12: tert-butyl (2S, 4R) -4-hydroxy-2-(((S) -1- (4- (4- (hydroxymethyl) thiazole-5-yl) phenyl) ethyl) carbamoyl) pyrrolidine- Preparation of 1-carboxylate.

[5- [4- [(1S) -1-aminoethyl] phenyl] thiazole-4-yl] methanol (328 mg, 1.21 mmol, 1.00 eq, hydrochloride) and (2S, 4R) -1-tert-butoxycarbonyl 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride in a mixture of N, N-dimethylformamide (15 ml) of -4-hydroxy-pyrrolidin-2-carboxylic acid (280 mg, 1.21 mmol, 1 eq). (348mg, 1.82 mmol
, 1.5 eq), 1-hydroxybenzotriazole (245 mg, 1.82 mmol, 1.5 eq) and N, N-diisopropylethylamine (782 mg, 6.05 mmol, 1.05 mL, 5 eq) were added all at once under nitrogen at 15 ° C. The mixture was stirred at 15 ° C. for 16 hours. The mixture was concentrated at 45 ° C. under reduced pressure. The residue was purified by half-taken reverse phase HPLC. Compound tert-butyl (2S, 4R) -4-hydroxy-2-[[(1S) -1- [4- [4- (hydroxymethyl) thiazole-5-yl] phenyl] ethyl] carbamoyl] pyrrolidine-1- Carboxylate (370 mg, 0.83 mmol, 68% yield) was obtained as a white solid. LC / MS (ESI) m / z: 448.2 [M + 1] ⁺ .
Step 13: Preparation of (2S, 4R) -4-hydroxy-N-((S) -1- (4- (4- (hydroxymethyl) thiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide.

tert-butyl (2S, 4R) -4-hydroxy-2-[[(1S) -1- [4- [4- (hydroxymethyl) thiazole-5-yl] phenyl] ethyl] carbamoyl] pyrrolidine-1-carboxylic acid Hydroxate (0.39 g, 0.87 mmol)
Hydrochloric acid / dioxane (4M, 10 ml) was added to a solution of dichloromethane (1 ml) of (1 eq), and the mixture was stirred for 1 hour at 15 ° C. The mixture was concentrated at 45 ° C. under reduced pressure. (2S, 4R) -4-Hydroxy-N-[(1S) -1- [4- [4- (Hydroxymethyl) Thiazole-5-yl] Phenyl] Ethyl] Pyrrolidine-2-Carboxamide
(360 mg, crude, hydrochloride) was obtained as a white solid.

Step 14: tert-butyl ((S) -1-((2S, 4R) -4-hydroxy-2-(((S) -1- (4- (4- (hydroxymethyl) thiazole-5-yl)) Preparation of phenyl) ethyl) carbamoyl) pyrrolidine-1-yl) -3,3-dimethyl-1-oxobutan-2-yl) carbamate.

(2S, 4R) -4-hydroxy-N-[(1S) -1- [4- [4- (hydroxymethyl) thiazole-5-yl] phenyl] ethyl] pyrrolidine-2-carboxamide (706 mg, 1.84 mmol, 1 equivalent, hydrochloride), (2S) -2- (tert-butoxycarbonylamino) -3,3-dimethyl-butanoic acid (425 mg, 1.84 mmol, 1 equivalent),
Hydroxybenzotriazole (298 mg, 2.21 mmol, 1.2 eq), diisopropylethylamine (1.43 g, 11.04 mmol, 6 eq), carbodiimide hydrochloride (705 mg, 3.68 mmol, 2 eq) in N, N-dimethylformamide (40 ml) solution. The mixture was stirred at 20 ° C. for 12 hours. The reaction solution was washed with water (100 mL). The aqueous layer was extracted with ethyl acetate (40 mLx8). All of the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue (dichloromethane: methanol = 10: 1) was purified by column chromatography on silica gel (ethyl acetate: methanol = 1: 0) to obtain a white solid. Tert-butyl N-[(1S) -1-[(2S, 4R) -4-hydroxy-2-[[(1S) -1- [4- [4- (hydroxymethyl) thiazole-5-yl] phenyl] ] Ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2,2-dimethyl-propyl] carbamic acid salt (400 mg, 0.71 mmol, yield 38%, purity 99%) was obtained as a white solid. LC / MS (ESI) m / z: 561.3 [M + 1] ⁺ .
Step 15: (2S, 4R) -1-((S) -2-amino-3,3-dimethylbutanoyl) -4-hydroxy-N-((S) -1- (4- (4- (hydroxy) Preparation of methyl) thiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide.

tert-butyl N-[(1S) -1-[(2S, 4R) -4-hydroxy-2-[[(1S) -1- [4- [4- (hydroxymethyl) thiazole-5-yl] phenyl] ] Ethyl] Carbamoyl] Pyrrolidine-1-carbonyl] -2,2-Dimethyl-propyl] Carbamate (400 mg, 0.71 mmol, 1 eq) in dichloromethane (20 ml) solution with hydrochloric acid / dioxane (4M, 20 mL, 113.10 eq) ) Was added. The mixture was stirred at 20 ° C. for 20 minutes. The mixture was concentrated to give a white solid. The white solid was used in the next step without further purification. (2S, 4R) -1-[(2S) -2-amino-3,3-dimethyl-butanoyl] -4-hydroxy-N-[(1S) -1- [4- [4- (hydroxymethyl) thiazole) -5-Il] Phenyl] Ethyl] Pyrrolidine-2-carboxamide (351 mg, crude, hydrochloride) was obtained as a white solid. LC / MS (ESI) m / z: 461.2 [M + 1] ⁺ .
Step 16: tert-butyl 4-(2-(((S) -1-((2S, 4R) -4-hydroxy-2-(((S) -1- (4- (4- (hydroxymethyl)) Preparation of thiazole-5-yl) phenyl) ethyl) carbamoyl) pyrrolidine-1-yl) -3,3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) piperazine-1-carboxylate.

(2S, 4R) -1-[(2S) -2-amino-3,3-dimethyl-butanoyl] -4-hydroxy-N-[(1S) -1- [4- [4- (hydroxymethyl) thiazole) -5-yl] phenyl] ethyl] pyrrolidine-2-carboxamide (351 mg, 0.70 mmol, 1 eq, hydrochloride), 2- (4-tert-butoxycarbonylpiperazin-1-yl) acetate (172 mg, 0.70 mmol, 1) N, N-dimethylformamide (20 ml), hydroxybenzotriazole (114 mg, 0.85 mmol, 1.2 equivalents), diisopropylethylamine (548 mg, 4.24 mmol, 6 equivalents), carbodiimide hydrochloride (271 mg, 1.41 mmol, 2 equivalents). The solution was stirred for 12 hours at 20 ° C. The reaction solution was washed with water (100 mL). The aqueous layer was extracted with ethyl acetate (40 mLx8). All of the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue (dioxide: methanol = 10: 1) was purified by column chromatography on silica gel (ethyl acetate: methanol = 1: 0) to purify tert-butyl 4- [2-[[(1S) -1- [). (2S, 4R) -4-Hydroxy-2-[[(1S) -1- [4- [4- (Hydroxymethyl) thiazole-5-yl] phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2 , 2-Dimethyl-propyl] amino] -2-oxo-ethyl] piperazin-1-carboxylate (340 mg, 0.48 mmol, 68% yield, 97% purity) was obtained as a white solid. LC / MS (ESI) m / z: 687.4 [M + 1] ⁺ .
Step 17: (2S, 4R) -1-((S) -3,3-dimethyl-2-(2- (piperazine-1-yl) acetamide) butanoyl) -4-hydroxy-N-((S)- Preparation of 1- (4- (4- (hydroxymethyl) thiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide.

tert-butyl 4- [2-[[(1S) -1-[(2S, 4R) -4-hydroxy-2-[[(1S) -1- [4- [4- (hydroxymethyl) thiazole-5) -Il] phenyl] ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2,2-dimethyl-propyl] amino] -2-oxo-ethyl] piperazine-1-carboxylate (340 mg, 0.48 mmol, 1 equivalent) Hydroxyl / dioxane (4M, 20 mL, 165.66 equivalent) was added to a solution of dichloromethane (10 ml). The mixture was stirred at 20 ° C. for 20 minutes. The mixture was concentrated to give a white solid. The white solid was used in the next step without further purification. (2S, 4R) -1-[(2S) -3,3-dimethyl-2-[(2-piperazine-1-ylacetyl) amino] butanoyl] -4-hydroxy-N-[(1S) -1- [ 4- [4- (Hydroxymethyl) thiazole-5-yl] phenyl] ethyl] pyrrolidine-2-carboxamide (300 mg, crude, hydrochloride) was obtained as a white solid. LC / MS (ESI) m / z: 587.4 [M + 1] ⁺ .
Step 18: (2S, 4R) -1-((S) -2- (2-(4-((1- (4- (3- (2,6-difluoro-3- (((R) -3) -3) -Fluoropyrolidin) -1-sulfonamide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperidine-4-yl) Methyl) Piperazin-1-yl) Acetamide) -3, Preparation of 3-dimethylbutanoyl) -4-hydroxy-N-((S) -1-(4-(4- (hydroxymethyl) thiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide.

(2S, 4R) -1-[(2S) -3,3-dimethyl-2-[(2-piperazine-1-ylacetyl) amino] butanoyl] -4-hydroxy-N-[(1S) -1- [ Triethylamine (195 mg, 1.93 mmol) in a dichloroethane (8 ml) solution of 4- [4- (hydroxymethyl) thiazole-5-yl] phenyl] ethyl] pyrrolidine-2-carboxamide (200 mg, 0.32 mmol, 1 eq, hydrochloride). , 6 equivalents) was added. The mixture was stirred for 20 minutes at 20 ° C. Then (3R) -N- [2,4-difluoro-3- [5- [4- (4-formyl-1-piperidyl) phenyl] -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] Phenyl] -3-fluoro-pyrrolidin-1-sulfonamide (196 mg, 0.32 mmol, 1 eq) was added to the mixture. The mixture was stirred at 20 ° C. for 20 minutes. Sodium triacetoxyborohydride (204 mg, 0.96 mmol, 3 eq) was then added to the mixture. The mixture was stirred at 20 ° C. for 3 hours. The reaction solution was washed with water (20 mL). The aqueous layer was extracted with ethyl acetate (20 mLx6). All of the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography to obtain a yellow solid. (2S, 4R) -1-[(2S) -2-[[2- [4-[[1- [4- [3- [2,6-difluoro-3- [[(3R) -3-fluoro Pyrrolidine-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl] -4-piperidyl] methyl] piperazine-1-yl] acetyl] amino] -3, 3-Dimethyl-butanoyl] -4-hydroxy-N-[(1S) -1- [4- [4- (hydroxymethyl) thiazole-5-yl] phenyl] ethyl] pyrrolidine-2-carboxamide (148 mg, 0.12 mmol) , Yield 37%, Purity 95%) was obtained as a yellow solid. LC / MS (ESI) m / z: 1182.4 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 12.94 (s, 1H), 9.85 (s, 1H), 9.03 (d, J = 2.8) Hz, 1H), 8.66 (d, J = 2.0 Hz, 1H), 8.56 (s, 1H), 8.41 (d, J = 8.0 Hz, 1H), 8.09 (s, 1H), 7.70 --7.58 (m, 3H) ), 7.58 --7.51 (m, 2H), 7.43 --7.32 (m, 2H), 7.27 (m, 1H), 7.16 (d, J = 8.0 Hz, 2H), 5.43 --5.19 (m, 2H), 5.01 - 4.83 (m, 1H), 4.61 --4.48 (m, 10H), 4.47 --4.40 (m, 4H), 4.33 --4.02 (m, 1H), 3.82 (br d, J = 11.6 Hz, 2H), 3.69 --3.46 (m, 5H), 3.06 --2.79 (m, 6H), 2.24 --1.58 (m, 8H), 1.52 --1.29 (m, 5H), 1.04 --0.88 (m, 9H).
(2S, 4R) -1-((R) -2-(3-(4-((1- (5- (3- (2,6-difluoro-3-(((R) -3-fluoropyrolidin) ) -1-sulfonamide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Pyrimidine-2-yl) Piperidine-4-yl) Methyl) Piperazin-1-yl) Isoxazole-5- Il) -3-methylbutanoyl) -4-hydroxy-N-((S) -1-(4-(4-methylthiazol-5-yl) phenyl) ethyl) pyrridin-2-carboxamide (eg 403) Exemplary Synthetic Step 1: Preparation of Benzyl 4- (dimethoxymethyl) piperidine-1-carboxylate.

P-toluenesulfonic acid (961 mg, 5.05 mmol, 0.05 equivalent) and trimethoxymethane (53.64 g, 53.64 g,) in a solution of benzyl 4-formylpiperidin-1-carboxylate (25 g, 101.10 mmol, 1 eq) in methanol (230 ml). 505.48 mmol, 55 mL, 5 eq) was added. The mixture was stirred at 25 ° C. for 12 hours. Saturated aqueous sodium bicarbonate solution (50 mL) was poured into the mixture until pH = 8. The aqueous layer was extracted with ethyl acetate (100 mLx3). The combined organic layers were washed with brine (100 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 30: 1-10: 1). The compound benzyl 4- (dimethoxymethyl) piperidine-1-carboxylate (29 g, 98.86 mmol, 97% yield) was obtained as a colorless oil. LC / MS (ESI) m / z: 316 [M + 23] ⁺ .
Step 2: Preparation of 4- (dimethoxymethyl) piperidine.

Palladium carbon (2 g, 10% purity) was added to a solution of benzyl 4- (dimethoxymethyl) piperidine-1-carboxylate (29 g, 98.86 mmol, 1 equivalent) in methanol (200 ml) under a nitrogen atmosphere. The suspension was degassed and purged with hydrogen three times. The mixture was stirred at 25 ° C. for 12 hours under hydrogen (50Psi). The reaction mixture was filtered and the filter was concentrated. The crude product was used in the next step without further purification. Compound 4- (dimethoxymethyl) piperidine (14.9 g, 93.58 mmol, yield 94%) was obtained as a bright yellow oil. LC / MS (ESI) m / z: 160.2 [M + 1] +; 1H-NMR (400)
MHz, CDCl3) δ 4.03 (d, J = 7.2 Hz, 1H), 3.34 (s, 6H), 3.28 (s, 1H), 3.17 --3.30 (m, 2H), 2.60 (dt, J = 2.4, 12.4 Hz) , 2H), 1.79 ―― 1.67 (m, 3H), 1.33 ―― 1.20 (m, 2H).
Step 3: Preparation of 5-bromo-2- (4- (dimethoxymethyl) piperidine-1-yl) pyrimidine.

Potassium carbonate (1.74 g) in a solution of 5-bromo-2-chloro-pyrimidine (1.21 g, 6.28 mmol, 1 eq) and 4- (dimethoxymethyl) piperidine (1.0 g, 6.28 mmol, 1 eq) in acetonitrile (20 ml). , 12.56 mmol, 2 eq). The mixture was stirred at 70 ° C. for 12 hours. The reaction mixture was extracted with ethyl acetate (40 mLx2) and washed with saturated aqueous brine solution (25 mLx2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10: 1 to 2: 1). Compound 5-bromo-2- [4- (dimethoxymethyl) -1-piperidyl] pyrimidine (1.46 g, 4.62 mmol, yield 73%) was obtained as a white solid. 1H-NMR (400MHz, CDCl3) δ 8.27 (s, 2H), 4.77-4.67 (m, 2H), 4.05 (d, J = 7.2 Hz, 1H), 3.37 (s, 6H), 2.83 (dt, J = 2.8, 13.2 Hz, 2H), 1.95 --1.79 (m, 3H), 1.33 --1.22 (m, 2H).
Step 4: (R) -N- (3- (5- (2- (4- (dimethoxymethyl) piperidin-1-yl) pyrimidine-5-yl) -1-((2- (trimethylsilyl) ethoxy) methyl) ) -1H-Pyrrolo [2,3-b] Pyridine-3-carbonyl) -2,4-difluorophenyl) -3-Fluoro-N-((2- (trimethylsilyl) ethoxy) methyl) pyrrolidine-1-sulfonamide Preparation.

5-bromo-2- [4- (dimethoxymethyl) -1-piperidyl] pyrimidin (327 mg, 1.04 mmol, 1.2 equivalents), (3R) -N- [2,4-difluoro-3- [5- (4,,) 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) -1- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b] Pyridine-3-carbonyl] phenyl] -3- Fluoro-N- (2-trimethylsilylethoxymethyl) pyrrolidine-1-sulfonamide (700 mg, 0.86 mmol, 1 equivalent), cesium fluoride (524 mg, 3.45 mmol, 0.1 mL, 4 equivalents) and 4-ditert-butylphosphanyl -N, N-Dimethyl-aniline; A mixture of dichloropalladium (61 mg, 0.09 mmol, 0.1 equivalent) of dioxane (5 ml) and water (1 ml) was degassed and purged with nitrogen three times. The mixture was then stirred under a nitrogen atmosphere for 12 hours at 90 ° C. The reaction mixture was extracted with ethyl acetate (30 mLx2) and washed with saturated aqueous brine solution (30 mLx2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC. Compound (3R) -N- [3- [5- [2- [4- (dimethoxymethyl) -1-piperidyl] pyrimidin-5-yl] -1- (2-trimethylsilylethoxymethyl) pyrolo [2,3-] b] Pyridine-3-carbonyl] -2,4-difluoro-phenyl] -3-fluoro-N- (2-trimethylsilylethoxymethyl) pyrrolidine-1-sulfonamide (445 mg, 0.45 mmol, yield 52%, purity 97) %, Gate) was obtained as a brown solid. LC / MS (ESI) m / z: 920.5 [M + 1] ⁺ .
Step 5: (R) -N- (3- (5- (2- (4- (dimethoxymethyl) piperidin-1-yl) pyrimidine-5-yl) -1H-pyrrolo [2,3-b] pyridine- Preparation of 3-carbonyl) -2,4-difluorophenyl) -3-fluoropyrrolidine-1-sulfonamide.

(3R) -N- [3- [5- [2- [4- (dimethoxymethyl) -1-piperidyl] pyrimidin-5-yl] -1- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b ] Pyridine-3-carbonyl] -2,4-difluoro-phenyl] -3-fluoro-N- (2-trimethylsilylethoxymethyl) pyrrolidine-1-sulfonamide (680 mg, 0.70 mmol, 1 equivalent, formate) methanol Hydrochloride (4M dioxane solution, 8 ml) was added to the (3 ml) solution. The mixture was stirred at 50 ° C. for 24 hours. The reaction mixture was concentrated under vacuum. Compound (3R) -N- [3- [5- [2- [4- (dimethoxymethyl) -1-piperidyl] pyrimidin-5-yl] -1H-pyrrolo [2,3-b] pyridine-3-carbonyl ] -2,4-Difluoro-Phenyl] -3-Fluoro-pyrrolidin-1-sulfonamide (560 mg, crude) was obtained as a yellow solid which was used directly in the next step without further purification. LC / MS (ESI) m / z: 684.4 [M + 23] ⁺ .
Step 6: (R) -N- (2,4-difluoro-3- (5- (2- (4-formylpiperidine-1-yl) pyrimidin-5-yl) -1H-pyrrolo [2,3-b ] Pyridine-3-carbonyl) phenyl) -3-fluoropyrrolidin-1-sulfonamide preparation.

(3R) -N- [3- [5- [2- [4- (dimethoxymethyl) -1-piperidyl] pyrimidine-5-yl] -1H-pyrrolo [2,3-b] pyridin-3-carbonyl] To a solution of -2,4-difluoro-phenyl] -3-fluoro-pyrrolidin-1-sulfonamide (560 mg, 0.85 mmol, 1 eq) in tetrahydrofuran (10 ml) was added sulfuric acid (2M, 15 mL, 35.34 eq). The mixture was stirred at 70 ° C. for 4 hours. The reaction mixture was basicized to pH 7-8 with saturated sodium bicarbonate. The reaction mixture was then extracted with ethyl acetate (30 mLx2) and washed with saturated brine (25 mLx2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by half-reverse phase HPLC. Compound (3R) -N- [2,4-difluoro-3- [5- [2- (4-formyl-1-piperidyl) pyrimidine
-5-yl] -1H-pyrrolo [2,3-b] pyridin-3-carbonyl] phenyl] -3-fluoro-pyrrolidin-1-sulfonamide (340 mg, 0.55 mmol, 65% yield) as a yellow solid Got as. LC / MS (ESI) m / z: 614.3 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 12.95 (s, 1H), 9.65 (s, 1H), 8.75 (s, 2H), 8.65 (s, 1H), 8.54 (s, 1H), 8.09 (s, 1H), 7.67 --7.53 (m, 1H), 7.23 (t, J = 8.8 Hz, 1H), 5.40 --5.18 (m, 1H) , 4.52 (d, J = 13.2 Hz, 2H), 3.46 (s, 1H), 3.38 (s, 3H), 3.27 --- 3.20 (m, 3H), 2.75 --- 2.60 (m, 1H), 2.08 (d, J) = 13.2 Hz, 2H), 2.00 --1.88 (m, 2H), 1.58 --1.41 (m, 2H).
Step 7: Preparation of methyl 3- (benzyloxy) isoxazole-5-carboxylate.

Potassium carbonate (13.91 g, 100.62 mmol, 2.00 eq) was added to a solution of methyl 3-hydroxyisoxazole-5-carboxylate (7.20 g, 50.31 mmol, 1.00 eq) in acetone (150 mL). The mixture was heated to 80 ° C. for 1 hour and then (bromomethyl) benzene (10.33 g, 60.37 mmol, 1.20 eq) was added. The resulting mixture was stirred for another 3 hours at 80 ° C. The solid was filtered and the filtrate was concentrated under vacuum. The residue was further purified by silica gel column chromatography (petroleum ether; ethyl acetate = 15: 1-10: 1) to 3-benzyloxyisoxazole-5-.
Methyl carboxylate (9.50 g, 40.73 mmol, 81% yield) was obtained as a colorless oil. The oil was allowed to stand at 15 ° C. for 15 hours and then coagulated. LC / MS (ESI) m / z: 256.0 [M + 23] +; 1H-NMR (400MHz, CDCl3) δ 7.49 --7.41 (m, 5H), 6.60 (s, 1H), 5.34 (s, 2H), 3.97 (s, 3H).
Step 8: Preparation of (3- (benzyloxy) isoxazole-5-yl) methanol.

Sodium borohydride (756 mg, 19.98 mmol, 2.00 eq) in a solution of methyl 3-benzyloxyisoxazole-5-carboxylate (2.33 g, 9.99 mmol, 1.00 eq) in methanol (50 mL) in several batches. Added. The resulting mixture was stirred for 3 hours at 15 ° C. The mixture was poured into hydrochloric acid (0.2M, 200mL) and then extracted with ethyl acetate (150mLx2). The combined organic layers were washed with saturated brine (200 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo as a colorless oil (3-benzyloxyisoxazole-5-. Il) Methanol (1.85 g, 9.02 mmol, 90% yield) was obtained. LC / MS (ESI) m / z: 206.1 [M + 1] ⁺ .
Step 9: Preparation of 2- (3- (benzyloxy) isoxazole-5-yl) acetonitrile.

Cyan bromide (334 mg, 3.15 mmol, 1.05 eq) and triphenylphosphine (787 mg, 3.00 mmol, 1.00 eq) in a solution of dichloromethane (10 mL) to (3-benzyloxyisoxazole-5-yl) methanol (616 mg). , 3.00 mmol, 1.00 eq) in a solution of dichloromethane (10 mL). The mixture is stirred for 1 hour at 15 ° C., then 2,3,4,6,7,8,9,10-octahydropyrimid [1,2-a].
Azepine (480 mg, 3.15 mmol, 1.05 eq) was added at 0 ° C. The resulting mixture was further stirred for 14 hours at 0-15 ° C. The solvent was concentrated in vacuo. The residue was further purified by silica gel column chromatography (petroleum ether; ethyl acetate = 5: 1-4: 1) to 2- (3-benzyloxyisoxazole-5-yl) acetonitrile (320 mg, 1.49 mmol, Yield 50%) was obtained as a colorless oil. LC / MS (ESI) m / z: 215.0 [M + 1] +; 1H-NMR (400MHz, CDCl3) δ 7.48-
7.41 (m, 5H), 6.06 (s, 1H), 5.30 (s, 2H), 3.82 (s, 2H).
Step 10: Preparation of 2- (3- (benzyloxy) isoxazole-5-yl) -3-methylbutanenitrile.

2- (3-benzyloxyisoxazole-5-yl) acetonitrile (214 mg, 1.00 mmol, 1.00)
Potassium carbonate (138 mg, 1.00 mmol, 1.00 equivalent) was added to a solution of N, N-dimethylformamide (3 mL) (equivalent). The mixture was stirred for 30 minutes at 15 ° C., then 2-iodopropane (170 mg, 1.00 mmol, 1.00 eq) was added. The resulting mixture was further stirred for 2.5 hours at 15 ° C. Potassium; 2-methylpropan-2-olate (90 mg, 0.8 mmol, 0.80 eq) was then added to the mixture and the mixture was further stirred for 12 hours at 15 ° C. The mixture was poured into hydrochloric acid (0.2M, 30mL) and then extracted with ethyl acetate (30mLx2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether; ethyl acetate = 10: 1-8: 1) to 2- (3-benzyloxyisoxazole-5-yl) -3-methyl-butanenitrile ( 150 mg, 0.56 mmol, 59% yield) was obtained as a colorless oil. 1H-NMR (400MHz, CDCl3) δ 7. 48 --7.41 (m, 5H), 6.04 (s, 1H), 5.28 (s, 2H), 3.85 (d, J = 5.6 Hz, 1H), 2.42 --2.37 ( m, 1H), 1.18 (d, J = 6.8 Hz, 3H), 1.10 (d, J = 6.8 Hz, 3H).
Step 11: Preparation of 2- (3-hydroxyisoxazole-5-yl) -3-methylbutanoic acid.

Hydrochloric acid (11.8 M, 120 mL) is added to a solution of 2- (3-benzyloxyisoxazole-5-yl) -3-methyl-butanenitrile (3.40 g, 13.27 mmol, 1.00 eq) in dioxane (30 mL). rice field. The mixture was heated to 100 ° C. and stirred at 100 ° C. for 15 hours. The mixture was cooled to 15 ° C. and then extracted with ethyl acetate (150 mLx3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was further purified by preparative HPLC to give 2- (3-hydroxyisoxazole-5-yl) -3-methyl-butanoic acid (230 mg, 1.19 mmol, 9% yield) as a yellow solid. Obtained. LC / MS (ESI) m / z: 186.1 [M + 1] ⁺ .
Step 12: Preparation of methyl 2- (3-hydroxyisoxazole-5-yl) -3-methylbutanoate.

2- (3-Hydroxyisoxazole-5-yl) -3-methyl-butanoic acid (1 g, 5.40 mmol, 1 equivalent)
Thionyl chloride (2.57 g, 21 mmol, 1.57 mL, 4 eq) was added to a solution of methanol (10 ml) at 0 ° C. The reaction mixture was stirred for 3 hours at 70 ° C. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with ethyl acetate (30 mLx3). The combined organic layers were washed with brine (80 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Methyl 2- (3-hydroxyisoxazole-5-yl) -3-methyl-butanoate (1 g, 5.02 mmol, 92% yield) was obtained as a yellow oil. LC / MS (ESI) m / z: 200.1 [M + 1] ⁺ .
Step 13: Preparation of methyl 3-methyl-2-(3-((((perfluorobutyl) sulfonyl) oxy) isoxazole-5-yl) butaneate.

Potassium carbonate (1.11 g, 8.03 mmol, 2) in a solution of methyl 2- (3-hydroxyisoxazole-5-yl) -3-methyl-butanoate (800 mg, 4.02 mmol, 1 eq) in acetonitrile (5 ml). Equivalent) and perfluorobutyl fluorinated sulfonyl (1.46 g, 4.82 mmol, 1.2 eq) were added. The reaction mixture was stirred at 25 ° C. for 12 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mLx3). The combined organic layers were washed with brine (80 mLx3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100/1 to 20/1). Methyl 3-Methyl-2- [3- (1,1,2,2,3,3,4,4,4-nonafluorobutylsulfonyloxy) isoxazole-5-yl] butanoate (530 mg, 1.10 mmol, Yield 27%) was obtained as a colorless oil. 1H-NMR (400MHz, DMSO-d6) δ 6.44 (s, 1H), 3.79 (s, 3H), 3.68 (d, J = 8.0 Hz, 1H), 2.49 --2.33 (m, 1H), 1.04 (d, J = 6.8 Hz, 3H), 0.96 (d, J = 6.8 Hz, 3H).
Step 14: Preparation of tert-butyl 4- (5- (1-methoxy-3-methyl-1-oxobutan-2-yl) isoxazole-3-yl) piperazine-1-carboxylate.

Methyl 3-methyl-2- [3- (1,1,2,2,3,3,4,4,4-nonafluorobutylsulfonyloxy) isoxazole-5-yl] butanoate (400 mg, 0.83 mmol, A solution of dimethylformamide (5 ml) of 1 equivalent) and tert-butyl piperazin-1-carboxylate (154 mg, 0.83 mmol, 1 equivalent) was stirred for 12 hours at 130 ° C. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mLx3). The combined organic layers were washed with brine (30 mLx3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 3: 1). Obtained Tert-butyl 4- [5- (1-methoxycarbonyl-2-methyl-propyl) isoxazole-3-yl] piperazine-1-carboxylate (130 mg, 0.35 mmol, 42% yield) as a colorless oil. rice field. 1H-NMR (400MHz, CDCl3) δ 5.93 (s, 1H), 3.73 (s, 3H), 3.58 --3.47 (m, 5H), 3.29 --3.19 (m, 4H), 2.43 --2.17 (m, 1H), 1.48 (s, 9H), 1.00 (d, J = 6.8 Hz, 3H), 0.93 (d, J = 6.8 Hz, 3H).
Step 15: Preparation of 2- (3- (4- (tert-butoxycarbonyl) piperazine-1-yl) isoxazole-5-yl) -3-methylbutanoic acid.

tert-Butyl 4- [5- (1-methoxycarbonyl-2-methyl-propyl) isoxazole-3-yl] piperazine-1-carboxylate (130 mg, 0.35 mmol, 1 equivalent) in methanol (2 ml), tetrahydrofuran ( To a solution of 2 ml) and water (2 ml) was added lithium hydroxide (44 mg, 1.06 mmol, 3 equivalents). The reaction mixture was stirred at 15 ° C. for 1 hour. Water (3 mL) was added. The pH was adjusted to 6 with hydrochloric acid (1 M aqueous solution), and the mixture was extracted with ethyl acetate (10 mLx5). The combined organic layers were washed with brine (50 mLx1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. 2- [3- (4-tert-Butoxycarbonylpiperazine-1-yl) isoxazole-5-yl] -3-methyl-butanoic acid (100 mg, 0.28 mmol, 79% yield) was obtained as a white solid. 1H-NMR (400MHz, DMSO-d6) δ 12.83 (s, 1H), 6.23 (s, 1H), 3.45 --3.36 (m, 5H), 3.20 --3.09 (m, 4H), 2.30 --2.16 (m, 1H) ), 1.41 (s, 9H), 0.95 (d, J = 6.8 Hz, 3H), 0.82 (d, J = 6.8 Hz, 3H).
Step 16: Preparation of tert-butyl (S)-(1- (4-bromophenyl) ethyl) carbamate.

Triethylamine (37.78 g, 373.36 mmol, 3 eq) was added to a solution of (1S) -1- (4-bromophenyl) ethaneamine (24.9 g, 124.45 mmol, 1 eq) in tetrahydrofuran (350 ml). Then di-tert-butyl bicarbonate (28.52 g, 130.68 mmol, 30 mL, 1.05 eq) was added dropwise at 0 ° C. under nitrogen. The mixture was then stirred for 12 hours at 25 ° C. The reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran. Water (400 mL) was poured into the mixture and stirred for 1 minute. The aqueous layer was extracted with ethyl acetate (200 mLx3). The combined organic layers were washed with brine (200 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was pulverized with petroleum ether (250 mL). Compound tert-butyl N-[(1S) -1- (4-bromophenyl) ethyl] carbamate (34.5 g, 114.93 mmol, yield 92%) was obtained as a white solid. LC / MS (ESI) m / z: 246.0 [M + 1-56] ⁺ .
Step 17: Preparation of tert-butyl (S)-(1- (4- (4-methylthiazole-5-yl) phenyl) ethyl) carbamate.

Dimethyl of tert-butyl N-[(1S) -1- (4-bromophenyl) ethyl] carbamate (14.5 g, 48.30 mmol, 1 eq) and 4-methylthiazole (7.18 g, 72.45 mmol, 1.5 eq). To a solution of acetamide (15 ml) was added palladium (II) acetate (542 mg, 2.42 mmol, 0.05 eq) and potassium acetate (9.48 g, 96.61 mmol, 2 eq). The mixture was stirred at 90 ° C. for 12 hours. Water (300 mL) was poured into the mixture and stirred for 1 minute. The aqueous layer was extracted with ethyl acetate (100 mLx3). The combined organic layers were washed with brine (100 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash C18 column chromatography [ACN / H2O (0.5% FA) = 5% -50%]. Compound tert-butyl N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] carbamic acid salt (9.8 g, 29.85 mmol, yield 61%, purity 97%) Obtained as a gray solid. LC / MS (ESI) m / z: 319.0 [M + 1] ⁺ .
Step 18: Preparation of (S) -1- (4- (4-methylthiazole-5-yl) phenyl) ethane-1-amine.

In a solution of tert-butyl N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] carbamate (1.5 g, 4.71 mmol, 1 eq) in dichloromethane (20 ml), Hydrochloric acid / dichloromethane (4M, 20 mL, 16.98 eq) was added. The mixture was stirred for 12 hours. The reaction mixture is concentrated under reduced pressure and
Dichloromethane was removed. The crude product was pulverized with petroleum ether (100 mL). Compound (1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethaneamine (1.1 g, crude, HCl) was obtained as a yellow solid. LC / MS (ESI) m / z: 219.1 [M + 1] ⁺ .
Step 19: tert-butyl (2S, 4R) -4-hydroxy-2-(((S) -1- (4- (4-methylthiazole-5-yl) phenyl) ethyl) carbamoyl) pyrrolidine-1-carboxylic acid Preparation of acid salt.

(2S, 4R) -1-tert-butoxycarbonyl-4-hydroxy-pyrrolidin-2-carboxylic acid (998 mg, 4.32 mmol, 1.1 eq) and o- (7-azabenzotriazole-1-yl) -n, n , n', n'-Tetramethyluronium hexafluorophosphate (1.79 g, 4.71 mmol, 1.2 eq) in dimethylformamide (10 ml) solution to (1S) -1- [4- (4-methylthiazole-). 5-Il) phenyl] ethaneamine (1 g, 3.92 mmol, 1 eq, hydrochloride) and diisopropylethylamine (1.52 g, 11.77 mmol, 2.05 mL, 3 eq) were added. The reaction mixture was stirred at 15 ° C. for 0.5 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (50 mLx3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100/1 to 30/1). Tert-butyl (2S, 4R) -4-hydroxy-2-[[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carboxylate ( 1.2 g, 2.78 mmol, 70% yield) was obtained as a white solid. LC / MS (ESI) m / z: 432.3 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 8.98 (s, 1H), 8.52 --8.28 (m, 1H), 7.46 --7.36 (m) , 4H), 5.03 --4.93 (m, 2H), 4.27 --4.13 (m, 2H), 3.45 --3.22 (m, 5H), 2.88 (s, 1H), 2.75 --2.77 (m, 1H), 2.44 (s) , 3H), 2.04 (q, J = 10.8 Hz, 1H), 1.80 --1.69 (m, 1H), 1.42 --1.37 (m, 5H), 1.31 (s, 7H).
Step 20: (2S, 4R) -4-hydroxy-N-((S) -1- (4- (4-methylthiazole-5-yl) phenyl)
Preparation of ethyl) pyrrolidine-2-carboxamide.

tert-butyl (2S, 4R) -4-hydroxy-2-[[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-carboxylate ( Hydrochloric acid (2.5 M dioxane solution, 5 mL, 5.39 eq) was added to a solution of dichloromethane (10 ml) in 1 g, 2.32 mmol, 1 eq. The reaction mixture was stirred at 15 ° C. for 0.5 hours. The reaction mixture was concentrated under reduced pressure. (2S, 4R) -4-hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (800 mg, 2.17 mmol, yield 93) %, Hydrochloride) was obtained as a colorless oil. LC / MS (ESI) m / z: 332.1 [M + 1] ⁺ .
Step 21: tert-butyl 4-(5-(1-((2S, 4R) -4-hydroxy-2-(((S) -1-(4- (4-methylthiazole-5-yl) phenyl)) Preparation of ethyl) carbamoyl) pyrrolidine-1-yl) -3-methyl-1-oxobutan-2-yl) isoxazole-3-yl) piperazine-1-carboxylate.

2- [3- (4-tert-Butoxycarbonylpiperazine-1-yl) isoxazole-5-yl] -3-methyl-butanoic acid (100 mg, 0.28 mmol, 1 equivalent) and o- (7-azabenzotriazole- (2S, 4R) -4- in a solution of 1-yl) -n, n, n', n'-tetramethyluronium hexafluorophosphate (129 mg, 0.33 mmol, 1.2 equivalents) in dimethylformamide (5 mL). Hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] piperazine-2-carboxamide (104 mg, 0.28 mmol, 1)
Equivalent, hydrochloride) and diisopropylethylamine (109 mg, 0.84 mmol, 3 eq) were added. The reaction mixture was stirred at 15 ° C. for 0.5 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (50 mLx3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane: methanol = 10: 1). tert-butyl 4- [5- [1-[(2S, 4R) -4-hydroxy-2-[[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] carbamoyl] ] Pyrrolidine-1-carbonyl] -2-methyl-propyl] isoxazole-3-yl] piperazine-1-carboxylate (180 mg, 0.26 mmol, yield 92%, purity 97%) was obtained as a colorless oil. LC / MS (ESI) m / z: 667.4 [M + 1] +; 1H-NMR (400MHz, CDCl3) δ 8.70 (d, J = 1.2 Hz, 1H), 8.03 (s, 1H), 7.45 --7.39 ( m, 3H), 7.38 --7.31 (m, 2H), 5.94 (d, J = 10.0 Hz, 1H), 5.13 --4.95 (m, 1H), 4.79 (dd, J = 4.4, 8.4 Hz, 1H), 4.70 --4.59 (m, 2H), 3.84 --3.71 (m, 1H), 3.67 --3.55 (m, 4H), 3.54 --3.47 (m, 5H), 3.21 (td, J = 5.2, 13.2 Hz, 4H), 2.98 (s, 4H), 2.90 (s, 4H), 2.82 (s, 6H), 2.55 (d, J = 1.6 Hz, 4H), 2.45 (ddd, J = 6.4, 9.6, 16.0 Hz, 1H), 2.08- 1.92 (m, 1H), 1.53 --1.37 (m, 13H), 1.06 (dd, J = 2.4, 6.4 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H).
Step 22: tert-butyl 4-(5-((R) -1-((2S, 4R) -4-hydroxy-2-(((S) -1- (4- (4-methylthiazole-5-) Preparation of yl) phenyl) ethyl) carbamoyl) pyrrolidine-1-yl) -3-methyl-1-oxobutan-2-yl) isoxazole-3-yl) piperazine-1-carboxylate.

Tert-butyl 4- [5- [1-[(2S, 4R) -4-hydroxy-2-[[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] carbamoyl] ] Pyrrolidine-1-carbonyl] -2-methyl-propyl] isoxazole-3-yl] piperazine-1-carboxylate (200 mg, 0.29 mmol, 1 equivalent) was separated by chiral supercritical fluid chromatography. tert-butyl 4- [5-[(1S) -1-[(2S, 4R) -4-hydroxy-2-[[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl) ] Ethyl] Carbamoyl] Pyrrolidine-1-carbonyl] -2-Methyl-propyl] Isoxazole-3-yl] Piperazin-1-carboxylate (80 mg, 0.11 mmol, yield 76%, purity 95%) as a white solid Got as. tert-butyl 4- [5-[(1R) -1-[(2S, 4R) -4-hydroxy-2-[[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl) ] Ethyl] Carbamoyl] Pyrrolidine-1-carbonyl] -2-Methyl-propyl] Isoxazole-3-yl] Piperazin-1-carboxylate (70 mg, 0.1 mmol, yield 68%, purity 98%) as a white solid Got as.

Step 23: (2S, 4R) -4-hydroxy-1-((R) -3-methyl-2-(3- (piperazine-1-yl) isoxazole-5-yl) butanoyl) -N-((S) )-1-(4- (4-Methylthiazole-5-yl) phenyl) ethyl) Pyrrolidine-2-carboxamide preparation.

tert-butyl 4- [5-[(1R) -1-[(2S, 4R) -4-hydroxy-2-[[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl) ] Ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2-methyl-propyl] isoxazole-3-yl] piperazin-1-carboxylate (70 mg, 0.1 mmol, 1 equivalent) in a solution of dichloromethane (2 ml) in hydrochloric acid (2 ml). 4 M dioxane solution, 3 ml) was added. The reaction mixture was stirred at 15 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. (2S, 4R) -4-hydroxy-1-[(2R) -3-methyl-2- (3-piperazin-1-ylisoxazole-5-yl) butanoyl] -N-[(1S) -1 -[4- (4-Methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (55 mg, 0.09 mmol, yield 91%, purity 99%) was obtained as a white solid. LC / MS (ESI) m / z: 567.2 [M + 1] ⁺ .
Step 24: (2S, 4R) -1-((R) -2- (3-(4-((1- (5- (3- (2,6-difluoro-3- (((R) -3) -3) -Fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) pyrimidine-2-yl) piperidine-4-yl) methyl) piperazin-1-yl) isoxazole Preparation of -5-yl) -3-methylbutanoyl) -4-hydroxy-N-((S) -1-(4-(4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide ..

(2S, 4R) -4-Hydroxy-1-[(2R) -3-Methyl-2- (3-Piperazine-1-ylisoxazole-5-)
Il) Butanoyl] -N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (68.81 mg, 0.11 mmol, 1 equivalent, hydrochloride) Sodium acetate (19 mg, 0.22 mmol, 2 eq) is added to a solution of methanol (0.5 ml) and dichloromethane (0.5 ml) to pH.
Was adjusted to about 8.0. Then (3R) -N- [2,4-difluoro-3- [5- [2- (4-formyl-1-piperidyl) pyrimidin-5-yl] -1H-pyrrolo [2,3-b] pyridine- 3-carbonyl] phenyl] -3-fluoro-pyrrolidin-1-sulfonamide (70 mg, 0.11 mmol, 1 eq) was added. The mixture was stirred at 30 ° C. for 15 minutes, followed by the addition of acetic acid (14 mg, 0.22 mmol, 2 eq) to adjust the pH to about 5.0. The mixture was stirred at 15 ° C. for 15 minutes. Sodium cyanoborohydride (14 mg, 0.22 mmol, 2 eq) was then added in several batches. The reaction mixture was stirred at 30 ° C. for 2.5 hours. Dichloromethane (30 mL x 2), methanol (5 mL), and water (25 mL x 2) were added and the organic layer was separated. The combined organic phases were concentrated under vacuum. The residue was purified by half-reverse phase HPLC. Compound (2S, 4R) -1-[(2R) -2- [3- [4-[[1- [5- [3- [2,6-difluoro-3- [(3R) -3-fluoropyrolidin -1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] ylimidin-2-yl] -4-piperidyl] methyl] piperazine-1-yl] isoxazole-5- Il] -3-methyl-butanoyl] -4-hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] piperidine-2-carboxamide (56.9 mg, 0.04) mmol, yield 37%, purity 95%, trifluoroacetic acid) was obtained as an off-white solid. LC / MS (ESI) m / z: 582.8 [M / 2 + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 12.99 (s, 1H), 9.82 (s, 1H), 8.98 (s, 1H) ), 8.76 (s, 2H), 8.66 (s, 1H), 8.56 (s, 1H), 8.37 (d, J = 6.8 Hz, 1H), 8.11 (s, 1H), 7.69 --7.56 (m, 1H) , 7.51 --7.41 (m, 2H), 7.40 --7.33 (m, 2H), 7.27 (t, J = 8.8 Hz, 1H), 6.34 --6.16 (m, 1H), 5.43 --5.21 (m, 1H), 5.11 (s, 1H), 4.99 --4.84 (m, 1H), 4.75 (d, J = 12.0 Hz, 2H), 4.52- 4.20 (m, 2H), 3.80 (s, 2H), 3.73 (d, J = 6.4) Hz, 1H), 3.63 (d, J = 9.2 Hz, 3H), 3.47 (d, J = 13.6 Hz, 3H), 3.41 (s, 3H), 3.24 (s, 2H), 3.13 (s, 3H), 3.07 --2.96 (m, 2H), 2.49 --2.44 (m, 1H), 2.46 (s, 3H), 2.30 --2.10 (m, 4H), 2.08 --1.97 (m, 2H), 1.92 --1.76 (m, 2H) ), 1.52 --1.34 (m, 3H), 1.24 (s, 3H), 0.98 (d, J = 6.0 Hz, 2H), 0.90 --0.77 (m, 3H).
(2S, 4R) -1- (2- (3- (3- (4- (5- (3- (2,6-difluoro-3- (((R) -3-fluoropyrrolidine) -1-sulfone) Amide) Benzoyl) -1H-Pyrrolidine [2,3-b] Pyridine-5-yl) Pyrimidine-2-yl) Pipe
Radin-1-yl) Azetidine-1-yl) Isoxazole-5-yl) -3-Methylbutanoyl) -4-H
Droxy-N- (4- (4-Methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide (
Example 322) Illustrative Synthesis Step 1: Preparation of tert-butyl 4- (1-((benzyloxy) carbonyl) azetidine-3-yl) piperazine-1-carboxylate.

Dichloromethane in tert-butyl piperazin-1-carboxylate (10.0 g, 53.69 mmol, 1 eq) and benzyl 3-oxoazetidine-1-carboxylate (11.0 g, 53.60 mmol, 1.00 eq) in a 250 mL round bottom flask. A (150 ml) solution was added, to which NaBH (OAc) 3 (34.1 g, 161.07 mmol, 3 eq) was added. The obtained mixture was stirred at room temperature for 3 hours. The reaction was then quenched with water (100 mL), extracted with dichloromethane (100 mLx3), washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (v: v = 2: 1). This gave 10.0 g (49.61%) of tert-butyl 4- [1-[(benzyloxy) carbonyl] azetidine-3-yl] piperazine-1-carboxylate as a light brown solid. LC / MS (ESI) m / z: 376.35 [M + 1] ⁺ .
Step 2: Preparation of tert-butyl 4- (azetidine-3-yl) piperazine-1-carboxylate.

In a 250 mL round-bottom flask, under nitrogen, tert-butyl 4- [1-[(benzyloxy) carbonyl] azetidine-3-yl] piperazine-1-carboxylate (10.0 g, 26.63 mmol, 1 eq). 30ml MeOH
Pd / C (10%, 2.0 g) was added to the solution. The flask was then evacuated and flushed with hydrogen. The reaction mixture was hydrogenated at room temperature for 2 hours in a hydrogen atmosphere using a hydrogen balloon, then filtered through a Celite bed and the filtrate was concentrated under reduced pressure. This gave 5.9 g (91.79%) of tert-butyl 4- (azetidine-3-yl) piperazine-1-carboxylate as a yellow oil. LC / MS (ESI) m / z: 242.20 [M + 1] ⁺ .
Step 3: Preparation of tert-butyl 2-isopropylbuta-3-enolate.

A solution of tert-butyl porcine-3-enolate (20.0 g, 140.6 mmol, 1.0 eq) in tetrahydrofuran (400 ml) was placed in a 1000 mL round bottom flask purged and maintained in an inert nitrogen atmosphere. Lithium diisopropylamide (30.0 g, 280.1 mmol, 2.0 eq) was added to the above mixture at -78 ° C. After stirring at -78 ° C for 30 minutes, 2-iodropan (36.0 g, 211.8 mmol, 1.5 eq) was added to the reaction mixture at -78 ° C in several batches. The resulting mixture was heated to room temperature and stirred at room temperature overnight. The reaction was then quenched by the addition of 300 mL of _{saturated NH 4 Cl solution.} The resulting solution was extracted with ethyl acetate (300 mLx3), the organic layers were combined and concentrated under vacuum.
The residue was applied on a silica gel column and eluted with ethyl acetate / petroleum ether (20: 1). As a result, 18.0 g (69.0%) of tert-butyl 2- (propane-2-yl) buta-3-enolate was obtained.

Step 4: Preparation of tert-butyl 2- (3-bromo-4,5-dihydroisoxazole-5-yl) -3-methylbutanoate.

In a 1000 mL round bottom flask purged and maintained in an inert nitrogen atmosphere, tert-butyl 2- (propane-2-yl) porcine-3-enolate (18.0 g, 97.7 mmol, 1.0 eq), methanepel. potassium oxyacid (potassium methaneperoxoate) (29.0g, 289.7mmol , 3.0 eq) was placed at -10 ° C. the _{DMF / H 2 0 (200 /} 200ml) solution of. 1-bromo-N-hydroxymethanecarboxylicimideyl bromide (35.0 g, 172.6 mmol, 1.8 eq) was then added to the above mixture at -10 ° C. The resulting mixture was stirred at room temperature overnight. The reaction was then quenched by the addition of 300 mL of water / ice. The resulting mixture was extracted with ethyl acetate (300 mLx3), the organic layers were combined and concentrated under vacuum. The residue was applied on a silica gel column and eluted with ethyl acetate / petroleum ether (10: 1). This gave 8.6 g (29.0%) of tert-butyl 2- (3-bromo-4,5-dihydro-1,2-oxazol-5-yl) -3-methylbutanoate as a solid. LC / MS (ESI) m / z: 306.40 [M + 1] ⁺ .
Step 5: tert-Butyl 4- (1- (5- (1- (tert-butoxy) -3-methyl-1-oxobutan-2-yl) -4,5-dihydroisoxazole-3-yl) azetidine -3-yl) Preparation of piperazine-1-carboxylate.

In a 60 mL closed tube purged and maintained in an inert nitrogen atmosphere, tert-butyl 4- (azetidine-3-yl) piperazine-1-carboxylate (4.0 g, 16.57 mmol, 1 eq), tert-butyl. 2- (3- (3-)
N-BuOH of bromo-4,5-dihydro-1,2-oxazol-5-yl) -3-methylbutaneate (10.2 g, 33.15 mmol, 2 eq), DIEA (6.4 g, 49.72 mmol, 3 eq) A solution of (20.0 ml) was added. The obtained mixed solution was stirred in an oil tank at 110 ° C. for 2 hours. The reaction was then quenched with water (50 mL), extracted with ethyl acetate (50 mLx3), washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (v: v = 1: 4). This resulted in 2.2 g (28.45%) of tert-butyl 4-(1- [5- [1- (tert-butoxy) -3-methyl-1-oxobutan-2-yl] -4,5-dihydro-1). , 2-Oxazole-3-yl] Azetidine-3-yl) Piperazine-1-carboxylate was obtained as a yellow oil. LC / MS (ESI) m / z: 467.45 [M + 1] ⁺ .
Step 6: tert-butyl 4-(1- (5- (1- (tert-butoxy) -3-methyl-1-oxobutan-2-yl))
Preparation of isoxazole-3-yl) azetidine-3-yl) piperazine-1-carboxylate.

In a 30 mL vial purged and maintained in an inert nitrogen atmosphere, tert-butyl 4-(1- [5- [1- (tert-butoxy) -3-methyl-1-oxobutan-2-yl] -4. , 5-Dihydro-1,2-oxazol-3-yl] azetidine-3-yl) piperazin-1-carboxylate (2.2 g, 4.71 mmol, 1 eq), pyridine (1.9 g, 23.57 mmol, 5 eq) , I2 (2.4 g, 9.46 mmol, 2.01 eq) in toluene (20 ml) was added. The resulting solution was stirred for 2 hours in an oil bath at 110 ° C. The reaction was then quenched with Na ₂ S ₂ O ₃ (50 mL), extracted with ethyl acetate (50 mLx3), washed with י ₃ (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated. .. The residue was run on a silica gel column with ethyl acetate / petroleum ether (v: v = 1: 1). This resulted in 1.0 g (45.65%) of tert-butyl 4-(1- [5- [1- (tert-butoxy) -3-methyl-1-oxobutan-2-yl] -1,2-oxazol-3. -Il] Azetidine-3-yl) Piperazine-1-carboxylate was obtained as a yellow oil. LC / MS (ESI) m / z: 465.1 [M + 1] ⁺ .
Step 7: Preparation of 3-methyl-2- (3- (3- (piperazine-1-yl) azetidine-1-yl) isoxazole-5-yl) butanoic acid.

In a 100 mL round bottom flask, tert-butyl 4-(1- [5- [1- (tert-butoxy) -3-methyl-1-oxobutan-2-yl] -1,2-oxazol-3-yl] A solution of azetidin-3-yl) piperazin-1-carboxylate (500.0 mg, 1.08 mmol, 1 eq) in DCM (20 ml) was added and 2,2,2-trifluoroacetic acid (8 ml) was added thereto. The obtained mixture was stirred at room temperature for 5 hours and concentrated under reduced pressure. This gives 270.0 mg of 3-methyl-2- [3- [3- [3- (piperazine-1-yl) azetidine-1-yl] -1,2-oxazol-5-yl] butanoic acid as a yellow oil. Was done. LC / MS (ESI) m / z: 309.30 [M + 1] ⁺ .
Step 8: (R) -N- (3- (5- (2-chloropyrimidine-5-yl) -1H-pyrrolo [2,3-b] pyridin-3-carbonyl) -2,4-difluorophenyl) Preparation of -3-fluoropyrrolidine-1-sulfonamide.

In a 30 mL closed tube under a nitrogen atmosphere, (3R) -N- (3- [5-bromo-1H-pyrrolo [2,3-b] pyridin-3-carbonyl] -2,4-difluorophenyl)- 3-Fluoropyrrolidine-1-sulfonamide (450.0 mg, 0.89 mmol, 1 eq), 2-chloro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2)
-Il) Pyrimidine (645.0 mg, 2.68 mmol, 3.00 eq), Na ₂ CO ₃ (284.0 mg, 2.68 mmol, 3.00 eq) and Pd (dppf) Cl ₂ .CH ₂ Cl ₂ (15.0 mg, 0.02 mmol, 0.02 eq) ) Dioxane (5 ml) and H2O (1 ml) solution were added. The obtained mixed solution was stirred at 105 ° C. for 3 hours in an oil tank under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was applied on a silica gel column and eluted with ethyl acetate / petroleum ether (1: 2). This resulted in 70.0 mg (14.58%) of (3R) -N- [3- [5- (2-chloropyrimidine-5-yl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl]-. 2,4-Difluorophenyl] -3-fluoropyrrolidine-1-sulfonamide was obtained as a bright yellow solid. LC / MS (ESI) m / z: 537.05 [M + 1] ⁺ .
Step 9: 2- (3-(3-(4-(5-(3-(2,6-difluoro-3-(((R) -3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H) -Pyrrolidine [2,3-b] Pyridine-5-yl) Pyrimidine-2-yl) Piperazine-1-yl) Azetidine-1-yl) Isoxazole-5-yl) -3-Methylbutanoic acid preparation.

In a 50 mL round bottom flask, 3-methyl-2- [3- [3- (piperazine-1-yl) azetidine-1-yl] -1,2-oxazol-5-yl] butanoic acid (40 mg, 0.13 mmol) , 1 equivalent), (3R) -N- [3- [5- (2-chloropyrimidine-5-yl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro A DCM (2 ml) solution of phenyl] -3-fluoropyrrolidin-1-sulfonamide (69.6 mg, 0.13 mmol, 1 eq) and Et ₃ N (50.3 mg, 0.39 mmol, 3 eq) was added. The resulting mixture was stirred at room temperature for 48 hours. The resulting mixture was concentrated under vacuum. The residue was loaded into a silica gel column with dichloromethane / methanol (v: v = 4: 1). This resulted in 53.0 mg (50.52%) of 2- (3- [3- [4- (5- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidine-1-). Ill] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] pyrimidine-2-yl) piperazine-1-yl] azetidine-1-yl] -1,2-oxazol- 5-Il) -3-methylbutanoic acid was obtained as a yellow oil. LC / MS (ESI) m / z: 809.05 [M + 1] ⁺ .
Step 10: (2S, 4R) -1- (2-(3-(3-(4-(5-(3-(2,6-difluoro-3-(((R) -3-fluoropyrrolidine)-)- 1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) pyrimidine-2-yl) piperazine-1-yl) azetidine-1-yl) isoxazole-5-yl) -3 Preparation of -methylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide.

In a 50 mL flask, 2- (3- [3- [4- (5- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino] ) Benzoyl] -1H-pyrrolidine [2,3-b] pyridin-5-yl] pyrimidine-2-yl) piperazine-1-yl] azetidine-1-yl] -1,2-oxazol-5-yl)- 3-Methylbutanoic acid (53 mg, 0.07 mmol, 1 equivalent), (2S, 4R) -4-hydroxy-N-[[4- (4-methyl-1,3-thiazole-5-yl) phenyl] methyl] pyrrolidine -2-Carboxamide (20.8 mg, 0.07 mmol, 1)
Equivalent), DIEA (25.4 mg, 0.20 mmol, 3 eq), BOP (43.5 mg, 0.10 mmol, 1.5 eq) in DMF (5 ml) solution. The obtained mixture was stirred at room temperature for 2 hours. The reaction was then quenched by the addition of 20 mL of water, extracted with dichloromethane (20 mL x 2) and washed with 20 mL of water and 20 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by HPLC. This resulted in 31.0 mg (42.69%) of (2S, 4R) -1- [2- (3- [3- [4- (5- [3- [2,6-difluoro-3- ([[(3R). ) -3-Fluoropyrrolidine-1-yl] Sulfonyl]
Amino) Benzoyl] -1H-pyrrolo [2,3-b] Pyridine-5-yl] Pyrimidine-2-yl) Piperazin-1-yl] Azetidine-1-yl] -1,2-oxazol-5-yl) -3-Methylbutanoyl] -4-hydroxy-N-[[4-(4-Methyl-1,3-thiazole-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide was obtained as a yellow oil. .. LC / MS (ESI) m / z: 1108.10 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 13.00 (s, 1H), 11.30 (brs, 1H), 9.80 (s, 1H), 8.97 (s, 1H), 8.85 (s, 2H), 8.67 (d, J = 2.2 Hz, 1H), 8.58 (s, 1H), 8.50-8.46 (m, 1H), 8.14-8.06 (m, 1H) , 7.69-7.55 (m, 1H), 7.46-6.91 (m, 5H), 5.97 (d, J = 2.7 Hz, 1H), 5.38 (s, 1H), 5.20 (s, 1H), 4.85-4.60 (m) , 2H), 4.43-4.26 (m, 4H), 4.25-4.15 (m, 4H), 3.83-3.74 (m, 2H), 3.69-3.28 (m, 10H), 3.12-2.98 (m, 1H), 2.43 -2.40 (m, 3H), 2.27-1.83 (m, 5H), 1.23 (d, J = 10.7 Hz, 1H), 0.95-0.90 (m, 2H), 0.85-0.71 (m, 2H), 0.63-0.52 (m, 1H).
(2S, 4R) -1-((S) -2-(2-(4-((4- (4- (3- (2,6-difluoro-3-((3-hydroxypropyl) sulfonamide)) Benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-i
L) Methyl) piperidine-1-yl) acetamide) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide (eg) 321) Illustrative Synthetic Step 1: Preparation of Sodium 3-acetoxypropane-1-sulfonate.

An anhydrous acetic acid (40 mL) of sodium 3-hydroxypropane-1-sulfonate (5 g, 30.84 mmol, 1 eq) was placed in a 100 mL round-bottom flask purged and maintained in an inert nitrogen atmosphere. The resulting solution was stirred for 7 hours in an oil bath at 120 ° C. After cooling to room temperature, the precipitated solid was collected by filtration and dried under vacuum. This will result in 6.2g (98.47%) sodium 3-
Acetoxypropane-1-sulfonate was obtained as a white solid.

Step 2: Preparation of 3- (chlorosulfonyl) propyl acetate.

A 50 mL round bottom flask was filled with a solution of sodium 3-acetoxypropane-1-sulfonate (3 g, 14.69 mmol, 1 eq) in oxalyl dichloride (20 mL). A catalytic amount of DMF (0.1 mL) was added to the above mixture. The obtained mixed solution was stirred in an oil tank at 68 ° C. for 5 hours. The reaction mixture was concentrated under vacuum. The residue was redissolved in EtOAc (100 mL). The insoluble solid was filtered and the filtrate was concentrated under vacuum. This gave 2.3 g (78.02%) of 3- (chlorosulfonyl) propyl acetate as a yellow oil.

Step 3: Preparation of 3-(N-(3- (5-bromo-1H-pyrrolo [2,3-b] pyridin-3-carbonyl) -2,4-difluorophenyl) sulfamoyl) propyl acetate.

In a 50 mL round bottom flask, 3- (chlorosulfonyl) propyl acetate (200 mg, 1.00 mmol, 1 eq), 3- [5-bromo-1H-pyrrolo [2,3-b] pyridin-3-carbonyl]- Pyridine (10 mL) of 2,4-difluoroaniline (351.0 mg, 1.00 mmol, 1 eq) and DMAP (12.2 mg, 0.10 mmol, 0.1 eq)
The solution was added. The resulting solution was stirred in an oil bath overnight at 40 ° C. The mixture was concentrated under vacuum. The residue was applied on a silica gel column and eluted with dichloromethane / methanol (20: 1). This resulted in 293 mg (56.93%) of 3-(N-(3- (5-bromo-1H-pyrrolo [2,3-b] pyridin-3-carbonyl) -2,4-difluorophenyl) sulfamoyl) propyl acetate. Salt was obtained as a yellow solid. LC / MS (ESI) m / z: 515.90 / 517.90.20 [M + 1] ⁺ .
Step 4: tert-butyl 2- (4-((4- (4- (3- (3-((3-acetoxypropyl) sulfonamide) -2,6-difluorobenzoyl) -1H-pyrrolo [2,3] -b] Preparation of pyridine-5-yl) phenyl) piperazine-1-yl) methyl) piperidine-1-yl) acetate.

In a 10 mL vial purged and maintained in an inert nitrogen atmosphere, under nitrogen atmosphere, 3-[(3- [5-bromo-1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2 , 4-Difluorophenyl) sulfamoyl] propyl acetate (293 mg, 0.57 mmol, 1 equivalent), 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 (340.2 mg, 0.68 mmol, 1.2 equivalents), Na ₂ CO ₃ (180.4 mg, 1.70 mmol, 3 equivalents), Pd (dppf) Cl ₂ (41.5 mg, 0.06 mmol, 0.1 equivalents _{) in a solution of dioxane (5 mL) and H 2} O (1 mL). The obtained mixed solution was stirred in an oil tank at 105 ° C. for 2 hours. The reaction was cooled to room temperature and diluted with water (20 mL). The resulting mixture was extracted with ethyl acetate (40 mLx3). The combined organic layers were washed with brine (20 mLx1), dried over anhydrous sodium and concentrated under vacuum. The residue was applied on a silica gel column and eluted with dichloromethane / methanol (10: 1). This resulted in 287 mg (62.52%) of tert-butyl 2- (4-((4- (4- (3- (3- (3- (3-acetoxypropyl sulfonamide) -2,6-difluorobenzoyl) -1H-pyrrolo). [2,3-b] Pyridine-5-yl) Phenyl) Piperazine-1-yl) Methyl) Piperidine-1-yl) Acetate was obtained as a yellow solid. LC / MS (ESI) m / z: 809.55 [M + 1] ⁺ .
Step 5: 2- (4-((4- (4- (3- (3-((3-acetoxypropyl) sulfonamide) -2,6-difluorobenzoyl) -1H-pyrrolo [2,3-b]] Preparation of pyridine-5-yl) phenyl) piperazine-1-yl) methyl) piperidine-1-yl) acetic acid.

In a 50 mL round bottom flask, 3-[[3- (5- [4- [4-([1- [2- (tert-butoxy) -2-oxoethyl] piperidine-4-yl] methyl) piperazine-1 -Il] Phenyl] -1H-Pyrrolo [2,3-b] Pyridine-3-carbonyl) -2,4-difluorophenyl] Sulfamoyl] Propyl acetate (287 mg, 0.35 mmol)
, 1 eq) in a solution of dichloromethane (20 mL). TFA (5 mL) was then added at room temperature. The resulting solution was stirred at room temperature overnight. The mixture was concentrated under vacuum. This results in 267 mg (99.97%)
2- (4-((4- (4- (3- (3- (3- (3-Acetoxypropylsulfonamide) -2,6-difluorobenzoyl) -1H-pyrrolo [2,3-b] pyridine-5- Il) phenyl) piperazine-1-yl) methyl) piperidine-1-yl) acetate HCl was obtained as a yellow oil. LC / MS (ESI) m / z: 753.10 [M + 1] ⁺ .
Step 6: 3-(N- (2,4-difluoro-3-) 5-(4-((1- (2-(((S) -1-((2S, 4R) -4-) Hydroxy-2-((4- (4-Methylthiazol-5-yl) benzyl) carbamoyl) piperidine-1-yl) -3,3-dimethyl-1-oxobutane-2-yl) amino) -2-oxoethyl) Preparation of piperidine-4-yl) methyl) piperazine-1-yl) phenyl) -1H-pyrrolo [2,3-b] pyridin-3-carbonyl) phenyl) sulfamoyl) propyl acetate.

In a 50 mL round bottom flask, 2- (4-((4- (4- (3- (3- (3- (3- (3- (3- (3-acetoxypropylsulfonamide) -2,6-difluorobenzoyl) -2,6-difluorobenzoyl) -1H-pyrrolo [2,3-] b] Pyridine-5-yl) phenyl) piperazine-1-yl) methyl) piperidine-1-yl) acetic acid (267 mg, 0.35 mmol, 1 equivalent) in DMF (20 mL) was added. BOP (188.2 mg, 0.43 mmol, 1.2 eq) and DIEA (137.5 mg, 1.06 mmol, 3 eq) were then added sequentially to the above solution. After stirring at room temperature for 5 minutes, the reaction mixture was mixed with (2S, 4R) -1-[(2S) -2-amino-3,3-dimethylbutanoyl] -4-hydroxy-N-[[4- (4). A solution of -methyl-1,3-thiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide HCl salt (152.7 mg, 0.35 mmol, 1 eq) in DMF (5 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction was then stopped by the addition of water (20 mL). The resulting mixture was extracted with dichloromethane / methanol (v: v = 10: 1, 40 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated. The residue is applied on a silica gel column and dichloromethane /
It was eluted with methanol (10: 1). This resulted in 283 mg (68.47%) of 3-(N- (2,4-difluoro-3-) 5-(4-(((1- (2-((S) -1-((2S,)). 4R) -4-Hydroxy-2- (4- (4-methylthiazole-5-yl) benzylcarbamoyl) piperidine-1-yl) -3,3-dimethyl-1-oxobutane-2-ylamino) -2-oxoethyl ) Piperidine-4-yl) Methyl) Piperazine-1-yl) Phenyl) -1H-pyrrolo [2,3-b] Pyridine-3-carbonyl) Phenyl) Sulfamoyl) Propyl acetate was obtained as a yellow solid. LC / MS (ESI) m / z: 1187.05 [M + 23] ⁺ .
Step 7: (2S, 4R) -1-((S) -2- (2- (4-((4- (4- (3- (2,6-difluoro-3- ((3-hydroxypropyl)) Sulfone amide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazin-1-yl) methyl) piperidine-1-yl) acetamide) -3,3-dimethylbutanoyl)- Preparation of 4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide.

In a 50 mL round bottom flask, 3-[(2,4-difluoro-3- [5- [4-(4-[[1-([[(2S) -1-[(2S, 4R) -4-]
Hydroxy-2- ([[4- (4-Methyl-1,3-thiazole-5-yl) phenyl] methyl] carbamoyl)
Pyrrolidine-1-yl] -3,3-dimethyl-1-oxobutane-2-yl] carbamoyl] methyl) piperidine-4-yl] met (273 mg, 0.23 mmol, 1 equivalent), MeOH (20 mL, 493.98 mmol, 2108.71) Equivalent), H ₂ O (1 mL, 55.51 mmol, 236.96 equivalents) and LiOH (16.8 mg, 0.70 mmol, 3 equivalents) were added. The resulting solution was stirred for 2 hours in an oil bath at 40 ° C. The crude product (263 mg) was purified by preparative HPLC. This resulted in 31.6 mg (11.93%) of (2S, 4R) -1-[(2S) -2- [2- (4- [[4- (4- [3- [2,6-difluoro-3-]. (3-Hydroxypropane sulfonamide) Benzoyl] -1H-pyrrolo [2,3-b] Pyridine-5-yl] Phenyl) Piperazine-1-yl] Methyl] Piperidine-1-yl) Acetamide] -3,3- Dimethylbutanoyl] -4-hyd was obtained as a bright yellow solid. LC / MS (ESI) m / z: 1123.20 [M + 1] +; 1H-NMR (400MHz, CD3OD) δ 8.90 (s, 1H), 8.73 (s, 1H), 8.62 (d, J = 2.1 Hz, 1H), 7.98 (s, 1H), 7.72 --7.54 (m, 3H), 7.48 --7.34 (m, 4H), 7.25 --7.07 (m, 3H), 4.65 (d, J = 10.9 Hz, 1H), 4.62 --4.51 (m, 3H), 4.39 (d, J = 15.5 Hz, 1H), 3.98 --3.79 (m, 2H), 3.66 (t, J = 6.0 Hz, 2H), 3.34 --3.12 (m, 8H), 3.06- 2.90 (m, 2H), 2.86 ―― 2.69 (m, 4H), 2.54 ―― 2.45 (m, 3H), 2.44 ―― 2.18 (m, 5H), 2.17 ―― 1.97 (m, 3H), 1.94 ―― 1.62 (m) , 3H), 1.49 --1.22 (m, 2H), 1.06 (d, J = 8.1 Hz, 9H).
(2S, 4R) -1-((2S) -2- (2- (4-((4- (4- (3- (3-((1-Cyclopentyl-2,2,2-trifluoroethyl)) Amino) -2,6-difluorobenzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazin-1-yl) methyl) piperidin-1-yl) acetamide) -3,3- Illustrative Synthesis Step 1: (E) -N-Benzyl- Preparation of 1-cyclopentylmethaneimine.

Cyclopentane carvaldehide (11.2 g, 114.1 mmol, 1 eq), 1-phenylmethaneamine (12.8 g, 119.7 mmol, 1.05 eq) and _{DDL 4} (69.9 g, 580.7 mmol, 5.09 eq) in dichloromethane (350 mL). The turbid liquid was stirred at room temperature for 21 hours. The solid was filtered. The filtrate was evaporated to dryness and dried under vacuum. This gave 21.5 g (100%) of (E) -benzyl (cyclopentyl methylidene) amine as a bright yellow liquid. LC / MS (ESI) m / z: 188.4 [M + 1] ⁺ .
Step 2: Preparation of N-benzyl-1-cyclopentyl-2,2,2-trifluoroethane-1-amine.

_{TFA (11.2 mL, 150.8 mmol, 1.30 eq), KHF 2} (7.35 g, 94.1 mmol, 1 equivalent) in a MeCN (220 mL) solution of (E) -benzyl (cyclopentylmethylidene) amine (21.8 g, 116.2 mmol, 1 eq). 0.81 eq) and DMF (33 mL) were added at 0 ° C. The reaction mixture was stirred at 0 ° C. for 5 minutes. Then, Me ₃ SiC F ₃ (24.9 g, 175.2 mmol, 1.51 eq) was added to the above mixed solution, and the obtained mixed solution was reacted at room temperature for another 17 hours with stirring. The reaction was then quenched by the addition of 43 mL of saturated Na ₂ CO _3. The mixture was stirred for 5 minutes and then diluted with water (300 mL). The resulting mixture was extracted with ethyl acetate (200 mLx3). The combined organic layers were washed with water (100 mLx2) and brine (100 mLx1) and dried over anhydrous sodium sulfate. The crude product is ethyl acetate /
Placed on a silica gel column with petroleum ether (1:20). This results in 7.34g (24.6%)
Benzyl (1-cyclopentyl-2,2,2-trifluoroethyl) amine was obtained as a bright yellow liquid. LC / MS (ESI) m / z: 258.10 [M + 1] +; 1H-NMR (400MHz, CDCl3) δ 1.44-1.87 (m, 9H), 2.09-2.23 (m, 1H), 2.97-3.06 (m) , 1H), 3.86 (d, J = 12.9 Hz, 1H), 4.11 (d, J = 13.2 Hz, 1H), 7.29-7.41 (m, 5H); 9F-NMR (300 MHz, CDCl3) δ 71.5, 72.1 , 72.2.
Step 3: Preparation of 1-cyclopentyl-2,2,2-trifluoroethane-1-amine hydrochloride.

In a 500 mL pressure tank reactor, add Pd / C (2.17 g) to a solution of benzyl (1-cyclopentyl-2,2,2-trifluoroethyl) amine (6.31 g, 24.52 mmol, 1 eq) in MeOH (80 mL). rice field. The mixture was filled with H ₂ at 50 atm and stirred at 50 ° C. for 19 hours. The mixture was filtered and a solution of HCl in methanol (30 mL) was added to the filtrate. The combined filtrates were concentrated under vacuum and dried. This gave 4.81 g (96.3%) of 1-cyclopentyl-2,2,2-trifluoroethane-1-amine hydrochloride as a white solid. LC / MS (ESI) m / z: 168.10 [M + 1] ⁺ .
Step 4: Preparation of methyl 3-bromo-2,6-difluorobenzoate.

Sulfuric acid (4 mL) was added to a solution of 3-bromo-2,6-difluorobenzoic acid (10 g, 42.2 mmol, 1 eq) in methanol (100 ml). The reaction solution was heated and refluxed for 17 hours. The reaction mixture was cooled to room temperature using a water tank. The resulting mixture was concentrated. The residue was extracted with ethyl acetate (100 mLx3) and the organic layers were combined into one. The resulting mixture was washed with brine (100 mLx2). The mixture was dried over anhydrous sodium sulfate. The residue was placed on a silica gel column with ethyl acetate / petroleum ether (1:20). This gave 9.04 g (85.4%) of methyl 3-bromo-2,6-difluorobenzoate as a white solid. 1H-NMR (400MHz, CDCl ₃ )
δ 3.98 (d, J = 8.7 Hz, 3H), 6.90-6.96 (m, 1H), 7.62-7.70 (m, 1H); 9F-NMR (300 MHz, CDCl ₃ ) δ 102.0, 110.9.
Step 5: Preparation of methyl 3-((1-cyclopentyl-2,2,2-trifluoroethyl) amino) -2,6-difluorobenzoate.

Methyl 3-bromo-2,6-difluorobenzoate (1.86 g, 7.41 mmol, 1.49 eq), 1-cyclopentyl-2, 2, 2-trifluoroethane-1-amine hydrochloride (1.01 g, 4.96 mmol), A mixture of 1 equivalent) and Cs ₂ CO ₃ (4.83 g, 14.8 mmol, 2.99 equivalent) in toluene (15 mL) was purged with _{N 2.} Then, RuPhos-PdCl-2nd G (386.9 mg, 0.50 mmol, 0.10 eq) was added thereto, the sealed tube was closed, and the obtained mixed solution was stirred at 100 ° C. for 3 hours. The crude product is flash chromatographed (
Pre-purified with silica gel, PE: EtOAc = 15: 1) and then further purified with preparative TLC (PE: EtOAc = 15: 1). This gave 319.6 mg (19.1%) of methyl 3-[(1-cyclopentyl-2,2,2-trifluoroethyl) amino] -2,6-difluorobenzoate as a colorless oil. LC / MS (ESI) m / z: 338.05 [M + 1] ⁺ .
Step 6: Preparation of 3-((1-cyclopentyl-2,2,2-trifluoroethyl) amino) -2,6-difluorobenzoic acid.

Methyl 3-[(1-cyclopentyl-2, 2, 2-trifluoroethyl) amino] -2,6-difluorobenzoate (298.4 mg, 0.88 mmol, 1 eq) THF (10 ml), methanol (5 mL) _{And LiOH.H 2} O (374.1 mg, 8.91 mmol, 10.1 eq) was added to the stirred solution of H ₂ O (5 mL). The resulting solution was stirred at room temperature for 19 hours. The mixed solution was evaporated to dryness. 20 mL of H ₂ O was added to the residual liquid. The pH was adjusted to 6 by adding 1M HCl. The mixture was extracted with ethyl acetate (40 mLx3). The organic layers were combined, washed with water and brine and dried over Na ₂ SO ₄ . The organic phase was concentrated under vacuum and dried. This gave 287 mg (100%) of 3-[(1-cyclopentyl-2,2,2-trifluoroethyl) amino] -2,6-difluorobenzoic acid as a colorless oil. LC / MS (ESI) m / z: 324.05 [M + 1] ⁺ .
Step 7: Preparation of 3-((1-Cyclopentyl-2,2,2-trifluoroethyl) amino) -2,6-difluorobenzoyl chloride.

3-[(1-Cyclopentyl-2,2,2-trifluoroethyl) amino] -2,6-difluorobenzoic acid (306.3 mg, 0.95 mmol, 1 eq) in a toluene (10 mL) solution with sulfooil dichloride (Sulfurooyl dichloride) (2.8 mL, 38.6 mmol, 40.7 eq) and DMF (0.06 mL, 0.78 mmol, 0.82 eq) were added. The resulting solution was heated and refluxed for 3 hours. The solution was evaporated to dryness and dried under vacuum. This gave 323.8 mg (100%) 3-[(1-cyclopentyl-2,2,2-trifluoroethyl) amino] -2,6-difluorobenzoyl chloride as a light brown oil.

Step 8: (5-bromo-1H-pyrrolo [2,3-b] pyridin-3-yl) (3-((1-cyclopentyl-2,2,2-)
Preparation of trifluoroethyl) amino) -2,6-difluorophenyl) methanone.

5-bromo-1H-pyrrolo [2,3-b] pyridine (187.2 mg, 0.95 mmol, 1.00 eq) in a mixture of dichloromethane (7 mL) of _{AlCl 3} (1.03 g, 7.73 mmol, 8.16 eq) at 0 ° C. Was added. Mix 1 at 0 ° C
Stir for hours. Then, at 0 ° C., a solution of 3-[(1-cyclopentyl-2,2,2-trifluoroethyl) amino] -2,6-difluorobenzoyl chloride (323.8 mg, 0.95 mmol, 1 eq) in dichloromethane (7 mL) Was added. The mixture was stirred for 1 hour at 0 ° C. and then heated to room temperature for an additional 15 hours. The reaction was then quenched by the addition of 15 mL of water and saturated NaHCO ₃ aqueous solution (15 mL). The mixture was extracted with ethyl acetate (30 mLx3). The combined organic layers were washed with brine (10 mLx1) and dried over anhydrous sodium sulfate. The crude product was placed on a silica gel column with ethyl acetate / petroleum ether (2: 5). This resulted in 395.3 mg (83.1%) of 3- [5-bromo-1H-pyrrolo [2,3-b] pyridin-3-carbonyl] -N- (1-cyclopentyl-2,2,2-trifluoroethyl). ) -2,4-Difluoroaniline was obtained as a bright yellow solid. LC / MS (ESI) m / z: 501.95 [M + 1] ⁺ .
Step 9: tert-Butyl 2- (4-((4- (4- (3- (3-((1-cyclopentyl-2,2,2-trifluoroethyl) amino) -2,6-difluorobenzoyl))) Preparation of -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) methyl) piperidine-1-yl) acetate.

3- [5-bromo-1H-pyrrolo [2,3-b] pyridin-3-carbonyl] -N- (1-cyclopentyl-2,2,2-
Trifluoroethyl) -2,4-difluoroaniline (200.7 mg, 0.40 mmol, 1 eq), 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 (358 mg, 0.72 mmol, 1.79 eq) and Na ₂ CO ₃ (127.9 mg, 1.21 mmol, 3.02 equivalent) of a mixture of dioxane (10 mL) and H ₂ O (2.5 mL), N ₂
Purged with. Then, to ^{_{this, Pd (dppf) Cl 2.}} CH 2 Cl 2 (51.4mg, 0.06mmol, 0.16 eq) was added. The closed tube was closed and the reaction mixture was stirred at 105 ° C. for 4 hours. The reaction was then stopped by the addition of water (50 mL). The mixture was extracted with ethyl acetate (40 mLx3), the combined organic layers were washed with brine (30 mLx1) and dried over anhydrous sodium sulfate. The crude product was subjected to a silica gel column with dichloromethane / methanol (15: 1). This resulted in 240.2 mg (75.6%) of tert-butyl 2- [4-([4- [4- (3- [3-[(1-cyclopentyl-2,2,2-trifluoroethyl) amino]- 2,6-Difluorobenzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl] piperazine-1-yl] methyl) piperidine-1-yl] acetate is obtained as a light brown solid. rice field. LC / MS (ESI) m / z: 795.30 [M + 1] ⁺ .
Step 10: 2- (4-((4- (4- (3- ((1-cyclopentyl-2,2,2-trifluoroethyl) amino) -2,6-difluorobenzoyl) -1H- Preparation of pyrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) methyl) piperidine-1-yl) acetic acid.

tert-butyl 2- [4-([4- [4- (3- [3-[(1-Cyclopentyl-2,2,2-trifluoroethyl) amino] -2,6-difluorobenzoyl] -1H- Pyrrolo [2,3-b] Pyridine-5-yl) Phenyl] Piperazine-1-yl] Methyl) Piperidine-1-yl] Acetate (185 mg, 0.23 mmol, 1 equivalent) in dichloromethane (15 mL) solution, TFA (4.0 mL) was added. The reaction solution was stirred at room temperature for 15 hours. The resulting solution was evaporated to dryness and dried under vacuum. This resulted in 171.9 mg (100%) of 2- [4-([4- [4- (3- [3-[(1-cyclopentyl-2,2,2-trifluoroethyl) amino] -2,6). -Difluorobenzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl] piperazine-1-yl] methyl) piperidine-1-yl] Acetic acid was obtained as a bright yellow oil. LC / MS (ESI) m / z: 739.25 [M + 1] ⁺ .
Step 11: (2S, 4R) -1-((2S) -2- (2- (4-((4- (4- (3- (3- ((1-Cyclopentyl-2,2,2-tri) Fluoroethyl) amino) -2,6-difluorobenzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) methyl) piperidine-1-yl) acetamide) -3 Preparation of 4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide.

2- [4-([4- [4- (3- [3-[(1-Cyclopentyl-2,2,2-trifluoroethyl) amino] -2,6-difluorobenzoyl] -1H-pyrrolo [2] , 3-b] Pyridine-5-yl) Phenyl] Piperazin-1-yl] Methyl) Piperidine-1-yl] Acetic acid (171.9 mg, 0.23 mmol, 1 equivalent) and (2S, 4R) -1-[(2S) ) -2-Amino-3,3-dimethylbutanoyl] -4-hydroxy-N-[[4- (4-methyl-1,3-thiazole-5-yl) phenyl] methyl] pyrridin-2-carboxamide hydrochloride DIEA (0.4 mL, 2.42 mmol, 10.40 equivalents) and BOP (200.3 mg, 0.45 mmol, 1.95 equivalents) were added to a DMF (6 mL) solution of salt (175.4 mg, 0.38 mmol, 1.61 equivalents). The reaction solution was stirred at room temperature for 3 hours. The reaction was then quenched by the addition of 30 mL of water. The resulting mixture was extracted with ethyl acetate (50 mLx3). The combined organic layer was washed with water (40 mLx1) and brine (40 mLx1), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by preparative HPLC. This resulted in 109.3 mg (40.8%) of (2S, 4R) -1-[(2S) -2- [2- [4-([4- [4- (3- [3- [(1-cyclopentyl-). 2,2,2-trifluoroethyl) amino] -2,6-difluorobenzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl] piperazine-1-yl] methyl) piperidine-1 -Il] acetamide] -3,3-dimethylbutanoyl] -4-hydroxy-N-[[4- (4-methyl-1,3-thiazole-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide Obtained as a bright yellow solid. LC / MS (ESI) m / z: 1152.20 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 0.96 (s, 9H), 1.10-1.27 (m, 2H), 1.28-1.62 (m) , 6H), 1.63-1.98 (m, 6H), 1.99-2.38 (m, 6H), 2.47 (s, 6H), 2.75-3.09 (m, 4H), 3.11-3.26 (m, 4H), 3.56-3.78 (m, 3H), 4.13-4.57 (m, 6H), 5.17 (s, 1H), 5.73 (d, J = 7.5Hz, 1H), 6.96-7.27 (m, 4H), 7.43 (s, 4H), 7.59 (d, J = 7.5Hz, 2H), 7.83 (d, J = 9.6Hz, 1H), 8.10 (s, 1H), 8.48 (s, 1H), 8.65 (s, 2H), 9.01 (s, 1H) ), 12.8 (br., 1H).
(2S, 4R) -1-((S) -2-(2-(4-((4- (4- (3- (2,6-difluoro-3- (((R) -3-fluoropyrrolidine) )-1-Sulfonamide) Phenoxy) -1H-Pyrrolidine [2,3-b] Pyridine-5-yl) Phenyl) Piperadi
N-1-yl) Methyl) Piperidine-1-yl) Acetamide) -3,3-Dimethylbutanoyl) -4-Hide
Illustrative Synthetic Steps for Roxy-N- (4- (4-Methylthiazole-5-yl) benzyl) Pyrrolidine-2-carboxamide (Example 371) 1: 5-bromo-1-tosyl-1H-pyrrolo [2,3 -b] Preparation of pyridine.

5-bromo-1H-pyrrolo [2,3-b] pyridine (5.91 g, 29.99) at 0 ° C. in a water / ice bath in a 250 mL three-necked round-bottom flask purged and maintained in an inert nitrogen atmosphere. THF (120 mL) of mmol (1 eq) was added, to which NaH (1.80 g, 45.00 mmol, 1.50 eq, 60%) was added in several batches. The obtained mixed solution was stirred at 0 ° C. for 0.5 hours. TsCl (6.29 g, 32.99 mmol, 1.10 eq) was then added and the resulting mixture was stirred for an additional 2 hours at room temperature. Then, water (200 m) was added to the reaction mixture.
It was quenched by the addition of L) and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied on a silica gel column and eluted with ethyl acetate / petroleum ether (1: 2). This gave 10.48 g (99.48%) of 5-bromo-1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b] pyridine as a bright yellow solid. LC / MS (ESI) m / z: 350.75 [M + 1] ⁺ .
Step 2: (2S, 3R) -5-bromo-N, N, N-triethyl-2-hydroxy-1-tosyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridine-3-odor Preparation of ammonium bromide.

In a 250 mL round bottom flask, 5-bromo-1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b] pyridine (7.02 g, 19.99 mmol, 1 eq) and H ₂ O (3.60 mL, A solution of 199.83 mmol (10.00 eq) in acetone (130 mL) was added, to which NBS (3.91 g, 21.97 mmol, 1.10 eq) was added. The resulting solution was stirred at room temperature for 4.5 hours, then TEA (3.0 mL, 21.58 mmol, 1.08 eq) was added. The reaction mixture was stirred at room temperature for an additional hour and then concentrated under vacuum. The residue was applied on a silica gel column and eluted with ethyl acetate / petroleum ether (1: 1). This resulted in 13.70 g (124.78%) of (2S, 3R) -5-bromo-N, N, N-triethyl-2-hydroxy-1- (4-methylbenzenesulfonyl) -1H, 2H, 3H-pyrrolo [ 2,3-b] Pyridine-3-Ammonium bromide was obtained as a brown solid. LC / MS (ESI) m / z: 467.90 [M + 1] ⁺ .
Step 3: Preparation of 2- (difluoromethoxy) -1,3-difluorobenzene.

2,6-Difluorophenol (20.00 g, 153.73 mmol, 1 eq), sodium 2-chloro-2,2-difluoroacetate (46.89 g) in a 500 mL round bottom flask purged and maintained in an inert nitrogen atmosphere. , 307.56 mmol, 2.00 eq), K ₂ CO ₃ (25.49 g, 184.44 mmol, 1.20 eq) DMF (200 mL)
And _{a solution of H 2} O (20 mL) was added. The obtained mixed solution was stirred in an oil tank at 100 ° C. for 3 hours. The reaction mixture was cooled to room temperature and quenched with HCl solution (13 mol / L, 30 mL). The mixture was diluted with water (300 mL) and extracted with ethyl acetate (300 mLx3). The combined organic layers were washed with brine (300 mLx2), dried over anhydrous sodium sulfate and concentrated under vacuum. This gave 17.17 g (62.01%) of 2- (difluoromethoxy) -1,3-difluorobenzene as a yellow liquid. 1H-NMR (300MHz, CDCl3) δ 7.24-7.09 (m, 1H), 7.03-6.93 (m, 2H), 6.69 (t, J = 73.4 Hz, 1H).
Step 4: Preparation of 2- (difluoromethoxy) -1,3-difluoro-4-nitrobenzene.

_{H 2} SO ₄ (35 mL) was placed in a 100 mL three-necked round bottom flask _{, to which HNO 3} (35 mL, 65%) was added in a liquid nitrogen / EtOH bath at -10 ° C. 2- (Difluoromethoxy) -1,3-difluorobenzene (7.00 g, 38.87 mmol, 1 eq) was then added slowly at -10 ° C. The resulting mixture was used for 0.5 hours, -10.
Stir at ° C. The reaction mixture was diluted with cold water (800 mL) and extracted with ethyl acetate (300 mLx3). The combined organic layers were washed with NaHCO ₃ (200 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied on a silica gel column and eluted with ethyl acetate / petroleum ether (1:50). This gave 4.68 g (53.49%) of 2- (difluoromethoxy) -1,3-difluoro-4-nitrobenzene as a yellow oil. 1H-NMR (300MHz, CDCl ₃ ) δ 8.15-8.07 (m, 1H), 7.29-7.17 (m, 1H), 6.69 (t, J = 72.0 Hz, 1H).
Step 5: Preparation of 2,6-difluoro-3-nitrophenol.

In a 250 mL round-bottom flask, a solution of 2- (difluoromethoxy) -1,3-difluoro-4-nitrobenzene (6.68 g, 29.68 mmol, 1 eq) in acetic acid (6 mL) was placed in it and a hydrogen bromide solution (40). %, 90 mL) was added at room temperature. The resulting solution was stirred for 40 hours in an oil bath at 130 ° C. The reaction mixture was cooled to room temperature and diluted with water (500 mL). The resulting mixture was extracted with ethyl acetate (400 mL x 2), the combined organic layers were washed with brine (400 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied on a silica gel column and eluted with ethyl acetate / petroleum ether (1: 4). This gave 3.50 g (67.36%) of 2,6-difluoro-3-nitrophenol as a yellow solid. LC / MS (ESI) m / z: 173.65 [M-1] ^- .
Step 6: Preparation of 5-bromo-3- (2,6-difluoro-3-nitrophenoxy) -1-tosyl-1H-pyrrolo [2,3-b] pyridine.

In a 250 mL round bottom flask, 2,6-difluoro-3-nitrophenol (1.05 g, 6.00 mmol, 1 eq), (2S, 3R) -5-bromo-N, N, N-triethyl-2-hydroxy- 1- (4-Methylbenzenesulfonyl) -1H, 2H, 3H-pyrrolo [2,3-b] pyridine-3-ammonium bromide (3.95 g, 7.19 mmol, 1.20 equivalent), TEA (1.21 g, 11.96 mmol, A 1.99 eq) solution of ethyl acetate (70 mL) was added, to which anhydrous 4 A MS (5 g) was added. The resulting mixture was stirred in an oil bath at 80 ° C. for 4 hours, then cooled to room temperature and ethoxyethanetrifluoroborane (4.26 g, 30.01 mmol, 5.01 eq) was added. The resulting mixture was stirred for another 2 hours in an oil bath at 50 ° C. The reaction mixture was cooled to room temperature and the solids were filtered. The filtrate was diluted with ethyl acetate (250 _{mL), washed with saturated Na 2} CO ₃ solution (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied on a silica gel column and eluted with ethyl acetate / petroleum ether (1: 7). This resulted in 1.13 g (35.94%) of 5-bromo-3- (2,6-difluoro-3-nitrophenoxy) -1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b] pyridine. Was obtained as a yellow solid. LC / MS (ESI) m / z: 523.75 [M + 1] ⁺ .
Step 7: Preparation of 3-((5-bromo-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) oxy) -2,4-difluoroaniline.

In a 50 mL round bottom flask, 5-bromo-3- (2,6-difluoro-3-nitrophenoxy) -1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b] pyridine (1.13 g) , 2.16 mmol, 1 eq) acetic acid (10 mL) solution was added. Subsequently, iron powder (965.6 mg, 17.29 mmol, 8.02 eq) was added at room temperature. The obtained mixed solution was stirred in an oil tank at 50 ° C. for 3 hours. The reaction mixture was cooled to room temperature and the pH value of the mixture was adjusted to 8 _{with saturated Na 2} CO _{3 solution.} The mixture was extracted with ethyl acetate (250 mLx3), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied on a silica gel column and eluted with ethyl acetate / petroleum ether (1/5). This resulted in 510 mg (47.87%) of 3-[[5-bromo-1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] oxy] -2,4- Difluoroaniline was obtained as a pink solid. LC / MS (ESI) m / z: 493.75 [M + 1] ⁺ .
Step 8: Preparation of 3-((5-bromo-1H-pyrrolo [2,3-b] pyridin-3-yl) oxy) -2,4-difluoroaniline.

In a 50 mL round bottom flask, 3-[[5-bromo-1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] oxy] -2,4-difluoroaniline A solution of TBAF (3.5 mL) in THF (7 mL) was added (510 mg, 1.03 mmol, 1 eq). The resulting solution was stirred at room temperature for 24 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (120 mLx3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied on a silica gel column and eluted with ethyl acetate / petroleum ether (2/3). This gave 290 mg (82.64%) of 3-([5-bromo-1H-pyrrolo [2,3-b] pyridin-3-yl] oxy) -2,4-difluoroaniline as a light brown solid. .. LC / MS (ESI) m / z: 339.80 [M + 1] ⁺ .
Step 9: (R) -N- (3-((5-bromo-1H-pyrrolo [2,3-b] pyridin-3-yl) oxy) -2,4-difluorophenyl) -3-fluoropyrrolidine- Preparation of 1-sulfonamide.

In an 8 mL closed tube, 3-([5-bromo-1H-pyrrolo [2,3-b] pyridin-3-yl] oxy) -2,4-difluoroaniline (200 mg, 0.59 mmol, 1 eq), DMAP Add a solution of pyridine (660 mL) (14.4 mg, 0.12 mmol, 0.20 eq) and slowly add (3R) -3-fluoropyrrolidin-1-sulfonyl chloride (220.6 mg, 1.18 mmol, 2.00 eq) at room temperature. rice field. The resulting solution was placed in an oil bath for 24 hours at 45 ° C.
Was stirred with. The reaction mixture was cooled to room temperature and diluted with water (50 mL). The mixture was extracted with ethyl acetate (50 mLx2), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied on a silica gel column and eluted with ethyl acetate / petroleum ether (1/1). This resulted in 216 mg (74.77%) of (3R) -N- [3-([5-bromo-1H-pyrrolo [2,3-b] pyridin-3-yl] oxy) -2,4-difluorophenyl]. -3-Fluoropyrrolidine-1-sulfonamide was obtained as a light brown solid. LC / MS (ESI) m / z: 490.75 [M + 1] ⁺ .
Step 10: tert-butyl (R) -2- (4-((4- (4- (4- (3- (2,6-difluoro-3-((3-fluoropyrrolidin) -1-sulfonamide) phenoxy)- Preparation of 1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) methyl) piperidine-1-yl) acetate.

In a 30 mL closed tube purged and maintained in an inert nitrogen atmosphere, (3R) -N- [3-([5-bromo-1H-pyrrolo [2,3-b] pyridin-3-yl] oxy) -2,4-difluorophenyl] -3-fluoropyrrolidine-1-sulfonamide (300 mg, 0.61 mmol, 1 equivalent), tert-butyl 2- [4-([4- [4- (4,4,5,,) Five-
Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine-1-yl] methyl) piperazine-1-yl] acetate (366 mg, 0.73 mmol, 1.20 equivalents), Na ₂ CO ₃ (194.2 mg) , 1.83 mmol, 3.00 eq), Pd (dppf) Cl _2- CH ₂ Cl ₂ (49.9 mg, 0.06 mmol, 0.10 eq _{) in a solution of dioxane (12 mL) and H 2} O (2 mL). The obtained mixed solution was stirred in an oil tank at 105 ° C. for 2 hours. The reaction mixture was cooled to room temperature and diluted with water (80 mL). The resulting mixture was extracted with ethyl acetate (80 mLx2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied on a silica gel column and eluted with dichloromethane / methanol (15/1). This resulted in 454 mg (94.84%) of tert-butyl 2- (4-[[4- (4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidine-1-). Il] sulfonyl] amino) phenoxy] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazine-1-yl] methyl] piperidine-1-yl) acetate was obtained as a brown solid. .. LC / MS (ESI) m / z: 784.05 [M + 1] ⁺ .
Step 11: (R) -2- (4-((4- (4- (3- (2,6-difluoro-3-((3-fluoropyrrolidin) -1-sulfonamide) phenoxy) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperazin-1-yl) Methyl) Piperidine-1-yl) Preparation of acetic acid.

In a 50 mL round-bottom flask, tert-butyl 2- (4-[[4- [3- [2,6-difluoro-3-([[(3R) -3-)
Fluoropyrrolidine-1-yl] sulfonyl] amino) phenoxy] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazine-1-yl] methyl] piperidine-1-yl) acetate (398 mg) , 0.51 mmol, 1 eq) in dichloromethane (6 ml), to which TFA (3 mL) was added at room temperature. The resulting mixture was stirred in an oil bath at 35 ° C. for 3 hours and then concentrated under vacuum. This resulted in 369 mg (99.86%) of 2- (4-[[4- [4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidine-1-yl]].
Sulfonyl] amino) phenoxy] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazine-1-yl] methyl] piperidine-1-yl) acetic acid was obtained as a brown oil. LC / MS (ESI) m / z: 728.05 [M + 1] ⁺ .
Step 12: (2S, 4R) -1-((S) -2- (2-(4-((4- (4- (3- (2,6-difluoro-3- (((R) -3) -3) -Fluoropyrrolidine) -1-sulfonamide) phenoxy) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) methyl) piperidine-1-yl) acetamide) -3, Preparation of 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide.

2- (4-[[4- (4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) phenoxy) in an 8 mL tube ] -1H-pyrrolidine [2,3-b] pyridin-5-yl] phenyl)
Piperazin-1-yl] methyl] piperidine-1-yl) acetic acid (218.3 mg, 0.30 mmol, 1 eq), (2S, 4R) -1-[(2S) -2-amino-3,3-dimethylbutanoyl) ] -4-Hydroxy-N-[[4- (4-methyl-1,3-thiazole-5-yl) phenyl] methyl] piperidine-2-carboxamide (168.1 mg, 0.39 mmol, 1.30 equivalent), DIEA (155 mg) , 1.20 mmol, 4.00 eq), BOP (159.1 mg, 0.36 mmol, 1.20 eq) in DMF (5 mL) solution. The resulting solution was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with a mixed solution of dichloromethane / methanol (10/1, 50 mLx2). The organic layers were combined into one, washed with brine (50 mLx2), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue is applied on a silica gel column and dichloromethane / methanol (13/1)
Was eluted using. The resulting product was further purified by preparative HPLC. This resulted in 64.2 mg (18.77%) of (2S, 4R) -1-[(2S) -2- [2- (4- [[4- (4- [3- [2,6-difluoro-3-]. ([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) phenoxy] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazine-1-yl] methyl] piperidine -1-yl) acetamide] -3,3-dimethylbutanoyl] -4-hydroxy-N-[[4- (4-methyl-1,3-thiazole-5-yl) phenyl] methyl
] Pyrrolidine-2-carboxamide was obtained as a white solid. LC / MS (ESI) m / z: 1140.2 [M + 1] +; 1H-NMR (300MHz, CD3OD) δ 8.87 (s, 1H), 8.43 (s, 1H), 7.99 (s, 1H), 7.51- 7.40 (m, 7H), 7.09-7.03 (m, 4H), 5.08 (d, J = 53.0 Hz, 1H), 4.63-4.48 (m, 4H), 4.38-4.33 (m, 1H), 3.91-3.76 ( m, 2H), 3.63-3.34 (m, 4H), 3.22-3.19 (m, 4H), 3.02
(s, 2H), 2.91-2.84 (m, 2H), 2.57-2.54 (m, 4H), 2.47 (s, 3H), 2.25-2.16 (m, 5H), 2.12-1.97 (m, 2H), 1.87 -1.76 (m, 3H), 1.60 (s, 1H), 1.36-1.27 (m, 2H), 1.04 (s, 9H).
(2S, 4R) -1-((S) -2- (2- (3- (2- (3- (3- (4- (3- (2,6-difluoro-3- (((R) -3-) -3-) Fluoropyrrolizi
N) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) azetidine-1-yl) ethyl) azetidine-1-yl) acetamide) -3,3- Dimethylbutanoyl) -4-hi
Droxy-N- (4- (4-Methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide
Illustrative synthesis (Example 441)
Step 1: Preparation of tert-butyl 3- (4- (benzyloxy) phenyl) azetidine-1-carboxylate.

Zinc (11 g) in a 1000 mL three-necked round-bottom flask purged and maintained in an inert nitrogen atmosphere.
, 168.25 mmol, 2.95 eq) in DMF (400 mL) solution, to which I ₂ (2.23 g, 8.79 mmol, 0.15 eq) was added at room temperature. The resulting mixture was stirred at room temperature for about 5 minutes and then filled with tert-butyl 3-iodoazetidine-1-carboxylate (16.2 g, 57.22 mmol, 1.00 eq) in several batches. The reaction mixture was stirred at room temperature for about 1 hour. Then, in the above mixture, 1- (benzyloxy) -4-bromobenzene (15 g, 57.01 mmol, 1.00 eq), SPhos (2.4 g, 5.85 mmol, 0.10 eq), Pd ₂ (dba) ₃ (3.6 g, 3.93). mmol, 0.07 eq) was added. The obtained mixed solution was stirred at 50 ° C. for another 3 hours under a nitrogen atmosphere. The reaction was then quenched by adding 2000 mL of water and the resulting mixture was extracted with ethyl acetate (3x700 mL). The organic layers were combined into one, washed with brine (3x700 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied on a silica gel column and eluted with ethyl acetate / petroleum ether (0% -33% gradient). This gave 13 g (67.25%) of tert-butyl 3- [4- (benzyloxy) phenyl] azetidine-1-carboxylate as a yellow solid. LC / MS (ESI) m / z: 340.10 [M + 1] ⁺ .
Step 2: Preparation of tert-butyl 3- (4-hydroxyphenyl) azetidine-1-carboxylate.

In a 100 mL round bottom flask, under nitrogen atmosphere, tert-butyl 3- [4- (benzyloxy) phenyl] azetidine-1-carboxylate (3 g, 8.84 mmol, 1.00 eq) and Pd / C (10%, 10%, 3 g, 28.18 mmol, 3.19 eq)) MeOH (30 mL) solution was added. The flask was then evacuated and flushed with hydrogen. The reaction mixture was hydrogenated at room temperature for 3 hours in a hydrogen atmosphere using a hydrogen balloon. The reaction mixture was then filtered through a bed of Celite and the filtrate was concentrated under reduced pressure. This gave 1.5 g (68.18%) of tert-butyl 3- (4-hydroxyphenyl) azetidine-1-carboxylate as a white solid. LC / MS (ESI) m / z: 250.10 [M + 1] ⁺ .
Step 3: Preparation of tert-butyl 3-(4-(((trifluoromethyl) sulfonyl) oxy) phenyl) azetidine-1-carboxylate.

In a 100 mL round bottom flask, tert-butyl 3- (4-hydroxyphenyl) azetidine-1-carboxylate (1.5 g, 0.006 mmol, 1.00 eq), phenyl (trifluoromethanesulfonyloxy)
A DCM (30 mL) solution of aminotrifluoromethanesulfonate (4.6 g, 11.82 mmol, 1.96 eq) and DIEA (2.30 g, 17.80 mmol, 2.96 eq) was added. The resulting solution was stirred at room temperature for 12 hours. The mixture was concentrated. The residue is applied on a silica gel column and ethyl acetate / petroleum ether (1).
: 100 to 3: 100 gradient). This gave 1.5 g (65.36%) of tert-butyl 3- [4- (trifluoromethanesulfonyloxy) phenyl] azetidine-1-carboxylate as an off-white oil. LC / MS (ESI) m / z: 382.10 [M + 1] ⁺ .
Step 4: Preparation of tert-butyl 3- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) azetidine-1-carboxylate.

In a 100 mL round bottom flask, tert-butyl 3- [4- (trifluoromethanesulfonyloxy)
Phenyl] azetidine-1-carboxylate (1.5 g, 3.93 mmol, 1.00 eq), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2) -Dioxaborolan-2-yl) -1,3,2-dioxaborolane (1.5 g, 5.90 mmol, 1.50 eq), KOAc (1.2 g, 12.23 mmol, 3.11 eq), Pd (dppf) Cl ₂ (140 mg, 0.19 mmol, A solution of (0.05 eq) dioxane (10 ml) was added under a nitrogen atmosphere. The obtained solution was stirred at 100 ° C. for 1 hour under a nitrogen atmosphere. The mixture was concentrated and the residue was applied on a silica gel column and eluted with ethyl acetate / petroleum ether (gradient 1: 100-1: 10). This resulted in 500 mg (35.38%) of tert-butyl 3- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] azetidine-1-carboxylate. Was obtained as a yellow oil. LC / MS (ESI) m / z: 360.23 [M + 1] ⁺ .
Step 5: Preparation of 3- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) azetidine.

In a 100 mL round bottom flask, tert-butyl 3- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] azetidine-1-carboxylate (500 mg) , 1.39 mmmo, 1.00 equivalent) DCM
A solution of (10 mL) was added and TFA (3 mL) was added thereto. The resulting solution was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. This gave 350 mg (crude) 3- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] azetidine as a yellow oil.

Step 6: Preparation of tert-butyl 3- (2-hydroxyethyl) azetidine-1-carboxylate.

In a 250 mL three-necked round-bottom flask, place a solution of 2- [1-[(tert-butoxy) carbonyl] azetidine-3-yl] acetic acid (10 g, 46.46 mmol, 1.00 eq) in THF (100 mL) into it. A _{solution of BH 3 in} THF (70 mL) was added dropwise at 0 ° C. The resulting solution was stirred at room temperature for 12 hours. The reaction was then quenched by the addition of NaOH solution (2M, 100 mL). The resulting mixture was extracted with ethyl acetate (3x100 mL), the combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. This gave 8.5 g (90.91%) of tert-butyl 3- (2-hydroxyethyl) azetidine-1-carboxylate as a bright yellow oil.

Step 7: Preparation of tert-butyl 3- (2- (tosyloxy) ethyl) azetidine-1-carboxylate.

In a 500 mL 3-neck round bottom flask, tert-butyl 3- (2-hydroxyethyl) azetidine-1-carboxylate (8.5 g, 42.23 mmol, 1.00 eq), TEA (12.8 g, 0.13 mmol, 3.00 eq) A solution of DCM (100 mL) was added thereto, and TsCl (10.5 g, 55.08 mmol, 1.30 eq) was slowly added to the solution. The resulting solution was stirred at room temperature for 12 hours. The reaction was then stopped by the addition of 100 mL of water. The resulting mixture was extracted with dichloromethane (2x50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was applied on a silica gel column and eluted with ethyl acetate / petroleum ether (1: 100-40: 100 gradient). This gave 8 g (53.33%) of tert-butyl 3- (2- (tosyloxy) ethyl) azetidine-1-carboxylate as a yellow oil.

Step 8: tert-butyl 3-(2- (3- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-)
Preparation of yl) phenyl) azetidine-1-yl) ethyl) azetidine-1-carboxylate.

In a 100 mL round bottom flask, 3- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] azetidine (350 mg, 1.35 mmol, 1.00 eq), tert -Butyl 3- [2-[(4-methylbenzenesulfonyl) oxy] ethyl] azetidine-1-carboxylate (480 mg, 1.35 mmol, 1.00 eq), K ₂ CO ₃ (932 mg, 6.74 mmol, 4.99 eq), A solution of NaI (20 mg, 0.133 mmol, 0.10 eq) in MeCN (50 mL) was added. The resulting solution was stirred for 12 hours in an oil bath at 70 ° C. The insoluble solid was filtered and the filtrate was concentrated. The residue is applied on a silica gel column and dichloromethane /
Elution was performed using methanol (gradient of 100: 1 to 100: 7). This resulted in 180 mg (30.13%) of tert-butyl 3-(2- [3- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] azetidine. -1-yl] ethyl) azetidine-1-carboxylate was obtained as a yellow solid. LC / MS (ESI) m / z: 443.25 [M + 1] ⁺ .
Step 9: tert-butyl (R) -3-(2-(3- (4- (3- (2,6-difluoro-3-((3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H) -Preparation of pyrrolidine [2,3-b] pyridin-5-yl) phenyl) azetidine-1-yl) ethyl) azetidine-1-carboxylate.

In a 100 mL round bottom flask, tert-butyl 3-(2- [3- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] azetidine-1 -Il] ethyl) Azetidine-1-carboxylate (180 mg, 0.41 mmol, 1.00 eq), (3R) -N- (3- [5-bromo-1H-pyrrolo [2,3-b] pyridine-3- Carbonyl] -2,4-difluorophenyl) -3-fluoropyrrolidin-1-sulfonamide (204 mg, 0.41 mmol, 1.00 eq), Na ₂ CO ₃ (130 mg, 1.227 mmol, 3.01 eq), Pd (dppf) Cl ₂ A solution of dioxane (17 mL) and water (3 mL) (60 mg, 0.082 mmol, 0.20 eq) was added under a nitrogen atmosphere. The obtained mixed solution was stirred in an oil tank at 85 ° C. for 2 hours. The residue was applied on a silica gel column and eluted with dichloromethane / methanol (gradient of 100: 1-100: 8). This resulted in 100 mg (33.27%) of tert-butyl 3- [2- [3- (4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidine-1-yl). ] Sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) azetidine-1-yl] ethyl] azetidine-1-carboxylate was obtained as a yellow solid. LC / MS (ESI) m / z: 739.25 [M + 1] ⁺ .
Step 10: (R) -N- (3- (5- (4- (1- (2- (azetidine-3-yl) ethyl) azetidine-3-yl) phenyl) -1H-pyrrolo [2,3- b] Preparation of pyridine-3-carbonyl) -2,4-difluorophenyl) -3-fluoropyrrolidine-1-sulfonamide.

In a 50 mL round bottom flask, tert-butyl 3- [2- [3- (4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] sulfonyl) ] Amino) benzoyl] -1H-pyrrolidine [2,3-b] pyridine-5-yl] phenyl) azetidine-1-yl] ethyl] azetidine-1-carboxylate (20 mg, 0.027 mmol, 1 equivalent) DCM A (3 mL) solution was added and TFA (0.2 mL) was added to it at room temperature. The resulting solution was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum. This resulted in 15 mg (coarse) (3R) -N- [3- [5- (4- [1- [2- (azetidine-3-yl) ethyl] azetidine-3-yl] phenyl) -1H-pyrrolo. [2,3-b] Pyridine-3-carbonyl] -2,4-difluorophenyl] -3-fluoropyrrolidine-1-sulfonamide was obtained as a yellow solid.

Step 11: (R) -2- (3- (2- (3- (4- (3- (2,6-difluoro-3- ((3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H) -Pyrrolidine [2,3-b] Pyridine-5-yl) Phenyl) Azetidine-1-yl) Ethyl) Azetidine-1-yl) Preparation of acetic acid.

In a 50 mL round bottom flask, (3R) -N- [3- [5-(4- [1- [2- (azetidine-3-yl) ethyl] azetidine-3-yl] phenyl) -1H-pyrrolo [ 2,3-b] pyridine-3-carbonyl] -2,4-difluorophenyl] -3-fluoropyrrolidin-1-sulfonamide (100 mg, 0.157 mmol, 1 equivalent), 2-oxoacetic acid (13 mg, 0.176 mmol, 1.12 equivalents) of DCE (10 mL) solution was added. The resulting mixture was stirred at room temperature for 10 hours, then NaBH (OAc) ₃ (100 mg, 0.472 mmol, 3.01 eq) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction was then stopped by the addition of 1 mL of water. The resulting mixture was extracted with dichloromethane (2x10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by preparative HPLC. This resulted in 20 mg (18.33% for 2 steps) 2-(3- [2- [3- (4- [3- [2,6-difluoro-3-([[(3R) -3-fluoro). Pyrrolidine-1-yl] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) azetidine-1-yl] ethyl] azetidine-1-yl) Acetic acid is a colorless oil Obtained as. LC / MS (ESI) m / z: 696.95 [M + 1] ⁺ .
Step 12: (2S, 4R) -1-((S) -2- (2- (3- (2- (3- (4- (3- (2,6-difluoro-3- (((R)) -3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) azetidine-1-yl) ethyl) azetidine-1-yl) acetamide)- Preparation of 3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide.

In a 100 mL round bottom flask, (3R) -N- [3- [5-(4- [1- [2- (azetidine-3-yl) ethyl] azetidine-3-yl] phenyl) -1H-pyrrolo [ 2,3-b] pyridine-3-carbonyl] -2,4-difluorophenyl] -3-fluoropyrrolidin-1-sulfonamide (120 mg, 0.172 mmol, 1.00 equivalent), (2S, 4R) -1-[() 2S) -2-amino-3,3-dimethylbutanoyl] -4-hydroxy-N-[[4- (4-methyl-1,3-thiazole-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide A solution of DMF (5 mL) of (74 mg, 0.172 mmol, 1.00 equivalent), DIEA (111 mg, 0.859 mmol, 4.99 equivalent), BOP (114 mg, 0.26 mmol, 1.50 equivalent) was added. The resulting solution was stirred at room temperature for 1 hour. The mixture was concentrated. The crude product was purified by preparative HPLC. This resulted in 46.2 mg (18.33%) of (2S, 4R) -1-((S) -2- (2- (3- (2- (3- (4- (3- (2,6-difluoro-) 3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) azetidine-1-yl) ethyl) azetidine
-1-yl) acetamide) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide is obtained as a yellow solid. rice field. LC / MS (ESI) m / z: 1109.35 [M + 1] +; 1H-NMR (300MHz, DMSO-d6) δ 8.96 (m, 1H), 8.67 (s,
1H), 8.56-8.54 (m, 2H), 8.01 (s, 1H), 7.95-7.89 (d, 1H), 7.78-7.75 (m, 2H), 7.54-7.45 (m, 4H), 7.39-7.37 ( m, 4H), 6.86 (m, 1H), 5.32 (m, 1H), 5.18 (m, 2H), 4.66-4.39 (m, 10H), 4.30-4.28 (m, 1H), 3.69-3.62 (m, 6H), 3.20-3.07 (m, 6H), 2.60 (m, 2H), 2.43-2.41 (m, 2H), 2.12-1.65 (m, 7H), 0.97 (s, 9H).
2- (4-((1- (4- (3- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2, 3-b] Pyridine-5-yl) phenyl) piperidine-4-yl) methyl) piperazine-1-yl) -N-((S) -1-((2S, 4R) -4-hydroxy-2-( Example of 5- (4- (4-methylthiazole-5-yl) phenyl) -1H-imidazol-2-yl) pyrrolidine-1-yl) -3,3-dimethyl-1-oxobutane-2-yl) acetamide Synthesis (eg 386)
Step 1: Preparation of benzyl (2S, 4R) -1-((S) -2-((tert-butoxycarbonyl) amino) -3,3-dimethylbutanoyl) -4-hydroxypyrrolidine-2-carboxylate ..

N, N-dimethylformamide (200 mL), (2S) -2-[[(tert-butoxy) carbonyl] amino] -3 in a 1000 mL three-necked round-bottom flask purged and maintained in an inert nitrogen atmosphere. , 3-Dimethylbutanoic acid (48.98 g, 211.77 mmol, 1.00 eq) was added. Then, after stirring for 20 minutes, HATU (96.69 g, 254.29 mmol, 1.20 eq) and DIEA (109.4 g, 846.49 mmol, 4.00 eq) were added at 0 ° C. To this was added benzyl (2S, 4R) -4-hydroxypyrrolidine-2-carboxylate (100.0 g, 254.45 mmol, 1.20 eq) in several batches at 0 ° C. The resulting solution was stirred at room temperature for 2 hours. The resulting solution was extracted with ethyl acetate (300 mLx3) and the organic layers were combined into one. The resulting mixture was washed with brine (100 mLx2). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (7/3). This resulted in 80 g (87%) of benzyl (2S, 4R) -1-[(2S) -2-[[(tert-butoxy) carbonyl] amino] -3,3-dimethylbutanoyl] -4-hydroxypyrrolidine. -2-Carboxylate was obtained as a bright yellow solid.

Step 2: Preparation of (2S, 4R) -1-((S) -2-((tert-butoxycarbonyl) amino) -3,3-dimethylbutanoyl) -4-hydroxypyrrolidine-2-carboxylic acid.

In a 100 mL round bottom flask, benzyl (2S, 4R) -1-[(2S) -2-[[(tert-butoxy) carbonyl] amino] -3,3-dimethylbutanoyl] -4-hydroxypyrrolidin-2 -Carboxylate (3 g, 6.90 mmol, 1 eq) and menthol (50 mL, 1.56 mmol, 0.23 eq) were added at room temperature in a nitrogen atmosphere. Pd / C (200 mg, 1.88 mmol, 0.27 eq) was added to the stirred solution in several portions under a nitrogen atmosphere at room temperature. The flask was then evacuated and flushed with hydrogen. The reaction mixture was hydrogenated at room temperature for 16 hours under a hydrogen atmosphere using a hydrogen balloon, then filtered through a bed of Celite, the filtered cake washed with menthol (120 mL) and concentrated under reduced pressure. This resulted in (2S, 4R) -1-[(2S) -2-[[(tert-butoxy) carbonyl] amino] -3,3-dimethylbutanoyl] -4-hydroxypyrrolidine-2-carboxylic acid (1.67). g, 70.23%) was obtained as a white solid.

Step 3: 2- (4-Bromophenyl) -2-oxoethyl (2S, 4R) -1-((S) -2-((tert-butoxycarbonyl) amino) -3,3-dimethylbutanoyl) -4 -Preparation of hydroxypyrrolidine-2-carboxylate.

2-Bromo-1- (4-bromophenyl) ethane-1-one (1.04 g, 3.74 mmol, 1 eq), N, N-diisopropylethylamine (1.5 g, 11.61 mmol, 3.10 eq) in a 50 mL round bottom flask. ) And (2S, 4R) -1- [(2S) -2-[[(tert-butoxy) carbonyl] amino] -3,3-dimethylbutanoyl] -4-hydroxypyrrolidin-2-carboxylic acid (1.3 g) , 3.77 mmol, 1.01 eq) in acetonitrile (40 mL) was added at room temperature. The resulting mixture was stirred at room temperature for 3 hours and then concentrated under vacuum.
The residue was purified by petroleum ether / ethyl acetate (1: 1) elution by silica gel column chromatography to 2- (4-bromophenyl) -2-oxoethyl (2S, 4R) -1-[(2S). -2-[[(tert-butoxy) carbonyl] amino] -3,3-dimethylbutanoyl] -4-hydroxypyrrolidin-2-carboxylate (2.16 g, 74.63%) was obtained as a white solid. LC / MS (ESI) m / z: 541.00 [M + 1] ⁺ .
Step 4: tert-butyl ((S) -1-((2S, 4R) -2- (5- (4-bromophenyl) -1H-imidazol-2-
Ill) -4-hydroxypyrrolidine-1-yl) -3,3-dimethyl-1-oxobutane-2-yl) Preparation of carbamate.

In a 100 mL round bottom flask, 2- (4-bromophenyl) -2-oxoethyl (2S, 4R) -1-[(2S) -2-[[(tert-butoxy) carbonyl] amino] -3,3- A solution of dimethylbutanoyl] -4-hydroxypyrrolidin-2-carboxylate (2.06 g, 3.80 mmol, 1 eq) and ammonium acetate (2.3 g, 29.84 mmol, 7.84 eq) in xylene (40 mL) was added at room temperature. The resulting mixture was stirred for 3 hours at 140 ° C. The reaction mixture was cooled to room temperature and diluted with water (100 mL). The mixture was extracted with ethyl acetate (50 mLx3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with ethyl acetate (100%) and tert-butyl N-[(2S) -1-[(2S, 4R) -2- [5- (4-bromo). Phenyl) -1H-imidazol-2-yl] -4-hydroxypyrrolidin-1-yl] -3,3-dimethyl-1-oxobutan-2-yl] carbamate (1.5 g, 75.61%) as a yellow solid Obtained as. L
C / MS (ESI) m / z: 522.95 [M + 1] ⁺ .
Step 5: tert-butyl ((S) -1-((2S, 4R) -4-hydroxy-2- (5-(4- (4-methylthiazole-5-yl) phenyl) -1H-imidazole-2) -Il) Preparation of pyrrolidine-1-yl) -3,3-dimethyl-1-oxobutan-2-yl) carbamate.

In a 10 mL closed tube, tert-butyl N-[(2S) -1-[(2S, 4R) -2- [5- (4-bromophenyl) -1H-imidazol-2-yl] -4-hydroxypyrrolidin -1-yl] -3,3-dimethyl-1-oxobutane-2-yl] carbamate (1.4 g, 2.68 mmol, 1 eq), potassium carbonate (1.1 g, 7.96 mmol, 2.96 eq), Pd (dppf) ) Cl ₂ CH ₂ Cl ₂ (219.3 mg, 0.27 mmol, 0.1 eq) and 4-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1 A solution of dioxane (50 mL) and water (10 mL) of 3-thiazole (785.7 mg, 3.49 mmol, 1.3 eq) was added at room temperature in a nitrogen atmosphere. The obtained mixed solution was stirred at 90 ° C. for 3 hours under a nitrogen atmosphere. The mixture was cooled to room temperature. The aqueous layer was extracted with ethyl acetate (100 mLx3). The combined organic layers were washed with brine (50 mLx2), dried over sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluting with methanol / methyl alcohol (10: 1) and tert-butyl N-[(2S) -1-[(2S, 4R) -4-hydroxy-2- [5]. -[4- (4-Methyl-1,3-thiazole-5-yl) phenyl] -1H-imidazol-2-yl] pyrrolidine-1-yl] -3,3-dimethyl-1-oxobutane-2-yl ] Carbamic acid salt (1.3 g, 89.72%) was obtained as a yellow solid. LC / MS (ESI) m / z: 540.10 [M + 1] ⁺ .
Step 6: (S) -2-amino-1-((2S, 4R) -4-hydroxy-2-(5-(4- (4-methylthiazole-5-yl) phenyl) -1H-imidazole-2) -Il) Preparation of pyrrolidine-1-yl) -3,3-dimethylbutane-1-one hydrochloride.

In a 50 mL round bottom flask, tert-butyl N-[(2S) -1-[(2S, 4R) -4-hydroxy-2- [5- [4- (4- (4- (4- (4-)
Methyl-1,3-thiazole-5-yl) phenyl] -1H-imidazol-2-yl] pyrrolidine-1-yl] -3,3-dimethyl-1-oxobutan-2-yl] carbamate (1.3 g) , 2.41 mmol, 1 eq) and a dioxane (20 mL, 4 mol / L) solution of hydrochloric acid was added at room temperature. The resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. As a result, (2S) -2-amino-1-[(2S, 4R) -4-hydroxy-2- [5- [4- (4-methyl-1,3-thiazole-5-yl) phenyl]- 1H-imidazol-2-yl] pyrrolidine-1-yl] -3,3-dimethylbutane-1-one hydrochloride (1.25 g, crude) was obtained as a yellow solid. LC / MS (ESI) m / z: 440.30 [M + 1] ⁺ .
Step 7: Preparation of tert-butyl 4-((1-((benzyloxy) carbonyl) piperidine-4-yl) methyl) piperazine-1-carboxylate.

In a 500 mL round bottom flask, benzyl 4-formylpiperidin-1-carboxylate (5 g, 20.22 mmol, 1.00 equivalent), tert-butyl piperazine-1-carboxylate (3.8 g, 20.40 mmol, 1.01 equivalent), dichloromethane. (200 mL) was added. Subsequently, sodium triacetoxyborohydride (5.15 g) was added in several portions at 25 ° C. for 10 minutes. The resulting solution was stirred for 3 hours at 25 ° C. The reaction was then quenched by the addition of water (50 mL) and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (3: 7-9: 1). This gave 7.62 g (90%) of tert-butyl 4-([1-[(benzyloxy) carbonyl] piperidine-4-yl] methyl) piperazine-1-carboxylate as a bright yellow solid. .. LC / MS (ESI) m / z: 418.20 [M + 1] ⁺ .
Step 8: Preparation of tert-butyl 4- (piperidine-4-ylmethyl) piperazine-1-carboxylate.

In a 500 mL round-bottom flask purged and maintained in an inert nitrogen atmosphere, tert-butyl 4-([1-[(benzyloxy) carbonyl] piperidine-4-yl] methyl) piperazine-1-carboxylate ( 7.62 g, 18.25 mmol, 1.00 equivalent), ethanol (200 mL) and palladium carbon (500 mg) were added. The flask was then evacuated and flushed with hydrogen using a hydrogen balloon. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through a bed of Celite, and the filtrate was concentrated under reduced pressure. As a result, 4.66 g (crude) of tert-butyl 4- (piperidine-4-ylmethyl) piperazine-1-carboxylate was obtained as a colorless oil. LC / MS (ESI) m / z: 284.10 [M + 1]
⁺ .
Step 9: Preparation of tert-butyl 4-((1- (4-bromophenyl) piperidine-4-yl) methyl) piperazine-1-carboxylate.

In a 250 mL three-necked round-bottomed flask, tert-butyl 4-[(piperidin-4-yl) methyl] piperazin-1-carboxylate (4.27 g, 15.07 mmol, 1 eq), (4-bromophenyl) boron Acid (3.63 g, 18.07 mmol, 1.20 eq), dichloromethane (100 mL), 4A MS (5 g), (acetyloxy) Carboxylic acid acetate (4.10 g, 22.57 mmol, 1.50 eq), TEA (8.4 mL, 60.43 mmol, 4.01 equivalent) was added. The resulting mixture was purged with air and stirred at room temperature for 20 hours. The solid was filtered and the filtrate was concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1: 2). This gave 3.87 g (58.59%) of tert-butyl 4-[[1- (4-bromophenyl) piperidine-4-yl] methyl] piperazine-1-carboxylate as a light brown solid. LC / MS (ESI) m / z: 438.00 [M + 1] ⁺ .
Step 10: Preparation of 1-((1- (4-bromophenyl) piperidine-4-yl) methyl) piperazine.

In a 100 mL round bottom flask, tert-butyl 4-[[1- (4-bromophenyl) piperidine-4-yl]
Methyl] piperazine-1-carboxylate (3.87 g, 8.83 mmol, 1 eq), dichloromethane (20 mL), trifluoroacetic acid (10 mL) were added. The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum. This gave 7.56 g (189.34%) of 1-[[1- (4-bromophenyl) piperidine-4-yl] methyl] piperazine; trifluoroacetic acid as a brown solid. LC / MS (ESI) m / z: 337.95 [M + 1] ⁺ .
Step 11: Preparation of tert-butyl 2- (4-((1- (4-bromophenyl) piperidine-4-yl) methyl) piperazine-1-yl) acetate.

In a 500 mL round bottom flask, 1-[[1- (4-bromophenyl) piperidine-4-yl] methyl] piperazine; trifluoroacetic acid (7.56 g, 16.71 mmol, 1 eq), TEA (23 mL, 165.47 mmol, 9.90 eq) and dichloromethane (130 mL) were added. Subsequently, tert-butyl 2-bromoacetate (3.59 g, 18.40 mmol, 1.10 eq) was added dropwise with stirring. The resulting solution was stirred at room temperature for 2 hours. The resulting solution was diluted with dichloromethane (200 mL) and washed with water (100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1: 1). This yields 3.43 g (45.36%) of tert-butyl 2- (4-[[1- (4-bromophenyl) piperidine-4-yl] methyl] piperazine-1-yl) acetate as a yellow solid. rice field. LC / MS (ESI) m / z: 451.95 [M + 1] ⁺ .
Step 12: tert-butyl 2- (4-((1- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperidine-4-yl)) Preparation of methyl) piperazine-1-yl) acetate.

In a 250 mL round bottom flask purged and maintained in an inert nitrogen atmosphere, tert-butyl 2-(4-[[1- (4-bromophenyl) piperidin-4-yl] methyl] piperazin-1-yl) Acetate (3.90 g, 8.62 mmol, 1 eq), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolane (4.38 g, 17.25 mmol, 2.00 eq), KOAc (2.53 g, 25.78 mmol, 2.99 eq), Pd (dppf) Cl ₂ .CH ₂ Cl ₂ (704 mg, 0.86 mmol, 0.10 eq) ), DMSO (70m)
L) was put in. The obtained mixed solution was stirred in an oil tank at 90 ° C. for 16 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (500 mL). The mixture was washed with water (200 mL) and brine (100 mLx1). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (2: 1). This resulted in 2.57 g (59.69%) of tert-butyl 2- [4-([1- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl). ] Piperidine-4-yl] Methyl) Piperazine-1-yl] Acetate was obtained as a light brown solid. LC / MS (ESI) m / z: 500.15 [M + 1] ⁺ .
Step 13: tert-butyl (R) -2- (4-((1- (4- (3- (2,6-difluoro-3-((3-fluoropyrrolidin) -1-sulfonamide) benzoyl)-)- Preparation of 1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperidine-4-yl) methyl) piperazine-1-yl) acetate.

In a 30 mL closed tube purged and maintained in an inert nitrogen atmosphere, 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 (1.09 g, 2.18 mmol, 1.10 eq), (3R) -N- (3- [5-bromo-1H) -Pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluorophenyl) -3-fluoropyrrolidin-1-sulfonamide (1.00 g, 1.99 mmol, 1 eq), dioxane (20 mL), H ₂ O (4 mL), was placed _{Na 2 CO 3 (632mg, 5.96mmol} , 3.00 _{eq), Pd (dppf) Cl 2} . CH 2 Cl 2 (162mg, 0.20mmol, 0.10 eq). The obtained mixed solution was stirred in an oil tank at 105 ° C. for 2 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (150 mL). The mixture was washed with water (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded into a silica gel column with dichloromethane / methanol (28: 1). This resulted in 1.15 g (72.72%) of tert-butyl 2- (4-[[1- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidine-1). -Il] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperidine-4-yl] methyl] piperazine-1-yl) acetate obtained as a brown solid rice field. LC / MS (ESI) m / z: 796.00 [M + 1] ⁺ .
Step 14: (R) -2- (4-((1- (4- (3- (2,6-difluoro-3-((3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperidine-4-yl) Methyl) Piperazine-1-yl) Preparation of acetic acid.

In a 100 mL round bottom flask, tert-butyl 2-(4-[[1-(4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidine-1-yl]] Sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperidine-4-yl] methyl] piperazine-1-yl) acetate (1.11 g, 1.39 mmol, 1 equivalent ), dichloromethane (10 mL) and trifluoroacetic acid (5 mL) were added. The resulting solution was stirred for 3 hours in an oil bath at 35 ° C. The resulting mixture was concentrated under vacuum. This resulted in 1.12g (108.55%) of 2- (4-[[1- (4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidine-1-).
Ill] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperidine-4-yl] methyl] piperazine-1-yl) Acetic acid was obtained as a brown solid. LC / MS (ESI) m / z: 740.40 [M + 1] ⁺ .
Step 15: 2-(4-((1- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) phenyl) piperidine-4-yl) methyl) piperazine-1-yl) -N-((S) -1-((2S, 4R) -4-hydroxy- 2- (5- (4- (4-Methylthiazole-5-yl) phenyl) -1H-imidazol-2-yl) pyrrolidine-1-yl) -3,3-dimethyl-1-oxobutane-2-yl) Preparation of acetamide.

In a 100 mL round bottom flask, (2S) -2-amino-1-[(2S, 4R) -4-hydroxy-2- [5- [4- (4-methyl-1,3-thiazole-5-yl) ) Phenyl] -1H-imidazol-2-yl] pyrrolidine-1-yl] -3,3-
Dimethylbutane-1-one hydrochloride (100 mg, 1 eq), 2- (4-[[1- (4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidin) -1-yl] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridine-5-yl] phenyl) piperidine-4-yl] methyl] piperazin-1-yl) acetic acid (336 mg, 2.0 eq) , 60%), N, N-diisopropylethylamine (1 mL, 3.0 eq), and (benzotriazole-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate (201 mg, 2.0 eq) N, N-dimethyl A solution of formamide (20 mL) was added under a nitrogen atmosphere at room temperature. The obtained mixed solution was stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction mixture was diluted with water and extracted with ethyl acetate (50 mLx2). The combined organic layers were washed with brine (20 mLx2), dried over sodium sulfate and concentrated under vacuum. The crude product was purified by preparative HPLC and 2-(4-[[1- (4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidine-1-) Il] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperidine-4-yl] methyl] piperazine-1-yl) -N-[(2S) -1 -[(2S, 4R) -4-hydroxy-2- [5- [4- (4-methyl-1,3-thiazole-5-yl) phenyl] -1H-imidazol-2-yl] pyrrolidine-1- Ill] -3,3-dimethyl-1-oxobutane-2-yl] acetamide (53.8 mg, 22.05%) was obtained as a yellow solid. LC / MS (ESI) m / z: 1161.20 [M + 1] +; 1H-NMR (400MHz, CD3OD) δ 8.88 (s, 1H), 8.69 (s, 1H), 8.61 (s, 1H), 7.90 ( s, 1H), 7.82 --7.71 (m, 3H), 7.63 -7.58 (m, 2H), 7.51 --7.46 (m, 2H), 7.41 --7.37 (m, 1H), 7.15 --7.08 (m, 3H), 5.33 --5.34 (m, 2H), 4.65 --4.48 (m, 2H), 3.99 (s, 2H), 3.80 --3.75 (m, 2H), 3.61 --3.39 (m, 5H), 3.09 (s, 1H), 2.84 --2.72 (m, 2H), 2.63 (s, 3H), 2.55 --2.38 (m, 8H), 2.36 --2.02 (m, 5H), 1.93 --1.86 (m, 2H), 1.81 --1.69 (m, 1H) ), 1.40 --1.26 (m, 3H), 1.05 (s, 2H), 0.98 (s, 7H).
N-((S) -1-((2S, 4R) -2- (5-benzyl-1H-imidazol-2-yl) -4-hydroxypyrrolidine-1-yl) -3,3-dimethyl-1-yl) Oxobutane-2-yl) -2- (4-((1- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl)) -1H-Pyrrolidine [2,3-b] Pyridine-
Il) Il) phenyl) piperidine-4-yl) methyl) piperazine-1-yl) exemplary of acetamide
Synthesis (Example 459)
Step 1: Preparation of 1-bromo-3-phenylpropan-2-one.

TMSCHN2 (13.30 g, 116.441 mmol, 3.00 eq) was added dropwise to a stirred solution of 2-phenylacetyl chloride (6 g, 38.812 mmol, 1 eq) in acetonitrile (50 mL) at room temperature under a nitrogen atmosphere. The obtained mixture was stirred at room temperature for 1 hour. The mixture was cooled to 0 ° C. and a solution of HBr in AcOH (40%, 12.56 g, 155.249 mmol, 4.0 eq) was added dropwise. The reaction mixture was stirred at room temperature for another 15 minutes under a nitrogen atmosphere. The mixture is then concentrated under reduced pressure, the residue is purified by silica gel column chromatography and eluted with DCM / PE (1: 1), 1-bromo-3-phenylpropan-2-one (4.5 g, 54.41). %) Was obtained as a bright yellow solid.

Step 2: 2-oxo-3-phenylpropyl (2S, 4R) -1-((S) -2-((tert-butoxycarbonyl) amino) -3,3-dimethylbutanoyl) -4-hydroxypyrrolidine- Preparation of 2-carboxylate.

1-bromo-3-phenylpropan-2-one (2.72 g, 12.766 mmol, 1 eq) and (2S, 4R) -1- [(2S) -2-[[(tert-butoxy) carbonyl] amino]- 3,3-Dimethylbutanoyl] -4-hydroxypyrrolidin-2-carboxylic acid (5.28 g, 15.319 mmol, 1.20 eq) in a stirred solution of acetonitrile (50 mL) with DIEA (7 mL, 40.188 mmol, 3.15 eq) in nitrogen. It was added dropwise at room temperature in an atmosphere. The obtained mixed solution was stirred at room temperature for 3 hours under a nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1: 2), and 2-oxo-3-phenylpropyl (2S, 4R) -1-[(2S) -2- [ [(tert-Butoxy) carbonyl] amino] -3,3-dimethylbutanoyl] -4-hydroxypyrrolidin-2-carboxylate (4.3 g, 70.68%) was obtained as an off-white solid. LC / MS (ESI) m / z: 477.25 [M + 1] ⁺ .
Step 3: tert-butyl ((S) -1-((2S, 4R) -2- (5-benzyl-1H-imidazol-2-yl) -4-hydroxypyrrolidine-1-yl) -3,3- Preparation of dimethyl-1-oxobutan-2-yl) carbamate.

In a 100 mL microwave vial, 2-oxo-3-phenylpropyl (2S, 4R) -1- [(2S) -2-[[(tert-butoxy) carbonyl] amino] -3,3-dimethylbutanoyl] A solution of -4-hydroxypyrrolidin-2-carboxylate (952 mg, 1.998 mmol, 1 eq) and NH ₄ OAc (1.23 g, 16.0 mmol, 8.0 eq) in xylene (50 mL) was added under a nitrogen atmosphere. The obtained mixed solution was irradiated with microwaves at 140 ° C. for 1 hour. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mLx3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane / methyl alcohol (10: 1) and tert-butyl N-[(2S) -1-[(2S, 4R) -2- (5-benzyl). -1H-imidazol-2-yl) -4-hydroxypyrrolidin-1-yl] -3,3-dimethyl-1-oxobutane-2-yl] carbamate (260.0 mg, 15.08%) off-white solid I got it as a thing. LC / MS (ESI) m / z: 457.30 [M + 1] ⁺ .
Step 4: (S) -2-amino-1-((2S, 4R) -2- (5-benzyl-1H-imidazol-2-yl) -4-hydroxypyrrolidine-1-yl) -3,3- Preparation of dimethylbutane-1-one hydrochloride.

tert-butyl N-[(2S) -1-[(2S, 4R) -2- (5-benzyl-1H-imidazol-2-yl) -4-hydroxypyrrolidin-1-yl] -3,3-dimethyl -1-oxobutane-2-yl] Carbamate (260.0 mg, 0.569 mmol, 1 eq) in a solution of 1,4-dioxane (5 mL) and hydrogen chloride in a 1,4-dioxane solution (4.0 M, 5 mL) Was added slowly. The resulting mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. This resulted in 200.0 mg of (2S) -2-amino-1-[(2S, 4R) -2- (5-benzyl-1H-imidazol-2-yl) -4-hydroxypyrrolidine-1-yl] -3. , 3-Dimethylbutane-1-one-hydrochloride was obtained as an off-white solid. LC / MS (ESI) m / z: 357.15 [M + 1] ⁺ .
Step 5: N-((S) -1-((2S, 4R) -2- (5-benzyl-1H-imidazol-2-yl) -4-hydroxypyrrolidine-1-yl) -3,3-dimethyl) -1-oxobutane-2-yl) -2- (4-((1- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) ) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperidine-4-yl) Methyl) Piperazine-1-yl) Preparation of acetamide.

(2S) -2-amino-1-[(2S, 4R) -2- (5-benzyl-1H-imidazol-2-yl) -4-hydroxypyrrolidine-1-yl] -3,3-dimethylbutane- 1-one hydrochloride (110 mg, 0.280 mmol, 1 eq) and 2- (4-[[1- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidine) -1-yl] sulfonyl]
Amino) benzoyl] -1H-pyrrolo [2,3-b] pyridine-5-yl] phenyl) piperidine-4-yl] methyl] piperazine-1-yl) acetic acid (207.11 mg, 0.280 mmol, 1.00 eq) DMF DIEA (1 mL, 5.471 mmol, 20.51 eq) and BOP (148.58 mg, 0.336 mmol, 1.2 eq) were added to the stirred solution (5 mL) at room temperature under a nitrogen atmosphere. The obtained mixed solution was stirred at room temperature for 1 hour under a nitrogen atmosphere. The reaction was then stopped by the addition of water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mLx2), dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with dichloromethane / methyl alcohol (10: 1) to give a crude product, which was further purified by preparative HPLC. As a result, N-[(2S) -1-[(2S, 4R) -2- (5-benzyl-1H-imidazol-2-yl) -4-hydroxypyrrolidine-1-yl] -3,3-dimethyl] -1-oxobutane-2-yl] -2- (4-[[1-(4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidine-1-yl]] Sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperidine-4-yl] methyl] piperazine-1-yl) acetamide (50.6 mg, 16.76%) bright yellow Obtained as a solid. LC / MS (ESI) m / z: 1078.35 [M + 1] +; 1H-NMR (300MHz, DMSO-d6) δ 12.92 (s, 1H), δ 11.50 (brs, 1H), 9.88 (brs, 1H) , 8.65 (d, J = 2.2 Hz, 1H), 8.53 (s, 1H), 8.08 (s, 1H), 7.80-7.64 (m, 1H), 7.68-7.54 (m, 3H), 7.30-7.20 (m) , 4H), 7.20-7.10 (m, 3H), 7.07 (d, J = 8.5 Hz, 2H), 6.64 (s, 1H), 5.39-5.01 (m, 3H), 4.46 (d, J = 9.1 Hz, 2H), 3.98-3.78 (m, 5H), 3.65-3.55 (m, 3H), 3.53-3.40 (m, 2H), 3.06-2.96 (m, 3H), 2.73 (t, J = 11.9 Hz, 3H) , 2.60 (s, 1H), 2.40-2.20 (m, 4H), 2.19-2.03 (m, 4H), 1.90-1.71 (m, 3H), 1.31-1.12 (m, 3H), 0.92-0.89 (m, 1H), 0.79 (s, 9H).
2- (4-((1- (4- (3- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2, 3-b] Pyridine-5-yl) phenyl) piperidine-4-yl) methyl) piperazine-1-yl) -N-((S) -1-((2S, 4R) -4-hydroxy-2- () Example of 5- (4- (4-methylthiazole-5-yl) benzyl) -1H-imidazol-2-yl) pyrrolidine-1-yl) -3,3-dimethyl-1-oxobutane-2-yl) acetamide Synthesis (eg 444)
Step 1: Preparation of 1-bromo-3- (4-bromophenyl) propan-2-one.

A 250 mL three-necked round-bottom flask purged and maintained in an inert nitrogen atmosphere is filled with a solution of 2- (4-bromophenyl) acetate (2.50 g, 11.63 mmol, 1.0 eq) in dichloromethane (150 mL). Oxalyl chloride (1.77 g, 13.95 mmol, 1.20 eq) and N, N-dimethylformamide (170 mg, 2.33 mmol, 0.20 eq) were added. The obtained mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in acetonitrile (150 mL). A solution of (trimethylsilyl) diazomethane (3.98 g, 34.85 mmol, 3.00 eq) in hexane (17.4 mL) was added to the above solution at room temperature. The resulting solution was stirred at room temperature for an additional 2 hours and then cooled to 0 ° C. in an ice / water tank. An acetic acid solution of hydrogen bromide (40%, 8.48 g, 41.85 mmol, 3.60 eq) was slowly added to the cooled mixture. Then, the reaction mixture was stirred at room temperature for another 2 hours to react. The reaction was stopped by the addition of 100 mL of water. Ethyl acetate (250 mL x 3) the obtained mixed solution
The organic layers extracted in 1 were washed with brine (150 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is applied on a silica gel column and dichloromethane /
Eluted with petroleum ether (1:10). This gave 1.80 g (53.03%) of 1-bromo-3- (4-bromophenyl) propan-2-one as a bright yellow oil.

Step 2: 3- (4-Bromophenyl) -2-oxopropyl (2S, 4R) -1-((S) -2-((tert-butoxycarbonyl) amino) -3,3-dimethylbutanoyl)- Preparation of 4-hydroxypyrrolidine-2-carboxylate.

In a 100 mL round bottom flask, 1-bromo-3- (4-bromophenyl) propan-2-one (1.80 g, 6.155 mmol, 1.06 eq), (2S, 4R) -1-[(2S) -2- [[(tert-Butoxy) carbonyl] amino] -3,3-dimethylbutanoyl] -4-hydroxypyrrolidin-2-carboxylic acid (2.00 g, 5.807 mmol, 1 eq) and N, N-diisopropylethylamine (10 mL) A solution of acetonitrile (30 mL) was added. The resulting mixture was stirred at room temperature overnight. The reaction was then stopped by the addition of 100 mL of water. The resulting mixture was extracted with ethyl acetate (250 mLx3). The combined organic layers were washed with brine (150 mL) and then concentrated under reduced pressure. The residue was applied on a silica gel column and eluted with dichloromethane / methanol (9: 1). As a result, 1.57 g (48.67%) of 3- (4-bromophenyl) -2-oxopropyl (2S, 4R) -1-[(2S) -2-[[(tert-butoxy) carbonyl] amino]- 3,3-Dimethylbutanoyl] -4-Hydroxypyrrolidine-2-carboxylate was obtained as a bright yellow solid. LC / MS (ESI) m / z: 555.20 [M + 1] ⁺ .
Step 3: tert-butyl ((S) -1-((2S, 4R) -2- (5- (4-bromobenzyl) -1H-imidazol-2-
Ill) -4-hydroxypyrrolidine-1-yl) -3,3-dimethyl-1-oxobutane-2-yl) Preparation of carbamate.

In a 30 mL closed tube purged and maintained in an inert nitrogen atmosphere, 3- (4-bromophenyl) -2-oxopropyl (2S, 4R) -1-[(2S) -2-[[(tert- Butoxy) carbonyl] amino] -3,3-dimethylbutanoyl] -4-hydroxypyrrolidine-2-carboxylate (1.37 g, 2.466 mmol, 1 equivalent),
A solution of ammonium acetate (2.85 g, 36.971 mmol, 14.99 eq) in p-xylene (20 mL) was added. The obtained mixed solution was stirred for 24 hours in an oil tank at 140 ° C. The mixture was concentrated under reduced pressure. The residue was applied on a silica gel column and eluted with dichloromethane / methanol (95: 5). This resulted in 160.0 mg (12.11%) of tert-butyl N-[(2S) -1-[(2S, 4R) -2- [5-[(4-bromophenyl) methyl] -1H-imidazol-2- Ill] -4-hydroxypyrrolidine-1-yl] -3,3-dimethyl-1-oxobutan-2-yl] carbamate was obtained as a light brown semi-solid.

Step 4: tert-butyl ((S) -1-((2S, 4R) -4-hydroxy-2- (5-(4- (4-methylthiazole-5-yl) benzyl) -1H-imidazole-2) -Il) Preparation of pyrrolidine-1-yl) -3,3-dimethyl-1-oxobutane-2-yl) carbamate.

In a 10 mL closed tube purged and maintained in an inert nitrogen atmosphere, tert-butyl N-[(2S) -1-[(2S, 4R) -2- [5-[(4-bromophenyl) methyl] -1H-imidazol-2-yl] -4-hydroxypyrrolidin-1-yl] -3,3-dimethyl-1-oxobutan-2-yl] carbamate (180.0 mg, 0.34 mmol, 1.0 eq), 4- Methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3-thiazole (151.0 mg, 0.67 mmol, 2.0 eq), potassium carbonate (141.0 mg) , 1.020 mmol, 3.04 eq) and ^{_{Pd (dppf) Cl 2. CH}} 2 Cl 2 (28.0mg, 0.034mmol, 0.10 a solution of dioxane (3 mL) and water (0.5 mL) eq) under a nitrogen atmosphere. The obtained mixed solution was stirred at 95 ° C. for 3 hours in an oil tank under a nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was applied on a silica gel column and eluted with dichloromethane / methanol (95: 5). This resulted in 108.0 mg (58.02%) of tert-butyl N-[(2S) -1-[(2S, 4R) -4-hydroxy-2-(5-[[4- (4-methyl-1,3). -Thiazole-5-yl) Phenyl] Methyl] -1H-imidazol-2-yl) Pyrrolidine-1-yl] -3,3-Dimethyl-1-oxobutan-2-yl] Carbamate is a red semi-solid Got as. LC / MS (ESI) m / z: 554.30 [M + 1] ⁺ .
Step 5: (S) -2-amino-1-((2S, 4R) -4-hydroxy-2- (5-(4- (4-methylthiazole-5-yl) benzyl) -1H-imidazole-2) -Il) Preparation of pyrrolidine-1-yl) -3,3-dimethylbutane-1-one hydrochloride.

In a 100 mL round bottom flask, tert-butyl N-[(2S) -1-[(2S, 4R) -4-hydroxy-2- (5-[[4- (4-methyl-1,3-thiazole-)- 5-yl) phenyl] methyl] -1H-imidazol-2-yl) pyrrolidine-1-yl] -3,3-dimethyl-1-oxobutan-2-yl] carbamate (108.0 mg, 0.195 mmol, 1 equivalent) ) Dioxane (5 mL) solution, and hydrogen chloride 1,4-dioxane solution (4.0 M, 5 mL).
Was added. The obtained mixture was stirred at room temperature for 1.5 hours. The mixture was concentrated under reduced pressure. This resulted in 95.0 mg (99.39%) of (2S) -2-amino-1-[(2S, 4R) -4-hydroxy-2- (5-[[4- (4-methyl-1,3-thiazole). -5-Il) Phenyl] Methyl] -1H-imidazol-2-yl) Pyrrolidine-1-yl] -3,3-Dimethylbutane-1-one hydrochloride was obtained as a light brown solid. LC / MS (ESI) m / z: 454.25 [M + 1] ⁺ .
Step 6: 2- (4-((1- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) phenyl) piperidine-4-yl) methyl) piperazine-1-yl) -N-((S) -1-((2S, 4R) -4-hydroxy- 2- (5- (4- (4-Methylthiazole-5-yl) benzyl) -1H-imidazol-2-yl) piperidine-1-yl) -3,3-dimethyl-1-oxobutane-2-yl) Preparation of acetamide.

In a 100 mL round bottom flask, (2S) -2-amino-1-[(2S, 4R) -4-hydroxy-2- (5-[[4- (4-methyl-1,3-thiazole-5-) Il) phenyl] methyl] -1H-imidazol-2-yl) pyrrolidine-1-yl] -3,3-dimethylbutane-1-one hydrochloride (93.0 mg, 0.190 mmol, 1 eq), 2- (4-) [[1- (4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3- b] Pyridine-5-yl] phenyl) piperidin-4-yl] methyl] piperazin-1-yl) acetic acid (159.0 mg, 0.190 mmol, 1.00 eq), N, N-diisopropylethylamine (74.0 mg, 0.573 mmol, 3.02) Equivalent) and BOP (126.0 mg, 0.285 mmol, 1.50 eq) in N, N-dimethylformamide (10 mL) were added. The obtained mixture was stirred at room temperature for 1.5 hours. The reaction mixture was then quenched by adding 100 mL of water and extracted with ethyl acetate (250 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied on a silica gel column and eluted with dichloromethane / methanol (9: 1). The resulting product was dissolved in dichloromethane / methanol (4: 1, 50 mL) and filtered through a 0.22 μm syringe filter. The filtrate was concentrated under reduced pressure. This resulted in 54.2 mg (24.30%) of 2- (4-[[1- (4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidine-1-yl]]. Sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperidine-4-yl] methyl] piperazine-1-yl) -N-[(2S) -1- [ (2S, 4R) -4-Hydroxy-2- (5-[[4- (4-methyl-1,3-thiazole-5-yl) phenyl] methyl] -1H-imidazol-2-yl) pyrrolidine-1 -Il] -3,3-dimethyl-1-oxobutane-2-yl] Acetamide was obtained as a bright yellow solid. LC / MS (ESI) m / z: 1175.50 [M + 1] +; 1H-NMR (300MHz, DMSO-d6) δ 12.89 (s, 1H), 9.90 (brs, 1H), 8.95 (s, 1H), 8.62 (s, 1H), 8.50 (s, 1H), 8.05 (s, 1H), 7.80-7.52 (m, 4H), 7.50-7.29 (m, 5H), 7.12-7.03 (m, 2H), 6.73 ( s, 1H), 5.43-4.90 (m, 3H), 4.50-4.42 (m, 2H), 3.91-3.75 (m, 5H), 3.59-3.40 (m, 5H), 3.20-2.80 (m, 2H), 2.81-2.67 (m, 3H), 2.45-2.41 (m, 4H), 2.40-1.96 (m, 7H), 1.94-1.71 (m, 3H), 1.42-1.10 (m, 7H), 0.97-0.90 (m) , 1H), 0.73 (s, 9H).
2- (4-((1- (4- (3- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2, 3-b] Pyridine-5-yl) phenyl) piperidine-4-yl) methyl) piperazine-1-yl) -N-((S) -1-((2S, 4R) -4-hydroxy-2- () 5- (4- (4-Methylthiazole-5-yl) benzyl) thiazole-2-yl) pyrrolidine-1-yl) -3,3-dimethyl-1-oxobutane-2-
Il) Illustrative synthesis of acetamide (Example 473)
Step 1: Preparation of tert-butyl (2S, 4R) -4-((tert-butyldiphenylsilyl) oxy) -2-carbamoylpyrrolidine-1-carboxylate.

In a 100 mL round bottom flask, tert-butyl (2S, 4R) -2-carbamoyl-4-hydroxypyrrolidin-1-carboxylate (1.00 g, 4.343 mmol, 1 eq), imidazole (739.0 mg, 10.855 mmol, 2.50). Equivalent) and TBDPSCl (1.43 g, 5.203 mmol, 1.20 eq) in N, N-dimethylformamide (20 mL) were added. The resulting mixture was stirred at room temperature overnight. Then add 150 mL to the reaction solution
The mixture was quenched by the addition of water, and the resulting mixture was extracted with ethyl acetate (250 mLx3). The organic layers were combined into one, washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied on a silica gel column and eluted with dichloromethane / methanol (98: 2). This will result in 1.55g (76.15%) of tert-butyl (2S, 4R) -4-[(tert-
Butyldiphenylsilyl) oxy] -2-carbamoylpyrrolidine-1-carboxylate was obtained as a colorless oil. LC / MS (ESI) m / z: 469.25 [M + 1] ⁺ .
Step 2: Preparation of tert-butyl (2S, 4R) -4-((tert-butyldiphenylsilyl) oxy) -2-carbamoti oil pyrrolidine-1-carboxylate.

In a 250 mL three-necked round-bottom flask purged and maintained in an inert nitrogen atmosphere, tert-butyl (2S, 4R) -4-[(tert-butyldiphenylsilyl) oxy] -2-carbamoylpyrrolidin-1- A solution of the carboxylate (1.80 g, 3.841 mmol, 1 eq) and the Lawesson reagent (1.71 g, 4.228 mmol, 1.10 eq) in THF (60 mL) was added. The obtained mixed solution was stirred for 12 hours in an oil tank at 70 ° C. The mixture was then concentrated under reduced pressure. The residue was applied on a silica gel column and eluted with ethyl acetate / petroleum ether (1: 4). This yielded 1.1 g (59.09%) of tert-butyl (2S, 4R) -4-[(tert-butyldiphenylsilyl) oxy] -2-carbamotioil pyrrolidine-1-carboxylate as a white solid. rice field. LC / MS (ESI) m / z: 485.30 [M + 1] ⁺ .
Step 3: Of tert-butyl (2S, 4R) -2- (5- (4-bromobenzyl) thiazole-2-yl) -4-((tert-butyldiphenylsilyl) oxy) pyrrolidine-1-carboxylate Preparation.

In a 100 mL round bottom flask, tert-butyl (2S, 4R) -4-[(tert-butyldiphenylsilyl) oxy] -2-carbamotioil pyrrolidine-1-carboxylate (1.0 g, 2.1 mmol, 1 equivalent) ), A solution of pyridine (244 mg, 3.085 mmol, 1.50 eq) and 1-bromo-3- (4-bromophenyl) propan-2-one (904.0 mg, 3.1 mmol, 1.50 eq) in ethanol (50 mL) was added. The resulting solution was stirred for 1 hour in an oil bath at 80 ° C. The mixture was then concentrated under reduced pressure. The residue was applied on a silica gel column and eluted with ethyl acetate / petroleum ether (1: 9). This resulted in 960.0 mg (68.66%) of tert-butyl (2S, 4R) -2- [5-[(4-bromophenyl) methyl] -1,3-thiazole-2-yl] -4-[(tert). -Butyldiphenylsilyl) oxy] pyrrolidine-1-carboxylate was obtained as a bright yellow oil. LC / MS (ESI) m / z: 677.20 [M + 1] ⁺ .
Step 4: tert-butyl (2S, 4R) -4-((tert-butyldiphenylsilyl) oxy) -2- (5- (4- (4-methylthiazole-5-yl) benzyl) thiazole-2-yl ) Preparation of pyrrolidine-1-carboxylate.

In a 30 mL closed tube purged and maintained in an inert nitrogen atmosphere, tert-butyl (2S, 4R) -2- [5-[(4-bromophenyl) methyl] -1,3-thiazole-2-yl ] -4-[(tert-butyldiphenylsilyl) oxy] pyrrolidine-1-carboxylate (800.0 mg, 1.180 mmol, 1 equivalent), 4-methyl-5- (4,4,5,5-tetramethyl-) 1,3,2-dioxaborolan-2-yl) -1,3-thiazole (398.0 mg, 1.768 mmol, 1.50 equivalent), potassium carbonate (489.0 mg, 3.538 mmol, 3.00 equivalent) and Pd (dppf) Cl ₂ (86.0) A solution of dioxane (15 mL) and water (3 mL) in mg, 0.118 mmol, 0.10 equivalent) was added. The obtained mixed solution was stirred in an oil tank at 95 ° C. for 3 hours. The mixture was then concentrated under reduced pressure. The residue was applied on a silica gel column and eluted with ethyl acetate / petroleum ether (1: 4).
This resulted in 590.0 mg (71.82%) of tert-butyl (2S, 4R) -4-[(tert-butyldiphenylsilyl) oxy] -2- (5-[[4- (4-methyl-1,3-). Thiazole-5-yl) phenyl] methyl] -1,3-thiazole-2-yl) pyrrolidine-1-carboxylate was obtained as a bright yellow solid. LC / MS (ESI) m / z: 696.20 [M + 1] ⁺ .
Step 5: 2-((2S, 4R) -4-((tert-butyldiphenylsilyl) oxy) pyrrolidine-2-yl) -5- (4- (4-methylthiazole-5-yl) benzyl) thiazole hydrochloride Preparation of salt.

In a 100 mL round bottom flask, tert-butyl (2S, 4R) -4-[(tert-butyldiphenylsilyl) oxy] -2- (5-[[4- (4-methyl-1,3-thiazole-5) -Il) phenyl] methyl] -1,3-thiazole-2-yl) pyrrolidine-1-carboxylate (600.0 mg, 0.862 mmol, 1 equivalent) in a dioxane (10 mL) solution, to which 1 of hydrogen chloride , 4-Dioxane solution (4.0 M, 10 mL) was added. The obtained mixture was stirred at room temperature for 2 hours. The mixture was then concentrated under reduced pressure. This resulted in 540.0 mg (99.06%) of 2-[(2S, 4R) -4-[(tert-butyldiphenylsilyl) oxy] pyrrolidine-2-yl] -5-[[4- (4-methyl-1). , 3-Thiazole-5-yl) Phenyl] Methyl] -1,3-Thiazole hydrochloride was obtained as a bright yellow semi-solid. LC / MS (ESI) m / z: 596.30 [M + 1] ⁺ .
Step 6: tert-butyl ((S) -1-((2S, 4R) -4-((tert-butyldiphenylsilyl) oxy) -2- (5- (4- (4-methylthiazole-5-yl) yl) ) Benzyl) Thiazole-2-yl) Pyrrolidine-1-yl) -3,3-Dimethyl-1-oxobutan-2-yl) Preparation of carbamate.

In a 100 mL round bottom flask, 2-[(2S, 4R) -4-[(tert-butyldiphenylsilyl) oxy] pyrrolidine-2-yl] -5-[[4- (4-methyl-1,3-) Thiazol-5-yl) phenyl] methyl] -1,3-thiazole hydrochloride (530.0 mg, 0.838 mmol, 1 eq), (2S) -2-[[(tert-butoxy) carbonyl] amino] -3,3 -N, N-dimethylformamide of dimethylbutanoic acid (582.0 mg, 2.516 mmol, 3.00 eq), N, N-diisopropylethylamine (650.0 mg, 5.029 mmol, 6.00 eq) and BOP (1.11 g, 2.510 mmol, 2.99 eq) (35 mL) solution was added. The resulting mixture was stirred at room temperature for 12 hours. The reaction was then stopped by the addition of 100 mL of water. The resulting mixture was extracted with ethyl acetate (250 mLx3). The organic layers were combined into one, washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied on a silica gel column and eluted with ethyl acetate / petroleum ether (1: 3). This resulted in 340.0 mg (50.13%) of tert-butyl N-[(2S) -1-[(2S, 4R) -4-[(tert-butyldiphenylsilyl) oxy] -2- (5-[4 -(4-Methyl-1,3-thiazole-5-yl) phenyl] methyl] -1,3-thiazole-2-yl) pyrrolidine-1-yl] -3,3-dimethyl-1-oxobutane-2-yl Il] Carbamate was obtained as a bright yellow oil. LC / MS (ESI) m / z: 809.30 [M + 1] ⁺ .
Step 7: tert-butyl ((S) -1-((2S, 4R) -4-hydroxy-2- (5-(4- (4-methylthiazole-5-yl) benzyl) thiazole-2-yl)) Preparation of pyrrolidine-1-yl) -3,3-dimethyl-1-oxobutane-2-yl) carbamate.

In a 100 mL round bottom flask, tert-butyl N-[(2S) -1-[(2S, 4R) -4-[(tert-butyldiphenylsilyl) oxy] -2- (5-[[4- (4) -Methyl-1,3-thiazole-5-yl) phenyl] methyl] -1,3-
Thiazole-2-yl) pyrrolidine-1-yl] -3,3-dimethyl-1-oxobutan-2-yl] carbamate (390.0 mg, 0.482 mmol, 1 equivalent) in a solution in tetrahydrofuran (20 mL) was added and this was added. A solution of Bu ₄ NF (1.0 M, 1.45 ml THF solution) was added to the mixture. The obtained mixture was stirred at room temperature for 2 hours. The reaction was then stopped by the addition of 100 mL of water. The resulting mixture was extracted with ethyl acetate (250 mLx3). The organic layers were combined into one, washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied on a silica gel column and eluted with ethyl acetate / petroleum ether (3: 1). This resulted in 250 mg (90.88%) of tert-butyl N-[(2S) -1-[(2S, 4R) -4-hydroxy-2- (5-[[4- (4-methyl-1,3-). Thiazole-5-yl) phenyl] methyl] -1,3-
Thiazole-2-yl) pyrrolidine-1-yl] -3,3-dimethyl-1-oxobutane-2-yl] carbamate was obtained as a bright yellow semi-solid. LC / MS (ESI) m / z: 571.25 [M + 1] ⁺ .
Step 8: (S) -2-amino-1-((2S, 4R) -4-hydroxy-2- (5-(4- (4-methylthiazole-5-yl) benzyl) thiazole-2-yl) Preparation of pyrrolidine-1-yl) -3,3-dimethylbutane-1-one hydrochloride.

In a 100 mL round bottom flask, tert-butyl N-[(2S) -1-[(2S, 4R) -4-hydroxy-2- (5-[[4- (4-methyl-1,3-thiazole-)- 5-yl) phenyl] methyl] -1,3-thiazol-2-yl) pyrrolidine-1-yl] -3,3-dimethyl-1-oxobutan-2-yl] carbamate (250 mg, 0.438 mmol, 1 Equivalent) of a dioxane (20 mL) solution is added to this with a 1,4-dioxane solution of hydrogen chloride (4.0 M, 15 mL).
Was added. The obtained mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. This resulted in 220.0 mg (99.05%) of (2S) -2-amino-1-[(2S, 4R) -4-hydroxy-2- (5-[[4- (4-methyl-1,3-thiazole). -5-Il) Phenyl] Methyl] -1,3-Thiazole-2-yl) Pyrrolidine-1-yl] -3,3-Dimethylbutane-1-one hydrochloride was obtained as a white solid. LC / MS (ESI) m / z: 471.15 [M + 1] ⁺ .
Step 9: 2-(4-((1- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) phenyl) piperidine-4-yl) methyl) piperazine-1-yl) -N-((S) -1-((2S, 4R) -4-hydroxy- Preparation of 2- (5- (4- (4-Methylthiazol-5-yl) benzyl) thiazole-2-yl) piperidine-1-yl) -3,3-dimethyl-1-oxobutane-2-yl) acetamide ..

2-(4-[[1- (4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidine-1-yl] sulfonyl] amino] in a 100 mL round bottom flask ) Benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperidine-4-yl] methyl] piperazine-1-yl) acetic acid (459.55 mg, 0.621 mmol, 1.50 equivalent), (2S )-2-Amino-1-[(2S, 4R) -4-Hydroxy-2- (5-[[4- (4-Methyl-1,3-thiazole-5-)
Ill) Phenyl] Methyl] -1,3-Thiazole-2-yl) Pyrrolidine-1-yl] -3,3-Dimethylbutane-1-one hydrochloride (210 mg, 0.414 mmol, 1 equivalent), N, N- Diisopropylethylamine (161 mg)
, 1.246 mmol, 3.01 eq) and BOP (275 mg, 0.622 mmol, 1.50 eq) in N, N-dimethylformamide (30 mL) solutions. The resulting solution was stirred at room temperature for 2 hours. The reaction was then stopped by the addition of 100 mL of water. The resulting mixture was extracted with ethyl acetate (250 mLx3). The organic layers were combined into one, washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied on a silica gel column and eluted with dichloromethane / methanol (8: 1). The resulting product was dissolved in 50 mL of dichloromethane and the solution was filtered through a 0.22 μm syringe filter. The filtrate was concentrated under reduced pressure. This resulted in 57.1 mg (11.56%) of 2- (4-[[1- (4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidin-1-yl]]. Sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperidine-4-yl] methyl] piperazine-1-yl) -N-[(2S) -1- [ (2S, 4R) -4-Hydroxy-2- (5-[[4- (4-methyl-1,3-thiazole-5-yl) phenyl] methyl] -1,3-thiazole-2-yl) pyrrolidine -1-yl] -3,3-dimethyl-1-oxobutane-2-yl] acetamide was obtained as a yellow solid. LC / MS
(ESI) m / z: 1192.60 [M + 1] +; 1H-NMR (300MHz, DMSO-d6) δ 12.88 (s, 1H), 9.83 (s,
1H), 8.96 (s, 1H), 8.63 (s, 1H), 8.51 (s, 1H), 8.05 (s, 1H), 7.80-7.70 (m, 1H),
7.69-7.56 (m, 3H), 7.39 (d, J = 8.0 Hz, 2H), 7.35-7.18 (m, 4H), 7.04 (d, J = 8.4 Hz, 2H), 5.74 (s, 1H), 5.44 -5.06 (m, 3H), 4.51 (d, J = 9.3 Hz, 1H), 4.49-4.38 (m, 1H), 4.03 (s, 2H), 3.85-3.72 (m, 3H), 3.70-3.62 (m) , 1H), 3.48-3.39 (m, 3H), 3.16-2.82 (m, 2H), 2.69 (t, J = 11.8 Hz, 2H), 2.45-2.35 (m, 6H), 2.25-2.05 (m, 7H) ), 1.80-1.60 (m, 3H), 1.23-1.19 (m, 6H), 0.83 (s, 9H).
2- (4-((4- (4- (3- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2, 3-b] Pyridine-5-yl) phenyl) piperazine-1-yl) methyl) pi
Pyrrol-1-yl) -N-((S) -1-((2S, 4R) -4-hydroxy-2- (5-(4- (4-methylthiazole-5-yl) phenyl) -1H- Illustrative Synthesis of Imidazole-2-yl) Pyrrolidine-1-yl) -3,3-Dimethyl-1-oxobutan-2-yl) Acetamide (Example 445)
Step 1: 2- (4-((4- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) phenyl) piperazin-1-yl) methyl) piperidine-1-yl) -N-((S) -1-((2S, 4R) -4-hydroxy- 2- (5- (4- (4-Methylthiazole-5-yl) phenyl) -1H-imidazol-2-yl) pyrrolidine-1-yl) -3,3-dimethyl-1-oxobutane-2-yl) Preparation of acetamide.

2- (4-[[4- (4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidine-1-yl] sulfonyl] amino] in a 100 mL round bottom flask ) Benzoyl] -1H-pyrrolidine [2,3-b] pyridine-5-yl] phenyl) piperazine-1-yl] methyl] piperidine-1-yl) acetic acid (252.45 mg, 0.341 mmol, 1.00 equivalent), (2S) ) -2-Amino-1-[(2S, 4R) -4-hydroxy-2- [5- [4- (4-methyl-1,3-thiazole-5-yl) phenyl] -1H-imidazole-2 -Il] Pyrrolidine-1-yl] -3,3-dimethylbutane-1-one (150 mg, 0.341 mmol, 1 equivalent), DIEA (88.20 mg, 0.682 mmol, 2 equivalents), BOP (226.38 mg, 0.512 mmol, 1.5 equivalents) of DMF (5 mL) solution was added. The obtained mixture was stirred at room temperature for 1 hour.
The reaction was then quenched by adding 20 mL of water and the mixture was extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied on a silica gel column and eluted with ethyl acetate / MeOH (5: 1). This resulted in 72.0 mg (18.17%) of 2- (4-[[4- (4- [3- [2,6-difluoro-3- ([[(3R) -3-fluoropyrrolidine-1-yl]]. Sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazine-1-yl] methyl] piperidine-1-yl) -N-[(2S) -1- [ (2S, 4R) -4-Hydroxy-2- [5- [4- (4-methyl-1,3-thiazole-5-yl) phenyl] -1H-imidazol-2-yl] pyrrolidine-1-yl] -3,3-Dimethyl-1-oxobutane-2-yl] acetamide was obtained as a yellow solid. LC / MS (ESI) m / z: 1161.35 [M + 1] +; 1H-NMR (300MHz, DMSO-d6) δ 12.89 (br s, 1H), 11.95 (s, 1H), 9.83 (br s, 1H) ), 8.95 (s, 1H), 8.62 (d, J = 2.2 Hz, 1H), 8.51 (s, 1H), 8.05 (s, 1H), 7.78-7.70 (m, 3H), 7.57-7.50 (m, 4H), 7.42 (d, J = 8.0 Hz, 2H), 7.24-7.20 (m, 1H), 7.10-7.01 (m, 2H), 5.49-5.27 (m, 2H), 5.11-5.03 (m, 1H) , 4.61-4.50 (m, 2H), 3.95-3.84 (m, 1H), 3.71-3.61 (m, 1H), 3.47-3.42 (m, 1H), 3.41-3.37 (m, 2H), 3.30-3.20 ( m, 1H), 3.19-3.10 (m, 4H), 2.93-2.72 (m, 4H), 2.46 (s, 3H), 2.41-1.89 (m, 9H), 1.89-1.70 (m, 2H), 1.68- 1.52 (m, 1H), 1.28-1.22 (m, 1H), 1.21-1.11 (m, 3H), 0.95-0.91 (m, 1H), 0.85-0.72 (m, 9H).
(2S, 4R) -1-((S) -5-(4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfo
Namide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenoxy) -2- (3-Methylisoxazole-5-yl) Pentanoyl) -4-Hydroxy-N-((S) )-1-(4- (4-Methylthiazole-5-)
Il) Phenyl) Ethyl) Pyrrolidine-2-carboxamide (Example 475) and (2S, 4R) -1-((R) -5- (4- (3- (2,6-difluoro-3- (((R)) ) -3-Fluoropyrrolidine) -1-Sulfonamide) Benzoyl)-
1H-pyrrolo [2,3-b] pyridin-5-yl) phenoxy) -2- (3-methylisoxazole-5-yl) pe
Illustrative Synthetic Steps for Internoyl) -4-Hydroxy-N-((S) -1-(4- (4-Methylthiazole-5-yl) Phenyl) Ethyl) Pyrrolidine-2-Carboxamide (Example 476) 1: 3 -Preparation of (4-bromophenoxy) propan-1-ol.

3-bromopropan-1-ol (2.89 g, 20.81 mmol, 1.2 eq) and potassium carbonate (7.19 g) in a solution of 4-bromophenol (3 g, 17.34 mmol, 1 eq) in N, N-dimethylformamide (100 mL). , 52.02 mmol, 3 eq), and the mixture was stirred for 2 hours at 70 ° C. The mixture was diluted with water (100 mL), extracted with ethyl acetate (100 mLx3) and washed with brine (300 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product. The residue was purified by silica gel column chromatography (pure petroleum ether). The product 3- (4-bromophenoxy) propan-1-ol (3.10 g, 13.41 mmol, 77% yield) was obtained as a colorless oil. 1H-NMR (400MHz, CDCl ₃ ) δ 7.41 --7.30 (m, 2H), 6.84 --6.69 (m, 2H), 4.16 --3.95 (m, 2H), 3.83 (t, J = 6.0 Hz, 2H), 2.23 --1.90 (m, 4H).
Step 2: Preparation of 1-bromo-4- (3-bromopropoxy) benzene.

Carbon tetrabromide (6.67 g, 20.12 mmol, 1.5 eq) and triphenylphosphine (1.67 g, 20.12 mmol, 1.5 eq) in a solution of 3- (4-bromophenoxy) propan-1-ol (3.1 g, 13.41 mmol, 1 eq) in tetrahydrofuran (150 mL). 5.28 g, 20.12 mmol, 1.5 eq) was added. The reaction mixture was stirred at 20 ° C. for 1 hour. The mixture was diluted with water (70 mL), extracted with ethyl acetate (40 mLx3) and washed with brine (60 mLx2). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product. The residue was purified by silica gel column chromatography (pure petroleum ether). Product 1-bromo-4- (3-bromopropoxy) benzene (3 g, 10.20 mmol, 76% yield)
Was obtained as a yellow solid. 1H-NMR (400MHz, CDCl ₃ ) δ 7.43 --7.35 (m, 2H), 6.83 --6.75 (m, 2H), 4.18 --4.01 (m, 2H), 3.60 (t, J = 6.4 Hz, 2H), 2.32 (quin, J = 6.0 Hz, 2H).
Step 3: Preparation of 2- (3-methylisoxazole-5-yl) acetic acid.

N-Butyllithium (2.5 M, 19.98 mL, 1 eq) was added dropwise to a solution of 3,5-dimethylisoxazole (4.85 g, 49.94 mmol, 4.93 mL, 1 eq) in tetrahydrofuran (80 mL) at -70 ° C. Added.
When the addition was complete, the mixture was stirred for 30 minutes at -70 ° C. Carbon dioxide (2.20 g, 49.94 mmol, 1 eq) gas was then whipped in the mixture at −70 ° C. for 30 minutes. The resulting mixture was stirred for an additional 3 hours at -70-0 ° C. The mixture was poured into 100 mL of ice water and the pH was adjusted to 3.0 with 1.0 M hydrochloric acid. The mixture was extracted with ethyl acetate (100 mLx2). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was used directly in the next step without further purification. 2- (3-Methylisoxazole-5-yl) acetic acid (4.5 g, crude) was obtained as an off-white solid.

Step 4: Preparation of methyl 2- (3-methylisoxazole-5-yl) acetate.

Thionyl chloride (7.08 g, 59.52 mmol, 4.32 mL, 2 eq) in a solution of 2- (3-methylisoxazole-5-yl) acetic acid (4.2 g, 29.76 mmol, 1 eq) in methanol (50 mL) is 0. It was added dropwise at ° C. When the addition was complete, the mixture was heated to 80 ° C and stirred for 2 hours at 80 ° C. The solvent was concentrated in vacuo and the residue was diluted with ethyl acetate (100 mL). The mixture was washed with saturated sodium bicarbonate solution (100 mL), brine (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography of residue (petroleum ether: ethyl acetate = 10: 1-5: 1
) To give methyl 2- (3-methylisoxazole-5-yl) acetate (3.6 g, 23.20 mmol, 77% yield) as a colorless oil. 1H-NMR (400MHz, CDCl3) δ 6.11 (s, 1H), 3.80
(s, 2H), 3.77 (s, 3H), 2.30 (s, 3H).
Step 5: Preparation of methyl 5- (4-bromophenoxy) -2- (3-methylisoxazole-5-yl) valerate.

Potassium tert-butoxide (825 mg, 7.35 mmol, 1.2 eq) was added to a solution of methyl 2- (3-methylisoxazole-5-yl) acetate (0.95 g, 6.12 mmol, 1 eq) in tetrahydrofuran (20 mL). , Stir at 15 ° C for 30 minutes and add 1-bromo-4- (4-bromobutoxy) benzene (1.98 g, 6.74 mmol, 1.1 eq) to the mixture at 20 ° C _{for 2 hours with N 2 protection.} added. The mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mLx3) and washed with brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product. The residue was purified by silicon dioxide column chromatography (petroleum ether / ethyl acetate = 1/0 to 60/1). The product methyl 5- (4-bromophenoxy) -2- (3-methylisoxazole-5-yl) valerate (370 mg, 1.00 mmol, 17% yield) was obtained as a colorless oil. LC / MS (ESI) m / z: 368.1 [M + 1] ⁺ ; ¹ H-NMR (400MHz, CDCl ₃ ) δ 7.39 --7.31 (m, 2H), 6.80 --6.69 (m, 2H), 6.11 --6.02 (m, 1H), 4.16 --3.82 (m, 3H), 3.81 --3.74 (m, 1H), 3.73 (s, 2H), 2.27 --2.27 (m, 1H), 2.30 --2.26 (m, 2H), 2.26 --2.02 (m, 1H), 1.86 --1.73 (m, 1H), 1.73 --1.71 (m, 1H), 1.88 --1.69 (m, 1H).
Step 6: Methyl 5-(4-(3- (2,6-difluoro-3-(((R) -3-fluoro-N-((2- (trimethylsilyl) ethoxy) methyl) pyrrolidine) -1-sulfone) Amide) benzoyl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenoxy) -2- (3-methylisoxazole-5- Il) Preparation of valerate.

Place the flask in the form of methyl 5- (4-bromophenoxy) -2- (3-methylisoxazole-5-yl) valerate (100 mg, 0.27 mmol, 1 equivalent), cesium fluoride (165 mg, 1.09 mmol, 4). Equivalent), 4-ditert-butylphosphanyl-N, N-dimethyl-aniline; dichloropalladium (19 mg, 0.03 mmol, 0.1 equivalent), (3R) -N- [2,4-difluoro-3- [5-( 4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) -1- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b] Pyridine-3-carbonyl]
Phenyl] -3-fluoro-N- (2-trimethylsilylethoxymethyl) pyrrolidine-1-sulfonamide (220 mg, 0.27 mmol, 1 eq), dioxane (10 mL) and water (2 mL) were filled. The mixture was heated at 120 ° C. for 1 hour under a nitrogen atmosphere. The reaction mixture was quenched by the addition of water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 1: 1). The desired product, methyl 5- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl- (2-trimethylsilylethoxymethyl) amino] Benzoyl] -1- (2-trimethylsilylethoxymethyl) pyrolo [2,3-b] pyridin-5-yl] phenoxy] -2- (3-methylisoxazole-5-yl) valerate (50 mg, 0.05) mmol, yield 19%) was obtained as a yellow oil. LC / MS (ESI) m / z: 972.4 [M + 1] ⁺ .
Step 7: Methyl 5- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b ] Pyridine-5-yl) Phenoxy) -2- (3-Methylisoxazole-5-yl) Preparation of valerate.

Methyl Methyl 5- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl- (2-trimethylsilylethoxymethyl) amino] benzoyl] -1- (2-trimethylsilylethoxymethyl) pyrolo [2,3-b] pyridin-5-yl] phenoxy] -2- (3-methylisoxazole-5-yl) valerate (200 mg, 0.20 mmol, 1 equivalent) Hydrochloride / dioxane (4M, 10 mL, 464.12 equivalents) was added to the solution of methanol (5 mL). The solution was stirred at 40 ° C. for 20 hours. The reaction mixture was concentrated in vacuo. The residue was used in the next reaction and was not purified. Product methyl
5- [4- [3- [2,6-difluoro-3- [[(3R) -3-fluoropyrrolidine-1-yl] sulfonylamino]]
Benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenoxy] -2- (3-methylisoxazole-5-yl) valerate (150 mg, crude, HCl) in yellow oil Got as. LC / MS (ESI) m / z: 712.2 [M + 1] ⁺ .
Step 8: 5- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] Preparation of pyridine-5-yl) phenoxy) -2- (3-methylisoxazole-5-yl) valeric acid.

Methyl 5- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridine -5-yl] phenoxy] -2- (3-methylisoxazole-5-yl) valerate (150 mg, 0.20 mmol, 1 eq, HCl) in a solution of methanol (2 mL) and water (2 mL), Lithium hydroxide (42 mg, 1.00 mmol, 5 eq) was added and the mixture was stirred for 2 hours at 15 ° C. Slowly add hydrogen chloride (1M) to the reaction mixture to adjust the pH to 4-5, wash the mixture with water (20 mL), then extract with ethyl acetate (15 mL x 3) and brine (15 mL). The organic layer was then concentrated in vacuo to give a residue. Product 5- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b ] Pyridine-5-yl] Phenoxy] -2- (3-Methylisoxazole-5-yl) Valeric acid (130 mg, crude) was obtained as a yellow solid. LC / MS (ESI) m / z: 698.2 [M + 1] ⁺ .
Step 9: (2S, 4R) -1-((S) -5-(4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidin) -1-sulfonamide)) Benzoyl) -1H-pyrrolo [2,3-b] pyridine-5-yl) phenoxy) -2- (3-methylisoxazole-5-yl) pentanoyl) -4-hydroxy-N-((S)- 1-(4- (4-Methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide, and (2S, 4R) -1-((R) -5- (4- (3- (2,,,) 6-Difluoro-3-(((R) -3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridine-5-yl) phenoxy) -2- (3-) Preparation of Methylisoxazole-5-yl) pentanoyl) -4-hydroxy-N-((S) -1-(4- (4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide.

5- [4- [3- [2,6-difluoro-3- [[(3R) -3-fluoropyrrolidine-1-yl] sulfonylamino]]
Benzoyl] -1H-pyrrolo [2,3-b] pyridine-5-yl] phenoxy] -2- (3-methylisoxazole-5-yl) valeric acid (130 mg, 0.19 mmol, 1 eq) and (2S) , 4R) -4-hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (69 mg, 0.19 mmol, 1 equivalent, HCl) 1-Hydroxybenzotriazole (31 mg, 0.23 mmol, 1.2 eq) and N, N-diisopropylethylamine (73 mg, 0.56 mmol, 3 eq) were added to the solution of N, N-dimethylformamide (5 mL). The mixture was stirred at 15 ° C. for 30 minutes, N- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride (43 mg, 0.23 mmol, 1.2 eq) was added to the mixture, and then the mixture was stirred at 40 ° C. for 2 hours. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC. The first product, (2S, 4R) -1-[(2S) -5- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1- Il] sulfonylamino] benzoyl] -1H-pyrrolidine [2,3-b] pyridin-5-yl] phenoxy] -2- (3-methylisoxazole-5-yl) pentanoyl] -4-hydroxy-N- [(1S) -1- [4- (4-Methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (23.7 mg, 0.02 mmol, yield 12%, purity 99%) as a white solid Obtained. LC / MS (ESI) m / z: 1011.3 [M + 1] +; 1H-NMR (300MHz, DMSO-d6) δ 9.04 --8.91 (m, 1H), 8.65 (s, 1H), 8.56 (s, 1H) ), 8.41 (d, J = 7.5 Hz, 1H), 8.07 (s, 1H), 7.72 --7.55 (m, 3H), 7.49 --7.31 (m, 5H), 7.21 (s, 1H), 7.13 --7.00 ( m, 2H), 6.36 --6.03 (m, 1H), 5.40 --5.19 (m, 1H), 5.13 (s, 1H), 5.00 --4.84 (m, 1H), 4.48 --4.37 (m, 1H), 4.31 ( s, 1H), 4.18 (t, J = 7.1 Hz, 1H), 4.11 --3.95 (m, 2H), 3.78 (dd, J = 4.5, 10.5 Hz, 1H), 3.58 (d, J = 11.4 Hz, 1H) ), 3.45 (s, 1H), 2.47 ―― 2.39 (m, 4H), 2.27 ―― 2.16 (m, 4H), 2.15 ―― 2.00 (m, 4H), 2.00 ―― 1.88 (m, 2H), 1.88 ―― 1.65 (m) , 3H), 1.25 --0.98 (m, 1H), 1.38 (d, J = 6.8 Hz, 3H). The second product (2S, 4R) -1-[(2R) -5- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridine-5-yl] phenoxy ] -2- (3-Methylisoxazole-5-yl) pentanoyl] -4-hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine -2-Carboxamide (15.7 mg, 0.02 mmol, yield 8%, purity 98%) was obtained as a white solid. LC / MS (ESI) m / z: 1011.3 [M + 1] +; 1H-NMR (300MHz, DMSO-d6) δ 9.04 --8.94 (m, 1H), 8.65 (d, J = 2.1 Hz, 1H), 8.56 (s, 1H), 8.40 (d, J = 7.7 Hz, 1H), 8.05 (s, 1H), 7.67 (d, J = 8.7 Hz, 2H), 7.62 --7.53 (m, 1H), 7.48 --7.41 (m, 2H), 7.40 --7.30 (m, 3H), 7.21 --7.01 (m, 1H), 7.11 --7.01 (m, 2H), 6.28 --6.22 (m, 1H), 6.33 (s, 1H), 5.43 --5.19 (m, 1H), 5.17 (s, 1H), 5.03 (s, 1H), 4.92 (t, J = 7.3 Hz, 1H), 4.65 --4.56 (m, 1H), 4.54 --4.37 (m, 1H) ), 4.29 (s, 1H), 4.21 (t, J = 7.2 Hz, 1H), 4.06 (t, J = 6.1 Hz, 2H), 4.02 --3.90 (m, 1H), 3.73 (t, J = 7.7 Hz) , 1H), 3.60 (d, J = 10.0 Hz, 1H), 2.47 --2.43 (m, 4H), 2.33 (d, J = 1.8 Hz, 1H), 2.25 --2.16 (m, 4H), 2.13 --1.91 ( m, 5H), 1.78 (dd, J = 7.5, 12.5 Hz, 3H), 1.26 --1.13 (m, 1H), 1.44 --1.10 (m, 5H).
(2S, 4R) -1-((S) -6- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfo
Namide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenoxy) -2- (3-Methylisoxazole-5-yl) Hexanoyl) -4-Hydroxy-N-((S) )-1-(4- (4-Methylthiazole-5-)
Il) Phenyl) Ethyl) pyrrolidine-2-carboxamide (Example 452) and (2S, 4R) -1-((R) -6- (4- (3- (2,6-difluoro-3-) (((() R) -3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenoxy) -2- (3-methylisoxazole-5-yl) Hexanoyl) -4-Hydroxy-N-((S) -1-(4- (4-Methylthiazol-5-yl) Phenyl) Ethyl) Pyrrolidine-2-Carboxamide (Example 453) Illustrative Synthesis Step 1: 1 -Preparation of bromo-4- (4-bromobutoxy) benzene.

1,4-Dibromobutane (18.72 g, 86.70 mmol, 5 eq) and potassium carbonate (7.19 g, 52.02) in a solution of 4-bromophenol (3 g, 17.34 mmol, 1 eq) in N, N-dimethylformamide (100 mL). Phenol (3 eq) was added and the mixture was stirred for 2 hours at 70 ° C. Dilute the mixture with water (100 mL) and
Extracted with ethyl acetate (100 mLx3) and washed with brine (300 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product. The residue was purified by silica gel column chromatography (pure petroleum ether). The product 1-bromo-4- (4-bromobutoxy) benzene (4.1 g, 13.31 mmol, 77% yield) was obtained as a colorless oil. LC / MS (ESI) m / z: 308.1 [M + 1] +; 1H-NMR (400MHz, CDCl3) δ 7.44 --7.31 (m, 2H), 6.87 --6.71 (m, 2H), 4.03 --3.88 (m) , 2H), 3.55 --3.37 (m, 2H), 2.12 --1.87 (m)
, 4H).
Step 2: Preparation of methyl 6- (4-bromophenoxy) -2- (3-methylisoxazole-5-yl) hydroxyate.

Potassium tert-butoxide (456 mg, 4.06 mmol, 1.5 eq) was added to a solution of methyl 2- (3-methylisoxazole-5-yl) acetate (420 mg, 2.71 mmol, 1 eq) in tetrahydrofuran (20 mL). Stir at 15 ° C. for 30 minutes, then 1-bromo-4- (4-bromobutoxy) benzene (1 g, 3.25 mmol, 1.2 eq) was added to the mixture at 20 ° C. _{for 2 hours with N 2 protection.} .. The mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mLx3) and washed with brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product. The residue was purified by preparative HPLC. The product, methyl 6- (4-bromophenoxy) -2- (3-methylisoxazole-5-yl) hexaneate (150 mg, 0.39 mmol, 15% yield) was obtained as a white solid. LC / MS (ESI) m / z: 382.0 [M + 1] +; 1H-NMR (400MHz, CDCl3) δ 7.41 --7.31 (m, 2H), 6.81 --6.71 (m, 2H), 6.08 (s, 1H) ), 3.96 --3.82 (m, 3H), 3.74 (s, 3H), 2.34 (s, 3H), 2.20 --2.07 (m, 1H), 2.06 --1.90 (m, 1H), 1.89 --1.69 (m, 2H) ), 1.58 --1.41 (m, 2H).
Step 3: Methyl 6-(4-(3-(2,6-difluoro-3-(((R) -3-fluoro-N-((2- (trimethylsilyl) ethoxy) methyl) pyrrolidine) -1-sulfone) Amide) benzoyl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenoxy) -2- (3-methylisoxazole-5- Il) Preparation of hexanelate.

Place the flask in the form of methyl 6- (4-bromophenoxy) -2- (3-methylisoxazole-5-yl) hexanate (150 mg, 0.39 mmol, 1 equivalent), cesium fluoride (239 mg, 1.57 mmol, 4). Equivalent), 4-ditert-butylphosphanyl-N, N-dimethyl-aniline; dichloropalladium (28 mg, 0.04 mmol, 0.1 equivalent), (3R) -N- [2,4-difluoro-3- [5-(equivalent)) 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b] pyridine-3-carbonyl] phenyl]- It was filled with 3-fluoro-N- (2-trimethylsilylethoxymethyl) pyrrolidine-1-sulfonamide (318 mg, 0.39 mmol, 1 equivalent), dioxane (10 mL) and water (2 mL). The mixture was heated at 120 ° C. for 1 hour under a nitrogen atmosphere. The reaction mixture was quenched by the addition of water (10 mL), diluted with water (20 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine (30 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 1: 1). The product methyl 6- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1-
Il] sulfonyl- (2-trimethylsilylethoxymethyl) amino] benzoyl] -1- (2-trimethylsilylethoxymethyl) pyrolo [2,3-b] pyridin-5-yl] phenoxy] -2- (3-methylisoxa) Zol-5-yl) hexanelate (170 mg, 0.17 mmol, 44% yield) was obtained as a yellow oil.

Step 4: Methyl 6- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b ] Pyridine-5-yl) Phenoxy) -2- (3-Methylisoxazole-5-yl) Hexanoate preparation.

Methyl 6- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl- (2-trimethylsilylethoxymethyl) amino] benzoyl] -1-( 2-trimethylsilylethoxymethyl) pyrrolo [2,3-b] pyridin-5-yl] phenoxy] -2- (3-methylisoxazole-5-yl) hydroxyate (170 mg, 0.17 mmol, 1 equivalent) Hydrogen chloride / dioxane (4M, 20 mL, 464.12 equivalent) was added to the methanol (5 mL) solution. The solution was stirred at 40 ° C. for 68 hours. The reaction mixture was concentrated in vacuo. The residue was used in the next reaction without further purification. The desired product, methyl 6- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2 , 3-b] Pyridine-5-yl] Phenoxy] -2- (3-Methylisoxazole-5-yl) hexanenate (120 mg, 0.16 mmol, yield 91%, HCl) is obtained as a colorless solid. rice field. LC / MS (ESI) m / z: 726.1 [M + 1] ⁺ .
Step 5: 6- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] Preparation of pyridine-5-yl) phenoxy) -2- (3-methylisoxazole-5-yl) hexanoic acid.

Methyl 6- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridine -5-yl] phenoxy] -2- (3-methylisoxazole-5-yl) hexanelate (120 mg, 0.16 mmol, 1 eq, HCl) in a solution of methanol (2 mL) and water (2 mL), Lithium hydroxide (33 mg, 0.79 mmol, 5 eq) was added and the mixture was stirred at 15 ° C. for 2 hours. Hydrogen chloride (1M) was slowly added to the reaction mixture to adjust the pH to 4-5, the mixture was washed with water (20 mL), then extracted with ethyl acetate (15 mL x 3) and brine (15 mL). The organic layer was then concentrated in vacuo to give a residue. The product 6- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3- b] Pyridine-5-yl] Phenoxy] -2- (3-Methylisoxazole-5-yl) Caproic acid (110 mg)
, Coarse) was obtained as a yellow solid. LC / MS (ESI) m / z: 712.1 [M + 1] ⁺ .
Step 6: (2S, 4R) -1-((S) -6- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidin) -1-sulfonamide)) Benzoyl) -1H-pyrrolo [2,3-b] pyridine-5-yl) phenoxy) -2- (3-methylisoxazole-5-yl) hexanoyl) -4-hydroxy-N-((S)- 1-(4- (4-Methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide, and (2S, 4R) -1-((R) -6- (4- (3- (2,,,) 6-Difluoro-3-(((R) -3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridine-5-yl) phenoxy) -2- (3-) Preparation of Methylisoxazole-5-yl) Hexanoyl) -4-hydroxy-N-((S) -1-(4-(4-Methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide.

6- [4- [3- [2,6-difluoro-3- [[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridine- 5-Il] Phenoxy] -2- (3-Methylisoxazole-5-yl) Hydrochloride (110 mg, 0.16 mmol, 1 equivalent) and (2S, 4R) -4-hydroxy-N-[(1S)- 1- [4- (4-Methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (57 mg, 0.16 mmol, 1 equivalent, HCl) in a solution of N, N-dimethylformamide (5 mL), 1 -Hydroxybenzotriazole (25 mg, 0.19 mmol, 1.2 equivalents) and N, N-diisopropylethylamine (60 mg, 0.47 mmol, 3 equivalents) were added and the mixture was stirred at 15 ° C. for 30 minutes and N- (3-dimethylamino). Add propyl) -N-ethylcarbodiimide hydrochloride (36 mg, 0.19 mmol, 1.2 equivalents) to the mixture and add 40 ° C.
Stir for 2 hours. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC. Product 1 is (2S, 4R) -1- [(2S) -6- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1-yl]] Sulfonylamino] Benzoyl] -1H-Pyrrolidine [2,3-b] Pyridine-5-yl] Phenoxy] -2- (3-Methylisoxazole-5-yl) Hexanoyl] -4-Hydroxy-N-[((3-Methylisoxazole-5-yl) Hexanoyl] 1S) -1- [4- (4-Methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (45.2 mg, 0.04 mmol, yield 28%, purity 98%) was obtained as a white solid. .. LC / MS (ESI) m / z: 1025.3 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 9.04 --8.92 (m, 1H), 8.64 (d, J = 2.0 Hz, 1H), 8.55 (s, 1H), 8.38 (d, J = 8.0 Hz, 1H), 8.06 (s, 1H), 7.75 --7.54 (m, 3H), 7.52 --7.27 (m, 4H), 7.19 (t, J = 8.8 Hz, 1H), 7.11 --6.99 (m, 2H), 6.34 --6.02 (m, 1H), 5.38 --5.04 (m, 2H), 5.01 --4.80 (m, 1H), 4.76 --4.58 (m, 1H) , 4.51 --4.35 (m, 1H), 4.30 (s, 1H), 4.10 (t, J = 7.6 Hz, 1H), 4.05 --3.86 (m, 3H), 3.76 (dd, J = 4.4, 10.0 Hz, 1H) ), 3.56 --3.49 (m, 2H), 3.51 --3.43 (m, 1H), 2.47 --2.35 (m, 5H), 2.26 --2.14 (m, 3H), 2.13 --1.89 (m, 4H), 1.88 --1.64 (m, 4H), 1.59 --1.09 (m, 5H). Product 2
(2S, 4R) -1- [(2R) -6- [4- [3- [2,6-difluoro-3- [[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino]] Benzoyl] -1H-Pyrrolidine [2,3-b] Pyridine-5-yl] Phenoxy] -2- (3-Methylisoxazole-5-yl) Hexanoyl] -4-Hydroxy-N-[(1S)- 1- [4- (4-Methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (18.6 mg, 0.02 mmol, yield 11%, purity 97%) was obtained as a white solid. LC / MS (ESI) m / z: 1026.2 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 9.02 --8.94 (m, 1H), 8.65 (d, J = 1.6 Hz, 1H), 8.56 (s, 1H), 8.38 (d, J = 7.6 Hz, 1H), 8.20 (s, 1H), 8.07 (s, 1H), 7.72 --7.56 (m, 3H), 7.48 --7.37 (m, 3H) , 7.36 --7.27 (m, 2H), 7.22 (t, J = 8.8 Hz, 1H), 7.07 (d, J = 8.8 Hz, 2H), 6.34 --6.17 (m, 1H), 5.35 (s, 1H), 5.22 (s, 1H), 5.13 (s, 1H), 5.04 --4.86 (m, 1H), 4.51 --4.38 (m, 1H), 4.28 (s, 1H), 4.16 --3.90 (m, 2H), 3.73 ( d, J = 7.6 Hz, 1H), 3.62 --3.51 (m, 1H), 3.46 (s, 2H), 2.42 (d, J = 8.8 Hz, 5H), 2.27 --2.
14 (m, 3H), 2.07 (d, J = 15.2 Hz, 2H), 2.12 --2.01 (m, 1H), 1.99 --1.88 (m, 2H), 1.87 --1.69 (m, 3H), 1.52 --1.35 ( m, 5H).
(2S, 4R) -1- (4- (2- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H) -1H -Pyrrolidine [2,3-b] Pyridine-5-yl) Phenoxy) ethoxy) -2- (3-me
Illustrative of chillisoxazole-5-yl) butanoyl) -4-hydroxy-N-((S) -1-(4-(4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide Synthesis (eg 460)
Step 1: Preparation of 1-bromo-4- (2- (2-bromoethoxy) ethoxy) benzene.

In an N, N-dimethylformamide (10 mL) solution of 4-bromophenol (3 g, 17.34 mmol, 1 eq) and 1-bromo-2- (2-bromoethoxy) ethane (4.02 g, 17.34 mmol, 1 eq). Potassium carbonate (4.79 g, 34.68 mmol, 2 eq) was added. The reaction mixture was stirred at 60 ° C. for 12 hours. The reaction mixture was quenched by the addition of water (10 mL), diluted with water (20 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine (30 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 1: 0-50: 1) to 1-bromo-4- [2- (2-bromoethoxy) ethoxy] benzene (2.8 g, 8.64 mmol). , Yield 49%) was obtained as a colorless oil. 1H-NMR (400MHz, CDCl3) δ 7.43 --7.34 (m, 2H), 6.86 --6.77 (m, 2H), 4.17-
4.08 (m, 2H), 3.94 --3.87 (m, 4H), 3.50 (t, J = 6.2 Hz, 2H).
Step 2: Methyl 4- (2- (4-bromophenoxy) ethoxy) -2- (3-methylisoxazole-5-
Il) Preparation of butaneate.

Potassium tert-butoxide (190 mg, 1.70 mmol) in a solution of N, N-dimethylformamide (5 mL) of methyl 2- (3-methylisoxazole-5-yl) acetate (239 mg, 1.54 mmol, 1 eq), 1.1 eq) and potassium iodide (25 mg, 0.15 mmol, 0.1 eq) were added. Then 1-bromo-4- [2- (2-bromoethoxy) ethoxy] benzene (500 mg, 1.54 mmol, 1 eq) was added. The mixture was stirred at 40 ° C. for 2 hours. The mixture was diluted with saturated ammonium hydrochloride (20 mL) and extracted with ethyl acetate (20 mLx3). The combined organic layers were washed with saturated brine (30 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 1: 0 to 15: 1) and methyl 4- [2- (4-bromophenoxy) ethoxy] -2- (3-methylisoxazole). -5-Il) Butaneate (125 mg, crude) was obtained as a colorless oil. 1H-NMR (400MHz, CDCl3) δ 7.42 --7.32 (m, 2H), 6.84 --6.76 (m, 2H), 6.01 (s, 1H), 4.10 --4.03 (m, 3H), 3.79 --3.69 (m, 5H) ), 3.63 --3.56 (m, 1H), 3.52 --3.44 (m, 1H), 2.46 --2.32 (m, 1H), 2.27 (s, 3H), 2.21 --2.11 (m, 1H).
Step 3: Methyl 4-(2-(4-(3-(2,6-difluoro-3-(((R) -3-fluoro-N-((2- (trimethylsilyl) ethoxy) methyl) pyrrolidine)- 1-Sulfone amide) Benzoyl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenoxy) ethoxy) -2- (3-methyliso) Preparation of xazole-5-yl) butaneate.

Methyl 4- [2- (4-bromophenoxy) ethoxy] -2- (3-methylisoxazole-5-yl) butanoate (125 mg, 0.31 mmol, 1 equivalent), (3R) -N- [2 , 4-Difluoro-3- [5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1- (2-trimethylsilylethoxymethyl) pyrrolo [2,3- b] Butyl-3-carbonyl] phenyl] -3-fluoro-N- (2-trimethylsilylethoxymethyl) pyrrolidine-1-sulfonamide (305 mg, 0.37 mmol, 1.2 equivalent), CsF (190 mg, 1.26 mmol, 0.05uL, 4 equivalents), 4-ditert-butylphosphanyl-N, N-dimethyl-aniline; dichloro-palladium (22 mg, 0.03 mmol, 0.02 mL, 0.1 equivalent) with dioxane (10 mL) and water (2 mL) removed. I felt it and purged it with nitrogen (3 times). The mixture was then stirred at 120 ° C. for 1 hour under a nitrogen atmosphere. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (40 mLx3). The combined organic layers were washed with brine (30 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue is purified by preparative TLC (petroleum ether: ethyl acetate = 1: 1) and methyl 4- [2- [4- [3- [2,6-difluoro-3- [[(3R) -3). -Fluoropyrrolidin-1-yl] sulfonyl- (2-trimethylsilylethoxymethyl) amino] benzoyl] -1- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b] pyridin-5-yl] phenoxy] ethoxy]- 2- (3-Methylisoxazole-5-yl) butaneate (130 mg, 0.12 mmol, yield 40%, purity 98%) was obtained as a colorless oil. 1H-NMR (400MHz, CDCl3) δ 8.84 (d, J = 1.6 Hz, 1H), 8.65 (d, J = 2.2 Hz, 1H), 7.79 --7.68 (m, 2H), 7.62 (d, J = 8.8 Hz) , 2H), 7.12 --6.91 (m, 3H), 6.04 (s, 1H), 5.33 --5.28 (m, 1H), 4.22 --4.06 (m, 4H), 3.84 --3.40 (m, 16H), 2.27 (s) , 3H), 2.24 --2.12 (m, 2H), 1.65 (s, 3H), 1.53 (s, 1H), 1.00 --0.89 (m, 4H), 0.03 (s, 9H), -0.05 (s, 9H) ..
Step 4: Methyl 4- (2- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2, 3-b] Preparation of pyridin-5-yl) phenoxy) ethoxy) -2- (3-methylisoxazole-5-yl) butaneate.

Methyl 4- [2- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl- (2-trimethylsilylethoxymethyl) amino] benzoyl]- 1- (2-trimethylsilylethoxymethyl) pyrolo [2,3-b] pyridin-5-yl] phenoxy] ethoxy] -2- (3-methylisoxazole-5-yl) butanoate (120 mg, 0.12 mmol) , 1 equivalent) to a solution of methanol (1 mL) was added hydrogen chloride / dioxane (4M, 4 mL, 133.63 equivalents). The mixture was stirred for 24 hours at 40 ° C. The reaction mixture was concentrated under reduced pressure to make methyl 4- [2- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino]]. Benzoyl] -1H-Pyrrolidine [2,3-b] Pyridine-5-yl] Phenoxy] ethoxy] -2- (3-Methylisoxazole-5-yl) Butaneate (130 mg, crude, hydrogen chloride) Obtained as a colorless liquid, which was used in the next step without further purification.

Step 5: 4- (2- (4- (3- (2-,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3 -b] Preparation of pyridine-5-yl) phenoxy) ethoxy) -2- (3-methylisoxazole-5-yl) butanoic acid.

Methyl 4- [2- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3- b] Pyridine-5-yl] Phenoxy] ethoxy] -2- (3-Methylisoxazole-5-yl) butanoate (130 mg, 0.17 mmol, 1 eq) in water (2 mL) and methanol (2 mL) Lithium hydroxide (80 mg, 1.91 mmol, 10.88 eq) was added to the solution. The mixture was stirred at 20 ° C. for 0.5 hours. The mixture is adjusted to PH (5) with hydrogen chloride (1M), extracted with ethyl acetate (10mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, 4- [2- [4. -[3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] Phenoxy] ethoxy] -2- (3-methylisoxazole-5-yl) butanoic acid (50 mg, crude) was obtained as a colorless oil which was used in the next step without further purification.

Step 6: (2S, 4R) -1- (4- (2- (4- (3- (2-,6-difluoro-3- (((R) -3-fluoropyrrolidine) -1-)
Sulfonamide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenoxy) ethoxy) -2- (3-Methylisoxazole-5-yl) Butanoyl) -4-Hydroxy-N- Preparation of ((S) -1- (4- (4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide.

(2S, 4R) -4-Hydroxy-N-[(1S) -1- [4- (4-Methylthiazole-5-yl) Phenyl] Ethyl]
N, N-diisopropylethylamine (26 mg, 0.21 mmol, 3 eq) was added to a solution of pyrrolidine-2-carboxamide (25 mg, 0.07 mmol, 1 eq, hydrogen chloride) in N, N-dimethylformamide (1 mL). The mixture was stirred at 20 ° C. for 10 minutes. Then 4- [2- [4- [3- [2,6-difluoro-3-[[(3R))
-3-fluoropyrrolidine-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenoxy] ethoxy] -2- (3-methylisoxazole-5-yl] ) Butanoic acid (50 mg, 0.07 mmol, 1 eq) and 1-hydroxybenzotriazole (11 mg, 0.08 mmol, 1.2 eq)
Was added, and the mixture was stirred at 20 ° C. for 10 minutes. Then N- (3-dimethylamino-propyl) -N-ethylcarbodiimide hydrochloride (16 mg, 0.08 mmol, 1.2 eq) was added. The mixture was stirred at 20 ° C. for 2 hours and 40 minutes. The mixture was quenched with water (5 mL), extracted with (dichloromethane: methanol = 10: 1) (10 mLx2), washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC and (2S, 4R) -1- [4- [2- [4- [3- [2,6-difluoro-3- [[(3R) -3-fluoropyrrolidine). -1-yl] Hydroxyamino] Benzoyl] -1H-Pyrrolidine [2,3-b] Pyridine-5-yl] Phenoxy] ethoxy] -2- (3-Methylisoxazole-5-yl) Butanoyl] -4 -Hydroxy-N-[(1S) -1- [4- (4-Methylthiazole-5-yl) phenyl] ethyl] Pyrrolidine-2-carboxamide (11.9 mg, 0.01umol, yield 16%, purity 100%) Was obtained as an off-white solid. LC / MS (ESI) m / z: 521.3 [M / 2 + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 9.01 --8.91 (m, 1H), 8.64 (dd, J = 2.2, 13.6 Hz) , 1H), 8.55 (s, 1H), 8.47 --8.35 (m, 1H), 8.06 (s, 1H), 7.67 (d, J = 8.6 Hz, 1H), 7.64 --7.55 (m, 2H), 7.46- 7.32 (m, 5H), 7.19 (t, J = 8.4 Hz, 1H), 7.08 (dd, J = 8.8, 18.2 Hz, 2H), 6.32 --6.21 (m, 1H), 5.41 --5.06 (m, 2H) , 4.99 --4.85 (m, 1H), 4.50 --4.35 (m, 1H), 4.32 --4.14 (m, 4H), 3.76 (d, J = 4.6 Hz, 3H), 3.57 --3.41 (m, 5H), 2.47 --2.39 (m, 4H), 2.18 (d, J = 6.4 Hz, 4H), 2.12 --1.94 (m, 5H), 1.84 --1.164 (m, 1H), 1.42 --1.32 (m, 4H), 1.23 (s) , 1H).
(2S, 4R) -1-((S) -4-(2-(2-(4-(3-(2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-)
Sulfonamide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenoxy) ethoxy)
Ethoxy) -2- (3-methylisoxazole-5-yl) butanoyl) -4-hydroxy-N-((S) -1-(4- (4-methylthiazole-5-yl) phenyl) ethyl) Pyrrolidine-2-carboxamide (eg 461)
And (2S, 4R) -1-((R) -4-(2-(2-(4-(3-(2,6-difluoro-3-(((R) -3-fluoropyrrolidin) -1) -Sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenoxy) ethoxy) ethoxy) -2- (3-methylisoxazole-5-yl) butanoyl) -4-hydroxy -N-((S) -1- (4- (4-Methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (Example 462)
Exemplary Synthesis Steps 1: Preparation of 2- (2- (2-Hydroxyethoxy) ethoxy) ethyl 4-methylbenzenesulfonate.

In a mixture of 2- [2- (2-hydroxyethoxy) ethoxy] ethanol (5.00 g, 33.29 mmol, 1.00 eq) and 4-methylbenzenesulfonyl chloride (1.59 g, 8.32 mmol, 0.25 eq) in dichloromethane (50 ml). , Triethylamine (1.68 g, 16.65 mmol, 2.3 mL, 0.5 eq) was added all at once under nitrogen at 25 ° C. The mixture was stirred at 25 ° C. for 12 hours. The mixture was washed with brine (30 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 1/1 to 0: 1) to 2- [2- (2-hydroxyethoxy) ethoxy] ethyl 4-methylbenzenesulfonate (1.72 g). , 5.65 mmol, yield 17%) was obtained as a colorless oil. LC / MS (ESI) m / z: 327.0 [M + 23] +; 1H-NMR (400MHz, CDCl3) δ 7.81 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H) , 4.22 --4.15 (m, 2H), 3.79 --3.67 (m, 4H), 3.67 --3.56 (m, 6H), 2.46 (s, 3H).
Step 2: Preparation of 2- (2- (2- (4-bromophenoxy) ethoxy) ethoxy) ethane-1-ol.

N, N- of 2- [2- (2-hydroxyethoxy) ethoxy] ethyl 4-methylbenzenesulfonate (2 g, 6.57 mmol, 1 equivalent) and 4-bromophenol (1.36 g, 7.89 mmol, 1.2 equivalent) To a solution of dimethylformamide (10 mL) was added potassium carbonate (1.82 g, 13.14 mmol, 2 equivalents). The reaction mixture was stirred at 60 ° C. for 12 hours. The reaction mixture was quenched by the addition of water (20 mL), then diluted with water (30 mL), filtered and extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 20: 1 to 3: 1). The desired compound 2- [2- [2- (4-bromophenoxy) ethoxy] ethoxy] ethanol (1.09 g, 3.57 mmol, 54% yield) was obtained as a colorless oil. 1H-NMR (400MHz, CDCl3) δ 7.44 --7.33 (m, 2H), 6.81 (d, J = 8.8 Hz, 2H), 4.18 --4.06 (m, 2H), 3.92 --3.83 (m, 2H), 3.79- 3.67 (m, 6H), 3.65 --3.60 (m, 2H).
Step 3: Preparation of 1-bromo-4- (2- (2- (2-bromoethoxy) ethoxy) ethoxy) benzene.

A solution of 2- [2- [2- (4-bromophenoxy) ethoxy] ethoxy] ethanol (1.09 g, 3.57 mmol, 1 eq) and triphenylphosphine (1.41 g, 5.36 mmol, 1.5 eq) in tetrahydrofuran (10 mL). Perbromomethane (1.78 g, 5.36 mmol, 1.5 eq) was added to the mixture. The reaction mixture was stirred at 20 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 50: 1-10: 1). The desired compound, 1-bromo-4- [2- [2- [2- (2-bromoethoxy) ethoxy] ethoxy] benzene (1.2 g, 3.26 mmol, 91% yield), was obtained as a bright yellow oil. 1H-NMR (400MHz, CDCl3) δ 7.43 --7.31 (m, 2H), 6.86 --6.70 (m, 2H), 4.16 --4.06 (m, 2H), 3.92 --3.79 (m, 4H), 3.76 --3.66 (m) , 4H), 3.48 (t, J = 6.4 Hz, 2H).
Step 4: Preparation of methyl 4- (2- (2- (4-bromophenoxy) ethoxy) ethoxy) -2- (3-methylisoxazole-5-yl) butaneate.

N, N-dimethylformamide (5 mL) of methyl 2- (3-methylisoxazole-5-yl) acetate (211 mg, 1.36 mmol, 1 eq) and potassium iodide (23 mg, 0.14 mmol, 0.1 eq) Add potassium tert-butoxide (183 mg, 1.63 mmol, 1.2 eq) and 1-bromo-4- [2- [2- (2-bromoethoxy) ethoxy] ethoxy] benzene (500 mg, 1.36 mmol, 1 eq) to the solution. added. The reaction mixture was stirred at 40 ° C. for 2 hours. The reaction mixture was quenched by the addition of water (10 mL), then diluted with water (20 mL), filtered and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 20: 1 to 3: 1). The desired compound, methyl 4- [2- [2- (4-bromophenoxy) ethoxy] ethoxy] -2- (3-methylisoxazole-5-yl) butanoate (250 mg, 0.57 mmol, yield) 41%) was obtained as a colorless oil. 1H-NMR (400MHz, CDCl3) δ 7.44 --7.32 (m, 2H), 6.87 --6.77 (m, 2H), 6.03 (s, 1H), 4.16 --4.08 (m, 3H), 3.87 --3.82 (m, 2H) ), 3.72 (s, 3H), 3.70 --- 3.67 (m, 2H), 3.64 --3.50 (m, 3H), 3.48 --3.38 (m, 1H), 2.42 --2.31 (m, 1H), 2.28 (s, 3H) ), 2.20 --2.09 (m, 1H).
Step 5: Methyl 4-(2-(2-(4-(3-(2,6-difluoro-3-(((R) -3-fluoro-N-((2- (trimethylsilyl) ethoxy) methyl)) Pyrrolidine) -1-sulfonamide) benzoyl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenoxy) ethoxy) ethoxy) -2- Preparation of (3-methylisoxazole-5-yl) butaneate.

Methyl 4- [2- [2- (4-bromophenoxy) ethoxy] ethoxy] -2- (3-methylisoxazole-5-yl) butanate (180 mg, 0.41 mmol, 1 equivalent) and (3R) -N- [2,4-difluoro-3- [5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b] pyridine-3-carbonyl] phenyl] -3-fluoro-N- (2-trimethylsilylethoxymethyl) pyrrolidine-1-sulfonamide (330 mg, 0.41 mmol, 1 equivalent) with dioxane (10 mL) To a solution of water (2 mL), add 4-ditert-butylphosphanyl-N, N-dimethyl-aniline; dichloropalladium (29 mg, 0.04 mmol, 0.1 equivalent) and cesium fluoride (247 mg, 1.63 mmol, 4 equivalent). rice field. The reaction mixture was stirred at 120 ° C. for 1 hour. The reaction mixture was quenched by the addition of water (10 mL), then diluted with water (20 mL), filtered and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (petroleum ether: ethyl acetate = 1: 1). The desired compound, methyl 4- [2- [2- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl- (2-trimethylsilyl) Ethoxymethyl) amino] benzoyl] -1- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b] pyridin-5-yl] phenoxy] ethoxy] ethoxy] -2- (3-methylisoxazole-5- Il) Butaneate (160 mg, 0.14 mmol, yield 35%, purity 92%) was obtained as a bright yellow oil. LC / MS (ESI) m / z: 1046.0 [M + 1] ⁺ .
Step 6: Methyl 4- (2- (2- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo Preparation of [2,3-b] Pyridine-5-yl) Phenoxy) ethoxy) ethoxy) -2- (3-Methylisoxazole-5-yl) butaneate.

Methyl 4- [2- [2- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl- (2-trimethylsilylethoxymethyl) amino] Benzoyl] -1- (2-trimethylsilylethoxymethyl) pyrolo [2,3-b] pyridin-5-yl] phenoxy] ethoxy] ethoxy] -2- (3-methylisoxazole-5-yl) butaneate Hydrogen chloride / dioxane (4M, 2 mL, 52.32 equivalents) was added to a solution of methanol (1 mL) (160 mg, 0.15 mmol, 1 equivalent). The reaction mixture was stirred at 40 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. This product was transferred to the next step without purification. The desired compound, methyl 4- [2- [2- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl]- 1H-Pyrrolidine [2,3-b] Pyridine-5-yl] Phenoxy] ethoxy] ethoxy] -2- (3-Methylisoxazole-5-yl) Butaneate (120 mg, crude) as a bright yellow oil Got as. LC / MS (ESI) m / z: 786.3 [M + 1] ⁺ .
Step 7: 4- (2- (2- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [ 2,3-b] Pyridine-5-yl) Phenoxy) ethoxy) ethoxy) -2- (3-Methylisoxazole-5-yl) Butanoic acid preparation.

Methyl 4- [2- [2- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2 , 3-b] Pyridine-5-yl] Phenoxy] ethoxy] ethoxy] -2- (3-Methylisoxazole-5-yl) butanoate (120 mg, 0.15 mmol, 1 eq) with methanol (4 mL) To a solution of water (1 mL) was added lithium hydroxide (26 mg, 0.61 mmol, 4 eq).
The reaction mixture was stirred at 20 ° C. for 1 hour. The pH of the residue was adjusted to 4-5 with 1M hydrogen chloride and then extracted with ethyl acetate (30 mLx2). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. This product was transferred to the next step without purification. The desired compound 4- [2- [2- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H -Pyrrolidine [2,3-b] Pyridine-5-yl] Phenoxy] ethoxy] ethoxy] -2- (3-Methylisoxazole-5-yl) Butanoic acid (110 mg, crude) is obtained as a bright yellow oil. rice field.

Step 8: (2S, 4R) -1-((S) -4-(2-(2- (4- (3- (2-,6-difluoro-3-(((R) -3-fluoropyrrolidin)) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridine-5-yl) phenoxy) ethoxy) ethoxy) -2- (3-methylisoxazole-5-yl) butanoyl) -4 -Hydroxy-N-((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide, and (2S, 4R) -1-((R) -4 -(2-(2-(4-(3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3- b] pyridine-5-yl) phenoxy) ethoxy) ethoxy) -2- (3-methylisoxazole-5-yl) butanoyl) -4-hydroxy-N-((S) -1- (4- (4) -Preparation of methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide.

4- [2- [2- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2, 3-b] pyridine-5-yl] phenoxy] ethoxy] ethoxy] -2- (3-methylisoxazole-5-yl) butanoic acid (110 mg, 0.14 mmol, 1 equivalent) and (2S, 4R) -4 -Hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (52 mg, 0.14 mmol, 1 equivalent, HCl) N, N- To a solution of dimethylformamide (1 mL) was added N, N-diisopropylethylamine (55 mg, 0.43 mmol, 3 equivalents) and hydroxybenzotriazole (23 mg, 0.17 mmol, 1.2 equivalents). The mixture was stirred at 20 ° C. for 0.15 hours, then 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (33 mg, 0.17 mmol, 1.2 eq) was added to the mixture. The reaction mixture was stirred at 20 ° C. for 1 hour. Water (10 mL) of reaction mixture
Was quenched by the addition of, diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (dichloromethane: methanol = 10: 1). The desired compound was obtained as a white solid. Product 1 is (2S, 4R) -1-[(2S) -4- [2- [2- [4- [3- [2,6-difluoro-3- [[(3R) -3-fluoro Pyrrolidine-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenoxy] ethoxy] ethoxy] -2- (3-methylisoxazole-5-yl) butanoyl ] -4-Hydroxy-N-[(1S) -1- [4- (4-Methylthiazole-5-yl)
Phenyl] ethyl] pyrrolidine-2-carboxamide (22.7 mg, 0.021 mmol, yield 29%, purity 100)
%). LC / MS (ESI) m / z: 543.2 [M / 2 + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 12.93 (s, 1H), 9.84 (s, 1H), 8.96 (s, 1H) ), 8.72 --8.52 (m, 2H), 8.41 (d, J = 7.6 Hz, 1H), 8.08 (s, 1H), 7.71 --7.54 (m, 3H), 7.48 --7.31 (m, 4H), 7.26 ( t, J = 8.8 Hz, 1H), 7.07 (d, J = 8.8 Hz, 2H), 6.26 --6.01 (m, 1H), 5.41 --5.52 (m, 1H), 5.15 --5.02 (m, 1H), 5.00 --4.86 (m, 1H), 4.40 (t, J = 7.6 Hz, 1H), 4.33 --4.08 (m, 4H), 3.84 --3.34 (m, 13H), 2.45 --2.40 (m, 3H), 2.23 --1.93 (m, 6H), 1.88 --1.71 (m, 1H), 1.38 (d, J = 6.8 Hz, 3H). Product 2 (2S, 4R) -1-[(2R) -4- [2-] [2- [4- [3- [2,6-difluoro-3- [[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridine -5-yl] phenoxy] ethoxy] ethoxy] -2- (3-methylisoxazole-5-yl) butanoyl] -4-hydroxy-N-[(1S) -1- [4- (4-methylthiazole) -5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (14.7 mg, 0.013 mmol, yield 18%, purity 99%). LC / MS (ESI) m / z: 543.2 [M / 2 + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 12.92 (s, 1H), 9.84 (s, 1H), 9.03 --8.92 (m) , 1H), 8.69 --8.89 (m, 2H), 8.35 (d, J = 7.6 Hz, 1H), 8.08 (s, 1H), 7.77 --7.53 (m, 3H), 7.47 --7.20 (m, 5H), 7.09 (d, J = 8.4 Hz, 2H), 6.37 --6.19 (m, 1H), 5.43 --5.52 (m, 1H), 5.12 (d, J = 3.2 Hz, 1H), 5.04 --4.85 (m, 1H) , 4.65-
4.38 (m, 1H), 4.34 --4.09 (m, 4H), 3.79 (s, 2H), 3.66 --3.36 (m, 11H), 2.47 --2.38 (m, 3H), 2.24 --1.97 (m, 6H), 1.83 ―― 1.70 (m, 1H), 1.47 ―― 1.29 (m, 3H).
(2S, 4R) -1-((S) -4-(2-(2-(2-(4-(3-(2,6-difluoro-3-(((R) -3-fluoropyrrolidin)) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridine-5-yl) phenoxy) ethoxy) ethoxy) ethoxy) -2- (3-methylisoxazole-5-yl) butanoyl) -4-Hydroxy-N-((S) -1- (4- (4-Methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (Example 463) and (2S, 4R) -1- ((R) -4- (2- (2- (2- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidin) -1-sulfonamide) benzoyl)) -1H-pyrrolo [2,3-b] pyridine-5-yl) phenoxy) ethoxy) ethoxy) ethoxy) -2- (3-methylisoxazole-5-yl) butanoyl) -4-hydroxy-N-( (S)-1- Preparation of hydroxyethoxy) ethoxy) ethoxy) ethyl 4-methylbenzenesulfonate

2- [2- [2- (2-Hydroxyethoxy) ethoxy] ethoxy] Ethanol (5 g, 25.74 mmol, 4.4 mL, 1 eq) and 4-Methylbenzene sulfonyl chloride (1.23 g, 6.44 mmol, 0.25 eq) dichloromethane Triethylamine (1.30 g, 12.87 mmol, 1.8 mL, 0.5 eq) in a mixture of (50 mL)
Was added at a time at 25 ° C. under nitrogen. The mixture was stirred at 25 ° C. for 12 hours. The mixture was washed with brine (30 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue is purified by silica gel chromatography (petroleum ether: ethyl acetate = 1/1 to 0/1) to 2- [2- [2- [2- (2-hydroxyethoxy) ethoxy] ethoxy] ethyl 4-methylbenzenesulfon. The acid salt (1.98 g, 5.68 mmol, 22% yield) was obtained as a colorless oil. LC / MS (ESI) m / z: 371.0 [M + 23] +; 1H-NMR (400MHz, CDCl3) δ 7.82 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.2 Hz, 2H) , 4.21 --4.11 (m, 2H), 3.75 --3.61 (m, 14H), 2.47 (s, 3H).
Step 2: Preparation of 2- (2- (2- (2- (4-bromophenoxy) ethoxy) ethoxy) ethoxy) ethane-1-ol.

2- [2- [2- (2-Hydroxyethoxy) ethoxy] ethoxy] ethyl 4-methylbenzenesulfonate (2 g, 5.74 mmol, 1 equivalent) and 4-bromophenol (1.09 g, 6.31 mmol, 1.1 equivalent) To a solution of N, N-dimethylformamide (10 mL) was added potassium carbonate (1.59 g, 11.48 mmol, 2 equivalents). The reaction mixture was stirred at 60 ° C. for 12 hours. The reaction mixture was quenched by the addition of water (20 mL), then diluted with water (30 mL), filtered and extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 20: 1 to 3: 1). The desired compound 2- [2- [2- [2- (4-bromophenoxy) ethoxy] ethoxy] ethoxy] ethanol (1.34 g, 3.84 mmol, yield 66%)
Was obtained as a colorless oil. LC / MS (ESI) m / z: 351.1 [M + 1] +; 1H-NMR (400MHz, CDCl3)
δ 7.44 --7.33 (m, 2H), 6.87 --6.75 (m, 2H), 4.17 --4.07 (m, 2H), 3.91 --3.81 (m, 2H), 3.79 --3.57 (m, 12H).
Step 3: Preparation of 1-bromo-4- (2- (2- (2- (2-bromoethoxy) ethoxy) ethoxy) ethoxy) benzene.

Perbromomethane (1.91 g, 1.91 g, 1 eq) in a solution of 2- [2- [2- [2- (4-bromophenoxy) ethoxy] ethoxy] ethoxy] ethanol (1.34 g, 3.84 mmol, 1 eq) in tetrahydrofuran (10 mL). 5.76 mmol (1.5 eq) and triphenylphosphine (1.51 g, 5.76 mmol, 1.5 eq) were added. The reaction mixture was stirred at 20 ° C. for 1 hour. The reaction mixture was quenched by the addition of water (10 mL), diluted with water (20 mL) and extracted with ethyl acetate (40 mL x 3). Brine (organic layer combined into one)
It was washed with 30 mLx2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. Silica gel chromatography (petroleum ether: ethyl acetate = 50: 1)
Purified according to ~ 10: 1). The desired compound 1-bromo-4- [2- [2- [2- [2- (2-bromoethoxy) ethoxy] ethoxy] ethoxy] benzene (1.1 g, 2.67 mmol, 69% yield) as a colorless oil. Obtained. 1H-NMR (400MHz, CDCl3) δ 7.42 --7.33 (m, 2H), 6.87 --6.73 (m, 2H), 4.14 --4.07 (m, 2H), 3.91 --3.77 (m, 4H), 3.76 --3.66 (m) , 8H), 3.47 (t, J = 6.4 Hz, 2H).
Step 4: Preparation of methyl 4- (2- (2- (2- (4-bromophenoxy) ethoxy) ethoxy) ethoxy) -2- (3-methylisoxazole-5-yl) butaneate.

N, N- of methyl 2- (3-methylisoxazole-5-yl) acetate (188 mg, 1.21 mmol, 1 eq)
To a solution of dimethylformamide (6 mL), potassium tert-butoxide (150 mg, 1.33 mmol, 1.1 eq) and potassium iodide (20 mg, 0.12 mmol, 0.1 eq) were added, followed by 1-bromo-4- [2- [2]. -[2- (2-Bromoethoxy) ethoxy] ethoxy] ethoxy] benzene (500 mg, 1.21 mmol, 1 eq) was added. The reaction mixture was stirred at 40 ° C. for 2 hours. The reaction mixture was quenched by the addition of water (10 mL), then diluted with water (20 mL), filtered and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 20: 1 to 3: 1). The desired compound is methyl 4- [2- [2- [2- (4-bromophenoxy) ethoxy] ethoxy] ethoxy] -2- (3-methylisoxazole-5-yl) butarate (220 mg, 0.45 mmol (yield 37%) was obtained as a colorless oil. 1H-NMR (400MHz, CDCl3) δ 7.37 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.8 Hz, 2H), 6.03 (s, 1H), 4.16 --4.07 (m, 3H), 3.90 --3.81 (m, 2H), 3.76 --3.71 (m, 5H), 3.70 --3.65 (m, 2H), 3.65 --3.60 (m, 2H), 3.58 --3.49 (m, 3H), 3.46 --3.36 (m, 3H) 1H), 2.41 --2.31 (m, 1H), 2.30 --2.27 (m, 3H), 2.20 --2.07 (m, 1H).
Step 5: Methyl 4-(2-(2-(4-(3-(2,6-difluoro-3-(((R) -3-fluoro-N-((2- (trimethylsilyl) ethoxy) ) Methyl) pyrrolidine) -1-sulfonamide) benzoyl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenoxy) ethoxy) ethoxy) Preparation of ethoxy) -2- (3-methylisoxazole-5-yl) butaneate.

Methyl 4- [2- [2- [2- (4-bromophenoxy) ethoxy] ethoxy] ethoxy] -2- (3-methylisoxazole-5-yl) butanoate (220 mg, 0.45 mmol, 1 equivalent) ) And (3R) -N- [2,4-difluoro-3- [5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1- (2-) Trimethylsilylethoxymethyl) pyrolo [2,3-b] pyridine-3-carbonyl] phenyl] -3-fluoro-N- (2-trimethylsilylethoxymethyl) pyrrolidine-1-sulfonamide (367 mg, 0.45 mmol, 1 equivalent) In a solution of dioxane (10 mL) and water (2 mL), cesium fluoride (275 mg, 1.81 mmol, 4 equivalents) and 4-ditert-butylphosphanyl-N, N-dimethyl-aniline; dichloropalladium (32 mg, 0.04 umol,) 0.1 equivalent) was added. The reaction mixture was stirred at 100 ° C. for 12 hours. The reaction mixture was quenched by the addition of water (10 mL), then diluted with water (20 mL), filtered and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 1: 1). The desired compound, methyl 4- [2- [2- [2- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl-( 2-trimethylsilylethoxymethyl) amino] benzoyl] -1- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b] pyridin-5-yl] phenoxy] ethoxy] ethoxy] ethoxy] -2- (3-methyliso Xaxazole-5-yl) butaneate (270 mg, 0.23 mmol, 51% yield, 94% purity) was obtained as a bright yellow oil. LC / MS (ESI) m / z: 546.2 [M / 2 + 1] +; 1H-NMR (400MHz, CDCl3) δ 8.84 (d, J = 1.6 Hz, 1H), 8.65 (d, J = 2.0 Hz, 1H), 7.83 --7.68 (m, 2H), 7.61 (d, J = 8.8 Hz, 2H), 7.16 --7.01 (m, 3H), 6.04 (s, 1H), 5.70 (s, 2H), 5.33 --5.13 (m, 1H), 5.07 --4.93 (m, 2H), 4.26 --4.18 (m, 2H), 3.98 --3.88 (m, 2H), 3.81 --3.37 (m, 22H), 2.46 --2.32 (m, 1H) , 2.31 --2.09 (m, 6H), 1.31 --1.19 (m, 4H), 0.03 (s, 9H), -0.05 (s, 9H).
Step 6: Methyl 4-(2-(2-(4-(3-(2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl))- Preparation of 1H-pyrrolidine [2,3-b] pyridin-5-yl) phenoxy) ethoxy) ethoxy) ethoxy) -2- (3-methylisoxazole-5-yl) butaneate.

Methyl 4- [2- [2- [2- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1-yl]]
Sulfonyl- (2-trimethylsilylethoxymethyl) amino] benzoyl] -1- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b] pyridin-5-yl] phenoxy] ethoxy] ethoxy]
Hydrogen chloride / dioxane (4M, 2mL, 32.31 eq) in a solution of ethoxy] -2- (3-methylisoxazole-5-yl) butaneate (270 mg, 0.25 mmol, 1 eq) in methanol (2 mL). Was added. The reaction mixture was stirred at 40 ° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. This product was transferred to the next step without purification. The desired compound, methyl 4- [2- [2- [2- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1-yl] sulfonylamino]] Benzoyl] -1H-Pyrrolidine [2,3-b] Pyridine-5-yl] Phenoxy] ethoxy] ethoxy] ethoxy] -2- (3-Methylisoxazole-5-yl) Butaneate (250 mg, crude) Was obtained as a bright yellow oil. LC / MS (ESI) m / z: 830.1 [M + 1] ⁺ .
Step 7: 4- (2- (2- (2- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H) -Preparation of pyrrolidine [2,3-b] pyridin-5-yl) phenoxy) ethoxy) ethoxy) ethoxy) -2- (3-methylisoxazole-5-yl) butanoic acid.

Methyl 4- [2- [2- [2- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1-yl]]
Lithium Amino] Benzoyl] -1H-Pyrrolo [2,3-b] Pyridine-5-yl] Phenoxy] ethoxy] ethoxy] ethoxy] -2- (3-Methylisoxazole-5-yl) Butaneate (250 mg) , 0.3 mmol, 1 eq) to a solution of tetrahydrofuran (10 mL) and water (2 mL) was added lithium hydroxide (51 mg, 1.21 mmol, 4 eq). The reaction mixture was stirred at 20 ° C. for 1 hour. The pH of the residue was adjusted to 4-5 with 1M hydrogen chloride and then extracted with ethyl acetate (30 mLx2). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. This product was transferred to the next step without purification. The desired compound 4- [2- [2- [2- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] ] -1H-Pyrrolidine [2,3-b] Pyridine-5-yl] Phenoxy] ethoxy] ethoxy] ethoxy] -2- (3-Methylisoxazole-5-yl) Butanoic acid (200mg, crude) Obtained as a yellow solid. LC / MS (ESI) m / z: 816.0 [M + 1] ⁺ .
Step 8: (2S, 4R) -1-((S) -4- (2- (2- (2- (4- (3- (2,6-difluoro-3- (((R) -3-) -3-) Fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenoxy) ethoxy) ethoxy) ethoxy) -2- (3-methylisoxazole-5-yl) ) Butanoyl) -4-hydroxy-N-((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide, and (2S, 4R) -1-( (R) -4- (2- (2- (2- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidin) -1-sulfonamide) benzoyl)- 1H-pyrrolo [2,3-b] pyridin-5-yl) phenoxy) ethoxy) ethoxy) ethoxy) -2- (3-methylisoxazole-5-yl) butanoyl) -4-hydroxy-N-((( Preparation of S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide.

4- [2- [2- [2- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] Pyridine-5-yl] Phenoxy] ethoxy] ethoxy] ethoxy] -2- (3-Methylisoxazole-5-yl) Butanoic acid (100 mg, 0.12 mmol, 1 equivalent)
And (2S, 4R) -4-hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (45 mg, 0.12 mmol, 1 equivalent) , HCl) to a solution of N, N-dimethylformamide (2 mL) to N, N-diisopropylethylamine (48 mg, 0.37 mmol, 3 eq) and hydroxybenzotriazole (20 mg, 0.15 mmol, 1.2 eq). The mixture was stirred at 20 ° C. for 0.25 hours and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (28 mg, 0.15 mmol, 1.2 eq) was added to the mixture. The reaction mixture was stirred at 20 ° C. for 1.25 hours. The reaction mixture was quenched by the addition of water (10 mL), diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (basic conditions). The residue was then purified by preparative TLC (dichloromethane: methanol = 10: 1). The desired compound was obtained as a white solid. Product 1, (2S, 4R) -1- [(2S) -4- [2- [2- [2- [4- [3- [2,6-difluoro-3- [[(3R) -3) -Fluoropyrrolidine-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenoxy] ethoxy] ethoxy] ethoxy] -2- (3-methylisoxazole-5) -Il) Butanoyl] -4-hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (16.97 mg, 0.014 mmol, yield) 24%, purity 99%). LC / MS (ESI) m / z: 562.4 [M / 2 + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 8.96 (s, 1H), 8.71 --8.52 (m, 2H), 8.43 (s) , 1H), 8.08 (s, 1H), 7.64 (s, 3H), 7.49 --7.91 (m, 6H), 7.08 (s, 2H), 6.34 --6.04 (m, 1H), 5.41 --4.81 (m, 3H) ), 4.45 --4.07 (m, 4H), 3.77 (s, 2H), 3.62 --3.50 (m, 12H), 2.43 (s, 3H), 2.28 --1.91 (m, 10H), 1.81 (s, 1H), 1.37 (s, 4H). Product 2, (2S, 4R) -1-[(2R) -4- [2- [2- [2- [4- [3- [2,6-Difluoro-3-] [[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridine-5-yl] phenoxy] ethoxy] ethoxy] ethoxy] -2- (3 -Methylisoxazole-5-yl) butanoyl] -4-hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (15.25) mg, 0.013 mmol, yield 22%, purity 100%). LC / MS (ESI) m / z: 562.4 [M / 2 + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 12.93 (s, 1H), 9.86 (s, 1H), 9.08 --8.91 (m) , 1H), 8.73 --8.53 (m, 2H), 8.36 (d, J = 8.0 Hz, 1H), 8.08 (s, 1H), 7.73 --7.55 (m, 3H), 7.50 --7.22 (m, 5H), 7.15 --7.03 (m, 2H), 6.36 --6.20 (m, 1H), 5.41 --5.18 (m, 2H), 5.12 (d, J = 3.6 Hz, 1H), 5.05 --4.84 (m, 1H), 4.69- 4.38 (m, 3H), 4.32 --4.12 (m, 4H), 3.79 (d, J = 4.8 Hz, 2H), 3.68 --3.37 (m, 9H), 2.44 (s, 3H), 2.36 --1.85 (m, 8H), 1.84 --1.68 (m, 1H), 1.48 --1.17 (m, 4H).
(2S, 4R) -1- (4- (4-((1- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide)) Benzoyl) -1H-pyrrolidine [2,3-b] pyridin-5-yl) phenyl) piperidine-4-i
L) Methyl) piperazine-1-yl) -3,3-dimethyl-2- (3-methylisoxazole-5-yl) pig
Illustrative Synthesis of Noyl) -4-Hydroxy-N-((S) -1-(4- (4-Methylthiazole-5-yl) Phenyl) Ethyl) Pyrrolidine-2-Carboxamide (Example 477)
Step 1: 1- (tert-butyl) 4-methyl 2,2-dimethyl-3- (3-methylisoxazole-5-yl)
Preparation of succinate.

Methyl 2- (3-methylisoxazole-5-yl) acetate (4 g, 25.78 mmol, 1 eq) and tert-butyl 2-bromo-2-methyl-propanoate (11.50 g, 51.56 mmol, 2 eq) ) Into a solution of N, N-dimethylformamide (30 mL) with potassium tert-butoxide (4.34 g, 38.67 mmol, 1.5 eq).
Was added, and the mixture was stirred for 2 hours at 50 ° C. The mixture was diluted with water (100 mL), extracted with ethyl acetate (100 mL, twice), the organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give the crude product. This crude material was purified by preparative HPLC and the mixture was adjusted to pH = 8 using sodium bicarbonate. The mixture was extracted with ethyl acetate (500 mL, twice), the organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give the product. The compound 1-tert-butyl 4-methyl 2,2-dimethyl-3- (3-methylisoxazole-5-yl) succinate (5 g, 16.82 mmol, 65% yield) was obtained as a brown oil. rice field. 1H-NMR (400MHz, CDCl3) δ 6.08 (s, 1H), 4.36 (s, 1H), 3.73 --3.37 (m, 3H), 2.30 (s, 3H), 1.45 (s, 9H), 1.28 (s, 3H), 1.16 (s, 3H).
Step 2: Preparation of 4-methoxy-2,2-dimethyl-3- (3-methylisoxazole-5-yl) -4-oxobutanoic acid.

In a solution of 1-tert-butyl 4-methyl 2,2-dimethyl-3- (3-methylisoxazole-5-yl) succinate (4.9 g, 16.48 mmol, 1 eq) in dichloromethane (5 mL), Hydrochloric acid / dichloromethane (4M, 10 mL, 2.43 eq) was added and the mixture was stirred at 20 ° C. for 11 hours. The mixture was concentrated to give the product. The compound 4-methoxy-2,2-dimethyl-3- (3-methylisoxazole-5-yl) -4-oxo-butanoic acid (4.0 g, crude) was obtained as a pale yellow oil. 1H-NMR (400MHz, DMSO-d6) δ 12.65 (br s, 1H), 6.35 (s, 1H), 4.40 (s, 1H), 3.62 (s, 3H), 2.23 (s, 3H), 1.21 (s) , 3H), 1.08 (s, 3H).
Step 3: Preparation of tert-butyl 4- (4-methoxy-2,2-dimethyl-3- (3-methylisoxazole-5-yl) -4-oxobutanoyl) piperazine-1-carboxylate.

4-methoxy-2,2-dimethyl-3- (3-methylisoxazole-5-yl) -4-oxo-butanoic acid (3.4 g, 14.09 mmol, 1 eq) and tert-butyl piperazin-1-carboxylic acid To a solution of N, N-dimethylformamide (30 mL) of acid salt (3.41 g, 18.32 mmol, 1.3 eq) is added diisopropylethylamine (3.64 g, 28.19 mmol, 2 eq), followed by O- (7-azabenzotriazole). -1-yl) -N, N, N, N-tetramethyluronium hexafluorophosphate (5.89 g, 15.50 mmol, 1.1 eq) was added and the mixture was stirred at 20 ° C. for 1 hour. The mixture was diluted with water (100 mL), extracted with dichloromethane (100 mL, twice), the organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give the crude product. The crude product was purified by silica gel chromatography (ethyl acetate: petroleum ether = 0: 1 to 1:20) to obtain a product. tert-butyl 4- [4-Methoxy-2,2-dimethyl-3- (3-methylisoxazole-5-yl) -4-oxo-butanoyl] piperazine-1-carboxylate (5.3 g, 12.94 mmol) , Yield 91%) was obtained. 1H-NMR (400MHz, CDCl3) δ 6.16 --6.01 (m, 1H), 4.39 (s, 1H), 3.70 (s, 3H), 3.67 --3.56 (m, 4H), 3.50 --3.41 (m, 4H), 2.36 --2.24 (m, 3H), 1.53 (s, 3H), 1.47 (s, 9H), 1.31 (s, 3H).
Step 4: Preparation of tert-butyl 4- (4-methoxy-2,2-dimethyl-3- (3-methylisoxazole-5-yl) -4-oxobutyl) piperazine-1-carboxylate.

tert-butyl 4- [4-Methoxy-2,2-dimethyl-3- (3-methylisoxazole-5-yl) -4-oxo-butanoyl] piperazine-1-carboxylate (4.3 g, 10.50 mmol) , 1 eq) of dimethylsulfideboran (10M, 10.5 mL, 10 eq) was added to a solution of tetrahydrofuran (60 mL) at 0 ° C. and the mixture was stirred at 40 ° C. for 1 hour. The mixture was quenched with methanol (20 mL) and the residue was concentrated to give a crude product. The crude material was purified by preparative HPLC and the mixture was adjusted to pH = 8 using a saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate (200 mL, twice), the organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give the product. Compound tert-
Butyl 4- [4-Methoxy-2,2-dimethyl-3- (3-methylisoxazole-5-yl) -4-oxo-butyl] piperazine-1-carboxylate (2.7 g, 6.83 mmol, yield) A rate of 65%) was obtained as a colorless oil. 1H-NMR (400MHz, CDCl3) δ 6.16 (s, 1H), 4.24 --4.06 (m, 1H), 3.70 (s, 3H), 3.40 (br s, 4H), 2.51 (s, 4H), 2.31 --2.15 (m, 5H), 1.46 (s, 9H), 1.05 (s, 3H), 0.92 (s, 3H).
Step 5: Preparation of 4- (4- (tert-butoxycarbonyl) piperazine-1-yl) -3,3-dimethyl-2- (3-methylisoxazole-5-yl) butanoic acid.

tert-Butyl 4- [4-Methoxy-2,2-dimethyl-3- (3-methylisoxazole-5-yl) -4-oxo-butyl] piperazine-1-carboxylate (2.7 g, 6.83 mmol) , 1 equivalent) of methanol (10 mL)
And in a solution of tetrahydrofuran (10 mL), lithium hydroxide monohydrate (2.86 g, 68.27 mmol, 10)
An aqueous solution (10 mL) of (equivalent) was added, and the mixture was stirred at 20 ° C. for 10 hours. The mixed solution was adjusted to pH = 5 using an aqueous solution of hydrochloric acid (1M). The mixture was extracted with dichloromethane (100 mL, 3 times), the organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give the product. The product was purified by preparative HPLC, the acetonitrile fraction was removed and the residue was lyophilized to give the product. The compound 4- (4-tert-butoxycarbonylpiperazine-1-yl) -3,3-dimethyl-2- (3-methylisoxazole-5-yl) butanoic acid (1.2 g, 3.15 mmol) was added as a white solid. I got it as a thing. 1H-NMR (400MHz, DMSO-d6) δ 6.25 (s, 1H), 3.87 (s, 1H), 3.27 --3.21 (m, 4H), 2.53 (s, 4H), 2.29 (d, J = 8.9 Hz, 2H), 2.20 (s, 3H), 1.38 (s, 9H), 0.99 (s, 3H), 0.92 (s, 3H).
Step 6: tert-butyl 4-(4-((2S, 4R) -4-hydroxy-2-(((S) -1-(4- (4-methylthiazole-5-yl) phenyl) ethyl) carbamoyl) ) Preparation of pyrrolidine-1-yl) -2,2-dimethyl-3- (3-methylisoxazole-5-yl) -4-oxobutyl) piperazine-1-carboxylate.

4- (4-tert-Butoxycarbonylpiperazin-1-yl) -3,3-dimethyl-2- (3-methylisoxazole-5-yl) butanoic acid (1.2 g, 3.15 mmol, 1 eq) and ( 2S, 4R) -4-hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (1.5 g, 4.08 mmol, 1.30 equivalents, To a solution of 1,2-dichloroethane (15 mL) of hydrochloride) is added diisopropylethylamine (1.22 g, 9.44 mmol, 1.64 mL, 3 eq), followed by 1-hydroxybenzotriazole (510 mg, 3.77 mmol, 1.2 eq) and N- (3-Dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride (724 mg, 3.77 mmol, 1.2 eq) was added and the mixture was stirred at 80 ° C. for 5 hours. The mixture was diluted with dichloromethane (100 mL), washed with water (100 mL), the organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give the crude product. The crude material was purified by silica gel chromatography (dichloromethane: methanol = 50: 1 to 10: 1) to obtain a product. The product was further purified by preparative HPLC, the acetonitrile fraction was removed and the residue was lyophilized to give the product. The product was further purified by preparative HPLC, the acetonitrile fraction was removed and the residue was lyophilized to give the final product. The compound tert-butyl 4- [4-[(2S, 4R) -4-hydroxy-2-[[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] carbamoyl] Pyrrolidine-1-yl] -2,2-dimethyl-3- (3-methylisoxazole-5-yl) -4-oxo-butyl] piperazine-1-carboxylate (490 mg, 0.71 mmol, yield 22.4) %) Was obtained as a white solid. 1H-NMR (400MHz, CDCl3) δ 8.68 (s, 1H), 7.50 --7.34 (m, 5H), 6.27 --6.08 (m, 1H), 5.13 --4.97 (m, 1H), 4.71 --4.55 (m, 2H) ), 4.47 --4.32 (m, 1H), 3.90 (dd, J = 5.4, 10.5 Hz, 1H), 3.53 (dd, J = 4.2, 10.4 Hz, 1H), 3.41 (s, 4H), 2.67 --2.43 ( m, 8H), 2.31 --2.25 (m, 3H), 2.22 (d, J = 3.3 Hz, 2H), 1.97 --1.85 (m, 1H), 1.52 (d, J = 6.8 Hz, 2H), 1.48 --1.40 (m, 10H), 1.11 (s, 3H), 1.04 --0.96 (m, 3H).
Step 7: (2S, 4R) -1- (3,3-dimethyl-2- (3-methylisoxazole-5-yl) -4- (piperazine-1-yl) butanoyl) -4-hydroxy-N -Preparation of ((S) -1- (4- (4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide.

tert-butyl 4- [4-[(2S, 4R) -4-hydroxy-2-[[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine- 1-yl] -2,2-dimethyl-3- (3-methylisoxazole-5-yl) -4-oxo-butyl] piperazine-1-carboxylate (200 mg, 0.29 mmol, 1)
Hydrochloric acid / dioxane (4M, 3 mL, 41.69 eq) was added to a solution of dichloromethane (3 mL) (equivalent), and the mixture was stirred at 20 ° C. for 1 hour. Concentrate the mixture to (2S, 4R) -1- [3,3-dimethyl-2- (3-methylisoxazole-5-yl) -4-piperazin-1-yl-butanoyl] -4- Hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (230 mg, crude, hydrochloride) was obtained as a white solid. LC / MS (ESI) m / z: 595.2 [M + 1] ⁺ .
Step 8: (2S, 4R) -1- (4-(4-((1- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrolidin) -1- Sulfone amide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperidine-4-yl) Methyl) Piperazine-1-yl) -3,3-dimethyl-2- (3-) Preparation of methylisoxazole-5-yl) butanoyl) -4-hydroxy-N-((S) -1-(4-(4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide.

(2S, 4R) -1- [3,3-dimethyl-2- (3-methylisoxazole-5-yl) -4-piperazin-1-yl-butanoyl] -4-hydroxy-N-[(1S) ) -1- [4- (4-Methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (50 mg, 0.08 mmol, 1 eq, hydrochloride) in a mixture of methanol (2 mL) and sodium acetate. (13 mg, 0.16 mmol, 2 eq) were added at one time at 15 ° C. 1 mixture
Stir for minutes at 15 ° C., then (3R) -N- [2,4-difluoro-3- [5- [4- (4-formyl-1-piperidyl) phenyl] -1H-pyrrolo [2,3- b] Pyridine-3-carbonyl] Phenyl] -3-Fluoro-pyrrolidin-1-sulfonamide (44 mg, 0.071 mmol, 0.9 equivalent) in dichloromethane (0.5 mL) was added. The mixture was stirred at 15 ° C. for an additional 30 minutes and acetic acid (0.87 mmol, 0.05 mL, 11.04 eq) was added to adjust the pH to 4-5. Then sodium cyanoborohydride (10 mg, 0.16 mmol, 2 eq) was added and stirred at 30 ° C. for 1 hour. The reaction mixture was diluted with 10 mL of water and extracted with dichloromethane (5 mLx3). The combined organic layers were washed with brine (10 mLx3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by half-reverse phase HPLC. Compound (2S, 4R) -1- [4- [4- [[1- [4- [3- [2,6-difluoro-3- [[(3R) -3-fluoropyrrolidin-1-yl]] Sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl] -4-piperidyl] methyl] piperazine-1-yl] -3,3-dimethyl-2- (3-methyl) Isoxazole-5-yl) butanoyl] -4-hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (22 mg, 0.01) mmol, yield 21%, purity 96%, formate) was obtained as a bright yellow solid. LC / MS (ESI) m / z: 1190.4 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 12.94 (s, 1 H), 8.97 --9.03 (m, 1 H), 8.65 (d) , J = 2.0 Hz, 1 H), 8.53 (s, 1 H), 8.41 (d, J = 8.0 Hz, 1 H), 8.18 (s, 1 H), 8.06 (s, 1 H), 7.56 --7.66 (m, 3 H), 7.34 --7.74 (m, 4 H), 7.25 (t, J = 8.8 Hz, 1 H), 7.06 (d, J = 8.8 Hz, 2 H), 6.11 --6.28 (m, 1) H), 5.20 --5.54 (m, 1 H), 4.87 --4.99 (m, 1 H), 4.21 --4.43 (m, 3 H), 4.10 (s, 1 H), 3.77 (d, J = 10.4 Hz, 4 H), 3.47 (s, 8 H), 3.17 (s, 5 H), 2.71 --2.75 (m, 1 H), 2.47 (s, 6 H), 2.05 --2.27 (m, 8 H), 1.75- 1.86 (m, 3 H), 1.70 (s, 1 H), 1.36 --1.47 (m, 3 H), 1.21 (d, J = 8.8 Hz, 2 H), 0.98 --1.07 (m, 3 H), 0.88 (s, 3 H).
(2S, 4R) -1-((S) -2-(2-(4-((4- (4- (3- (2,6-difluoro-3- (((R) -3-fluoro-) N-Methylpyrrolidin) -1-sulfonamide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperazin-1-yl) Methyl) Piperidine-1-yl) Acetamide) -3 , 3-Dimethylbutanoyl) -4-Hydroxy-N- (4- (4-Methylthiazole-5-yl) benzyl) Pyrrolidine-2-Carboxamide Illustrative Synthesis (Example 330)
Step 1: (5-bromo-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) (2,6-difluoro-3-nitrophenyl) Preparation of methanone.

(5-bromo-1H-pyrrolo [2,3-b] pyridine-3-yl)-(2,6-difluoro-3-nitro-phenyl) dimethylformamide (25 mL) of methanone (2 g, 5.23 mmol, 1 eq) ), 2- (Chloromethoxy) ethyl-trimethyl-silane (1.05 g, 6.28 mmol, 1 mL, 1.2 eq) and diisopropylethylamine (1.01 g, 7.85 mmol, 1 mL, 1.5 eq) were added. The mixture was stirred at 80 ° C. for 1.5 hours. The reaction mixture was washed with saturated brine (30 mLx2) and extracted with ethyl acetate (50 mLx2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 12/1 to 10: 1). Compound [5-bromo-1- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b] pyridin-3-yl]-(2,6-difluoro-3-nitro-phenyl) methanone (1.74g, 3.40) mmol, yield 64%) was obtained as a yellow solid. LC / MS (ESI) m / z: 513.9 [M + 1] +; 1H-NMR (400MHz, CDCl3) δ 8.87 (d, J = 2.0 Hz, 1H), 8.52 (d, J = 2.0 Hz, 1H) , 8.28 (ddd, J = 5.6, 8.4, 9.2 Hz, 1H), 7.70 (s, 1H), 7.20 (ddd, J = 1.6, 7.2, 9.2 Hz, 1H), 5.68 (s, 2H), 3.63 --3.55 (m, 2H), 0.96 --0.87 (m, 2H), -0.04 --- 0.06 (m, 9H).
Step 2: (3-Amino-2,6-difluorophenyl) (5-bromo-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) Preparation of methanone.

[5-bromo-1- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b] pyridine-3-yl]-(2,6-difluoro-3-nitro-phenyl) methanone (1.72 g, 3.36 mmol, 1 equivalent) of ethyl alcohol (5 mL), tetrahydrofuran (5 mL) and water (5 mL) with iron (1.87 g, 33.57 mmol, 10 equivalents) and ammonium chloride (898 mg, 16.78 mmol, 0.6 mL, 5 equivalents). added. The mixture was stirred at 80 ° C. for 5 hours. The reaction mixture was filtered, washed with brine (30 mLx2) and extracted with ethyl acetate (50 mLx2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 10/1 to 4: 1). Compound (3-amino-2,6-difluoro-phenyl)-[5-bromo-1- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b] pyridin-3-yl] methanone (1.33 g, 2.56) mmol, yield 76%, purity 93%) was obtained as a yellow oil. LC / MS (ESI) m / z: 484.1 [M + 2
] +; 1H-NMR (400MHz, CDCl3) δ 8.86 (d, J = 2.0 Hz, 1H), 8.48 (d, J = 2.4 Hz, 1H), 7.74 (s, 1H), 6.90 --6.80 (m, 2H) ), 5.66 (s, 2H), 3.60 --3.54 (m, 2H), 0.94 --0.88 (m, 2H), -0.04 --- 0.07 (m, 9H).
Step 3: (R) -N- (3- (5-bromo-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolidine [2,3-b] pyridin-3-carbonyl) -2, Preparation of 4-difluorophenyl) -3-fluoropyrrolidine-1-sulfonamide.

(3-Amino-2,6-difluoro-phenyl)-[5-bromo-1- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b] pyridin-3-yl] methanone (985 mg, 1.90 mmol, 1) To a solution of (equivalent) pyridine (15 mL) was added dimethylaminopyridine (464 mg, 3.80 mmol, 2 equivalents) and (3R) -3-fluoropyrrolidin-1-sulfonyl chloride (712 mg, 3.80 mmol, 2 equivalents). The mixture was stirred at 50 ° C. for 12 hours. The reaction mixture was washed with saturated brine (30 mLx2) and extracted with ethyl acetate (40 mLx2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by half-reverse phase HPLC. A saturated aqueous solution of sodium bicarbonate was added to adjust the pH to 9. The aqueous layer was extracted with ethyl acetate (50 mLx3). The combined organic layers were washed with brine (30 mLx3), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Compound (3R) -N- [3- [5-bromo-1- (2-trimethylsilylethoxymethyl) pyrrolidine [2,3-b] pyridin-3-carbonyl] -2,4-difluoro-phenyl] -3 -Fluoro-pyrrolidine-1-sulfonamide (210 mg, 0.33 mmol, 17% yield) was obtained as a colorless oil. 1H-NMR (400MHz, CDCl3) δ 8.85 (d, J = 2.0 Hz, 1H), 8.49 (d, J = 2.4 Hz, 1H), 7.78 --7.68 (m, 2H), 7.10 --6.99 (m, 1H) , 6.54 (s, 1H), 5.65 (s, 2H), 5.31 (s, 1H), 3.66 --3.60 (m, 2H), 3.57 (d, J = 8.4 Hz, 2H), 3.55 --3.43 (m, 2H) ), 2.38 --2.23 (m, 1H), 2.16 --1.96 (m, 1H), 0.94 --0.88 (m, 2H), -0.05 (s, 9H).
Step 4: (R) -N- (3- (5-bromo-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolidine [2,3-b] pyridin-3-carbonyl) -2, Preparation of 4-difluorophenyl) -3-fluoro-N-methylpyrrolidine-1-sulfonamide.

(3R) -N- [3- [5-bromo-1- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl] -3-fluoro -Add diisopropylethylamine (64 mg, 0.50 mmol, 1.5 eq) and iodomethane (70 mg, 0.50 mmol, 1.5 eq) to a solution of dimethylformamide (2 mL) of pyrrolidine-1-sulfonamide (210 mg, 0.33 mmol, 1 eq). rice field. The mixture was stirred at 50 ° C. for 2 hours. The reaction mixture was washed with saturated aqueous brine solution (30 mLx2) and extracted with ethyl acetate (30 mLx2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (petroleum ether / ethyl acetate = 1: 1, Rf = 0.6). Compound (3R) -N- [3- [5-bromo-1- (2-trimethylsilylethoxymethyl) pyrrolidine [2,3-b] pyridin-3-carbonyl] -2,4-difluoro-phenyl] -3 -Fluoro-N-methyl-pyrrolidin-1-sulfonamide (165 mg, 0.25 mmol, 76% yield) was obtained as a colorless oil. LC / MS (ESI) m / z: 649.2 [M + 2] +; 1H-NMR (400MHz, CDCl3) δ 8.85 (d, J = 2.0 Hz, 1H), 8.49 (d, J = 2.4 Hz, 1H) , 7.74 (s, 1H), 7.66 (dt, J = 6.0, 8.8 Hz, 1H), 7.08 --7.01 (m, 1H), 5.65 (s, 2H), 5.34 --5.14 (m, 1H), 3.71 --3.64 (m, 1H), 3.64 --3.59 (m, 2H), 3.59 --3.53 (m, 2H), 3.53 --3.47 (m, 1H), 3.25 (s, 3H), 2.39 --2.06 (m, 2H), 0.95 --0.88 (m, 2H), -0.06 (s, 9H).
Step 5: tert-butyl (R) -2- (4-((4- (4- (3- (2,6-difluoro-3-((3-fluoro-N-methylpyrrolidin) -1-sulfonamide) ) Benzoyl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) methyl) piperidine-1-yl) Preparation of acetate.

(3R) -N- [3- [5-bromo-1- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl] -3-fluoro -N-Methyl-pyrrolidin-1-sulfonamide (165 mg, 0.25 mmol, 1 equivalent), tert-butyl 2- [4-[[4- [4- (4,4,5,5-tetramethyl-1,) 3,2-Dioxaborolan-2-yl) phenyl] piperazin-1-yl] methyl] -1-piperidyl] acetate (152 mg, 0.30 mmol, 1.2 equivalents), cesium fluoride (154 mg, 1.02 mmol, 4 equivalents) and 4-ditert-butylphosphanyl-N, N-dimethyl-aniline; Dichloropalladium (18 mg, 0.02 mmol, 0.1 equivalent) degassed a mixture of dioxane (2 mL) and water (0.5 mL), 3 times with nitrogen. Purged. The mixture was then stirred at 100 ° C. for 12 hours under a nitrogen atmosphere. The reaction mixture was washed with saturated aqueous brine solution (15 mLx2) and extracted with ethyl acetate (30 mLx2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (dichloromethane: methanol = 10: 1, Rf = 0.5). Compound tert-butyl 2- [4- [[4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl-methyl-amino]] Benzoyl] -1- (2-trimethylsilylethoxymethyl) pyrolo [2,3-b] pyridin-5-yl] phenyl] piperazine-1-yl] methyl] -1-piperidyl] acetate (93 mg, 0.09 mmol, yield A rate of 38%) was obtained as a white solid. LC / MS (ESI) m / z: 940.5 [M]
⁺ .
Step 6: Methyl (R) -2- (4-((4- (4- (3- (2,6-difluoro-3-((3-fluoro-N-methylpyrrolidin) -1-sulfonamide) benzoyl) ) -1H-Pyrrolidine [2,3-b] Pyridine-5-yl) Phenyl) Piperazine-1-yl) Methyl) Piperidine-1-yl) Preparation of acetate.

tert-butyl 2- [4- [[4- [4- [3- [2,6-difluoro-3- [[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl-methyl-amino] benzoyl]] -1- (2-trimethylsilylethoxymethyl) pyrolo [2,3-b] pyridine-5-yl] phenyl] piperazine-1-yl] methyl] -1-piperidyl] acetate (93 mg, 0.10 mmol, 1 equivalent) Hydroxyl / dioxane (4M, 4 mL, 161.75 equivalents) was added to the solution of methanol (2 mL). The mixture was stirred at 40 ° C. for 14 hours. The reaction mixture was concentrated under vacuum to give a residue. Compound Methyl 2- [4- [[4- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1-yl] sulfonyl-methyl-amino] benzoyl]] -1H-Pyrrolidine [2,3-b] Pyridine-5-
Il] phenyl] piperazine-1-yl] methyl] -1-piperidyl] acetate (120 mg, crude, hydrochloride) was obtained as a yellow solid. LC / MS (ESI) m / z: 768.1 [M + 1] ⁺ .
Step 7: (R) -2- (4-((4- (4- (3- (2,6-difluoro-3-((3-fluoro-N-methylpyrrolidin) -1-sulfonamide) benzoyl))) Preparation of -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) methyl) piperidine-1-yl) acetic acid.

Methyl 2- [4- [[4- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl-methyl-amino] benzoyl] -1H] -Pyrrolo [2,3-b] Pyridine-5-yl] phenyl] Piperazine-1-yl] Methyl] -1-piperidyl] Acetate (120 mg, 0.15 mmol, 1 equivalent, hydrochloride) in methanol (1 mL), Lithium hydrate (11 mg, 0.45 mmol, 3 equivalents) was added to a solution of water (0.5 mL) and methanol (1 mL). The mixture was stirred at 20 ° C. for 1 hour. The reaction mixture was concentrated under vacuum to give a residue. The residue was diluted with 20 mL of water and then acidified with hydrochloric acid (1M) to pH = 5-6. The suspension was concentrated under vacuum to give a residue. Compound 2- [4- [[4- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1-yl] sulfonyl-methyl-amino] benzoyl]- 1H-Pyrrolidine [2,3-b] Pyridine-5-yl] phenyl] piperazine-1-yl] Methyl] -1-piperidyl] Acetic acid (0.1 g, crude, hydrochloride) was obtained as a yellow solid. LC / MS (ESI) m / z: 754.3 [M + 1] ⁺ .
Step 8: (2S, 4R) -1-((S) -2- (2- (4-((4- (4- (3- (2,6-difluoro-3- (((R) -3) -3) -Fluoro-N-
Methylpyrrolidine) -1-sulfonamide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl)
Phenyl) piperazine-1-yl) methyl) piperidine-1-yl) acetamide) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine -2- Preparation of carboxamide.

2- [4- [[4- [4- [3- [2,6-difluoro-3- [[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl-methyl-amino] benzoyl] -1H- Pyrrolo [2,3-b] pyridine-5-yl] phenyl] piperazine-1-yl] methyl] -1-piperidyl] acetic acid (0.1 g, 0.13 mmol, 1 eq, hydrochloride) of dimethylformamide (2 mL) In solution, hydroxybenzotriazole (20 mg, 0.15 mmol, 1.2 eq), diisopropylethylamine (49 mg, 0.38 mmol, 3 eq) and (2S, 4R) -1-[(2S) -2-amino-3,3-dimethyl) -Butanoyl] -4-hydroxy-N-[[4- (4-methylthiazole-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (59 mg, 0.13 mmol, 1 eq, hydrochloride) at 20 ° C. 15 Added over minutes. After the addition, dimethylamine carbon hydrochloride (36 mg, 0.19 mmol, 1.5 eq) was added. The resulting mixture was stirred for 1.75 hours at 35 ° C. The reaction mixture was washed with saturated brine (25 mLx2) and extracted with dichloromethane (30 mLx2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by half-reverse phase HPLC. Compound (2S, 4R) -1-[(2S) -2-[[2- [4-[[4- [4- [3- [2,6-difluoro-3- [[(3R) -3) --Fluoropyrrolidine-1-yl] sulfonyl-methyl-amino] benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl] piperazine-1-yl] methyl] -1-piperidyl] acetyl] Amino] -3,3-dimethyl-butanoyl] -4-hydroxy-N-[[4- (4-methylthiazole-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (19.1 mg, 0.01 mmol, yield) 11%, 100% purity, trifluoroacetic acid) was obtained as a yellow solid. LC / MS (ESI) m / z: 583.8 [M / 2 + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 12.98 (s, 1H), 10.12 --9.59 (m, 2H), 9.03 --8.97 (m, 1H), 8.78 (d, J = 8.4 Hz, 1H), 8.61 (d, J = 6.0 Hz, 2H), 8.12 (s, 1H), 7.76 (dt, J = 6.0, 8.8 Hz, 1H) , 7.68 (d, J = 8.8 Hz, 2H), 7.41 (q, J = 8.4 Hz, 4H), 7.33 (t, J = 8.8 Hz, 1H), 7.17 (d, J = 8.8 Hz, 2H), 5.41 (s, 1H), 5.28 (s, 1H), 4.60 (d, J = 9.2 Hz, 2H), 4.52 --4.34 (m, 5H), 4.22 (dd, J = 5.2, 15.6 Hz, 1H), 4.15- 3.84 (m, 5H), 3.71 (d, J = 7.2 Hz, 1H), 3.68 --3.55 (m, 4H), 3.54 --3.44 (m, 4H), 3.43 --3.34 (m, 1H), 3.14 (s, 3H), 3.06 (s, 1H), 2.20 (d, J = 6.4 Hz, 2H), 2.13 (d, J = 7.6 Hz, 2H), 2.10 --2.02 (m, 3H), 2.01 --1.84 (m, 5H) ), 1.56 (s, 3H), 0.99 --0.93 (m, 9H).
(2S, 4R) -1-((S) -2-(2-(4-((4- (4- (3- (2-fluoro-5-(((R) -3-fluoropyrrolidine)-)- 1-
Sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazin-1-yl) methyl) piperidine-1-yl) acetamide) -3,3-dimethylbutanoyl)- 4-Hydroki
Illustrative of si-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide
Synthesis (Example 312)
Step 1: Preparation of 2-fluoro-5-nitrobenzoyl chloride.

A solution of 2-fluoro-5-nitro-benzoic acid (5 g, 27 mmol, 1 eq) and thionyl chloride (49 g, 413 mmol, 30 mL, 15 eq) in toluene (30 mL) and dimethylformamide (1.5 mL). The mixture was stirred at 80 ° C. for 12 hours. The reaction mixture was quenched by the addition of methanol. The reaction mixture was concentrated under reduced pressure to remove the solvent. The compound 2-fluoro-5-nitro-benzoyl chloride (5.8 g, crude) was obtained as a yellow oil.

Step 2: Preparation of (5-bromo-1H-pyrrolo [2,3-b] pyridin-3-yl) (2-fluoro-5-nitrophenyl) methanone.

5-bromo-1H-pyrrolo [2,3-b] pyridine (5.86 g, 29.72 mmol, 1.1 eq) with 1,2-dichloroethane (100 mL), aluminum trichloride (23 g, 172.93 mmol, 9 mL, 6.4 eq) Added in small portions.
The reaction mixture was stirred at 20 ° C. for 1 hour, and 2-fluoro-5-nitro-benzoyl chloride (5.5 g, 27.02 mmol, 1 eq) was added. The mixture was stirred at 50 ° C. for an additional 12 hours. The reaction mixture was washed with saturated aqueous brine solution (35 mLx2) and extracted with ethyl acetate (50 mLx3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by powdering with ethyl acetate (15 mL) and methanol (15 mL). The compound (5-bromo-1H-pyrrolo [2,3-b] pyridin-3-yl)-(2-fluoro-5-nitro-phenyl) metanone (2.11 g, 5.79 mmol, 21% yield) was browned. Obtained as a solid. LC / MS (ESI) m / z: 365.8 [M + 1] ⁺ .
Step 3: Preparation of (5-amino-2-fluorophenyl) (5-bromo-1H-pyrrolo [2,3-b] pyridin-3-yl) methanone.

(5-Bromo-1H-pyrrolo [2,3-b] pyridine-3-yl)-(2-fluoro-5-nitro-phenyl) methanone (2.11 g, 5.79 mmol, 1 eq), hydrochloric acid (12M, 14.5) mL, 30 eq), iron powder (1.62 g, 28.97 mmol, 5 eq), ammonium chloride (930 mg, 17.38 mmol, 3 eq) in tetrahydrofuran (10 mL) and ethanol (10 mL) for 16 hours at 80 ° C. Stirred. Aqueous sodium hydroxide solution (1M) was added to adjust the pH to 8-9. Ethyl acetate (50 mL) was added and the mixture was stirred for 5 minutes. The mixture was filtered and the filtrate was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mLx3), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was slurried with a solution of petroleum ether and ethyl acetate (30 mL, v: v = 1: 1). Product (5-amino-2-fluoro-phenyl)-(5-bromo-1H-pyrrolo [2,3-b] pyridin-3-yl) methanone (730 mg, 2.06 mmol, yield 35%, purity 94) %) Was obtained as a brown solid. LC / MS (ESI) m / z: 333.9 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 12.93 (br s, 1H), 8.57
(d, J = 2.4 Hz, 1H), 8.46 (d, J = 2.4 Hz, 1H), 8.07 (d, J = 1.6 Hz, 1H), 7.08 --6.95 (m, 1H), 6.79 --6.66 (m, 2H), 5.20 (s, 2H).
Step 4: Of (R) -N- (3- (5-bromo-1H-pyrrolo [2,3-b] pyridin-3-carbonyl) -4-fluorophenyl) -3-fluoropyrrolidine-1-sulfonamide Preparation.

(5-Amino-2-fluoro-phenyl)-(5-bromo-1H-pyrrolo [2,3-b] pyridin-3-yl) methanone (680 mg, 2.04 mmol, 1 eq) and (3R) -3- To a solution of fluoropyrrolidin-1-sulfonyl chloride (572 mg, 3.05 mmol, 1.5 eq) in pyridine (15 mL) was added 4-dimethylaminopyridine (49 mg, 0.4 mmol, 0.2 eq). The mixture was stirred at 40 ° C. for 12 hours. The pH of the reaction mixture was adjusted to 8 using a saturated aqueous sodium bicarbonate solution. Water (100 mL) was poured into the mixture and stirred for 1 minute. The aqueous layer was extracted with ethyl acetate (100 mLx3). The combined organic layers were washed with brine (100 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum.
Residues are column chromatographed (dichloromethane: methanol = 400: 1-10: 1)
Purified by. Compound (3R) -N- [3- (5-bromo-1H-pyrrolo [2,3-b] pyridin-3-carbonyl) -4-fluoro-phenyl] -3-fluoro-pyrrolidin-1-sulfonamide (780 mg, 1.61 mmol
, Yield 78%) was obtained as a brown solid. LC / MS (ESI) m / z: 486.9 [M + 1] +; 1H-NMR (400MHz, CDCl3) δ 8.89 (s, 1H), 8.47 (s, 1H), 7.77 (s, 1H), 7.46- 7.36 (m, 2H), 7.18 (t, J = 9.2 Hz, 1H), 6.69 (s, 1H), 5.42 --5.14 (m, 1H), 3.78 --3.59 (m, 4H), 3.54 --3.43 (m, 1H) 2H), 2.97 --2.88 (m, 1H).
Step 5: tert-butyl (R) -2- (4-((4- (4- (3- (2-fluoro-5-((3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-) Preparation of pyrrolidine [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) methyl) piperidine-1-yl) acetate.

(3R) -N- [3- (5-bromo-1H-pyrrolo [2,3-b] pyridine-3-carbonyl) -4-fluoro-phenyl] -3-fluoro-pyrrolidin-1-sulfonamide (430 mg) , 0.88 mmol, 1 equivalent) and tert-butyl 2- [4- [[4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine] 4-ditert-butylphosphanyl-N, N-dimethyl in a solution of -1-yl] methyl] -1-piperidyl] acetate (442 mg, 0.88 mmol, 1 equivalent) in water (1 mL) and dioxane (10 mL). -Aniline; dichloropalladium (62 mg, 0.08 mmol, 0.1 equivalent) and cesium fluoride (538 mg, 3.54 mmol, 4 equivalent) were added. The mixture was stirred at 100 ° C. for 5 hours. Water (100 mL) was poured into the mixture and stirred for 1 minute. The aqueous layer was extracted with ethyl acetate (40 mLx3). The combined organic layers were washed with brine (100 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by preparative thin layer chromatography (dichloromethane: methanol = 10: 1). Compound tert-butyl 2- [4- [[4- [3- [2-fluoro-5-[[(3R) -3-fluoropyrrolidine-1-yl] sulfonylamino] benzoyl] -1H- Pyrrolidine [2,3-b] Pyridine-5-yl] Phenyl] Piperazine-1-yl] Methyl] -1-Piperidyl] Acetate (260 mg, 0.30 mmol, yield 34%, purity 92%) as a brown solid Got as. LC / MS (ESI) m / z: 778.1 [M + 1] ⁺ .
Step 6: (R) -2- (4-((4- (4- (3- (2-fluoro-5-((3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [2 , 3-b] Pyridine-5-yl) Phenyl) Piperazine-1-yl) Methyl) Piperidine-1-yl) Preparation of acetic acid.

tert-butyl 2- [4- [[4- [4- [3- [2-fluoro-5-[[(3R) -3-fluoropyrrolidine-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [ 2,3-b] Pyridine-5-yl] phenyl] piperazine-1-yl] methyl] -1-piperidyl] acetate (200 mg, 0.25 mmol, 1 eq) in a solution of dioxane (10 mL) in 4M hydrochloric acid A solution of dioxane (6.67 mL, 103.72 eq) was added. The mixture was stirred at 50 ° C. for 3 hours. The reaction mixture was concentrated under reduced pressure to remove hydrochloric acid, dioxane and dioxane. The crude product was used in the next step without further purification. Compound 2- [4- [[4- [4- [3- [2-Fluoro-5-[[(3R) -3-fluoropyrrolidine-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2 , 3-b] Pyridine-5-yl] phenyl] piperazine-1-yl] methyl] -1-piperidyl] acetic acid (194 mg, 0.25 mmol, 99% yield, hydrochloride) was obtained as a yellow solid.

Step 7: (2S, 4R) -1-((S) -2- (2-(4-((4- (4- (3- (2-fluoro-5-(((R) -3-fluoro Pyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) methyl) piperidine-1-yl) acetamide) -3,3- Preparation of dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide.

2- [4- [[4- [4- [3- [2-Fluoro-5-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3] -b] Pyridine-5-yl] phenyl] piperazin-1-yl] methyl] -1-piperidyl] acetic acid (194 mg, 0.25 mmol, 1 equivalent, hydrochloride) in a solution of N, N-dimethylformamide (3 mL). , Triethylamine (39 mg, 0.38 mmol, 1.5 equivalents), hydroxybenzotriazole (41 mg, 0.30 mmol, 1.2 equivalents), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (74 mg, 0.38 mmol, 1.5 equivalents) And (2S, 4R) -1-[(2S) -2-amino-3,3-dimethyl-butanoyl] -4-hydroxy-N-[[4- (4-methylthiazole-5-yl) phenyl] methyl ] Pyridine-2-carboxamide (119 mg, 0.25 mmol, 1 equivalent, hydrochloric acid hydrochloride) was added. The mixture was stirred at 20 ° C. for 3 hours. Water (10 mL) was poured into the mixture and stirred for 1 minute. The aqueous layer was extracted with dichloromethane (10 mLx3). The combined organic layers were washed with brine (10 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by half-reverse phase HPLC. Compound (2S, 4R) -1-[(2S) -2-[[2- [4-[[4- [4- [3- [2-Fluoro-5-[[(3R) -3-fluoro Pyrrolidine-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl] piperazine-1-yl] methyl] -1-piperidyl] acetyl] amino] -3, 3-Dimethyl-butanoyl] -4-hydroxy-N-[[4- (4-methylthiazole-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (119 mg, 0.09 mmol, yield 38%, purity 96%) , Gyate) was obtained as a yellow solid. LC / MS (ESI) m / z: 567.7 [M / 2] +; 1H-NMR (400MHz, DMSO-d6) δ 12.91 (s, 1H), 9.00 (s, 1H), 8.65 --8.55 (m, 3H) ), 8.19 (s, 1H), 7.97 (s, 1H), 7.81 (d, J = 9.2 Hz, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.45 --7.74 (m, 4H), 7.40 --7.31 (m, 3H), 7.06 (d, J = 8.8 Hz, 2H), 5.34 (s, 1H), 5.21 (s, 1H), 4.50 (d, J = 9.6 Hz, 1H), 4.47 --4.41 ( m, 1H), 4.41 --4.32 (m, 2H), 4.30 --4.24 (m, 1H), 3.71 --3.54 (m, 2H), 3.47 (d, J = 3.2 Hz, 2H), 3.18 (s, 5H) , 3.05 ―― 2.87 (m, 3H), 2.83 (s, 2H), 2.52 (d, J = 2.0 Hz, 3H), 2.45 (s, 3H), 2.25 ―― 1.85 (m, 10H), 1.81 ―― 1.69 (m) , 2H), 1.55 (s, 1H), 1.23 --1.09 (m, 2H), 0.99 --0.91 (m, 9H).
(2S, 4R) -1-((S) -2-(2-(4-((4- (4- (3- (2-fluoro-3-(((R) -3-fluoropyrrolidine)-)- 1-
Sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) methyl) piperidine-1-yl) acetamide) -3,3-dimethylbutanoyl)- 4-Hydroki
Illustrative of si-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide
Synthesis (Example 313)
Step 1: Preparation of (5-bromo-1H-pyrrolo [2,3-b] pyridin-3-yl) (2-fluoro-3-nitrophenyl) methanone.

Thionyl chloride (14 g, 118.85 mmol, 8.6 mL, 2.2 eq) and N, N-dimethylformamide (1 mL) in a solution of 2-fluoro-3-nitro-benzoic acid (10 g, 54 mmol, 1 eq) in dichloromethane (100 mL). ) Was added. The mixture was stirred at 60 ° C. for 12 hours. The mixture was concentrated. 2-Fluoro-3-nitro-benzoyl chloride (11 g, crude) was obtained as a yellow oil. Ammonium trichloride (46.1 g, 345.85 mmol, 6.4 eq) was added to a solution of 5-bromo-1H-pyrrolo [2,3-b] pyridine (11.7 g, 59.44 mmol, 1.1 eq) in dichloromethane (100 mL). .. A solution of 2-fluoro-3-nitro-benzoyl chloride (11 g, 54.04 mmol, 1 eq) in dichloromethane (50 mL) was then added to the mixture. The mixture was stirred at 60 ° C. for 12 hours. Water (300 mL) was added to the mixed solution, and the mixture was extracted with ethyl acetate (300 mL × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated. Ethyl acetate (30 mL) was added to the residue and filtered to give the desired product. (5-Bromo-1H-pyrrolo [2,3-b] pyridin-3-yl)-(2-fluoro-3-nitro-phenyl) methanone (12 g, 32.96 mmol, yield 60%) as a yellow solid Obtained. LC / MS (ESI) m / z: 363.8 [M + 1] ⁺ .
Step 2: Preparation of (3-amino-2-fluorophenyl) (5-bromo-1H-pyrrolo [2,3-b] pyridin-3-yl) methanone.

(5-bromo-1H-pyrrolo [2,3-b] pyridine-3-yl)-(2-fluoro-3-nitro-phenyl) methanone (6 g, 16.48 mmol, 1 equivalent), ammonium chloride (3 g, 57.67) A mixture of ethanol (50 mL) and tetrahydrofuran (50 mL) of mmol, 3.5 eq), iron (4.5 g, 80.74 mmol, 4.9 eq), hydrochloride (12 M, 20 mL, 14.57 eq) was stirred at 78 ° C. for 2 hours. Sodium hydroxide (1M) was added to the mixed solution to adjust the pH to 8. The mixture was extracted with ethyl acetate (200 mLx3). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was pulverized with ethyl acetate (30 mL) to give the desired product. (3-Amino-2-fluoro-phenyl)-(5-bromo-1H-pyrrolo [2,3-b] pyridin-3-yl)
Metanone (2.7 g, 8.08 mmol, 49% yield) was obtained as a yellow solid. LC / MS (ESI) m / z: 335.9 [M + 1] +; 1H-NMR (400MHz, CDCl3) δ 8.89 (d, J = 2.0 Hz, 1H), 8.47 (d, J = 2.0 Hz, 1H) , 7.77 (d, J = 3.2 Hz, 1H), 7.08 --7.02 (m, 1H), 6.99 --6.86 (m, 2H), 3.89 (br s, 2H).
Step 3: Of (R) -N- (3- (5-bromo-1H-pyrrolo [2,3-b] pyridin-3-carbonyl) -2-fluorophenyl) -3-fluoropyrrolidine-1-sulfonamide Preparation.

A solution of (3-amino-2-fluoro-phenyl)-(5-bromo-1H-pyrrolo [2,3-b] pyridin-3-yl) methanone (700 mg, 2.09 mmol, 1 eq) in pyridine (7 mL). To (3R) -3-fluoropyrrolidin-1-sulfonyl chloride (589 mg, 3.14 mmol, 1.5 eq) and 4-dimethylaminopyridine (51 mg, 0.418 mmol, 0.2 eq) were added. The mixture was stirred at 40 ° C. for 12 hours. Saturated sodium bicarbonate (50 mL) was added to the mixture and extracted with ethyl acetate (50 mLx3). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by preparative TLC (dichloromethane: methanol = 20: 1). (3R) -N- [3- (5-bromo-1H-pyrrolo [2,3-b] pyridin-3-carbonyl) -2-fluoro-phenyl] -3-fluoro-pyrrolidin-1-sulfonamide (400 mg) , 0.824 mmol, yield 39%) was obtained as a yellow solid. LC / MS (ESI) m / z: 486.9 [M + 1] +; 1H-NMR (400MHz, CDCl3) δ 11.12 (br s, 1H), 8.91 (d, J = 2.0 Hz, 1H), 8.52 --8.44 (m, 1H), 7.86 --7.72 (m, 2H), 7.38 --7.31 (m, 1H), 7.13 --6.94 (m, 1H), 5.36 --5.14 (m, 1H), 3.68 --3.58 (m, 2H) , 3.57 --3.46 (m, 2H), 2.36 --2.22 (m, 1H), 2.18 --1.97 (m, 1H).
Step 4: tert-butyl (R) -2- (4-((4- (4- (3- (2-fluoro-3-((3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-) Preparation of pyrrolidine [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) methyl) piperidine-1-yl) acetate.

(3R) -N- [3- (5-bromo-1H-pyrrolo [2,3-b] pyridine-3-carbonyl) -2-fluoro-phenyl] -3-fluoro-pyrrolidin-1-sulfonamide (100 mg) , 0.20 mmol, 1 equivalent) and tert-butyl 2- [4- [[4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine] 4-ditert-butylphosphanyl-N, N- in a solution of dioxane (2 mL) and water (0.2 mL) of -1-yl] methyl] -1-piperidyl] acetate (102 mg, 0.20 mmol, 1 equivalent). Dimethyl-aniline; dichloropalladium (29 mg, 0.041 mmol, 0.2 equivalent) and cesium fluoride (125 mg, 0.82 mmol, 4 equivalent) were added. The mixture was stirred at 110 ° C. for 6 hours. Water (30 mL x 3) was added to the mixed solution, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative TLC (dichloromethane: methanol = 20: 1). Tert-butyl 2- [4-[[4- [4- [3- [2-fluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [ 2,3-b] Pyridine-5-yl] phenyl] piperazine-1-yl] methyl] -1-piperidyl] acetate (40 mg, 0.038 mmol, yield 18%, purity 74%) was obtained as a yellow solid. rice field. LC / MS (ESI) m / z: 778.5 [M + 1] ⁺ .
Step 5: (R) -2- (4-((4- (4- (3- (2-fluoro-3-((3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [2 , 3-b] Pyridine-5-yl) Phenyl) Piperazine-1-yl) Methyl) Piperidine-1-yl) Preparation of acetic acid.

tert-butyl 2- [4- [[4- [4- [3- [2-fluoro-3-[[(3R) -3-fluoropyrrolidine-1-yl]]
Hydrochloride] benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl] piperazine-1-yl] methyl] -1-piperidyl] acetate (100 mg, 0.128 mmol, 1 eq) dichloromethane Hydrochloride / dioxane (4M, 7.50 mL) was added to the solution of (5 mL). The mixture was stirred at 20 ° C. for 12 hours. The mixture was concentrated. The residue was used in the next step without further purification. 2- [4- [[4- [4- [3- [2-Fluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3] -b] Pyridine-5-yl] phenyl] piperazine-1-yl] methyl] -1-piperidyl] acetic acid (100 mg, crude, hydrochloride) was obtained as a yellow solid. LC / MS (ESI) m / z: 722.4 [M + 1] ⁺ .
Step 6: (2S, 4R) -1-((S) -2- (2-(4-((4- (4- (3- (2-fluoro-3-(((R) -3-fluoro) Pyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) methyl) piperidine-1-yl) acetamide) -3,3- Preparation of dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide.

2- [4- [[4- [4- [3- [2-Fluoro-3- [[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3] -b] pyridine-5-yl] phenyl] piperazin-1-yl] methyl] -1-piperidyl] acetic acid (100 mg, 0.138 mmol, 1 equivalent) and (2S, 4R) -1- [(2S) -2- Amino-3,3-dimethyl-butanoyl] -4-hydroxy-N-[[4- (4-methylthiazole-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (59 mg, 0.138 mmol, 1 equivalent) Hydroxybenzotriazole (22 mg, 0.166 mmol, 1.2 equivalents), triethylamine (21 mg, 0.207 mmol, 1.5 equivalents) and 1- (3-dimethylaminopropyl) -3-ethyl in a solution of N, N-dimethylformamide (2 mL). Carbodiimide hydrochloride (39 mg, 0.207 mmol, 1.5 equivalents) was added. The mixture was stirred at 20 ° C. for 0.5 hours. The mixture was quenched with water (30 mLx3) and extracted with dichloromethane / methanol (10: 1, 30 mLx3). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by preparative HPLC. (2S, 4R) -1-[(2S) -2-[[2- [4-[[4- [4- [3- [2-Fluoro-3-[[(3R) -3-fluoropyrrolidine- 1-yl] Sulfonylamino] Benzoyl] -1H-Pyrrolidine [2,3-b] Pyridine-5-yl]
Phenyl] piperazine-1-yl] methyl] -1-piperidyl] acetyl] amino] -3,3-dimethyl-butanoyl] -4-hydroxy-N-[[4- (4-methylthiazole-5-yl) phenyl ] Methyl] pyrrolidine-2-carboxamide (5.9 mg, .0.04 mmol, yield 3.47%, purity 100%, digiate) was obtained as a yellow solid. LC / MS (ESI) m / z: 1134.4 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 9.00 (s, 1H), 8.63 (s, 2H), 8.56 (s, 1H), 8.25 (s, 2H), 7.92 (s, 1H), 7.82 (br d, J = 9.6 Hz, 1H), 7.67 --7.56 (m, 3H), 7.48 --7.38 (m, 4H), 7.35 --7.23 (m) , 2H), 7.06 (br d, J = 8.8 Hz, 2H), 5.37 --5.52 (m, 1H), 4.54 --4.21 (m, 7H), 3.63 (br d, J = 14.2 Hz, 1H), 3.18 ( br s, 3H), 3.04 --2.76 (m, 4H), 2.45 (br s, 7H), 2.23 --1.85 (m, 12H), 1.82- 1.69 (m, 2H), 1.56 (br s, 1H), 1.25 --1.07 (m, 3H), 0.94 (s,
10H).
(2S, 4R) -1-((S) -2- (2- (4-((4- (4- (3- (2-chloro-6-fluoro-3- (((R) -3-) Fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) methyl) piperidine-1-yl) acetamide) -3,3 -Dimethylbutanoyl) -4-
Hydroxy-N- (4- (4-Methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide
Illustrative synthesis of (Example 352)
Step 1: Preparation of 2-chloro-6-fluoro-3-nitrobenzoic acid.

Nitric acid (7.22 g, 114.58 mmol, 5.16 mL, 2 eq) was added to a solution of 2-chloro-6-fluoro-benzoic acid (10 g, 57.29 mmol, 1 eq) in sulfuric acid (100 mL) at 0 ° C. The reaction mixture was heated to 20 ° C. and stirred for 1 hour. The reaction solution was poured into ice water (1000 mL), stirred for 10 minutes and extracted with ethyl acetate (200 mL × 3). The organic layers were combined and washed with water (200 mLx2) and then brine (100 mL). The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated in vacuo. 2-Chloro-6-fluoro-3-nitro-benzoic acid (11.7 g, 53.29 mmol, 93% yield) was obtained as a white solid.

Step 2: Preparation of (5-bromo-1H-pyrrolo [2,3-b] pyridin-3-yl) (2-chloro-6-fluoro-3-nitrophenyl) methanone.

2-Chloro-6-fluoro-3-nitro-benzoic acid (11.3 g, 51.47 mmol, 1 eq) in a solution of toluene (100 mL) with sulfoxide (30.62 g, 257.34 mmol, 5 eq) and N, N- Dimethylformamide (1 mL) was added. The mixture was heated to 110 ° C. for 2 hours. The solvent was removed in vacuo. Dissolve the residue in dichloromethane (200 mL), 5-bromo-1H-pyrrolo [2,3-b] pyridine (11.15 g, 56.61 mmol, 1.1 eq), ammonium trichloride (20.59 g, 154.40 mmol, 3 eq). Was added to the solution. The mixture was heated to 40 ° C. for 3 hours. The solvent was removed in vacuo and the residue was poured into ice water (500 mL) and stirred for 30 minutes. The mixture was extracted with tetrahydrofuran (300 mLx3). The organic layer was washed with brine (300 mL x 2) and dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was pulverized with methanol (50 mL) and (5-bromo-1H-pyrrolo [2,3-b] pyridin-3-yl)-(2-chloro-6-fluoro-3-nitro-phenyl). Methanol (9.3 g, 22.40 mmol, 43% yield, 96% purity) was obtained as a yellow solid. LC / MS (ESI) m / z: 399.8 [M + 1] ⁺ .
Step 3: Preparation of (3-amino-2-chloro-6-fluorophenyl) (5-bromo-1H-pyrrolo [2,3-b] pyridin-3-yl) methanone.

(5-Bromo-1H-pyrrolo [2,3-b] pyridine-3-yl)-(2-chloro-6-fluoro-3-nitro-phenyl) Methanone (9.3 g, 23.33 mmol, 1 eq) tetrahydrofuran In a solution of (60 mL) and ethyl alcohol (60 mL), hydrochloric acid (12M, 3.89 mL, 2 eq), ammonium chloride (3.74 g, 70.00 mmol, 3 eq) and iron powder (6.52 g, 116.67 mmol, 5 eq). Was added. Mix the mixture at 80 ° C 12
Stir for hours. The pH of the reaction mixture was adjusted to 8 using a saturated aqueous sodium bicarbonate solution.
The reaction mixture was filtered and the filtrate was concentrated. Water (100 mL) was poured into the mixture and stirred for 1 minute. The aqueous layer was extracted with tetrahydrofuran (100 mLx3). The combined organic layers were washed with brine (100 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was pulverized with petroleum ether: ethyl acetate = 1: 1 (30 mL) and (3-amino-2-chloro-6-fluoro-phenyl)-(5-bromo-1H-pyrrolo [2,3-]. b] Pyridine-3-yl) Metanone (8.03 g, 21.13 mmol, 90% yield, 97% purity) was obtained as a yellow solid. LC / MS (ESI) m / z: 369.8 [M + 1] ⁺ .
Step 4: (R) -N- (3- (5-bromo-1H-pyrrolo [2,3-b] pyridin-3-carbonyl) -2-chloro-4-fluorophenyl) -3-fluoropyrrolidine-1 -Preparation of sulfonamides.

(3-Amino-2-Chloro-6-Fluoro-Phenyl)-(5-Bromo-1H-Pyrrolo [2,3-b] Pyridine-3-
4-Dimethylaminopyridine (1 g, 2.71 mmol, 1 eq) and 4-dimethylaminopyridine (3R) -3-fluoropyrrolidine-1-sulfonyl chloride (610 mg, 3.26 mmol, 1.2 eq) in a solution of pyridine (10 mL). 66 mg, 0.54 mmol, 0.2 eq) was added. The mixture was stirred at 40 ° C. for 12 hours. The pH of the reaction mixture was adjusted to 8 using a saturated aqueous sodium bicarbonate solution. Water (100 mL) was poured into the mixture and stirred for 1 minute. The aqueous layer was extracted with ethyl acetate (100 mLx3). The combined organic layers were washed with brine (100 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by preparative reverse phase HPLC. Compound (3R) -N- [3- (5-bromo-1H-pyrrolo [2,3-b] pyridin-3-carbonyl) -2-chloro-4-fluoro-phenyl] -3-fluoro-pyrrolidin- 1-Sulfonamide (270 mg, 0.51 mmol, 19% yield) was obtained as a yellow solid. LC / MS (ESI) m / z: 521.1 [M + 1] ⁺ .
Step 5: (R) -N- (3- (5-bromo-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolidine [2,3-b] pyridin-3-carbonyl) -2- Preparation of chloro-4-fluorophenyl) -3-fluoro-N-((2- (trimethylsilyl) ethoxy) methyl) pyrrolidine-1-sulfonamide.

(3R) -N- [3- (5-bromo-1H-pyrrolo [2,3-b] pyridine-3-carbonyl) -2-chloro-4-fluoro-phenyl] -3-fluoro-pyrrolidin-1- Sodium hydride (78 mg, 1.97 mmol, 60% in mineral oil, 2.5 eq) is added to a solution of sulfone amide (410 mg, 0.78 mmol, 1 eq) in N, N-dimethylformamide (4.5 mL) at 0 ° C. rice field. Then (2- (chloromethoxy) ethyl) trimethylsilane (328 mg, 1.97 mmol, 2.5 eq) was added to the mixture at 15 ° C. The mixture was stirred at 0-15 ° C. for 12 hours. A saturated aqueous solution of ammonium chloride (10 mL) was added to the mixed solution. Water (10 mL) was poured into the mixture and stirred for 1 minute. The aqueous layer was extracted with ethyl acetate (15 mLx3). The combined organic layers were washed with brine (15 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by preparative thin layer chromatography (petroleum ether: ethyl acetate = 3/1). (3R) -N- [3- [5-bromo-1- (2-trimethylsilylethoxymethyl) pyrrolidine [2,3-b] pyridin-3-carbonyl] -2-chloro-4-fluoro-phenyl] -3 -Fluoro-N- (2-trimethylsilylethoxymethyl) pyrrolidine-1-sulfonamide (330 mg, 0.42 mmol, 53% yield) was obtained as a yellow oil. LC / MS (ESI) m / z: 781.0 [M + 1] ⁺ .
Step 6: tert-butyl (R) -2- (4-((4- (4- (3- (2-chloro-6-fluoro-3-((3-fluoro-N- ((2- (trimethylsilyl) ) Ethoxy) methyl) pyrrolidine) -1-sulfonamide) benzoyl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine- Preparation of 1-yl) methyl) piperidine-1-yl) acetate.

(3R) -N- [3- [5-bromo-1- (2-trimethylsilylethoxymethyl) pyrrolidine [2,3-b] pyridin-3-carbonyl] -2-chloro-4-fluoro-phenyl] -3 -Fluoro-N- (2-trimethylsilylethoxymethyl) pyrrolidine-1-sulfonamide (330 mg, 0.42 mmol, 1 eq) and tert-butyl
2- [4- [[4- [4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazin-1-yl] methyl] -1-piperidyl ] In a solution of acetate (211 mg, 0.42 mmol, 1 eq) dioxane (5 mL) and water (0.5 mL), 4-ditert-butylphosphanyl-N, N-dimethyl-aniline; dichloropalladium (29 mg, 0.04 mmol) , 0.1 eq) and cesium fluoride (256 mg, 1.69 mmol, 4 eq) were added. The mixture was stirred at 90 ° C. for 3 hours. Water (100 mL) was poured into the mixture and stirred for 1 minute. The aqueous layer was extracted with ethyl acetate (50 mLx3). The combined organic layers were washed with brine (100 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by preparative TLC (dichloromethane: methanol = 10: 1). Compound tert-butyl 2- [4- [[4- [4- [3- [2-chloro-6-fluoro-3-[[(3R) -3-fluoropyrrolidine-1-yl] sulfonyl- (2) -Trimethylsilylethoxymethyl) amino] benzoyl] -1- (2-trimethylsilylethoxymethyl) pyrrolidine [2,3-b] pyridin-5-yl] phenyl] piperazine-1-yl] methyl] -1-piperidyl] acetate (340 mg, 0.28 mmol, 68% yield, 91% purity) was obtained as a yellow oil. LC / MS (ESI) m / z: 537.8 [M / 2 + 1] ⁺ .
Step 7: Methyl (R) -2- (4-((4- (4- (3- (2-chloro-6-fluoro-3-((3-fluoropyrrolidin) -1-sulfonamide) benzoyl)-)- Preparation of 1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) methyl) piperidine-1-yl) acetate.

tert-butyl 2- [4- [[4- [4- [3- [2-Chloro-6-fluoro-3-[[(3R) -3-fluoropyrrolidine-1-yl] sulfonyl- (2-trimethylsilyl) Ethoxymethyl) amino] benzoyl] -1- (2-trimethylsilylethoxymethyl) pyrrolidine [2,3-b] pyridin-5-yl] phenyl] piperazine-1-
Hydrochloric acid hydrochloride / dioxane (4M, 14 mL) was added to a solution of methanol (7 mL) of yl] methyl] -1-piperidyl] acetate (340 mg, 0.31 mmol, 1 eq). The mixture was stirred at 40 ° C. for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was used in the next step without further purification. Methyl 2- [4- [[4- [4- [3- [2-Chloro-6-fluoro-3-[[(3R) -3-fluoropyrrolidine-1-yl] sulfonylamino] benzoyl] -1H- Pyrrolidine [2,3-b] Pyridine-5-yl] phenyl] piperazine-1-yl] methyl] -1-piperidyl] acetate (250 mg, 0.30 mmol, yield 97%, hydrochloride) as a yellow solid Obtained. LC / MS (ESI) m / z: 770.1 [M + 1] ⁺ .
Step 8: (R) -2- (4-((4- (4- (3- (2-Chloro-6-fluoro-3-((3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H) -Pyrrolidine [2,3-b] Pyridine-5-yl) Phenyl) Piperazine-1-
Preparation of yl) methyl) piperidine-1-yl) acetic acid.

Methyl 2- [4- [[4- [4- [3- [2-Chloro-6-fluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H- Pyrrolo [2,3-b] Pyridine-5-yl] phenyl] Piperazine-1-yl] Methyl] -1-piperidyl] Acetate (250 mg, 0.30 mmol, 1 equivalent, hydrochloride) in water (3 mL), tetrahydrofuran To a solution of (8 mL) and methanol (8 mL) was added lithium hydroxide monohydrate (78 mg, 1.86 mmol, 6 equivalents). The mixture was stirred at 15 ° C. for 2 hours. Sodium hydroxide (24 mg, 0.61 mmol, 2 eq) was added to the mixture and the mixture was stirred at 40 ° C. for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The reaction mixture was then adjusted to pH 7 with hydrochloric acid (1M). The residue was purified by preparative reverse phase HPLC. Compound 2- [4- [[4- [4- [3- [2-Chloro-6-fluoro-3-[[(3R) -3-fluoropyrrolidine-1-yl] sulfonylamino] benzoyl] -1H -Pyrrolidine [2,3-b] Pyridine-5-yl] phenyl] piperazine-1-yl] Methyl] -1-piperidyl] Acetic acid (100 mg, 0.12 mmol, yield 80%, formate) as a yellow solid Obtained. LC / MS (ESI) m / z: 756.1 [M + 1] ⁺ .
Step 9: (2S, 4R) -1-((S) -2- (2- (4-((4- (4- (3- (2-Chloro-6-fluoro-3- (((R))) -3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperidine-1-yl) methyl) piperidin-1-yl) acetamide)- Preparation of 3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide.

2- [4- [[4- [4- [3- [2-Chloro-6-fluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] Pyridine-5-yl] Phenyl] Piperazine-1-
Il] Methyl] -1-piperidyl] Acetic acid (100 mg, 0.12 mmol, 1 eq, pseudoate) and (2S, 4R) -1- [(2S) -2-amino-3,3-dimethyl-butanoyl]- N, N-dimethylformamide (3 mL) of 4-hydroxy-N-[[4- (4-methylthiazole-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (58 mg, 0.12 mmol, 1 eq, hydrochloride) ) To the solution of hydroxybenzotriazole (20 mg, 0.14 mmol, 1.2 eq) and triethylamine (18 mg, 0.18 mmol, 1.5 eq). The mixture was stirred at 15 ° C. for 0.5 hours. 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (28 mg, 0.14 mmol, 1.2 eq) was added to the mixture and the mixture was stirred at 15 ° C. for 11.5 hours. Water (30 mL) was poured into the mixture and stirred for 1 minute. The aqueous layer was extracted with dichloromethane (10 mLx3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative reverse phase HPLC. Compound (2S, 4R) -1-[(2S) -2-[[2- [4-[[4- [4- [3- [2-Chloro-6-fluoro-3- [[(3R)) -3-Fluoropyrrolidine-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl] piperazine-1-yl] methyl] -1-piperidyl] acetyl] amino ] -3,3-dimethyl-butanoyl] -4-hydroxy-N-[[4- (4-methylthiazole-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (72.1 mg, 0.05 mmol, yield 45) %, Purity 100%, Dilate) was obtained as a yellow solid. LC / MS (ESI) m / z: 1168.4 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 13.04 --.12.70 (m, 1H), 9.00 (s, 1H), 8.66 --8.61 (m) , 2H), 8.17 (s, 1H), 8.19 --8.15 (m, 1H), 7.98 (s, 1H), 7.83 (d, J = 9.6 Hz, 1H), 7.66 (dd, J = 6.0, 8.8 Hz, 1H), 7.58 (d, J = 7.6 Hz, 2H), 7.48 --7.30 (m, 6H), 7.06 (d, J = 8.0 Hz, 2H), 5.37 --5.21 (m, 1H), 4.50 (d, J) = 9.2 Hz, 1H), 4.48 --4.40 (m, 2H), 4.37 (d, J = 6.4 Hz, 2H), 4.32 --4.23 (m, 2H), 3.70 --3.57 (m, 1H), 3.46 (s, 4H), 3.19 (s, 2H), 3.02 (d, J = 16.0 Hz, 3H), 2.94 --2.79 (m, 3H), 2.21 --2.02 (m, 13H), 1.90 (s, 2H), 1.73 (d) , J = 14.8 Hz, 2H), 1.55 (s, 1H), 1.22 --1.10 (m, 2H), 0.95 (s, 9H).
(2S, 4R) -1-((S) -2-(3-(3-(4-(4-(3-(2,6-difluoro-3-(((R) -3-fluoropyrolidin)) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) propyl) ureido) -3,3-dimethylbutanoyl) -4-hydroxy Illustrative Synthesis of -N-((S) -1- (4- (4-Methylthiazole-5-yl) Phenyl) Ethyl) Pyrrolidine-2-Carboxamide
(Example 366)
Step 1: Preparation of benzyl (3,3-dimethoxypropyl) carbamate.

P-methylbenzenesulfonic acid (166 mg, 0.96 mmol, 0.2 eq) and trimethoxymethane (166 mg, 0.96 mmol, 0.2 eq) in a solution of benzyl N- (3-oxopropyl) carbamic acid salt (1 g, 4.83 mmol, 1 eq) in methanol (10 mL). 2.56 g, 24.1 mmol, 2.6 mL, 5 eq) was added. The mixture was stirred at 30 ° C. for 2 hours. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (10 mLx2). The combined organic layers were washed with saturated brine (10 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 20: 1-5: 1) and benzyl N- (3,3-dimethoxypropyl) carbamate (1.1 g, 4.34 mmol, 89% yield). ) Was obtained as a colorless oil.

Step 2: Preparation of 3,3-dimethoxypropane-1-amine.

Palladium activated carbon catalyst (300 mg, 10%, 1.00 eq) in a solution of benzyl N- (3,3-dimethoxypropyl) carbamate (1 g, 3.95 mmol, 1 eq) in tetrahydrofuran (15 mL) under a nitrogen atmosphere. added. The suspension was degassed and purged with hydrogen three times. The mixture was stirred at 15 ° C. for 12 hours under hydrogen (15 psi). The reaction mixture was filtered and the filtrate was concentrated to give 3,3-dimethoxypropane-1-amine (340 mg, 2.85 mmol, 72% yield) as a colorless oil. 1H-NMR (400MHz, CDCl3) δ 4.48 (t, J = 5.6 Hz, 1H), 3.34 (s, 6H), 2.79 (t, J = 6.4 Hz, 2H), 1.77 (q, J = 6.4 Hz, 2H) ), 1.21 (s, 2H).
Step 3: (2S, 4R) -1-((S) -2- (3- (3,3-dimethoxypropyl) ureido) -3,3-dimethylbutanoyl) -4-hydroxy-N-((S) )-1-(4- (4-Methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide preparation.

N, N-carbonyldiimidazole (490 mg, 3.02 mmol, 1.5 eq) and triethylamine (407 mg, 4.03) in a solution of 3,3-dimethoxypropane-1-amine (240 mg, 2.01 mmol, 1 eq) in tetrahydrofuran (4 mL). mmol, 0.56 mL, 2 eq) was added. The mixture was stirred at 15 ° C. for 4 hours. (2S, 4R) -1-[(2S) -2-amino-3,3-dimethyl-butanoyl] -4-hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-) A solution of tetrahydrofuran (4 mL) of yl) phenyl] ethyl] pyrrolidine-2-carboxamide (484 mg, 1.01 mmol, 0.5 eq, hydrochloride) was added dropwise to the mixture, and the mixture was stirred at 40 ° C. for an additional 12 hours. .. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mLx3). The combined organic layers were washed with saturated brine (10 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (dimethane: methanol = 100: 1-30: 1) to (2S, 4R) -1-[(2S) -2- (3,3-dimethoxypropylcarbamoylamino)). -3,3-dimethyl-butanoyl] -4-hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (380 mg, 0.65 mmol) , 31% yield) was obtained as a white solid.

Step 4: (2S, 4R) -1-((S) -3,3-dimethyl-2-(3- (3-oxopropyl) ureido) butanoyl) -4-hydroxy-N-((S) -1 -Preparation of (4- (4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide.

(2S, 4R) -1-[(2S) -2- (3,3-dimethoxypropylcarbamoylamino) -3,3-dimethyl-butanoyl] -4-hydroxy-N-[(1S) -1- [4 -(4-Methylthiazole-5-yl) phenyl] ethyl]
Sulfuric acid (2M, 6.8 mL, 40 eq) was added to a solution of pyrrolidine-2-carboxamide (200 mg, 0.33 mmol, 1 eq) in tetrahydrofuran (30 mL). The mixture was stirred at 60 ° C. for 10 minutes. The reaction mixture was adjusted to pH 8-9 with saturated sodium bicarbonate and water (15 mL), then the mixture was extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with saturated brine (10 mLx2), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and the crude product (2S, 4R) -1-[(2S)). -3,3-dimethyl-2- (3-oxopropylcarbamoylamino) butanoyl] -4-hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] Pyrrolidine-2-carboxamide (180 mg, crude) was obtained as a white solid and used in the next step without further purification.

Step 5: Preparation of tert-butyl 4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-1-carboxylate.

4,4,5,5-Tetramethyl-2- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-Dioxaborolan (893 mg, 3.52 mmol) , 1.2 eq), tert-butyl 4- (4-bromophenyl) piperazine-1-carboxylate (1 g, 2.93 mmol, 1 eq), potassium acetate (575 mg, 5.86 mmol, 2 eq) and [1,1' -Bis (diphenylphosphino) ferrocene] A mixture of dichloropalladium (ii) (214 mg, 0.29 mmol, 0.1 eq) dioxane (15 mL) was degassed and purged with nitrogen three times. The mixture was then stirred at 90 ° C. for 12 hours under a nitrogen atmosphere. The reaction mixture was filtered, washed with saturated aqueous brine solution (30 mLx3), and extracted with ethyl acetate (50 mLx3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 15/1 to 5: 1). The compound tert-butyl 4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine-1-carboxylate (1.07 g, 2.59 mmol, Yield 88%, purity 94%) was obtained as a white solid. LC / MS (ESI) m / z: 389.3 [M + 1] ⁺ .
Step 6: tert-butyl (R) -4-(4-(3-(2,6-difluoro-3-((3-fluoro-N-((2- (trimethylsilyl) ethoxy) methyl) pyrrolidine) -1) -Preparation of sulfonamide) benzoyl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-carboxylate.

tert-butyl 4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine-1-carboxylate (1.07 g, 2.59 mmol, 1 equivalent) ), (3R) -N- [3- [5-bromo-1- (2-trimethylsilylethoxymethyl) pyrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl] -3 -Fluoro-N- (2-trimethylsilylethoxymethyl) pyrrolidine-1-sulfonamide (2.2 g, 2.88 mmol, 1.11 eq), 4-ditert-butylphosphanyl-N, N-dimethyl-aniline; dichloropalladium (183 mg,) A mixture of 0.26 mmol, 0.2 mL, 0.1 eq) and cesium fluoride (1.57 g, 10.35 mmol, 0.4 mL, 4 eq) with dioxane (10 mL) and water (2 mL) was degassed and purged with nitrogen three times. .. The mixture was then stirred for 12 hours under a nitrogen atmosphere at 100 ° C. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 15: 1 to 2: 1). The compound tert-butyl 4- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1-yl] sulfonyl- (2-trimethylsilylethoxymethyl) amino] benzoyl]] -1- (2-trimethylsilylethoxymethyl) pyrrolidine [2,3-b] pyridin-5-yl] phenyl] piperazine-1-carboxylate
(1.54 g, 1.59 mmol, yield 62%, purity 97%) was obtained as a yellow oil. LC / MS (ESI) m / z: 945.2 [M] ⁺ .
Step 7: (R) -N- (2,4-difluoro-3- (5- (4- (piperazine-1-yl) phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl) Preparation of phenyl) -3-fluoropyrrolidine-1-sulfonamide.

tert-butyl 4- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1-yl] sulfonyl- (2-trimethylsilylethoxymethyl) amino] benzoyl] -1 -(2-trimethylsilylethoxymethyl) pyrrolidine [2,3-b] pyridin-5-yl] phenyl] piperazine-1-carboxylate
Hydrochloric acid / dioxane (4M, 15 mL, 37.85 eq) was added to a solution of dichloromethane (5 mL) (1.54 g, 1.59 mmol, 1 eq). The mixture was stirred at 40 ° C. for 4 hours. Methyl alcohol (5 mL) was then added and the mixture was stirred at 40 ° C. for an additional 12 hours. The reaction mixture was concentrated under vacuum to give a residue. Compound (3R) -N- [2,4-difluoro-3- [5- (4-piperazine-1-ylphenyl) -1H-pyrrolidine [2,3-b] pyridine-3-carbonyl] phenyl]- 3-Fluoro-pyrrolidin-1-sulfonamide (1.22 g, crude, dihydrochloride) was obtained as a yellow solid. LC / MS (ESI) m / z: 585.1 [M] +; 1H-NMR (400MHz, DMSO-d6) δ 12.98 (s, 1H), 9.87 (s, 1H), 9.18 (s, 2H), 8.67 ( d, J = 2.4 Hz, 1H), 8.57 (s, 1H), 8.08 (s, 1H), 7.66 (d, J = 8.8 Hz, 2H), 7.27 (t, J = 8.8 Hz, 1H), 7.14 ( d, J = 8.8 Hz, 2H), 5.39 --5.21 (m, 1H), 3.64 (s, 1H), 3.61 --3.55 (m, 1H), 3.49 --3.43 (m, 6H), 3.40 (s, 3H) , 3.24 (s, 5H).
Step 8: (2S, 4R) -1-((S) -2- (3- (3- (4- (4- (3- (2,6-difluoro-3- (((R) -3-) -3-) Fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridine-5-yl) phenyl) piperazine-1-yl) propyl) ureido) -3,3-dimethylbutanoyl)- Preparation of 4-hydroxy-N-((S) -1- (4- (4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide.

(2S, 4R) -1-[(2S) -3,3-dimethyl-2- (3-oxopropylcarbamoylamino) butanoyl] -4-hydroxy-N-[(1S) -1- [4- (4) -Methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (140 mg, 0.25 mmol, 1 eq) in a solution of 1,2-dichloroethane (5 mL) with triethylamine (78 mg, 0.77 mmol, 3 eq) And (3R) -N- [2,4-difluoro-3- [5- (4-piperazin-1-ylphenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] phenyl] -3 -Fluoro-pyrrolidin-1-sulfonamide (160 mg, 0.25 mmol, 1 eq, hydrochloride) was added. The mixture was stirred at 15 ° C. for 0.5 hours. Sodium triacetoxyborohydride (109 mg, 0.51 mmol, 2)
Equivalent) was added, and then the mixture was stirred at 15 ° C. for 3 hours. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mLx2). Saturated brine (5mLx2) of organic layers combined into one
), Dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by half-reverse phase HPLC and (2S, 4R) -1-[(2S) -2- [3- [4- [4- [3- [2,6-difluoro-3- []. [(3R) -3-fluoropyrrolidine-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl] piperazine-1-yl] propylcarbamoylamino] -3 , 3-Dimethyl-butanoyl] -4-hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (89.5 mg, 0.07 mmol, Yield 30%, purity 100%, formate) was obtained as a white solid. LC / MS (ESI) m / z: 1112.3 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 12.90 (s, 1H), 8.97 (s, 1H), 8.65 (d, J = 2.0) Hz, 1H), 8.53 (s, 1H), 8.36 (d, J = 7.6 Hz, 1H), 8.19 (s, 1H), 8.05 (s, 1H), 7.66 --7.56 (m, 3H), 7.46 --7.41 (m, 2H), 7.40 --7.35 (m, 2H), 7.25 (t, J = 8.0 Hz, 1H), 7.12 --7.01 (m, 2H), 6.15 (t, J = 5.6 Hz, 1H), 6.08 ( d, J = 9.6 Hz, 1H), 5.38 ―― 5.19 (m, 1H), 4.91 (q, J = 7.2 Hz, 1H), 4.44 (t, J = 8.0 Hz, 1H), 4.35 ―― 4.26 (m, 2H) ), 3.66 --3.57 (m, 2H), 3.48 (s, 1H), 3.43 --3.36 (m, 2H), 3.33 --3.27 (m, 1H), 3.26 --3.12 (m, 5H), 3.11 --2.97 (m) , 2H), 2.55 --2.53 (m, 2H), 2.45 (s, 3H), 2.35 (br t, J = 7.2 Hz, 2H), 2.15 --1.94 (m, 3H), 1.80 (ddd, J = 4.8, 8.4, 12.8 Hz, 1H), 1.62 --1.53 (m, 2H), 1.38 (d, J = 7.2 Hz, 3H), 1.00 (s, 2H), 0.93 (s, 9H).
(2S, 4R) -1- (4- (4-((1- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide)) Benzoyl) -1H-pyrrolidine [2,3-b] pyridin-5-yl) phenyl) piperidine-4-i
L) Methyl) piperazine-1-yl) -2- (3-methylisoxazole-5-yl) butanoyl) -4-hydroxy-N-((S) -1- (4- (4-methylthiazole-)- 5-Il) Phenyl) Ethyl) Pyrrolidine-2-cal
Illustrative Synthesis of Boxamide (Example 440)
Step 1: Preparation of methyl 4,4-dimethoxy-2- (3-methylisoxazole-5-yl) butaneate.

Potassium tert-butoxide (867 mg, 7.73 mmol, 1.2 eq) in a solution of dimethylformamide (10 mL) of methyl 2- (3-methylisoxazole-5-yl) acetate (1 g, 6.45 mmol, 1 eq). added. The mixture was stirred for 30 minutes at 15 ° C., then 2-bromo-1,1-dimethoxy-ethane (1.31 g, 7.73 mmol, 1.2 eq) was added. The obtained mixture was further stirred for 1.5 hours at 15 ° C. The mixture was then heated to 50 ° C. and stirred for another 1 hour at 50 ° C. The mixture was poured into 100 mL of brine and the pH was adjusted to 5.0 with 2.0 M hydrochloric acid. The mixture was extracted with ethyl acetate (50 mLx2).
The combined organic layers were washed with brine (50 mLx2), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1-5: 1) to methyl 4,4-dimethoxy-2- (3-methylisoxazole-5-yl) butaneate. (620 mg, 1.53 mmol, yield 23%, purity 60%) was obtained as a colorless oil. LC / MS (ESI) m / z: 244.1 [M + 1] ⁺ .
Step 2: Preparation of 2- (3-methylisoxazole-5-yl) -4-oxobutanoic acid.

Sulfuric acid (2 mL) was added to a solution of dioxane (2 mL) of methyl 4,4-dimethoxy-2- (3-methylisoxazole-5-yl) butaneate (0.4 g, 1.64 mmol, 1 eq). .. The mixture was heated to 50 ° C and stirred at 50 ° C for 2 hours. The mixture was poured into 20 mL of brine and the pH was adjusted to 4.0 with 2.0 M hydrochloric acid. The mixture was extracted with ethyl acetate (30 mLx2). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was used directly in the next step without further purification. 2- (3-Methyloxyacid-5-yl) -4-oxo-butanoic acid (340 mg)
, Crude) was obtained as a colorless oil. LC / MS (ESI) m / z: 184.1 [M + 1] ⁺ .
Step 3: Preparation of 4- (4- (tert-butoxycarbonyl) piperazine-1-yl) -2- (3-methylisoxazole-5-yl) butanoic acid.

2- (3-Methylisoxazole-5-yl) -4-oxo-butanoic acid (330 mg, 1.80 mmol, 1 eq) and tert-butyl piperazine-1-carboxylate (335 mg, 1.80 mmol, 1 eq) Acetic acid (10 mg, 0.18 mmol, 0.1 eq) was added to a mixture of methanol (3 mL) and dichloromethane (1 mL). The mixture was stirred at 15 ° C. for 30 minutes. Sodium cyanoborohydride (169 mg, 2.70 mmol, 1.5 eq) was then added to the mixture. The resulting mixture was stirred for another 30 minutes at 15 ° C. The mixture was poured into 20 mL of water and the pH was adjusted to 8.0 with a saturated sodium bicarbonate solution. The mixture was then extracted with ethyl acetate (20 mL) and the organic layer was discarded. The pH of the aqueous layer was adjusted to about 4.0 with 2.0 M sulfuric acid, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over sodium sulphate, filtered and concentrated in vacuo. The residue was used directly in the next step without further purification. 4- (4-tert-Butoxycarbonylpiperazine-1-yl) -2- (3-methylisoxazole-5-yl) butanoic acid (320 mg, crude) was obtained as a colorless oil. LC / MS (ESI) m / z: 354.1 [M + 1] ⁺ .
Step 4: tert-butyl 4-(4-((2S, 4R) -4-hydroxy-2-(((S) -1-(4- (4-methylthiazole-5-yl) phenyl) ethyl) carbamoyl) ) Preparation of pyrrolidine-1-yl) -3- (3-methylisoxazole-5-yl) -4-oxobutyl) piperazine-1-carboxylate.

4- (4-tert-butoxycarbonylpiperazin-1-yl) -2- (3-methylisoxazole-5-yl) butanoic acid (300 mg, 0.84 mmol, 1 eq), hydroxybenzotriazole (137 mg, 1.02 mmol) , 1.2 eq) and diylamine carbonamine hydrochloride (244 mg, 1.27 mmol, 1.5 eq) in a solution of dimethylformamide (4 mL) to (2S, 4R) -4-hydroxy-N-[(1S) -1- [4. -(4-Methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (312 mg, 0.84 mmol, 1 eq, hydrochloride) and diisopropylethylamine (219 mg, 1.70 mmol, 2 eq) were added. The mixture was stirred at 20 ° C. for 2 hours. The mixture was poured into 30 mL saturated brine and extracted with ethyl acetate (30 mLx2). The combined organic layers were washed with brine (30 mLx3), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was further purified by preparative HPLC, neutralized with sodium bicarbonate solution and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated brine (30 mLx3), dried over sodium sulfate, filtered and concentrated in vacuo. tert-Butyl 4- [4-[(2S, 4R) -4-hydroxy-2-[[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] carbamoyl] piperazine- 1-yl] -3- (3-Methylisoxazole-5-yl) -4-oxo-butyl] piperazine-1-carboxylate (180 mg, 0.27 mmol, 31% yield) off-white solid I got it as a thing. 1H-NMR (400MHz, DMSO-d6) δ 8.99 (s, 1H), 8.46 --8.35 (m, 1H), 7.47 --7.28 (m, 4H), 6.28 --6.21 (s, 1H), 5.14 (d, J) = 3.6 Hz, 1H), 5.02 --4.84 (m, 1H), 4.44 (t, J = 7.6 Hz, 1H), 4.32 --4.09 (m, 2H), 3.63 --3.57 (m, 1H), 3.55 --3.35 ( m, 2H), 3.30 (s, 3H), 2.52 (s, 2H), 2.47 --2.45 (m, 3H), 2.31 --2.25 (m, 4H), 2.21 --2.16 (m, 3H), 2.12 --2.00 ( m, 2H), 1.95 --1.86 (m, 1H), 1.84 --1.74 (m, 1H), 1.45 --1.30 (m, 12H).
Step 5: (2S, 4R) -4-hydroxy-1- (2- (3-methylisoxazole-5-yl) -4- (piperazine)
Preparation of -1-yl) butanoyl) -N-((S) -1- (4- (4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide.

tert-butyl 4- [4-[(2S, 4R) -4-hydroxy-2-[[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine- 1-yl] -3- (3-methylisoxazole-5-yl) -4-oxo-butyl] piperazin-1-carboxylate (80 mg, 0.12 mmol, 1 equivalent) in a solution of dichloromethane (2 mL) , Hydrogen chloride / methanol (4M, 5 mL, 166.71 equivalents) was added and the mixture was stirred at 15 ° C. for 1 hour. The reaction mixture was concentrated in vacuo to give a residue. The crude product was used in the next step without further purification. Product (2S, 4R) -4-hydroxy-1- [2- (3- (3-)
Methylisoxazole-5-yl) -4-piperazin-1-yl-butanoyl] -N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2 -Carboxamide (70 mg, 0.12 mmol, 97% yield, HCl) was obtained as a yellow solid. LC / MS (ESI) m / z: 567.2 [M + 1] ⁺ .
Step 6: (2S, 4R) -1- (4-(4-((1- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrolidin) -1- Sulfone amide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperidine-4-yl) Methyl) Piperazine-1-yl) -2- (3-Methylisoxazole-5) -Preparation of yl) butanoyl) -4-hydroxy-N-((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide.

(2S, 4R) -4-Hydroxy-1- [2- (3-Methylisoxazole-5-yl) -4-piperazin-1-yl-
Butanoyl] -N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (98 mg, 0.16umol, 1 equivalent, hydrochloride) and sodium acetate ( A solution of 40 mg, 0.49 mmol, 3 eq) of dichloromethane (2 mL) and methanol (3 mL) was stirred for 0.5 hours at 25 ° C. Then (3R) -N- [2,4-difluoro-3- [5- [4- (4-formyl-1-piperidyl) phenyl] -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] Phenyl] -3-fluoro-pyrrolidin-1-sulfonamide (100 mg, 0.16 mmol, 1 eq) and acetic acid (9 mg, 0.16 mmol, 1 eq) were added and stirred for 0.5 hours. Sodium cyanoborohydride (30 mg, 0.49 mmol, 3 eq) was then added. The reaction mixture was stirred at 25 ° C. for 0.5 hours. The reaction mixture was filtered and concentrated under reduced pressure. Residue, preparative H
Purified by PLC. The residue was purified by preparative TLC (dichloromethane: methanol = 10: 1). (2S, 4R) -1- [4- [4- [[1- [4- [3- [2,6-difluoro-3- [[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] ] Benzoyl] -1H-pyrrolo [2,3-b] Pyridine-5-yl] Phenyl] -4-piperidyl] Methyl] Piperazine-1-yl] -2- (3-Methylisoxazole-5-yl) Butanoyl] -4-hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (59 mg, 51.02umol, yield 31%, purity) 99%) was obtained as a yellow solid. LC / MS (ESI) m / z: 1165.3 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 12.89 (s, 1H), 9.03 --8.94 (m, 1H), 8.64 (s, 1H) ), 8.53 (s, 1H), 8.44 --8.28 (m, 1H), 8.06 (s, 1H), 7.68 --7.53 (m, 3H), 7.50 --7.22 (m, 6H), 7.06 (d, J = 8.8) Hz, 2H), 6.30 --6.18 (m, 1H), 5.43 --5.10 (m, 2H), 4.98 --4.87 (m, 1H), 4.52 --4.37 (m, 1H), 4.30 (d, J = 4.0 Hz, 1H), 4.24 --4.12 (m, 1H), 3.95 --3.72 (m, 3H), 3.63 --3.51 (m, 2H), 3.44 (s, 6H), 2.72 (t, J = 11.6 Hz, 2H), 2.46 (d, J = 1.6 Hz, 4H), 2.45 --2.25 (m, 10H), 2.22 --2.19 (m, 2H), 2.18 --1.95 (m, 9H), 1.88 --1.62 (m, 5H), 1.39 --1.33 (m, 5H), 1.24 --1.19 (m, 2H).
(2S, 4R) -1-((S) -2-(2-(4-(4-(4-(3-(3-((N-ethyl-N-methylsulfamoyl) amino) -2)-2 , 6-difluorobenzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazin-1-yl) piperidine-1-yl) acetamide) -3,3-dimethylbutanoyl) -4 Illustrative Synthesis of -Hydroxy-N-((S) -1- (4- (4-Methylthiazole-5-yl) Phenyl) Ethyl) Pyrrolidine-2-Carboxamide (Example 480)
Step 1 Preparation of ethyl (methyl) sulfamoyl chloride.

A solution of N-methylethaneamine (500 mg, 8.46 mmol, 1 eq) and triethylamine (856 mg, 8.46 mmol, 1.18 mL, 1 eq) in dichloromethane (8 mL). A solution of sulfuryl chloride (1.14 g, 8.46 mmol, 1 eq) in dichloromethane (3 mL) was then added to the mixture at 0 ° C. The mixture was stirred for 2 hours at 0 ° C. The reaction was poured into glacial hydrochloric acid (1N, 30 mL). The combined organic layers were washed with brine (50 mLx1) and hydrochloric acid (1N, 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was used in the next step without further purification. The compound N-ethyl-N-methyl-sulfamoyl chloride (1 g, crude) was obtained as a colorless oil.

Step 2: Preparation of [(3- {5-bromo-1H-pyrrolo [2,3-b] pyridin-3-carbonyl} -2,4-difluorophenyl) sulfamoyl] (ethyl) methylamine.

(3-Amino-2,6-difluoro-phenyl)-(5-bromo-1H-pyrrolo [2,3-b] pyridin-3-yl) Pyridine (1.19 g, 3.38 mmol, 1 eq) pyridine (5 mL) ) In solution of 4-dimethylaminopyridine (82 mg, 0.67 mmol, 0.2 eq) and N-ethyl-N-methyl-sulfamoyl chloride (800 mg).
, 5.08 mmol, 1.5 eq). The mixture was stirred at 40 ° C. for 12 hours. The pH of the reaction mixture was adjusted to 8 using a saturated aqueous sodium bicarbonate solution. Water (100 mL) was poured into the mixture and stirred for 1 minute. The aqueous layer was extracted with ethyl acetate (100 mLx3). The combined organic layers were washed with brine (100 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum.
The residue was purified by preparative HPLC. Compound 5-bromo-3- [3-[[ethyl (methyl) sulfamoyl] amino] -2,6-difluoro-benzoyl] -1H-pyrrolo [2,3-b] pyridine (550 mg, 1.16 mmol, yield) 34%) was obtained as a yellow solid. LC / MS (ESI) m / z: 474.9 [M + 1] ⁺ .
Step 3: {[3- (5-bromo-1- {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrrolo [2,3-b] pyridin-3-carbonyl) -2,4-difluorophenyl] Preparation of ({[2- (trimethylsilyl) ethoxy] methyl}) sulfamoyl} (ethyl) methylamine.

5-bromo-3- [3-[[ethyl (methyl) sulfamoyl] amino] -2,6-difluoro-benzoyl] -1H-pyrrolo [2,3-b] pyridine (550 mg, 1.16 mmol, 1 equivalent) Sodium hydride (139 mg, 3.49 mmol, purity 60%, 3 equivalents) and (2- (chloromethoxy) ethyl) trimethylsilane (484 mg, 2.91 mmol, 2.5 equivalents) in a solution of N, N-dimethylformamide (6 mL). Was added. The mixture was stirred at 40 ° C. for 12 hours. Water (100 mL) was poured into the mixture and stirred for 1 minute. The aqueous layer was extracted with ethyl acetate (70 mLx3). The combined organic layers were washed with brine (100 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1: 0-20: 1). Compound [5-bromo-1- (2-trimethylsilylethoxymethyl) pyrolo [2,3-b] pyridin-3-yl]-[3-[[ethyl (methyl) sulfamoyl]-(2-trimethylsilylethoxymethyl) Amino] -2,6-difluoro-phenyl] methanone (550 mg, 0.74 mmol, 64% yield) was obtained as a bright yellow oil. LC / MS (ESI) m / z: 734.8 [M + 1] ⁺ .
Step 4: tert-butyl 2-(4-(4-(3-(3-((N-ethyl-N-methylsulfamoyl) ((2- (trimethylsilyl) ethoxy) methyl) amino)- 2,6-difluorobenzoyl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) piperidine-1- Il) Preparation of acetate.

[5-bromo-1- (2-trimethylsilylethoxymethyl) pyrolo [2,3-b] pyridine-3-yl]-[3-[[ethyl (methyl) sulfamoyl]-(2-trimethylsilylethoxymethyl) amino] -2,6-difluoro-phenyl] methanone (350 mg, 0.47 mmol, 1 equivalent) and tert-butyl 2- [4- [4- [4- (4,4,5,5-tetramethyl-1,3,) 2-Dioxaborolan-2-yl) Phenyl] Piperazin-1-yl]
-1-piperidyl] Acetate (231 mg, 0.47 mmol, 1 eq) in a solution of dioxane (3 mL) and water (0.3 mL), cesium fluoride (289 mg, 1.91 mmol, 4 eq) and 4-ditert-butylphos. Fanyl-N, N-dimethyl-aniline; dichloropalladium (33 mg, 0.04 mmol, 0.1 eq) was added. The mixture was stirred at 90 ° C. for 3 hours. Water (80 mL) was poured into the mixture and stirred for 1 minute. The aqueous layer was extracted with ethyl acetate (40 mLx3). The combined organic layers were washed with brine (100 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 0: 0-5: 1). Compound tert-butyl 2- [4- [4- [4- [3- [3- [[ethyl (methyl) sulfamoyl]-(2-trimethylsilylethoxymethyl) amino] -2,6-difluoro-benzoyl]- 1- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b] pyridin-5-yl] phenyl] piperazine-1-yl] -1-piperidyl] acetate (250 mg, 0.24 mmol, 51% yield) Obtained as a yellow solid. LC / MS (ESI) m / z: 506.3 [M / 2] ⁺ .
Step 5: Methyl 2- (4- (4- (4- (3- (3-((N-Ethyl-N-Methyl Sulfamoyl) Amino) -2,6-)
Preparation of difluorobenzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) piperidine-1-yl) acetate.

tert-butyl 2- [4- [4- [4- [3- [3- [[ethyl (methyl) sulfamoyl]-(2-trimethylsilylethoxymethyl) amino] -2,6-difluoro-benzoyl] -1- (2-trimethylsilylethoxymethyl) pyrolo [2,3-b] pyridin-5-yl] phenyl] piperazine-1-yl] -1-piperidyl]
Hydrochloric acid / dioxane (4M, 10 mL, 161.98 eq) was added to a solution of acetate (250 mg, 0.24 mmol, 1 eq) in methanol (2 mL). The mixture was stirred at 40 ° C. for 12 hours. The reaction mixture was concentrated under reduced pressure. The crude product was used in the next step without further purification. Compound Methyl 2- [4- [4- [4- [3- [3- [[ethyl (methyl) sulfamoyl] amino] -2,6-difluoro-benzoyl] -1H-pyrrolo [2,3-b] Pyridine-5-yl] phenyl] piperazine-1-yl] -1-piperidyl] acetate (175 mg, crude) was obtained as a yellow oil. LC / MS (ESI) m / z: 701.1 [M / 2 + 1] ⁺ .
Step 6: 2- (4- (4- (4- (3- (3-((N-ethyl-N-methylsulfamoyl) amino) -2,6-difluorobenzoyl) -1H-pyrrolo [2, 3-b] Pyridine-5-yl) Phenyl) Piperazine-1-yl) Piperidine-1-yl) Preparation of acetic acid.

Methyl 2- [4- [4- [4- [3- [3- [[Ethyl (Methyl) Sulfamoyl] Amino] -2,6-Difluoro-
Benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl] piperazine-1-yl] -1-piperidyl] acetate (175 mg, 0.24 mmol, 1 equivalent) in tetrahydrofuran (2 mL), methanol Lithium hydroxide monohydrate (41 mg, 0.98 mmol, 4 equivalents) was added to a solution of (2 mL) and water (1 mL). The mixture was stirred at 40 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. Hydrochloric acid (1M) was used as the reaction mixture.
) Was used to adjust the pH to 7. The precipitate was collected by filtration. The crude product was used in the next step without further purification. Compound 2- [4- [4- [4- [3- [3- [[ethyl (methyl) sulfamoyl] amino] -2,6-difluoro-benzoyl] -1H-pyrrolo [2,3-b] pyridine -5-Il] phenyl] piperazine-1-yl] -1-piperidyl] acetic acid (100 mg, 0.14 mmol, 58% yield) was obtained as a yellow solid. LC / MS (ESI) m / z: 696.1 [M + 1] ⁺ .
Step 7: (2S, 4R) -1-((S) -2- (2- (4- (4- (4- (3- (3-((N-ethyl-N-methylsulfamoyl) amino) amino ) -2,6-difluorobenzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazin-1-yl) piperidine-1-yl) acetamide) -3,3-dimethylbutanoyl ) -4-Hydroxy-N-((S) -1-(4- (4-Methylthiazole-5-yl) phenyl) ethyl) Preparation of pyrrolidine-2-carboxamide.

2- [4- [4- [4- [3- [3- [[Ethyl (methyl) sulfamoyl] amino] -2,6-difluoro-benzoyl] -1H-pyrrolo [2,3-b] pyridine-5 -Il] phenyl] piperazine-1-yl] -1-piperidyl]
Acetic acid (100 mg, 0.14 mmol, 1 eq) and (2S, 4R) -1-[(2S) -2-amino-3,3-dimethyl-butanoyl] -4-hydroxy-N-[(1S) -1- [4- (4-Methylthiazol-5-yl) phenyl] ethyl] Pyrrolidine-2-carboxamide (69 mg, 0.14 mmol, 1.00 eq, hydrochloride) in a solution of N, N-dimethylformamide (2 mL) with hydroxybenzo. Add triazole (23 mg, 0.17 mmol, 1.2 eq), triethylamine (22 mg, 0.21 mmol, 1.5 eq) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (33 mg, 0.17 mmol, 1.2 eq). I am. The mixture was stirred at 30 ° C. for 12 hours. Water (50 mL) was poured into the mixture and stirred for 1 minute. Dichloromethane in aqueous layer (20mLx3)
). The combined organic layers were washed with brine (20 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by preparative HPLC. Compound (2S, 4R) -1- [(2S) -2-[[2- [4- [4- [4- [3- [3- [[ethyl (methyl) sulfamoyl] amino] -2,6] -Difluoro-benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl] piperazin-1-yl] -1-piperidyl] acetyl] amino] -3,3-dimethyl-butanoyl] -4 -Hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (105.2 mg, 0.093 mmol, yield 65%, purity 100%) Was obtained as a yellow solid. LC / MS (ESI) m / z: 562.0 [M / 2 + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 13.15 --12.64 (m, 1H), 8.98 (s, 1H), 8.65 (d) , J = 2.0 Hz, 1H), 8.57 --8.43 (m, 2H), 8.18 (s, 1H), 8.09 (s, 1H), 7.77 (d, J = 9.2 Hz, 1H), 7.64 --7.55 (m, 3H), 7.47 --7.41 (m, 2H), 7.40 --7.33 (m, 2H), 7.27 (t, J = 8.4 Hz, 1H), 7.07 (d, J = 8.8 Hz, 2H), 4.94 --4.85 (m) , 1H), 4.53 --4.41 (m, 2H), 4.28 (s, 1H), 3.14 --3.06 (m, 4H), 3.03 (s, 1H), 2.90 (d, J = 16.0 Hz, 3H), 2.72 ( s, 3H), 2.67 (s, 4H), 2.45 (s, 4H), 2.30 --2.18 (m, 2H), 2.17 (s, 1H), 2.14 --2.02 (m, 2H), 2.14 --2.02 (m, 1H), 1.86 (s, 2H), 1.79 --1.72 (m, 1H), 1.57 --1.42 (m, 3H), 1.38 (d, J = 7.2 Hz, 3H), 1.01 (t, J = 7.2 Hz, 3H) ), 0.95 (s, 9
H).
(2S, 4R) -1-((S) -2- (2-((2S, 6R) -4-((1- (4- (3- (2,6-difluoro-3- (((R) ) -3-Fluoropi
Loridine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperidine-4-yl) methyl) -2,6-dimethylpiperazine-1-yl) acetamide )-3,3-Dimethylbutanoyl) -4-Hydroxy-N-((S) -1-(4-(4-Methylthiazole-5-yl) phenyl) Echi
Le) Illustrative synthesis of pyrrolidine-2-carboxamide (Example 351)
Step 1: Preparation of tert-butyl (3S, 5R) -4- (2-ethoxy-2-oxoethyl) -3,5-dimethylpiperazine-1-carboxylate.

acetonitrile (10 mL) of tert-butyl (3S, 5R) -3,5-dimethylpiperazine-1-carboxylate (1 g, 4.67 mmol, 1 equivalent) and ethyl 2-bromoacetate (701 mg, 4.20 mmol, 0.9 equivalent) ) To the solution of diisopropylethylamine (1.81 g, 14.00 mmol, 3 equivalents). The reaction mixture was stirred at 80 ° C. for 12 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mLx3). The combined organic layers were washed with brine (80 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30/1 to 1/1). White tert-butyl (3S, 5R) -4- (2-ethoxy-2-oxo-ethyl) -3,5-dimethyl-piperazine-1-carboxylate (1.09 g, 3.63 mmol, 77% yield) Obtained as a solid. LC / MS (ESI) m / z: 301.1 [M + 1] +; 1H-NMR (400MHz, CDCl3) δ 4.16 (q, J = 7.2 Hz, 2H), 4.02 --3.72 (m, 2H), 3.56 ( s, 2H), 2.96 --2.82 (m, 2H), 2.53 (s, 2H), 1.46 (s, 9H), 1.27 (t, J = 7.2 Hz, 3H), 1.08 (d, J = 6.4 Hz, 6H) ).
Step 2: Preparation of ethyl 2-((2S, 6R) -2,6-dimethylpiperazine-1-yl) acetate.

dichloromethane (10 mL) of tert-butyl (3S, 5R) -4- (2-ethoxy-2-oxo-ethyl) -3,5-dimethyl-piperazine-1-carboxylate (200 mg, 0.66 mmol, 1 eq) Hydrochloric acid (4M dioxane solution, 2 mL, 10 eq) was added to the solution of. The reaction mixture was stirred at 15 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. Ethyl 2-[(2S, 6R) -2,6-dimethylpiperazine-1-yl] acetate (140 mg, 0.59 mmol, 88% yield, hydrochloride) was obtained as a white solid.

Step 3: Ethyl 2-((2S, 6R) -4-((1- (4- (3- (2-,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) ) Benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperidine-4-yl) methyl) -2,6-dimethylpiperazine-1-yl) Preparation of acetate.

Ethyl 2-[(2S, 6R) -2,6-dimethylpiperazine-1-yl] acetate (69 mg, 0.29 mmol, 1.2 eq, hydrochloride) and triethylamine (74 mg, 0.73 mmol, 3 eq) in methanol (2 mL) ) And a solution of dichloromethane (2 mL), (3R) -N- [2,4-difluoro-3- [5- [4- (4-formyl-1-piperidyl) phenyl] -1H-pyrrolo [2,3 -b] pyridine-3-carbonyl] phenyl] -3-fluoro-pyrrolidin-1-sulfonamide (150 mg, 0.24 mmol, 1 eq) was added. The reaction mixture was stirred at 15 ° C. for 0.5 hours. Sodium triacetoxyborohydride (155 mg, 0.73 mmol, 3 eq) was added. The reaction mixture was stirred at 15 ° C. for 0.5 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mLx3). The combined organic layers were washed with brine (50 mLx3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100/1 to 30/1). Ethyl 2-[(2S, 6R) -4-[[1- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1-yl] sulfonylamino] benzoyl] ] -1H-pyrrolidine [2,3-b] pyridin-5-yl] phenyl] -4-piperidyl] methyl] -2,6-dimethyl-piperazin-1-yl] acetate (180 mg, 0.22 mmol, yield 92%) was obtained as a yellow solid. LC / MS (ESI) m / z: 796.1 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 12.91 (s, 1H), 9.87 (s, 1H), 8.64 (d, J = 2.0) Hz, 1H), 8.53 (s, 1H), 8.07 (s, 1H), 7.67 --7.52 (m, 3H), 7.27 (t, J = 8.4 Hz, 1H), 7.05 (d, J = 8.8 Hz, 2H) ), 5.46 --5.12 (m, 1H), 4.16 --4.00 (m, 3H), 3.77 (d, J = 12.0 Hz, 2H), 3.50 --3.43 (m, 3H), 3.39 (s, 2H), 3.32- 3.24 (m, 2H), 3.16 (d, J = 5.2 Hz, 1H), 2.85 (s, 2H), 2.76 --2.62 (m, 4H), 2.09 (d, J = 7.2 Hz, 4H), 1.84 --1.59 (m, 5H), 1.25 --1.13 (m, 5H), 0.96 (d, J = 6.0 Hz, 6H).
Step 4: 2-((2S, 6R) -4-((1- (4-(3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide))) Preparation of benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperidine-4-yl) methyl) -2,6-dimethylpiperazine-1-yl) acetic acid.

Ethyl 2-[(2S, 6R) -4-[[1- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] ] -1H-Pyrrolidine [2,3-b] Pyridine-5-yl] Phenyl] -4-
Piperidyl] methyl] -2,6-dimethyl-piperazin-1-yl] acetate (150 mg, 0.18 mmol, 1 equivalent) in a solution of methanol (4 mL), water (4 mL) and tetrahydrofuran (4 mL), lithium hydroxide Monohydrate (31 mg, 0.75 mmol, 4 equivalents) was added. The reaction mixture was stirred at 15 ° C. for 2 hours. The pH was adjusted to 6 with 1M hydrochloric acid and concentrated under reduced pressure. The residue was purified by preparative HPLC. 2-[(2S, 6R) -4-[[1- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1-yl] sulfonylamino] benzoyl]] -1H-pyrrolidine [2,3-b] pyridin-5-yl] phenyl] -4-piperidyl] methyl] -2,6-dimethyl-piperazine-1-yl] acetic acid (110 mg, 0.13 mmol, 71% yield) , Formate) was obtained as a yellow solid.

Step 5: (2S, 4R) -1-((S) -2-(2-((2S, 6R) -4-((1- (4- (3- (2,6-difluoro-3- ( ((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperidine-4-yl) methyl) -2,6- Dimethylpiperazine-1-yl) acetamide) -3,3-dimethylbutanoyl) -4-hydroxy-N-((S) -1-(4-(4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine -2-Preparation of carboxamide.

2-[(2S, 6R) -4-[[1- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1-yl]]
Sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl] -4-piperidyl] methyl] -2,6-dimethyl-piperazine-1-yl] acetic acid (70 mg, 0.09 mmol) , 1 equivalent), hydroxybenzotriazole (24 mg, 0.18 mmol, 2 equivalents), 1- (3-dimethylaminopropyl) -3-
(2S, 4R) -1-[(2S) -2-amino-3,3-dimethyl-butanoyl] -4 in a solution of ethylcarboxamide hydrochloride (34 mg, 0.18 mmol, 2 eq) in dimethylformamide (5 mL). -Hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (65 mg, 0.13 mmol, 1.5 eq, hydrochloride) and triethylamine (46 mg) , 0.45 mmol, 5 eq). The reaction mixture was stirred at 40 ° C. for 12 hours. The pH was adjusted to 6 with 1M hydrochloric acid. The residue was purified by preparative HPLC. (2S, 4R) -1- [(2S) -2- [[2-[(2S, 6R) -4- [[1- [4- [3- [2,6-difluoro-3- [[( 3R) -3-fluoropyrrolidine-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl] -4-piperidyl] methyl] -2,6-dimethyl- Piperazine-1-yl] acetyl] amino] -3,3-dimethyl-butanoyl] -4-hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] Pyrrolidine-2-carboxamide (41 mg, 0.032 mmol, yield 35%, purity 97%, formate) was obtained as a yellow solid. LC / MS (ESI) m / z: 848.2 [M + 1]
+; 1H-NMR (400MHz, DMSO-d6) δ 8.98 (s, 1H), 8.64 (d, J = 2.0 Hz, 1H), 8.49 (d, J = 7.5 Hz, 1H), 8.21 (s, 1H) , 8.07 (s, 1H), 8.02 --7.94 (m, 1H), 7.67 --7.53 (m, 3H), 7.47 --7.41 (m, 2H), 7.39 --7.32 (m, 2H), 7.25 (t, J = 8.4 Hz, 1H), 7.06 (d, J = 8.8 Hz, 2H), 5.39 ―― 5.19 (m, 1H), 4.93 ―― 4.86 (m, 1H), 4.51 ―― 4.42 (m, 2H), 4.27 (s, 1H) ), 3.79 (s, 1H), 3.32 --3.24 (m, 4H), 3.14 (d, J = 18.0 Hz, 3H), 2.96 (d, J = 18.0 Hz, 2H), 2.82 --2.67 (m, 4H) , 2.57 (s, 2H), 2.45 (s, 4H), 2.17 --1.92 (m, 6H), 1.90 --1.61 (m, 7H), 1.41 --1.35 (m, 3H), 1.21 (d, J = 11.6 Hz) , 2H), 0.98 (d, J = 6.0 Hz, 3H), 0.94 (s, 10H), 0.86 (d, J = 6.0 Hz, 3H), 0.89 --0.83 (m, 1H).
(2S, 4R) -1-((S) -2- (1- (4-((1- (4- (3- (2,6-difluoro-3- (((R) -3-fluoropyrrolidine) )-1-Sulfonamide) Benzoyl) -1H-Pyrrolidine [2,3-b] Pyridine-5-yl) Phenyl) Piperidi
Phenyl) methyl) piperazine-1-yl) cyclopropane-1-carboxamide) -3,3-dimethylbutanoyl) -4-hydroxy-N-((S) -1- (4- (4- (4-) Illustrative Synthesis of Methylthiazole-5-yl) Phenyl) Ethyl) Pyrrolidine-2-carboxamide (Example 361)
Step 1: Preparation of benzyl 3,4-dihydroxypyrrolidine-1-carboxylate.

Potassium ferricyanide (40.50 g, 123.01 mmol, 2.5 eq) in a solution of tertiary butanol (120 mL) and water (100 mL) of benzyl 2,5-dihydropyrrole-1-carboxylate (10 g, 49.20 mmol, 1 eq). , Potassium carbonate (17.00 g, 123.01 mmol, 2.5 eq), methanesulfonamide (4.68 g, 49.20 mmol, 1 eq) and potassium osmate (vi) dihydrate (1.81 g, 4.92 mmol, 0.1 eq).
Was added. The mixture was stirred at 0-5 ° C. for 12 hours. The reaction mixture was quenched with saturated sodium sulfite (50 mL). The reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (200 mLx2). The combined organic layers were washed with saturated brine (200 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (dichloromethane: methanol = 100: 1-30: 1). Benzyl 3,4-dihydroxypyrrolidine-1-carboxylate (14 g, crude) was obtained as a yellow oil. LC / MS (ESI) m / z: 260.0 [M + 23] ⁺ .
Step 2: Preparation of benzyl bis (2-oxoethyl) carbamate.

Sodium periodate (1.35 g, 6.32 mmol, 1.5 eq) in a solution of benzyl 3,4-dihydroxypyrrolidin-1-carboxylate (1 g, 4.21 mmol, 1 eq) in tetrahydrofuran (20 mL) and water (10 mL). Was added. The mixture was stirred at 15 ° C. for 2 hours. Water (100 mL) was poured into the mixture and stirred for 1 minute. The aqueous layer was extracted with ethyl acetate (100 mLx3). The combined organic layers were washed with brine (100 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was used in the next step without further purification. Benzyl N, N-bis (2-oxoethyl) carbamate (900 mg, 3.83 mmol, 90% yield) was obtained as a yellow oil.

Step 3: Preparation of benzyl 4- (1- (methoxycarbonyl) cyclopropyl) piperazine-1-carboxylate.

Methyl 1-aminocyclopropanecarboxylate (805 mg, 6.99 mmol, 1 eq) in a solution of benzyl N, N-bis (2-oxoethyl) carbamate (3.29 g, 13.99 mmol, 2 eq) in methanol (30 mL). ) And acetic acid (2 mL) were added. The mixture was stirred at 15 ° C. for 30 minutes. Borane; 2-methylpyridine (1.50 g, 13.99 mmol, 2 eq) was added, then the mixture was stirred at 15 ° C. for an additional 11.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash C18 chromatography [acetonitrile: water (0.5% TFA) = 5% -90%]. The mixture was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution (30 mL) was added. The aqueous layer was extracted with ethyl acetate (50 mLx3). The combined organic layers were washed with brine (50 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The compound benzyl 4- (1-methoxycarbonylcyclopropyl) piperazine-1-carboxylate (2.20 g, 6.91 mmol, 98% yield) was obtained as a colorless oil. LC / MS (ESI) m / z: 319.1 [M + 1] +; 1H-NMR (400MHz, CDCl3) δ 7.39 --7.35 (m, 4H),
7.35 --7.30 (m, 1H), 5.15 (s, 2H), 3.66 (s, 3H), 3.62 --3.04 (m, 4H), 2.92 (s, 4H), 1.33 --1.28 (m, 2H), 0.96 ( q, J = 3.6 Hz, 2H).
Step 4: Preparation of methyl 1- (piperazine-1-yl) cyclopropane-1-carboxylate.

Palladium on carbon (30 mg, 10%) in a solution of benzyl 4- (1-methoxycarbonylcyclopropyl) piperazine-1-carboxylate (2.2 g, 6.91 mmol, 1 equivalent) in tetrahydrofuran (30 mL).
Was added under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred at 30 ° C. for 12 hours under hydrogen (15 psi). The mixture was then stirred at 30 ° C. for 16 hours under hydrogen (50 psi). The reaction mixture was filtered and the filtrate was concentrated. Methyl 1-piperazine-1-ylcyclopropanecarboxylate (1.05 g, crude) was obtained as a colorless oil. LC / MS (ESI) m / z: 185.1 [M + 1] +; 1H-NMR (400MHz, CDCl3) δ 3.74 --3.59 (m, 3H), 3.02 --2.81 (m, 4H), 2.79 --2.73 (m) , 3H), 2.43 --2.22 (m, 1H), 1.73 --1.49 (m, 1H), 1.30 --1.22 (m, 2H), 0.98 --0.87 (m, 2H).
Step 5: Methyl (R) -1- (4-((1- (4- (3- (2,6-difluoro-3-((3-fluoropyrrolidine) -1-)
Preparation of sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperidine-4-yl) methyl) piperazine-1-yl) cyclopropan-1-carboxylate.

Methyl 1-piperazin-1-ylcyclopropanecarboxylate (72 mg, 0.39 mmol, 1.2 eq) and (3R) -N- [2,4-difluoro-3- [5- [4- (4-formyl-1) -Piperidyl) phenyl] -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] phenyl] -3-fluoro-pyrrolidin-1-sulfonamide (200 mg, 0.32 mmol, 1 eq) 1,2-dichloroethane To the solution (2 mL) was added sodium triacetoxyborohydride (207 mg, 0.98 mmol, 3 eq). The mixture was stirred at 15 ° C. for 1 hour. Water (50 mL) was poured into the mixture and stirred for 1 minute. The aqueous layer was extracted with dichloromethane (30 mLx3). The combined organic layers were washed with brine (30 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (dichloromethane: methanol = 200: 1-50: 1). Compound Methyl 1- [4- [[1- [4- [3- [2,6-,6-
Difluoro-3- [[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl] -4-piperidyl] methyl] Piperazine-1-yl] cyclopropanecarboxylate (210 mg, 0.26 mmol, 82% yield) was obtained as a yellow solid. LC / MS (ESI) m / z: 780.1 [M + 1] ⁺ .
Step 6: (R) -1- (4-((1- (4- (3- (2,6-difluoro-3-((3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] Preparation of pyridine-5-yl) phenyl) piperidine-4-yl) methyl) piperazine-1-yl) cyclopropan-1-carboxylic acid.

Methyl 1- [4- [[1- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [ 2,3-b] Pyridine-5-yl] phenyl] -4-piperidyl] methyl] piperazine-1-yl] cyclopropanecarboxylate (210 mg, 0.26 mmol, 1 equivalent)
Lithium hydroxide monohydrate (45 mg, 1.08 mmol, 4 eq) was added to a solution of methanol (2 mL), tetrahydrofuran (2 mL) and water (2 mL). The mixture was stirred at 40 ° C. for 12 hours. The reaction mixture was adjusted to pH 5 with hydrochloric acid (1M) and then concentrated under reduced pressure. The crude product was used in the next step without further purification. Compound 1- [4- [[1- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] Pyridine-5-yl] Phenyl] -4-piperidyl] Methyl] Piperazine-1-yl] Cyclopropanecarboxylic acid (200 mg, containing an inorganic salt) was obtained as a yellow oil. LC / MS (ESI) m / z: 766.4 [M + 1]
⁺ .
Step 7: (2S, 4R) -1-((S) -2- (1- (4-((1- (4- (3- (2,6-difluoro-3- (((R) -3) -3) -Fluoropyrrolidin) -1-sulfonamide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperidine-4-yl) Methyl) Piperazin-1-yl) Cyclopropan-1- Carboxamide) -3,3-dimethylbutanoyl) -4-hydroxy-N-((S) -1- (4- (4-methylthiazole-5-yl) phenyl)
Preparation of ethyl) pyrrolidine-2-carboxamide.

1- [4- [[1- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2 , 3-b] pyridine-5-yl] phenyl] -4-piperidyl] methyl] piperazine-1-yl] cyclopropanecarboxylic acid (200 mg, 0.26 mmol, 1 equivalent) and (2S, 4R) -1-[() 2S) -2-amino-3,3-dimethyl-butanoyl] -4-hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2- Carboxamide (125 mg, 0.26 mmol)
, 1 eq, hydrochloride) in a solution of N, N-dimethylformamide (5 mL) with hydroxybenzotriazole (42 mg, 0.31 mmol, 1.2 eq), triethylamine (39 mg, 0.39 mmol, 1.5 eq) and 1- (3- (3-). Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (60 mg, 0.31 mmol, 1.2)
Equivalent) was added. The mixture was stirred at 40 ° C. for 12 hours. Water (50 mL) was poured into the mixture and stirred for 1 minute. The aqueous layer was extracted with dichloromethane (10 mLx3). The combined organic layers were washed with brine (10 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by preparative HPLC. Compound (2S, 4R) -1-[(2S) -2-[[1- [4-[[1- [4- [3- [2,6-difluoro-3- [[(3R) -3) -Fluoropyrrolidine-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl] -4-piperidyl] methyl] piperazine-1-yl] cyclopropanecarbonyl] amino ] -3,3-dimethyl-butanoyl] -4-hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (27.3 mg, 0.022 mmol, yield 8%, purity 99%, formate) in 2 steps) was obtained as a yellow solid. LC / MS (ESI) m / z: 596.9 [M / 2 + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 13.16 --.12.44 (m, 1H), 8.98 (s, 1H), 8.64 (d) , J = 2.0 Hz, 1H), 8.51 (s, 1H), 8.45 (d, J = 7.6 Hz, 1H), 8.36 (d, J = 10.0 Hz, 1H), 8.23 (s, 1H), 8.04 (s) , 1H), 7.65 --7.55 (m, 3H), 7.46 --7.41 (m, 2H), 7.40 --7.32 (m, 2H), 7.21 (t, J = 8.8 Hz, 1H), 7.06 (d, J = 8.8) Hz, 2H), 5.39 --5.18 (m, 1H), 4.95 --4.83 (m, 1H), 4.53 --4.40 (m, 2H), 4.28 (s, 1H), 3.77 (d, J = 12.8 Hz, 2H) , 3.58 (d, J = 7.6 Hz, 1H), 3.45 (s, 1H), 3.27 (d, J = 6.8 Hz, 3H), 2.72 (t, J = 11.2 Hz, 2H), 2.46 (s, 3H) , 2.40 (s, 6H), 2.21 (d, J = 6.8 Hz, 3H), 2.13 --2.00 (m, 4H), 1.85 --1.65 (m, 5H), 1.40 (d, J = 7.2 Hz, 3H), 1.30 --1.15 (m, 2H), 1.08 (d, J = 7.0 Hz, 1H), 1.04 --0.89 (m, 13H).
(2S, 4R) -1-((S) -2-(2-(4-((1- (4- (3- (2,6-difluoro-3- (((R) -3-fluoropyrrolidine) )-1-Sulfonamide) Benzoyl) -1H-Pyrrolidine [2,3-b] Pyridine-5-yl) Phenyl) Piperidi
Phenyl-methyl) -1,4-diazepan-1-yl) acetamide) -3,3-dimethylbutanoyl) -4-hydroxy-N-((S) -1- (4- (4- (4- (4-) Methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-
Illustrative Synthesis of Carboxamide (Example 412)
Step 1: Preparation of benzyl 4- (2- (tert-butoxy) -2-oxoethyl) -1,4-diazepan-1-carboxylate.

N, N-diisopropylethylamine (938 mg, 7.26 mmol, 2 eq), tert-butyl in a solution of benzyl 1,4-diazepan-1-carboxylate (0.85 g, 3.63 mmol, 1 eq) in acetonitrile (10 mL). 2-bromoacetate (707 mg, 3.63 mmol, 0.5 mL, 1 eq) was added. The mixture was stirred at 70 ° C. for 2 hours. The reaction mixture was extracted with ethyl acetate (40 mLx2). The combined organic layers were washed with saturated aqueous brine solution (30 mLx2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10/1 to 2: 1). The compound benzyl 4- (2-tert-butoxy-2-oxo-ethyl) -1,4-diazepan-1-carboxylate (1.08 g, 2.82 mmol, 77% yield, 91% purity) is a colorless oil. Got as. LC / MS (ESI) m / z: 349.1 [M + 1] ⁺ .
Step 2: Preparation of tert-butyl 2- (1,4-diazepan-1-yl) acetate.

Palladium activation in a solution of benzyl 4- (2-tert-butoxy-2-oxo-ethyl) -1,4-diazepan-1-carboxylate (1.31 g, 3.42 mmol, 1 eq) in tetrahydrofuran (10 mL). A carbon catalyst (0.2 g, purity 10%) was added under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred at 40 ° C. for 24 hours under hydrogen (15 psi). The reaction mixture was filtered and the filtrate was concentrated. The compound tert-butyl 2- (1,4-diazepan-1-yl) acetate (750 mg, 2.06 mmol, yield 60%, purity 59%) is obtained as a yellow oil and further purified. It was used directly in the next step. LC / MS (ESI) m / z: 215.2 [M + 1] ⁺ .
Step 3: tert-butyl (R) -2- (4-((1- (4- (3- (2,6-difluoro-3-((3-fluoropyrrolidin) -1-sulfonamide) benzoyl)-)- Preparation of 1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperidine-4-yl) methyl) -1,4-diazepan-1-yl) acetate.

Triethylamine (33 mg, 0.32) in a solution of tert-butyl 2- (1,4-diazepan-1-yl) acetate (131 mg, 0.36 mmol, 1.1 eq) in 1,2- dichloromethane (2 mL) and methanol (1 mL). mmol, 1 eq) and (3R) -N- [2,4-difluoro-3- [5- [4- (4-formyl-1-piperidyl) phenyl] -1H-pyrrolo [2,3-b] pyridine -3-carbonyl] phenyl] -3-fluoro-pyrrolidin-1-sulfonamide (0.2 g, 0.32 mmol, 1 eq) was added. The mixture was stirred at 30 ° C. for 10 minutes, then sodium triacetoxyborohydride (139 mg, 0.65 mmol, 2 eq) was added. 110 mixed solution at 30 ° C
Stir for minutes. The reaction mixture was extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with brine (20 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Preparative thin layer chromatography of crude product (dichloromethane: methanol = 10: 1)
, Rf = 0.4). Compound tert-butyl 2- [4- [[1- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl]- 1H-Pyrrolidine [2,3-b] Pyridine-5-yl] Phenyl] -4-piperidyl] Methyl] -1,4-Diazepan-1-yl] Acetate (192 mg, 0.22 mmol, yield 68%, purity 94%) was obtained as a yellow solid. LC / MS (ESI) m / z: 810.4 [M + 1] ⁺ .
Step 4: (R) -2- (4-((1- (4- (3- (2,6-difluoro-3-((3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperidine-4-yl) Methyl) -1,4-Diazepan-1-yl) Preparation of acetic acid.

tert-butyl 2- [4-[[1- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1-yl] sulfonylamino] benzoyl] -1H- Pyrrolidine [2,3-b] Pyridine-5-yl] Phenyl] -4-piperidyl] Methyl] -1,4-Diazepan-1-yl] Acetate (240 mg, 0.27 mmol, 1 equivalent) dichloromethane (5 mL) Trifluoroacetic acid (1 mL) was added to the solution of. The mixture was stirred at 15 ° C. for 16 hours. The reaction mixture was concentrated under reduced pressure. Compound 2- [4- [[1- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] Pyridine-5-yl] Phenyl] -4-piperidyl] Methyl] -1,4-Diazepan-1-yl] Acetic acid (240 mg, crude, trifluoroacetic acid) was obtained as a yellow solid. , This was used directly in the next step without further purification. LC / MS (ESI) m / z: 754.2 [M + 1] ⁺ .
Step 5: (2S, 4R) -1-((S) -2- (2-(4-((1- (4- (3- (2,6-difluoro-3- (((R) -3) -3) -Fluoropyrrolidin) -1-sulfonamide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperidine-4-yl) Methyl) -1,4-Diazepan-1-yl) Preparation of acetamide) -3,3-dimethylbutanoyl) -4-hydroxy-N-((S) -1-(4- (4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide.

2- [4- [[1- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2 , 3-b] pyridine-5-yl] phenyl] -4-piperidyl] methyl] -1,4-diazepan-1-yl] N, N- of acetic acid (240 mg, 0.27 mmol, 1 eq, trifluoroacetic acid) Hydroxybenzotriazole (45 mg, 0.33 mmol, 1.2 eq), N, N-diisopropylethylamine (72 mg, 0.55 mmol, 2 eq) and 1- (3-dimethylaminopropyl) -3- in a solution of dimethylformamide (2 mL). Ethylcarbodiimide hydrochloride (79 mg, 0.41 mmol, 1.5 eq) was added. The mixture is stirred at 30 ° C. for 10 minutes, then (2S, 4R) -1-[(2S) -2-amino-3,3-dimethyl-butanoyl] -4-hydroxy-N-[(1S) -1. -[4- (4-Methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (159 mg, 0.33 mmol, 1.20 equivalents, hydrochloride) was added. The mixture was stirred at 30 ° C. for an additional 110 minutes. The reaction mixture was extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with brine (15 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by half-reverse phase HPLC. Compound (2S, 4R) -1-[(2S) -2-[[2- [4-[[1- [4- [3- [2,6-difluoro-3- [[(3R) -3) -Fluoropyrrolidine-1-yl]
Sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl] -4-piperidyl] methyl] -1,4-diazepan-1-yl] acetyl] amino] -3,3 -Dimethyl-butanoyl] -4-hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (89.4 mg, 0.07 mmol, yield) 25%, purity 97%, formate) was obtained as a pink solid. LC / MS (ESI) m / z: 591.0 [M / 2 + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 8.97 (s, 1H), 8.64 (d, J = 2.0 Hz, 1H), 8.52 (s, 1H), 8.42 (d, J = 8.4 Hz, 1H), 8.20 (s, 1H), 8.03 (s, 1H), 7.81 (d, J = 10.0 Hz, 1H), 7.64 --7.54 (m) , 3H), 7.45 --7.41 (m, 2H), 7.39 --7.34 (m, 2H), 7.24 --7.71 (m, 1H), 7.06 (d, J = 8.8 Hz, 2H), 5.41 --5.17 (m, 1H) ), 5.02 --4.83 (m, 1H), 4.61 --4.39 (m, 2H), 4.29 (s, 1H), 3.78 (d, J = 12.4 Hz, 3H), 3.64 --3.52 (m, 2H), 3.13 - 3.10 (m, 2H), 2.73 ―― 2.65 (m, 10H), 2.45 (s, 4H), 2.40 ―― 2.25 (m, 5H), 2.17 ―― 1.96 (m, 4H), 1.91 ―― 1.68 (m, 6H), 1.64 (s, 1H), 1.43 --1.34 (m, 3H), 1.29 --1.15 (m, 2H), 0.95 (s, 9H).
(2S, 4R) -1-((S) -2- (2- (4- (1- (4- (3- (2-,6-difluoro-3- (((R) -3-fluoropyrrolidine)) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperidine-4-yl) -1,4-diazepan-1-yl) acetamide) -3,3 -Dimethylbutanoyl) -4-hydroxy-N-((S) -1- (4- (4-Methylthiazole-5-yl) phenyl) ethyl) Pyrrolidine-2-carboki
Illustrative synthesis of samide (Example 437)
Step 1: Preparation of 8- (4-bromophenyl) -1,4-dioxa-8-azaspiro [4.5] decane.

1-bromo-4-iodo-benzene (5 g, 17.67 mmol, 1 eq) and 1,4-dioxa-8-azaspiro [4.5] decane (2.53 g, 17.67 mmol, 2.26 mL, 1 eq) dimethylsulfoxide (40 mL) ), L-PROLINE (813 mg, 7.07 mmol, 0.4 eq), copper iodide (673 mg, 3.53 mmol, 0.2 eq) and potassium carbonate (4.89 g, 35.35 mmol, 2 eq) were added. The mixture was stirred at 80 ° C. for 12 hours. Water (300 mL) was poured into the mixture and stirred for 1 minute. The aqueous layer was extracted with ethyl acetate (100 mLx3). The combined organic layers were washed with brine (100 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 1: 0 to 10: 1). The compound 8- (4-bromophenyl) -1,4-dioxa-8-azaspiro [4.5] decane (3.2 g, 10.73 mmol, 60% yield) was obtained as a yellow solid. LC / MS (ESI) m / z: 297.9 [M + 1] ⁺ .
Step 2: Preparation of 8- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) -1,4-dioxa-8-azaspiro [4.5] decane ..

8- (4-Bromophenyl) -1,4-dioxa-8-azaspiro [4.5] decane (3.2 g, 10.73 mmol, 1)
Equivalent) and 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolan (2.73) Potassium acetate (2.11 g, 21.46 mmol, 2 eq) and ditert-butyl (cyclopentyl) phosphan; dichloropalladium; iron (699.45 mg, 1.07 mmol, 0.1) in a solution of dioxane (90 mL) of g, 10.73 mmol, 1 eq. Equivalent) was added. Mix liquid at 80 ° C
Stir for 12 hours. Water (100 mL) was poured into the mixture and stirred for 1 minute. The aqueous layer was extracted with ethyl acetate (100 mLx3). The combined organic layers were washed with brine (100 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 1: 0 to 30: 1). Compound 8- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -1,4-dioxa-8-azaspiro [4.5] decane (2.2 g) , 6.37 mmol, yield 59%) as a brown oil. LC / MS (ESI) m / z: 346.1 [M + 1] ⁺ .
Step 3: (R) -N- (3-(5-(4- (1,4-dioxa-8-azaspiro [4.5] decane-8-yl) phenyl) -1-((2- (trimethylsilyl) ethoxy) ) Methyl) -1H-pyrrolo [2,3-b] pyridin-3-carbonyl) -2,4-difluorophenyl) -3-fluoro-N-((2- (trimethylsilyl) ethoxy) methyl) pyrrolidine-1- Preparation of sulfonamides.

8- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -1,4-dioxa-8-azaspiro [4.5] decane (1.4 g, 4.06) mmol, 1 equivalent) and (3R) -N- [3- [5-bromo-1- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro- Phenyl] -3-fluoro-N- (2-trimethylsilylethoxymethyl) pyrrolidine-1-sulfonamide (3.10 g, 4.06 mmol, 1 eq) in a solution of dioxane (10 mL) and water (1 mL), 4-ditert- Butylphosphanyl-N, N-dimethyl-aniline; dichloropalladium (287 mg, 0.40 mmol, 0.1 eq) and cesium fluoride (2.46 g, 16.22 mmol, 4 eq) were added. The mixture was stirred at 90 ° C. for 12 hours. Water (100 mL) was poured into the mixture and stirred for 1 minute. The aqueous layer was extracted with ethyl acetate (100 mLx3). The combined organic layers were washed with brine (100 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 1: 0 to 20: 1). Compound (3R) -N- [3- [5- [4- (1,4-dioxa-8-azaspiro [4.5] decane-8-yl) phenyl] -1- (2-trimethylsilylethoxymethyl) pyrrolo [ 2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl] -3-fluoro-N- (2-trimethylsilylethoxymethyl) pyrrolidine-1-sulfonamide (2.2 g, 2.44 mmol, yield) 60%) was obtained as a brown oil. LC / MS (ESI) m / z: 902.4 [M + 1] ⁺ .
Step 4: (R) -N- (3- (5- (4- (1,4-dioxa-8-azaspiro [4.5] decane-8-yl) phenyl) -1H-pyrrolo [2,3-b] Preparation of pyridine-3-carbonyl) -2,4-difluorophenyl) -3-fluoropyrrolidine-1-sulfonamide.

(3R) -N- [3- [5- [4- (1,4-dioxa-8-azaspiro [4.5] decane-8-yl) phenyl] -1- (2-trimethylsilylethoxymethyl) pyrrolo [2, 3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl] -3-fluoro-N- (2-trimethylsilylethoxymethyl) pyrrolidine-1-sulfonamide (2.2 g, 2.44 mmol, 1 eq) To a solution of methanol (30 mL) was added a solution of 4M hydrochloride dioxane (55 mL, 90.22 eq). The mixture was stirred at 50 ° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was used in the next step without further purification. Compound (3R) -N- [3- [5- [4- (1,4-dioxa-8-azaspiro [4.5] decane-8-yl) phenyl] -1H-pyrrolo [2,3-b] pyridine -3-carbonyl] -2,4-difluoro-phenyl] -3-fluoro-pyrrolidin-1-sulfonamide (1.5 g, crude) was obtained as a yellow solid. LC / MS (ESI) m / z: 642.1 [M + 1]
⁺ ..
Step 5: (R) -N- (2,4-difluoro-3- (5- (4- (4-oxopiperidine-1-yl) phenyl) -1H-
Preparation of pyrolo [2,3-b] pyridin-3-carbonyl) phenyl) -3-fluoropyrrolidine-1-sulfonamide.

(3R) -N- [3- [5- [4- (1,4-dioxa-8-azaspiro [4.5] decane-8-yl) phenyl] -1H-pyrrolo [2,3-b] pyridine-3 -Maldo] -2,4-difluoro-phenyl] -3-fluoro-pyrrolidin-1-sulfonamide (1.5 g, 2.34 mmol, 1 eq) in hydrochloric acid (20 mL) in hydrochloride (3M, 34.09 mL, 43.75 equivalents) was added. The mixture was stirred at 50 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative reverse phase HPLC. Compound (3R) -N- [2,4-difluoro-3- [5- [4- (4-oxo-1-piperidyl) phenyl] -1H-pyrrolo [2,3-b] pyridine-3-carbonyl ] Phenyl] -3-fluoro-pyrrolidin-1-sulfonamide (450 mg, 0.75 mmol, 64% yield) was obtained as a yellow solid. LC / MS (ESI) m / z: 598.1 [M + 1] ⁺ .
Step 6: tert-butyl (R) -2- (4- (1- (4- (3- (2,6-difluoro-3-((3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H) -Preparation of pyrrolidine [2,3-b] pyridin-5-yl) phenyl) piperidine-4-yl) -1,4-diazepan-1-yl) acetate.

tert-butyl 2- (1,4-diazepan-1-yl) acetate (149 mg, 0.41 mmol, 1 equivalent) and (3R) -N- [2,4-difluoro-3- [5- [4- ( 4-oxo-1-piperidyl) phenyl] -1H-pyrrolo [2,3-b] pyridin-3-carbonyl] phenyl] -3-fluoro-pyrrolidin-1-sulfonamide (300 mg, 0.41 mm)
Sodium cyanoborohydride (77 mg, 1.23 mmol, 3 eq) was added to a solution of ol, 1 eq) of N, N-dimethylformamide (6 mL) and acetic acid (0.6 mL). The mixture was stirred at 15 ° C. for 12 hours. Water (50 mL) was poured into the mixture and stirred for 1 minute. The aqueous layer was extracted with ethyl acetate (20 mLx3). The combined organic layers were washed with brine (40 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by preparative thin layer chromatography (dichloromethane: methanol = 10: 1). The compound tert-butyl 2- [4- [1- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1-yl] sulfonylamino] benzoyl] -1H -Pyrrolidine [2,3-b] Pyridine-5-yl] Phenyl] -4-piperidyl] -1,4-Diazepan-1-yl] Acetate (140 mg)
, 0.17 mmol, yield 42%) as a yellow solid. LC / MS (ESI) m / z: 796.2 [M + 1] ⁺ .
Step 7: (R) -2- (4- (1- (4- (3- (2,6-difluoro-3-((3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [ 2,3-b] Pyridine-5-yl) Phenyl) Piperidine-4-yl) -1,4-Diazepan-1-yl) Preparation of acetic acid.

tert-butyl 2- [4- [1- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridine-5-yl] phenyl] -4-piperidyl] -1,4-diazepan-1-yl] acetate (200 mg, 0.25 mmol, 1 eq) in a solution of dichloromethane (3 mL) , A solution of dioxane (4.4 mL, 70.75 eq) of 4M hydrochloric acid was added. The mixture was stirred at 15 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. The crude product was used in the next step without further purification. Compound 2- [4- [1- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [ 2,3-b] Pyridine-5-yl] phenyl] -4-piperidyl] -1,4-diazepan-1-yl] Acetic acid (200 mg, crude, hydrochloride) was obtained as a yellow solid.

Step 8: (2S, 4R) -1-((S) -2- (2- (4- (1- (4- (3- (2,6-difluoro-3- (((R) -3-) -3-) Fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperidine-4-yl) -1,4-diazepan-1-yl) acetamide)- 3,3-Dimethylbutanoyl) -4-
Hydroxy-N-((S) -1- (4- (4-Methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-
Preparation of carboxamide.

(2S, 4R) -1-[(2S) -2-amino-3,3-dimethyl-butanoyl] -4-hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-) Il) phenyl] ethyl] pyrrolidine-2-carboxamide (123 mg, 0.25 mmol, 1.00 equivalent, hydrochloride) and 2- [4- [1- [4- [3- [2,6-difluoro-3- [[() 3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl] -4-piperidyl] -1,4-diazepan-1- Il] Triethylamine (130 mg, 1.29 mmol, 5 equivalents), 1- (3-dimethylaminopropyl)-in a solution of N, N-dimethylformamide (3 mL) of acetic acid (200 mg, 0.25 mmol, 1 equivalent, hydrochloride). 3-Ethylcarboxamide hydrochloride (59 mg, 0.30 mmol)
, 1.2 eq) and hydroxybenzotriazole (41 mg, 0.30 mmol, 1.2 eq) were added. The mixture was stirred at 30 ° C. for 12 hours. Water (50 mL) was poured into the mixture and stirred for 1 minute. The water layer,
Extracted with ethyl acetate (20 mLx3). The combined organic layers were washed with brine (20 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by preparative HPLC. Compound (2S, 4R) -1-[(2S) -2-[[2- [4- [1- [4- [3- [2,6-difluoro-3- [[(3R) -3-] Fluoropyrrolidine-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl] -4-piperidyl] -1,4-diazepan-1-yl] acetyl] amino ] -3,3-dimethyl-butanoyl] -4-hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (57.8 mg, 0.04 mmol, yield 17%, purity 97%) was obtained as a yellow solid. LC / MS (ESI) m / z: 583.9 [M / 2] +; 1H-NMR (400MHz, DMSO-d6) δ 12.94 (s, 1H), 8.98 (s, 1H), 8.64 (d, J = 2.0) Hz, 1H), 8.53 (s, 1H), 8.45 (d, J = 7.6 Hz, 1H), 8.17 (s, 2H), 8.06 (s, 1H), 7.82 (d, J = 9.6 Hz, 1H), 7.66 --7.54 (m, 3H), 7.46 --7.74 (m, 2H), 7.40 --7.33 (m, 2H), 7.25 (t, J = 8.4 Hz, 1H), 7.07 (d, J = 8.8 Hz, 2H) , 5.39 --5.52 (m, 1H), 4.98 --4.84 (m, 1H), 4.50 (d, J = 9.6 Hz, 1H), 4.44 (t, J = 8.4 Hz, 1H), 4.28 (s, 1H), 3.84 (d, J = 11.2 Hz, 2H), 3.63 --3.53 (m, 2H), 3.47 (s, 3H), 3.11 (d, J = 8.8 Hz, 2H), 2.79 (d, J = 15.2 Hz, 4H) ), 2.75 --2.68 (m, 6H), 2.45 (s, 4H), 2.14 --2.01 (m, 3H), 1.85 --1.69 (m, 6H), 1.63 --1.44 (m, 3H), 1.38 (d, J) = 6.8 Hz, 3H), 0.95 (s, 9H).
(2S, 4R) -1-((S) -2-(2-(4-((4- (4- (3- (2,6-difluoro-3- (((R) -3-fluoropyrrolidine) )-1-Sulfonamide) Benzoyl) -1H-Pyrrolidine [2,3-b] Pyridine-5-yl) Phenyl) Piperadi
N-1-yl) methyl) phenyl) acetamide) -3,3-dimethylbutanoyl) -4-hydroxy-N-((S) -1- (4- (4-methylthiazole-5-yl) phenyl) Ethyl) pyrrolidine-2-carboxamide
Illustrative synthesis of (Example 377)
Step 1: Methyl (R) -2- (4-((4- (4- (3- (2,6-difluoro-3-((3-fluoropyrrolidine) -1-)
Preparation of sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) methyl) phenyl) acetate.

(3R) -N- [2,4-difluoro-3- [5- (4-piperazin-1-ylphenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] phenyl] -3- Sodium acetate (50 mg, 0.61 mmol, 2 eq) was added to a solution of fluoro-pyrrolidin-1-sulfonamide (200 mg, 0.30 mmol, 1 eq, dihydrochloride) in methyl alcohol (2 mL) and dichloromethane (1 mL). , The pH was adjusted to about 8.0. Methyl 2- (4-formylphenyl) acetate (108 mg, 0.61 mmol, 2 eq) was then added. The mixture was stirred at 30 ° C. for 15 minutes, followed by the addition of acetic acid (36 mg, 0.61 mmol, 2 eq) to adjust the pH to about 5.0. The mixture was stirred at 15 ° C. for 15 minutes. Then sodium cyanoborohydride (38 mg, 0.61 mmol, 2 eq)
Was added in several batches. The reaction mixture was stirred at 30 ° C. for 1.5 hours. Water (30 mL) the reaction mixture
It was poured into the water and extracted with ethyl acetate (30 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (dichloromethane: methanol = 10: 1, Rf = 0.4). Compound Methyl 2- [4- [[4- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1-yl] sulfonylamino] benzoyl] -1H- Pyrrolidine [2,3-b] pyridin-5-yl] phenyl] piperazine-1-yl] methyl] phenyl] acetate (140 mg, 0.18 mmol, yield 60%, purity 98%) was obtained as a colorless oil. .. LC / MS (ESI) m / z: 747.2 [M + 1] ⁺ .
Step 2: (R) -2- (4-((4- (4- (3- (2,6-difluoro-3-((3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] Preparation of pyridine-5-yl) phenyl) piperazine-1-yl) methyl) phenyl) acetic acid.

Methyl 2- [4- [[4- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [ 2,3-b] Pyridine-5-yl] Phenyl] Piperazine-1-yl] Methyl] Phenyl] Acetate (140 mg, 0.19 mmol, 1 equivalent) in a solution of tetrahydrofuran (2 mL) and water (0.5 mL). Lithium hydrate (14 mg, 0.56 mmol, 3 equivalents) was added. Mix liquid at 30 ° C
Stirred for 12 hours. The reaction mixture was concentrated under vacuum. The residue was diluted with 5 mL of water and then acidified with hydrochloric acid (1M) to pH = 5-6. The suspension was concentrated under vacuum. The residue was purified by half-reverse phase HPLC. Compound 2- [4- [[4- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] Pyridine-5-yl] Phenyl] Piperazine-1-yl] Methyl] Phenyl] Acetic acid (65 mg, 0.1 mmol, yield 44%, purity 94%)
) Was obtained as a yellow solid. LC / MS (ESI) m / z: 733.1 [M + 1] ⁺ .
Step 3: (2S, 4R) -1-((S) -2- (2-(4-((4- (4- (3- (2,6-difluoro-3- (((R) -3) -3) -Fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) methyl) phenyl) acetamide) -3,3-dimethylbuta Preparation of noyl) -4-hydroxy-N-((S) -1-(4- (4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide.

2- [4- [[4- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2 , 3-b] Pyridine-5-yl] phenyl] piperazine-1-yl] methyl] phenyl] acetic acid (115 mg, 0.15 mmol, 1 equivalent) and (2S, 4R) -1- [(2S) -2-amino -3,3-
Dimethyl-butanoyl] -4-hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (71 mg, 0.15 mmol, 1.00 eq, hydrochloric acid Hydroxybenzotriazole (24 mg, 0.18 mmol, 1.2 eq), N, N-diisopropylethylamine (57 mg, 0.44 mmol, 3 eq) and 1- (3- (3-equivalent) in a solution of N, N-dimethylformamide (1 mL) of salt). Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (42.42 mg, 0.22 mmol, 1.5 eq) was added. The mixture was stirred at 30 ° C. for 2 hours. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (40 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by half-reverse phase HPLC. Compound (2S, 4R) -1-[(2S) -2-[[2- [4-[[4- [4- [3- [2,6-difluoro-3- [[(3R) -3) -Fluoropyrrolidine-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridine-5-yl] phenyl] piperazine-1-yl] methyl] phenyl] acetyl] amino] -3,3 -Dimethyl-butanoyl] -4-hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (93.8 mg, 0.07 mmol, yield) 51%, purity 97%, formic acid) was obtained as a yellow solid. LC / MS (ESI) m / z: 580.3 [M / 2 + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 12.90 (s, 1H), 9.01 --8.95 (m, 1H), 8.64 (d) , J = 2.4 Hz, 1H), 8.53 (s, 1H), 8.44 --8.36 (m, 1H), 8.15 (s, 1H), 8.06 (s, 1H), 7.99 (d, J = 9.2 Hz, 1H) , 7.69 --7.53 (m, 3H), 7.47 --7.41 (m, 2H), 7.41 --7.35 (m, 2H), 7.30 --7.21 (m, 5H), 7.06 (d, J = 8.8 Hz, 2H), 5.41 --5.19 (m, 1H), 5.10 (s, 1H), 5.00 --4.84 (m, 1H), 4.50 (d, J = 9.2 Hz, 1H), 4.43 (t, J = 8.0 Hz, 1H), 4.27 ( s, 1H), 3.66 --3.55 (m, 3H), 3.49 (d, J = 14.4 Hz, 4H), 3.39 (s, 3H), 3.21 (s, 3H), 2.56 --2.53 (m, 2H), 2.52 (s, 3H), 2.45 (s, 3H), 2.25 --1.87 (m, 4H), 1.84 --1.167 (m, 1H), 1.38 (d, J = 7.2 Hz, 3H), 1.00 --0.80 (m, 9H) ).
(2S, 4R) -1-((S) -2-(3-(4-(4-(4-(3-(2,6-difluoro-3-(((R) -3-fluoropyrrolidin)) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridine-5-yl) phenyl) piperazin-1-yl) butoxy) isoxazole-5-yl) -3-methylbutanoyl) -4 -Hydroxy-N-((S) -1- (4- (4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (eg 383) and (2S, 4R) -1-((R) ) -2- (3- (4- (4- (4- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-) Pyrrolo [2,3-b] Pylidin-5-yl) Phenyl) Piperazin-1-yl) Butoxy) Isoxazole-5-yl) -3-Methylbutanoyl) -4-Hydroxy-N-((S) -1 -(4- (4-Methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxa
Exemplary Synthesis of Mido (Example 384) 1: Preparation of methyl 2- (3- (4,4-dimethoxybutoxy) isoxazole-5-yl) -3-methylbutanoate.

4-Chloro-1,1-dimethoxy-butane (383 mg, 2.51 mmol, 1 eq) and methyl 2- (3-hydroxyisoxazole-5-yl) -3-methyl-butaneate (500 mg, 2.51 mmol,) To a solution of 1 equivalent) of N, N-dimethylformamide (10 mL) was added cesium carbonate (1.64 g, 5.02 mmol, 2 equivalents). The mixture was stirred at 80 ° C. for 2 hours. Water (100 mL) was poured into the mixture and stirred for 1 minute. The water layer,
Extracted with ethyl acetate (100 mLx3). The combined organic layers were washed with brine (100 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 1: 0 to 30: 1). The compound methyl 2- [3- (4,4-dimethoxybutoxy) isoxazole-5-yl] -3-methyl-butanoate (500 mg, 1.36 mmol, yield 54%, purity 86%) was used as a colorless oil. Obtained. LC / MS (ESI)
m / z: 338.4 [M + 23] ⁺ .
Step 2: Preparation of methyl 3-methyl-2- (3- (4-oxobutoxy) isoxazole-5-yl) butaneate.

Sulfuric acid (2M, 2M,) in a solution of methyl 2- [3- (4,4-dimethoxybutoxy) isoxazole-5-yl] -3-methyl-butanoate (500 mg, 1.36 mmol, 1 eq) in tetrahydrofuran (20 mL). 27 mL, 40 eq) was added. The mixture was stirred at 70 ° C. for 0.5 hours. The pH of the reaction mixture was adjusted to 8 using a saturated aqueous sodium bicarbonate solution. Water (50 mL) was poured into the mixture and stirred for 1 minute. The aqueous layer was extracted with ethyl acetate (30 mLx3). The combined organic layers were washed with brine (30 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was used in the next step without further purification. The compound methyl 3-methyl-2- [3- (4-oxobutoxy) isoxazole-5-yl] butanoate (270 mg, 1.00 mmol, 73% yield) was obtained as a colorless oil.

Step 3: Methyl 2-(3-(4-(4-(3-(2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl)-)- Preparation of 1H-pyrrolidine [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) butoxy) isoxazole-5-yl) -3-methylbutanoate.

Methyl 3-methyl-2- [3- (4-oxobutoxy) isoxazole-5-yl] butaneate (150 mg, 0.55 mmol, 1 eq) and (3R) -N- [2,4-difluoro-3- [5- (4-Piperazine-1-ylphenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] phenyl] -3-fluoro-pyrrolidin-1-sulfonamide (345 mg, 0.55 mmol, 1) To a solution of 1,2-dichloroethane (5 mL) (equivalent, hydrochloride) was added triethylamine (112 mg, 1.11 mmol, 2 eq) and sodium triacetoxyborohydride (354 mg, 1.67 mmol, 3 eq). The mixture was stirred at 15 ° C. for 2 hours. Water (100 mL) was poured into the mixture and stirred for 1 minute. The aqueous layer was extracted with ethyl acetate (30 mLx3). The combined organic layers were washed with brine (30 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by preparative TLC (dichloromethane: methanol = 10: 1). Compound Methyl 2- [3- [4- [4- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1-yl] sulfonylamino] benzoyl]- 1H-pyrrolidine [2,3-b] pyridin-5-yl] phenyl] piperazine-1-yl] butoxy] isoxazole-5-yl] -3-methyl-butanoate (300 mg, 0.35 mmol, 64% yield) ) Was obtained as a yellow solid. LC / MS (ESI) m / z: 838.1 [M + 1] ⁺ ; ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 12.89 (s, 1H), 9.82 (s, 1H), 8.65 (d, J) = 2.4 Hz, 1H), 8.53 (s, 1H), 8.06 (s, 1H), 7.66 --7.56 (m, 3H), 7.26 (t, J = 8.8 Hz, 1H), 7.07 (d, J = 8.8)
Hz, 2H), 6.20 (s, 1H), 5.23 (s, 1H), 4.20 (t, J = 6.4 Hz, 2H), 3.67 --3.65 (m, 3H), 3.48 (s, 1H), 3.43 --3.36 (m, 2H), 3.21 (s, 4H), 2.89 (s, 1H), 2.60 --2.51 (m, 6H), 2.40 (t, J = 6.8 Hz, 2H), 2.33 --2.25 (m, 1H), 2.14 --2.06 (m, 1H), 1.81 --1.72 (m, 2H), 1.59 (quin, J = 7.2 Hz, 2H), 0.93 (d, J = 6.8 Hz, 3H), 0.85 (d, J = 6.8 Hz) , 3H).
Step 4: 2- (3- (4- (4- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H) -Preparation of pyrrolidine [2,3-b] pyridine-5-yl) phenyl) piperazine-1-yl) butoxy) isoxazole-5-yl) -3-methylbutanoic acid.

Methyl 2- [3- [4- [4- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1-yl] sulfonylamino] benzoyl] -1H- Pyrrolidine [2,3-b] Pyridine-5-yl] Phenyl] Piperazine-1-yl] Butoxy] Isoxazole-5-yl] -3-Methyl-butaneate (300 mg, 0.35 mmol, 1
Lithium hydroxide monohydrate (30 mg, 0.71 mmol, 2 eq) was added to a solution of (equivalent) in tetrahydrofuran (5 mL), methanol (5 mL) and water (3 mL). The mixture was stirred at 40 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The reaction mixture was adjusted to pH 5 with hydrochloric acid (1M). The residue was purified by preparative HPLC. Compound 2- [3- [4- [4- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H -Pyrrolidine [2,3-b
] Pyridine-5-yl] phenyl] piperazine-1-yl] butoxy] isoxazole-5-yl] -3-methyl-butanoic acid (200 mg, 0.24 mmol, 67% yield) was obtained as a yellow solid. LC / MS (ESI) m / z: 824.4 [M + 1] ⁺ .
Step 5: (2S, 4R) -1- (2- (3- (4- (4- (4- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidin))- 1-Sulfone amide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperazin-1-yl) Butoxy) Isoxazole-5-yl) -3-Methylbutanoyl) -4- Preparation of hydroxy-N-((S) -1- (4- (4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide.

2- [3- [4- [4- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridine-5-yl] phenyl] piperazin-1-yl] butoxy] isoxazole-5-yl] -3-methyl-butanoic acid (200 mg, 0.24 mmol, 1 equivalent) and (2S, 4R) ) -4-Hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (89.mg, 0.24 mmol, 1.00 equivalent, HCl) Triethylamine (36 mg, 0.36 mmol, 1.5 equivalents), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (55 mg, 0.29 mmol, 1.2 equivalents) in a solution of N, N-dimethylformamide (5 mL). And hydroxybenzotriazole (39 mg, 0.29 mmol, 1.2 equivalents) was added. The mixture was stirred at 30 ° C. for 12 hours. Water (50 mL) was poured into the mixture and stirred for 1 minute. The aqueous layer was extracted with dichloromethane (20 mLx3). The combined organic layers were washed with brine (20 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by preparative HPLC. Compound (2S, 4R) -1- [2- [3- [4- [4- [4- [3- [2,6-difluoro-3- [[(3R) -3-fluoropyrrolidine-1- Ill] sulfonylamino] benzoyl] -1H-pyrrolidine [2,3-b] pyridine-5-yl] phenyl] piperazine-1-yl] butoxy] isoxazole-5-yl] -3-methyl-butanoyl] -4- Hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (130 mg, 0.10 mmol, yield 43%, purity 96%, formate) ) Was obtained as a white solid. LC / MS (ESI) m / z: 569.4 [M / 2 + 1] ⁺ .
Step 6: (2S, 4R) -1-((S) -2- (3- (4- (4- (4- (3- (2,6-difluoro-3- (((R) -3-) -3-) Fluoropyrrolidine) -1-sulfonamide) Benzoyl) -1H-pyrrolo [2,3-b] pyridine-5-yl) Phenyl) Piperazin-1-yl) Butoxy) Isoxazole-5-yl) -3-Methylbutanoyl ) -4-Hydroxy-N-((S) -1- (4- (4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide, and (2S, 4R) -1-((R) ) -2- (3- (4- (4- (4- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-) Pyrrolo [2,3-b] Pylidin-5-yl) Phenyl) Piperazin-1-yl) Butoxy) Isoxazole-5-yl) -3-Methylbutanoyl) -4-Hydroxy-N-((S) -1 -Preparation of (4- (4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide.

2S, 4R) -1- [2- [3- [4- [4- [4- [3- [2,6-difluoro-3- [[(3R) -3-fluoropyrrolidine-1-yl] sulfonyl] Amino] benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl] piperazine-1-yl] butoxy] isoxazole-5-yl] -3-methyl-butanoyl] -4-hydroxy-N -[(1S) -1- [4- (4-Methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (130 mg, 0.10 mmol, 1 equivalent, formate) is a chiral supercritical fluid chromatography. Was separated by. Compound (2S, 4R) -1-[(2S) -2- [3- [4- [4- [4- [3- [2,6-difluoro-3- [[(3R) -3-fluoro Pyrrolidine-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridine-5-yl] phenyl] piperazine-1-yl] butoxy] isoxazole-5-yl] -3-methyl-butanoyl ] -4-Hydroxy-N-[(1S) -1- [4- (4-Methylthiazole-5-yl) phenyl] ethyl] Pyrrolidine-2-carboxamide (22.68 mg, 0.01 mmol, yield 32%, purity) 91%, formate) was obtained as a yellow solid. LC / MS (ESI) m / z: 569.3 [M / 2 + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 12.86 (s, 1H), 9.01 --8.96 (m, 1H), 8.95 --8.82 (m, 1H), 8.63 (d, J = 2.1 Hz, 1H), 8.52 (s, 1H), 8.30 (d, J = 7.6 Hz, 1H), 8.03 (s, 1H), 7.63 --7.46 (m, 4H), 7.45 --7.38 (m, 2H), 7.35 --7.30 (m, 2H), 7.13 (s, 1H), 7.05 (d, J = 8.8 Hz, 2H), 6.16 --6.07 (m, 1H), 5.37 --5.17 (m, 1H), 5.11 (d, J = 3.2 Hz, 1H), 5.05 --4.96 (m, 1H), 4.90 (t, J = 7.2 Hz, 1H), 4.42 (t, J = 7.6 Hz, 1H), 4.26 (s, 1H), 4.22 --4.11 (m, 2H), 3.75 (d, J = 8.8 Hz, 1H), 3.59 --3.36 (m, 4H), 3.29 --3.12 (m, 6H), 2.45 (s, 3H), 2.41 --2.31 (m, 3H), 2.30 --2.22 (m, 1H), 2.11 --2.02 (m, 3H), 1.82- 1.68 (m, 3H), 1.56 (dd, J = 7.6, 14.5 Hz, 2H), 1.48 --1.41 (m, 1H), 1.35 (d, J = 7.2 Hz, 3H), 0.96 (d, J = 6.4 Hz, 3H), 0.83 (d, J = 6.8 Hz, 3H) The compound (2S, 4R) -1-[(2R) -2- [3- [4- [4- [4-[3- [2,6-difluoro-3- [[(3R) -3-] Fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridine-5-yl] phenyl] piperazine-1-yl] butoxy] isoxazole-5-yl] -3-methyl- Butanoyl] -4-hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (52.44 mg, 0.04 mmol, yield 76%) , 95% purity, formate) was obtained as a yellow solid. LC / MS (ESI) m / z: 569.3 [M / 2 + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 12.95 (s, 1H), 9.90 (s, 1H), 8.99 (s, 1H) ), 8.92 (s, 1H), 8.67 (d, J = 2.0 Hz, 1H), 8.56 (s, 1H), 8.44 (d, J = 7.6 Hz, 1H), 8.17 --8.06 (m, 1H), 7.69 --7.58 (m, 3H), 7.50 --7.42 (m, 2H), 7.41 --7.34 (m, 2H), 7.28 (t, J = 8.0 Hz, 1H), 7.12 (d, J = 8.4 Hz, 2H), 6.14 --5.93 (m, 1H), 5.39 --5.22 (m, 1H), 5.39 --5.22 (m, 1H), 5.15 --5.01 (m, 1H), 4.99 --4.84 (m, 1H), 4.37 (t, J) = 8.0 Hz, 1H), 4.29 (s, 1H), 4.20 (s, 2H), 3.75 --3.62 (m, 2H), 3.53 --3.36 (m, 6H), 2.54 --2.52 (m, 3H), 2.46 ( s, 3H), 2.35 (td, J = 2.0, 8.4 Hz, 2H), 2.30 --2.17 (m, 2H), 2.10 --2.01 (m, 2H), 1.84 --1.72 (m, 5H), 1.49 --1.42 ( m, 1H), 1.41 --1.34 (m, 3H), 1.24 (s, 1H), 1.00 --0.94 (m, 3H), 0.87 --0.78 (m, 4H).
(2S, 4R) -1-((S) -2-(3-(3-(4-(4-(3-(2,6-difluoro-3-(((R) -3-fluoropyrrolidin)) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridine-5-yl) phenyl) piperazine-1-yl) propoxy) isoxazole-5-yl) -3-methylbutanoyl) -4 -Hydroxy-N-((R) -2-hydroxy-1-(4- (4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (Example 493) and (2S, 4R) -1 -((R) -2- (3- (3- (4- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidin) -1-sulfonamide) benzoyl) ) -1H-pyrrolo [2,3-b] pyridine-5-yl) phenyl) piperazin-1-yl) propoxy) isoxazole-5-yl) -3-methylbutanoy
Lu) -4-Hydroxy-N-((R) -2-Hydroxy-1- (4- (4-Methylthiazole-5-yl) phenyl) ethyl) Pyrrolidine-2-carboxamide (Example 479). Step 1: Preparation of tert-butyl (R)-(1- (4-bromophenyl) -2-hydroxyethyl) carbamate.

Triethylamine (2.79 g, 27.56 mmol, 3.84 mL) in a solution of (1.74 g, 6.89 mmol, 1 eq, hydrochloride) in tetrahydrofuran (25 mL) of (2R) -2-amino-2- (4-bromophenyl) ethanol, 4 eq) and tert-butoxycarbonyl tert-butyl carbonate (1.80 g, 8.27 mmol, 1.90 mL, 1.2 eq) were added. The mixture was stirred at 30 ° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran. The residue was extracted with ethyl acetate (50 mLx2). The combined organic layers were washed with aqueous brine solution (40 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was pulverized with petroleum ether / ethyl acetate (22 mL, v: v = 10: 1). The compound tert-butyl N-[(1R) -1- (4-bromophenyl) -2-hydroxy-ethyl] carbamate (2 g, 6.33 mmol, 91% yield) was obtained as a white solid. 1H-NMR (400MHz, CDCl3) δ 7.51 --7.46 (m, 2H), 7.20 (d, J = 8.4 Hz, 2H), 5.27 (s, 1H), 4.73 (s, 1H), 3.92 --3.75 (m, 2H), 2.12 (s, 1H), 1.51 --1.32 (m, 9H).
Step 2: Preparation of tert-butyl (R)-(2-hydroxy-1-(4- (4-methylthiazole-5-yl) phenyl) ethyl) carbamate.

tert-butyl N-[(1R) -1- (4-bromophenyl) -2-hydroxy-ethyl] carbamate (2.0 g, 6.33 mmol, 1 equivalent), 4-methylthiazole (1.25 g, 12.65 mmol,) 1.15 mL, 2 eq), potassium acetate (1.24 g, 12.65 mmol, 2 eq) and palladium acetate (142 mg, 0.63 mmol, 0.1 eq) dimethylacetamide (40 mL) degassed, 3 times with nitrogen Purged. The mixture was then stirred at 100 ° C. for 12 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to remove dimethylacetamide. The residue was extracted with ethyl acetate (40 mLx2) and washed with saturated brine (40 mLx2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 5/1 to 1/2). The compound tert-butyl N-[(1R) -2-hydroxy-1- [4- (4- (4- (4-)
Methylthiazole-5-yl) phenyl] ethyl] carbamate (1.45 g, 3.98 mmol, 63% yield, 91% purity) was obtained as a yellow oil. LC / MS (ESI) m / z: 335.1 [M + 1] ⁺ .
Step 3: Preparation of (R) -2-amino-2-(4- (4-methylthiazole-5-yl) phenyl) ethane-1-ol.

tert-butyl N-[(1R) -2-hydroxy-1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] carbamate (1.45 g, 3.98 mmol, 1 eq) dichloromethane (5 mL) ), Hydrochloric acid (4M dichloromethane solution, 18 mL, 18.33 eq) was added. The mixture was stirred at 20 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. The crude product was pulverized with ethyl acetate (10 mL) at 15 ° C. for 10 minutes. Compound (2R) -2-amino-2- [4- (4-methylthiazole-5-yl) phenyl] ethanol (1.08 g, 3.99 mmol, yield 100%, hydrochloride) was obtained as a yellow solid. .. LC / MS (ESI) m / z: 235.0 [M + 1] ⁺ .
Step 4: tert-butyl (2S, 4R) -4-hydroxy-2-(((R) -2-hydroxy-1-(4- (4-methylthiazole-5-yl) phenyl) ethyl) carbamoyl) pyrrolidine Preparation of -1-carboxylate.

(2R) -2-amino-2- [4- (4-methylthiazole-5-yl) phenyl] ethanol (1.08 g, 3.99 mmol, 1 eq, hydrochloride) and (2S, 4R) -1-tert- Hydroxybenzotriazole (647 mg, 4.79 mmol, 1.2 eq), N in a solution of N, N-dimethylformamide (15 mL) of butoxycarbonyl-4-hydroxy-pyrrolidin-2-carboxylic acid (922 mg, 3.99 mmol, 1 eq). , N-diisopropylethylamine (1.55 g, 11.97 mmol, 2 mL, 3 eq), and 1- (3-dimethylaminopropyl) -3-
Ethylcarbodiimide hydrochloride (1.15 g, 5.98 mmol, 1.5 eq) was added. The mixture was stirred at 30 ° C. for 12 hours. The reaction mixture was extracted with dichloromethane (30 mLx3) and washed with saturated brine (25 mLx3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol = 50/1 to 20: 1). The compound tert-butyl (2S, 4R) -4-hydroxy-2-[[(1R) -2-hydroxy-1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine- 1-Carboxylate (1.67 g, 2.90 mmol, 72% yield, 77% purity) was obtained as a yellow solid. LC / MS (ESI) m / z: 448.1 [M + 1] ⁺ .
Step 5: Preparation of (2S, 4R) -4-hydroxy-N-((R) -2-hydroxy-1-(4- (4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide ..

tert-butyl (2S, 4R) -4-hydroxy-2-[[(1R) -2-hydroxy-1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1- Hydrochloric acid / dioxane (4M, 20 mL) was added to a solution of carboxylate (1.67 g, 2.90 mmol, 1 equivalent) in dichloromethane (8 mL). The mixture was stirred at 15 ° C. for 2 hours. The reaction mixture was concentrated under vacuum. Residue, half-reverse phase HPLC
Purified by. Compound (2S, 4R) -4-hydroxy-N-[(1R) -2-hydroxy-1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (930 mg,) 2.42 mmol
, Yield 83%, Hydrochloride) was obtained as a white solid. LC / MS (ESI) m / z: 348.0 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 9.84 (s, 1H), 9.17 (s, 1H), 9.00 (s, 1H), 8.61 (s, 1H), 7.51 --7.35 (m, 4H), 4.96 --4.88 (m, 1H), 4.48 --4.37 (m, 3H), 3.69 --3.55 (m, 2H), 3.29 (d, J = 6.4) Hz, 1H), 3.09 (s, 1H), 2.46 (s, 3H), 2.41 (dd, J = 7.6, 13.1 Hz, 1H), 1.89 --1.74 (m, 1H).
Step 6: Preparation of methyl 2- (3- (3,3-dimethoxypropoxy) isoxazole-5-yl) -3-methylbutanoate.

Potassium carbonate (2.08) in a solution of N, N-dimethylformamide (40 mL) of methyl 2- (3-hydroxyisoxazole-5-yl) -3-methyl-butaneate (2 g, 10.04 mmol, 1 eq). g, 15.06 mmol, 1.5 eq) and 3-bromo-1,1-dimethoxy-propane (2.02 g, 11.04 mmol, 1.5 mL, 1.1 eq) were added. The mixture was stirred at 70 ° C. for 12 hours. The reaction mixture was extracted with ethyl acetate (50 mLx3). The combined organic layers were washed with brine (40 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 50/1 to 20: 1). The compound methyl 2- [3- (3,3-dimethoxypropoxy) isoxazole-5-yl] -3-methyl-butanoate (1.97 g, 6.54 mmol, 65% yield) was obtained as a colorless oil. LC / MS (ESI) m / z: 324.1 [M + 23] +; 1H-NMR (400MHz, DMSO-d6) δ 6.19 (s, 1H), 4.53 (t, J = 5.6 Hz, 1H), 4.17 ( t, J = 6.4 Hz, 2H), 3.76 --3.61 (m, 4H), 3.24 (s, 6H), 2.34 --2.22 (m, 1H), 1.99 (q, J = 6.4 Hz, 2H), 0.93 (d) , J = 6.8 Hz, 3H), 0.85 (d, J = 6.7 Hz, 3H).
Step 7: Preparation of methyl 3-methyl-2- (3- (3-oxopropoxy) isoxazole-5-yl) butaneate.

Sulfuric acid (100 mL) in a mixture of methyl 2- [3- (3,3-dimethoxypropoxy) isoxazole-5-yl] -3-methyl-butanoate (1.97 g, 6.54 mmol, 1 eq) in tetrahydrofuran (100 mL). 1 M, 100 mL, 15.30 eq) was added at a time at 20 ° C. The mixture was stirred at 70 ° C. for 0.5 hours. The reaction mixture was basicized to pH 7-8 with saturated sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (50 mLx3). The combined organic layers were washed with brine (30 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The compound methyl 3-methyl-2- [3- (3-oxopropoxy) isoxazole-5-yl] butanoate (1.47 g, 5.76 mmol, 88% yield) was obtained as a colorless oil, which was further added. It was used directly in the next step without purification.

Step 8: Methyl 2-(3-(3-(4-(3-(2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl))- Preparation of 1H-pyrrolidine [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) propoxy) isoxazole-5-yl) -3-methylbutanoate.

(3R) -N- [2,4-difluoro-3- [5- (4-piperazine-1-ylphenyl) -1H-pyrrolo [2,3-b] pyridin-3-carbonyl] phenyl] -3- Sodium acetate (547 mg, 6.67 mmol, 2 eq) was added to a mixture of fluoro-pyrridine-1-sulfonamide (1.45 g, 2.33 mmol, 0.7 eq, hydrochloride) in methanol (8 mL) at a time at 15 ° C. .. The mixture is stirred at 15 ° C. for 15 minutes, then methyl 3-methyl-2- [3- (3-oxopropoxy) isoxazole-5-yl] butanoate (852 mg, 3.34 mmol).
, 1 Eq) of a solution of dichloromethane (5 mL) was added. Stir the mixture at 15 ° C for an additional 15 minutes.
Acetic acid (0.5 mL) was added to adjust the pH to 4-5. Sodium cyanoborohydride (419 mg, 6.67 mmol, 2 eq) was then added and stirred at 15 ° C. for 11.5 hours. The reaction mixture was extracted with dichloromethane (40 mLx2). The combined organic layers were washed with brine (25 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by half-reverse phase HPLC. Compound Methyl 2- [3- [3- [4- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1-yl] sulfonylamino] benzoyl]- 1H-pyrrolidine [2,3-b] pyridin-5-yl] phenyl] piperazine-1-yl] propoxy] isoxazole-5-yl] -3-methyl-butanoate (0.7g, 0.84 mmol, yield 25) %, Purity 99%) was obtained as a yellow solid. LC / MS (ESI) m / z: 824.3
[M + 1] ⁺ .
Step 9: 2- (3- (3- (4- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H) -Preparation of pyrrolidine [2,3-b] pyridine-5-yl) phenyl) piperazine-1-yl) propoxy) isoxazole-5-yl) -3-methylbutanoic acid.

Methyl 2- [3- [3- [4- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1-yl]]
Sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridine-5-yl] phenyl] piperazin-1-yl] propoxy] isoxazole-5-yl] -3-methyl-butanoate (320 mg, 0.40) Lithium hydrate (28 mg, 1.17 mmol, 3 eq) was added to a solution of mmol (1 eq) in tetrahydrofuran (1 mL), water (0.5 mL) and methanol (2 mL). The mixture was stirred at 40 ° C. for 2 hours. The reaction mixture was acidified to pH 5-6 with hydrochloric acid (2M). The reaction mixture was then concentrated under vacuum. The residue was purified by half-reverse phase HPLC. Compound 2- [3- [3- [4- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1-yl] sulfonylamino] benzoyl] -1H -Pyrrolidine [2,3-b] Pyridine-5-yl] Phenyl] Piperazine-1-yl] Propoxy] Isoxazole-5-yl] -3-Methyl-butanoic acid (195 mg, 0.23 mmol, yield 60%, purity) 97%) was obtained as a yellow solid. LC / MS (ESI) m / z: 810.4 [M + 1] ⁺ .
Step 10: (2S, 4R) -1-((S) -2- (3- (3- (4- (4- (3- (2,6-difluoro-3- (((R) -3-) -3-) Fluoropyrrolidine) -1-sulfonamide) Benzoyl) -1H-pyrrolo [2,3-b] pyridine-5-yl) Phenyl) Piperazin-1-yl) Propoxy) Isoxazole-5-yl) -3-Methylbutanoyl ) -4-Hydroxy-N-((R) -2-hydroxy-1-(4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide, and (2S, 4R) -1 -((R) -2- (3- (3- (4- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidin) -1-sulfonamide) benzoyl) ) -1H-pyrrolo [2,3-b] pyridine-5-yl) phenyl) piperazin-1-yl) propoxy) isoxazole-5-yl) -3-methylbutanoyl) -4-hydroxy-N-(((() Preparation of R) -2-hydroxy-1-(4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide.

2- [3- [3- [4- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] Pyridine-5-yl] Phenyl] Piperazin-1-yl] Propoxy] Isoxazole-5-yl] -3-Methyl-butanoic acid (340 mg, 0.42 mmol, 1 eq), (2S, 4R) ) -4-Hydroxy-N-[(1R) -2-hydroxy-1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (161 mg, 0.42 mmol, 1.00 eq, 1.00 eq, Hydrochloride), hydroxybenzotriazole (68 mg, 0.50 mmol, 1.2 eq), N, N-diisopropylethylamine (109 mg, 0.84 mmol, 0.2 mL, 2 eq), and 1- (3-dimethylaminopropyl) -3-ethyl A mixture of N, N-dimethylformamide (2 mL) of carbodiimide hydrochloride (121 mg, 0.63 mmol, 1.5 eq) was stirred at 15 ° C. for 2 hours. The reaction mixture was extracted with dichloromethane (30 mLx3). The combined organic layers were washed with brine (20 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by half-reverse phase HPLC. Compound (2S, 4R) -1-[(2S) -2- [3- [3- [4- [4- [3- [2,6-difluoro-3- [[(3R) -3-fluoro Pyrrolidine-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridine-5-yl] phenyl] piperazine-1-yl] propoxy] isoxazole-5-yl] -3-methyl-butanoyl ] -4-Hydroxy-N-[(1R) -2-Hydroxy-1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] Pyrrolidine-2-carboxamide (44.9 mg, 0.04 mmol, yield) 10%, purity 95%) was obtained as a yellow solid. LC / MS (ESI) m / z: 570.3 [M / 2 + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 12.87 (s, 1H), 9.83 (s, 1H), 9.03 --8.94 (m) , 1H), 8.67 --8.61 (m, 1H), 8.53 (s, 1H), 8.29 (d, J = 8.0 Hz, 1H), 8.05 (s, 1H), 7.66 --7.54 (m, 3H), 7.50- 7.33 (m, 4H), 7.24 (t, J = 8.8 Hz, 1H), 7.09 --7.02 (m, 2H), 5.95 --5.72 (m, 1H), 5.41 --5.18 (m, 1H), 5.14 (d, J = 3.6 Hz, 1H), 5.10 ―― 4.91 (m, 1H), 4.89 ―― 4.80 (m, 1H), 4.61 ―― 4.43 (m, 1H), 4.34 ―― 4.19 (m, 1H), 3.92 ―― 3.77 (m, 1H) 2H), 3.71 --3.64 (m, 1H), 3.62 --3.49 (m, 4H), 3.47 (s, 3H), 3.31 --3.24 (m, 3H), 3.23 --3.15 (m, 4H), 2.56 --2.52 ( m, 2H), 2.47 --2.43 (m, 3H), 2.39 --2.26 (m, 3H), 2.13 --2.04 (m, 2H), 2.02- 1.88 (m, 1H), 1.86 --1.67 (m, 3H), 0.99 (d, J = 6.4 Hz, 2H), 0.91 (d, J = 6.8 Hz, 2H), 0.89 --0.77 (m, 2H). Compound (2S, 4R) -1-[(2R) -2- [3- [3- [4- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2 , 3-b] pyridine-5-yl] phenyl] piperazin-1-yl] propoxy] isoxazole-5-yl] -3-methyl-butanoyl] -4-hydroxy-N-[(1R) -2-hydroxy- Yellow 1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (97.1 mg, 0.09 mmol, yield 22%, purity 100%) Obtained as a color solid. LC / MS (ESI) m / z: 570.3 [M / 2 + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 12.91 (s, 1H), 9.86 (s, 1H), 9.04 --8.91 (m) , 1H), 8.65 (d, J = 2.4 Hz, 1H), 8.54 (s, 1H), 8.42 (d, J = 8.0 Hz, 1H), 8.07 (s, 1H), 7.66 --7.57 (m, 3H) , 7.48 --7.36 (m, 4H), 7.26 (t, J = 8.8 Hz, 1H), 7.15 --7.00 (m, 2H), 5.77 (s, 1H), 5.41 --5.19 (m, 1H), 5.13 (d) , J = 3.6 Hz, 1H), 4.84 (t, J = 5.6 Hz, 2H), 4.46 (t, J = 8.0 Hz, 1H), 4.34 --4.21 (m, 1H), 3.90 --3.80 (m, 2H) , 3.75 --3.52 (m, 4H), 3.48 (s, 2H), 3.43 --3.35 (m, 3H), 3.32 --3.25 (m, 3H), 3.24 --3.15 (m, 4H), 2.47 --2.42 (m, 4H), 2.40 --2.34 (m, 2H), 2.26 (d, J = 16.0 Hz, 2H), 2.14 --1.98 (m, 3H), 1.85 --1.73 (m, 3H), 1.00 --0.94 (m, 3H) , 0.93 --0.86 (m, 3H).
(2S, 4R) -1-((S) -2-(3-(3-(4-(4-(3-(2,6-difluoro-3-(((R) -3-fluoropyrrolidin)) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridine-5-yl) phenyl) piperazin-1-yl) azetidine-1-yl) isoxazole-5-yl) -3-methylbuta Noyl) -4-hydroxy-N-((R) -2-hydroxy-1-(4- (4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (Example 507), and ( 2S, 4R) -1-((R) -2-(3-(3-(4-(4-(3-(2,6-difluoro-3-(((R) -3-fluoropyrrolidin))- 1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridine-5-yl) phenyl) piperazin-1-yl) azetidine-1-yl) isoxazole-5-yl) -3-methylbutanoyl ) -4-Hydroxy-N-((R) -2-Hydroxy-1- (4- (4-Methylthiazo)
Il-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (eg 508) exemplary synthetic step 1: tert-butyl 3- (4- (4-bromophenyl) piperazine-1-yl) azetidine-1 -Preparation of carboxylate.

Methanol (130 mL) of 1- (4-bromophenyl) piperazine (8 g, 28.82 mmol, 1 eq, hydrochloride) and tert-butyl 3-oxoazetidine-1-carboxylate (5.92 g, 34.58 mmol, 1.2 eq) And 2-methylpyridine (6.17 g, 57.64 mmol, 2 eq) were added to the solution of acetic acid (13 mL). The mixture was stirred at 15 ° C. for 12 hours. The reaction mixture was extracted with dichloromethane (80 mLx3). The combined organic layers were washed with brine (50 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15/1 to 1/1). Compound tert-butyl 3- [4- (4- (4-)
Bromophenyl) Piperazine-1-yl] Azetidine-1-carboxylate (11.29 g, 26.49 mmol)
, Yield 91%, Purity 93%) was obtained as a white solid. LC / MS (ESI) m / z: 341.9 [M-56 + 1] ⁺ .
Step 2: Preparation of 1- (azetidine-3-yl) -4- (4-bromophenyl) piperazine.

tert-butyl 3- [4- (4-bromophenyl) piperazine-1-yl] azetidine-1-carboxylate
Trifluoroacetic acid (22 mL) was added to a solution of dichloromethane (100 mL) (11.29 g, 26.49 mmol, 1 eq). The mixture was stirred at 15 ° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The pH of the residue was adjusted to 8 using saturated aqueous sodium bicarbonate solution (100 mL). During this time, a white precipitate was formed. Precipitates were collected by filtration and concentration. The compound 1- (azetidine-3-yl) -4- (4-bromophenyl) piperazine (8.6 g, crude) was obtained as a white solid. LC / MS (ESI) m / z: 298.0 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 8.74 (s, 1H), 7.34 (d, J = 8.8 Hz, 2H), 6.91 ( d, J = 8.8 Hz, 2H), 4.04 --3.95 (m, 2H), 3.87 (dd, J = 6.4, 10.8 Hz, 2H), 3.31 --3.27 (m, 1H), 3.19 --3.10 (m, 4H) , 2.47 --2.42 (m, 4H).
Step 3: Preparation of methyl 2- (3- (3- (4- (4-bromophenyl) piperazine-1-yl) azetidine-1-yl) isoxazole-5-yl) -3-methylbutanoate.

N, N-diisopropylethylamine (6.54 g, 1 equivalent) in a solution of N-methylpyrrolidone (80 mL) of 1- (azetidine-3-yl) -4- (4-bromophenyl) piperazine (5 g, 16.88 mmol, 1 eq) 50.64 mmol
, 8.82 mL, 3 equivalents) and methyl 3-methyl-2- [3- (1,1,2,2,3,3,4,4,4-nonafluorobutylsulfonyloxy) isoxazole-5-yl] butane The acid salt (8.12 g, 16.88 mmol, 1 eq) was added. The mixture was stirred at 110 ° C. for 2 hours. The reaction mixture was extracted with ethyl acetate (40 mLx3). The combined organic layers were washed with brine (30 mLx3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC. The mixture was basified to pH 7-8 with saturated sodium bicarbonate. The mixture was then extracted with ethyl acetate (60 mLx2). The combined organic layers were washed with saturated aqueous brine solution (30 mLx2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound Methyl 2- [3- [3- [4- (4-Bromophenyl) Piperazine-1-yl] Azetidine-1-yl] Isoxazole-5-yl] -3-Methyl-butaneate (1.43 g, 2.78 mmol, yield 16%, purity 92%) was obtained as a yellow solid. The compound methyl 2- (3-hydroxyisoxazole-5-yl) -3-methyl-butanoate (2 g, 10.04 mmol, 59% yield) was obtained as a yellow oil. LC / MS (ESI) m / z: 478.9 [M + 1] ⁺ .
Step 4: Methyl 2-(3-(3-(4-(3-(2,6-difluoro-3-(((R) -3-fluoro-N-((2- (trimethylsilyl) ethoxy) ) Methyl) pyrrolidine) -1-sulfonamide) benzoyl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazin-1- Ill) Azetidine-1-yl) Isoxazole-5-yl) -3-Methylbutaneate preparation.

Methyl 2- [3- [3- [4- (4-bromophenyl) piperazin-1-yl] azetidine-1-yl] isoxazole-5-yl] -3-methyl-butanoate (1.43 g, 3.00 mmol) , 1 equivalent), (3R) -N- [2,4-difluoro-3- [5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1- (2-trimethylsilylethoxymethyl) pyrolo [2,3-b] pyridine-3-carbonyl] phenyl] -3-fluoro-N- (2-trimethylsilylethoxymethyl) pyrrolidine-1-sulfonamide (2.43g, 3.00 mmol, 1 equivalent), 4-ditert-butylphosphanyl-N, N-dimethyl-aniline; dichloropalladium (212 mg, 0.30 mmol, 0.1 equivalent), cesium fluoride (1.82 g, 11.98 mmol, 4 equivalents) dioxane (10 mL) The mixture of water and water (2 mL) was degassed and purged with nitrogen three times. The mixture was then stirred at 100 ° C. for 12 hours under a nitrogen atmosphere. The reaction mixture was extracted with ethyl acetate (40 mLx2). The combined organic layers were washed with brine (25 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10/1 to 1/1). Methyl 2- [3- [3- [4- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1-yl] sulfonyl- (2-trimethyl) of the compound Cyrilethoxymethyl) amino] benzoyl] -1- (2-trimethylsilylethoxymethyl) pyrrolidine [2,3-b] pyridin-5-yl] phenyl] piperazine-1-yl] azetidine-1-yl] isoxazole-5- Il] -3-methyl-butaneate (1.95 g, 1.78 mmol, 59% yield, 98% purity) was obtained as a yellow oil. LC / MS (ESI) m / z: 541.3 [M / 2 + 1] ⁺ .
Step 5: Methyl 2-(3-(3-(4-(3-(2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl))- Preparation of 1H-pyrrolidine [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) azetidine-1-yl) isoxazole-5-yl) -3-methylbutaneate.

Methyl 2- [3- [3- [4- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl- (2-trimethylsilylethoxymethyl ) Amino] Benzoyl] -1- (2-trimethylsilylethoxymethyl) pyrrolo [2,3-b] pyridine-5-yl] phenyl] Piperazin-1-yl] Azetidine-1-yl] Isoxazole-5-yl]- Trifluoroacetic acid (3.05 g, 26.74 mmol, 2 mL, 15 equivalents) was added to a solution of 1,2-dichloromethane (6 mL) of 3-methyl-butaneate (1.95 g, 1.78 mmol, 1 equivalent). The mixture was stirred at 30 ° C. for 16 hours. The reaction mixture was concentrated under reduced pressure. Compound Methyl 2- [3- [3- [4- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1-yl] sulfonylamino] benzoyl]- 1H-pyrrolidine [2,3-b] pyridin-5-yl] phenyl] piperazine-1-yl] azetidine-1-yl] isoxazole-5-yl] -3-methyl-butaneate (1.67 g)
, Crude, trifluoroacetic acid) was obtained as a yellow oil, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 411.4 [M / 2 + 1] ⁺ .
Step 6: 2- (3-(3- (4- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H) -Pyrrolidine [2,3-b] Pyridine-5-yl) Phenyl) Piperazine-1-yl) Azetidine-1-yl) Isoxazole-5-yl) -3-Methylbutanoic acid.

Methyl 2- [3- [3- [4- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1-yl]]
Sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridine-5-yl] phenyl] piperazin-1-yl] azetidine-1-yl] isoxazole-5-yl] -3-methyl-butaneate Sodium hydroxide (285 mg, 7.15 mmol, 4 eq) was added to a solution of (1.67 g, 1.79 mmol, 1 eq, trifluoroacetate) in tetrahydrofuran (8 mL) and water (2 mL). The mixture was stirred at 40 ° C. for 2 hours. The reaction mixture was acidified to pH 5-6 with sulfuric acid (1M). The reaction mixture was then concentrated under vacuum. The residue was purified by half-reverse phase HPLC. Compound 2- [3- [3- [4- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1-yl] sulfonylamino] benzoyl] -1H -Pyrrolidine [2,3-b] Pyridine-5-yl] Phenyl] Piperazine-1-yl] Azetidine-1-yl] Isoxazole-5-yl] -3-Methyl-butanoic acid (520 mg, 0.64 mmol, yield 36%, purity 99%) was obtained as a yellow solid. LC / MS (ESI) m / z: 807.3 [M + 1] ⁺ .
Step 7: (2S, 4R) -1-(2-(3-(3-(4-(4-(4-(2-(2,6-difluoro-3-(((R) -3-fluoropyrrolidine)-)- 1-Sulfone amide) Benzoyl) -1H-Pyrrolidine [2,3-b] Pyridine-5-yl) Phenyl) Piperazin-1-yl) Azetidine-1-yl) Isoxazole-5-yl) -3-Methylbutanoyl ) -4-Hydroxy-N-((R) -2-hydroxy-1-(4- (4-methylthiazole-5-yl) phenyl) ethyl) Preparation of pyrrolidine-2-carboxamide.

2- [3- [3- [4- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridine-5-yl] phenyl] piperazin-1-yl] azetidine-1-yl] isoxazole-5-yl] -3-methyl-butanoic acid (170 mg, 0.21 mmol, 1 eq) and (2S, 4R) -4-hydroxy-N-[(1R) -2-hydroxy-1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (89 mg, 0.23 mmol) , 1.1 eq, hydrochloride) in a solution of N, N-dimethylformamide (1 mL), hydroxybenzotriazole (34 mg, 0.25 mmol, 1.2 eq), N, N-diisopropylethylamine (82 mg, 0.63 mmol, 0.1 mL, 3). Equivalent) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (61 mg, 0.32 mmol, 1.5 eq) were added. The mixture was stirred at 15 ° C. for 12 hours. The reaction mixture was extracted with dichloromethane (30 mLx2). The combined organic layers were washed with brine (20 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC. Compound (2S, 4R) -1-[(2R) -2- [3- [3- [4- [4- [3- [2,6-difluoro-3- [[(3R) -3-fluoro Pyrrolidine-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridine-5-yl] phenyl] piperazine-1-yl] azetidine-1-yl] isoxazole-5-yl] -3 -Methyl-butanoyl] -4-hydroxy-N-[(1R) -2-hydroxy-1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (160 mg, 0.14 mmol) , Yield 65%, Purity 97%) was obtained as a yellow solid. LC / MS (ESI) m / z: 568.9 [M / 2 + 1] ⁺ .
Step 8: (2S, 4R) -1-((S) -2- (3- (3- (4- (4- (3- (2,6-difluoro-3- (((R) -3-) -3-) Fluoropyrrolidine) -1-sulfonamide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperazine-1-yl) Azetidine-1-yl) Isoxazole-5-yl) -3 -Methylbutanoyl) -4-
Hydroxy-N-((R) -2-Hydroxy-1- (4- (4-Methylthiazole-5-yl) Phenyl) Ethyl)
Pyrrolidine-2-carboxamide, and (2S, 4R) -1-((R) -2- (3- (3- (4- (4- (3- (2,6-difluoro-3- (((R) ) -3-Fluoropyrrolidine) -1-sulfonamide) Benzoyl) -1H-pyrrolo [2,3-b] pyridine-5-yl) Phenyl) Piperazin-1-yl) Azetidine-1-yl) Isoxazole-5- Il) -3-methylbutanoyl) -4-hydroxy-N-((R) -2-hydroxy-1-(4- (4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide Preparation.

(2S, 4R) -1-[(2R) -2- [3- [3- [4- [4- [3- [2,6-Difluoro-3- [[(3R) -3-fluoropyrrolidine- 1-Il] Sulfonylamino] Benzoyl] -1H-Pyrrolidine [2,3-b] Pyridine-5-Il] Phenyl]
Piperazine-1-yl] Azetidine-1-yl] Isoxazole-5-yl] -3-Methyl-butanoyl] -4-hydroxy-N-[(1R) -2-hydroxy-1- [4- (4-methyl) Thiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (160 mg, 0.15 mmol, 1 equivalent) was separated by SFC. Fractions were concentrated under vacuum and the residue was purified by preparative HPLC. Compound (2S, 4R) -1-[(2S) -2- [3- [3- [4- [4- [3- [2,6-difluoro-3- [[(3R) -3-fluoro Pyrrolidine-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridine-5-yl] phenyl] piperazine-1-yl] azetidine-1-yl] isoxazole-5-yl] -3 -Methyl-butanoyl] -4-hydroxy-N-[(1R) -2-hydroxy-1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (38 mg, 0.03 mmol) , Yield 43%, Purity 98%) was obtained as a yellow solid. LC / MS (ESI) m / z: 568.8 [M / 2 + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 12.73 (s, 1H), 8.99 (s, 1H), 8.88 (d, J) = 8.4 Hz, 1H), 8.63 (d, J = 2.0 Hz, 1H), 8.49 (s, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.96 (s, 1H), 7.60 (d, J) = 8.4 Hz, 2H), 7.56 --7.46 (m, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.38 --7.33 (m, 1H), 7.07 (d, J = 8.8 Hz, 2H), 6.96 (s, 1H), 5.96 ―― 5.88 (m, 1H), 5.36 ―― 5.16 (m, 1H), 5.14 (d, J = 3.6 Hz, 1H), 5.08 ―― 4.91 (m, 1H), 4.89 ―― 4.79 (m) , 1H), 4.65 --4.44 (m, 1H), 4.34 --4.19 (m, 1H), 4.03 --3.97 (m, 2H), 3.81 --3.64 (m, 4H), 3.58 (dd, J = 6.0, 12.0 Hz) , 4H), 3.30 --3.04 (m, 3H), 2.47 (d, J = 2.4 Hz, 9H), 2.31 --2.22 (m, 1H), 2.11 (s, 1H), 2.09 --2.00 (m, 2H), 2.00 --1.89 (m, 2H), 1.88 --1.80 (m, 1H), 1.06 --0.79 (m, 6H), 0.76 (d, J = 6.8 Hz, 1H). Compound (2S, 4R) -1- [ (2R) -2- [3- [3- [4- [4- [4- [3- [2,6-difluoro-3- [[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl]] -1H-pyrrolo [2,3-b] pyridine-5-yl] phenyl] piperazin-1-yl] azetidine-1-yl] isoxazole-5-yl] -3-methyl-butanoyl] -4-hydroxy-N -[(1R) -2-Hydroxy-1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (61.1 mg, 0.05 mmol, yield 71%, purity 98%) The yellow Obtained as a solid. LC / MS (ESI) m / z: 568.7 [M / 2 + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 12.88 (s, 1H), 8.98 (s, 1H), 8.93 --8.68 (m) , 1H), 8.65 (d, J = 2.0 Hz, 1H), 8.52 (s, 1H), 8.38 (d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 7.69 --7.55 (m, 3H) , 7.50 --7.34 (m, 4H), 7.17 (t, J = 8.8 Hz, 1H), 7.09 (d, J = 8.8 Hz, 2H), 5.94 --5.82 (m, 1H), 5.41 --5.18 (m, 1H) ), 5.13 (d, J = 3.6 Hz, 1H), 5.03 --4.73 (m, 2H), 4.43 (t, J = 8.0 Hz, 1H), 4.29 (s, 1H), 3.97 (br t, J = 6.8) Hz, 2H), 3.83 --3.37 (m, 4H), 3.67 --3.54 (m, 4H), 3.29 --3.20 (m, 6H), 3.17 (d, J = 5.2 Hz, 1H), 2.57 --2.52 (m, 4H) 3H), 2.46 (s, 4H), 2.28 --2.17 (m, 1H), 2.11 (s, 1H), 2.09 --1.91 (m, 3H), 1.87 --1.76 (m, 1H), 1.04 --0.74 (m, 6H).
Exemplary Synthesis of 3- (1-oxo-5- (Piperazine-1-yl) Isoindoline-2-yl) Piperidine-2,6-dione (Intermediate X) Step 1: Methyl 2-bromo-4-fluoro Preparation of benzoate.

Sulfur dichloride (108.64 g, 913.21 mmol, 2 eq) was added to a solution of 2-bromo-4-fluoro-benzoic acid (100 g, 456.60 mmol, 1 eq) in methanol (800 mL) at 0 ° C. The mixture was stirred at 80 ° C. for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with 500 mL of water and extracted with ethyl acetate (200 mLx2). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (200 mL), then washed with saturated brine (200 mLx2), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and methyl 2-. Bromo-4-fluoro-benzoate (102 g, 437.70 mmol, 95% yield) was obtained as a brown oil.

Step 2: Preparation of tert-butyl 4- (3-bromo-4- (methoxycarbonyl) phenyl) piperazine-1-carboxylate.

Tert-Butyl piperazine-1-carboxylate (111.82 g, 502.07 mmol, 1.3 eq) in a solution of dimethylsulfoxide (500 mL) of methyl 2-bromo-4-fluoro-benzoate (90 g, 386.21 mmol, 1 eq). , Hydrochloride) and N, N-diisopropylethylamine (199.66 g, 1.54 mol, 269 mL, 4 eq). The mixture was heated to 130 ° C. and stirred at 130 ° C. for 36 hours. The mixture was poured into 1.0 L of water and extracted with ethyl acetate (500 mL x 2). The combined organic layers were washed with water (1000 mL), 0.5 M hydrochloric acid (500 mL), saturated brine (500 mL), then dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was pulverized with (petroleum ether: ethyl acetate = 5: 1, 300 mL), the solid was filtered and dried under vacuum. tert-butyl 4- (3-bromo-4-)
Methoxycarbonyl-phenyl) piperazine-1-carboxylate (93 g, 232.92 mmol, 60% yield) was obtained as an off-white solid. LC / MS (ESI) m / z: 422.1 [M + 23] +; 1H-NMR (400MHz, DMSO-d6) δ 7.73 (d, J = 8.8 Hz, 1H), 7.18 (d, J = 2.4 Hz, 1H), 6.98 (dd, J = 8.8, 2.4 Hz, 1H), 3.77 (s, 3H), 3.45-3.42 (m, 4H), 3.34-3.31 (m, 4H), 1.42 (s, 9H).
Step 3: Preparation of 2-bromo-4- (4- (tert-butoxycarbonyl) piperazine-1-yl) benzoic acid.

tert-Butyl 4- (3-bromo-4-methoxycarbonyl-phenyl) piperazine-1-carboxylate
Sodium hydroxide (27.65 g, 691.25 mmol, 3 eq) was added to a mixed solution of (92 g, 230.42 mmol, 1 eq) in tetrahydrofuran (400 mL), water (200 mL) and methanol (200 mL). The mixture was stirred at 60 ° C. for 2 hours. The mixture was poured into 1.0 L of water, the pH was adjusted to 5.0 with 11.8 M hydrochloric acid and then extracted with ethyl acetate (800 mLx2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. 2-Bromo-4- (4-tert-butoxycarbonylpiperazine-1-yl) benzoic acid (85 g, 220.63 mmol, 95% yield) was obtained as an off-white solid. LC / MS (ESI) m / z: 406.9 [M + 23] +; 1H-NMR (400MHz, DMSO-d6) δ 7.75 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 2.0 Hz, 1H), 6.96 (dd, J = 8.8, 2.0 Hz, 1H),
3.44 --3.42 (m, 4H), 3.34 --3.31 (m, 4H), 1.42 (s, 9H).
Step 4: Preparation of 4- (4- (tert-butoxycarbonyl) piperazine-1-yl) -2-formylbenzoic acid.

Methyllithium (1.6 M, 88 mL, 1.0 eq) in a solution of 2-bromo-4- (4-tert-butoxycarbonylpiperazine-1-yl) benzoic acid (54 g, 140.17 mmol, 1 eq) in tetrahydrofuran (600 mL). Was added at -70 ° C. The mixture was stirred for 30 minutes at -70 ° C and n-butyllithium (2.5 M, 67 mL, 1.2 eq) was added at -70 ° C. The mixture was stirred for 30 minutes at -70 ° C., then dimethylformamide (30.74 g, 420.50 mmol, 32 mL, 3 eq) was added. The resulting mixture was stirred for an additional hour at -70 to -50 ° C. The mixture was poured into 1.0 L of water, the pH was adjusted to 5.0 with 2.0 M hydrochloric acid and then extracted with ethyl acetate (800 mLx3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was pulverized with petroleum ether: ethyl acetate (V / V = 1: 3, 500 mL). 4- (4-tert-Butoxycarbonylpiperazine-1-yl) -2-formyl-benzoic acid (36 g, 107.67 mmol, 77% yield) was obtained as a brown solid. LC / MS (ESI) m / z: 357.1 [M + 23] +; 1H-NMR (400MHz, DMSO-d6) δ 7.98 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.12 (dd, J = 8.4, 2.0 Hz, 1H), 6.48 (d, J = 6.4 Hz, 1H), 3.60 --3.39 (m, 8H), 1.43 (s, 9H).
Step 5: Preparation of 4- (4- (tert-butoxycarbonyl) piperazine-1-yl) -2-(((2,6-dioxopiperidine-3-yl) amino) methyl) benzoic acid.

A solution of 3-aminopiperidine-2,6-dione (11.81 g, 71.78 mmol, 1.2 eq, hydrochloride) and sodium acetate (9.81 g, 119.63 mmol, 2 eq) in methanol (250 mL) for 0.5 hours at 15 ° C. Then 4- (4-tert-butoxycarbonylpiperazin-1-yl) -2-formyl-benzoic acid (20 g, 59.81 mmol, 1 eq) was added. The mixture was stirred at 15 ° C. for an additional 30 minutes and sodium cyanoborohydride (7.52 g, 119.63 mmol, 2 eq) was added. Add the resulting mixture for another 2 hours, 15
Stir at ° C. The mixture was poured into 800 mL of water, the pH was adjusted to 5.0 with 2.0 M hydrochloric acid and then extracted with ethyl acetate (400 mLx3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Residue petroleum ether: ethyl acetate (V / V = 3: 1, 200 mL)
). 4- (4-tert-Butoxycarbonylpiperazine-1-yl) -2-[[(2,6-dioxo-3-piperidyl) amino] methyl] Benzoic acid (26 g, 49.38 mmol, yield 82%, purity 84) %) Was obtained as a gray solid. LC / MS (ESI) m / z: 447.1 [M + 1] ⁺ .
Step 6: Preparation of tert-butyl 4- (2- (2,6-dioxopiperidine-3-yl) -1-oxoisoindoline-5-yl) piperazine-1-carboxylate.

4- (4-tert-Butoxycarbonylpiperazin-1-yl) -2-[[(2,6-dioxo-3-piperidyl) amino] methyl] benzoic acid (27 g, 51.10 mmol, 1 eq) and O-benzo Diisopropylethylamine (19.81 g, 153.29 mmol, 3 eq) was added to a solution of dimethylformamide (250 mL) of triazole-1-yl-tetramethyluronium hexafluorophosphate (23.31 g, 61.32 mmol, 1.2 eq). .. The mixture was stirred at 15 ° C. for 1 hour. The mixture was poured into 800 mL of water and the mixture was stirred at 15 ° C. for 30 minutes. The solids formed were filtered, washed with 100 mL of ethyl acetate and then dried in vacuo. tert-butyl 4- [2- (2,6-dioxo-3-piperidyl) -1-oxo-isoindoline-5-yl] piperazine-1-carboxylate (14.5 g, 33.84 mmol, 66% yield) Was obtained as a yellow solid. LC / MS (ESI) m / z: 429.2 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 10.97 (s, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.08- 7.06 (m, 2H), 5.03 (dd, J = 13.2, 5.2 Hz, 1H), 4.36 --4.19 (m, 2H), 3.48-3.45 (m, 4H), 3.27 --3.26 (m, 4H), 2.89- 2.87 (m, 1H), 2.60 --2.56 (m, 1H), 2.38 --2.34 (m, 1H), 1.98 --1.96 (m, 1H), 1.43 (s, 9H).
Step 7: 3- (1-oxo-5- (piperazine-1-yl) isoindoline-2-yl) piperidine-2,6-
Preparation of Zeon.

Hydrochloride of tert-butyl 4- [2- (2,6-dioxo-3-piperidyl) -1-oxo-isoindoline-5-yl] piperazine-1-carboxylate (14.5 g, 33.84 mmol, 1 eq) The salt / dioxane (4.0 M, 250 mL) suspension was stirred at 15 ° C. for 3 hours. The solvent was concentrated under vacuum. The residue was pulverized with ethyl acetate (50 mL). 3- (1-oxo-5-piperazine-1-yl-isoindoline-2-yl) piperidine-2,6-dione (12 g, 32.89 mmol, 97% yield, hydrochloride) was obtained as a white solid. .. LC / MS
(ESI) m / z: 329.1 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 10.98 (s, 1H), 9.43 (s, 2H), 7.58 (d, J = 8.8 Hz, 1H ), 7.16 --7.11 (m, 2H), 5.07 (dd, J = 13.2, 5.2 Hz, 1H), 4.38 --4.21 (m, 2H), 3.55 --3.53 (m, 4H), 3.20 --3.19 (m, 4H) ), 2.90 --2.86 (m, 1H), 2.60 --2.56 (m, 1H), 2.38 --2.34 (m, 1H), 1.98 --1.96 (m, 1H).
(3R) -N- (3- (5- (4- (4-((1- (2- (2,6-dioxopiperidine-3-yl) -1-oxoisoindoline-5-yl) piperidine) piperidine -4-yl) Methyl) piperazine-1-yl) phenyl) -1H-pyrrolo [2,3-b]
Illustrative Synthesis of Pyridine-3-carbonyl) -2,4-difluorophenyl) -3-fluoropyrrolidine-1-sulfonamide (exemplary compound 522) Step 1: 5- (4- (dimethoxymethyl) piperidine-1-) Il) Isobenzofuran-1 (3H) -on preparation.

To a solution of 5-fluoro-3H-isobenzofuran-1-one (1.6 g, 10.52 mmol, 1 eq) in dimethyl sulfoxide (20 mL), 4- (dimethoxymethyl) piperidine (1.67 g, 10.52 mmol, 1 eq) and Add N, N-diisopropylethylamine (2.72 g, 21.04 mmol, 2 eq) and add 120 reaction solutions.
The mixture was stirred at ° C for 2 hours. The residue was washed with water (30 mL) and extracted with ethyl acetate (30 mLx3). The combined organic layers were washed with brine (30x3 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 20: 1 to pure ethyl acetate). The product 5- [4- (dimethoxymethyl) -1-piperidyl] -3H-isobenzofuran-1-one (1.9 g, 6.52 mmol, 62% yield) was obtained as a yellow solid. LC / MS (ESI) m / z: 292.2 [M + 1] +; 1H-NMR (400MHz, CDCl3) δ 7.70
--7.78 (m, 1H), 7.15 --6.91 (m, 2H), 5.23 (s, 2H), 4.06 (d, J = 6.8 Hz, 1H), 3.96
(d, J = 13.2 Hz, 2H), 3.26 (s, 5H), 3.14 --3.13 (m, 1H), 3.11 --2.97 (m, 1H), 2.95 --2.76 (m, 2H), 2.00 --1.78 (m) , 1H), 1.70 (d, J = 12.8 Hz, 2H), 1.39 --1.16 (m, 2H).
Step 2: Preparation of 4- (4- (dimethoxymethyl) piperidine-1-yl) -2- (hydroxymethyl) benzoic acid.

Sodium hydroxide (1.30 g, 32.61) in a solution of 5- [4- (dimethoxymethyl) -1-piperidyl] -3H-isobenzofuran-1-one (1.9 g, 6.52 mmol, 1 eq) in methanol (10 mL). mmol, 5 eq)
, Water (10 mL) was added, and the mixture was stirred at 20 ° C. for 1 hour. The residue was washed with water (30 mL) and extracted with ethyl acetate (30 mLx3). The combined organic layers were washed with brine (30 mLx3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The organic layer is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to produce the product 4- [4- (dimethoxymethyl) -1-piperidyl] -2- (hydroxymethyl) benzoic acid (1.64 g). Was obtained as a colorless oil.

Step 3: Preparation of methyl 4- (4- (dimethoxymethyl) piperidine-1-yl) -2- (hydroxymethyl) benzoate.

4- [4- (Dimethoxymethyl) -1-piperidyl] -2- (hydroxymethyl) benzoic acid (1.64 g, 5.30 mmol, 1 eq) in a solution of methanol (10 mL) and ethyl acetate (10 mL) (diazomethyl) ) Trimethylsilane (2M, 7.95 mL, 3 eq) was added at -10 ° C. The reaction mixture was stirred at -10 ° C for 0.25 hours. The solution was quenched with water (20 mL) and extracted with ethyl acetate (30 mLx3). The organic layer was dried over sodium sulfate and filtered. The filtrate is concentrated to make the product methyl 4- [4- (dimethoxymethyl) -1-piperidyl] -2- (hydroxymethyl) benzoate (1.7 g, 5.26 mmol, 99% yield) colorless. Obtained as an oil.

Step 4: Preparation of methyl 2- (bromomethyl) -4- (4- (dimethoxymethyl) piperidine-1-yl) benzoate.

Perbromomethane (2.62 g) in a solution of methyl 4- [4- (dimethoxymethyl) -1-piperidyl] -2- (hydroxymethyl) benzoate (1.7 g, 5.26 mmol, 1 eq) in tetrahydrofuran (20 mL). , 7.89 mmol, 1.5 eq) and triphenylphosphine (2.07 g, 7.89 mmol, 1.5 eq) were added. The reaction mixture was stirred at 20 ° C. for 1 hour. The solution was quenched with water (20 mL) and extracted with ethyl acetate (30 mLx3). The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated to give a crude product. The residue was purified by column chromatography (silicon dioxide, petroleum ether: ethyl acetate = 40: 1 to 20: 1). The product, methyl 2- (bromomethyl) -4- [4- (dimethoxymethyl) -1-piperidyl] benzoate (1.2 g, 3.11 mmol, 59% yield) was obtained as a yellow solid. LC / MS (ESI) m / z: 388.1 [M + 1] +; 1H-NMR (400MHz, CDCl3) δ 7.96 --7.77 (m, 1H), 6.95 --6.74 (m, 2H), 4.97 (s, 2H) ), 4.07 (d, J = 6.8 Hz, 1H), 3.94 --3.83 (m, 5H), 3.38 (s, 6H), 2.84 (dt, J = 2.0, 12.8 Hz, 2H), 1.94 --1.76 (m, 3H), 1.61 --1.33 (m, 3H).
Step 5: 3- (5- (4- (dimethoxymethyl) piperidine-1-yl) -1-oxoisoindoline-2-
Il) Preparation of piperidine-2,6-dione.

Methyl 2- (bromomethyl) -4- [4- (dimethoxymethyl) -1-piperidyl] benzoate (300 mg)
, 0.78 mmol, 1 eq), and N, N-diisopropylethylamine (301 mg, 2.33 mmol) in a solution of acetonitrile (20 mL) of 3-aminopiperidine-2,6-dione (192 mg, 1.16 mmol, 1.5 eq, HCl). , 3 equivalents) was added. The reaction mixture was stirred at 100 ° C. for 15 hours. Water (20 ml) was added to the solution and extracted with dichloromethane (30 mL x 3). The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated to give a crude product. The crude product was pulverized with ethyl acetate (50 mL) at 25 ° C. for 10 minutes. The product 3- [5- [4- (dimethoxymethyl) -1-piperidyl] -1-oxo-
Isoindoline-2-yl] piperidine-2,6-dione (200 mg, 0.50 mmol, 64% yield) was obtained as a gray solid. LC / MS (ESI) m / z: 402.1 [M + 1] ⁺ .
Step 6: Preparation of 1- (2- (2,6-dioxopiperidine-3-yl) -1-oxoisoindoline-5-yl) piperidine-4-carbaldehyde.

3- [5- [4- (dimethoxymethyl) -1-piperidyl] -1-oxo-isoindoline-2-yl] piperidine -2,6-dione (50 mg, 0.13 mmol, 1 eq) in tetrahydrofuran (1 mL) Pyridinium p-toluenesulfonate (63 mg, 0.25 umol, 2 eq) was added to a solution of water (0.2 mL) and the mixture was stirred at 70 ° C. for 8 hours. The mixture is concentrated in vacuo to produce the product 1- [2- (2,6-dioxo-3-piperidyl) -1-oxo-isoindolin -5-yl] piperidine-4-carbaldehyde (40 mg). Was obtained as a colorless oil. LC / MS (ESI) m / z: 356.2 [M + 1] ⁺ .
Step 7: (3R) -N- (3-(5-(4-(4-((1- (2- (2,6-dioxopiperidine-3-yl) -1-oxoisoindoline-5-) Ill) piperidine-4-yl) methyl) piperazine-1-yl) phenyl) -1H-pyrrolo [2,3-b] pyridin-3-carbonyl) -2,4-difluorophenyl) -3-fluoropyrrolidine-1 -Preparation of sulfonamide.

1- [2- (2,6-dioxo-3-piperidyl) -1-oxo-isoindoline-5-yl] piperidine-4-
Carvaldehide (50 mg, 0.14 mmol, 1 eq) and (3R) -N- [2,4-difluoro-3- [5- (4-piperazin-1-ylphenyl) -1H-pyrrolo [2,3-b ] Pylin-3-carbonyl] phenyl] -3-fluoro-pyrrolidin-1-sulfonamide (83 mg, 0.14 mmol, 1 eq) in a solution of N, N-dimethylformamide (2 mL) with acetic acid (0.85 mg, 0.02 mmol). , 0.1 eq), adjust pH at 25 ° C to 5, stir for 20 minutes, then add sodium cyanoborohydride (18 mg, 0.28 mmol, 2 eq) to the mixture and add the mixture to 25 ° C. Stirred for 1 hour. The residue was filtered to give a crude product. The residue was purified by preparative HPLC. The product is ((3R) -N- [3- [5- [4- [4- [[1- [2- (2,6-dioxo-3-piperidyl) -1-oxo-isoindrin-5). -Il] -4-piperidyl] methyl] piperazine-1-yl] phenyl] -1H-pyrrolo [2,3-b] pyridin-3-carbonyl] -2,4-difluoro-phenyl] -3-fluoro-pyrrolidin -1-sulfonamide (37.7 mg, 0.04 mmol, yield 28%, purity 98%) was obtained as a green solid. LC / MS (ESI) m / z: 924.5 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 10.93 (s, 1H), 8.65 (d, J = 2.0 Hz, 1H), 8.53 (s, 1H), 8.20 (s, 1H), 8.05 (s, 1H), 7.67- 7.55 (m, 3H), 7.50 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.3 Hz, 1H), 7.13 --6.99 (m, 4H), 5.43 --5.19 (m, 1H), 5.03 (dd, J = 5.2, 13.2 Hz, 1H), 4.37 --4.12 (m, 1H), 4.16 --4.12 (m, 1H), 3.88 (d, J = 12.4 Hz, 2H), 3.35 --3.29 (m, 15H) ), 3.00 --2.72 (m, 3H), 2.22 (d, J = 6.4 Hz, 2H), 2.10 --1.95 (m, 1H), 1.96 (dd, J = 4.9, 10.0 Hz, 2H), 1.87 --1.72 ( m, 3H), 1.26 --1.11 (m, 2H).
(3-(5-(4-((4- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H- Pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperazine-1-yl) Methyl) Piperidine-1-yl) -1-oxoisoindrin-2-yl) -2,6-dioxopiperidine- 1-Il) Methyl (2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65- Illustrative Synthesis of Docosaoxaheptahexacontan-67-yl) Carbonate (Exemplary Compound 862) Step 1: Chloromethyl (2,5,8,11,14,17,20,23,26,29,32, 35,38,41,44,47,50,53,56,59,62,65-docosaoxaheptahexacontan-67-yl) Preparation of carbonate.

2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2-] [2- [2- [2- [2- (2-Methoxyethoxy) ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] Ethoxy]
Chloromethyl in a mixture of ethoxy] ethoxy] ethoxy] ethanol (20 g, 19.98 mmol, 1 eq) and pyridine (6.32 g, 79.90 mmol, 6.5 mL, 4 eq) in tetrahydrofuran (200 mL).
Carbonochloride salt (5.15 g, 39.95 mmol, 3.5 mL, 2 eq) was added dropwise at 0 ° C. under a nitrogen atmosphere. The mixture was stirred at 30 ° C. for 12 hours. Water (300 mL) was poured into the mixture and stirred for 1 minute. The aqueous layer was extracted with dichloromethane (200 mLx3). The combined organic layers were washed with brine (200 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (1000 mesh silica gel, dichloromethane: methanol = 100/1, 20/1). The product chloromethyl 2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2-] [2- [2- [2- [2- [2- [2- (2-Methoxyethoxy) ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] Ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethyl carbonate (18 g, 16.46 mmol, 82% yield) was obtained as a bright yellow solid. 1H-NMR (400MHz, CDCl3) δ 5.73 (s, 2H), 4.43 --4.99 (m, 2H), 3.85 --3.44 (m, 86H), 3.38 (s, 3H).
Step 2: (3- (5- (4- (dimethoxymethyl) piperidine-1-yl) -1-oxoisoindoline-2-yl) -2,6-dioxopiperidine-1-yl) methyl (2, 5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65-docosaoxaheptahexacontan-67- Il) Preparation of carbonate.

3- [5- [4- (dimethoxymethyl) -1-piperidyl] -1-oxo-isoindolin-2-yl] piperidin-2,6-dione (1 g, 2.49 mmol, 1 equivalent) and chloromethyl 2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2] -[2- [2- [2- (2-Methylethoxy) ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] Cesium carbonate powder (1.62 g, 4.98 mmol, 2 eq) at a time at 15 ° C in a mixture of anhydrous dimethylformamide (10 mL) of ethoxy] ethoxy] ethoxy] ethyl carbonate (3.23 g, 2.95 mmol, 1.19 eq). added. The mixture was stirred at 15 ° C. for 12 hours. The mixture was filtered. The filtrate was purified by preparative reverse phase HPLC. The product [3- [5- [4- (dimethoxymethyl) -1-piperidyl] -1-oxo-isoindoline-2-yl] -2,6-dioxo-1-piperidyl] methyl 2- [2 -[2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [ 2- [2- [2- (2-Methoxyethoxy) ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] Ethoxy] ethoxy] ethyl carbonate (1.4 g, 0.96 mmol, yield 38%, purity 100%) was obtained by freeze-drying as an off-white oil. 1H-NMR (400MHz, CDCl3) δ 9.72 (s, 1H), 7.80 --7.66 (m, 1H), 7.06 --6.95 (m, 1H), 6.93 --6.82 (m, 1H), 5.98 --5.76 (m, 2H) ), 5.31 (s, 2H), 5.22 (dd, J = 5.2, 13.6 Hz, 1H), 4.49 --4.40 (m, 4H), 4.08 (d, J = 6.8 Hz, 1H), 3.95 --3.44 (m, 87H), 3.38 (s, 8H), 3.11 --2.76 (m, 4H), 2.33 (dq, J = 4.4, 13.2 Hz, 1H), 2.24 --2.12 (m, 1H), 1.93 --1.83 (m, 2H) , 1.54 --1.34 (m, 2H).
Step 3: (3- (5- (4-formylpiperidine-1-yl) -1-oxoisoindoline-2-yl) -2,6-dioxopiperidine-1-yl) methyl (2,5,8) , 11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65-docosaoxaheptahexacontan-67-yl) Carbonate Preparation of salt.

[3- [5- [4- (Dimethoxymethyl) -1-piperidyl] -1-oxo-isoindoline-2-yl] -2,6-dioxo-1-piperidyl] methyl 2- [2- [2-] [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2] -[2- (2-Methoxyethoxy) ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] Trifluoroacetic acid (5.47 g, 47.99 mmol, 3.5) in a mixture of dichloromethane (20 mL) of ethyl carbonate (1.4 g, 0.96 mmol, 1 eq).
mL, 50 eq) were added at one time at 15 ° C. The mixture was stirred at 15 ° C. for 12 hours. The mixture was concentrated in vacuo. The product [3- [5- (4-formyl-1-piperidyl) -1-oxo-isoindoline-2-yl] -2,6-dioxo-1-piperidyl] methyl 2- [2- [2 -[2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [ 2- [2- (2-Methoxyethoxy) ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy ] Ethyl carbonate (1.4 g, crude) was obtained as a brown oil. LC / MS (ESI) m / z: 707.3 [M / 2 + 1] ⁺ .
Step 4: (3-(5-(4-((4- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl))) -1H-Pyrrolidine [2,3-b] Pyridine-5-yl) Phenyl) Piperazine-1-yl) Methyl) Piperidine-1-yl) -1-oxoisoindrin-2-yl) -2,6-di Oxopiperidin-1-yl) Methyl (2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62 , 65-docosaoxaheptahexacontan-67-yl) Preparation of carbonate.

[3- [5- (4-formyl-1-piperidyl) -1-oxo-isoindoline-2-yl] -2,6-dioxo-1-piperidyl] Methyl 2- [2- [2- [2-] [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2] -(2-Methoxyethoxy) ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethyl carbonate (200 mg, 0.14 mmol, 1 equivalent)
, And (3R) -N- [2,4-difluoro-3- [5- (4-piperazine-1-ylphenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] phenyl]- Add sodium acetate (12 mg, 0.14 mmol, 1 eq) to a mixture of dimethylformamide (2 mL) of 3-fluoro-pyrrazine-1-sulfonamide (83 mg, 0.14 mmol, 1 eq) to adjust the pH to 8. did. Acetic acid (42 mg, 0.71 mmol, 5 eq) was then added at once. The mixture was stirred at 30 ° C. for 10 minutes. Sodium cyanoborohydride (18 mg, 0.28 mmol, 2 eq) was then added at one time. The mixture was stirred at 30 ° C. for 1 hour. The mixture was filtered to obtain a filtrate. The yellow filtrate was purified by half-taken reverse phase HPLC. The product [3- [5- [4- [[4- [4- [3- [2,6-difluoro-3- [[(3R) -3-fluoropyrrolidine-1-yl] sulfonylamino]] Benzoyl] -1H-pyrrolidine [2,3-b] pyridin-5-yl] phenyl] piperazine-1-yl] methyl] -1-piperidyl] -1-oxo-isoindrin-2-yl] -2,6 -Dioxo-1-piperidyl] Methyl 2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [ 2- [2- [2- [2- [2- [2- [2- (2-Methoxyethoxy) ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] Ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethyl carbonate (203.4 mg, 0.10 mmol, yield 46%, purity 99%, formate) was obtained as a yellow resin. LC / MS (ESI) m / z: 991.7 [M / 2 + 1] +; 1H-NMR (400MHz, CDCl3) δ 8.87 (s, 1H), 8.62 (d, J = 2.0 Hz, 1H), 8.26 ( s, 1H), 7.80 --7.76 (m, 3H), 7.60 (d, J = 8.8 Hz, 2H), 7.09 --6.96 (m, 4H), 6.89 (s, 1H), 5.97 --5.75 (m, 2H) , 5.31 (s, 1H), 5.30 --5.13 (m, 2H), 4.49 --4.17 (m, 4H), 3.86 (d, J = 12.4 Hz, 2H), 3.74 --3.53 (m, 90H), 3.38 (s) , 3H), 3.31 (s, 4H), 3.07 --3.00 (m, 1H), 2.93 --2.84 (m, 3H), 2.69 --2.62 (m, 4H), 2.38 --1.84 (m, 10H), 1.42 --1.32 (m, 2H).
(3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -5- (4- (4-((1- (2- (2,,)) 6-dioxopiperidine-3-yl) -1-oxoisoindrin-5-yl) piperidin-4-yl) methyl) piperidine-1-yl) phenyl) -1H-pyrrolo [2,3-b] pyridine- 1-Il) Methyl 69-Methyl-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62 , 65,68-Exemplary Synthesis of TricosaoxaHeptane-70-Aide (Exemplary Compound 866) Step 1: Chloromethyl 69-Methyl-2,5,8,11,14,17,20,23, Preparation of 26,29,32,35,38,41,44,47,50,53,56,59,62,65,68-tricosaoxaheptacontane-70-acid salt.

2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2-] [2- [2- [2- [2- [2- [2- (2-Methoxyethoxy) ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy]
Ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] propanoic acid (0.90 g, 0.84 mmol, 1 equivalent), hydrogen sulfate; tetrabutylammonium (28 mg, 28 mg,) 0.08 mmol (0.1 eq) and potassium carbonate (579 mg, 4.19 mmol, 5 eq) were added to a mixture of dichloromethane (10 mL) and water (10 mL). Then, a mixed solution of dichloromethane (5 mL) of chloro (chlorosulfonyloxy) methane (415 mg, 2.52 mmol, 3 equivalents) was added dropwise to the mixed solution. The mixture was stirred under nitrogen at 20 ° C. for 10 hours. The mixture was diluted with dichloromethane (20 mL) and water (10 mL) to separate the layers. The aqueous layer was extracted with dichloromethane (50 mLx3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue is purified by silica gel column chromatography (dichloromethane: methanol = 1: 0 to 15: 1) and chloromethyl 2- [2- [2- [2- [2- [2- [2- [2- [2-] [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- (2-Methoxyethoxy) ethoxy]] Ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] propanoate (0.50 g, 0.45 mmol, (Yield 53%) was obtained as a yellow solid. 1H-NMR (400MHz, CDCl3) δ 5.82 --5.72 (m, 2H), 4.15 (q, J = 6.8 Hz, 1H), 3.71 --3.63 (m, 114H), 3.58 --3.54 (m, 2H), 3.39 ( s, 3H), 1.45 (d, J = 6.8 Hz, 3H).
Step 2: (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -5- (4- (4-((1- (2-) 2- (2,6-dioxopiperidine-3-yl) -1-oxoisoindrin-5-yl) piperidin-4-yl) methyl) piperazine-1-yl) phenyl) -1H-pyrrolo [2,3-b ] Pyridine-1-yl) Methyl 69-Methyl-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56, Preparation of 59,62,65,68-tricosaoxaheptacontane-70-acid salt.

(3R) -N- [3- [5- [4- [4- [[1- [2- (2,6-dioxo-3-piperidyl) -1-oxo-isoindrin-5-yl] -4 -Piperidil] Methyl] Piperazine-1-yl] Phenyl] -1H-Pyrrolidine [2,3-b] Pyridine-3-carbonyl] -2,4-Difluoro-phenyl] -3-Fluoro-pyrrolidin-1-sulfonamide (0.23 g, 0.25 mmol, 1 equivalent), and chloromethyl 2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [ 2-
[2- [2- [2- [2- [2- [2- [2- [2- [2- (2-Methoxyethoxy) ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy ] Ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] propanoate (418 mg, 0.37 mmol, 1.5 eq) in a mixture of N, N-dimethylformamide (3 mL) To which potassium carbonate (103 mg, 0.75 mmol, 3 eq) was added. The mixture was stirred at 40 ° C. for 5 hours. The mixture was filtered to give a residue. The residue was purified by half-prepared reverse phase HPLC and then further purified by preparative thin layer chromatography (dimethane: methanol = 15: 1) to [3- [2,6-difluoro-3-[[]. (3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -5- [4- [4- [[1- [2- (2,6-dioxo-3-piperidyl) -1-oxo- Isoindrin-5-yl] -4-piperidyl] methyl] piperazine-1-yl] phenyl] pyrolo [2,3-b] pyridin-1-yl] methyl 2- [2- [2- [2- [2] -[2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [ 2- (2-Methylethoxy) ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] Propanate (36.3 mg, 0.02 mmol, yield 6%, purity 95%, formic acid) was obtained as a yellow resin. 1H-NMR (400MHz, CDCl3) δ 8.84 (d, J = 2.0 Hz, 1H), 8.68 (d, J = 2.0 Hz, 1H), 8.11 (s, 1H), 7.86 (s, 1H), 7.80 --7.70 (m, 2H), 7.60 (d, J = 8.8 Hz, 2H), 7.08 --6.97 (m, 4H), 6.89 (s, 1H), 6.38 --6.26 (m, 2H), 5.36 --5.16 (m, 2H) ), 4.46 --4.36 (m, 1H), 4.29 --4.23 (m, 1H), 4.07 (q, J = 6.8 Hz, 1H), 3.90 --3.78 (m, 4H), 3.73 --3.44 (m, 112H), 3.38 (s, 3H), 3.36 --3.22 (m, 2H), 2.98 --2.50 (m, 7H), 2.44 --2.14 (m, 6H), 2.09 --1.91 (m, 6H), 1.38 --1.32 (m, 5H) ).
(3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -5- (4- (4-((1- (2- (2,,)) 6-dioxopiperidine-3-yl) -1-oxoisoindrin-5-yl) piperidine-4-yl) methyl) piperazine-1-yl) phenyl) -1H-pyrrolo [2,3-b] pyridine- 1-Il) Methyl 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68 -Exemplary synthesis of tricosaoxaheptacontane-70-acid acid (exemplary compound 860) Step 1: tert-butyl 2,5,8,11,14,17,20,23,26,29,32,35 , 38,41,44,47,50,53,56,59,62,65,68-Preparation of tricosaoxaheptacontane-70-acid salt.

2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2-] [2- [2- [2- [2- (2- (2-Methoxyethoxy) ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] Ethoxy]
Ethoxy] ethoxy] ethoxy] ethanol (50.00 g, 49.94 mmol, 1 eq) and sodium; 2-methylpropane-2-olate (24.00 g, 249.70 mmol, 5.0 eq) in toluene (500 mL) at 125 ° C. After stirring for 2 hours, the reaction mixture was cooled to 80 ° C. and tert-butyl 2-bromoacetate (97.41 g, 499.40 mmol, 73.80 mL, 10.0 eq) was added to the mixture. Mix liquid at 125 ° C 28
Stir for hours. The mixture was filtered through a Celite bed. The pad was rinsed with high temperature toluene (about 70 ° C., 100 mL × 3), and the combined filtrate was concentrated under vacuum. The resulting oil was taken up in ethyl acetate (100 mL) and added to petroleum ether (600 mL) with good stirring. After allowing to stand for 15 minutes, the precipitate is collected, washed with abundant petroleum ether, dried under vacuum and tert-butyl 2- [2- [2- [2- [2- [2-] [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- (2) -Methoxyethoxy) ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] acetate (40.00) g, 35.86 mmol, 71% yield) was obtained as a yellow solid. The product is purified by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane: methanol = 5: 1: 0: 0 to 0: 0: 20: 1) and tert-butyl 2- [2- [2- [2-]. [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2] -[2- [2- (2-Methoxyethoxy) ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy ] Ethoxy] ethoxy] acetate (92% yield)
Got 1H-NMR (400MHz, CDCl3) δ 4.02 (s, 2H), 3.67 --3.62 (m, 90H), 3.57 --3.52 (m, 2H), 3.38 (s, 3H), 1.47 (s, 9H).
Process 2: 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68-Toriko Preparation of saoxaheptacontan-70-oic acid.

tert-butyl 2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2-] 2-] [2- [2- [2- [2- [2- [2- (2-Methoxyethoxy) ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] Trifluoroacetic acid (405.18 mmol, 30 mL, 37.66 eq) in a mixture of dichloromethane (100 mL) of ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] acetate (12.00 g, 10.76 mmol, 1 eq). Was added. The mixture was stirred at 20 ° C. for 6 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was filled with methyl tert-butyl ether (100 mL) and stirred at 20 ° C. for 2 hours. The mixture is filtered and the cake is washed with methyl tert-butyl ether (50 mLx3) and then concentrated under reduced pressure to 2- [2- [2- [2- [2- [2- [2- [2-] 2-]. [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- (2-Methoxyethoxy) ethoxy]] Ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] acetic acid (11.00 g, 10.38 mmol, yield 96%) was obtained as a yellow rubbery substance. 1H-NMR (400MHz, CDCl3) δ 4.19 (s, 2H), 3.81 --3.75 (m, 2H), 3.67 (s, 100H), 3.61 --3.57 (m, 2H), 3.41 (s, 3H).
Step 3: Chloromethyl 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68 -Preparation of tricosaoxaheptacontane-70-acid salt.

2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2-] [2- [2- [2- [2- [2- [2- (2-Methoxyethoxy) ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy]
Ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] acetic acid (5.00 g, 4.72 mmol, 1 equivalent), hydrogen sulfate; tetrabutylammonium (160 mg, 0.47) Millim (0.1 eq) and potassium carbonate (2.61 g, 18.88 mmol, 4 eq) were added to a mixture of dichloromethane (20 mL) and water (20 mL). A solution of chloro (chlorosulfonyloxy) methane (1.17 g, 7.08 mmol, 1.5 eq) in dichloromethane (5 mL) was then added dropwise to the mixture. The mixture was stirred under nitrogen at 20 ° C. for 10 hours. The mixture was then diluted with water (20 mL) and dichloromethane (30 mL) to separate the layers. The aqueous layer was extracted with dichloromethane (50 mLx3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue is purified by silica gel column chromatography (dichloromethane: methanol = 1: 0 to 10: 1) to purify chloromethyl 2- [2- [2- [2- [2- [2- [2- [2-] 2-]. [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- (2-Methoxyethoxy) ethoxy]]
Ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] acetate (3.00 g, 2.71 mmol, yield A rate of 57%) was obtained as a yellow rubbery substance. 1H-NMR (400MHz, CDCl3) δ 5.72 ―― 5.68 (m, 2H), 4.26 ―― 4.15 (m, 2H), 3.72 ―― 3.67 (m, 2H), 3.58 (d, J = 4.6 Hz, 86H), 3.51 ―― 3.45 (m, 2H), 3.34 --- 3.29 (m, 3H).
Step 4: (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -5- (4- (4-((1- (2-) 2- (2,6-dioxopiperidine-3-yl) -1-oxoisoindrin-5-yl) piperidin-4-yl) methyl) piperazine-1-yl) phenyl) -1H-pyrrolo [2,3-b ] Pyridine-1-yl) Methyl 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62, Preparation of 65,68-tricosaoxaheptacontane-70-acid salt.

(3R) -N- [3- [5- [4- [4- [[1- [2- (2,6-dioxo-3-piperidyl) -1-oxo-isoindrin-5-yl] -4] -Piperidyl] Methyl] Piperazin-1-yl] Phenyl] -1H-Pyrrolo [2,3-b] Pyridine-3-carbonyl] -2,4-Difluoro-phenyl] -3-Fluoro-pyrrolidin-1-sulfonamide (120 mg, 0.13 mmol, 1 equivalent) and chloromethyl 2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2-] 2-] [2- [2- [2- [2- [2- [2- [2- [2- [2- (2-Methoxyethoxy) ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy ] Ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] acetate (172 mg, 0.16 mmol, 1.2 equivalents) in a mixture of DMF (1 mL) with potassium carbonate (54 mg) , 0.39 mmol, 3 equivalents). The mixture was stirred at 40 ° C. for 5 hours. The mixture was filtered to give a residue. The residue was purified by half-reverse phase HPLC. The compound was further purified by preparative TLC (dichloromethane: methanol = 15: 1). The compound was further purified by half-taken reverse phase HPLC and [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -5- [ 4- [4- [[1- [2- (2,6-dioxo-3-piperidyl) -1-oxo-isoindolin-5-yl] -4-piperidyl] methyl] piperazine-1-yl] phenyl] Pyrrolidine [2,3-b] Pyridine-1-yl] Methyl 2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2-] [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- (2-methoxyethoxy) ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] Ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] acetate (36.53 mg, 0.02 mmol, yield 13%, purity 96%, piperidine) yellow Obtained as a resin. LC / MS (ESI) m / z: 1020.2 [M / 2 + 1] +; 1H-NMR (400MHz, CDCl3) δ 8.84 (d, J = 2.0 Hz, 1H), 8.69 (d, J = 2.0 Hz, 1H), 8.50 --8.16 (m, 1H), 7.86 (s, 1H), 7.80 --7.68 (m, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.10 --6.97 (m, 4H), 6.90 (s, 1H), 6.37 --6.29 (m, 2H), 5.37 --5.13 (m, 2H), 4.46 --4.35 (m, 1H), 4.31 --4.16 (m, 3H), 3.91 --3.79 (m, 2H) , 3.73 --3.54 (m, 100H), 3.52 --3.43 (m, 2H), 3.39 (s, 3H), 3.34 --3.24 (m, 4H), 2.95 --2.81 (m, 4H), 2.67 --2.59 (m, 4H), 2.36 --1.76 (m, 10H), 1.42 --1.29 (m, 2H).
(3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -5- (4- (4-((1- (2- (2,,)) 6-dioxopiperidine-3-yl) -1-oxoisoindrin-5-yl) piperidine-4-yl) methyl) piperazine-1-yl) phenyl) -1H-pyrrolo [2,3-b] pyridine- 1-Il) Methyl (2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65- Illustrative Synthesis of DocosaoxaHeptahexacontane-67-yl) Carbonate (Exemplary Compound 857) Step 1: (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidin) -1) -Sulphonamide) Benzoyl) -5-(4-(((1- (2- (2,6-dioxopiperidine-3-yl) -1-oxoisoindrin-5-yl) piperidine-4-yl) Il) Methyl) Piperazine-1-yl) Phenyl) -1H-pyrrolo [2,3-b] Pyridine-1-yl) Methyl (2,5,8,11,14,17,20,23,26,29 , 32,35,38,41,44,47,50,53,56,59,62,65-docosaoxaheptahexacontan-67-yl) Preparation of carbonate.

Chloromethyl 2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [ 2- [2- [2- [2- [2- (2-Methoxyethoxy) ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] Ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethyl carbonate (189 mg, 0.17 mmol, 1.00 equivalent), (3R) -N- [3- [5- [4- [4- [[1- [2- (2) , 6-dioxo3-piperidyl) -1-oxo-isoindrin-5-yl] -4-piperidyl] methyl] piperazin-1-yl] phenyl] -1H-pyrrolo [2,3-b] pyridine-3- N, N-dimethyl of carbonyl] -2,4-difluoro-phenyl] -3-fluoro-pyrrolidin-1-sulfonamide (160 mg, 0.17 mmol, 1.00 equivalent) and potassium carbonate (71 mg, 0.52 mmol, 3.00 equivalent) The mixture of formamide (3 mL) was stirred at 40 ° C. for 5 hours. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was first purified by half-prepared reverse phase HPLC and then by preparative TLC (dimethane: methanol = 15: 1, Rf = 0.2) to [3- [2,6-difluoro-3-]. [[(3R) -3-fluoropyrrolidine-1-yl] sulfonylamino] benzoyl] -5- [4- [4- [[1- [2- (2,6-dioxo-3-piperidyl) -1-] Oxo-isoindolin-5-yl] -4-piperidyl] methyl] piperazine-1-yl] phenyl] pyrrolidine [2,3-b] pyridin-1-yl] methyl-2- [2- [2- [2] -[2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [ 2- (2-Methoxyethoxy) ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethyl carbonate A salt (49.4 mg, 0.02 mmol, yield 14%, purity 95%) was obtained as a yellow solid. LC / MS (ESI) m / z: 881.0 [M / 2 + 1] +; 1H-NMR (400MHz, CDCl3) δ 8.82 (d, J = 2.0 Hz, 1H), 8.68 (d, J = 2.0 Hz, 1H), 8.21 (br s, 1H), 7.86 (s, 1H), 7.78 --7.69 (m, 2H), 7.59 (d, J = 8.8 Hz, 2H), 7.09 --6.97 (m, 5H), 6.89 ( s, 1H), 6.28 (s, 2H), 5.33 --5.16 (m, 2H), 4.44 --4.36 (m, 1H), 4.31 --4.22 (m, 3H), 3.86 (d, J = 12.8 Hz, 3H) , 3.73 --3.42 (m, 76H), 3.38 (s, 3H), 3.32 --3.25 (m, 4H), 2.95 --2.59 (m, 9H), 2.40 --1.73 (m, 15H), 1.42 --1.23 (m, 3H).
(3R) -N- (3- (5- (4- (6-((1- (2- (2,6-dioxopiperidine-3-yl) -1-oxoisoindrin-5-yl) piperidine) -4-yl) Methyl) -2,6-diazaspiro [3.3] heptane-2-yl) phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl) -2,4-difluorophenyl)- Exemplary Synthesis of 3-Fluoropyridine-1-sulfonamide (Exemplary Compound 536) Step 1: Of tert-butyl 6- (4-bromophenyl) -2,6-diazaspiro [3.3] heptane-2-carboxylate. Preparation.

In a 250 mL three-necked round-bottomed flask, oxalic acid; tert-butyl 2,6-diazaspiro [3.3] heptane-2-carboxylate (1.45 g, 5.029 mmol, 1 eq), (4-bromophenyl) boronic acid (1.20 g, 5.975 mmol, 1.19 eq), TEA (2.53 g, 25.002 mmol, 4.97 eq), Cu (OAc) ₂ (1.36 g, 7.488 mmol, 1.49 eq), DCM (150 mL), 4A MS (5 g) I put it in. Purge the mixture with air and at room temperature 12
Stir for hours. The solids were filtered off. The filtrate was washed with water (100 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. Residue, ethyl acetate / petroleum ether (1/5
) And the silica gel column was filled. This gave 1.02 g (57%) of tert-butyl 6- (4-bromophenyl) -2,6-diazaspiro [3.3] heptane-2-carboxylate as a bright yellow solid. LC / MS (ESI) m / z: 352.90 / 354.90 [M + 1] ⁺ .
Step 2: tert-Butyl 6- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) -2,6-diazaspiro [3.3] heptane-2- Preparation of carboxylate.

In a 30 mL closed tube purged and maintained in an inert nitrogen atmosphere, tert-butyl 6- (4-bromophenyl) -2,6-diazaspiro [3.3] heptane-2-carboxylate (706.40 mg, 2.000 mmol). , 1.00 equivalent), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolan (761.70mg, 3.000mmol, 1.50 eq), KOAc (588.00mg, 5.991mmol, 3.00 _{eq), Pd (dppf) Cl 2} . CH 2 Cl 2 (163.30mg, 0.200mmol, 0.10 eq), DMSO (12.00mL) I put in. The obtained mixed solution was stirred in an oil tank at 90 ° C. for 5 hours. The reaction mixture was cooled to room temperature and diluted with water (100 mL). The obtained mixed solution was extracted with ethyl acetate (100 mLx2), and the organic layers were combined into one. The organic layer was washed with brine (100 mLx2), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1/5). This resulted in 743 mg (93%) of tert-butyl 6- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -2,6-diazaspiro [3.3]. ] Heptane-2-
Carboxylate was obtained as a yellow solid. LC / MS (ESI) m / z: 401.05 [M + 1] ⁺ .
Step 3: tert-butyl (R) -6- (4- (3- (2,6-difluoro-3-((3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3] -b] Preparation of pyridine-5-yl) phenyl) -2,6-diazaspiro [3.3] heptane-2-carboxylate.

In a 30 mL closed tube purged and maintained in an inert nitrogen atmosphere, tert-butyl 6- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl ] -2,6-Diazaspiro [3.3] heptane-2-carboxylate (288.20 mg, 0.720 mmol, 1.20 equivalents), (3R) -N- (3- [5-bromo-1H-pyrrolo [2,3-] b] pyridine-3-carbonyl] -2,4-difluorophenyl) -3-fluoropyrrolidin-1-
Sulfonamide (302.00 mg, 0.600 mmol, 1.00 eq), K ₂ CO ₃ (248.80 mg, 1.800 mmol, 3.00)
_{Eq), Pd (dppf) Cl 2} . CH 2 Cl 2 (49.00mg, 0.060mmol, 0.10 eq), dioxane (12.00ML), was placed in H2 O (2.00 mL). The obtained mixed solution was stirred in an oil tank at 95 ° C. for 2 hours. The reaction mixture was cooled to room temperature and diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (80 mLx2), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography (CH ₂ Cl ₂ / MeOH 30: 1) followed by preparative TLC (CH ₂ Cl ₂ / MeOH 10: 1). This resulted in 203 mg (49%) of tert-butyl 6- (4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) benzoyl). ] -1H-Pyrrolidine [2,3-b] Pyridine-5-yl] Phenyl) -2,6-Diazaspiro [3.3] Heptane-2-carboxylate was obtained as a yellow solid. LC / MS (ESI) m / z: 697.10 [M + 1] ⁺ .
Step 4: (R) -N- (3- (5- (4- (2,6-diazaspiro [3.3] heptane-2-yl) phenyl) -1H-pyrrolo [2,3-b] pyridine-3- Carbonyl) -2,4-difluorophenyl) -3-fluoropyrrolidine-1-
Preparation of sulfonamides.

In a 100 mL round bottom flask, tert-butyl 6-(4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) benzoyl]- 1H-pyrrolidine [2,3-b] pyridin-5-yl] phenyl) -2,6-diazaspiro [3.3] heptane-2-carboxylate (203.00 mg, 0.291 mmol, 1.00 equivalent), DCM (6.00 mL) , TFA (1.50 mL) was added. The resulting solution was stirred at room temperature for 1 hour. The acid was neutralized using DIEA. This resulted in 173.8 mg (99.98%) of (3R) -N- [3- [5- (4- [2,6-diazaspiro [3.3] heptane-2-yl] phenyl) -1H-pyrrolo [2,3]. A DCM solution of -b] pyridine-3-carbonyl] -2,4-difluorophenyl] -3-fluoropyrrolidine-1-sulfonamide was obtained as a light brown solution. LC / MS (ESI) m / z: 597.10 [M + 1] ⁺ .
Step 5: Preparation of methyl 2-cyano-4-(4- (hydroxymethyl) piperidine-1-yl) benzoate.

Methyl 2-cyano-4-fluorobenzoate (3.58 g, 19.983 mmol) in a 100 mL round bottom flask
, 1 eq), (piperidine-4-yl) methanol (3.45 g, 29.954 mmol, 1.50 eq), DIEA (9.9 mL, 56.837 mmol, 2.84 eq), DMSO (40 mL). The obtained mixed solution was stirred in an oil tank at 110 ° C. for 2 hours. The reaction mixture was cooled to room temperature and diluted with water (200 mL). The obtained mixed solution was extracted with ethyl acetate (200 mLx2), and the organic layers were combined into one. The combined organic layers were washed with brine (200 mLx2), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1/1). This gave 5.21 g (95%) of methyl 2-cyano-4- [4- (hydroxymethyl) piperidine-1-yl] benzoate as a yellow-green semi-solid. LC / MS (ESI) m / z: 274.95 [M + 1] ⁺ .
Step 6: Preparation of methyl 2-formyl-4- (4- (hydroxymethyl) piperidine-1-yl) benzoate.

_{H 2} O (10 mL), AcOH (10 mL), pyridine (20 mL), methyl 2-cyano-4- [4- (hydroxymethyl) piperidin) in a 100 mL round bottom flask purged and maintained in an inert nitrogen atmosphere. -1-yl] benzoate (2.3 g, 8.384 mmol, 1 eq), sodium diphosphate monohydrate (8.89 g, 83.873 mmol, 10.00 eq), Rainey-Ni (1 g, 11.672 mmol, 1.39 eq) ) Was put in. The obtained mixed solution was stirred in an oil tank at 70 ° C. for 16 hours. The reaction mixture was cooled to room temperature and the solids were filtered. The filtrate was diluted with water (100 mL) and extracted with ethyl acetate (100 mLx2). The organic layers were combined and washed with brine (100 mLx2). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1/1). This gave 553 mg (24%) of methyl 2-formyl-4- [4- (hydroxymethyl) piperidine-1-yl] benzoate as a yellow-green oil. LC / MS (ESI) m / z: 277.95 [M + 1] ⁺ .
Step 7: 3- (5- (4- (Hydroxymethyl) piperidine-1-yl) -1-oxoisoindoline-2-
Il) Preparation of piperidine-2,6-dione.

In a 100 mL round bottom flask, methyl 2-formyl-4- [4- (hydroxymethyl) piperidine-1-
Il] Benzoate (500 mg, 1.803 mmol, 1 eq), 3-aminopiperidin-2,6-dione hydrochloride (356.1 mg, 2.164 mmol, 1.20 eq), DIEA (0.6 mL), DCM (30 mL), AcOH (1 mL) was added. The obtained mixed solution was stirred in an oil tank at 35 ° C. for 4 hours. Then NaBH (OAc) ₃ (1.15 g, 5.426 mmol, 3.01 eq) was added and the resulting mixture was reacted for another 16 hours at room temperature with stirring. The reaction was then quenched by the addition of water (50 mL) and the pH was adjusted to 8 using _{saturated NaHCO 3.}
The resulting mixture was extracted with DCM / MeOH (10/1, 100 mLx6) and the organic layers were combined into one. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded into a silica gel column with dichloromethane / methanol (20/1). This resulted in 504 mg (78%) of 3- [5- [4- (hydroxymethyl) piperidine-1-yl] -1-oxo-2,3-dihydro-1H-isoindole-2-yl] piperidine-2. , 6-Zeon was obtained as a light green solid. LC / MS (ESI) m / z: 358.00 [M + 1] ⁺ .
Step 8: Preparation of 1- (2- (2,6-dioxopiperidine-3-yl) -1-oxoisoindoline-5-yl) piperidine-4-carbaldehyde.

In a 250 mL round bottom flask, 3- [5- [4- (hydroxymethyl) piperidine-1-yl] -1-oxo-2,3-dihydro-1H-isoindole-2-yl] piperidine-2,6 -Dione (150.00 mg, 0.420 mmol, 1.00 eq), DCM (40.00 mL), DMP (356.00 mg, 0.839 mmol, 2.00 eq) were added. The obtained mixed solution was stirred for 1 hour in an oil tank at 35 ° C. The solids were filtered and the filtrate was concentrated under vacuum <. The residue was purified by preparative TLC (CH ₂ Cl ₂ : MeOH = 8: 1). This resulted in 115 mg (77%) of 1- [2- (2,6-dioxopiperidine-3-yl) -1-oxo-2,3-dihydro-1H-isoindole-5-yl] piperidine-4. -Calvaldehyde was obtained as a yellow solid. LC / MS (ESI) m / z: 355.95 [M + 1] ⁺ .
Step 9: (3R) -N- (3- (5- (4- (6-((1- (2- (2,6-dioxopiperidine-3-yl) -1-oxoisoindoline-5- Ill) piperidine-4-yl) methyl) -2,6-diazaspiro [3.3] heptane-2-yl) phenyl) -1H-pyrrolidine [2,3-b] pyridin-3-carbonyl) -2,4-difluoro Preparation of phenyl) -3-fluoropyrrolidine-1-sulfonamide.

In a 100 mL round-bottom flask, (3R) -N- [3- [5- (4- [2,6-Diazaspiro [3.3] heptane-2-yl]]
Phenyl) -1H-pyrrolo [2,3-b] pyridin-3-carbonyl] -2,4-difluorophenyl] -3-fluoropyrrolidin-1-sulfonamide (173.80 mg, 0.291 mmol, 1.00 equivalent), 1- [2- (2,6-dioxopiperidin-3-yl) -1-oxo-2,3-dihydro-1H-isoindole-5-yl] Piperidine-4-carbaldehyde (113.90 mg, 0.320 mmol, 1.10) Equivalent amount), DCM (40.00 mL) was added. The resulting solution was stirred for 2 hours in an oil bath at 35 ° C. Then NaBH ₃ CN (54.80 mg, 0.872 mmol, 2.99 eq) was added and the resulting mixture was further reacted for 0.5 hours at room temperature with stirring. The reaction was then stopped by the addition of water (50 mL) and extracted with DCM / MeOH (10/1, 60 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by preparative TLC (CH ₂ Cl ₂ : MeOH = 8: 1). This resulted in 69.0 mg (25%) of (3R) -N- [3- (5- [4- [6- ([1- [2- (2,6-dioxopiperidine-3-yl) -1). -Oxo-2,3-dihydro-1H-isoindole-5-yl] piperidine-4-yl] methyl) -2,6-diazaspiro [3.3] heptane-2-yl] phenyl] -1H-pyrrolo [2, 3-b] Pyridine-3-carbonyl) -2,4-difluorophenyl] -3-fluoropyrrolidine-1-sulfonamide was obtained as a yellowish green solid. LC / MS (ESI) m / z: 936.25 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 12.90 (s, 1H), 10.96 (s, 1H), 8.62 (s, 1H), 8.50 (s, 1H), 8.07 (s, 1H), 7.66-7.49 (m, 4H), 7.29-7.23 (m, 1H), 7.05-7.02 (m, 2H), 6.58-6.55 (m, 2H), 5.30 (d, J = 52.8 Hz, 1H), 5.08-5.02 (m, 1H), 4.35-4.16 (m, 2H), 3.94-3.84 (m, 6H), 3.51-3.49 (m, 1H), 3.39- 3.38 (m, 5H), 3.30-3.23 (m, 1H), 2.91-2.76 (m, 3H), 2.61-2.55 (m, 1H), 2.39-2.35 (m, 3H), 2.18-1.93 (m, 3H) ), 1.77-1.73 (m, 2H), 1.52 (s, 1H), 1.23-1.18 (m, 4H).
(3R)-N-(3-(5-(4-(4-((6- (2- (2,6-dioxopiperidine-3-yl) -1-oxoisoindrin-5-yl)-)- 2,6-Diazaspiro [3.3] heptane-2-yl) methyl) piperidine-1-yl) phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl) -2,4-difluorophenyl)- Exemplary Synthesis of 3-Fluoropyridine-1-sulfonic Amide (Exemplary Compound 537) Step 1: tert-butyl 6- (3-cyano-4- (methoxycarbonyl) phenyl) -2,6-diazaspiro [3.3] heptane -2-Preparation of carboxylate.

Methyl 2-cyano-4-fluorobenzoate (896.00 mg, 5.001 mmol, 1.00 eq), oxalic acid; tert-butyl 2,6-diazaspiro [3.3] heptane-2-carboxylate (896.00 mg, 5.0001 mmol, 1.00 eq) in a 30 mL closed tube. 1.59g
, 5.515 mmol, 1.10 eq), DIEA (4.20 mL, 24.113 mmol, 4.82 eq), DMSO (12.00 mL). The obtained mixed solution was stirred in an oil tank at 110 ° C. for 2 hours. The reaction mixture was cooled to room temperature and diluted with water (100 mL). The obtained mixed solution was extracted with ethyl acetate (100 mLx2), and the organic layers were combined into one. The organic layer was washed with brine (100 mLx2), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1/1). This resulted in 1.75 g (98%) of tert-butyl 6- [3-cyano-4- (methoxycarbonyl) phenyl] -2,6-diazaspiro [3.3] heptane-2-carboxylate as a yellow-green solid. Got as. LC / MS (ESI) m / z: 358.00 [M + 1] ⁺ .
Step 2: Preparation of tert-butyl 6- (3-formyl-4- (methoxycarbonyl) phenyl) -2,6-diazaspiro [3.3] heptane-2-carboxylate.

In a 250 mL round-bottom flask purged and maintained in an inert nitrogen atmosphere, H ₂ O (15.00 mL), A.
cOH (15.00 mL), pyridine (30.00 mL), tert-butyl 6- [3-cyano-4- (methoxycarbonyl) phenyl] -2,6-diazaspiro [3.3] heptane-2-carboxylate (1.66 g, 4.645 mmol, 1.00 equivalent), sodium diphosphate monohydrate (4.89 g, 46.135 mmol, 9.93 equivalent), Rainey-Ni (1.00 g)
, 11.672 mmol, 2.51 eq). The obtained mixed solution was stirred in an oil tank at 70 ° C. for 4 hours. The reaction mixture was cooled to room temperature and diluted with water (150 mL). The solid was filtered and saturated NaHCO ₃ was added to the filtrate to adjust the pH to 8. The obtained mixed solution was extracted with ethyl acetate (200 mLx2), and the organic layers were combined into one. The organic layer was washed with brine (200 mLx2), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1/1). This gives 500 mg (45%) of tert-butyl 6- [3-formyl-4- (methoxycarbonyl) phenyl] -2,6-diazaspiro [3.3] heptane-2-carboxylate as a yellow-green solid. Obtained. LC / MS (ESI) m / z: 361.00 [M + 1] ⁺ .
Step 3: tert-Butyl 6- (2- (2,6-dioxopiperidine-3-yl) -1-oxoisoindoline-5-yl) -2,6-diazaspiro [3.3] heptane-2-carboxylic acid Preparation of salt.

In a 100 mL round bottom flask, tert-butyl 6- [3-formyl-4- (methoxycarbonyl) phenyl] -2,6-diazaspiro [3.3] heptane-2-carboxylate (684.80 mg, 1.900 mmol, 1.00 eq) ), 3-Aminopiperidin-2,6-dione hydrochloride (375.30 mg, 2.280 mmol, 1.20 eq), DCM (30.00 mL), DIEA (0.80 mL, 4.593 mmol, 2.42 eq), AcOH (1.50 mL, 26.177 mmol) , 13.78 equivalent) was added. The obtained mixed solution was stirred in an oil tank at 35 ° C. for 4 hours. Then NaBH (OAc) ₃ (1.21 g, 5.709 mmol, 3.00 eq) was added and the resulting mixture was reacted for another 3 hours with stirring while maintaining the temperature at 35 ° C. in an oil bath. The reaction was then quenched by the addition of water (50 mL) and the pH value of the solution was adjusted to 8 with _{saturated NaHCO 3.} The resulting mixture was extracted with DCM / MeOH (10/1, 100 mLx2), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded into a silica gel column with dichloromethane / methanol (25/1). This resulted in 620 mg (74%) of tert-butyl 6- [2- (2,6-dioxopiperidine-3-yl) -1-oxo-2,3-dihydro-1H-isoindole-5-yl]. -2,6-Diazaspiro [3.3] heptane-2-carboxylate was obtained as a light green solid. LC / MS (ESI) m / z: 441.00 [M + 1] ⁺ .
Step 4: Preparation of 3- (1-oxo-5- (2,6-diazaspiro [3.3] heptane-2-yl) isoindoline-2-yl) piperidine-2,6-dione.

In a 50 mL round bottom flask, tert-butyl 6- [2- (2,6-dioxopiperidin-3-yl) -1-oxo-2,3-dihydro-1H-isoindole-5-yl] -2 , 6-Diazaspiro [3.3] heptane-2-carboxylate (110.10 mg, 0.250 mmol, 1.00 eq), DCM (8.00 mL), TFA (1.50 mL) were added. The resulting solution was stirred at room temperature for 1 hour. The acid was neutralized with DIEA. This resulted in 85.1 mg of 3- (5- [2,6-
Diazaspiro [3.3] Heptane-2-yl] -1-oxo-2,3-dihydro-1H-isoindole-2-yl
) A DCM solution of piperidine-2,6-dione was obtained as a light brown solution. LC / MS (ESI) m / z: 341.00
[M + 1] ⁺ .
Step 5: (3R) -N- (3- (5- (4- (4-((6- (2- (2,6-dioxopiperidine-3-yl) -1-oxoisoindoline-5-) Il) -2,6-diazaspiro [3.3] heptane-2-yl) methyl) piperidine-1-yl) phenyl) -1H-pyrrolo [2,3-b] pyridin-3-carbonyl) -2,4-difluoro Preparation of phenyl) -3-fluoropyrrolidine-1-sulfonamide.

In a 50 mL round-bottom flask, (3R) -N- (2,4-difluoro-3- [5- [4- (4-formylpiperidine-1-)
Il) phenyl] -1H-pyrrolo [2,3-b] pyridin-3-carbonyl] phenyl) -3-fluoropyrrolidin-1-sulfonamide (113.00 mg, 0.185 mmol, 1.00 eq), 3- (5- [ 2,6-Diazaspiro [3.3] heptane-2-yl] -1-oxo-2,3-dihydro-1H-isoindole-2-yl) piperidine-2,6-dione (75.50 mg, 0.222 mmol, 1.20 equivalents) ), DCM (45.00 mL) was added. The resulting solution was stirred for 2 hours in an oil bath at 35 ° C. Then NaBH ₃ CN (34.80 mg, 0.554 mmol, 3.00 eq) was added and the resulting mixture was further reacted for 0.5 hours at room temperature with stirring. The reaction was then stopped by the addition of water (50 mL) and extracted with DCM / MeOH (10/1, 60 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. Residue, preparative TLC
Purified by (CH ₂ Cl ₂ / MeOH = 7: 1). The crude product was purified by preparative HPLC. This resulted in 27 mg (16%) of (3R) -N- [3- (5- [4- [4- ([6- [2- (2,6-dioxopiperidine-3-yl) -1-yl) -1-. Oxo-2,3-dihydro-1H-isoindole-5-yl] -2,6-diazaspiro [3.3] heptane-2-yl] methyl) piperidine-1-yl] phenyl] -1H-pyrrolo [2,3 -b] Pyridine-3-carbonyl) -2,4-difluorophenyl] -3-fluoropyrrolidine-1-sulfonamide was obtained as a yellowish green solid. LC / MS (ESI) m / z: 936.30 [M + 1] +; 1H-NMR (300MHz, DMSO-d6) δ 12.91 (s, 1H), 10.95 (s, 1H), 8.65 (s, 1H), 8.53 (s, 1H), 8.16 (s, 1H), 8.07 (s, 1H), 7.66-7.57 (m, 3H), 7.51-7.48 (m, 1H), 7.30-7.24 (m, 1H), 7.08- 7.05 (m, 2H), 6.53-6.48 (m, 2H), 5.30 (d, J = 53.1 Hz, 1H), 5.06-5.00 (m, 1H), 4.34-4.15 (m, 3H), 4.00 (s, 5H), 3.79-3.75 (m, 3H), 2.96-2.81 (m, 2H), 2.74-2.66 (m, 3H), 2.61-2.56 (m, 1H), 2.44-2.28 (m, 4H), 2.14- 1.94 (m, 4H), 1.79-1.75 (m, 2H), 1.49 (s, 1H), 1.30-1.19 (m, 3H).
(3R) -N- (3- (5- (4- (4-((4- (2- (2,6-dioxopiperidine-3-yl) -1-oxoisoindoline-5-yl) piperidine) piperidine -1-yl) Methyl) Piperidine-1-yl) Phenyl) -1H-Pyrrolo [2,3-b]
Illustrative Synthesis of Pyridine-3-carbonyl) -2,4-difluorophenyl) -3-fluoropyrrolidine-1-sulfonamide (exemplary compound 579) Step 1: 3- (5-bromo-1-oxoisoindoline-) 2-Il) Preparation of piperidine-2,6-dione.

N, N-dimethylformamide (30 mL) of methyl 4-bromo-2- (bromomethyl) benzoate (10.0 g, 32.47 mmol, 1.00 eq) in a 100 mL round bottom flask purged and maintained in an inert nitrogen atmosphere. ), 3-Aminopiperidin-2,6-dione (4.2 g, 32.78 mmol, 1.00 eq) and triethylamine (8.2 g, 81.04 mmol, 2.50 eq) were added. The resulting solution was stirred at 80 ° C. for 12 hours. The reaction was then stopped by the addition of water. The solids were collected and the resulting solution was extracted with ethyl acetate to combine the organic layers into one. The resulting mixture was washed with brine. The mixture was dried over anhydrous sodium sulfate. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1: 5). The collected fractions were combined and concentrated under vacuum. This yields 5.6 g (53%) of 3- (5-bromo-1-oxo-2,3-dihydro-1H-isoindole-2-yl) piperidine-2,6-dione as a purple solid. rice field. LC / MS (ESI) m / z: 323.00 / 325.00
[M + 1] ⁺ .
Step 2: tert-Butyl 4- (2- (2,6-dioxopiperidine-3-yl) -1-oxoisoindoline-5-yl) -3,6-dihydropyridine-1 (2H) -carboxylate Preparation.

In a 250 mL 3-neck round bottom flask purged and maintained in an inert nitrogen atmosphere, tert-butyl 4- (tetramethyl-1,3,2-dioxaborolan-2-yl) -1,2,3,6 -A solution of dioxane (60 mL) of tetrahydropyridine-1-carboxylate (2.9 g, 9.38 mmol, 3.00 eq), potassium carbonate (1.3 g, 9.41 mmol, 3.00 eq), 3- (5-bromo-1-oxo). -2,3-dihydro-1H-isoindole-2-yl) piperidine-2,6-dione (1.0 g, 3.09 mmol, 1.00 eq), tetrakis (triphenylphosphine) palladium (358.0 mg, 0.31 mmol, 0.10 eq) ) Was put in. The resulting solution was stirred overnight in an oil bath at 90 ° C. under nitrogen. The filtrate was collected by filtration. The resulting mixture was concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1/1). The collected fractions were combined and concentrated under vacuum. This resulted in 260.0 mg (20%) of tert-butyl 4- [2- (2,6-dioxopiperidine-3-yl) -1-oxo-2,3-dihydro-1H-isoindole-5-yl. ] -1,2,3,6-tetrahydropyridin-1-carboxylate was obtained as a yellow solid. LC / MS (ESI) m / z: 426.15 [M + 1] ⁺ .
Step 3: Preparation of tert-butyl 4- (2- (2,6-dioxopiperidine-3-yl) -1-oxoisoindoline-5-yl) piperidine-1-carboxylate.

In a 50 mL round bottom flask, tert-butyl 4- [2- (2,6-dioxopiperidine-3-yl) -1-oxo-2,3-dihydro-1H-isoindole-5-yl] -1 , 2,3,6-Tetrahydropyridine-1-carboxylate (200.0 mg, 0.47 mmol, 1.00 eq) in tetrahydrofuran (mL), palladium carbon (300.0 mg, 1.69 mmol, 8.00 eq) under nitrogen atmosphere. I put it in. The flask was then evacuated and flushed with hydrogen. The reaction mixture was hydrogenated at room temperature for 4 hours in a hydrogen atmosphere using a hydrogen balloon, then filtered through a Celite bed and concentrated under reduced pressure. This will result in
190.0 mg (95%) of tert-butyl 4- [2- (2,6-dioxopiperidine-3-yl) -1-oxo-2,3-dihydro-1H-isoindole-5-yl] piperidine- 1-Carboxylate was obtained as a yellow solid.

Step 4: 3- (1-oxo-5- (piperidine-4-yl) isoindoline-2-yl) piperidine-2,6-
Preparation of Zeon.

In a 50 mL round bottom flask, tert-butyl 4- [2- (2,6-dioxopiperidin-3-yl) -1-oxo-2,3-dihydro-1H-isoindole-5-yl] piperidin- A solution of 1-carboxylate (90.0 mg, 0.21 mmol, 1.00 eq) in dichloromethane (4 mL) and trifluoroacetic acid (2.0 mL) was added. The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum. This yields 80.0 mg (86%) of 3- (1-oxo-5- (piperidine-4-yl) isoindoline-2-yl) piperidine-2,6-dione (TFA salt) as a yellow oil. rice field.

Step 5: (3R) -N- (3-(5-(4-(4-((4- (2- (2,6-dioxopiperidine-3-yl) -1-oxoisoindoline-5-yl) Ill) piperidine-1-yl) methyl) piperidine-1-yl) phenyl) -1H-pyrrolo [2,3-b] pyridin-3-carbonyl) -2,4-difluorophenyl) -3-fluoropyrrolidine-1 -Preparation of sulfonamide.

In a 50 mL round bottom flask, 3- [1-oxo-5- (piperidine-4-yl) -3H-isoindole-2-yl] piperidine-2,6-dione; trifluoroacetic acid (91.00 mg, 0.206 mmol) , 1.00 equivalent), dichloromethane (15.00 mL), (3R) -N- (2,4-difluoro-3- [5- [4- (4-formylpiperidine-1-yl))
Phenyl] -1H-pyrrolo [2,3-b] pyridin-3-carbonyl] phenyl) -3-fluoropyrrolidine-1-sulfonamide (126.10 mg, 0.206 mmol, 1.00 eq) was added. The mixture was stirred at room temperature for 2 hours and NaBH ₃ CN (64.78 mg, 1.031 mmol, 5.00 eq) was added. The resulting solution was stirred at room temperature overnight. The reaction was then stopped by the addition of water (20 mL). The resulting solution was extracted with dichloromethane (2x20 mL) and dried over anhydrous sodium sulfate. The residue was loaded into a silica gel column with dichloromethane / methanol (10/1). The crude product was purified by preparative HPLC. The collected fractions were combined and concentrated under vacuum. This resulted in 56.1 mg (29.48%) of (3R) -N- [3- (5- [4- [4-([4- [2- (2,6-dioxopiperidine-3-yl) -1). -Oxo-3H-isoindole-5-yl] piperidine-1-yl] methyl) piperidine-1-yl] phenyl] -1H-pyrrolo [2,3-b] pyridin-3-carbonyl) -2,4- Difluorophenyl] -3-fluoropyrrolidine-1-sulfonamide was obtained as a yellow solid. LC / MS (ESI) m / z: 923.30 [M + 1] +; 1H-NMR (300MHz, DMSO-d6) δ 12.91 (s, 1H), 10.99 (s, 1H), 9.85 (s, 1H), 8.67 (s, 1H), 8.66 (s, 1H), 8.08 (s, 1H), 7.68-7.52 (m, 5H), 7.44-7.41 (d, J = 7.8Hz, 1H), 7.30-7.25 (m, 1H
), 7.10-7.07 (d, J = 8.4Hz, 2H), 5.40-5.09 (m, 2H), 4.47-4.28 (m, 2H), 3.83-3.79 (m, 2H), 3.51-3.29 (m, 4H) ), 3.04-3.00 (d, J = 10.5Hz, 2H), 2.93-2.52 (m, 5H), 2.27-2.25 (d, J = 6.3Hz, 2H), 2.15-1.99 (m, 5H), 1.87- 1.73 (m, 7H), 1.28-1.25 (d, J = 9.6Hz, 2H).
(3R) -N-(3- (5- (4- (2- (4- (2- (2,6-dioxopiperidine-3-yl) -1-oxoisoindoline-5-yl) piperazine- 1-Il) Ethyl) Phenyl) -1H-Indol-3-carbonyl) -2,4-Difluorophenyl) -3-Fluoropyrrolidine-1-sulfonic Amide Exemplary Synthesis Step 1: 1- Preparation of bromo-4- (2,2-dimethoxyethyl) benzene.

P-toluenesulfonic acid in a mixture of 2- (4-bromophenyl) acetaldehyde (2 g, 10.05 mmol, 1 eq) and trimethoxymethane (5.33 g, 50.24 mmol, 5.51 mL, 5 eq) in methanol (30 mL). A hydrated complex (96 mg, 0.50 mmol, 0.05 eq) was added all at once under nitrogen at 15 ° C. The mixture was stirred at 15 ° C. for 16 hours. Saturated aqueous sodium bicarbonate solution was added to adjust the pH to 8-9. The mixture was poured into water (20 mL) and stirred for 1 minute. The aqueous layer was extracted with ethyl acetate (60 mLx2). The combined organic layers were washed with brine (30 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 15/1 to 5: 1). The compound 1-bromo-4- (2,2-dimethoxyethyl) benzene (1.97 g, 8.04 mmol, 80% yield) was obtained as a colorless oil. 1H-NMR (400MHz, CDCl3) δ 7.47 --7.34 (m, 2H), 7.16 --7.05 (m, 2H), 4.55 --4.44 (m, 1H), 3.39 --3.30 (m, 6H), 2.92 --2.79 (m) , 2H).
Step 2: Preparation of 2- (4- (2,2-dimethoxyethyl) phenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

1-bromo-4- (2,2-dimethoxyethyl) benzene (1.63 g, 6.65 mmol, 1 equivalent), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl) -1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolan (2.20 g, 8.65 mmol, 1.3 eq), potassium acetate (1.31 g, 13.30 mmol, 2 eq), and ditert-butyl (2.20 g, 8.65 mmol, 1.3 eq). Cyclopentyl) phosphan; dichloropalladium; iron (433 mg, 0.66 mmol)
, 0.1 Eq) of the mixture of dioxane (25 mL) was degassed and purged with nitrogen 3 times. The mixture was then stirred at 95 ° C. for 12 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 50/1 to 20: 1). Compound 2- [4- (2,2-dimethoxyethyl) phenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.9 g, 6.50 mmol, 98% yield) brown Obtained as an oil. 1H-NMR (400MHz, CDCl3) δ 7.71 --7.74 (m, 2H), 7.19 (s, 2H), 4.51 --4.42 (m, 1H), 3.29 --3.19 (m, 6H), 2.89 --2.80 (m, 2H) ), 1.28 --1.25 (m, 12H).
Step 3: (R) -N- (3- (5- (4- (2,2-dimethoxyethyl) phenyl) -1H-pyrrolidine [2,3-b] pyridine-3-carbonyl) -2,4- Preparation of difluorophenyl) -3-fluoropyrrolidine-1-sulfonamide.

(3R) -N- [3- (5-bromo-1H-pyrrolo [2,3-b] pyridine-3-carbonyl) -2,4-difluoro-phenyl] -3-fluoro-pyrrolidin-1-sulfonamide (1.95 g, 3.87 mmol, 1 equivalent), 2- [4- (2,2-dimethoxyethyl) phenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.25 g, 4.26) mmol, 1.1 eq), 4-ditert-butylphosphanyl-N, N-dimethyl-aniline; dichloropalladium (274 mg, 0.39 mmol, 0.3 mL, 0.1 eq), cesium fluoride (2.35 g, 15.50 mmol, 0.6 mL, A mixture of 4 equivalents) of dioxane (20 mL) and water (4 mL) was degassed and purged with nitrogen 3 times. The mixture was then stirred at 90 ° C. for 12 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mLx2). The combined organic layers were washed with brine (40 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 1 / 10: 1). The crude product was then further purified by preparative HPLC. Compound (3R) -N- [3- [5- [4- (2,2-dimethoxyethyl) phenyl] -1H-indole-3-carbonyl] -2,4-difluoro-phenyl] -3-fluoro- Pyrrolidine-1-sulfonamide (1.31 g, 2.23 mmol, 57% yield) was obtained as a yellow solid. LC / MS (ESI) m / z: 589.2 [M + 1] ⁺ .
Step 4: (R) -N- (2,4-difluoro-3- (5- (4- (2-oxoethyl) phenyl) -1H-pyrrolo [2,3-b] pyridin-3-carbonyl) phenyl) Preparation of -3-fluoropyrrolidine-1-sulfonamide.

(3R) -N- [3- [5- [4- (2,2-dimethoxyethyl) phenyl] -1H-indole-3-carbonyl] -2,4-difluoro-phenyl] -3-fluoro-pyrrolidin- Sulfonamide (2M, 15 mL, 13.46 eq) was added to a solution of 1-sulfonamide (1.31 g, 2.23 mmol, 1 eq) in tetrahydrofuran (15 mL). The mixture was stirred at 70 ° C. for 2 hours. PH the reaction mixture using saturated aqueous sodium bicarbonate solution
Basicized to = 8. The reaction mixture was then diluted with water (40 mL) and extracted with tetrahydrofuran (30 mL) and ethyl acetate (30 mLx2). The combined organic layers were washed with brine (30 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Compound (3R) -N- [2,4-difluoro-3- [5- [4- (2-oxoethyl) phenyl] -1H-indole-3-carbonyl] phenyl] -3-fluoro-pyrrolidin-1- Sulfonamide (1.26 g) was obtained as a yellow solid. LC / MS (ESI) m / z: 543.2 [M + 1] ⁺ .
Step 5: (3R) -N- (3- (5- (4- (2- (2- (2- (2- (2,6-dioxopiperidine-3-yl))-1-oxoisoindoline-5-yl) ) Piperazine-1-yl) ethyl) phenyl) -1H-indole-3-carbonyl) -2,4-difluorophenyl) -3-fluoropyrrolidine-1-sulfonamide preparation.

3- (1-oxo-5-piperazine-1-yl-isoindoline-2-yl) piperidine-2,6-dione (70 mg, 0.19 mmol, 1 eq, hydrochloride) in methanol (2 mL) and dichloromethane (1 mL) ), Sodium acetate (31 mg, 0.38 mmol, 2 eq) was added to adjust the pH to about 8. The mixture is stirred at 30 ° C. for 5 minutes, then (3R) -N- [2,4-difluoro-3- [5- [4- (2-oxoethyl) phenyl] -1H-pyrrolo [2,3-b ] Pyridine-3-carbonyl] Phenyl] -3-Fluoro-pyrrolidin-1-sulfonamide
(104 mg, 0.19 mmol, 1 eq) was added. The mixture was stirred at 30 ° C. for 5 minutes, followed by the addition of acetic acid (23.04 mg, 0.38 mmol, 2 eq) to adjust the pH to about 5.0. The mixture was stirred at 15 ° C. for 20 minutes.
Sodium cyanoborohydride (24 mg, 0.38 mmol, 2 eq) was then added in several batches. The reaction mixture was stirred at 30 ° C. for 1.5 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (25 mLx2) and tetrahydrofuran (20 mL). The combined organic layers were washed with saturated brine (20 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC. Compound 3R) -N- [3- [5- [4- [2- [4- [2- (2,6-dioxo-3-piperidyl) -1-oxo-isoindoline-5-yl] piperazine- 1-yl] ethyl] phenyl] -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl] -3-fluoro-pyrrolidin-1-sulfonamide (104.5 mg, 0.10) mmol, yield 55%, purity 98%, trifluoroacetate) was obtained as a white solid. LC / MS (ESI) m / z: 855.3 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 13.05-- 12.95 (m, 1H), 10.96 (s, 1H), 9.85 (s, 1H) ), 8.72 (d, J = 2.4Hz, 1H), 8.64 (d, J = 0.8 Hz, 1H), 8.13 (d, J = 2.8 Hz, 1H), 7.81 --7.73 (m, 2H), 7.67 --7.56 (m, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.28 (t, J = 8.4 Hz, 1H), 7.24 --7.15 (m, 2H), 5.41 --5.18 (m, 1H), 5.07 ( dd, J = 5.2, 13.2 Hz, 1H), 4.42 --4.33 (m, 1H), 4.29 --4.22 (m, 1H), 4.14 --4.02 (m, 3H), 3.72 (d, J = 11.2 Hz, 3H) , 3.42 --3.38 (m, 2H), 3.37 --3.21 (m, 4H), 3.20 --3.09 (m, 4H), 2.99 --2.85 (m, 1H), 2.64 --2.54 (m, 2H), 2.39 (dd, dd, J = 4.8, 13.2 Hz, 1H), 2.13 --2.07 (m, 1H), 2.01 --1.95 (m, 1H).
(3R) -N- (3- (5-(4-(((1R, 3S) -3-((1- (2- (2,6-dioxopiperidine-3-yl) -1-oxoiso) Indoline-5-yl) piperidine-4-yl) oxy) cyclohexyl) oxy) phenyl) -1H-pyrrolo [2,3-b] pyridin-3-carbonyl) -2,4-difluorophenyl) -3-fluoropyrrolidin Exemplary Synthesis of -1-sulfonamide (Exemplary Compound 709) Step 1: tert-butyl (R) -5-bromo-3- (2,6-difluoro-3-((3-fluoropyrrolidin) -1-) Preparation of sulfone amide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-1-carboxylate.

In a 250 mL round bottom flask, (3R) -N- (3- [5-bromo-1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl) -3-fluoro Pyrrolidine-1-sulfonamide (10.0 g, 19.9 mmol, 1.0 eq), DCM (120 mL), TEA (6.0 g, 59.3 mmol, 3.0 eq) and (Boc) ₂ O (6.0 g, 29.7 mmol, 1.5 eq) I put it in. The obtained mixture was stirred at room temperature for 6 hours. The resulting mixture was concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1: 3). This resulted in 9.0 g (75.1%) of tert-butyl 5-bromo-3- (2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-ylsulfonyl] amino] benzoyl) pyrolo [ 2,3-b] Pyridine-1-carboxylate was obtained as an off-white solid. LC / MS (ESI) m / z: 605.10 [M + 1] ⁺ .
Step 2: tert-butyl (R) -3- (2,6-difluoro-3-((3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -5- (4,4,5,5-tetramethyl) Preparation of -1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine-1-carboxylate.

In a 250 mL round-bottom flask purged and maintained in an inert nitrogen atmosphere, tert-butyl 5-
Bromo-3- (2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1-ylsulfonyl] amino]
Benzoyl) pyrolo [2,3-b] pyridin-1-carboxylate (9.0 g, 14.9 mmol, 1.0 eq), bis (pinacolat) diboron (7.6 g, 29.9 mmol, 2.0 eq), Pd (dppf) Cl ₂ (1.6g, 2.2mmol, 0.15
Equivalent), KOAc (4.4 g, 44.8 mmol, 3.0 eq), and dioxane (150 mL) were added. The resulting suspension was stirred for 5 hours in an oil bath at 90 ° C. The solids were filtered off and then washed with DCM (3x100 mL). The combined filter liquids were concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1: 1). This resulted in 5.5 g (57%) of tert-butyl 3- (2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-ylsulfonyl] amino] benzoyl) -5- (4, 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) pyrrolidine [2,3-b]
Pyridine-1-carboxylate was obtained as a bright yellow solid. LC / MS (ESI) m / z: 651.20 [M + 1] ⁺ .
Step 3: Preparation of 3- (4-iodophenoxy) cyclohexane-1-ol.

_{PPh 3} (17.9 g, 68.2 mmol, 1.5 eq), THF (500 mL), and DIAD (13.8 g, 68.2 mmol, 1.5 eq) in a 1 L three-necked round-bottom flask purged and maintained in an inert nitrogen atmosphere. Was placed in a water / ice tank at 0 ° C. After stirring the reaction mixture for 30 minutes at 0 ° C., cyclohexane-1,3-diol (7.9 g, 68.0 mmol, 1.5 eq) and 4-iodophenol (10.0 g, 45.4 mmol, 1.0 eq) were placed in a flask. added. The resulting mixture was stirred at 0 ° C. for 30 minutes and then the cooling tank was removed. The resulting mixture was reacted overnight at room temperature with stirring. The resulting mixture was concentrated under vacuum. The residue was then quenched by the addition of 200 mL of water. The resulting mixture was extracted with 3x250 mL of ethyl acetate. The organic layers were combined into one, washed with 3x150 ml brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1: 4). This gave 5.5 g (38.0%) of 3- (4-iodophenoxy) cyclohexane-1-ol as a white solid.

Step 4: Preparation of ((3- (4-iodophenoxy) cyclohexyl) oxy) trimethylsilane.

3- (4-Iodophenoxy) cyclohexane-1-ol (5.5 g, 17.3 mmol, 1.0 eq), DCM (100 mL), TEA (5.5 g, 54.4 mmol, 3.1 eq) and TMSCl (5.5 g, 54.4 mmol, 3.1 eq) in a 250 mL round-bottom flask. 2.8 g, 25.8 mmol, 1.5 eq) was added. The resulting mixture was stirred at room temperature for 5 hours. The reaction was then quenched by the addition of _{150 mL NaHCO 3 aqueous solution.} The resulting mixture was extracted with 2x100 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. This gave 6.5 g (96.3%) of ((3- (4-iodophenoxy) cyclohexyl) oxy) trimethylsilane as a white semi-solid.

Step 5: Preparation of (((1S, 3R) -3- (4-iodophenoxy) cyclohexyl) oxy) trimethylsilane.

[[3- (4-Iodophenoxy) cyclohexyl] oxy] trimethylsilane (6.5 g, 16.65 mmol, 1.0 eq) was purified by flash preparative HPLC. As a result, 2.0 g (30.8%) of [[(1S, 3R) -3- (4-iodophenoxy) cyclohexyl] oxy] trimethylsilane was obtained as a white solid.

Step 6: Preparation of 4-(((1S, 3R) -3- (4-iodophenoxy) cyclohexyl) oxy) piperidine.

In a 100 mL three-necked round-bottom flask purged and maintained in an inert nitrogen atmosphere, [[(1S, 3R) -3- (4-iodophenoxy) cyclohexyl] oxy] trimethylsilane (1.9 g, 4.8 mmol, 1.0 1.0
Equivalent) and DCM (50 mL) were added. The solution was cooled to -70 ° C using an EtOH / N _{2 (liquid) bath.} Then in a flask, tert-butyl 4-oxopiperidine-1-carboxylate (0.97 g, 4.8 mmol, 1.0 eq), Et ₃ SiH (0.62 g, 5.4 mmol, 1.1), keeping the temperature below -60 ° C. Equivalent) and TMSOTf (0.54 g, 2.4 mmol, 0.5 eq) were added in succession. The obtained mixed solution was heated to room temperature over 2 hours, and further stirred at room temperature for 2 hours. The reaction was then quenched by the addition of _{150 mL of NaHCO 3 aqueous solution.} The resulting mixture was extracted with 3x150 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The silica gel column was loaded with the residue with dichloromethane / methanol / Et _{3 N (80: 15: 5).} This gave 580 mg (29.7%) of 4-[[(1S, 3R) -3- (4-iodophenoxy) cyclohexyl] oxy] piperidine as a brown oil. LC / MS (ESI) m / z: 402.10 [M + 1] ⁺ .
Step 7: Preparation of methyl 4-fluoro-2-formylbenzoate.

Methyl 2-cyano-4-fluorobenzoate (5.38 g, 30.031 mmol) in a 250 mL round bottom flask
, 1.00 eq), formic acid (50.00 mL, 88%), H ₂ O (5.00 mL), PtO ₂ (1.36 g, 5.989 mmol, 0.20 eq). The obtained mixed solution was stirred in an oil tank at 80 ° C. for 2 hours. The rest of PtO ₂ (0.10 eq) was added and the resulting mixture was reacted for another 2 hours with stirring while maintaining the temperature at 80 ° C. in an oil bath. The reaction mixture was cooled to room temperature. The resulting mixture was diluted with water (100 mL) and ethyl acetate (200 mL). The solids were filtered off. The aqueous layer was extracted back with ethyl acetate (100 mL). The organic layers were combined and washed with brine (150 mLx2). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1/25). This gave 2.17 g (40%) of methyl 4-fluoro-2-formylbenzoate as white crystals. LC / MS (ESI) m / z: 182.95 [M + 1] +; 1H-NMR (300MHz, CDCl3) δ 10.68-10.65 (m, 1H), 8.10-8.03 (m, 1H), 7.64-7.60 (m) , 1H), 7.36-7.28 (m, 1H), 3.99 (s, 3H).
Step 8: Methyl 2-formyl-4- (4-(((1S, 3R) -3- (4-iodophenoxy) cyclohexyl))
Preparation of oxy) piperidine-1-yl) benzoate.

In a 30 mL closed tube, 4-[[(1S, 3R) -3- (4-iodophenoxy) -cyclohexyl] oxy] piperidine (550 mg, 1.4 mmol, 1.0 eq), methyl 4-fluoro-2-formylbenzoic acid Salt (380 mg, 2.1 mmol, 1.5 eq), DMSO (10 mL), and DIEA (2 mL, 11.5 mmol, 8.4 eq) were added. The tubes were purged and maintained in an inert nitrogen atmosphere. The resulting mixture was stirred overnight in an oil bath at 110 ° C. The reaction was then stopped by the addition of 150 mL of water. The resulting mixture was extracted with 3x150 mL of ethyl acetate. The organic layers were combined, washed with 3x100 ml brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1: 4). This resulted in 95 mg (12.3%) of methyl 2-formyl-4- (4-[[(1S, 3R) -3- (4-iodophenoxy) cyclohexyl] oxy] piperidine-1-.
Il) Benzoate was obtained as a yellow solid. LC / MS (ESI) m / z: 564.05 [M + 1] ⁺ .
Step 9: 3- (5-(4-((((1S, 3R) -3- (4-iodophenoxy) cyclohexyl) oxy) piperidine-1-yl) -1-oxoisoindoline-2-yl) piperidine- Preparation of 2,6-dione.

3-Aminopiperidin-2,6-dione hydrochloride (33 mg, 0.20 mmol, 1.2 eq), MeOH (1.5 mL), DIEA (44 mg, 0.34 mmol, 2.0 eq), DCM (25 mL) in a 100 mL round bottom flask. , Methyl 2-formyl-4- (4-[[(1S, 3R) -3- (4-iodophenoxy) cyclohexyl] -oxy] piperidin-1-yl) benzoate (95 mg, 0.17 mmol, 1.0 eq) And HOAc (81 mg, 1.35 mmol, 8.0 eq) were added.
The obtained mixed solution was stirred in an oil tank at 35 ° C. for 4 hours, and then NaBH ₃ CN (32 mg, 0.51 mmol, 3.0 eq).
Was added to the flask. The resulting mixture was stirred overnight in an oil bath while maintaining a temperature of 35 ° C. The reaction was then quenched by the addition of _{50 mL of NaHCO 3 aqueous solution.} The resulting mixture was extracted with 3x150 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by flash preparative HPLC. This resulted in 65 mg (59.9%) 3- [5- (4-[[(1S, 3R) -3- (4-iodophenoxy) cyclohexyl] oxy] piperidine-1-yl) -1-oxo-3H- Isoindole-2-yl] piperidine-2,6-dione was obtained as a white solid. LC / MS (ESI) m / z: 644.15 [M + 1] ⁺ .
Step 10: tert-butyl 3-(2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -5-(4-(((1R, 3S)-)- 3-((1- (2- (2,6-dioxopiperidine-3-yl) -1-oxoisoindoline-5-yl) piperidin-4-yl) oxy) cyclohexyl) oxy) phenyl) -1H- Preparation of pyrrolin [2,3-b] pyridin-1-carboxylate.

In an 8 mL closed tube, 3- [5-(4-[[(1S, 3R) -3- (4-iodophenoxy) cyclohexyl] oxy]
Piperidine-1-yl) -1-oxo-3H-isoindole-2-yl] -piperidine-2,6-dione (60 mg, 0.09 mmol, 1.0 equivalent), tert-butyl 3- (2,6-difluoro-) 3-[[(3R) -3-fluoropyrrolidin-1-ylsulfonyl] amino] benzoyl) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrrolo [2,3-b] pyridine-1-carboxylate (91 mg, 0.14 mmol, 1.5 equivalents), K ₂ CO ₃ (39 mg, 0.28 mmol, 3.0 equivalents), Pd (dtbpf) Cl ₂ (6 mg, 0.009 mmol, 0.1 equivalent), dioxane (2.1 _{mL), and H 2} O (0.3 mL) were added. The tubes were purged and maintained in an inert nitrogen atmosphere. The obtained mixed solution was stirred in an oil tank at 90 ° C. for 1.5 hours. The crude product was purified by flash preparative HPLC. This resulted in 75 mg (77.3%) of tert-butyl 3-(2,6-difluoro-3-[[(3R) -3-fluoro-pyrrolidin-1-ylsulfonyl] amino] benzoyl) -5- (4-). [[(1R, 3S) -3-([1- [2- (2,6-dioxopiperidine-3-yl) -1-oxo-3H-isoindole-5-yl] piperidine-4-yl] Oxy) cyclohexyl] oxy] phenyl) pyrrolin [2,3-b] pyridin-1-carboxylate was obtained as an off-white solid. LC / MS (ESI) m / z: 1040.35 [M + 1] ⁺ .
Step 11: (3R) -N- (3-(5-(4-(((1R, 3S) -3-((1- (2- (2,6-dioxopiperidine-3-yl) -1) ---
Oxoisoindoline-5-yl) piperidine-4-yl) oxy) cyclohexyl) oxy) phenyl) -1H-pyrrolo [2,3-b] pyridin-3-carbonyl) -2,4-difluorophenyl) -3- Preparation of fluoropyrrolidine-1-sulfonamide.

In a 100 mL round bottom flask, tert-butyl 3-(2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-ylsulfonyl] amino] benzoyl) -5- (4-[[( 1R, 3S) -3-([1- [2- (2,6-dioxopiperidine-3-yl) -1-oxo-3H-isoindole-5-yl] piperidin-4-yl] oxy) cyclohexyl ] Oxy] phenyl) pyrrolidine [2,3-b] pyridin-1-carboxylate (75 mg, 0.07 mmol, 1.0 equivalent), DCM (10 mL), and TFA (2 mL) were added. The resulting solution was stirred at room temperature for 1 hour and then concentrated under vacuum. The crude product was purified by flash preparative HPLC. This resulted in 25.0 mg (36.9%) of (3R) -N- [3- [5- (4-[[(1R, 3S) -3-([1- [2- (2,6-dioxopiperidine). -3-yl) -1-oxo-3H-isoindole-5-yl] piperidine-4-yl] oxy) cyclohexyl] oxy] phenyl) -1H-pyrrolo [2,3-b] pyridin-3-carbonyl] -2,4-Difluorophenyl] -3-fluoropyrrolidine-1-sulfonamide was obtained as a white solid. LC / MS (ESI) m / z: 940.25
[M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 12.94 (brs, 1H), 10.95 (s, 1H), 9.87 (brs,
1H), 8.68 (s, 1H), 8.57 (brs, 1H), 8.11 (s, 1H), 7.72-7.60 (m, 3H), 7.51 (d, J = 8.4 Hz, 1H), 7.29 (t, J) = 8.8 Hz, 1H), 7.17-7.03 (m, 4H), 5.31 (d, J = 53.4 Hz, 1H), 5.05 (d, J = 12.6 Hz, 1H), 4.41 (s, 1H), 4.33 (d , J = 16.7 Hz, 1H), 4.21 (d, J = 16.4 Hz, 1H), 3.79-3.55 (m, 4H), 3.50-3.39 (m, 3H), 3.13-3.03 (m, 2H), 2.98- 2.84 (m, 1H), 2.45-2.32 (s, 2H), 2.20-1.85 (m, 8H), 1.84-1.72 (m, 1H), 1.58-1.45 (m, 2H), 1.43-1.05 (m, 5H) ).
(3R) -N- (3- (5- (4- (4- (3- (2- (2,6-dioxopiperidine-3-yl) -1-oxoisoindoline-5-yl) -3) -3 -Hydroxypropyl) piperazine-1-yl) phenyl) -1H-pyrrolo [2,3-b] pyridin-3-carbonyl) -2,4-difluorophenyl) -3-fluoropyrrolidine-1-sulfonamide
Exemplary Synthesis of (Exemplary Compound 766) Step 1: 3- (5- (3,3-diethoxyprop-1-in-1-yl) -1-oxoisoindoline-2-yl) piperidine-2, Preparation of 6-dione.

In a 30 mL sealed tube, 3- (5-bromo-1-oxo-3H-isoindole-2-yl) piperidine-2,6-
Dione (2.00 g, 6.189 mmol, 1.00 eq), dimethylformamide (15.00 mL), CuI (0.12 g, 0.619 mmol, 0.10 eq), diisopropylethylamine (2.40 g, 18.567 mmol, 3.00 eq), Pd (PPh ₃ ) ₂ Cl ₂ (0.43 g, 0.619 mmol, 0.10 eq) and 3,3-diethoxy-propine (1.19 g, 9.284 mmol, 1.50 eq) were added. The resulting solution was stirred for 3 hours in an oil bath at 65 ° C. The reaction was then stopped by the addition of water (20 mL). The resulting solution was extracted with ethyl acetate (2x20 mL). The resulting mixture was washed with brine (2x10 mL). The mixture was dried over anhydrous sodium sulfate. The residue was loaded into a silica gel column with dichloromethane / methanol (10/1). The collected fractions were combined and concentrated under vacuum. This resulted in 1.2 g (52.34%) of 3- [5- (3,3-diethoxyprop-1-in-1-yl) -1-oxo-3H-isoindole-2-yl] piperidine-2, 6-Zeon was obtained as a yellow solid. LC / MS (ESI) m / z: 371.05 [M + 1] ⁺ .
Step 2: Preparation of 3- (2- (2,6-dioxopiperidine-3-yl) -1-oxoisoindoline-5-yl) propiolaldehyde.

In a 50 mL round bottom flask, 3- [5- (3,3-diethoxyprop-1-in-1-yl) -1-oxo-3H-isoindole-2-yl] piperidine-2,6-dione (200.00 mg, 0.540 mmol, 1.00 eq), tetrahydrofuran (5.00 mL), H ₂ SO ₄ (5.00 mL, 93.803 mmol, 173.73 eq) were added. The resulting solution was stirred at room temperature for 2 hours. The reaction was then stopped by the addition of water (10 mL). The pH value of the solution _{was adjusted to 8 with Na 2} CO ₃ (1 mol / L). The resulting solution was extracted with dichloromethane (2x20 mL). The collected fractions were combined and concentrated under vacuum. This resulted in 120 mg (75.01%) of 3- [2- (2,6-dioxopiperidine-3-yl) -1-oxo-3H-isoindole-5-yl] propa-2-
Inal was obtained as a yellow solid.

Step 3: (3R) -N- (3-(5-(4- (4- (3- (2- (2,6-dioxopiperidine-3-yl) -1-oxoisoindoline-5-yl) ) -3-Hydroxypropyl) Piperazine-1-yl) Phenyl) -1H-Pyrrolidine [2,3-b] Pylin-3-carbonyl) -2,4-difluorophenyl) -3-Fluoropyrrolidin-1-sulfonamide Preparation.

In a 50 mL round bottom flask, (3R) -N- (2,4-difluoro-3- [5- [4- (piperazine-1-yl) phenyl] -1H-pyrrolo [2,3-b] pyridine- 3-carbonyl] phenyl) -3-fluoropyrrolidin-1-sulfonamide; trifluoroacetic acid (254.67 mg, 0.365 mmol, 1.20 eq), dichloromethane (15.00 mL), diisopropylethylamine (117.78 mg, 0.911 mmol, 3.00 eq), 3- [2- (2,6-dioxopiperidin-3-yl) -1-oxo-3H-isoindole-5-yl] propa-2-inal (90.00 mg, 0.304 mmol, 1.00 eq), HOAc ( 36.48 mg, 0.608 mmol, 2.00 eq) and NaBH ₃ CN (57.27 mg, 0.911 mmol, 3.00 eq) were added. The resulting solution was stirred in an oil bath overnight at 35 ° C. Then
The reaction was stopped by the addition of water (20 mL). The resulting solution was extracted with dichloromethane (2x20 mL) and dried over anhydrous sodium sulfate. The residue was loaded into a silica gel column with dichloromethane / methanol (10/1). The crude product was purified by preparative HPLC. The collected fractions were combined and concentrated under vacuum. As a result, 29.5 mg (10.97%) of (3R) -N- (3- [5- [4- (4- [
3- [2- (2,6-dioxopiperidine-3-yl) -1-oxo-3H-isoindole-5-yl] -3-hydroxypropyl] piperazine-1-yl) phenyl] -1H-pyrrolo [2,3-b] Pyridine-3-carbonyl] -2,4-difluorophenyl) -3-fluoropyrrolidine-1-sulfonamide was obtained as a yellow solid. LC / MS (ESI) m / z: 885.20 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 12.91 (s, 1H), 10.99 (s, 1H), 9.81 (s, 1H), 8.66 (s, 1H), 8.54 (s, 1H), 8.07 (s, 1H), 7.70-7.50 (m, 6H), 7.29-7.24 (m, 1H), 7.09-7.07 (d, J = 8.8Hz, 2H), 5.62 (s, 1H), 5.37-5.10 (m, 2H), 4.83-4.79 (m, 1H), 4.49-4.31 (m, 2H), 3.48-3.32 (m, 3H), 3.29-3.23 ( m, 5H), 2.92-2.86 (m, 1H), 2.63-2.38 (m, 8H), 2.12-2.00 (m, 3H), 1.88-1.83 (m, 2H).
(2S, 4R) -1-((S) -2-(2-(4-(((S) -4- (4- (3- (2,6-difluoro-3-(((R)-)- 3-Fluoropyrrolidine) -1-sulfonamide) Benzoyl) -1H-pyrrolo [2,3-b] pyridine-5-yl) Phenyl) -2- (hydroxymethyl) piperazin-1-yl) Methyl) piperidine-1 -Il) acetamide) -3,3-dimethylbutanoyl) -4-hydroxy-N-((S) -1- (4- (4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide Exemplary Synthesis of (Exemplary Compound 773) Step 1: tert-butyl (S) -2- (hydroxymethyl) -4- (4-iodophenyl) piperazine-1-
Preparation of carboxylate.

DMSO of tert-butyl (2S) -2- (hydroxymethyl) piperazine-1-carboxylate (11.4 g, 52.7 mmol, 1.0 eq) in a 250 mL round bottom flask purged and maintained in an inert nitrogen atmosphere. (60 mL) solution, 1,4-diiodobenzene (19.1 g, 59.9 mmol, 1.1 eq), CuI (0.9 g, 5.2 mmol, 0.1 eq), K ₂ CO ₃ (14.5 g, 105.4 mmol, 2.0 eq), L-proline (1.2 g, 10.4 mmol, 0.2 eq) was added. The obtained mixed solution was stirred for 12 hours in an oil tank at 90 ° C. The reaction was then stopped by adding 200 mL of water / ice. The resulting solution was extracted with ethyl acetate (200 mLx2). The residue was applied on a silica gel column and eluted with ethyl acetate / petroleum ether (1: 1). This gave 4.2 g (18.8%) of tert-butyl (2S) -2- (hydroxymethyl) -4- (4-iodophenyl) piperazine-1-carboxylate as a solid. LC / MS (ESI) m / z: 419.05 [M + 1] ⁺ .
Step 2: Preparation of (S)-(4- (4-iodophenyl) piperazine-2-yl) methanol.

DCM (20 mL) of tert-butyl (2S) -2- (hydroxymethyl) -4- (4-iodophenyl) piperazine-1-carboxylate (4.2 g, 9.9 mmol, 1 eq) in a 50 mL round bottom flask ) And a solution of TFA (2 mL) were added. The obtained mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. As a result, 3.2 g of [(2S) -4- (4-iodophenyl) piperazine-2-yl] methanol was obtained as a solid substance. LC / MS (ESI) m / z: 318.95 [M + 1] ⁺ .
Step 3: Preparation of tert-butyl (S) -4-((2- (hydroxymethyl) -4- (4-iodophenyl) piperazin-1-yl) methyl) piperidine-1-carboxylate.

In a 100 mL round bottom flask, [(2S) -4- (4-iodophenyl) piperazine-2-yl] methanol (3.2 g, 9.9 mmol, 1.0 eq), tert-butyl 4-formylpiperidine-1-carboxylic acid Salt (2.5g
, 12.1 mmol, 1.2 eq), trimethyl orthoformate (1.1 g, 9.9 mmol, 1.0 eq) in DCM (30 mL). The obtained mixed solution was stirred at room temperature for 16 hours, NaBH (OAc) ₃ (3.2 g, 15.2 mmol, 1.5 eq) was added, and the reaction solution was stirred at room temperature for 3 hours. The reaction was then quenched by the addition of 100 mL of water / ice. The resulting solution was extracted with dichloromethane (50 mL x 3). The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1: 1). This resulted in 3.6 g (67.1%) of tert-butyl 4-[[(2S) -2- (hydroxymethyl) -4- (4-iodophenyl) piperazine-1-yl] methyl] piperidine-1-carboxylic acid. Salt was obtained as a solid. LC / MS (ESI) m / z: 516.15 [M + 1] ⁺ .
Step 4: Preparation of (S)-(4- (4-iodophenyl) -1- (piperidine-4-ylmethyl) piperazin-2-yl) methanol.

In a 100 mL round bottom flask, tert-butyl 4-[[(2S) -2- (hydroxymethyl) -4- (4-iodophenyl) piperazine-1-yl] methyl] piperidine-1-carboxylate (3.6) A solution of DCM (30 mL) and TFA (3 mL) (g, 6.2 mmol, 1.0 equivalent) was added. The obtained mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated. This gave 2.5 g (85.6%) of [(2S) -4- (4-iodophenyl) -1-[(piperidine-4-yl) methyl] piperazine-2-yl] methanol as a solid. LC / MS (ESI) m / z: 416.10 [M + 1] ⁺ .
Step 5: Preparation of tert-butyl (S) -2- (4-((2- (hydroxymethyl) -4- (4-iodophenyl) piperazin-1-yl) methyl) piperidine-1-yl) acetate ..

In a 100 mL round bottom flask, [(2S) -4- (4-iodophenyl) -1-[(piperidin-4-yl) methyl] piperazine-2-yl] methanol (2.5 g, 5.7 mmol, 1.0 eq) A solution of DCM (30 mL) of tert-butyl 2-bromoacetate (1.1 g, 5.7 mmol, 1.0 eq) and N, N-diisopropylethylamine (1.4 g, 11.5 mmol, 2.0 eq) was added. The resulting mixture was stirred at room temperature for 16 hours. Then
The reaction was stopped by the addition of 100 mL of water. The resulting solution was extracted with dichloromethane (50 mL x 3). The residue was applied on a silica gel column and eluted with ethyl acetate / petroleum ether (1: 1). This resulted in 1.2 g (44.2%) of tert-butyl 2- (4-[[(2S) -2- (hydroxymethyl) -4- (4-iodophenyl) piperazine-1-yl] methyl] piperidine-1. -Il) Acetate was obtained as a solid. LC / MS (ESI) m / z: 530.25 [M + 1] ⁺ .
Step 6: tert-butyl (S) -2- (4-((((tert-butyldiphenylsilyl) oxy) methyl) -4- (4-iodophenyl) piperazine-1-yl) methyl) piperidine -1-yl) Preparation of acetate.

In a 100 mL round bottom flask, tert-butyl 2- (4-[[(2S) -2- (hydroxymethyl) -4- (4-iodophenyl) piperazin-1-yl] methyl] piperidin-1-yl) A solution of acetate (1.2 g, 2.4 mmol, 1.0 eq), tert-butyl (chloro) diphenylsilane (754.6 mg, 2.5 mmol, 1.1 eq), imidazole (339.6 mg, 4.9 mmol, 2.0 eq) in DCM (30 mL) I put it in. The obtained mixture was stirred at room temperature for 2 hours. The reaction was then stopped by the addition of 50 mL of water. The resulting mixture was extracted with dichloromethane (50 mLx3). The residue was applied on a silica gel column and eluted with ethyl acetate / petroleum ether (1: 1). This resulted in 920.0 mg (61.1%) of tert-butyl 2- (4-[[(2S) -2-[[(tert-butyldiphenylsilyl) oxy] methyl] -4- (4-iodophenyl) piperazine- 1-Il] Methyl] Piperidine-1-yl) Acetate was obtained as a solid. LC / MS (ESI) m / z: 768.35 [M + 1] ⁺ .
Step 7: (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 preparation.

In a 250 mL round bottom flask purged and maintained in an inert nitrogen atmosphere, (3R) -N- (3- [5-bromo-1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2 , 4-Difluorophenyl) -3-fluoropyrrolidin-1-sulfonamide (5 g, 9.93 mmol, 1.0 eq), bis (pinacholate) diboron (13 g, 51.19 mmol, 5.15 eq), KOAc (5 g, 50.94 mmol, 5.13 eq) ), Pd (dppf) Cl ₂ (1.7 g, 2.32 mmol, 0.23 eq) and dioxane (100 mL) were added. The obtained solution was stirred for 16 hours in an oil tank under a nitrogen atmosphere at 100 ° C. The resulting mixture was concentrated under reduced pressure. The residue was loaded into a silica gel column with dichloromethane / ethyl acetate (1: 1). This will result in
4.05g (74%) of (3R) -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 was obtained as a light brown solid. LC / MS (ESI) m / z: 551.10 [M + 1] ⁺ .
Step 8: tert-Butyl 2- (4-(((S) -2-(((tert-butyldiphenylsilyl) oxy) methyl) -4- (4- (3- (2,6-difluoro-3-) (((R) -3-fluoropyrrolidine) -1-sulfonamide) Benzoyl
) -1H-Pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperazine-1-yl) Methyl) Piperidine-1-yl) Preparation of acetate.

In a 30 mL sealed tube purged and maintained in an inert nitrogen atmosphere, tert-butyl 2-(4-[[(2S) -2-[[(tert-butyldiphenylsilyl) oxy] methyl] -4- (4-Iodophenyl) Piperazine-1-
Il] Methyl] piperidin-1-yl) acetate (920.0 mg, 1.1 mmol, 1.0 eq _{) in a solution of dioxane / H 2} O (4/1 = 10 mL), (3R) -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-Fluoropyrrolidin-1-sulfonamide (1.0 mg, 1.9 mmol, 1.5 eq), potassium phosphate, tribasic acid (796.2 mg, 3.4 mmol, 3.0 eq), Pd (DtBPF) Cl ₂ (162.9 mg, 0.3 mmol) , 0.2 equivalent) was added. The final reaction mixture was irradiated with microwave radiation at 95 ° C. under _{N 2 for 1 hour.} The resulting mixture was concentrated under reduced pressure. The residue was loaded into a silica gel column with dichloromethane / methanol (15: 1). This resulted in 465.0 mg of tert-butyl 2- (4-[[(2S) -2-[[(tert-butyldiphenylsilyl) oxy] methyl] -4- (4- [3- [2,6-difluoro] -3-([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazine-1-yl] Methyl] piperidine-1-yl) acetate was obtained as a solid. LC / MS (ESI) m / z: 1064.40 [M + 1] ⁺ .
Step 9: 2- (4-(((S) -2-(((tert-butyldiphenylsilyl) oxy) methyl) -4- (4- (3- (2,6-difluoro-3-(((() R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) methyl) piperidine-1-yl) acetic acid Preparation.

In a 50 mL round bottom flask, tert-butyl 2- (4-[[(2S) -2-[[(tert-butyldiphenylsilyl) oxy] methyl] -4- (4- [3- [2,6-,6-] Difluoro-3-([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazine-1-yl ] Methyl] Piperidine-1-yl) acetate (465.0 mg, 0.5 mmol, 1.0 equivalent) DCM (10 mL)
And a solution of TFA (2.0 mL) was added. The obtained mixture was stirred at room temperature for 4 hours. The resulting mixture was concentrated under reduced pressure. This resulted in 415.0 mg (98.0%) of 2- (4-[[(2S) -2-[[(tert-butyldiphenylsilyl) oxy] methyl] -4- (4- [3- [2,6-] Difluoro-3-([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazine-1-yl ] Methyl] piperidine-1-yl) Acetic acid was obtained as a solid. LC / MS (ESI) m / z: 1008.45 [M + 1] ⁺ .
Step 10: (2S, 4R) -1-((S) -2-(2-(4-(((S) -2-(((tert-butyldiphenylsilyl) oxy))
Methyl) -4- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide))
Benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) methyl) piperidine-1-yl) acetamide) -3,3-dimethylbutanoyl) -4-hydroxy Preparation of -N-((S) -1- (4- (4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide.

In a 50 mL round bottom flask, 2- (4-[[(2S) -2-[[(tert-butyldiphenylsilyl) oxy] methyl] -4- (4- [3- [2,6-difluoro-3) -([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridine-5-yl] phenyl) piperazin-1-yl] methyl] Piperidine-1-yl) acetic acid (415.0 mg, 0.5 mmol, 1.0 equivalent), (2S, 4R) -1-[(2S) -2-amino-3,3-dimethylbutanoyl] -4-hydroxy-N- [(1S) -1- [4- (4-Methyl-1,3-thiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (225.2 mg, 0.5 mmol, 1.1 equivalent), N, N-diisopropyl A solution of DMF (10 mL) of ethylamine (120.9 mg, 0.8 mmol, 2.0 equivalents) and BOP (249.4 mg, 0.6 mmol, 1.3 equivalents) was added. The resulting mixture was stirred at room temperature for 30 minutes. The reaction was then stopped by the addition of 50 mL of water. The resulting solution was extracted with ethyl acetate (50 mLx3). The residue was loaded into a silica gel column with dichloromethane / methanol (10: 1). This resulted in 365.0 mg (63.3%) of (2S, 4R) -1-[(2S) -2- [2- (4-[[(2S) -2-[[(tert-butyldiphenylsilyl) oxy]. Methyl] -4-(4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3] -b] Pyridine-5-yl] Phenyl) Piperazine-1-yl] Methyl] Piperidine-1-yl) Acetamide] -3,3-Dimethylbutanoyl] -4-Hydroxy-N-[(1S) -1- [4- (4-Methyl-1,3-thiazole-5-yl) phenyl] ethyl] Piperidine-2-carboxamide was obtained as a solid. LC / MS (ESI) m / z: 1435.75 [M + 1] ⁺ .
Step 11: (2S, 4R) -1-((S) -2- (2-(4-(((S) -4- (4- (3- (2,6-difluoro-3- (((() R) -3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridine-5-yl) phenyl) -2- (hydroxymethyl) piperazin-1-yl) methyl) Piperidine-1-yl) acetamide) -3,3-dimethylbutanoyl) -4-hydroxy-N-((S) -1-(4-(4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine- 2-Preparation of carboxamide.

In a 50 mL round bottom flask, (2S, 4R) -1-[(2S) -2- [2- (4-[[(2S) -2-[[(tert-butyldiphenylsilyl) oxy] methyl]- 4- (4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] Pylin-5-yl] Phenyl) Piperazin-1-yl] Methyl] Piperidine-1-yl) Acetamide] -3,3-Dimethylbutanoyl] -4-Hydroxy-N-[(1S) -1- [4-] DMSO (10 mL) of (4-methyl-1,3-thiazole-5-yl) phenyl] ethyl] piperidine-2-carboxamide (365.0 mg, 0.2 mmol, 1.0 equivalent) and CsF (88.2 mg, 0.4 mmol, 2.0 equivalent) ) Solution was added. The obtained mixed solution was stirred in an oil tank at 40 ° C. for 48 hours.
The reaction was then stopped by the addition of 50 mL of water. The resulting solution was extracted with ethyl acetate (50 mLx3) and concentrated. The crude product was purified by preparative HPLC. As a result, 69.8 mg (23.9%) of (2S, 4R) -1-[(2S) -2- [2- (4-[[(2S) -4- (4- [3- [2,6-] Difluoro-3-([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) -2- (hydroxy) Methyl) piperazin-1-yl] methyl] piperidine-1-yl) acetamide] -3,3-dimethylbutanoyl] -4-hydroxy-N-[(1S) -1- [4- (4-methyl-1) , 3-Thiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide was obtained as a solid. LC / MS (ESI) m / z: 1196.55 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 12.90 (s, 1H), 8.98 (s, 1H), 8.72 (s, 1H), 8.60-8.53 (m, 1H), 8.10 (s, 1H), 7.78-7.72 (m, 1H), 7.62-7.55 (m, 3H), 7.47 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 9.5 Hz, 2H), 7.25-7.16 (m, 1H), 7.10-7.08 (m, 2H), 5.35-5.20 (m, 1H), 5.12 (s, 1H), 4.93-4.80 (m, 1H) , 4.65-4.60 (m, 1H), 4.51-4.45 (m, 1H), 4.30-4.20 (m, 1H), 3.75-3.70 (m, 1H), 3.65-3.57 (m, 2H), 3.55-3.52 ( m, 3H), 3.45-3.33 (m, 3H), 3.32-3.16 (m, 1H), 3.11-3.02 (m, 2H), 3.00-2.56 (m, 7H), 2.50-2.46 (m, 4H), 2.33 (s, 1H), 2.29-2.07 (m, 6H), 1.90-1.70 (m, 3H), 1.51 (m, 1H), 1.38 (s, 3H), 1.25-1.06 (s, 3H), 0.94 ( s, 9H).
(2S, 4R) -1-((S) -2- (2- (4-((1- (4- (3- (2,6-difluoro-3- (((R) -3-fluoropyrolidin) ) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperidine-4-yl) methyl) piperazine-1-yl) acetamide) -3,3-dimethyl Illustrative Synthesis of Butanoyl) -4-Hydroxy-N-((S) -1- (4- (Pyridine-4-yl) Phenyl) Ethyl) Pyrrolidine-2-Carboxamide (Exemplary Compound 776) Step 1: Methyl Preparation of (2S, 4R) -4-hydroxypyrrolidin-2-carboxylate.

1-tert-Butyl 2-methyl (2S, 4R) -4-hydroxypyrrolidine-1,2-dicarboxylate (10g)
, 40.77 mmol, 1 eq) in a mixture of dichloromethane (10 mL) was added hydrogen chloride / dioxane (4 M, 10 eq) at 20 ° C. The mixture was stirred for 1 hour at 20 ° C. The mixture was concentrated under reduced pressure to give methyl (2S, 4R) -4-hydroxypyrrolidine-2-carboxylate (7.4 g, hydrochloride) as a yellow oil.

Step 2: Preparation of methyl (2S, 4R) -1-((S) -2-((tert-butoxycarbonyl) amino) -3,3-dimethylbutanoyl) -4-hydroxypyrrolidine-2-carboxylate ..

Methyl (2S, 4R) -4-hydroxypyrrolidine-2-carboxylate (7.4 g, 40.75 mmol, 1 equivalent, 1 equivalent,
Carbodiimide hydrochloride in a mixture of dimethylformamide (200 mL) of (2S) -2- (tert-butoxycarbonylamino) -3,3-dimethyl-butanoic acid (9.42 g, 40.75 mmol, 1 eq). (15.62 g, 81.49 mmol, 2 eq), hydroxybenzotriazole (6.61 g, 48.89 mmol, 1.2 eq) and diisopropylethylamine (31.60 g, 244.47 mmol, 6 eq) were added. The mixture was stirred at 20 ° C. for 12 hours. The mixture was quenched by the addition of water (1000 mL), extracted with ethyl acetate (200 mLx4), the combined organic layers were washed with brine (100 mLx2), dried over anhydrous sodium sulfate, filtered and filtered. Concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1 to 1: 1). Compound Methyl (2S, 4R) -1-[(2S) -2- (tert-butoxycarbonylamino) -3,3-dimethyl-butanoyl] -4-hydroxy-pyrrolidin-2-carboxylate (13.5 g, 37.66 mmol, yield 92%) was obtained as a yellow oil. LC / MS (ESI) m / z: 381.2 [M + 23] ⁺ .
Step 3: Preparation of methyl (2S, 4R) -1-((S) -2-amino-3,3-dimethylbutanoyl) -4-hydroxypyrrolidine-2-carboxylate.

Methyl (2S, 4R) -1-[(2S) -2- (tert-butoxycarbonylamino) -3,3-dimethyl-butanoyl] -4-hydroxy-pyrrolidin-2-carboxylate (13g, 36.27 mmol, Hydrochloride / dioxane (4M, 10 eq) was added to a mixture of 1 equivalent) dichloromethane (5 mL). The mixture was stirred at 20 ° C. for 20 minutes. The mixture is concentrated under reduced pressure to methyl (2S, 4R) -1-[(2S) -2-amino-3,3-dimethyl-butanoyl] -4-hydroxy-pyrrolidin-2-carboxylate (11g). , Hydrochloride) was obtained as a colorless oil.

Step 4: tert-butyl 4-(2-(((S) -1-((2S, 4R) -4-hydroxy-2- (methoxycarbonyl) pyrrolidine-1-yl) -3,3-dimethyl-1) -Preparation of oxobutane-2-yl) amino) -2-oxoethyl) piperazine-1-carboxylate.

Methyl (2S, 4R) -1-[(2S) -2-amino-3,3-dimethyl-butanoyl] -4-hydroxy-pyrrazine-2-carboxylate (11 g, 37.32 mmol, 1 equivalent, hydrochloride) , 2- (4-tert-Butoxycarbonylpiperazine-1-yl) acetic acid (10.03 g, 41.05 mmol, 1.1 eq) dimethylformamide (400 mL)
Carbonimide hydrochloride (14.31 g, 74.63 mmol, 2 eq), hydroxybenzotriazole (6.05 g, 44.78 mmol, 1.2 eq) and diisopropylethylamine (28.94 g, 223.90 mmol, 6 eq) were added to the mixture. The mixture was stirred at 20 ° C. for 12 hours. The mixture was quenched by the addition of water (1000 mL), extracted with ethyl acetate (100 mLx6), the combined organic layers were washed with brine (100 mLx2), dried over anhydrous sodium sulfate, filtered and filtered. Concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3: 1 to 0: 1). Compound tert-butyl 4- [2-[[(1S) -1-[(2S, 4R) -4-hydroxy-2-methoxycarbonyl-pyrrolidin-1-carbonyl] -2,2-dimethyl-propyl] amino ] -2-oxo-ethyl] piperazine-1-carboxylate (5 g, 10.32 mmol, 27% yield) was obtained as a white solid. LC / MS (ESI) m / z: 485.3 [M + 1] ⁺ .
Step 5: Methyl (2S, 4R) -1-((S) -3,3-dimethyl-2-(2- (piperazine-1-yl) acetamide) butanoyl) -4-hydroxypyrrolidine-2-carboxylate Preparation.

tert-butyl 4- [2-[[(1S) -1-[(2S, 4R) -4-hydroxy-2-methoxycarbonyl-pyrrolidin-1-carbonyl] -2,2-dimethyl-propyl] amino]- Hydrogen chloride / dioxane (4M, 10 equivalents) was added to a mixture of dichloromethane (50 mL) of 2-oxo-ethyl] piperazin-1-carboxylate (600 mg, 1.24 mmol, 1 equivalent). The mixture was stirred at 25 ° C. for 30 minutes. The mixture is concentrated under reduced pressure to methyl (2S, 4R) -1-[(2S) -3,3-dimethyl-2-[(2-piperazin-1-ylacetyl) amino] butanoyl] -4-hydroxy. -Pyrrolidine-2-carboxylate (520 mg, hydrochloride) was obtained as a white solid. LC / MS (ESI) m / z: 385.1 [M + 1] ⁺ .
Step 6: Methyl (2S, 4R) -1-((S) -2- (2-(4-((1- (4- (3- (2,6-difluoro-3- (((R)-)- 3-Fluoropyrrolidine) -1-sulfonamide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperidine-4-yl) Methyl) Piperazin-1-yl) Acetamide) -3 , 3-Dimethylbutanoyl) -4-hydroxypyrrolidine-2-carboxylate preparation.

Methyl (2S, 4R) -1-[(2S) -3,3-dimethyl-2-[(2-piperazine-1-ylacetyl) amino] butanoyl] -4-hydroxy-pyrrolidin-2-carboxylate (520 mg) , 1.24 mmol, 1.2 eq, hydrochloride) to a mixture of dichloroethane (20 mL) was added triethylamine (625 mg, 6.18 mmol, 6 eq). The mixture was stirred at 25 ° C. for 15 minutes. Then (3R) -N- [2,4-difluoro-3- [5- [4- (4- (4- (4-)
Formyl-1-piperidyl) phenyl] -1H-pyrrolo [2,3-b] pyridin-3-carbonyl] phenyl] -3-fluoro-pyrrolidin-1-sulfonamide (629 mg, 1.03 mmol, 1 equivalent) as a reaction solution In addition to
The mixture was stirred at 25 ° C. for 15 minutes. Then sodium borohydride (436 mg, 2.06 mmol, 2 eq) was added to the reaction mixture and the mixture was stirred at 25 ° C. for 12 hours. The mixture was quenched by the addition of water (150 mL), extracted with ethyl acetate (30 mLx5), the combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and filtered. Concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1 to 0: 1). Compound Methyl (2S, 4R) -1-[(2S) -2-[[2- [4-[[1- [4- [3- [2,6-difluoro-3-] [(3R)- 3-Fluoropyrrolidine-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl] -4-piperidyl] methyl] piperazine-1-yl] acetyl] amino] -3,3-dimethyl-butanoyl] -4-hydroxy-pyrrolidin-2-carboxylate (500 mg, 0.51 mmol, 49% yield) was obtained as a white solid. LC / MS (ESI) m / z: 980.5 [M] ⁺ .
Step 7: (2S, 4R) -1-((S) -2- (2-(4-((1- (4- (3- (2,6-difluoro-3- (((R) -3) -3) -Fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperidine-4-yl) methyl) piperazin-1-yl) acetamide) -3, Preparation of 3-dimethylbutanoyl) -4-hydroxypyrrolidine-2-carboxylic acid.

Methyl (2S, 4R) -1-[(2S) -2-[[2- [4-[[1- [4- [3- [2,6-Difluoro-3- [[(3R) -3-] Fluoropyrrolidine-1-yl] Sulfonylamino] Benzoyl] -1H-Pyrrolidine [2,3-b] Pyridine-5-yl]
Phenyl] -4-piperidyl] methyl] piperazine-1-yl] acetyl] amino] -3,3-dimethyl-butanoyl] -4-hydroxy-pyrrolidin-2-carboxylate (500 mg, 0.51 mmol, 1 equivalent) Sodium hydroxide (4M, 4 eq) was added to the mixture of methanol (10 mL). The mixture was stirred at 40 ° C. for 1 hour. The mixture was concentrated under reduced pressure to remove methanol and the residue was adjusted to pH = 3-4. The solution was purified by preparative HPLC. Compound (2S, 4R) -1-[(2S) -2-[[2- [4-[[1- [4- [3- [2,6-difluoro-3- [[(3R) -3) -Fluoropyrrolidine-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl] -4-piperidyl] methyl] piperazin-1-yl]
Acetyl] amino] -3,3-dimethyl-butanoyl] -4-hydroxy-pyrrolidin-2-carboxylic acid (400 mg, 0.41 mmol, 81% yield) was obtained as a yellow solid. LC / MS (ESI) m / z: 966.1 [M] ⁺ .
Step 8: Preparation of tert-butyl (S)-(1- (4- (pyridin-4-yl) phenyl) ethyl) carbamate.

tert-butyl N-[(1S) -1- (4-bromophenyl) ethyl] carbamate (500 mg, 1.67 mmol)
, 1 eq), 4-pyridylboronic acid (245 mg, 2.00 mmol, 1.2 eq), [1,1-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (121 mg, 0.16 mmol, 0.1 eq), and phosphorus. A mixture of dioxane (50 mL) and water (5 mL) of potassium acid (707 mg, 3.33 mmol, 2 eq) was degassed and then heated to 80 ° C. for 12 hours under nitrogen. The mixture was filtered and concentrated under reduced pressure. Residues are subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 15: 1-5: 1)
Purified by. The compound tert-butyl N-[(1S) -1- [4- (4-pyridyl) phenyl] ethyl] carbamate (400 mg, 1.34 mmol, 80% yield) was obtained as a white solid. LC / MS (ESI) m / z:
299.2 [M + 1] ⁺ .
Step 9: Preparation of (S) -1- (4- (pyridin-4-yl) phenyl) ethane-1-amine.

Hydrogen chloride / dioxane in a mixture of tert-butyl N-[(1S) -1- [4- (4-pyridyl) phenyl] ethyl] carbamic acid salt (400 mg, 1.34 mmol, 1 eq) in dichloromethane (10 mL). (4M, 3.35 mL, 10 eq) was added. The mixture was stirred at 25 ° C. for 30 minutes. The mixture was concentrated under reduced pressure to give (1S) -1- [4- (4-pyridyl) phenyl] ethaneamine (380 mg, hydrochloride) as a white solid. LC / MS (ESI) m / z: 199.1 [M + 1] ⁺ .
Step 10: (2S, 4R) -1-((S) -2- (2-(4-((1- (4- (3- (2,6-difluoro-3- (((R) -3) -3) -Fluoropyrrolidine) -1-sulfonamide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperidine-4-yl) Methyl) Piperazin-1-yl) Acetamide) -3, Preparation of 3-dimethylbutanoyl) -4-hydroxy-N-((S) -1- (4- (pyridin-4-yl) phenyl) ethyl) pyrrolidine-2-carboxamide.

(1S) -1- [4- (4-pyridyl) phenyl] ethaneamine (54 mg, 0.23 mmol, 1.5 eq, hydrochloride)
, (2S, 4R) -1-[(2S) -2-[[2- [4-[[1- [4- [3- [2,6-difluoro-3- [[(3R) -3-] Fluoropyrrolidine-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridine-5-yl] phenyl] -4-piperidyl] methyl] piperazine-1-yl] acetyl] amino] -3 , 3-Dimethyl-butanoyl] -4-hydroxy-pyrrolidin-2-carboxylic acid (150 mg, 0.15 mmol, 1 equivalent) in a mixture of dimethylformamide (10 mL) with hydroxybenzotriazole (25 mg, 0.18 mmol, 1.2 equivalent) , Diisopropylethylamine (120 mg, 0.93 mmol, 6 equivalents) and carbodiimide hydrochloride (59 mg, 0.31 mmol, 2 equivalents) were added. The mixture was stirred at 25 ° C. for 12 hours. The mixture was quenched by the addition of water (100 mL), extracted with ethyl acetate (30 mLx3), the combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and filtered. Concentrated under reduced pressure. The residue was purified by preparative HPLC. Compound (2S, 4R) -1-[(2S) -2-[[2- [4-[[1- [4- [3- [2,6-difluoro-3- [[(3R) -3) -Fluoropyrrolidine-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl] -4-piperidyl] methyl] piperazine-1-
Il] Acetyl] Amino] -3,3-Dimethyl-Butanoyl] -4-Hydroxy-N-[(1S) -1- [4- (4-pyridyl) phenyl] Ethyl] Pyrrolidine-2-carboxamide (61 mg, 0.04) mmol, yield 31%, purity 99%, 2 formate) was obtained as a yellow solid. LC / MS (ESI) m / z: 573.8 [M / 2 + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 13.14 --.12.31 (m, 1H), 8.68 --8.59 (m, 3H), 8.56 --8.43 (m, m,
2H), 8.22 --8.13 (m, 2H), 8.06 (s, 1H), 7.81 --7.76 (m, 5H), 7.64 --7.54 (m, 3H), 7.47 --7.37 (m, 2H), 7.25 (t, J = 9.2 Hz, 1H), 7.07 (d, J = 8.8 Hz, 2H), 5.41 --5.91 (m, 1H), 5.18 --4.87 (m, 2H), 4.55 --4.37 (m, 2H), 4.31 --4.23 (m, 1H), 3.83 --3.75 (m, 2H), 3.63 --3.53 (m, 6H), 3.01 --2.94 (m, 2H), 2.78 --2.68 (m, 3H), 2.44 (s, 3H), 2.21 (d, J = 6.8 Hz, 3H), 2.14 --1.99 (m, 4H), 1.86 --1.66 (m, 5H), 1.48 --1.37 (m, 3H), 1.30 --1.13 (m, 3H), 0.95 (s) , 9H).
(2S, 4R) -1- (2- (5- (4-((1- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-
Sulfonamide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperidine-4-yl) Methyl) Piperidine-1-yl) Pyridine-3-yl) -3-Methylbutanoyl ) -4-Hydroxy-N-((S) -1- (4- (4-Methylthiazole-5-yl) phenyl) ethyl) Pyridine-2-carboxamide (Exemplary Compound 752) Illustrative Synthesis Step 1: Preparation of ethyl 2- (5-bromopyridin-3-yl) acetate.

_{Concentrated H 2} SO ₄ (4.0 mL) was added to a solution of 2- (5-bromopyridin-3-yl) acetonitrile (510 mg, 2.6 mmol) in ethanol (13 mL). The reaction mixture was stirred at 90 ° C. for 16 hours. After the reaction was complete, the pH of the mixture _{was adjusted to 10 with saturated NaHCO 3} and then extracted with ethyl acetate (10 x 3 mL) and washed with brine (5 mL). The organic phase was concentrated under vacuum. The residue was purified by column chromatography (PE: EA = 2: 1 to 1: 5) to give ethyl 2- (5-bromopyridin-3-yl) acetate (550 mg) as a yellow oil. LC / MS (ESI) m / z: 244.1 [M + 1] ⁺ .
Step 2: Preparation of ethyl 2- (5-bromopyridin-3-yl) -3-methylbutanoate.

A solution of 1 mL of anhydrous THF in ethyl 2- (5-bromopyridin-3-yl) acetate (100 mg, 0.41 mmol) was cooled to −78 ° C. and LiHMDS (0.45 mL, 0.45 mmol) was added dropwise. After 30 minutes, 2-iodopropane (76.5 mg, 0.45 mmol) was added. The mixture was stirred at −78 ° C. for 1 hour and then left at room temperature for 12 hours. After the reaction was completed, it was quenched with water at 0 ° C. The mixture was extracted with EA (5 mLx3) and washed with brine (2 mL). The organic phase was concentrated under vacuum. The residue was purified by column chromatography (PE: EA = 1: 5 to 1: 1) with 2- (5-bromopyridin-3-yl) -3-methylbutanoate (320 mg) as a yellow oil. Obtained. LC / MS (ESI) m / z: 287.0 [M + 1] ⁺ .
Step 3: Preparation of tert-butyl 4- (5- (1-ethoxy-3-methyl-1-oxobutan-2-yl) pyridin-3-yl) piperazine-1-carboxylate.

2- (5-bromopyridin-3-yl) -3-methylbutanoate (220 mg, 0.77 mmol), tert-butyl
Piperazine-1-carboxylate (216 mg, 1.16 mmol), Ru (phos) (145 mg, 0.31 mmol), Cs ₂ CO ₃ (378 mg, 1.16 mmol) and Pd (OAc) ₂ (34 mg, 0.15 mmol) toluene ( 4 mL) of the mixture under _{N 2 4}
Stir at 100 ° C for hours. The mixture is concentrated and purified by a chromatographic column with PE: EA = 10: 10 to 1: 1 to tert-butyl 4- (5- (1-ethoxy-3-methyl-1-oxobutane-2-yl) ) Pyridine-3-yl) piperazine-1-carboxylate (280 mg) was obtained as a white solid. LC / MS (ESI) m / z: 392.2 [M + 1] ⁺ .
Step 4: Preparation of ethyl 3-methyl-2- (5- (piperazine-1-yl) pyridin-3-yl) butaneate.

In a 50 mL round bottom flask, tert-butyl 4- [5- (1-ethoxy-3-methyl-1-oxobutane-2-)
Il) Pylin-3-yl] Piperazine-1-carboxylate (450 mg, 1.149 mmol, 1 eq) in a solution of dioxane (15 mL), to which is a solution of HCl in 1,4-dioxane (4M, 15 mL). Was added. The resulting solution was stirred at room temperature for 7 hours. The resulting mixture was concentrated under reduced pressure. This gave 460 mg of a hydrochloride hydrochloride of ethyl 3-methyl-2- [5- (piperazine-1-yl) pyridin-3-yl] butaneate as a yellow solid. LC / MS (ESI) m / z: 292.20 [M + 1] ⁺ .
Step 5: Preparation of ethyl 2- (5-(4-((1- (4-bromophenyl) piperidine-4-yl) methyl) piperazine-1-yl) pyridin-3-yl) -3-methylbutanoate ..

In a 100 mL round bottom flask, ethyl 3-methyl-2- [5- (piperazin-1-yl) pyridine-3-yl] butaneate (146.70 mg, 0.503 mmol, 1 eq), DIEA (195.20 mg, 1.510) DCM (320.10 mg, 1.510 mmol, 3 eq), 1- (4-bromophenyl) piperidin-4-carbaldehyde (135 mg, 0.503 mmol, 1 eq), acetylsodiboranyl acetate (320.10 mg, 1.510 mmol, 3 eq) 50 mL) of the solution was added. The resulting solution was stirred at room temperature for 8 hours. The reaction was then quenched by the addition of 20 mL of water / ice. The resulting solution was extracted with ethyl acetate (40 mLx3) and the organic layers were combined into one. The resulting mixture was washed with brine (20 mL x 1), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied on a silica gel column and eluted with dichloromethane / methanol (20/1). The collected fractions were combined and concentrated under vacuum. This resulted in 105 mg (38.37%) of ethyl 2- [5- (4-[[1- (4-bromophenyl) piperidine-4-yl] methyl] piperazine-1-yl) pyridin-3-yl] -3. -Methylbutanoate was obtained as a yellow solid. LC / MS (ESI) m / z: 545.30 [M + 1] ⁺ .
Step 6: Ethyl 2- (5-(4-((1- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl))) Preparation of -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperidine-4-yl) methyl) piperazine-1-yl) pyridin-3-yl) -3-methylbutaneate.

In a 20 mL closed tube purged and maintained in an inert nitrogen atmosphere, ethyl 2- [5-(4-[[1- (4-bromophenyl) piperidine-4-yl] methyl] piperazin-1-yl) Ppyridine-3-yl] -3-methylbutaneate (105 mg, 0.193 mmol, 1 equivalent), (3R) -N- [2,4-difluoro-3- [5- (4,4,5,5-tetra) Methyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] phenyl] -3-fluoropyrrolidin-1-sulfonamide (159.47 mg, 0.290 mmol, 1.50 equivalents), K ₃ PO ₄ (123.01 mg, 0.580 mmol, 3.00 equivalents) in H ₂ O (2 mL), Pd (DtBPF) Cl ₂ (62.95 mg, 0.097 mmol, 0.5 equivalents) in dioxane (8 mL). The solution was added. The final reaction mixture was irradiated with microwave radiation at 85 ° C. for 1 hour. The reaction was then stopped by adding 10 mL of water / ice. The resulting solution was extracted with ethyl acetate (40 mLx3). The combined organic layers were washed with brine (20 mLx1), dried over anhydrous sodium sulfate and concentrated. The residue was applied on a silica gel column and eluted with dichloromethane / methanol (10/1). This resulted in 31 mg of ethyl 2- [5- (4- [[1- (4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidine-1-yl] sulfonyl] sulfonyl). ] Amino) Benzoyl] -1H-pyrrolo [2,3-b] Pyridine-5-yl] Phenyl) Piperidine-4-yl] Methyl] Piperazine-1-yl) Pyridine-3-yl] -3-Methylbutaneate Was obtained as a brown solid. LC / MS (ESI) m / z: 887.20 [M + 1] ⁺ .
Step 7: 2- (5-(4-((1- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl))- Preparation of 1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperidine-4-yl) methyl) piperazine-1-yl) pyridin-3-yl) -3-methylbutanoic acid.

In a 50 mL round bottom flask, ethyl 2- [5-(4-[[1- (4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidin-1-yl) ] Sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridine-5-yl] phenyl) piperidine-4-yl] methyl] piperazine-1-yl) pyridine-3-yl] -3-methylbutane A solution of MeOH (5 mL) of the acid salt (31 mg, 0.035 mmol, 1 equivalent) was added, and a solution _{of H 2} O (2 mL) of _{LiOH.H 2} O (14.67 mg, 0.349 mmol, 10 equivalents) was added thereto. .. The resulting solution was stirred for 8 hours in an oil bath at 40 ° C. The pH value of the solution was adjusted to 5 with HCl (2 mol / L). The resulting mixture was concentrated under vacuum. This resulted in 79 mg of 2- [5-(4-[[1- (4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidine-1-yl] sulfonyl] sulfonyl]]. Amino) benzoyl] -1H-pyrrolo [2,3-b] pyridine-5-yl] phenyl) piperidine-4-yl] methyl] piperazine-1-yl) pyridin-3-yl] -3-methylbutanoic acid; lithiumol (Lithiumol) was obtained as a brown solid.

Step 8: (2S, 4R) -1- (2- (5- (4-((1- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrolidin)) -1-Sulfone amide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperidine-4-yl) Methyl) Piperazine-1-yl) Pyridine-3-yl) -3- Preparation of Methylbutanoyl) -4-hydroxy-N-((S) -1-(4-(4-Methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide.

In a 25 mL round bottom flask, 2- [5-(4-[[1- (4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidin-1-yl]] Sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperidine-4-yl] methyl] piperazine-1-yl) pyridin-3-yl] -3-methylbutanoic acid (79 mg, 0.092 mmol, 1 equivalent), DIEA (35.66 mg, 0.276 mmol, 3 equivalents), (2S, 4R) -4-hydroxy-N-[(1S) -1- [4- (4-methyl-1) , 3-Thiazole-5-yl) phenyl] ethyl] pyrridin-2-carboxamide (60.96 mg, 0.184 mmol, 2.00 equivalents) and BOP (81.35 mg, 0.184 mmol, 2 equivalents) in DMF (10 mL). .. The resulting solution was stirred at room temperature for 1 hour. The reaction was then stopped by adding 10 mL of water / ice. The resulting solution was extracted with ethyl acetate (40 mLx3). The combined organic layers were washed with brine (20 mLx2), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by preparative HPLC. As a result, 10.2 mg (9.46%) of (2S, 4R) -1- [2- [5- (4-[[1- (4- [3- [2,6-difluoro-3- ([[( 3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperidine-4-yl] methyl] piperazin-1-yl ) Pyridine-3-yl] -3-methylbutanoyl] -4-hydroxy-N-[(1S) -1- [4- (4-methyl-1,3-thiazole-5-yl) phenyl] ethyl] Pyridine-2-
Carboxamide was obtained as a yellow solid. LC / MS (ESI) m / z: 1172.65 [M + 1] +; 1H-NMR (400MHz, CD3OD) δ 8.77 (s, 1H), 8.76 (s, 1H), 8.50 (s, 1H), 8.02 ( s, 1H), 7.79-7.48 (m, 1H), 7.47 (s, 1H), 7.39 (s, 2H), 7.36-7.32 (m, 5H), 7.12-7.00 (m, 3H), 5.21-5.11 ( m, 2H), 4.62-4.55 (m, 5H), 4.51-4.31 (m, 2H), 3.67-3.63 (m, 3H), 3.47-3.39 (m, 4H), 2.64-2.56 (m, 2H), 2.55-2.51 (m, 4H), 2.47 (s, 3H), 2.39-2.37 (m, 3H), 2.14-2.10 (m, 3H), 1.86-1.82 (m, 4H), 1.76-1.72 (m, 1H) ), 1.43-1.45 (t, J = 8 Hz, 2H), 1.35-1.18 (m, 5H), 1.18 (s, 3H), 0.65-0.61 (m, 3H).
(2S, 4R) -1-((S) -2-(5-(2-(4-(4-(3-(2,6-difluoro-3-(((R) -3-fluoropyrrolidin)) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) ethoxy) -1-methyl-1H-pyrazol-3-yl) -3 Illustrative of -methylbutanoyl) -4-hydroxy-N-((S) -1-(4-(4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (exemplary compound 753) Synthesis Step 1: Preparation of methyl 2- (5-hydroxy-1-methyl-1H-pyrazol-3-yl) acetate.

Methylhydrazine (21.83 g, 189.49 mmol, 25 mL, 1.1 eq) in a mixture of toluene (200 mL) with dimethyl 3-oxopentane hydrochloride (30 g, 172.26 mmol, 24.79 mL, 1 eq) and diisopropylethylamine (26.72 g). , 206.72 mmol, 36 mL, 1.2 eq). The mixture was stirred at 140 ° C. for 2 hours and the water was distilled off. The mixture was then stirred for 12 hours at 140 ° C. The reaction mixture was quenched by the addition of water (400 mL) and extracted with ethyl acetate (100 mLx3). The aqueous layer was adjusted to pH = 3-4 with 1M hydrochloric acid and then extracted with ethyl acetate (100mLx10). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The compound methyl 2- (5-hydroxy-1-methyl-pyrazol-3-yl) acetate (8.5 g, 49.95 mmol, 1.00 eq) was purified by preparative reverse phase HPLC. The product methyl 2- (5-hydroxy-1-methyl-pyrazole-3-yl) acetate (5.38 g, 31.62 mmol, 63% yield) was obtained as an off-white solid. LC / MS (ESI) m / z: 171.2 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 10.81 (br s, 1H), 5.42 --5.11 (m, 1H), 3.59 (s, 3H), 3.43 (s, 3H), 3.40 (s, 2H).
Step 2: Preparation of methyl 2- (5- (2,2-dimethoxyethoxy) -1-methyl-1H-pyrazole-3-yl) acetate.

Potassium carbonate (2.24 g, 16.22 mmol, 2) in a solution of dimethylformamide (30 mL) of methyl 2- (5-hydroxy-1-methyl-pyrazole-3-yl) acetate (1.38 g, 8.11 mmol, 1 eq). Equivalent) and 2-bromo-1,1-dimethoxy-ethane (1.44 g, 8.52 mmol, 1 mL, 1.05 equivalent) were added. The mixture was stirred at 70 ° C. for 12 hours. Water (50 mL) was poured into the mixture and stirred for 1 minute. The aqueous layer was extracted with ethyl acetate (50 mLx3). The combined organic layers were washed with brine (50 mLx3), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20/1 to 2/1). Product Methyl 2- [5- (2,2-dimethoxyethoxy) -1-methyl-pyrazole-3-yl] acetate (744 mg)
, 2.74 mmol, yield 33%, purity 95%) was obtained as a colorless oil. LC / MS (ESI) m / z: 259.2 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 5.52 (s, 1H), 4.68 (t, J = 5.2 Hz, 1H), 4.03 ( d, J = 5.2 Hz, 2H), 3.71 (s, 3H), 3.61 (s, 3H), 3.57 (s, 2H), 3.44 (s, 6H).
Step 3: Methyl 2- (5- (2,2-dimethoxyethoxy) -1-methyl-1H-pyrazole-3-yl) -3-
Preparation of methylbutanoate.

Methyl 2- [5- (2,2-dimethoxyethoxy) -1-methyl-pyrazole-3-yl] acetate (744 mg)
, 2.88 mmol, 1 eq) to a solution of tetrahydrofuran (12 mL) was added lithium diisopropylamide (2M, 2.88 mL, 2 eq) at -70 ° C. The mixture was stirred at −70 ° C. for 0.5 hours. 2-Iodine propane (734 mg, 4.32 mmol, 0.45 mL, 1.5 eq) was then added dropwise at -70 ° C. The mixture was stirred at 25 ° C. for 3 hours. The mixture was poured into water (50 mL) and stirred for 1 minute. The aqueous layer was extracted with ethyl acetate (30 mLx3). The combined organic layers were washed with brine (30 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20/1 to 4/1). Product Methyl 2- [5- (2,2-dimethoxyethoxy) -1-methyl-pyrazole-3-yl] -3-methyl-butanoate (300 mg, 0.86 mmol, yield 29%, purity 85% ) Was obtained as a bright yellow oil. LC / MS (ESI) m / z: 301.1 [M + 1] ⁺ .
Step 4: Preparation of 2- (5- (2,2-dimethoxyethoxy) -1-methyl-1H-pyrazole-3-yl) -3-methylbutanoic acid.

Methyl 2- [5- (2,2-dimethoxyethoxy) -1-methyl-pyrazole-3-yl] -3-methyl-butanoate (300 mg, 0.99 mmol, 1 eq) in tetrahydrofuran (5 mL), methanol ( Lithium hydroxide (167 mg, 4.00 mmol, 4 eq) was added to a solution of 2 mL) and water (1 mL). Mix liquid at 40 ° C
Stirred for 12 hours. Hydrochloric acid (1M, 5 mL) was added to the reaction mixture to adjust the pH to about 4-5, then the mixture was extracted with ethyl acetate (30 mL x 3). Brine (50mLx2) of organic layers combined into one
) Was washed, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The compound 2- [5- (2,2-dimethoxyethoxy) -1-methyl-pyrazole-3-yl] -3-methyl-butanoic acid (260 mg, 0.90 mmol, 90% yield) was obtained as a brown oil. rice field. LC / MS (ESI) m / z: 287.2 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 5.61 (s, 1H), 4.66 (t, J = 5.2 Hz, 1H), 4.06- 3.98 (m, 2H), 3.52 --- 3.47 (m, 3H), 3.34 (d, J = 0.8 Hz, 6H), 2.99 (d, J = 10.0 Hz, 1H), 2.12 (qd, J = 6.4, 16.4 Hz) , 1H), 0.94 (d, J = 6.4 Hz, 3H), 0.75 (d, J = 6.8 Hz,
3H).
Step 5: (2S, 4R) -1- (2- (5- (2,2-dimethoxyethoxy) -1-methyl-1H-pyrazole-3-yl) -3-methylbutanoyl) -4-hydroxy- Preparation of N-((S) -1-(4- (4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide.

(2S, 4R) -4-hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (334 mg, 0.90 mmol, 1 equivalent, 1 equivalent, Hydrochloride), 2- [5- (2,2-dimethoxyethoxy) -1-methyl-pyrazole-3-yl] -3-methyl-butanoic acid (260 mg, 0.90 mmol, 1)
To a solution of (equivalent) dimethylformamide (5 mL), O- (7-azabenzotriazole-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate (517 mg, 1.36 mmol). , 1.5 eq) and N, N-diisopropylethylamine (352 mg, 2.72 mmol, 3 eq) were added. The mixture was stirred for 1 hour at 15 ° C. The reaction mixture was diluted with 30 mL of water and extracted with ethyl acetate (50 mLx3). The combined organic layers were washed with brine (50 mLx3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% dichloromethane / methanol eluent). Compound (2S, 4R) -1- [2- [5- (2,2-dimethoxyethoxy) -1-methyl-pyrazole-3-yl] -3-methyl-butanoyl] -4-hydroxy-N- [ (1S) -1- [4- (4-Methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (300 mg, 0.47 mmol, yield 52.33%, purity 95%) as a white rubber-like substance Obtained. LC / MS (ESI) m / z: 600.3 [M + 1] +; 1H-NMR (400MHz, CDCl3) δ 8.68 (s, 1H), 7.44-
7.30 (m, 5H), 5.57 --5.53 (m, 1H), 4.82 --4.95 (m, 1H), 4.74 --4.53 (m, 3H), 4.11 --3.95 (m, 2H), 3.93 --3.82 (m, 1H) ), 3.58 (d, J = 3.2 Hz, 4H), 3.45 --3.42 (m, 3H), 3.41 (s, 2H), 3.38 (s, 2H), 2.53 (d, J = 1.6 Hz, 3H), 2.39 (s, 1H), 1.48 (d, J = 7.2 Hz, 1H), 1.32 (d, J = 7.2 Hz, 3H), 1.03 (d, J = 6.6 Hz, 3H), 0.94 --0.86 (m, 2H) , 0.86 --0.77 (m, 3H).
Step 6: (2S, 4R) -1-((S) -2- (5- (2,2-dimethoxyethoxy) -1-methyl-1H-pyrazole-3-)
Preparation of yl) -3-methylbutanoyl) -4-hydroxy-N-((S) -1-(4-(4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide.

(2S, 4R) -1- [2- [5- (2,2-dimethoxyethoxy) -1-methyl-pyrazole-3-yl] -3-methyl-butanoyl] -4-hydroxy-N-[(1S) ) -1- [4- (4-Methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (300 mg, 0.50 mmol, 1 eq) was purified by chiral SFC. Product (2S, 4R) -1- [(2S) -2- [5- (2,2-dimethoxyethoxy) -1-methyl-pyrazole-3-yl] -3-methyl-butanoyl] -4- Hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (85 mg, 0.14 mmol, yield 84%, purity 98.1%) white Obtained as a solid.

Step 7: (2S, 4R) -4-hydroxy-1-((S) -3-methyl-2-(1-methyl-5- (2-oxoethoxy) -1H-pyrazole-3-yl) butanoyl) Preparation of -N-((S) -1- (4- (4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide.

(2S, 4R) -1-[(2S) -2- [5- (2,2-dimethoxyethoxy) -1-methyl-pyrazole-3-yl] -3-
Methyl-butanoyl] -4-hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (80 mg, 0.13 mmol, 1 equivalent) Sulfuric acid (2M, 2 mL, 30 eq) was added to a solution of tetrahydrofuran (5 mL). The mixture was stirred at 70 ° C. for 2 hours. Water (10 mL) was added to the mixture and saturated sodium bicarbonate solution was added to adjust the pH to about 8. The mixture was then extracted with 40 mL (20 mLx2) of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Compound (2S, 4R) -4-hydroxy-1-[(2S) -3-methyl-2- [1-methyl-5- (2-oxoethoxy) pyrazole-3-yl] butanoyl] -N- [ (1S) -1- [4- (4-Methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (55 mg, 0.10 mmol, yield 74%) was obtained as a colorless rubbery substance. LC / MS (ESI) m / z: 277.6 [M / 2 + 1]
⁺ .
Step 8: (2S, 4R) -1-((S) -2- (5-(2- (4- (4- (3- (2,6-difluoro-3- (((R) -3-) -3-) Fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) ethoxy) -1-methyl-1H-pyrazol-3-yl ) -3-Methylbutanoyl) -4-
Hydroxy-N-((S) -1- (4- (4-Methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-
Preparation of carboxamide.

(3R) -N- [2,4-difluoro-3- [5- (4-piperazin-1-ylphenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] phenyl] -3- (2S, 4R) -4-hydroxy-1-[(2S) -3-methyl-2 in a solution of dimethylformamide (1.5 mL) of fluoro-pyrrolidin-1-sulfonamide (58 mg, 0.099 mmol, 1.00 equivalent) -[1-Methyl-5- (2-oxoethoxy) pyrazole-3-yl] butanoyl] -N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine -2-Carboxamide (55 mg, 0.099 mmol, 1 equivalent) was added. Sodium cyanoborohydride (13 mg, 0.20 mmol, 2 eq) was then added. The mixture was stirred at 30 ° C. for 12 hours. The reaction mixture was diluted with 10 mL of water and extracted with dichloromethane / methanol (10 mLx3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by half-reverse phase HPLC. Compound (2S, 4R) -1-[(2S)-2- [5- [2- [4- [4- [3- [2,6-difluoro-3- [[(3R) -3-fluoro Pyrrolidine-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl] piperazine-1-yl] ethoxy] -1-methyl-pyrazol-3-yl]- 3-Methyl-butanoyl] -4-hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (40.2 mg, 0.03 mmol, yield) (Ratio 32%, purity 95%, formate) was obtained as a yellow solid. LC / MS (ESI) m / z: 1122.4 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 12.88 (s, 1H), 8.98 (s, 1H), 8.65 (s, 1H), 8.53 (s, 1H), 8.32 (d, J = 7.5 Hz, 1H), 8.05 (s, 1H), 7.60 (d, J = 8.8 Hz, 3H), 7.45 --7.41 (m, 2H), 7.38 (s) , 2H), 7.23 (d, J = 8.8 Hz, 1H), 7.08 (d, J = 9.2 Hz, 2H), 5.56 (s, 1H), 5.39 --5.19 (m, 1H), 5.03 (d, J = 4.0 Hz, 1H), 4.95 ―― 4.87 (m, 1H), 4.34 ―― 4.24 (m, 2H), 4.18 (d, J = 5.2 Hz, 2H), 3.70 (s, 1H), 3.50 (s, 4H), 3.47 (s, 3H), 3.25 --- 3.20 (m, 7H), 2.67 (s, 5H), 2.45 (s, 4H), 2.08 (d, J = 10.4 Hz, 3H), 1.96 (s, 2H), 1.80 (s, 1H), 1.39 (d, J = 7.2 Hz, 3H), 0.92 (d, J = 6.4 Hz, 3H), 0.71 (d, J = 6.8 Hz, 3H).
(2S, 4R) -1-((R) -2-(5-(2-(4-(4-(3-(2,6-difluoro-3-(((R) -3-fluoropyrrolidine)) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) ethoxy) -1-methyl-1H-pyrazole-3-yl) -3 Illustrative of -methylbutanoyl) -4-hydroxy-N-((S) -1-(4-(4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (exemplary compound 757) Synthesis Step 1: (2S, 4R) -1-((R) -2- (5- (2,2-dimethoxyethoxy) -1-methyl-1H-pyrazole-3-
Preparation of yl) -3-methylbutanoyl) -4-hydroxy-N-((S) -1-(4-(4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide.

(2S, 4R) -1- [2- [5- (2,2-dimethoxyethoxy) -1-methyl-pyrazole-3-yl] -3-methyl-butanoyl] -4-hydroxy-N-[(1S) ) -1- [4- (4-Methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (300 mg, 0.50 mmol, 1 eq) was purified by chiral SFC. Product (2S, 4R) -1- [(2R) -2- [5- (2,2-dimethoxyethoxy) -1-methyl-pyrazole-3-yl] -3-methyl-butanoyl] -4- Hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (150 mg, 0.24 mmol, yield 74%, purity 97.8%) colorless Obtained as a rubber-like substance.

Step 2: (2S, 4R) -4-hydroxy-1-((R) -3-methyl-2-(1-methyl-5- (2-oxoethoxy) -1H-pyrazole-3-yl) butanoyl) Preparation of -N-((S) -1- (4- (4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide.

(2S, 4R) -1-[(2R) -2- [5- (2,2-dimethoxyethoxy) -1-methyl-pyrazole-3-yl] -3-methyl-butanoyl] -4-hydroxy-N -[(1S) -1- [4- (4-Methylthiazole-5-yl) phenyl]
Sulfuric acid (2M, 1 mL, 8.00 eq) was added to a solution of ethyl] pyrrolidine-2-carboxamide (150 mg, 0.25 mmol, 1 eq) in tetrahydrofuran (2 mL). The mixture was stirred at 70 ° C. for 2 hours. Water (10 mL) was added to the mixture and saturated sodium bicarbonate solution was added to adjust the pH to about 8. The mixture was then extracted with 40 mL (20 mLx2) of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Compound (2S, 4R) -4-hydroxy-1-[(2R) -3-methyl-2- [1-methyl-5- (2-oxoethoxy) pyrazole-3-yl] butanoyl] -N- [ (1S) -1- [4- (4-Methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (130 mg, 0.23 mmol, yield 93%) was obtained as a colorless rubbery substance. LC / MS (ESI) m / z: 554.3 [M + 1] ⁺ .
Step 3: (2S, 4R) -1-((R) -2- (5-(2- (4- (4- (3- (2,6-difluoro-3- (((R) -3-) -3-) Fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) ethoxy) -1-methyl-1H-pyrazol-3-yl ) -3-Methylbutanoyl) -4-
Hydroxy-N-((S) -1- (4- (4-Methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-
Preparation of carboxamide.

(3R) -N- [2,4-difluoro-3- [5- (4-piperazin-1-ylphenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] phenyl] -3- Fluoro-pyrrolidin-1-sulfonamide (137 mg, 0.23 mmol, 1.00 equivalent) in a solution of dimethylformamide (1.5 mL) to (2S, 4R) -4-hydroxy-1-[(2R) -3-methyl-2 -[1-Methyl-5- (2-oxoethoxy) pyrazole-3-yl] butanoyl] -N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine -2-Carboxamide (130 mg, 0.23 mmol, 1 equivalent) was added. Sodium cyanoborohydride (29 mg, 0.46 mmol, 2 eq) was then added. The mixture was stirred at 30 ° C. for 12 hours. The reaction mixture was diluted with 10 mL of water and extracted with dichloromethane / methanol (10 mLx3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by half-reverse phase HPLC. Compound (2S, 4R) -1-[(2R) -2- [5- [2- [4- [4- [3- [2,6-difluoro-3- [[(3R) -3-fluoro Pyrrolidine-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl] piperazine-1-yl] ethoxy] -1-methyl-pyrazol-3-yl]- 3-Methyl-butanoyl] -4-hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (53.9 mg, 0.04 mmol, yield) (Rate 19%, purity 100%, formate) was obtained as a yellow solid. LC / MS (ESI) m / z: 561.8 [M / 2 + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 12.88 (s, 1H), 8.99 --8.96 (m, 1H), 8.64 (d) , J = 2.2 Hz, 1H), 8.53 (s, 1H), 8.06 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.65 --7.56 (m, 3H), 7.44 (d, J = 4.4 Hz, 1H), 7.40 (d, J = 8.4 Hz, 2H), 7.35 --7.25 (m, 2H), 7.11 --6.99 (m, 2H), 5.62 --5.52 (m, 1H), 5.41 --5.17 (m) , 1H), 5.05 (d, J = 3.6 Hz, 1H), 4.93 --4.81 (m, 1H), 4.48 --4.37 (m, 1H), 4.28 --4.02 (m, 3H), 3.57 --3.50 (m, 2H) ), 3.50 --3.42 (m, 5H), 3.39 (s, 2H), 3.34 (s, 2H), 3.22 (s, 1H), 3.17 (s, 3H), 2.73 --2.62 (m, 3H), 2.59 ( s, 3H), 2.48 --2.41 (m, 4H), 2.20 (s, 1H), 2.09 (d, J = 15.6 Hz, 2H), 1.99 (s, 1H), 1.85 (br d, J = 5.6 Hz, 1H), 1.45 (d, J = 6.4 Hz, 1H), 1.31 (d, J = 7.2 Hz, 2H), 0.94 (d, J = 6.4 Hz, 2H), 0.77 (d, J = 6.4 Hz, 3H) , 0.68 (d, J = 6.4 Hz, 1H).
(2S, 4R) -1-((S) -4-(4-((1- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidin))-1 -Sulphonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridine-5-yl) phenyl) piperidine-4-yl) methyl) piperazine-1-yl) -3,3-dimethyl-2- (3) -Methylisoxazole-5-yl) butanoyl) -4-hydroxy-N-((S) -1-(4-(4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (example) Exemplary Synthesis of Compound 754) Step 1: tert-butyl 4-((S) -4-((2S, 4R) -4-hydroxy-2-(((S) -1- (4- (4- (4- (4-) Methylthiazole-5-yl) phenyl) ethyl) carbamoyl) pyrrolidine-1-yl) -2,2-dimethyl-3-(3-methylisoxazole-5-yl) -4-oxobutyl) piperazin-1-carboxylic acid Preparation of acid salt.

Tert-Butyl 4- [4-[(2S, 4R) -4-Hydroxy-2-[[(1S) -1- [4- (4-Methylthiazole-5-yl) phenyl] ethyl] Carbamoyl] Pyrrolidine- 1-yl] -2,2-dimethyl-3- (3-methylisoxazole-5-yl) -4-oxo-butyl] piperazin-1-carboxylate (80 mg, 0.12 mmol, 1 equivalent) to SFC Purified with tert-butyl 4-[(3S) -4-[(2S, 4R) -4-hydroxy-2-[[(1S) -1- [4- (4-methylthiazole-) 5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-yl] -2,2-dimethyl-3- (3-methylisoxazole-5-yl) -4-oxo-butyl] piperazin-1-carboxylic acid The salt was obtained as a white solid. The product was further purified by preparative HPLC to remove the acetonitrile fraction and the residue was lyophilized to tert-butyl 4-[(3S) -4-[(2S, 4R) -4-hydroxy-. 2-[[(1S) -1- [4- (4-Methylthiazole-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-yl] -2,2-dimethyl-3- (3-methylisoxa) Zol-5-yl) -4-oxo-butyl] piperazin-1-carboxylate (19.7 mg, 0.023 mmol, yield 20%, purity 97%, TFA) was obtained as a white solid. LC / MS (ESI) m / z: 695.3 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 8.96 (s, 1H), 7.52 --7.37 (m, 4H), 6.47 (s, 1H) ), 5.04 (q, J = 7.1 Hz, 1H), 4.65 --4.55 (m, 1H), 4.48 --4.39 (m, 2H), 4.32- 4.14 (m, 2H), 3.89 (dd, J = 3.9, 11.3) Hz, 1H), 3.70 (d, J = 12.1 Hz, 1H), 3.56 (d, J = 11.2 Hz, 2H), 3.44 --3.30 (m, 2H), 3.23 --3.02 (m, 3H), 2.97 --2.87 (m, 1H), 2.49 (s, 3H), 2.32 (s, 3H), 2.30 --2.23 (m, 1H), 1.97 (ddd, J = 4.3, 9.5, 13.4 Hz, 1H), 1.53 (d, J) = 7.1 Hz, 3H), 1.50 (s, 9H), 1.48 (s, 3H), 1.11 (s, 3H).
Step 2: (2S, 4R) -1-((S) -3,3-dimethyl-2- (3-methylisoxazole-5-yl) -4- (piperazine-1-yl) butanoyl) -4 Preparation of -hydroxy-N-((S) -1- (4- (4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide.

tert-Butyl 4-[(3S) -4-[(2S, 4R) -4-hydroxy-2-[[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl]] Carbamoyl] pyrrolidine-1-yl] -2,2-dimethyl-3- (3-methylisoxazole-5-yl) -4-oxo-butyl] piperazine-1-carboxylate (330 mg, 0.47 mmol, 1) Hydroxyl / dioxane (4M, 4 mL, 33.69 equivalents) was added to a solution of (equivalent) dichloromethane (4 mL). The mixture was stirred for 0.5 hours at 20 ° C. Concentrate the mixture to make (2S, 4R) -1-[(2S) -3,3-dimethyl-2- (3-methylisoxazole-5-yl) -4-piperazin-1-yl-butanoyl). ] -4-Hydroxy-N-[(1S) -1- [4- (4-Methylthiazole-5-yl) phenyl] ethyl] Pyrrolidine-2-carboxamide (310 mg, HCl) was obtained as a yellow solid. LC / MS (ESI) m / z: 595.2 [M + 1] ⁺ .
Step 3: (2S, 4R) -1-((S) -4-(4-((1- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidin) )-1-Sulfone amide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperidine-4-yl) Methyl) Piperazine-1-yl) -3,3-dimethyl-2 -(3-Methylisoxazole-5-yl) butanoyl) -4-hydroxy-N-((S) -1- (4- (4-methylthiazole-5-yl) phenyl)
Preparation of ethyl) pyrrolidine-2-carboxamide.

(2S, 4R) -1-[(2S) -3,3-dimethyl-2- (3-methylisoxazole-5-yl) -4-piperazin-1-yl-butanoyl] -4-hydroxy-N -[(1S) -1- [4- (4-Methylthiazole-5-yl) phenyl]
To a solution of ethyl pyrrolidine-2-carboxamide (120 mg, 0.19 mmol, 1 eq, HCl) in methanol (2 mL) and dichloromethane (2 mL), add sodium acetate (31 mg, 0.38 mmol, 2 eq), then (3R). -N- [2,4-difluoro-3- [5- [4- (4-formyl-1-piperidyl) phenyl] -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] phenyl] -3 -Fluoro-pyrrolidin-1-sulfonamide (116 mg, 0.19 mmol, 1 eq) was added. Acetic acid (53 mg, 0.87 mmol, 4.60 eq) was added until the pH reached 6, and the mixture was stirred at 20 ° C. for 10 minutes. Sodium cyanoborohydride (48 mg, 0.76 mmol, 4 eq) was then added and the mixture was stirred at 20 ° C. for 1 hour. The mixture was concentrated to give a crude product, which was purified by preparative HPLC. The acetonitrile fraction was removed and the residue was lyophilized to give the product. Compound (2S, 4R) -1-[(2S) -4- [4-[[1- [4- [3- [2,6-difluoro-3- [[(3R) -3-fluoropyrrolidine- 1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl] -4-piperidyl] methyl] piperazine-1-yl] -3,3-dimethyl-2- (3-Methylisoxazole-5-yl) butanoyl] -4-hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (83.7 mg, 66.41 umol, yield 34.9%, purity 98.1%, FA) was obtained as a yellow solid. LC / MS (ESI) m / z: 1190.5 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 12.91 (br s, 1H), 9.01 --8.95 (m, 1H), 8.64 (d, J = 2.2 Hz, 1H), 8.52 (br s, 1H), 8.41 (d, J = 8.1 Hz, 1H), 8.18 (s, 1H), 8.07 (s, 1H), 7.65 --7.52 (m, 3H) , 7.48 --7.32 (m, 4H), 7.25 (t, J = 8.3 Hz, 1H), 7.05 (br d, J = 8.8 Hz, 2H), 6.28 --6.11 (m, 1H), 5.42 --5.17 (m, 1H), 5.14 ―― 4.87 (m, 1H), 4.99 ―― 4.65 (m, 1H), 4.40 ―― 4.18 (m, 3H), 3.94 (s, 1H), 3.76 (br d, J = 10.5 Hz, 2H), 3.47 (br s, 2H), 3.32 --3.23 (m, 6H), 2.77 --2.68 (m, 2H), 2.46 --2.45 (m, 1H), 2.46 (s, 3H), 2.47 --2.35 (m, 1H) , 2.39 (br s, 2H), 2.24 --1.95 (m, 11H), 1.85 --1.62 (m, 4H), 1.46 --1.35 (m, 3H), 1.20 (br d, J = 10.1 Hz, 2H), 1.07 --0.95 (m, 3H), 0.90 --0.81 (m, 3H).
(2S, 4R) -1-((R) -4-(4-((1- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidin))-1 -Sulphonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridine-5-yl) phenyl) piperidine-4-yl) methyl) piperazine-1-yl) -3,3-dimethyl-2- (3) -Methylisoxazole-5-yl) butanoyl) -4-hydroxy-N-((S) -1-(4-(4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (example) Exemplary Synthesis of Compound 755) Step 1: tert-butyl 4-((R) -4-((2S, 4R) -4-hydroxy-2-(((S) -1- (4- (4- (4- (4-) Methylthiazole-5-yl) phenyl) ethyl) carbamoyl) pyrrolidine-1-yl) -2,2-dimethyl-3-(3-methylisoxazole-5-yl) -4-oxobutyl) piperazin-1-carboxylic acid Preparation of acid salt.

Tert-Butyl 4- [4-[(2S, 4R) -4-hydroxy-2-[[(1S) -1- [4- (4-Methylthiazole-5-yl) phenyl] ethyl] Carbamoyl] Pyrrolidine- 1-yl] -2,2-dimethyl-3- (3-methylisoxazole-5-yl) -4-oxo-butyl] piperazin-1-carboxylate (80 mg, 0.12 mmol, 1 equivalent) to SFC Purified with tert-butyl 4-[(3R) -4-[(2S, 4R) -4-hydroxy-2-[[(1S) -1- [4- (4-methylthiazole-) 5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-yl] -2,2-dimethyl-3- (3-methylisoxazole-5-yl) -4-oxo-butyl] piperazin-1-carboxylic acid Salt (24.3 mg, 34.03 umol, yield 29.6%, purity 97.3%) was obtained as a white solid. LC / MS (ESI) m / z: 695.4 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 8.87 (s, 1H), 7.48 --7.36 (m, 4H), 6.24 (s, 1H) ), 5.06 --4.98 (m, 1H), 4.61 --4.50 (m, 1H), 4.41 (s, 2H), 3.78 (d, J = 10.9 Hz, 1H), 3.56 (dd, J = 4.2, 10.7 Hz, 1H), 3.43 (s, 4H), 2.66 --2.56 (m, 2H), 2.54 --2.41 (m, 6H), 2.29 (d, J = 13.0 Hz, 1H), 2.24 (s, 3H), 2.22 --2.14 (m, 1H), 1.92 (ddd, J = 4.7, 8.3, 13.2 Hz, 1H), 1.52 (d, J = 7.0 Hz, 3H), 1.45 (s, 9H), 1.10 (s, 3H), 0.98 ( s, 3H).
Step 2: (2S, 4R) -1-((R) -3,3-dimethyl-2- (3-methylisoxazole-5-yl) -4- (piperazine-1-yl) butanoyl) -4 Preparation of -hydroxy-N-((S) -1- (4- (4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide.

tert-butyl 4-[(3R) -4-[(2S, 4R) -4-hydroxy-2-[[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl]] Carbamoyl] pyrrolidine-1-yl] -2,2-dimethyl-3- (3-methylisoxazole-5-yl) -4-oxo-butyl] piperazin-1-carboxylate (120 mg, 0.17 mmol, 1) Hydrochloric acid / dioxane (2M, 2.9 mL, 33.69 equivalent) in a solution of dichloromethane (2 mL) of equivalent)
Was added, and the mixture was stirred at 20 ° C. for 0.5 hours. Concentrate the mixture to produce (2S, 4R) -1-[(2R) -3,3-dimethyl-2- (3-methylisoxazole-5-yl) -4-piperazin-1-yl) -Butanoyl] -4-hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-
2-Carboxamide (125 mg, HCl) was obtained as a yellow solid. LC / MS (ESI) m / z: 595.2 [M + 1] ⁺ .
Step 3: (2S, 4R) -1-((R) -4-(4-((1- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidin) ) -1-Sulfone amide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperidine-4-yl) Methyl) Piperazine-1-yl) -3,3-dimethyl-2 -(3-Methylisoxazole-5-yl) butanoyl) -4-hydroxy-N-((S) -1- (4- (4-methylthiazole-5-yl) phenyl)
Preparation of ethyl) pyrrolidine-2-carboxamide.

(2S, 4R) -1-[(2R) -3,3-dimethyl-2- (3-methylisoxazole-5-yl) -4-piperazin-1-yl-butanoyl] -4-hydroxy-N -[(1S) -1- [4- (4-Methylthiazole-5-yl) phenyl]
To a solution of ethyl pyrrolidine-2-carboxamide (100 mg, 0.17 mmol, 1 eq, HCl) in methanol (2 mL) and dichloromethane (2 mL), add sodium acetate (28 mg, 0.34 mmol, 2 eq), then (3R). -N- [2,4-difluoro-3- [5- [4- (4-formyl-1-piperidyl) phenyl] -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] phenyl] -3 -Fluoro-pyrrolidin-1-sulfonamide (103 mg, 0.17 mmol, 1 eq) was added and acetic acid (46 mg, 0.77 mmol, 4.60 eq) was added until pH 6 was reached. The mixture was stirred at 20 ° C. for 10 minutes, then sodium cyanoborohydride (42 mg, 0.67 mmol, 4 eq) was added and the mixture was stirred at 20 ° C. for 1 hour. The mixture was concentrated to give a crude product, which was purified by preparative HPLC. The acetonitrile fraction was removed and the residue was lyophilized to give the product. Compound (2S, 4R) -1-[(2R) -4- [4-[[1- [4- [3- [2,6-difluoro-3- [[(3R) -3-fluoropyrrolidine- 1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl] -4-piperidyl] methyl] piperazine-1-yl] -3,3-dimethyl-2- (3-Methylisoxazole-5-yl) butanoyl] -4-hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (90.4 mg, 73.11 umol, yield 43.5%, purity 100%, FA) was obtained as a yellow solid. LC / MS (ESI) m / z: 1190.5 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 12.91 (br s, 1H), 9.01 --8.96 (m, 1H), 8.64 (d, J = 2.2 Hz, 1H), 8.53 (br s, 1H), 8.31 (d, J = 7.8 Hz, 1H), 8.18 (s, 1H), 8.07 (s, 1H), 7.66 --7.54 (m, 3H) , 7.48 --7.31 (m, 4H), 7.25 (t, J = 8.7 Hz, 1H), 7.06 (br d, J = 8.8 Hz, 2H), 6.19 (s, 1H), 5.40 --5.52 (m, 1H) , 4.90 (quin, J = 7.1 Hz, 1H), 4.41 (t, J = 7.3 Hz, 1H), 4.27 (br s, 1H), 4.22 (s, 1H), 3.77 (br d, J = 11.9 Hz, 2H), 3.59 (br d, J = 9.0 Hz, 1H), 3.47 (br s, 2H), 3.33 --3.28 (m, 4H), 2.76 --2.98 (m, 2H), 2.46 --2.28 (m, 10H) , 2.20 --1.94 (m, 10H), 1.83 --1.63 (m, 4H), 1.37 (d, J = 7.0 Hz, 2H), 1.48 (br d, J = 7.2 Hz, 1H), 1.28 --1.11 (m, 2H), 1.04 --0.94 (m, 3H), 0.87 (s, 3H).
(2S, 4R) -1-((S) -3,3-dimethyl-2-(2-((((1R, 3R) -3-((2'-methyl-5-morpholino-5') -(3- (Trifluoromethyl) benzamide)-[3,3'-bipyridine] -6-yl) oxy) cyclohexyl) oxy) ethoxy) acetamide) butanoyl) -4-hydroxy-N-((S) -1 -(4- (4-Methylthiazol-5-yl) phenyl) ethyl) Pyrrolidine-2-carboxamide (exemplary compound 756) Illustrative synthesis Step 1: N- (5-bromo-6-methylpyridin-3-) Il) -3- (Trifluoromethyl) Preparation of benzamide.

Mixing 3- (trifluoromethyl) benzoic acid (10.16 g, 53.47 mmol, 1 eq) and 5-bromo-6-methyl-pyridine-3-amine (10 g, 53.47 mmol, 1 eq) with dimethylformamide (100 mL). In liquid, [dimethylamino (triazolo [4,5-b] pyridine-3-yloxy) methylene] -dimethyl-ammonium; hexafluorophosphate (30.49 g, 80.20 mmol, 1.5 eq) and triethylamine (10.82 g, 106.93). mmol, 2 eq) was added. The mixture was stirred at 20 ° C. for 12 hours. The mixture was quenched with water (300 mL). The aqueous layer was extracted with ethyl acetate (200 mLx3). All combined organic layers were washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated. The residue was pulverized in a solution of petroleum ether / ethyl acetate = 50: 1 (100 mL) and N- (5-bromo-6-methyl-3-pyridyl) -3- (trifluoromethyl) benzamide (17 g). , 46.01 mmol, yield 86%, purity 97%) was obtained as a yellow solid. LC / MS (ESI) m / z: 360.9 [M + 1] ⁺ .
Step 2: Preparation of (2-methyl-5-(3- (trifluoromethyl) benzamide) pyridin-3-yl) boronic acid.

4,4,5,5-Tetramethyl-2- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-Dioxaborolan (7.07g, 27.84) mmol, 2 eq), N- (5-bromo-6-methyl-3-pyridyl) -3- (trifluoromethyl) benzamide (5 g, 13.92 mmol, 1 eq), [1,1'-bis (diphenylphos) Fino) Ferrocene] Dichloropalladium (II) (1.14 g, 1.39 mmol, 0.1 eq), potassium acetate (4.10 g, 41.76 mmol, 3 eq) dioxane (100 mL) was degassed and purged 3 times with nitrogen. did. The mixture was then stirred at 100 ° C. for 12 hours under a nitrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated. The compound [2-methyl-5-[[3- (trifluoromethyl) benzoyl] amino] -3-pyridyl] boronic acid (5.5 g) was obtained as a dark brown oil. LC / MS (ESI) m / z: 325.1 [M + 1] ⁺ .
Step 3: Preparation of (1S, 3R) -3- (benzyloxy) cyclohexane-1-ol.

Dimethylformamide (250 m) of cyclohexane-1,3-diol (18 g, 154.96 mmol, 1 eq)
Sodium-hydrogen (6.20 g, 154.96 mmol, purity 60%, 1 eq) and boron tribromide (26.50 g, 154.96 mmol, 18.41 mL, 1 eq) were added to the solution of L). The mixture was stirred for 12 hours at 0-60 ° C. The reaction mixture was quenched with 1500 mL of water at 0 ° C. and then extracted with ethyl acetate (500 mlx3). The combined organic layers were washed with brine (500 mLx3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography. The compound (1S, 3R) -3-benzyloxycyclohexanol (10 g, 48.48 mmol, 62% yield) was obtained as a yellow oil. LC / MS (ESI) m / z: 259.0 [M-56] ⁺ .
Step 4: Preparation of 2-(((1R, 3R) -3- (benzyloxy) cyclohexyl) oxy) -5-bromo-3-nitropyridine.

5-bromo-3-nitro-pyridine-2-ol (8.76 g, 39.99 mmol, 1.1 eq) and (1S, 3R) -3-benzyloxycyclohexanol (7.5 g, 36.36 mmol, 1 eq) in tetrahydrofuran ( To a solution of 150 mL), add triphenylphosphine (14.30 g, 54.54 mmol, 1.5 eq) and isopropyl (NE) -N-isopropoxycarbonyliminocarbamate (11.03 g, 54.54 mmol, 10.60 mL, 1.5 eq). rice field. The mixture was stirred at 0-25 ° C. for 12 hours. The reaction mixture was quenched with 300 mL of water at 20 ° C. and then extracted with ethyl acetate (100 mlx3). The combined organic layers were washed with brine (100 mLx3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1: 0-50: 1). Compound 2-[(1R, 3R) -3-benzyloxycyclohexoxy] -5-bromo-3-nitro-pyridine (7.5 g, 18.42 mmol, 50% yield) was obtained as a yellow oil.

Step 5: Preparation of 2-(((1R, 3R) -3- (benzyloxy) cyclohexyl) oxy) -5-bromopyridin-3-amine.

2-[(1R, 3R) -3-benzyloxycyclohexoxy] -5-bromo-3-nitro-pyridine (13.1 g, 32.17 mmol, 1 eq), iron (8.98 g, 160.83 mmol, 5 eq), chloride A mixture of ethyl alcohol (250 mL) and water (50 mL) of ammonium (8.60 g, 160.83 mmol, 5 eq) was degassed and purged with nitrogen three times. The mixture was then stirred at 80 ° C. for 12 hours under a nitrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 50/1 to 10: 1). Compound 2-[(1R, 3R) -3-benzyloxycyclohexoxy] -5-bromo-pyridin-3-amine (11.5 g, 30.48 mmol, yield 94%) was obtained as a yellow oil. LC / MS (ESI) m / z: 377.1 [M + 1] ⁺ .
Step 6: Preparation of 4- (2-(((1R, 3R) -3- (benzyloxy) cyclohexyl) oxy) -5-bromopyridin-3-yl) morpholine.

2-[(1R, 3R) -3-benzyloxycyclohexoxy] -5-bromo-pyridin-3-amine (14.7 g, 38.96 mmol, 1 equivalent) in a mixture of dimethylformamide (200 mL) and sodium hydride. (7.79 g, 194.82 mmol, purity 60%, 5 eq) was added at 25 ° C. The mixture was stirred at 25 ° C. for 0.5 hours. Then 1-bromo-2- (2-bromoethoxy) ethane (27.11 g, 116.89 mmol, 14.65 mL, 3 eq)
Was added to the mixture. The mixture was stirred at 80 ° C. for 11.5 hours. The reaction mixture was quenched with 1000 mL of water at 0 ° C. and then extracted with ethyl acetate (200 mlx3). The combined organic layers were washed with brine (200 mLx3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 30: 1-10: 1). The compound 4- [2-[(1R, 3R) -3-benzyloxycyclohexoxy] -5-bromo-3-pyridyl] morpholine (17 g, 38.00 mmol, 97% yield) was obtained as a yellow oil. LC / MS
(ESI) m / z: 447.1 [M + 1] ⁺ .
Step 7: N- (6'-(((1R, 3R) -3- (benzyloxy) cyclohexyl) oxy) -2-methyl-5'-morpholino- [3,3'-bipyridine] -5-yl) Preparation of -3- (trifluoromethyl) benzamide.

[2-Methyl-5-[[3- (trifluoromethyl) benzoyl] amino] -3-pyridyl] boronic acid (4.78 g, 14.75 mmol, 1.1 eq), 4- [2-[(1R, 3R)- 3-benzyloxycyclohexoxy] -5-bromo-3-pyridyl] morpholine (6 g, 13.41 mmol, 1 eq), cyclopentyl (diphenyl) phosphan; dichloromethane; dichloropalladium; iron (1.10 g, 1.34 mmol, 0.1 eq), A mixture of potassium carbonate (5.56 g, 40.24 mmol, 3 eq) and water (2 mL) of dioxane (200 mL) was degassed and purged with nitrogen three times. The mixture was then stirred at 100 ° C. for 12 hours under a nitrogen atmosphere. The reaction mixture was quenched with 500 mL of water at 25 ° C. and then extracted with ethyl acetate (200 mlx3). The combined organic layers were washed with brine (100 mLx2), dried over anhydrous sodium sulfate, and dried.
It was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 20: 1-8: 1). Compound N- [5- [6-[(1R, 3R) -3-benzyloxycyclohexoxy] -5-morpholino-3-pyridyl] -6-methyl-3-pyridyl] -3- (trifluoromethyl) Benzamide (5.5 g, 8.50 mmol, 63% yield) was obtained as a yellow oil. LC / MS (ESI)
m / z: 647.1 [M + 1] ⁺ .
Step 8: N-(6'-(((1R, 3R) -3-hydroxycyclohexyl) oxy) -2-methyl-5'-morpholino- [3,3'-bipyridine] -5-yl) -3- Preparation of (trifluoromethyl) benzamide.

N- [5- [6-[(1R, 3R) -3-benzyloxycyclohexoxy] -5-morpholino-3-pyridyl] -6-methyl-3-pyridyl] -3- (trifluoromethyl) benzamide ( Boron tribromide (6.39 g, 25.51 mmol, 2.46 mL, 3 eq) was added to a solution of dichloromethane (100 mL) in 5.5 g, 8.50 mmol, 1 eq. The mixture was stirred at −68 ° C. for 1 hour. The reaction mixture was quenched with 100 mL of sodium bicarbonate at 25 ° C, then diluted with 150 mL of water and extracted with ethyl acetate (80 mLx3). The combined organic layers were washed with 150 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC. Compound N- [5- [6- [(1R, 3R) -3-hydroxycyclohexoxy] -5-morpholino-3-pyridyl] -6-methyl-3-pyridyl] -3- (trifluoromethyl) benzamide (4.2 g, 7.55 mmol, 88% yield) was obtained as a yellow solid. LC / MS (ESI) m / z: 557.2 [M + 1] ⁺ .
Step 9: Ethyl 2-(((1R, 3R) -3-((2'-methyl-5-morpholino-5'-(3- (trifluoromethyl) benzamide))-[3,3'-bipyridine]- Preparation of 6-yl) oxy) cyclohexyl) oxy) acetate.

N- [5- [6-[(1R, 3R) -3-hydroxycyclohexoxy] -5-morpholino-3-pyridyl] -6-methyl-3-pyridyl] -3- (trifluoromethyl) benzamide (1 g) , 1.80 mmol, 1 eq) to a solution of dichloromethane (10 mL) was added diacetoxylodium (39 mg, 0.18 mmol, 0.1 eq) and ethyl 2-diazoacetate (615 mg, 5.39 mmol, 3 eq). The mixture was stirred at 25 ° C. for 12 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 3: 1 to 1: 3). The compound ethyl 2-[(1R, 3R) -3-[[5- [2-methyl-5-[[3- (trifluoromethyl) benzoyl] amino] -3-pyridyl] -3-morpholino-2- Pyridyl] oxy] cyclohexoxy] acetate (500 mg, 0.18 mmol, 43% yield) was obtained as a yellow oil. LC / MS (ESI) m / z: 643.1 [M + 1] ⁺ .
Step 10: N-(6'-(((1R, 3R) -3- (2-hydroxyethoxy) cyclohexyl) oxy) -2-methyl-5'-morpholino- [3,3'-bipyridine] -5- Preparation of yl) -3- (trifluoromethyl) benzamide.

Ethyl 2-[(1R, 3R) -3-[[5- [2-methyl-5-[[3- (trifluoromethyl) benzoyl] amino] -3-pyridyl] -3-morpholino-2-pyridyl] To a solution of oxy] cyclohexoxy] acetate (700 mg, 1.09 mmol, 1 equivalent) in tetrahydrofuran (10 mL) was added lithium ammonium hydride (41 mg, 1.09 mmol, 1 equivalent). The mixture was stirred at 0-25 ° C. for 1 hour. The reaction mixture was quenched at 0 ° C. with 2 mL of water, then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane: methyl alcohol = 10: 1). Compound N- [5- [6- [(1R, 3R) -3- (2-hydroxyethoxy) cyclohexoxy] -5-morpholino-3-pyridyl] -6-methyl-3-pyridyl] -3-( Trifluoromethyl) benzamide (400 mg, 0.67 mmol, 61% yield) was obtained as a yellow oil. LC / MS (ESI) m / z: 601.1 [M + 1] ⁺ .
Step 11: Ethyl 2-(2-((((1R, 3R) -3-((2'-methyl-5-morpholino-5'-(3- (trifluoromethyl) benzamide))-[3,3'- Preparation of bipyridine] -6-yl) oxy) cyclohexyl) oxy) ethoxy) acetate.

N- [5- [6-[(1R, 3R) -3- (2-hydroxyethoxy) cyclohexoxy] -5-morpholino-3-pyridyl] -6-methyl-3-pyridyl] -3- (trifluoro) Methyl) benzamide (100 mg, 0.16 mmol, 1 eq) in a solution of dichloromethane (1 mL) with diacetoxylodium (7 mg, 0.03 mmol, 0.2 eq) and ethyl 2-diazoacetate (189 mg, 1.66 mmol, 10 eq). added. The mixture was stirred at 25 ° C. for 1 hour. The reaction mixture was filtered and the filter was concentrated. The residue was purified by preparative TLC (dichloromethane: methyl alcohol = 10: 1). The compound ethyl 2- [2- [(1R, 3R) -3-[[5- [2-methyl-5-[[3- (trifluoromethyl) benzoyl] amino] -3-pyridyl] -3-morpholino -2-Pyridyl] Oxy] Cyclohexoxy] ethoxy] Acetate (81 mg, 0.11 mmol, yield 70)
%) Was obtained as a yellow oil. LC / MS (ESI) m / z: 687.2 [M + 1] ⁺ .
Step 12: 2-(2-((((1R, 3R) -3-((2'-methyl-5-morpholino-5'-(3- (trifluoromethyl) benzamide))-[3,3'-bipyridine) ] -6-Il) Oxy) Cyclone) Oxy) ethoxy) Preparation of acetic acid.

Ethyl 2- [2-[(1R, 3R) -3-[[5- [2-methyl-5-[[3- (trifluoromethyl) benzoyl] amino] -3-pyridyl] -3-morpholino-2 -Pyridyl] oxy] cyclohexoxy] ethoxy] acetate (105 mg, 0.15 mmol, 1 eq) to a solution of tetrahydrofuran (2 mL) and water (0.2 mL), plus lithium hydroxide (19 mg, 0.46 mmol, 3 eq). rice field. The mixture was stirred at 40 ° C. for 0.5 hours. The reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran. The residue was diluted with 2 ml of water and the mixture was adjusted to pH = 5 with 2 mL of hydrochloric acid (1M). The residue was purified by preparative HPLC. Compound 2- [2- [(1R, 3R) -3-[[5- [2-methyl-5-[[3- (trifluoromethyl) benzoyl] amino] -3-pyridyl] -3-morpholino- 2-Pyridyl] oxy] cyclohexoxy] ethoxy] acetic acid (60 mg, 0.09 mmol, 59% yield) was obtained as a white solid. LC / MS (ESI) m / z: 659.2 [M + 1] ⁺ .
Step 13: (2S, 4R) -1-((S) -3,3-dimethyl-2-(2-((((1R, 3R) -3-((2'-methyl-5-morpholino) -5'-(3- (Trifluoromethyl) benzamide)-[3,3'-bipyridine] -6-yl) oxy) cyclohexyl) oxy) ethoxy) acetamide) butanoyl) -4-hydroxy-N-((S) )-1-(4- (4-Methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide preparation.

2- [2-[(1R, 3R) -3-[[5- [2-methyl-5-[[3- (trifluoromethyl) benzoyl] amino] -3-pyridyl] -3-morpholino-2- Pyridyl] oxy] cyclohexoxy] ethoxy] acetic acid (60 mg, 0.09 mmol, 1 equivalent), (2S, 4R) -1- [(2S) -2-amino-3,3-dimethyl-butanoyl] -4-hydroxy- N-[(1S) -1- [4- (4-methylthyazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (48 mg, 0.1 mmol, 1.1 equivalent, hydrochloride), hydroxybenzotriazole (14 mg, 0.10 mmol (1.2 equivalent), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (21 mg, 0.1 mmol, 1.2 equivalent) and triethylamine (27 mg, 0.27 mmol, 3 equivalent) dimethylformamide (3 mL) Was degassed and purged with nitrogen 3 times. Next, add the mixed solution in a nitrogen atmosphere at 40 ° C to 12
Stir for hours. The reaction mixture was quenched with 50 mL of water at 25 ° C. and then extracted with ethyl acetate (20 mlx3). The combined organic layers were washed with brine (15 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane: methyl alcohol = 10: 1). Compound (2S, 4R) -1-[(2S) -3,3-dimethyl-2-[[
2- [2-[(1R, 3R) -3-[[5- [2-methyl-5-[[3- (trifluoromethyl) benzoyl] amino] -3-pyridyl] -3-morpholino-2- Pyridyl] Oxy] Cyclohexoxy] ethoxy] Acetyl] Amino] Butanoyl] -4-Hydroxy-N-[(1S) -1- [4- (4-Methylthiazol-5-yl) Phenyl] Ethyl] Pyrrolidine-2- Carboxamide (34.4 mg, 0.03 mmol, yield 34%, purity 98%) was obtained as a white solid. LC / MS (ESI) m / z: 1086.2 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 10.65 (s, 1H), 8.96 (s, 1H), 8.84 (d, J = 2.4) Hz, 1H), 8.41 (d, J = 7.2 Hz, 1H), 8.31 (s, 1H), 8.27 (d, J = 7.3Hz, 1H), 8.03 (d, J = 2.4 Hz, 1H), 7.99 ( d, J = 7.6 Hz, 1H), 7.83 --7.75 (m, 2H), 7.46 --7.39 (m, 2H), 7.38 --7.30 (m, 3H), 7.19 (d, J = 1.6 Hz, 1H), 5.46 (s, 1H), 5.13 (d, J = 3.2 Hz, 1H), 4.95 --4.82 (m, 1H), 4.53 (d, J = 10.0 Hz, 1H), 4.43 (t, J = 8.4 Hz, 1H) , 4.28 (s, 1H), 4.01 --3.93 (m, 2H), 3.79 --3.65 (m, 6H), 3.61 (dd, J = 3.6, 8.4 Hz, 5H), 3.08 (s, 4H), 2.44 (s) , 6H), 2.11 --1.97 (m, 2H), 1.92 --1.63 (m, 6H), 1.60 --1.43 (m, 2H), 1.35 (dd, J = 3.6, 6.8 Hz, 3H), 0.92 (d, J) = 3.2 Hz, 9H).
4-((R) -2-((2S, 4R) -1-((S) -2- (2- (4-((4- (4- (3- (2,6-difluoro-3-) (((R) -3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridine-5-yl) phenyl) piperazin-1-yl) methyl) piperidin-1- Il) Acetamide) -3,3-dimethylbutanoyl) -4-hydroxypyrrolidin-2-carboxamide) -2- (4- (4-Methylthiazol-5-yl) phenyl) ethoxy) -4-oxobutanoic acid (Example) Exemplary Synthesis of Compound 758) Step 1: Benzyl (2S, 4R) -1-((S) -2-((tert-butoxycarbonyl) amino) -3,3-dimethylbutanoyl) -4-(( Preparation of tert-butyldimethylsilyl) oxy) pyrrolidine-2-carboxylate.

In a 150 mL round bottom flask, benzyl (2S, 4R) -1-[(2S) -2-[[(tert-butoxy) carbonyl] amino] -3,3-dimethylbutanoyl] -4-hydroxypyrrolidin-2 -Carboxylate (7 g, 16.11 mmol, 1.00 eq), imidazole (1.6 g, 23.51 mmol, 1.46 eq) dichloromethane (80 mL)
The solution was added at 0 ° C. This was followed by the addition of TBDMSCl (3.6 g, 23.89 mmol, 1.48 eq) at 0 ° C. in several batches. The resulting solution was stirred at room temperature for 6 hours. The reaction was then quenched by the addition of water (60 mL). The resulting mixture was extracted with dichloromethane (50 mL x 3), the organic layers were combined, washed with brine (100 mL x 2), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied on a silica gel column and eluted with ethyl acetate / petroleum ether (1: 9). This resulted in 5.8 g (66%) of benzyl (2S, 4R) -1-[(2S) -2-[[(tert-butoxy) carbonyl] amino] -3,3-dimethylbutanoyl] -4- [ (tert-Butyldimethylsilyl) oxy] pyrrolidine-2-carboxylate was obtained as a bright yellow oil. LC / MS (ESI) m / z: 549.20 [M + 1] ⁺ .
Step 2: (2S, 4R) -1-((S) -2-((tert-butoxycarbonyl) amino) -3,3-dimethylbutanoyl) -4-((tert-butyldimethylsilyl) oxy) pyrrolidine -2-Preparation of carboxylic acid.

Benzyl (2S, 4R) -1-[(2S) -2-[[(tert-butoxy) carbonyl] amino] -3,3-dimethylbutanoyl] -4-[(tert-butyldimethylsilyl) oxy] pyrrolidine -2-Carboxylate (500 mg)
, 0.91 mmol, 1.00 eq) in a solution of methanol (15 mL) was filled with Pd / C (10%, 100 mg) under a nitrogen atmosphere. The flask was then evacuated and flushed with hydrogen. The reaction mixture was hydrogenated at room temperature for 16 hours in a hydrogen atmosphere using a hydrogen balloon, then filtered through a Celite bed and concentrated under reduced pressure. This resulted in 273 mg (65%) of (2S, 4R) -1-[(2S) -2-[[(tert-butoxy) carbonyl] amino] -3,3-dimethylbutanoyl] -4-[(tert). -Butyldimethylsilyl) oxy] Pyrrolidine-2-carboxylic acid was obtained as a colorless oil. LC / MS (ESI) m / z: 459.30 [M + 1] ⁺ .
Step 3: tert-butyl ((S) -1-((2S, 4R) -4-((tert-butyldimethylsilyl) oxy) -2-(((R) -2-hydroxy-1- (4-) Preparation of (4-methylthiazole-5-yl) phenyl) ethyl) carbamoyl) pyrrolidine-1-yl) -3,3-dimethyl-1-oxobutan-2-yl) carbamate.

In a 25 mL round bottom flask, (2S, 4R) -1-[(2S) -2-[[(tert-butoxy) carbonyl] amino] -3,3-dimethylbutanoyl] -4-[(tert-butyl) Dimethylsilyl) oxy] pyrrolidine-2-carboxylic acid (930 mg, 1 equivalent), (2R) -2-amino-2- [4- (4-methyl-1,3-thiazole-5-yl) phenyl] ethane- A solution of 1-all hydrochloride (550 mg), HATU (930 mg), DIEA (1 g) in DMF (5 mL) was added. The resulting solution was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (50 mLx3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was applied on a silica gel column and eluted with ethyl acetate / petroleum ether (1: 0). This resulted in 460 mg of tert-butyl N-[(2S) -1-[(2S, 4R) -4-[(tert-butyldimethylsilyl) oxy] -2-[[(1R) -2-hydroxy-1). -[4- (4-Methyl-1,3-thiazole-5-yl) phenyl]
Ethyl] carbamoyl] pyrrolidine-1-yl] -3,3-dimethyl-1-oxobutane-2-yl] carbamate was obtained as a bright yellow oil. LC / MS (ESI) m / z: 675.20 [M + 1] ⁺ .
Step 4: (2S, 4R) -1-((S) -2-amino-3,3-dimethylbutanoyl) -4-((tert-butyldimethylsilyl) oxy) -N-((R) -2 -Preparation of hydroxy-1- (4- (4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide.

In a 25 mL round bottom flask, tert-butyl N-[(2S) -1-[(2S, 4R) -4-[(tert-butyldimethylsilyl) oxy] -2-[[(1R) -2-hydroxy -1- [4- (4-Methyl-1,3-thiazole-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-yl] -3,3-dimethyl-1-oxobutan-2-yl] carbamic acid A solution of the salt (660 mg, 980 mmol, 1 eq) in dichloromethane (10 mL) was added. TFA (3 mL) was added dropwise to the above mixture at 0 ° C. The resulting mixture was stirred at 0 ° C. for 0.5 hours and then quenched by the addition of saturated sodium bicarbonate solution (100 mL) at room temperature. The obtained mixture was extracted with DCM (10 mLx2). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. As a result, (2S, 4R) -1-[(2S) -2-amino-3,3-dimethylbutanoyl] -4-[(tert-butyldimethylsilyl) oxy] -N-[(1R) -2 -Hydroxy-1- [4- (4-methyl-1,3-thiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide, trifluoroacetate (760 mg) was obtained as a yellow oil. LC / MS (ESI) m / z: 575.20 [M + 1] ⁺ .
Step 5: tert-butyl (R) -2- (4-((4- (4- (4- (3- (2,6-difluoro-3-((3-fluoropyrrolidin) -1-sulfonamide) benzoyl)-)- Preparation of 1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) methyl) piperidine-1-yl) acetate.

In a 100 mL round bottom flask, tert-butyl 2-((4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine- 1-Il) Methyl) Piperidine-1-yl) Acetate
(783.4 mg, 1.57 mmol, 1.50 eq), (R) -N-(3- (5-bromo-1H-pyrrolo [2,3-b] pyridine-3-carbonyl) -2,4-difluorophenyl)- 3-Fluoropyrrolidin-1-sulfonamide (525.0 mg, 1.05 mmol, 1.00 eq), sodium carbonate (222.6 mg, 2.10 mmol, 2.00 eq), Pd (dppf) Cl ₂ (85.5 mg, 0.10 mmol, 0.10 eq) A solution of 1,4-dioxane (15 mL) and water (3 mL) was added. The solution obtained under nitrogen was stirred overnight in an oil bath at 100 ° C. The residue was evaporated under reduced pressure, concentrated and placed on a silica gel column with ethyl acetate / petroleum ether (1: 0). This resulted in 621.5 mg (75%) of (R) -tert-butyl 2- (4-((4- (4- (3- (2,6-difluoro-3- (3-fluoropyrrolidin-1-sulfon)). Amide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) methyl) piperidine-1-yl) acetate was obtained as a yellow solid. LC / MS (ESI) m / z: 796.20 [M + 1] ⁺ .
Step 6: (R) -2- (4-((4- (4- (3- (2,6-difluoro-3-((3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperazin-1-yl) Methyl) Piperidine-1-yl) Preparation of acetic acid.

In a 50 mL round bottom flask, (R) -tert-butyl 2- (4-((4- (4- (3- (2,6-difluoro-3- (3-fluoropyrrolidin-1-sulfonamide)) benzoyl) ) -1H-Pyrrolidine [2,3-b] Pyridine-5-yl) Phenyl) Piperazine-1-yl) Methyl) Piperidine-1-yl) Acetate (621.5mg, 0.78mmol, 1.00
Equivalent), a solution of 2,2,2-trifluoroacetaldehyde (8 mL) in dichloromethane (8 mL) was added. The resulting solution was stirred at room temperature for 5 hours. The residue was evaporated under reduced pressure, concentrated and placed on a silica gel column using methanol / chloroform (1: 2). This resulted in 500.0 mg (87%) of (R) -2- (4-((4- (4- (4- (3- (2,6-difluoro-3- (3-fluoropyrrolidin-1-sulfonamide)) benzoyl). ) -1H-Pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperazine-1-yl) Methyl) Piperidine-1-yl) Acetic acid was obtained as a yellow solid. LC / MS (ESI) m / z: 740.15 [M + 1] ⁺ .
Step 7: (2S, 4R) -4-((tert-butyldimethylsilyl) oxy) -1-((S) -2- (2- (4-((4- (4- (3- (2, 2,,)) 6-Difluoro-3-(((R) -3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazin-1-yl) Methyl) piperidine-1-yl) acetamide) -3,3-dimethylbutanoyl) -N-((R) -2-hydroxy-1- (4- (4-methylthiazole-5-yl) phenyl) ethyl) Preparation of pyrrolidine-2-carboxamide.

In a 50 mL round bottom flask, 2- (4-[[4- (4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino] ) Benzoyl] -1H-pyrrolo [2,3-b] pyridine-5-yl] phenyl) piperazine-1-yl] methyl] piperidine-1-yl) acetic acid (700 mg, 950 mmol, 1 equivalent), (2S, 4R) ) -1- [(2S) -2-amino-3,3-dimethylbutanoyl] -4-[(tert-butyldimethylsilyl) oxy] -N-[(1R) -2-hydroxy-1- [4] -(4-Methyl-1,3-thiazole-5-yl) phenyl] ethyl] piperidine-2-carboxamide, trifluoroacetate (736.5 mg 10 ml DMF solution, 1.07 mol, 1.13 equivalent), DIEA (50 mg, 0.39) A solution of DMF (5 mL) in mmol (3.25 equivalents) was added at room temperature. The obtained mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (22 mL) and extracted with EtOAc (30 mLx3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with dichloromethane / MeOH (9: 1) and (2R) -2-[[(2S, 4R) -1-[(2S) -2- [2-]. (4-[[4- (4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) benzoyl]]
-1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazine-1-yl] methyl] piperidine-1-yl) acetamide]-(760 mg, 65.60%) was obtained as a yellow oil.

Step 8: 4-((R) -2-((2S, 4R) -4-((tert-butyldimethylsilyl) oxy) -1-((S) -2- (2- (4-((4) -(4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridine-5- Il) phenyl) piperazine-1-yl) methyl) piperidine-1-yl) acetamide) -3,3-dimethylbutanoyl) pyrrolidine-2-carboxamide) -2- (4- (4-methylthiazole-5-yl) ) Preparation of phenyl) ethoxy) -4-oxobutanoic acid.

In a 50 mL flask purged and maintained in an inert nitrogen atmosphere, (2S, 4R) -4-[(tert-butyldimethylsilyl) oxy] -1-[(2S) -2- [2- (4-) [[4- (4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3- b] pyridine-5-yl] phenyl) piperazine-1-yl] methyl] piperidine-1-yl) acetamide] -3,3-dimethylbutanoyl] -N-[(1R) -2-hydroxy-1- [ 4- (4-Methyl-1,3-thiazole-5-yl) phenyl] ethyl] piperidine-2-carboxamide (100.00 mg, 0.077 mmol, 1.00 equivalent), DMAP (37.69 mg, 0.308 mmol, 4 equivalents), TEA A solution of DCM (20 mL) of (15.61 mg, 0.154 mmol, 2 equivalents) and oxolan-2,5-dione (30.87 mg, 0.308 mmol, 4.00 equivalents) was added. The resulting solution was stirred at room temperature for 16 hours. The resulting solution was extracted with dichloromethane (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 126 mg of 4-[(2R) -2-[[(2S, 4R) -4-[(tert-butyldimethylsilyl) oxy] -1-[(2S) -2- [2- (4-) [[4- (4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3- b] Pyridine-5-yl] phenyl) piperazine-1-yl] methyl] piperidine-1-yl) acetamide] -3,3-dimethylbutanoyl] pyrrolidine-2-yl] formamide] -2- [4-( 4-Methyl-1,3-thiazole-5-yl) phenyl] ethoxy] -4-oxobutanoic acid was obtained as a solid. LC / MS (ESI) m / z: 1396 [M + 1] ⁺ .
Step 9: 4-((R) -2-((2S, 4R) -1-((S) -2- (2- (4-((4- (4- (3- (2,6-difluoro) -3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl)
Phenyl) piperazine-1-yl) methyl) piperidine-1-yl) acetamide) -3,3-dimethylbutanoyl) -4-hydroxypyrrolidine-2-carboxamide) -2- (4- (4-methylthiazole-5) -Preparation of yl) phenyl) ethoxy) -4-oxobutanoic acid.

In a 100 mL round bottom flask, 4-[(2R) -2-[[(2S, 4R) -4-[(tert-butyldimethylsilyl) oxy] -1-[(2S) -2- [2-( 4-[[4- (4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidine-1-)
Il] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazine-1-yl] methyl] piperidine-1-yl) acetamide] -3,3-dimethylbuta Noyl] Piperidine-2-yl] Formamide] -2- [4- (4-Methyl-1,3-thiazole-5-yl) phenyl] ethoxy] -4-oxobutanoic acid (110.00 mg, 0.308 mmol, 1 equivalent) A solution of dioxane (8.00 mL) was added, and concentrated hydrogen chloride (1.00 mL) was added thereto. The resulting solution was stirred at room temperature for 1 hour. The resulting solution was extracted with dichloromethane (50 mL x 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative HPLC. As a result, 50 mg of 4-[(2R) -2-[[(2S, 4R) -1-[(2S) -2- [2- (4- [[4- (4- [3- [2,, 6-Difluoro-3-([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazine-1 -Il] methyl] piperidine-1-yl) acetamide] -3,3-dimethylbutanoyl] -4-hydroxypyrrolidin-2-yl] formamide] -2- [4- (4-methyl-1,3-thiazole) -5-Il) Phenyl] ethoxy] -4-oxobutanoic acid was obtained as a yellow solid. LC / MS (ESI) m / z: 1282 [M + 1] +; 1H-NMR (300MHz, DMSO-d6) δ 12.91 (s, 1H), 9.83 (s, 1H), 8.99 (s, 1H), 8.65 (s, 1H), 8.60 -8.55 (m, 2H), 8.07 (s, 1H), 7.62 (s, 3H), 7.60 -7.37 (m, 4H), 7.30-7.24 (m, 1H), 7.09- 7.07 (m, 2H), 5.21-5.13 (m, 2H), 4.54-4.44 (m, 2H), 4.29 -4.23 (m, 3H), 3.62-3.31 (m, 13H), 2.91-2.73 (m, 4H) ), 2.56-2.54 (m, 3H), 2.50-2.47 (m, 7H), 2.28-1.96 (m, 8H), 1.81-1.77 (m, 4H), 1.31-1.11 (m, 2H), 0.95-0.86 (s, 9H).
2- (2-((R) -2-((2S, 4R) -1-((S) -2- (2- (4-((4- (4- (3- (2,6-difluoro) -3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) methyl) piperidine -1-yl) acetamide) -3,3-dimethylbutanoyl) -4-hydroxypyrrolidine-2-carboxamide) -2- (4- (4-methylthiazole-5-yl)
Exemplary Synthesis of phenyl) ethoxy) -2-oxoethoxy) acetic acid (exemplary compound 759) Step 1: 2- (2-((R) -2-((2S, 4R) -4-((tert-butyl) Dimethylsilyl) Oxy) -1-((S) -2-(2-(4-((4- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) ) -1-sulfonamide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperazin-1-yl) Methyl) Piperidine-1-yl) Acetamide) -3,3-dimethyl Preparation of butanoyl) pyrrolidine-2-carboxamide) -2- (4- (4-methylthiazole-5-yl) phenyl) ethoxy) -2-oxoethoxy) acetic acid.

In a 25 mL flask purged and maintained in an inert nitrogen atmosphere, (2S, 4R) -4-[(tert-butyldimethylsilyl) oxy] -1-[(2S) -2- [2- (4-) [[4- (4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3- b] Pyridine-5-yl] phenyl) piperazine-1-yl] methyl] piperazine-1-yl) acetamide] -3,3-dimethylbutanoyl] -N-[(1R) -2-hydroxy-1- [ 4- (4-Methyl-1,3-thiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (100.00 mg, 0.077 mmol, 1.00 equivalent), DMAP (28.27 mg, 0.231 mmol, 3.00 equivalent), TEA A solution of DCM (5.00 mL) of (15.61 mg, 0.154 mmol, 2 equivalents), 1,4-dioxane-2,6-dione (35.81 mg, 0.308 mmol, 4.00 equivalents) was added. The resulting solution was stirred at room temperature for 16 hours. The resulting solution was extracted with dichloromethane (50 mLx3), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 137.7 mg of 2- [2- [(2R) -2-[[(2S, 4R) -4-[(tert-butyldimethylsilyl) oxy] -1-[(2S) -2- [2. -(4-[[4- (4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) benzoyl] -1H-pyrrolo [ 2,3-b] Pyridine-5-yl] phenyl) piperazine-1-yl] methyl] piperidin-1-yl) acetamide] -3,3-dimethylbutanoyl] pyrrolidine-2-yl] formamide] -2- [4- (4-Methyl-1,3-thiazole-5-yl) phenyl] ethoxy] -2-oxoethoxy] acetic acid was obtained as a solid. LC / MS (ESI) m / z: 1142 [M + 1] ⁺ .
Step 2: 2- (2-((R) -2-((2S, 4R) -1-((S) -2- (2- (4-((4- (4- (3- (2, 2,,) 6-Difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) Methyl) piperidine-1-yl) acetamide) -3,3-dimethylbutanoyl) -4-hydroxypyrrolidine-2-carboxamide) -2- (4- (4-methylthiazole-5-yl) phenyl) ethoxy)- Preparation of 2-oxoethoxy) acetic acid.

2- [2-[(2R) -2-[[(2S, 4R) -4-[(tert-butyldimethylsilyl) oxy] -1-[(2S) -2- [2- (4- [[ 4- (4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] Pyridine-5-yl] phenyl) piperazine-1-yl] methyl] piperidine-1-yl) acetamide] -3,3-dimethylbutanoyl] pyrrolidine-2-yl] formamide] -2- [4- (4- (4-) A solution of dioxane (8.00 mL) of methyl-1,3-thiazole-5-yl) phenyl] ethoxy] -2-oxoethoxy] acetic acid (137.70 mg) was filled with concentrated hydrogen chloride (1.00 mL). The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC. This resulted in 50 mg of 2- [2- [(2R) -2-[[(2S, 4R) -1-[(2S) -2- [2- (4- [[4- (4- [3-] 3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) Piperazine-1-yl] methyl] piperidine-1-yl) acetamide] -3,3-dimethylbutanoyl] -4-hydroxypyrrolidine-2-yl] formamide] -2- (4-methylphenyl) ethoxy] -2 -Oxoethoxy] acetic acid was obtained as a bright yellow solid. LC / MS (ESI) m / z: 1298.45 [M + 1] +; 1H-NMR (300MHz, DMSO-d6) δ 8.99 (s, 1H), 8.64-8.61 (m, 2H), 8.53 (s, 1H) ), 8.06 (s, 1H), 7.89-7.86 (m, 1H), 7.61 (s, 3H), 7.58-7.46 (m, 4H), 7.28-7.22 (m, 1H), 7.08-7.05 (d, J) = 8.1Hz, 2H), 5.31-5.19 (m, J = 2H), 4.53-4.43 (m, 2H), 4.38-4.16 (m, 6H), 4.06-3.95 (m, 3H), 3.49-3.38 (m) , 3H), 3.29-3.13 (m, 6H), 3.23-2.87 (m, 6H), 2.68-2.56 (m, 3H), 2.50-2.46 (m, 3H), 2.26-2.18 (m, 8H), 1.87 -1.71 (m, 3H), 1.70-1.53 (m, 1H), 1.31-1.12 (m, 3H), 1.01-0.87 (s, 9H).
(3R) -N- (3- (5- (4- (4-((((1r, 3r) -3-((2- (2,6-dioxopiperidine-3-yl) -1,3) -Dioxoisoindrin-5-yl) oxy) cyclobutyl) (isopropyl) amino) methyl) piperidine-1-yl) phenyl) -1H-pyrrolo [2,3-b] pyridin-3-carbonyl) -2,4 -Exemplary synthesis of difluorophenyl) -3-fluoropyrolidin-1-sulfonamide (exemplary compound 760) Step 1: Preparation of tert-butyl ((1s, 3s) -3-hydroxycyclobutyl) carbamate.

tert-butyl N- (3-oxocyclobutyl) carbamate (15.00 g, 80.98 mmol, 1.00 eq) in a solution of tetrahydrofuran (150 mL) and sodium borohydride (1.53 g, 40.49 mmol, 0.50 eq) in tetrahydrofuran. A solution of (100 mL) and water (100 mL) was added dropwise at −70 ° C. for 2 hours. The mixture was stirred at −70 ° C. for 2 hours. Then water (100 mL) was added to the mixture and heated to 20 ° C. The mixture was extracted with ethyl acetate (2x200 mL). The combined organic layers were washed with brine (2x400 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a white solid. The solid was dissolved in a solution of petroleum ether: ethyl acetate (50 mL, v: v = 20: 1). The suspension was stirred for 0.5 hours and then filtered to give tert-butyl N- (3-hydroxycyclobutyl) carbamate (13.80 g, 73.70 mmol, 91% yield). 1H-NMR (400MHz, DMSO-d6) δ 7.00 (d, J = 7.2 Hz, 1H), 4.96 (d, J = 5.6 Hz, 1H), 3.62 --3.82 (m, 1H), 3.33 --3.47 (m, 1H), 2.35 --- 2.47 (m, 2H), 1.63 --1.76 (m, 2H), 1.36 (s, 9H).
Step 2: Dimethyl 4-((1r, 3r) -3-((tert-butoxycarbonyl) amino) cyclobutoxy)
Preparation of phthalates.

Dimethyl 4-hydroxybenzene-1,2-dicarboxylate (17.04 g, 81.07 mmol, 1.10 eq), tert-butyl N- (3-hydroxycyclobutyl) carbamate (13.80 g, 73.70 mmol, 1.00)
To a solution of triphenylphosphine (25.13 g, 95.82 mmol, 1.30 eq) in tetrahydrofuran (150 mL) was added dropwise diisopropylazodicarboxylate (19.37 g, 95.82 mmol, 1.30 eq) at 0 ° C. .. The mixture was heated to 15 ° C. The mixture was stirred at 15 ° C. for 15 hours. The mixture was diluted with water (150 mL) and extracted with ethyl acetate (2x100 mL). The organic layer was washed with brine (2x100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1 to 3: 1) and dimethyl 4- [3- (tert-butoxycarbonylamino) cyclobutoxy] benzene-1,2-dicarboxylic. The acid salt (25.50 g, 67.21 mmol, 91% yield) was obtained as a red oil. LC / MS (ESI) m / z: 402.1 [M + 23] ⁺ .
Step 3: Preparation of dimethyl 4-((1r, 3r) -3-aminocyclobutoxy) phthalate salt.

Hydrochloric acid / ethyl acetate (4M) in a solution of dimethyl 4- [3- (tert-butoxycarbonylamino) cyclobutoxy] benzene-1,2-dicarboxylate (25.50 g, 67.21 mmol, 1.00 eq) in dichloromethane (30 mL). , 30 mL, 1.79 eq) was added at 20 ° C. The mixture was stirred at 20 ° C. for 1 hour. The mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in water (60 mL) and extracted with ethyl acetate (4x50 mL). The aqueous layer is adjusted to pH = 8 with ammonium hydroxide and concentrated under reduced pressure to give dimethyl 4- (3-aminocyclobutoxy) benzene-1,2-dicarboxylate (19.00 g) as a bright red solid. Obtained. 1H-NMR (400MHz, DMSO-d6) δ 7.92 --8.60 (m, 2H), 7.75 --7.80 (m,
1H), 7.02 --7.06 (m, 1H), 6.98 --7.01 (m, 1H), 5.09 --5.18 (m, 1H), 3.80 --3.84
(m, 1H), 3.80 (s, 3H), 3.77 (s, 3H), 2.58 --2.69 (m, 2H), 2.37 --2.46 (m, 2H).
Step 4: Dimethyl 4-((1r, 3r) -3-(((1- (tert-butoxycarbonyl) piperidine-4-yl))
Preparation of methyl) amino) cyclobutoxy) phthalates.

In a 100 mL round bottom flask, tert-butyl 4-formylpiperidin-1-carboxylate (680 mg, 3.18 mmol, 1.00 eq), 1,2-dimethyl 4-[(1r, 3r) -3-aminocyclobutoxy] A hydrochloride salt of benzene-1,2-dicarboxylate (1 g, 3.16 mmol, 0.99 eq) and dichloromethane (40 mL) was added.
Subsequently, DIEA (approximately 0.2 mL, adjusted to PH = 8-9) was added dropwise at room temperature for 1 hour with stirring. To this was added NaBH (OAc) ₃ (1.4 g, 6.60 mmol, 2.1 eq) at room temperature in several batches in 5 minutes. HOAc (approx. 0.4 mL, adjusted for PH = 5-6). The resulting solution was stirred at room temperature for 1 hour. The reaction was then quenched by the addition of 30 mL of water. The resulting solution was extracted with 3x30 mL dichloromethane and the organic layers were combined into one. The resulting mixture was washed with 1x30 mL saturated aqueous sodium chloride solution. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded into a silica gel column with dichloromethane / methanol (9: 1). Obtained by concentrating the desired product under vacuum. This resulted in 1.23 g (81%) of 1,2-dimethyl4-[(1r, 3r) -3-[([1-[(tert-butoxy) carbonyl] piperidine-4-yl] methyl) amino] cyclo. Butoxy] benzene-1,2-dicarboxylate was obtained as a bright yellow oil.

Step 5: Dimethyl 4-((1r, 3r) -3-(((1- (tert-butoxycarbonyl) piperidine-4-yl))
Preparation of methyl) (isopropyl) amino) cyclobutoxy) phthalates.

In a 100 mL round-bottom flask purged and maintained in an inert nitrogen atmosphere, 1,2-dimethyl 4-[(1r, 3r) -3-[([1-[(tert-butoxy) carbonyl] piperidine-4 ^{A solution of i} PrOH / acetone (20 / 20 mL) of -yl] methyl) amino] cyclobutoxy] benzene-1,2-dicarboxylate (1.23 g, 2.44 mmol, 1.00 eq) was added. Ti ( ⁱ PrO) ₄ (693 mg, 2.44 mmol, 1.00 eq) and 10 g of 4A MS were added to this. After stirring at room temperature for 1 hour, NaBH ₃ CN (461 mg, 7.32 mmol, 3.00 eq) was added. The resulting solution was stirred at 60 ° C. for 20 hours. The reaction mixture was cooled. The solids were filtered off. The resulting mixture was concentrated under vacuum. The residue was loaded into a silica gel column with dichloromethane / methanol (10/1). Obtained by concentrating the desired product under vacuum. This resulted in 841 mg (67%) of 1,2-dimethyl4-[(1r, 3r) -3-[([1-[(tert-butoxy) carbonyl] piperidine-4-yl] methyl) (propane-2). -Il) Amino] cyclobutoxy] benzene-1,2-dicarboxylate was obtained as a yellow solid. LC / MS (ESI) m / z: 518.30 [M + 1] ⁺ .
Step 6: Preparation of dimethyl 4-((1r, 3r) -3- (isopropyl (piperidine-4-ylmethyl) amino) cyclobutoxy) phthalate salt.

In a 100 mL round bottom flask, 1,2-dimethyl 4-[(1r, 3r) -3-[([1-[(tert-butoxy) carbonyl] piperidin-4-yl] methyl) (propane-2-yl) ) Amino] cyclobutoxy] benzene-1,2-dicarboxylate (841 mg, 1.62 mmol, 1.00 eq) and a solution of HCl (gas) 1,4-dioxane (20 mL, 4 mol / L) were added. The resulting solution was stirred at room temperature for 1 hour. Obtained by concentrating the desired product under vacuum. This resulted in 863 mg of 1,2-dimethyl4-[(1r, 3r) -3-[[(piperidine-4-yl) methyl] (propane-2-yl) amino] cyclobutoxy] benzene-1,2- Dicarboxylate
Hydrogen chloride was obtained as a yellow solid. LC / MS (ESI) m / z: 418.25 [M + 1] ⁺ .
Step 7: Preparation of dimethyl 4-((1r, 3r) -3-(((1- (4-bromophenyl) piperidine-4-yl) methyl) (isopropyl) amino) cyclobutoxy) phthalate salt.

In a 250 mL round bottom flask, 1,2-dimethyl 4-[(1r, 3r) -3-[[(piperidin-4-yl) methyl] (propane-2-yl) amino] cyclobutoxy] benzene-1, 2-Dicarboxylate (2.40 g, 5.734 mmol, 1.00 eq), (4-bromophenyl) boronic acid (2.30 g, 11.469 mmol, 2.00 eq), dichloromethane (100 mL), TEA (2.32 g, 22.937 mmol, 4.00 eq) ), Cu (OAc) ₂ (2.08 g, 11.469 mmol, 2.00 eq) was added. The obtained solution was stirred at room temperature for 72 hours under an air atmosphere. After filtration, it was diluted with water (100 mL). The resulting mixture was extracted with dichloromethane (200 mLx3), the combined organic layers were dried over anhydrous sodium and concentrated under vacuum. It is then eluted with ethyl acetate / petroleum ether (1: 3). This resulted in 880 mg (27%) of 1,2-dimethyl4-[(1r, 3r) -3-([[1- (4-bromophenyl) piperidine-4-yl] methyl] (propane-2-yl]). ) Amino) cyclobutoxy] benzene-1,2-dicarboxylate was obtained as a yellow oil. LC / MS (ESI) m / z: 572.19 [M + 1] ⁺ .
Step 8: Dimethyl 4-((1r, 3r) -3- (isopropyl ((1- (4- (4,4,5,5-tetramethyl-1,3,2-)
Preparation of dioxaborolan-2-yl) phenyl) piperidine-4-yl) methyl) amino) cyclobutoxy) phthalate salt.

In a 25 mL round bottom flask purged and maintained in an inert nitrogen atmosphere, 1,2-dimethyl 4-[(1r, 3r) -3-([[1- (4-bromophenyl) piperidin-4-yl) ] Methyl] (Propan-2-yl) amino) cyclobutoxy] benzene-1,2-dicarboxylate (740.00 mg, 1.290 mmol, 1.00 eq), 4,4,5,5-tetramethyl-2- (4) , 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolan (655.30 mg, 2.581 mmol, 2.00 eq), Dioxane (5.00 mL, 59.020 mmol, 45.74) Equivalent), KOAc (253.26 mg, 2.581 mmol, 2.00 equivalent) and Pd (dppf) Cl ₂ (94.41 mg, 0.129 mmol, 0.10 equivalent) were added. The resulting solution was stirred for 12 hours in an oil bath at 90 ° C. The reaction was cooled to room temperature, dried over anhydrous sodium and concentrated under vacuum. It is then eluted with ethyl acetate / petroleum ether (1: 1). This resulted in 590 mg (73%) of 1,2-dimethyl 4-[(1r, 3r) -3-[(propane-2-yl)) ([1- [4- (4,4,5,5-tetra). Methyl-1,3,2-dioxaborolan-2-yl) phenyl] piperidine-4-yl] methyl) amino] cyclobutoxy] benzene-1,2-dicarboxylate was obtained as a brown oil. LC / MS (ESI) m / z: 620.36 [M + 1] ⁺ .
Step 9: Dimethyl 4-((1r, 3r) -3-(((1- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfone) Preparation of amide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperidine-4-yl) methyl) (isopropyl) amino) cyclobutoxy) phthalate.

In a 25 mL closed tube purged and maintained in an inert nitrogen atmosphere, 1,2-dimethyl4-[(1r,3r) -3- [isopropyl ([1- [4- (4,4,5-trimethyl) -1,3,2-dioxaborolan-2-yl) phenyl] piperidine-4-yl] methyl) amino] cyclobutoxy] phthalate (570.00mg, 1.1 eq), (3R) -N- (3- [5 -Bromo-1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluorophenyl) -3-fluoropyrrolidin-1-sulfonamide (420 mg, 1.00 eq), dioxane (5 mL), H ₂ O (1 mL), Na ₂ CO ₃ (177 mg, 2.0 eq) and Pd (dppf) Cl ₂ (68 mg, 0.1 eq) were added. The final reaction mixture was irradiated with microwave radiation at 100 ° C. for 2 hours. The reaction was cooled to room temperature, dried over anhydrous sodium and concentrated under vacuum. The residue was applied on a silica gel column and eluted with ethyl acetate (100%). This resulted in 220 mg (29%) of 1,2-dimethyl 4-[(1r, 3r) -3-[[(1- [4- [3- (2,6-difluoro-3- [[(3R)). -3-Fluoropyrrolidine-1-ylsulfonyl] amino] benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl] piperidine-4-yl) methyl] (isopropyl) amino] cyclobutoxy] Phthalate was obtained as a yellow solid. LC / MS (ESI) m / z: 916.34 [M + 1] ⁺ .
Step 10: 4-((1r, 3r) -3-(((1- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) ) Benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperidine-4-yl) methyl) (isopropyl) amino) cyclobutoxy) Preparation of phthalic acid.

In a 25 mL round bottom flask, 1,2-dimethyl 4-[(1r, 3r) -3-[[(1- [4- [3- (2,6-difluoro-3- [[(3R) -3) -3 -Fluoropyrrolidine-1-ylsulfonyl] amino] benzoyl) -1H-pyrrolo [2,3-b]
Pyridine-5-yl] phenyl] piperidine-4-yl) methyl] (isopropyl) amino] cyclobutoxy] phthalate salt (200.00 mg, 0.218 mmol, 1.00 eq), MeOH (10.00 mL), H ₂ O (4.00 mL) ) Was put in. This was followed by the addition of NaOH (174.47 mg, 4.362 mmol, 20.00 eq) at 10 ° C. The resulting solution was stirred for 20 hours in an oil bath at 50 ° C. The reaction was cooled to room temperature, dried over anhydrous sodium and concentrated under vacuum. This resulted in 210 mg of 4-[(1r, 3r) -3-[[(1- [4- [3- (2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1-yl). Sulfonyl] amino] benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl] piperidine-4-yl) methyl] (isopropyl) amino] cyclobutoxy] benzene-1,2-dicarboxylic acid Obtained as a yellow solid. LC / MS (ESI) m / z: 888.31 [M + 1] ⁺ .
Step 11: (3R) -N-(3-(5-(4-(4-((((1r, 3r) -3-((2- (2,6-dioxopiperidine-3-yl))- 1,
3-Dioxoisoindoline-5-yl) oxy) cyclobutyl) (isopropyl) amino) methyl) piperidine-1-yl) phenyl) -1H-pyrrolo [2,3-b] pyridin-3-carbonyl) -2, Preparation of 4-difluorophenyl) -3-fluoropyrrolidine-1-sulfonamide.

In a 25 mL round bottom flask, 4-[(1r, 3r) -3-[[(1- [4- [3- (2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1) -Ilsulfonyl] amino] benzoyl) -1H-pyrrolo [2,3-b] pyridine-5-yl] phenyl] piperidine-4-yl) methyl] (isopropyl) amino] cyclobutoxy] benzene-1,2-dicarboxylic Acid (190.00 mg, 0.214 mmol, 1.00 equivalent), 3-aminopiperidine-2,6-dione (27.39 mg, 0.214 mmol, 1.00 equivalent), HOAc (10.00 mL), NaOAc (175.33 mg, 2.137 mmol, 10.00 equivalent) I put it in. The resulting solution was stirred for 1 hour in an oil bath at 120 ° C. The reaction was cooled to room temperature, dried over anhydrous sodium and concentrated under vacuum. The residue was applied on a silica gel column and eluted with dichloromethane / methanol (15: 1). The crude product was further purified by preparative HPLC. This resulted in 23 mg (11%) of (3R) -N- [2,4-difluoro-3- (5- [4- [4-([isopropyl [(1r, 3r) -3-[2-( 2,6-dioxopiperidine-3-yl) -1,3-dioxoisoindole-5-yl] oxy] cyclobutyl] amino] methyl) piperidine-1-yl] phenyl] -1H-pyrrolo [2,3 -b] Pyridine-3-carbonyl) Phenyl] -3-fluoropyrrolidin-1-sulfonamide was obtained as a bright yellow solid. LC / MS (ESI) m / z: 981.20 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 12.89 (s, 1H), 11.10 (s, 1H), 8.65 (s, 1H), 8.52 (s, 1H), 8.15 (s, 1H), 8.06 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.67-7.55 (m, 3H), 7.31- 7.21 (m, 3H) , 7.10-7.03 (m, 2H), 5.36 (d, J = 32.6 Hz, 1H), 5.22-5.20 (m, 1H), 4.92 (t, J = 6.6 Hz, 1H), 3.86-3.74 (m, 4H) ), 3.69 (t, J = 8.1 Hz, 2H), 2.89-2.86 (m, 2H), 2.72-2.70 (m, 3H), 2.59-2.56 (m, 2H), 2.29-2.28 (m, 3H), 2.20-2.17 (m, 2H), 2.13-2.00 (m, 3H), 1.86 (d, J = 12.4 Hz, 2H), 1.54 (b, 1H), 1.26 --1.13 (m, 3H), 0.94 (d, J = 6.6 Hz, 6H).
(3R)-N-(3-(5-(4-(4-((4- (4- (2,6-dioxopiperidine-3-yl) phenyl) piperazine-1-yl) methyl) piperidine- 1-Il) Phenyl) -1H-Pyrrolidine [2,3-b] Pyridine-3-carbonyl) -2,4-difluorophenyl) -3-Fluoropyrrolidine-1-sulfonamide (Example compound 761)
Exemplary Synthesis Step 1: Preparation of tert-butyl 4- (4- (2-methoxy-2-oxoethyl) phenyl) piperazine-1-carboxylate

Methyl 2- (4-) in a 500 mL round-bottom flask purged and maintained in an inert nitrogen atmosphere.
Bromophenyl) acetate (10.0 g, 43.6 mmol, 1.0 eq), tert-butyl piperazin-1-carboxylate (8.1 g, 43.6 mmol, 1.0 eq), Cs ₂ CO ₃ (28.5 g, 87.3 mmol, 2.0 eq) ), RuPhos-PdC
A solution of l-2ndg (3.4 g, 4.3 mmol, 0.1 eq) of PhMe (200 mL) was added. The resulting solution was stirred for 16 hours in an oil bath at 110 ° C. The resulting mixture was concentrated under reduced pressure. Residue,
Silica gel columns were loaded with ethyl acetate / petroleum ether (1: 1). This gave 6.5 g of tert-butyl 4- [4- (2-methoxy-2-oxoethyl) phenyl] piperazine-1-carboxylate as a solid. LC / MS (ESI) m / z: 335.00 [M + 1] ⁺ .
Step 2: Preparation of tert-butyl 4- (4- (2,6-dioxopiperidine-3-yl) phenyl) piperazine-1-carboxylate.

In a 250 mL round bottom flask purged and maintained in an inert nitrogen atmosphere, tert-butyl 4- [4- (2-methoxy-2-oxoethyl) phenyl] piperazine-1-carboxylate (6.5 g, 19.4 mmol). , 1.0 eq) and t-BuOK (2.4 g, 21.3 mmol, 1.1 eq) in a solution of THF (60.0 mL). Then polyacrylamide (1.2 g, 17.4 mmol, 0.9 eq) was added. The resulting mixture was stirred overnight in an oil bath at 50 ° C. The reaction was then stopped by the addition of 100 mL of water. The resulting solution was extracted with ethyl acetate (100x3 mL) and concentrated under reduced pressure. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (2: 1). This gave 2.1 g (30.0%) of tert-butyl 4- [4- (2,6-dioxopiperidine-3-yl) phenyl] piperazine-1-carboxylate as a solid. LC / MS (ESI) m / z: 374.05 [M + 1] ⁺ .
Step 3: Preparation of 3- (4- (piperazine-1-yl) phenyl) piperidine-2,6-dione.

DCM (20.0 mL) of tert-butyl 4- [4- (2,6-dioxopiperidine-3-yl) phenyl] piperazine-1-carboxylate (2.1 g, 1.0 eq) in a 50 mL round bottom flask. Was added, and a 1,4-dioxane solution of hydrogen chloride (4.0 M, 20 mL) was added thereto. The obtained mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. This gave 1.1 g of 3- [4- (piperazine-1-yl) phenyl] piperidine-2,6-dione as a solid. LC / MS (ESI) m / z: 274.00 [M + 1] ⁺ .
Step 4: (3R) -N- (3-(5-(4-(4-((4- (4- (2,6-dioxopiperidine-3-yl) phenyl) piperazine-1-yl) methyl) ) Piperidine-1-yl) Phenyl) -1H-Pyrrolidine [2,3-b] Pyridine-3-carbonyl) -2,4-Difluorophenyl) -3-Fluoropyrrolidine-1-sulfonamide preparation.

In a 100 mL round bottom flask, (3R) -N- (2,4-difluoro-3- [5- [4- (4-formylpiperidin-1-yl) phenyl] -1H-pyrrolo [2,3-b ] Phenyl-3-carbonyl] Phenyl) -3-fluoropyrrolidine-1-sulfonamide (150.0 mg, 0.25 mmol, 1.0 equivalent) and 3- [4- (piperazine-1-yl) phenyl] piperidine-2,6- A solution of DCM (15.0 mL) of dione (67.0 mg, 0.25 mmol, 1.0 equivalent) was added. The resulting mixture was stirred for 1 hour, then NaBH (OAc) 3 (62.3 mg, 0.29 mmol, 1.2 eq) was added. The resulting mixture was stirred at room temperature for 12 hours. The reaction was then stopped by the addition of 50 mL of water. The resulting solution was extracted with dichloromethane (50 mLx3). The organic layers were combined and concentrated under reduced pressure. The crude product was purified by preparative HPLC. This resulted in 15.6 mg (7.3%) of (3R) -N- [3- (5- [4- [4-([4- [4- (2,6-dioxopiperidine-3-yl) phenyl]]. Piperazine-1-yl] Methyl) Piperidine-1-yl] Phenyl] -1H-Pyrrolidine [2,3-b] Pyridine-3-carbonyl) -2,4-Difluorophenyl] -3-Fluoropyrrolidin-1-sulfon The amide was obtained as a solid. LC / MS (ESI) m / z: 869.15 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 12.94 (s, 1H), 10.80 (s, 1H), 9.86 (s, 1H), 9.51 (s, 1H), 8.66 (d, J = 2.2 Hz, 1H), 8.55 (s, 1H), 8.07 (d, J = 3.0 Hz, 1H), 7.68-7.57 (m, 3H), 7.26-7.20 (m, 1H), 7.17 -7.08 (m, 4H), 6.99-6.90 (m, 2H), 5.40-5.20 (m, 1H), 3.85-3.72 (m, 5H), 3.68-3.61 (m, 2H) , 3.51-3.40 (m, 2H), 3.29-3.16 (m, 5H), 2.92-2.71 (m, 2H), 2.72-2.59 (m, 1H), 2.22-2.09 (m, 3H), 2.12-1.95 ( m, 2H), 1.93-1.84 (m, 2H), 1.50-1.37 (m, 2H), 1.25-1.21 (s, 2H).
(2S, 4R) -1-((S) -2- (5-(4-((1- (4- (3- (2,6-difluoro-3- (((R) -3-fluoropyrrolidin) ) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridine-5-yl) phenyl) piperidine-4-yl) methyl) piperazine-1-yl) -1-methyl-1H-pyrazole -3-yl) -3-methylbutanoyl) -4-hydroxy-N-((S) -1-(4-(4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (example) Exemplary Synthesis of Compound 762) Step 1: Preparation of ethyl 5-amino-1-methyl-1H-pyrazol-3-carboxylate.

Sulfuric acid (10.42 g, 106.29 mmol, 5.6 mL, 1 eq) was added dropwise at 0 ° C. to a mixture of methanol (150 mL) of methylhydrazine (13.47 g, 116.92 mmol, 15.4 mL, 1.1 eq). The mixture is stirred for 0.5 hours at 25 ° C., then ethyl 3-cyano-2-oxo-propanoate (15 g, 106.29 mmol, 1).
Equivalent) was added at 25 ° C. and the mixture was stirred at 25 ° C. for 20.5 hours. The mixture was concentrated in vacuo.
The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1 to 1: 2). The product ethyl 5-amino-1-methyl-pyrazole-3-carboxylate (11.9 g, 70.34 mmol, 66% yield) was obtained as a brown oil. LC / MS (ESI) m / z: 170.2 [M + 1] +; 1H-NMR (400MHz, CDCl3) δ 6.16 --6.05 (m, 1H), 4.47 --4.32 (m, 2H), 3.83 --3.68 (m) , 3H), 3.28 --3.14 (m, 2H), 1.44 --1.35 (m, 3H).
Step 2: Preparation of benzyl 4- (3- (ethoxycarbonyl) -1-methyl-1H-pyrazole-5-yl) piperazine-1-carboxylate.

Benzyl N, N-bis (2-oxoethyl) carbamate (14.8 g, 62.92 mmol, 1.1 eq) and ethyl 5-amino-1-methyl-pyrazole-3-carboxylate (9.68 g, 57.20 mmol, 1 eq) ) To a solution of acetic acid (20 mL) and methanol (280 mL) was added borane; 2-methylpyridine (12.24 g, 114.39 mmol, 2 eq). The mixture was stirred at 25 ° C. for 1 hour. The mixture was then stirred for 11 hours at 25 ° C. A saturated aqueous sodium bicarbonate solution (about 180 mL) was added to the mixture to adjust the pH to 8. The aqueous layer was extracted with ethyl acetate (300 mLx3). The combined organic layers were washed with brine (500 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 30/1 to 1/1). The oil was further purified by preparative reverse phase HPLC. The solution was concentrated under vacuum. The aqueous layer was extracted with ethyl acetate (200 mLx3). The combined organic layers were washed with brine (200 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The product benzyl 4- (5-ethoxycarbonyl-2-methyl-pyrazole-3-yl) piperazine-1-carboxylate (11.55 g, 31.01 mmol, 54% yield) was obtained as a colorless oil. LC / MS (ESI) m / z: 373.3 [M + 1]
⁺ ..
Step 3: Preparation of 5- (4-((benzyloxy) carbonyl) piperazine-1-yl) -1-methyl-1H-pyrazole-3-carboxylic acid.

Benzyl 4- (5-ethoxycarbonyl-2-methyl-pyrazole-3-yl) piperazine-1-carboxylate (16.18 g, 43.45 mmol, 1 eq) in a mixture of water (20 mL) and tetrahydrofuran (200 mL). , Sodium hydroxide (4.34 g, 108.61 mmol, 2.5 eq) was added at 25 ° C. at a time. The mixture was stirred for 12 hours at 25 ° C. Water (100 mL) was poured into the mixture and stirred for 1 minute. The aqueous layer was extracted with ethyl acetate (100 mL). Hydrochloric acid (2M) was added to the aqueous layer to adjust the pH to 3-4. The aqueous layer was then extracted with ethyl acetate (150 mLx3). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The product 5- (4-benzyloxycarbonylpiperazin-1-yl) -1-methyl-pyrazole-3-carboxylic acid (13.12 g, 38.10 mmol, 87% yield) was obtained as a red rubbery substance. LC / MS (ESI) m / z: 345.0 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 8.69 (s, 1H), 7.67 --7.59 (m, 2H), 7.39 (d, J) = 8.4 Hz, 2H), 4.85 (s, 1H), 3.50 (s, 1H), 1.48 (d, J = 6.4 Hz, 3H), 1.44 (s, 9H).
Step 4: Preparation of benzyl 4- (3- (hydroxymethyl) -1-methyl-1H-pyrazole-5-yl) piperazine-1-carboxylate.

Borane sulfide dimethyl complex (5 g, 14.52 mmol, 1 eq) in solids of 5- (4-benzyloxycarbonylpiperazin-1-yl) -1-methyl-pyrazole-3-carboxylic acid (5 g, 14.52 mmol, 1 eq) in tetrahydrofuran (20 mL) 10 M, 7.3 mL, 5 eq) was added at 0 ° C. The mixture was stirred at 25 ° C. for 1 hour. The mixture was added dropwise to methanol (200 mL) at 0 ° C., and the mixture was stirred for 1 minute. The mixture was concentrated under vacuum.
Residues are subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1 to 1).
: Purified according to 2). The oil was dissolved in 100 mL of acetonitrile, 2 mL of trifluoroacetic acid was added, and the mixture was stirred at 25 ° C. for 2 hours. The column was then flushed with a gradient (dichloromethane: methanol = 50: 1-25: 1) to give another batch of product. Product benzyl
4- [5- (Hydroxymethyl) -2-methyl-pyrazole-3-yl] piperazine-1-carboxylate (3.8 g, 11.50 mmol, 79% yield) was obtained as a colorless rubbery substance. LC / MS (ESI) m / z: 331.5 [M + 1] +; 1H-NMR (400MHz, CDCl3) δ 7.44 --7.30 (m, 5H), 5.83 (s, 1H), 5.17 (s, 2H), 4.60 (s, 2H), 3.71 (s, 3H), 3.68 --3.61 (m, 4H), 2.87 (s, 4H), 2.05 --2.03 (m, 1H).
Step 5: Preparation of benzyl 4- (1-methyl-3-(((methylsulfonyl) oxy) methyl) -1H-pyrazole-5-yl) piperazine-1-carboxylate.

Benzyl 4- [5- (hydroxymethyl) -2-methyl-pyrazol-3-yl] piperazine-1-carboxylate (2.5 g, 7.57 mmol, 1 eq) and triethylamine (1.53 g, 15.13 mmol, 2.1 mL, Methyl methanechloride (1.30 g, 11.35 mmol, 1.5 eq) was added dropwise at 0 ° C. to a mixture of 2 equivalents) dichloromethane (35 mL). The mixture was stirred at 0 ° C. for 2 hours. Water (30 ml) was poured into the mixture and stirred for 1 minute. The aqueous layer was extracted with dichloromethane (30 mlx2). The combined organic layers were washed with brine (30 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The product benzyl 4- [2-methyl-5- (methylsulfonyloxymethyl) pyrazole-3-yl] piperazine-1-carboxylate (3 g was obtained as a bright yellow oil.

Step 6: Preparation of benzyl 4- (3- (cyanomethyl) -1-methyl-1H-pyrazole-5-yl) piperazine-1-carboxylate.

Cyan in a mixture of dimethylformamide (30 mL) of benzyl 4- [2-methyl-5- (methylsulfonyloxymethyl) pyrazole-3-yl] piperazine-1-carboxylate (3 g, 7.34 mmol, 1 equivalent). Sodium cyanide (720 mg, 14.69 mmol, 2 equivalents) was added at 25 ° C. at a time. Mix liquid at 50 ° C
Was stirred for 16 hours. Water (150 mL) was poured into the mixture and stirred for 1 minute. The aqueous layer was extracted with ethyl acetate (100 mLx3). The combined organic layers were washed with brine (100 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The aqueous layer was poured into an aqueous solution of sodium hypochlorite (1500 mL). The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3/1 to 1/1). The product benzyl 4- [5- (cyanomethyl) -2-methyl-pyrazole-3-yl] piperazine-1-carboxylate (820 mg, 2.42 mmol, 32.90% yield) was obtained as a bright yellow oil. LC / MS (ESI) m / z: 340.5 [M + 1] +; 1H-NMR (400MHz, CDCl3) δ 7.43 --7.30 (m, 5H), 5.85 (s, 1H), 5.17 (s, 2H), 3.70 (s, 3H), 3.68 --3.62 (m, 6H), 2.88 (d, J = 7.7 Hz, 4H).
Step 7: Preparation of benzyl 4- (3- (1-cyano-2-methylpropyl) -1-methyl-1H-pyrazole-5-yl) piperazine-1-carboxylate.

Potassium tert-butoxide in a solution of dimethylformamide (15 mL) of benzyl 4- [5- (cyanomethyl) -2-methyl-pyrazol-3-yl] piperazine-1-carboxylate (820 mg, 2.42 mmol, 1 eq). (298 mg, 2.66 mmol, 1.1 eq) was added at 0 ° C. The mixture was stirred at 25 ° C. for 0.5 hours. 2-Iodine propane (411 mg, 2.42 mmol, 1 eq) was then added to the mixture. The mixture was stirred at 25 ° C. for 2 hours. Water (50 mL) was poured into the mixture and stirred for 1 minute. The aqueous layer was extracted with ethyl acetate (20 mLx3). The combined organic layers were washed with brine (20 mLx3), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4/1 to 1/1). Product benzyl 4- [5- (1-cyano-2-methyl-propyl) -2-methyl-pyrazol-3-yl] piperazine-1-carboxylate (360 mg, 0.94 mmol, 39% yield) Obtained as a colorless oil. LC / MS (ESI) m / z: 382.2 [M + 1] +; 1H-NMR (400MHz, CDCl3) δ 7.43 --7.31 (m, 5H), 5.89 --5.79 (m, 1H), 5.22 --5.12 (m) , 2H), 3.72 --3.69 (m, 3H), 3.69 --3.68 (m, 1H), 3.68 --3.60 (m, 4H), 2.90 --2.84 (m, 4H), 2.29 --2.12 (m, 1H), 1.14 --1.03 (m, 6H).
Step 8: Preparation of 3-methyl-2- (1-methyl-5- (piperazine-1-yl) -1H-pyrazol-3-yl) butanoic acid.

Benzyl 4- [5- (1-cyano-2-methyl-propyl) -2-methyl-pyrazol-3-yl] piperazine-1-carboxylate (360 mg, 0.94 mmol, 1 equivalent) of dioxane (4 mL) Hydrochloric acid (12M) in the mixture
, 4 mL, 50 eq) at 25 ° C. The mixture was stirred at 100 ° C. for 12 hours. The mixture was concentrated in vacuo. The product 3-methyl-2- (1-methyl-5-piperazine-1-yl-pyrazole-3-yl) butanoic acid (250 mg) was obtained as a yellow oil. LC / MS (ESI) m / z: 267.2 [M + 1] ⁺ .
Step 9: Preparation of 2- (5-(4- (tert-butoxycarbonyl) piperazine-1-yl) -1-methyl-1H-pyrazole-3-yl) -3-methylbutanoic acid.

3-Methyl-2- (1-methyl-5-piperazine-1-yl-pyrazole-3-yl) butanoic acid (250 mg, 0.94 mmol, 1 eq) in a mixture of water (2 mL) and tetrahydrofuran (3 mL) , Sodium carbonate (497mg)
, 4.69 mmol, 5 eq), di-tert-butyl bicarbonate (410 mg, 1.88 mmol, 2 eq) at 25 ° C. The mixture was stirred at 25 ° C. for 2 hours. Water (20 mL) was poured into the mixture and stirred for 1 minute. The aqueous layer was extracted with ethyl acetate (20 mLx2). Hydrochloric acid (2M) was added to the aqueous layer to adjust the pH to 3-4. The aqueous layer was then extracted with ethyl acetate (20 mLx3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Product 2- [5- (4-tert-butoxycarbonylpiperazine-1-yl) -1-methyl-pyrazole-3-yl] -3-methyl-butanoic acid (330 mg, 0.79 mmol, 84% yield, 84% yield, Purity 87%) was obtained as a colorless oil. LC / MS (ESI) m / z: 367.2 [M + 1] ⁺ .
Step 10: tert-butyl 4-(3-(1-((2S, 4R) -4-hydroxy-2-(((S) -1- (4- (4-methylthiazole-5-yl) phenyl)) Preparation of ethyl) carbamoyl) pyrrolidine-1-yl) -3-methyl-1-oxobutan-2-yl) -1-methyl-1H-pyrazole-5-yl) piperazine-1-carboxylate.

2- [5- (4-tert-butoxycarbonylpiperazin-1-yl) -1-methyl-pyrazol-3-yl] -3-methyl-butanoic acid (330 mg, 0.79 mmol, 1 eq) dimethylformamide (5 mL) ), Diisopropylethylamine (306 mg, 2.37 mmol, 3 eq), 1-hydroxybenzotriazole (128 mg, 0.95 mmol, 1.2 eq), and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (227 mg). , 1.19 mmol, 1.5 eq) at 25 ° C. The mixture is stirred at 25 ° C. for 10 minutes, then (2S, 4R) -4-hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl]. Pyrrolidine-2-carboxamide (291 mg, 0.79 mmol, 1 eq, hydrochloride) was added and the mixture was stirred for 11 hours 50 minutes at 25 ° C. Water (40 mL) was poured into the mixture and stirred for 1 minute. The aqueous layer was extracted with ethyl acetate (20 mLx3). The combined organic layers were washed with brine (20 mLx3), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 200/1, 40/1). Product tert-butyl 4- [5- [1-[(2S, 4R) -4-hydroxy-2-[[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] Ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2-methyl-propyl] -2-methyl-pyrazol-3-yl] piperazine-1-carboxylate (360 mg, 0.
44 mmol, yield 56%, purity 84%) was obtained as a colorless oil. LC / MS (ESI) m / z: 680.3 [M + 1]
⁺ ..
Step 11: tert-butyl 4-(3-((S) -1-((2S, 4R) -4-hydroxy-2-(((S) -1- (4- (4-methylthiazole-5-) Preparation of yl) phenyl) ethyl) carbamoyl) pyrrolidine-1-yl) -3-methyl-1-oxobutan-2-yl) -1-methyl-1H-pyrazole-5-yl) piperazine-1-carboxylate.

Tert-butyl 4- [5- [1-[(2S, 4R) -4-hydroxy-2-[[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] carbamoyl] ] Pyrrolidine-1-carbonyl] -2-methyl-propyl] -2-methyl-pyrazol-3-yl] piperazine-1-carboxylate (360 mg, 0.44 mmol, 1 equivalent) was purified by chiral SFC. Product tert-butyl 4- [5-[(1S) -1-[(2S, 4R) -4-hydroxy-2-[[(1S) -1- [4- (4-methylthiazole-5-) Ill) Phenyl] Ethyl] Carbamoyl] Pyrrolidine-1-carbonyl] -2-Methyl-propyl] -2-Methyl-pyrazole-3-yl] Piperazin-1-carboxylate (150 mg, 0.20 mmol, 88% yield, Purity 89%) was obtained as a white solid.

Step 12: (2S, 4R) -4-hydroxy-1-((S) -3-methyl-2-(1-methyl-5- (piperazine-1-yl) -1H-pyrazole-3-yl) butanoyl) )-N-((S) -1- (4- (4-Methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide preparation.

tert-butyl 4- [5-[(1S) -1-[(2S, 4R) -4-hydroxy-2-[[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl) ] Ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2-methyl-propyl] -2-methyl-pyrazol-3-yl] piperazin-1-carboxylate (150 mg, 0.20 mmol, 1 equivalent) dichloromethane (5 mL) Hydroxyl (4M dioxane solution, 5 mL, 100 equivalents) was added to the mixture at 25 ° C. at a time. The mixture was stirred at 25 ° C. for 2 hours. The mixture was concentrated in vacuo. Product (2S, 4R) -4-hydroxy-1-[(2S) -3-methyl-2- (1-methyl-5-piperazine-1-yl-pyrazole-3-yl) butanoyl] -N- [(1S) -1- [4- (4-Methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (150 mg, hydrochloride) was obtained as an off-white solid. LC / MS
(ESI) m / z: 580.2 [M + 1] ⁺ .
Step 13: (2S, 4R) -1-((S) -2- (5-(4-((1- (4- (3- (2,6-difluoro-3- (((R) -3) -3) -Fluoropyrrolidin) -1-sulfonamide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperidine-4-yl) Methyl) Piperazin-1-yl) -1-Methyl- 1H-pyrazole-3-yl) -3-methylbutanoyl) -4-hydroxy-N-((S) -1-(4-(4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2- Preparation of carboxamide.

(2S, 4R) -4-Hydroxy-1-[(2S) -3-methyl-2- (1-methyl-5-piperazine-1-yl-pyrazol-3-yl) butanoyl] -N-[(1S) ) -1- [4- (4-Methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (140 mg, 0.23 mmol, 1 eq, hydrochloride) in a mixture of methanol (5 mL) and sodium acetate. (74 mg, 0.91 mmol, 4 eq) were added at one time at 30 ° C. The mixture is stirred at 30 ° C. for 1 minute, then (3R) -N- [2,4-difluoro-3- [5- [4- (4-formyl-1-piperidyl) phenyl] -1H-pyrrolo [2. , 3-b] Pyridine-3-carbonyl] Phenyl] -3-Fluoro-pyrrolidin-1-sulfonamide (104 mg, 0.17 mmol, 0.75 equivalent) in dichloromethane (2 mL) was added. The mixture was stirred at 30 ° C. for another 1 minute and acetic acid (0.02 mL) was added to adjust the pH to 4-5. Sodium cyanoborohydride (28 mg, 0.45 mmol, 2 eq) was then added and stirred for 58 minutes at 30 ° C.
The mixture was concentrated under vacuum. 4 mL of dimethylformamide was added. The mixture was filtered to obtain a filtrate. The yellow filtrate was purified by half-taken reverse phase HPLC. Product (2S, 4R) -1- [(2S) -2- [5- [4- [[1- [4- [3- [2,6-difluoro-3- [[(3R) -3) -Fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl] -4-piperidyl] methyl] piperazin-1-yl] -1-methyl- Pyrazole-3-yl] -3-methyl-butanoyl] -4-hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide ( 103.38 mg, 0.09 mmol, yield 38%, purity 99%, trifluoroacetate) was obtained as a yellow solid. LC / MS (ESI) m / z: 588.3 [M / 2 + 1] +; 1H-NMR (400MHz, DMSO-d6)
δ 12.95 ―― 12.88 (m, 1H), 9.84 (s, 1H), 9.43 ―― 9.20 (m, 1H), 9.06 ―― 8.95 (m, 1H), 8.66 (d, J = 2.0 Hz, 1H), 8.55 (s) , 1H), 8.30 (d, J = 8.0 Hz, 1H), 8.13 --8.01 (m, 1H), 7.74 --7.56 (m, 3H), 7.48 --7.34 (m, 4H), 7.27 (t, J = 8.8) Hz, 1H), 7.13 (d, J = 8.8 Hz, 2H), 5.83 (s, 1H), 5.40 --5.19 (m, 1H), 4.99 --4.84 (m, 1H), 4.38 --4.23 (m, 2H) , 3.85 (d, J = 11.6 Hz, 2H), 3.75 --3.69 (m, 2H), 3.61 (s, 4H), 3.41 (s, 2H), 3.32 --3.23 (m, 6H), 3.19 --3.14 (m) , 2H), 3.06 --2.91 (m, 2H), 2.83 (t, J = 11.7 Hz, 2H), 2.46 (s, 4H), 2.18 --1.75 (m, 9H), 1.50 --1.30 (m, 5H), 0.94 (d, J = 6.4 Hz, 3H), 0.69 (d, J = 6.4 Hz, 3H).
(2S, 4R) -1-((R) -2-(5-(4-((1- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidin) ) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridine-5-yl) phenyl) piperidin-4-yl) methyl) piperazin-1-yl) -1-methyl-1H-pyrazole -3-yl) -3-methylbutanoyl) -4-hydroxy-N-((S) -1-(4-(4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (example) Exemplary Synthesis of Compound 763) Step 1: tert-butyl 4-(3-((R) -1-((2S, 4R) -4-hydroxy-2-(((S) -1- (4-) (4-Methylthiazole-5-yl) phenyl) ethyl) carbamoyl) pyrrolidine-1-yl) -3-methyl-1-oxobutan-2-yl) -1-methyl-1H-pyrazole-5-yl) piperazin- Preparation of 1-carboxylate.

Tert-butyl 4- [5- [1-[(2S, 4R) -4-hydroxy-2-[[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] carbamoyl] ] Pyrrolidine-1-carbonyl] -2-methyl-propyl] -2-methyl-pyrazol-3-yl] piperazine-1-carboxylate (360 mg, 0.44 mmol, 1 equivalent) was purified by chiral SFC. Product tert-butyl 4- [5-[(1R) -1-[(2S, 4R) -4-hydroxy-2-[[(1S) -1- [4- (4-methylthiazole-5-) Ill) Phenyl] Ethyl] Carbamoyl] Pyrrolidine-1-carbonyl] -2-Methyl-propyl] -2-Methyl-pyrazole-3-yl] Piperazin-1-carboxylate (150 mg, 0.21 mmol, yield 93%, Purity 94%) was obtained as a white solid.

Step 2: (2S, 4R) -4-hydroxy-1-((R) -3-methyl-2-(1-methyl-5- (piperazine-1-yl) -1H-pyrazole-3-yl) butanoyl) )-N-((S) -1- (4- (4-Methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide preparation.

tert-butyl 4- [5-[(1R) -1-[(2S, 4R) -4-hydroxy-2-[[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl) ] Ethyl] carbamoyl] pyrrolidine-1-carbonyl] -2-methyl-propyl] -2-methyl-pyrazol-3-yl] piperazin-1-carboxylate (150 mg, 0.21 mmol, 1 equivalent) dichloromethane (5 mL) Hydroxyl (4M dioxane solution, 5 mL, 100 equivalents) was added to the mixture at 25 ° C. at a time. The mixture was stirred at 25 ° C. for 2 hours. The mixture was concentrated in vacuo. Product (2S, 4R) -4-hydroxy-1-[(2R) -3-methyl-2- (1-methyl-5-piperazine-1-yl-pyrazole-3-yl) butanoyl] -N- [(1S) -1- [4- (4-Methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (150 mg, hydrochloride) was obtained as an off-white solid. LC / MS (ESI) m / z: 580.2 [M + 1] ⁺ .
Step 3: (2S, 4R) -1-((R) -2- (5-(((1- (4- (3- (2,6-difluoro-3- (((R) -3) -3) -Fluoropyrrolidin) -1-sulfonamide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperidine-4-yl) Methyl) Piperazin-1-yl) -1-Methyl- 1H-pyrazole-3-yl) -3-methylbutanoyl) -4-hydroxy-N-((S) -1-(4-(4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2- Preparation of carboxamide.

(2S, 4R) -4-Hydroxy-1-[(2R) -3-methyl-2- (1-methyl-5-piperazine-1-yl-pyrazol-3-yl) butanoyl] -N-[(1S) ) -1- [4- (4-Methylthiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (140 mg, 0.23 mmol, 1 eq, hydrochloride) in a mixture of methanol (5 mL) and sodium acetate. (74 mg, 0.91 mmol, 4 eq) were added at one time at 30 ° C. The mixture is stirred at 30 ° C. for 1 minute, then (3R) -N- [2,4-difluoro-3- [5- [4- (4-formyl-1-piperidyl) phenyl] -1H-pyrrolo [2. , 3-b] Pyridine-3-carbonyl] Phenyl] -3-Fluoro-pyrrolidin-1-sulfonamide (104 mg, 0.17 mmol, 0.75 equivalent) in dichloromethane (2 mL) was added. The mixture was stirred at 30 ° C. for another 1 minute and acetic acid (0.02 mL) was added to adjust the pH to 4-5. Sodium cyanoborohydride (28 mg, 0.45 mmol, 2 eq) was then added and stirred for 58 minutes at 30 ° C. The mixture was concentrated under vacuum. 4 mL of dimethylformamide was added. The mixture was filtered to obtain a filtrate. The yellow filtrate was purified by half-taken reverse phase HPLC. Product (2S, 4R) -1- [(2R) -2- [5- [4- [[1- [4- [3- [2,6-difluoro-3- [[(3R) -3) -Fluoropyrrolidine-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl] -4-piperidyl] methyl] piperazine-1-yl] -1-methyl- Pyrazole-3-yl] -3-methyl-butanoyl] -4-hydroxy-N-[(1S) -1- [4- (4-methylthiazole-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide ( 135.5 mg, 0.11 mmol, yield 50%, purity 91%, trifluoroacetate) was obtained. LC / MS (ESI) m / z: 1175.4 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 13.03 --12.84 (m, 1H), 9.84 (s, 1H), 9.50 --9.19 (m) , 1H), 8.99 (s, 1H), 8.78 (d, J = 8.0 Hz, 1H), 8.66 (d, J = 2.0 Hz, 1H), 8.61 --8.47 (m, 1H), 8.25 --8.13 (m, 1H), 8.07 (d, J = 2.4 Hz, 1H), 7.70 --7.57 (m, 3H), 7.51 --7.39 (m, 3H), 7.38 --7.31 (m, 1H), 7.27 (t, J = 9.2 Hz) , 1H), 7.19 --7.06 (m, 2H), 5.92 --5.75 (m, 1H), 5.41 --5.17 (m, 1H), 5.07 --4.97 (m, 1H), 4.92 --4.77 (m, 1H), 4.69 ―― 4.60 (m, 1H), 4.50 ―― 4.38 (m, 1H), 4.29 ―― 4.17 (m, 1H), 3.85 ―― 3.80 (m, 3H), 3.49 (s, 3H), 3.41 ―― 3.36 (m, 3H) , 3.32 --3.15 (m, 8H), 2.89 --2.77 (m, 2H), 2.47 --2.44 (m, 4H), 2.20 --1.78 (m, 9H), 1.47 --1.32 (m, 5H), 0.95 (d, J = 6.8 Hz, 2H), 0.84 --0.71 (m, 3H), 0.70 --0.64 (m, 1H).
3- (5- (2- (2- (2- (2- (4- (4- (4-Chloro-3-hydroxyphenyl) -3- (pyridin-4-yl) -1H-pyrazole-1-) Il) Phenoxy) ethoxy) ethoxy) ethoxy) ethoxy) -1-oxoisoindoline-2-yl) Piperidine-2,6-Dione (Exemplary Compound 764) Illustrative Synthesis Step 1: 4- (4-bromo- Preparation of 1-(4-((tetrahydro-2H-pyran-2-yl) oxy) phenyl) -1H-pyrazole-3-yl) pyridine.

4- (4-bromo-1H-pyrazol-3-yl) pyridine (4 g, 17.85 mmol, 1 eq), (4-tetrahydropyran-2-yloxyphenyl) boronic acid (3.96 g, 17.85 mmol, 1 eq) , (4-Tetrahydropyran-2-yloxyphenyl) Boronic acid (3.96 g, 17.85 mmol, 1 eq) and copper acetate (4.86 g, 26.78 mmol, 1.5 eq) in dichloromethane (80 mL). , Purged 3 times with nitrogen. The mixture was then stirred at 15 ° C. for 12 hours under a nitrogen atmosphere. The reaction mixture was diluted with 50 mL of dichloromethane, washed with ammonium hydroxide (100 mLx3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography. Compound 4- [4-bromo-1- (4-tetrahydropyran-2-yloxyphenyl) pyrazole-3-yl] pyridine (3.6 g, 8.63 mmol, yield 48%, purity 96%) is a bright yellow solid. I got it as a thing. LC / MS (ESI) m / z: 401.9 [M + 1] +; 1H-NMR (400MHz, CDCl3) δ 8.75 --8.65 (m, 2H), 8.01 --7.92 (m, 3H), 7.67 --7.56 (m) , 2H), 7.22 --7.71 (m, 2H), 5.46 (t, J = 3.2 Hz, 1H), 3.91 (ddd, J = 3.2, 10.0, 11.2 Hz, 1H), 3.64 (dtd, J = 1.2, 4.0) , 11.2 Hz, 1H), 2.05 --1.97 (m, 1H), 1.90 (td, J = 3.8, 7.6 Hz, 2H), 1.75 --1.63 (m, 3H).
Step 2: Preparation of 4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenol.

4- [4-Bromo-1- (4-tetrahydropyran-2-yloxyphenyl) pyrazole-3-yl] pyridine (3.6 g, 8.45 mmol, 1 eq) in a solution of dichloromethane (20 mL) with hydrogen chloride / Dioxane (4M, 10.57 mL, 5 eq) was added. The mixture was stirred at 15 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The compound 4- [4-bromo-3- (4-pyridyl) pyrazole-1-yl] phenol (3.4 g, hydrochloride) was obtained as a yellow solid. LC / MS (ESI) m / z: 316.1 [M + 1]
⁺ ..
Step 3: 2- (2- (2- (2- (4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenoxy) ethoxy) ethoxy) ethoxy) ethane- 1-Oll preparation.

Cesium carbonate (20 mL) in a solution of 4- [4-bromo-3- (4-pyridyl) pyrazole-1-yl] phenol (880 mg, 2.27 mmol, 1 eq, hydrochloride) in N, N-dimethylformamide (20 mL). 1.48g, 4.54mmol
, 2 eq) and 2- [2- [2- [2- (2-hydroxyethoxy) ethoxy] ethoxy] ethyl 4-methylbenzenesulfonate (790 mg, 2.27 mmol, 1 eq) were added. The mixture was stirred at 80 ° C. for 3 hours. The reaction mixture was diluted with 30 mL of water and extracted with ethyl acetate (50 mLx3). The combined organic layers were washed with brine (50 mLx3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 1: 1 to 0: 1, dichloromethane / methanol = 10: 1). Compound 2- [2- [2- [2- [4- [4-bromo-3- (4-pyridyl) pyrazole-1-yl] phenoxy] ethoxy] ethoxy] ethoxy] ethanol (0.85 g, 1.73 mmol, Yield 76%) was obtained as a brown oil. LC / MS (ESI) m / z: 494.0 [M + 1] ⁺ .
Step 4: tert-butyl 5-amino-4-(5-(2-(2-(2-(4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazole-1) -Il) Phenoxy) ethoxy) ethoxy) ethoxy) ethoxy) -1-oxoisoindoline-2-yl) -5-Preparation of oxovalerate.

2- [4- [4-Bromo-3- (4-pyridyl) pyrazole-1-yl] phenoxy] ethanol (880 mg, 1.62 mmol, 1 eq) in tetrahydrofuran (15 mL) in tert-butyl 5-amino -4- (5-Hydroxy-1-oxo-isoindrin-2-yl) -5-oxo-valerate (527 mg, 1.40 mmol, 1 eq), triphenylphosphine (554 mg, 2.11 mmol, 1.3 eq) and Diisopropylazodigitate (427 mg, 2.11 mmol, 1.3 eq) was added at 0 ° C. The mixture was stirred at 60 ° C. for 12 hours. The reaction mixture was diluted with 20 mL of water and extracted with ethyl acetate (30 mLx3). The combined organic layers were washed with brine (50 mLx3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography. The product was further purified by half-taken reverse phase HPLC. Compound tert-butyl 5-amino-4- [5- [2- [2- [2- [2- [4- [4-bromo-3- (4-pyridyl) pyrazole-1-yl] phenoxy] ethoxy] ] Ethoxy] ethoxy] ethoxy] -1-oxo-isoindoline-2-yl] -5-oxo-valerate (850 mg, 1.05 mmol, 64% yield) was obtained as a yellow rubbery substance. LC / MS (ESI) m / z: 810.0 [M + 1] +; 1H-NMR (400MHz, CDCl3) δ 8.75 --8.61 (m, 2H), 8.06 --7.90 (m, 3H), 7.73 (d, J) = 8.4 Hz, 1H), 7.61 (d, J = 9.2 Hz, 2H), 7.08 --6.97 (m, 3H), 6.95 (s, 1H), 6.36 (s, 1H), 5.38 (s, 1H), 4.86 (dd, J = 6.4, 8.8 Hz, 1H), 4.52 --4.32 (m, 2H), 4.18 (q, J = 4.8 Hz, 4H), 3.95 --3.83 (m, 4H), 3.79 --3.64 (m, 8H) ), 2.43 --2.07 (m, 4H), 1.4
2 (s, 9H).
Step 5: tert-butyl 5-amino-4-(5-(2- (2- (2- (2- (4- (4- (4- (4-chloro-3-hydroxyphenyl) -3- (pyridine-4) -Il) -1H-Pyrazole-1-yl) Phenoxy) ethoxy) ethoxy) ethoxy) ethoxy) -1-oxoisoindoline-2-yl) -5-oxovalerate preparation.

tert-butyl 5-amino-4- [5- [2- [2- [2- [2- [4- [4-bromo-3- (4-pyridyl) pyrazole-1-yl] phenoxy] ethoxy] ethoxy] ] Ethoxy] ethoxy] -1-oxo-isoindrin-2-yl] -5-oxo-valerate (400 mg, 0.49 mmol, 1 eq), (4-chloro-3-hydroxy-phenyl) boric acid (85 mg) , 0.49 mmol, 1 eq), ditert-butyl (cyclopentyl) phosphan; dichloropalladium; iron (32 mg, 0.049 mmol, 0.1 eq) and cesium fluoride (300 mg, 1.98 mmol, 4 eq) dioxane (1.5 mL) and water. The (0.3 mL) mixture was degassed and purged with nitrogen 3 times. The mixture was then stirred at 90 ° C. for 3 hours under a nitrogen atmosphere. The reaction mixture was diluted with 10 mL of water and extracted with dichloromethane (20 mLx3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography. The compound tert-butyl 5-amino-4- [5- [2- [2- [2- [2- [4- [4- (4-chloro-3-hydroxy-phenyl) -3- (4-pyrazole) ) Pyrazole-1-yl] Phenoxy] ethoxy] ethoxy] ethoxy] ethoxy] -1-oxo-isoindoline-2-yl] -5-oxo-valerate (230 mg, 0.25 mmol, yield 51%, purity 95 %) Was obtained as a brown rubbery substance. LC / MS (ESI) m / z: 856.1 [M + 1] ⁺ .
Step 6: 3- (5- (2- (2- (2- (2- (4- (4- (4- (4-Chloro-3-hydroxyphenyl) -3- (pyridin-4-yl) -1H-pyrazole) -1H-pyrazole Preparation of -1-yl) phenoxy) ethoxy) ethoxy) ethoxy) ethoxy) -1-oxoisoindoline-2-yl) piperidine-2,6-dione.

tert-butyl 5-amino-4- [5- [2- [2- [2- [2- [4- [4- (4-chloro-3-hydroxy-phenyl) -3- (4-pyridyl) pyrazole -1-yl] phenoxy] ethoxy] ethoxy] ethoxy] ethoxy] -1-oxo-isoindoline-2-yl] -5-oxo-valerate (230 mg, 0.25 mmol, 1 eq) of acetonitrile (10 mL) Benzenesulfonic acid (80 mg, 0.51 mmol, 2 eq) was added to the solution. The mixture was stirred at 80 ° C. for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by half-reverse phase HPLC. Compound 3- [5- [2- [2- [2- [2- [4- [4- (4-chloro-3-hydroxy-phenyl) -3- (4-pyridyl) pyrazole-1-yl]] Phenoxy] ethoxy] ethoxy] ethoxy] ethoxy]-
1-oxo-isoindoline-2-yl] piperidine-2,6-dione (118.4 mg, 0.12 mmol, yield 49)
%, Purity 96%, Trifluoroacetic acid salt) was obtained as a yellow solid. LC / MS (ESI) m / z: 782.2 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 10.95 (s, 1H), 10.43 ―― 10.21 (m, 1H), 8.96 ―― 8.60 (m) , 3H), 7.92 --7.84 (m, 2H), 7.81 (d, J = 5.6 Hz, 2H), 7.60 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.18 --7.09 (m, 3H), 7.04 (dd, J = 2.0, 8.4 Hz, 1H), 6.96 (d, J = 2.0 Hz, 1H), 6.86 (dd, J = 2.0, 8.0 Hz, 1H), 5.05 ( dd, J = 5.2, 13.3 Hz, 1H), 4.41 --4.32 (m, 1H), 4.29 --4.21 (m, 1H), 4.20 --4.11 (m, 4H), 3.82 --3.74 (m, 6H), 3.60 ( d, J = 2.8 Hz, 6H), 2.96 ―― 2.80 (m, 1H), 2.59 (d, J = 2.2 Hz, 1H), 2.42 ―― 2.35 (m, 1H), 2.03 ―― 1.90 (m, 1H).
3- (5-((14-(4- (4- (4- (4-Chloro-3-hydroxyphenyl) -3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenoxy) -3,6 , 9,12-Tetraoxatetradecyl) Oxy) -1-oxoisoindoline-2-yl) Piperidine-2,6-Dione (Example Compound 765) Illustrative Synthesis Step 1: 14-Hydroxy-3,6 Preparation of 9,12-Tetraoxatetradecyl 4-methylbenzenesulfonate.

_{Ag 2} O (1.5 eq), TsCl (1.1 eq) and KI (0.2 eq) were added to a cooled stirred solution of DCM (quantity x 10 mL) of pentaethylene glycol (1 eq). After stirring for 30-60 minutes, the precipitated silver salts were removed by filtration through a bed of Celite and washed thoroughly with EtOAc. The combined filtrates were concentrated under vacuum and the residue was purified by silica gel chromatography to give a colorless oil in 77% yield. LC / MS (ESI) m / z: 393.2 [M + 1] +; 1H-NMR (400MHz, CDCl3) δ 2.45 (s, 3H), 3.59-3.73 (m, 18H), 4.16 (t, J = 4.8) Hz, 2H), 7.34 (d, J
= 8.0 Hz, 2H), 7.80 (d, J = 8.0 Hz, 2H).
Step 2: 14- (4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenoxy) -3,6,9,12-tetraoxatetradecane-1-ol Preparation.

4- [4-Bromo-3- (4-pyridyl) pyrazole-1-yl] phenol (500 mg, 1.42 mmol, 1 eq, hydrochloride) in a solution of N, N-dimethylformamide (10 mL), 2- [ 2- [2- [2- (2-Hydroxyethoxy) ethoxy] ethoxy] ethoxy] ethyl 4-methylbenzenesulfonate (556 mg, 1.42 mmol, 1 eq) and cesium carbonate (924 mg, 2.84 mmol, 2 eq) added. The mixture was stirred at 80 ° C. for 2 hours. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mLx3). The combined organic layers were washed with brine (50 mLx3), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product is purified by column chromatography (petroleum ether: ethyl acetate = 3: 1 to dichloromethane: methanol = 20: 1) and 2- [2- [2- [2- [2- [4- []. 4-bromo-3- (4-pyridyl) pyrazole-1-yl] phenoxy] ethoxy] ethoxy] ethoxy]
Ethoxy] ethanol (500 mg, 0.93 mmol, 65% yield) was obtained as a bright yellow oil. LC / MS (ESI) m / z: 538.2 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 8.86 (s, 1H), 8.75 --8.65 (m, 2H), 7.96 --7.88 (m) , 2H), 7.82 (d, J = 9.2 Hz, 2H), 7.11 (d, J = 9.2 Hz, 2H),
4.56 (t, J = 5.6 Hz, 1H), 4.19 --4.11 (m, 2H), 3.81 --3.73 (m, 2H), 3.63 --3.58 (m, 2H), 3.57 --3.54 (m, 2H), 3.53 - 3.49 (m, 8H), 3.49 --3.45 (m, 2H), 3.43 --3.38 (m, 2H).
Step 3: tert-butyl 5-amino-4-(5-((14-(4- (4-bromo-3- (pyridin-4-yl) -1H-pyrazol-1-yl) phenoxy) -3, Preparation of 6,9,12-tetraoxatetradecyl) oxy) -1-oxoisoindoline-2-yl) -5-oxovalerate.

2- [2- [2- [2- [2- [4- [4-bromo-3- (4-pyridyl) pyrazole-1-yl] phenoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethanol (600 mg, 1.12 mmol (1 eq) and tert-butyl 5-amino-4- (5-hydroxy-1-oxo-isoindrin-2-yl) -5-oxo-valerate (374 mg, 1.12 mmol, 1 eq) in tetrahydrofuran To a solution of (12 mL) was added triphenylphosphine (352 mg, 1.34 mmol, 1.2 eq) and diisopropylazodicarboxylate (271 mg, 1.34 mmol, 1.2 eq) at 0 ° C. under a nitrogen atmosphere. The mixture was stirred at 60 ° C. for 12 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1: 1 to dichloromethane: methanol = 10: 1). The product is further purified by preparative reverse phase TLC (dichloromethane: methanol = 15: 1) to tert-butyl 5-amino-4- [5- [2- [2- [2- [2- [2]. -[4- [4-bromo-3- (4-pyridyl) pyrazole-1-yl] phenoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] -1-oxo-isoindoline-2-yl] -5-oxo -Isoindoline (300 mg, 0.35 mmol, 31% yield) was obtained as a bright yellow solid. LC / MS (ESI) m / z: 853.7 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 8.86 (s, 1H), 8.74 --8.65 (m, 2H), 7.96 --7.89 (m) , 2H), 7.85 --7.79 (m, 2H), 7.57 (d, J = 8.4 Hz, 1H), 7.54 (s, 1H), 7.15 (s, 2H), 7.13 --7.08 (m, 2H), 7.01 ( dd, J = 2.0, 8.4 Hz, 1H), 4.75 ―― 4.64 (m, 1H), 4.54 (d, J = 17.6 Hz, 1H), 4.43 ―― 4.30 (m, 1H), 4.15 (td, J = 2.8, 5.6 Hz, 4H), 3.79 --3.71 (m, 4H), 3.61 --3.56 (m, 4H), 3.56 --3.53 (m, 4H), 3.52 (s, 4H), 3.17 (d, J = 5.2 Hz, 2H) ), 2.12 --2.06 (m, 1H), 2.02 --1.89 (m, 1H), 1.32 (s, 9H).
Step 4: tert-butyl 5-amino-4-(5-((14-(4- (4- (4-chloro-3-hydroxyphenyl) -3- (pyridin-4-yl) -1H-pyrazole- Preparation of 1-yl) phenoxy) -3,6,9,12-tetraoxatetradecyl) oxy) -1-oxoisoindoline-2-yl) -5-oxovalerate.

tert-butyl 5-amino-4- [5- [2- [2- [2- [2- [2- [4- [4-bromo-3- (4-pyridyl) pyrazole-1-yl] phenoxy] Ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] -1-oxo-isoindrin-2-yl] -5-oxo-valerate (300 mg, 0.35 mmol, 1 eq) and (4-chloro-3-hydroxy-phenyl) ) Boronic acid (60 mg, 0.35 mmol, 1 eq) in a solution of dioxane (6 mL) and water (1 mL), cesium fluoride (106 mg, 0.70 mmol, 2 eq) and ditert-butyl (cyclopentyl)
Phosphine; dichloropalladium; iron (23 mg, 0.035 mmol, 0.1 eq) was added. The mixture was stirred at 90 ° C. for 2 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product is purified by preparative reverse phase TLC (dichloromethane: methanol = 10: 1) and tert-butyl 5-amino-4- [5- [2- [2- [2- [2- [2]. 2- [4- [4- (4-Chloro-3-hydroxy-phenyl) -3- (4-pyridyl) pyrazole-1-yl] phenoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] -1-oxo- Isoindoline-2-yl] -5-oxo-valerate (170 mg, 0.18 mmol, 53% yield) was obtained as a yellow oil. LC / MS (ESI) m / z: 900.2 [M + 1] ⁺ .
Step 5: 3-(5-((14-(4- (4- (4-chloro-3-hydroxyphenyl) -3- (pyridin-4-yl) -1H-pyrazole-1-yl) phenoxy)- Preparation of 3,6,9,12-tetraoxatetradecyl) oxy) -1-oxoisoindoline-2-yl) piperidine-2,6-dione.

tert-butyl 5-amino-4- [5- [2- [2- [2- [2- [2- [4- [4- (4-chloro-3-hydroxy-phenyl) -3- (4-) Pyridyl) pyrazole-1-yl] phenoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] -1-oxo-isoindoline-2-yl] -5-oxo-valerate (170 mg, 0.18 mmol, 1 equivalent) To a solution of acetonitrile (5 mL) was added benzenesulfonic acid (60 mg, 0.37 mmol, 2 eq). The mixture was stirred at 80 ° C. for 12 hours. The mixture was concentrated under vacuum. The crude product is purified by preparative reverse phase HPLC and 3- [5- [2- [2- [2- [2- [2- [4- [4- (4-chloro-3-hydroxy-). Phenyl) -3- (4-pyridyl) pyrazole-1-yl] phenoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] -1-oxo-isoindoline-2-yl] piperidine-2,6-dione (111.8 mg) , 0.12 mmol, yield 66%, purity 97%, formate) was obtained as a yellow solid. LC / MS (ESI) m / z: 826.3 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 11.07 --10.85 (m, 1H), 8.66 (s, 1H), 8.61 --8.54 (m) , 2H), 8.40 (s, 1H), 7.87 --7.82 (m, 2H), 7.61 (d, J = 8.4 Hz, 1H), 7
.51 --7.75 (m, 2H), 7.35 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 2.0 Hz, 1H), 7.12 --7.08 (m, 2H), 7.04 (dd, J = 2.0) , 8.4 Hz, 1H), 6.95 (d, J = 2.0 Hz, 1H), 6.80 (dd, J = 2.0, 8.4 Hz, 1H), 5.06 (dd, J = 5.1, 13.3 Hz, 1H), 4.41 --4.32 (m, 1H), 4.29 --4.21 (m, 1H), 4.20 --4.13 (m, 4H), 3.78 --3.74 (m, 4H), 3.60 --3.57 (m, 4H), 3.56 --3.54 (m, 4H) , 3.52 (s, 4H), 2.93 --2.83 (m, 1H), 2.62 --2.57 (m, 2H), 2.41 --2.33 (m, 1H), 2.02 --1.92 (m, 1H).
(3R) -N- (3- (5- (4- (3-((4- (2- (2,6-dioxopiperidine-3-yl) -1-oxoisoindoline-5-yl) piperazine) -1-yl) Methyl) Azetidine-1-yl) Phenyl) -1H-Pyrrolo [2,3-b]
Illustrative Synthesis of Pyridine-3-carbonyl) -2,4-difluorophenyl) -3-fluoropyrrolidine-1-sulfonamide (exemplary compound 767) Step 1: Preparation of azetidine-3-ylmethanol.

Trifluoroacetic acid (15 mL, 7.59 eq) was added to a solution of tert-butyl 3- (hydroxymethyl) azetidine-1-carboxylate (5 g, 26.70 mmol, 1 eq) dichloromethane (60 mL). The mixture was stirred at 15 ° C. for 0.5 hours. The reaction mixture was concentrated to give azetidine-3-ylmethanol (4.3 g, trifluoroacetate) as a bright yellow oil.

Step 2: Preparation of (1- (4-iodophenyl) azetidine-3-yl) methanol.

Potassium carbonate (14.77 g, 106.89 mmol, 5 eq) was added to a solution of dimethylsulfoxide (100 mL) of azetidine-3-ylmethanol (4.3 g, 21.38 mmol, 1 eq, trifluoroacetate). The mixture was stirred at 15 ° C. for 0.5 hours. Add 1,4-diiodobenzene (7.76 g, 23.52 mmol, 1.1 eq), L-proline (984 mg, 8.55 mmol, 0.4 eq) and copper iodide (814 mg, 4.28 mmol, 0.2 eq), then add the mixture. The mixture was stirred at 90 ° C. for 12 hours. The reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (150 mLx2). The combined organic layers were washed with saturated brine (200 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 20: 1 to 3: 1) and [1- (4-iodophenyl) azetidine-3-yl] methanol (3.5 g, 12.11 mmol, yield). A rate of 56%) was obtained as a white solid. LC / MS (ESI) m / z: 290.4 [M + 1] ⁺ .
Step 3: Preparation of 1- (4-iodophenyl) azetidine-3-carbaldehyde.

A solution of dimethyl sulfoxide (3.73 g, 47.73 mmol, 3.73 mL, 4.6 eq) in dichloromethane (20 mL) to a solution of oxalyl chloride (3.03 g, 23.87 mmol, 2.1 mL, 2.3 eq) in dichloromethane (40 mL) at -70 ° C. It was added by dropping in. The mixture was stirred at −70 ° C. for 0.5 hours. [1- (4-Iodophenyl) azetidine-3-yl] A solution of methanol (3 g, 10.38 mmol, 1 eq) in dichloromethane (30 mL) is added dropwise to the mixture, and the mixture is stirred at -70 ° C for 0.5 hours. did. Triethylamine (5.46 g, 53.96 mmol, 7.5 mL, 5.2 eq) was added at −70 ° C. and heated to 15 ° C. The mixture was stirred at 15 ° C. for 2 hours. The reaction mixture was diluted with water (200 mL) and extracted with dichloromethane (150 mLx2). The combined organic layers were washed with saturated brine (150 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 20: 1-5: 1) and 1- (4-iodophenyl) azetidine-3-carbaldehyde (870 mg, 3.03 mmol, yield 29%). ) Was obtained as a yellow oil. LC / MS (ESI) m / z: 320.4 [M + 32 + 1] ⁺ .
Step 4: 3- (5-(4-((1- (4-iodophenyl) azetidine-3-yl) methyl) piperazine-1-yl) -1-oxoisoindoline-2-yl) piperidine-2, Preparation of 6-dione.

3- (1-oxo-5-piperazine-1-yl-isoindoline-2-yl) piperidine-2,6-dione (1.11 g, 3.03 mmol, 1 eq, hydrochloride) in methanol (20 mL) and dimethylformamide Sodium acetate (745 mg, 9.09 mmol, 3 eq) was added to the solution of (5 mL). The mixture was stirred at 30 ° C. for 0.5 hours. 1- (4-Iodophenyl) azetidine-3-carbaldehyde (870 mg, 3.03 mmol, 1 eq) was added, then the mixture was stirred at 30 ° C. for 12 hours. Sodium cyanoborohydride (380 mg, 6.06 mmol, 2 eq) was added and the mixture was further stirred for 0.5 hours at 30 ° C. Mix and react with water (50 mL)
) And stirred for 10 minutes. The reaction mixture was filtered and the filtered cake was collected. The crude product is pulverized with methanol (30 mLx3) and 3- [5- [4-[[1- (4-iodophenyl) azetidine-3-yl] methyl] piperazine-1-yl] -1-oxo-iso. Indoline-2-yl] piperidine-2,6-dione (680 mg, 1.13 mmol, 37% yield) was obtained as a white solid. LC / MS (ESI) m / z: 600.1 [M + 1] ⁺ .
Step 5: tert-butyl 3-(2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -5- (4- (3-((4- ( 2- (2,6-dioxopiperidine-3-yl) -1-oxoisoindrin-5-yl) piperazin-1-yl) methyl) azetidine-1-yl) phenyl) -1H-pyrrolo [2,3 -b] Preparation of pyridine-1-carboxylate.

3- [5- [4- [[1- (4-iodophenyl) azetidine-3-yl] methyl] piperazine-1-yl] -1-oxo-isoindoline-2-yl] piperidine-2,6- Dione (500 mg, 0.83 mmol, 1 eq), tert-
Butyl 3- [2,6-difluoro-3- [[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -5- (4,4,5,5-tetramethyl-1,3 , 2-Dioxaborolan-2-yl) Pyrrolidine [2,3-b]
Pylin-1-carboxylate (651 mg, 1.00 mmol, 1.2 eq), ditert-butyl (cyclopentyl) phosphan; dichloropalladium; iron (54 mg, 0.083 mmol, 0.1 eq), potassium carbonate (172 mg,)
A mixture of 1.25 mmol (1.5 eq) and water (2 mL) of dimethylformamide (20 mL) was degassed and purged with nitrogen three times. The mixture was then stirred at 90 ° C. for 1.5 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (50 mL) and extracted with tetrahydrofuran / ethyl acetate (V / V = 2: 1, 50 mLx2). The combined organic layers were washed with saturated brine (50 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (dimethane: methanol = 100: 1-10: 1) and tert-butyl 3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-). 1-yl] sulfonylamino] benzoyl] -5- [4- [3- [[4- [2- (2,6-dioxo-3-piperidyl) -1-oxo-isoindoline-5-yl] piperazine- 1-Il] Methyl] Azetidine-1-yl] Phenyl] Pyrrolidine [2,3-b] Pyridine-1-carboxylate (210 mg, 0.17 mmol, 20% yield, 82% purity) obtained as a yellow solid rice field. LC / MS (ESI) m / z: 896.2 [M-99] ⁺ .
Step 6: (3R) -N- (3- (5- (4- (3-((4- (2- (2,6-dioxopiperidine-3-yl) -1-oxoisoindoline-5-yl) Ill) piperazine-1-yl) methyl) azetidine-1-yl) phenyl) -1H-pyrrolo [2,3-b] pyridin-3-carbonyl) -2,4-difluorophenyl) -3-fluoropyrrolidine-1 -Preparation of sulfonamide.

tert-butyl 3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1-yl] sulfonylamino] benzoyl] -5- [4- [3- [[4- [2-] (2,6-dioxo-3-piperidyl) -1-oxo-isoindoline-5-yl] piperazine-1-yl] methyl] azetidine-1-yl] phenyl] pyrolo [2,3-b]
Trifluoroacetic acid (2.46 mL, 192.18 eq) was added to a solution of pyridine-1-carboxylate (210 mg, 0.17 mmol, 1 eq) in dichloromethane (10 mL). The mixture was stirred at 15 ° C. for 0.5 hours. The reaction mixture was concentrated. The residue was purified by preparative HPLC and (3R) -N- [3- [5- [4- [3- [[4- [2- (2,6-dioxo-3-piperidyl) -1- Oxo-isoindoline-5-yl] piperazine-1-yl] methyl] azetidine-1-yl] phenyl] -1H-pyrrolidine [2,3-b] pyridin-3-carbonyl] -2,4-difluoro-phenyl ] -3-Fluoro-pyrrolidine-1-sulfonamide (99 mg, 0.10 mmol, yield 60%, purity 99%, formate) was obtained as a yellow solid. LC / MS (ESI) m / z: 896.3 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 12.90 (s, 1H), 10.96 (s, 1H), 8.62 (d, J = 2.0) Hz, 1H), 8.50 (s, 1H), 8.15 (s, 1H), 8.06 (s, 1H), 7.62 (dt, J = 6.0, 8.8 Hz, 1H), 7.54 (dd, J = 8.8, 12.0 Hz) , 3H), 7.26 (t, J = 8.8 Hz, 1H), 7.12 --7.03 (m, 2H), 6.57 (d, J = 8.8 Hz, 2H), 5.39 --5.19 (m, 1H), 5.05 (dd, J = 5.2, 13.2 Hz, 1H), 4.38 ―― 4.29 (m, 1H), 4.25 ―― 4.17 (m, 1H), 4.01 (t, J = 7.4 Hz, 2H), 3.58 --3.52 (m, 2H), 3.49 --3.45 (M, 2H), 3.41 --3.38 (m, 4H), 3.05 --2.84 (m, 3H), 2.62 --2.58 (m, 1H), 2.58 --2.52 (m, 8H), 2.43 --2.34 (m, 3H) 1H), 2.13 --2.04 (m, 1H), 1.99 --1.93 (m, 1H).
(3R)-N-(3-(5-(4-(4-((4- (3- (2,6-dioxopiperidine-3-yl) phenyl) piperazine-1-yl) methyl) piperidine- 1-Il) Phenyl) -1H-Pyrrolidine [2,3-b] Pyridine-3-carbonyl) -2,4-difluorophenyl) -3-Fluoropyrrolidine-1-sulfonamide (Example compound 768)
Exemplary Synthesis of Step 1: Preparation of tert-butyl 4- (3- (2-methoxy-2-oxoethyl) phenyl) piperazine-1-carboxylate.

Methyl 2- (3-) in a 250 mL round-bottom flask purged and maintained in an inert nitrogen atmosphere.
Bromophenyl) acetate (10.0 g, 43.65 mmol, 1.0 eq), tert-butyl piperazine-1-carboxylate (8.1 g, 43.65 mmol, 1 eq), Cs ₂ CO ₃ (28.5 g, 87.31 mmol, 2 eq) ), RuPhos-PdCl-2ndg (3.4 g, 4.37 mmol, 0.1 eq) and toluene (150 mL) were added. The resulting solution was stirred at 80 ° C. overnight. The resulting mixture was concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:19). This gave 10.1 g (69.2%) of tert-butyl 4- [3- (2-methoxy-2-oxoethyl) phenyl] piperazine-1-carboxylate as a yellow liquid. LC / MS (ESI) m / z: 335.19 [M + 1] ⁺ .
Step 2: Preparation of 5-ethyl 1-methyl 2- (3- (4- (tert-butoxycarbonyl) piperazine-1-yl) phenyl) pentane diate.

Tert-Butyl 4- [3- (2-methoxy-2-oxoethyl) phenyl] piperazine-1-carboxylate (3.0 g) in a 100 mL three-necked round-bottom flask purged and maintained in an inert nitrogen atmosphere. , 8.97 mmol, 1.0 equivalent), tetrahydrofuran (30 mL) was placed in a water / ice tank at 0 ° C. The resulting mixture was stirred at 0 ° C. for 30 minutes, then tert-butoxysodium (1.7 g, 17.94 mmol, 2.0 eq) and ethyl acrylate (1.1 g, 10.76 mmol, 1.2 eq) were added to the flask. .. The resulting solution was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1: 1). This gave 1.3 g (33.4%) of 5-ethyl 1-methyl 2- [3- [4- (tert-butoxycarbonyl) piperazine-1-yl] phenyl] pentane diate as a yellow solid. LC / MS (ESI) m / z: 435.25 [M + 1] ⁺ .
Step 3: Preparation of tert-butyl 4- (3- (5-amino-1-methoxy-1,5-dioxopentane-2-yl) phenyl) piperazine-1-carboxylate.

In a 20 mL closed tube maintained with inert nitrogen, add 5-ethyl 1-methyl 2- [3- [4- (tert-butoxycarbonyl) piperazine-1-yl] phenyl] pentane diate (590.0 mg). I put it in. A _{solution of NH 3} (g) in MeOH (13.00 mL) was added to the above solution. The resulting solution was stirred at 35 ° C. for 20 hours. The resulting mixture was concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (100%). This gave 220 mg (37.3%) of 5-amino1-methyl 2- [3- [4- (tert-butoxycarbonyl) piperazine-1-yl] phenyl] pentane diate as a white solid. LC / MS (ESI) m / z: 406.15 [M + 1] ⁺ .
Step 4: Preparation of tert-butyl 4- (3- (2,6-dioxopiperidine-3-yl) phenyl) piperazine-1-carboxylate.

In an 8 mL closed tube purged and maintained in an inert nitrogen atmosphere, tert-butyl 4- [3- (4-carbamoyl-1-methoxy-1-oxobutane-2-yl) phenyl] piperazine-1-carboxylic acid Salt (200.0 mg, 0.49 mmol, 1.0 eq), Cs ₂ CO ₃ (322.4 mg, 0.99 mmol, 2 eq), acetonitrile (5 mL)
I put in. The resulting solution was stirred at 85 ° C. for 8 hours. The resulting mixture was concentrated under vacuum. The residue was loaded into a silica gel column with dichloromethane / methanol (19: 1). This gave 58 mg (31.5%) of tert-butyl 4- [3- (2,6-dioxopiperidine-3-yl) phenyl] piperazine-1-carboxylate as a yellow solid. LC / MS (ESI) m / z: 374.25 [M + 1] ⁺ .
Step 5: Preparation of 3- (3- (piperazine-1-yl) phenyl) piperidine-2,6-dione.

In a 25 mL round-bottom flask, tert-butyl 4- [3- (2,6-dioxopiperidine-3-yl) phenyl] piperazine-1-carboxylate (58.00 mg, 0.155 mmol, 1.00 equivalent), DCM ( 3.00 mL, 0.035 mmol, 0.23 equivalent) and trifluoroacetaldehyde (0.50 mL, 0.005 mmol, 0.03 equivalent) were added. The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated. This gave 50 mg (117.78%) of 3- [3- (piperazine-1-yl) phenyl] piperidine-2,6-dione as a bright yellow oil.

Step 6: (3R) -N- (3-(5-(4-(4-((4- (3- (2,6-dioxopiperidine-3-yl) phenyl) piperazine-1-yl) methyl) ) Piperidine-1-yl) phenyl) -1H-pyrrolid [2,3-b] pyridin-3-carbonyl) -2,4-difluorophenyl) -3-fluoropyrrolidine-1-sulfonamide preparation.

In a 100 mL round bottom flask, 3- [3- (piperazine-1-yl) phenyl] piperidine-2,6-dione (40.22 mg, 0.147 mmol, 1.00 eq), DCE (15.00 mL), DIEA (0.50 mL, 0.004 mmol, 0.03 equivalent)
, (3R) -N- (2,4-difluoro-3- [5- [4- (4-formylpiperidine-1-yl) phenyl] -1H-pyrrolo [2,3-b] pyridine-3-carbonyl ] Phenyl) -3-fluoropyrrolidine-1-sulfonamide (90.00 mg, 0.147 mmol, 1.00 eq), HOAc (0.50 mL, 0.008 mmol, 0.06 eq), 3 at 35 ° C.
After stirring for hours, NaBH ₃ CN (27.74 mg, 0.441 mmol, 3.0 eq) was added to the solution. The resulting solution was stirred for 16 hours in an oil bath at 35 ° C. The resulting solution was extracted with dichloromethane (100 mL). The residue was loaded into a silica gel column with dichloromethane / methanol (10/1). The crude product was purified by flash preparative HPLC. This resulted in 22.7 mg (17.75%) of (3R) -N- [3- (5- [4- [4-([4- [3- (2,6-dioxopiperidine-3-yl) phenyl]. Piperazine-1-yl] methyl) piperidine-1-yl] phenyl] -1H-pyrrolo [2,3-b] pyridin-3-carbonyl) -2,4-difluorophenyl] -3-fluoropyrrolidin-1-sulfone The amide was obtained as a bright yellow solid. LC / MS (ESI) m / z: 869.35 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 12.90 (s, 1H), 10.80 (s, 1H), 9.86 (s, 1H), 8.66 (s, 1H), 8.54 (s, 1H), 8.07 (s, 1H), 7.66-7.58 (m, 3H), 7.30-7.25 (m, 1H), 7.19-7.15 (m, 1H), 7.09- 7.07 (d, J = 8.0Hz, 2H), 6.85-6.82 (m, 1H), 6.64-6.62 (d, J = 8.0Hz, 1H), 5.37-5.24 (m, 1H), 3.82-3.75 (m, 3H), 3.52-3.39 (m, 5H), 3.15 (m, 4H), 2.79-2.73 (m, 4H), 2.65-2.51 (m, 3H), 2.26-2.03 (m, 3H), 1.87-1.83 ( m, 3H), 1.27-1.25 (m, 2H).
5- (6-((1- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2, 3-b] Pyridine-5-yl) Phenyl) Piperidine-4-yl) Methyl) -2,6-Diazaspiro [3.3] Heptane-2-yl) -N- (2,6-dioxopiperidine-3-yl) )-3,4-Dihydro-1,8-naphthylidine-1 (2H) -Carboxamide Exemplary Synthesis Step 1: 3- (3-Chloropropyl) -2-Fluoro-4-iodopyridine Preparation.

Lithium diisopropylamide (2M, 20.72 mL, 1.20 eq) was added to a solution of 2-fluoro-4-iodo-pyridine (7.70 g, 34.53 mmol, 1.00 eq) in tetrahydrofuran (80 mL) at -78 ° C for 1.5 hours. .. The mixture was then added to a solution of 1-chloro-3-iodo-propane (14.12 g, 69.06 mmol, 7.43 mL, 2.00 eq) in tetrahydrofuran (10 mL) at -78 ° C and stirred for 0.5 hours. The mixture was then heated to 15 ° C. and stirred for 1 hour. The mixture was quenched with saturated ammonium chloride solution (80 mL) and extracted with ethyl acetate (2x40 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate and concentrated to give a residue. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1: 0 to 10: 1) and 3- (3-chloropropyl) -2-fluoro-4-iodo-pyridine (9.00 g, 30.05). mmol, yield 87%) was obtained as a bright yellow oil. 1H-NMR (400MHz, CDCl3) δ 7.69 (d, J = 5.6 Hz, 1H), 7.61 (d, J = 5.2 Hz, 1H), 3.61 (t, J = 6.4 Hz, 2H), 2.90 --2.97 (m) , 2H), 2.04 --2.08 (m, 1H), 1.99 --2.03 (m, 1H).
Step 2: Preparation of 1- (2,4-dimethoxybenzyl) -5-iodo-1,2,3,4-tetrahydro-1,8-naphthylidine.

N, 3- (3-chloropropyl) -2-fluoro-4-iodo-pyridine (3 g, 10.02 mmol, 1 eq) and (2,4-dimethoxyphenyl) methaneamine (2.01 g, 12.02 mmol, 1.2 eq) Potassium iodide (2.00 g, 12.02 mmol, 1.2 eq), pyridine (47) in a solution of N-dimethylformamide (30 mL)
5 mg, 6.01 mmol, 0.6 eq), and potassium carbonate (2.49 g, 18.03 mmol, 1.8 eq) were added. The mixture was stirred at 70 ° C. for 12 hours. The mixture was diluted with water (50 mL) and stirred for 15 minutes at 15 ° C.

The mixture was filtered and the filtrate was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (100 mLx3), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product is powdered with petroleum ether and ethyl acetate (V: V = 10: 1) and 1-[(2,4-dimethoxyphenyl) methyl] -5-iodo-3,4-dihydro-2H-1, 8-naphthylidine (3 g, 7.31 mmol)
, Yield 73.01%) was obtained as a brown solid. LC / MS (ESI) m / z: 398.1 [M-12] ⁺ .
Step 3: tert-Butyl 6- (8- (2,4-dimethoxybenzyl) -5,6,7,8-tetrahydro-1,8-naphthylidine-4-yl) -2,6-diazaspiro [3.3] heptane -2-Preparation of carboxylate.

1-[(2,4-dimethoxyphenyl) methyl] -5-iodo-3,4-dihydro-2H-1,8-naphthylidine (1.1 g, 2.68 mmol, 1 equivalent) 2-methylbutane-2-ol (1 equivalent) In a solution of 8.89 g, 100.78 mmol, 37.60 eq), tert-butyl 2,6-diazaspiro [3.3] heptane-2-carboxylate; oxalic acid (912 mg, 1.88 mmol, 0.7 eq), sodium tert-butoxide (2 M). , 4.02 mL, 3 eq) and methanesulfonato (2-dicyclohexylphosphino-2', 6'-di-i-propoxy-1,1'-biphenyl) (2'-amino-1,1'-biphenyl- 2-Il) Palladium (II) (224 mg, 0.26 mmol, 0.1 eq) was added under a nitrogen atmosphere. The mixture was stirred at 90 ° C. for 12 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mLx3). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1-5: 1) to tert-butyl 6- [8-[(2,4-dimethoxyphenyl) methyl] -6, 7-Dihydro-5H-1,8-naphthylidine-4-yl] -2,6-diazaspiro [3.3] heptane-2-carboxylate (1 g, 2.08 mmol, 77% yield) was obtained as a bright yellow oil. rice field. LC / MS (ESI) m / z: 481.3 [M + 1] ⁺ .
Step 4: Preparation of 5- (2,6-diazaspiro [3.3] heptane-2-yl) -1,2,3,4-tetrahydro-1,8-naphthylidine.

tert-butyl 6- [8-[(2,4-dimethoxyphenyl) methyl] -6,7-dihydro-5H-1,8-naphthylidine-4-yl] -2,6-diazaspiro [3.3] heptane-2 -Trifluoroacetic acid (7.70 g, 67.53 mmol, 32.45 eq) was added to a solution of toluene (10 mL) of the carboxylate (1 g, 2.08 mmol, 1 eq). The mixture was stirred at 65 ° C. for 1 hour. The mixture was filtered and the filtrate was concentrated under vacuum. Compound 5- (2,6-diazaspiro [3.3] heptane-2-yl) -1,2,3,4-tetrahydro-1,8-naphthalene (500 mg, 1.45 mmol, yield 69%, trifluoroacetic acid salt) ) Was obtained as a brown oil. LC / MS (ESI) m / z: 231.2 [M + 1] ⁺ .
Step 5: Preparation of tert-butyl 6- (5,6,7,8-tetrahydro-1,8-naphthylidine-4-yl) -2,6-diazaspiro [3.3] heptane-2-carboxylate.

5- (2,6-diazaspiro [3.3] heptane-2-yl) -1,2,3,4-tetrahydro-1,8-naphthalene
Di-tert-butyl bicarbonate (380 mg, 1.74 mmol, 1.2 eq), triethylamine (734 mg, 7.26 mmol, 5) in a solution of dichloromethane (10 mL) of (500 mg, 1.45 mmol, 1 eq, trifluoroacetic acid s). Equivalent), and 4-dimethylaminopyridine (17 mg, 0.14 mmol, 0.1 equivalent) were added. The mixture was stirred at 15 ° C. for 1 hour. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product is purified by preparative reverse phase TLC (dichloromethane: methanol = 8: 1) and tert-butyl 6- (5,6,7,8-tetrahydro-1,8-naphthylidine-4-yl). ) -2,6-Diazaspiro [3.3] heptane-2-carboxylate (380 mg, 1.15 mmol, 79% yield)
Was obtained as a bright yellow solid. LC / MS (ESI) m / z: 331.5 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 7.48 (d, J = 5.6 Hz, 1H), 6.06 (s, 1H), 5.66 ( d, J = 5.9 Hz, 1H), 4.07 (s,
4H), 3.99 (s, 4H), 3.16 (s, 2H), 2.47 (s, 2H), 1.74 --1.65 (m, 2H), 1.37 (s, 9H).
Step 6: tert-butyl 6-(8-((2,6-dioxopiperidine-3-yl) carbamoyl) -5,6,7,8-
Preparation of tetrahydro-1,8-naphthalidine-4-yl) -2,6-diazaspiro [3.3] heptane-2-carboxylate.

tert-butyl 6- (5,6,7,8-tetrahydro-1,8-naphthylidine-4-yl) -2,6-diazaspiro [3.3] heptane-2-carboxylate (380 mg, 1.15 mmol, 1 equivalent) ) To a solution of tetrahydrofuran (10 mL) was added triethylamine (698 mg, 6.90 mmol, 6 eq) and bis (trichloromethyl) carbonate (341 mg, 1.15 mmol, 1 eq) at 0 ° C. The mixture was stirred at 25 ° C. for 3 hours. 3-Aminopiperidine-2,6-dione (227.14 mg, 1.38 mmol, 1.2 eq, hydrochloride) was then added to the mixture. The mixture was stirred at 50 ° C. for 36 hours. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 mLx3). The combined organic layers were washed with brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by preparative reverse phase TLC (dichloromethane: methanol = 15: 1) and tert-butyl 6- [8-[(2,6-dioxo-3-piperidyl) carbamoyl] -6,7. -Dihydro-5H-1,8-naphthalidine-4-yl] -2,6-diazaspiro [3.3] heptane-2-carboxylate (220 mg, 0.45 mmol, 39% yield) was obtained as a white solid. LC / MS (ESI) m / z: 485.2 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 11.19 (d, J = 6.4 Hz, 1H), 10.79 (s, 1H), 7.80 ( d, J = 5.6 Hz, 1H), 6.12 (d, J = 5.6 Hz, 1H), 4.58 --4.46 (m, 1H), 4.17 (s, 4H), 4.05 --3.97 (m, 4H), 3.84 --3.72 (m, 2H), 2.80 ―― 2.67 (m, 1H), 2.57 (t, J = 6.0 Hz, 2H), 2.20 ―― 2.09 (m, 1H), 2.07 ―― 1.89 (m, 2H), 1.81 ―― 1.66 (m) , 2H), 1.38 (s, 9H).
Step 7: N- (2,6-dioxopiperidine-3-yl) -5- (2,6-diazaspiro [3.3] heptane-2-yl) -3,4-dihydro-1,8-naphthylidine-1 (2H)-Preparation of carboxamide.

tert-butyl 6- [8-[(2,6-dioxo-3-piperidyl) carbamoyl] -6,7-dihydro-5H-1,8-naphthalidine-4-yl] -2,6-diazaspiro [3.3] Triethylamine (3.85 g, 33.77 mmol, 74.37 eq) was added to a solution of heptan-2-carboxylate (220 mg, 0.45 mmol, 1 eq) in dichloromethane (5 mL). The mixture was stirred at 15 ° C. for 1 hour. The mixture was concentrated under vacuum. Compound 5- (2,6-diazaspiro [3.3] heptane-2-yl) -N- (2,6-dioxo-3-piperidyl) -3,4-dihydro-2H-1,8-naphthylidine-1- Carboxamide (220 mg, 0.44 mmol, 97.21% yield, trifluoroacetate) was obtained as a bright yellow solid. LC / MS (ESI) m / z: 385.3 [M + 1] ⁺ .
Step 8: 5-(6-((1- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) phenyl) piperidine-4-yl) methyl) -2,6-diazaspiro [3.3] heptane-2-yl) -N- (2,6-dioxopiperidine- Preparation of 3-yl) -3,4-dihydro-1,8-naphthalidine-1 (2H) -carboxamide.

5- (2,6-diazaspiro [3.3] heptane-2-yl) -N- (2,6-dioxo-3-piperidyl) -3,4-dihydro-2H-1,8-naphthalidine-1-carboxamide ( Sodium acetate (90 mg, 1.10 mmol) in a solution of N, N-dimethylformamide (5 mL) of 110 mg, 0.22 mmol, 1 equivalent, trifluoroacetic acid salt).
, 5 equivalents) was added. The mixture was stirred at 15 ° C. for 0.5 hours. Then (3R) -N- [2,4-difluoro-3- [5- [4- (4-formyl-1-piperidyl) phenyl] -1H-pyrrolo [2,3-b] pyridin-3-carbonyl]
Phenyl] -3-fluoro-pyrrolidin-1-sulfonamide (134 mg, 0.22 mmol, 1 eq) and acetic acid (26 mg, 0.44 mmol, 2 eq) were added to the mixture. The mixture was stirred at 15 ° C. for 0.5 hours. Sodium cyanoborohydride (27 mg, 0.44 mmol, 2 eq) was then added to the mixture. 15 mixed liquids
The mixture was stirred at ° C for 2 hours. The mixture is filtered and the filtrate is purified by preparative HPLC and 5- [6-[[1- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoro). Pyrrolidine-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl] -4-piperidyl] methyl] -2,6-diazaspiro [3.3] heptane-2- Il] -N- (2,6-dioxo-3-piperidyl) -3,4-dihydro-2H-1,8-naphthylidine-1-carboxamide (44.5 mg, 0.04 mmol, yield 19%, purity 98%, Filtrate) was obtained as a yellow solid. LC / MS (ESI) m / z: 981.3 [M + 1] +; 1H-NMR (400MHz, DMSO-d6)
δ 11.20 (d, J = 6.8 Hz, 1H), 10.79 (s, 1H), 8.64 (s, 1H), 8.52 (d, J = 2.8 Hz, 1H), 8.17 (s, 1H), 8.05 (s, 1H), 7.79 (d, J = 5.2 Hz, 1H), 7.66 --7.60 (m, 1H), 7.53 (d, J = 2.8 Hz, 2H), 7.24 (t, J = 8.4 Hz, 1H), 7.05 ( d, J = 8.0 Hz, 2H), 6.13 (d, J = 5.6 Hz, 1H), 5.40 --5.15 (m, 1H), 4.58 --4.45 (m, 1H), 4.12 (s, 4H), 3.82 --3.74 (m, 4H), 3.47 (s, 4H), 3.27 --3.26 (m, 4H), 2.75 --.2.64 (m, 4H), 2.54 --2.52 (m, 3H), 2.34 --2.31 (m, 2H), 2.18 --2.04 (m, 3H), 2.04 --1.91 (m, 2H),
1.83 --1.71 (m, 4H), 1.51 --1.39 (m, 1H), 1.30 --1.18 (m, 2H).
4- (6-((1- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [2, 3-b] Pyridine-5-yl) Phenyl) Piperidine-4-yl) Methyl) -2,6-Diazaspiro [3.3] Heptane-2-yl) -N- (2,6-dioxopiperidine-3-yl) )-2-Exemplary synthesis of methoxybenzamide (exemplary compound 790) Step 1: tert-butyl 6- (3-methoxy-4- (methoxycarbonyl) phenyl) -2,6-diazaspiro [3.3] heptane-2- Preparation of carboxylate.

Methyl 4-fluoro-2-methoxy-benzoate (500 mg, 2.71 mmol, 1 equivalent) and tert-butyl 2,6-diazaspiro [3.3] heptane-2-carboxylate; oxalic acid (660 mg, 1.36 mmol, 0.5)
To a solution of (equivalent) dimethyl sulfoxide (10 mL) was added diisopropylethylamine (701 mg, 5.43 mmol, 945.80 uL, 2 equivalents). The mixture was stirred at 120 ° C. for 2 hours. Water (50 mL) was poured into the mixture and stirred for 1 minute. The aqueous layer was extracted with ethyl acetate (20 mLx3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 10/1 to 1/1). Compound tert-butyl 6- (3-methoxy-4-methoxycarbonyl-phenyl) -2,6-diazaspiro [3.3] heptane-2-carboxylate (250 mg, 0.68 mmol, 25% yield) as a white solid Got as. LC / MS (ESI) m / z: 363.2 [M + 1] ⁺ .
Step 2: Preparation of 4- (6- (tert-butoxycarbonyl) -2,6-diazaspiro [3.3] heptane-2-yl) -2-methoxybenzoic acid.

tert-Butyl 6- (3-Methoxy-4-methoxycarbonyl-Phenyl) -2,6-Diazaspiro [3.3]
Lithium hydroxide monohydrate (115. mg, 2.76 mmol) in a solution of heptane-2-carboxylate (250 mg, 0.68 mmol, 1 eq) in tetrahydrofuran (5 mL), methanol (5 mL) and water (5 mL), 4 equivalents) was added. The mixture was stirred at 20 ° C. for 12 hours. Water (50 mL) was poured into the mixture and stirred for 1 minute. The aqueous layer was extracted with ethyl acetate (20 mLx3). Brine (20 mL) of organic layers combined into one
It was washed with × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by column chromatography (dichloromethane: methanol = 1: 0-20: 1).
The compound 4- (2-tert-butoxycarbonyl-2,6-diazaspiro [3.3] heptane-6-yl) -2-methoxy-benzoic acid (230 mg, 0.66 mmol, 95% yield) was obtained as a white solid. rice field. LC / MS (ESI) m / z: 349.3 [M + 1] ⁺ .
Step 3: Of tert-butyl 6-(4-((2,6-dioxopiperidine-3-yl) carbamoyl) -3-methoxyphenyl) -2,6-diazaspiro [3.3] heptane-2-carboxylate Preparation.

4- (2-tert-Butoxycarbonyl-2,6-diazaspiro [3.3] heptane-6-yl) -2-methoxy-benzoic acid (230 mg, 0.66 mmol, 1 eq) N, N-dimethylformamide (5 mL) To the solution of o- (7-azabenzotriazole-1-yl) -n, n, n', n'-tetramethyluronium hexafluorophosphate (376 mg, 0.99 mmol, 1.5 eq) and 3-amino. Piperidine-2,6-dione (108 mg, 0.66 mmol, 1 eq, hydrochloride) was added. The mixture was stirred at 15 ° C. for 0.5 hours. Diisopropylethylamine (170 mg, 1.32 mmol, 229.98 uL, 2 eq) was added to the mixture and stirred at 15 ° C. for 11.5 hours. Water (40 mL) was poured into the mixture and stirred for 1 minute. The aqueous layer was extracted with ethyl acetate (10 mLx3). The combined organic layers were washed with brine (10 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by preparative TLC (dichloromethane: methanol = 10: 1). The compound tert-butyl 6- [4-[(2,6-dioxo-3-piperidyl) carbamoyl] -3-methoxy-phenyl] -2,6-diazaspiro [3.3] heptane-2-carboxylate (120 mg, 0.26 mmol (yield 39%)) was obtained as a white solid. LC / MS (ESI) m / z: 459.2 [M + 1] ⁺ .
Step 4: Preparation of N- (2,6-dioxopiperidine-3-yl) -2-methoxy-4- (2,6-diazaspiro [3.3] heptane-2-yl) benzamide.

tert-butyl 6- [4-[(2,6-dioxo-3-piperidyl) carbamoyl] -3-methoxy-phenyl] -2,6-diazaspiro [3.3] heptane-2-carboxylate (120 mg, 0.26 mmol) , 1 eq) to a solution of dichloromethane (2 mL) was added trifluoroacetic acid (770 mg, 6.75 mmol, 0.5 mL, 25.80 eq). The mixture was stirred at 20 ° C. for 12 hours. The compound 4- (2,6-diazaspiro [3.3] heptane-2-yl) -N- (2,6-dioxo-3-piperidyl) -2-methoxy-benzamide (120 mg, trifluoroacetate) is a white solid. I got it as a thing. LC / MS (ESI) m / z: 359.2 [M + 1] ⁺ .
Step 5: 4-(6-((1- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperidine-4-yl) Methyl) -2,6-Diazaspiro [3.3] Heptane-2-yl) -N- (2,6-dioxopiperidine- 3-Il) -2-Preparation of methoxybenzamide.

4- (2,6-diazaspiro [3.3] heptane-2-yl) -N- (2,6-dioxo-3-piperidyl) -2-methoxy-benzamide (120 mg, 0.25 mmol, 1 equivalent, trifluoroacetate) ), And (3R) -N- [2,4-difluoro-3- [5- [4- (4-formyl-1-piperidyl) phenyl] -1H-pyrrolo [2,3-b] pyridine-3- Triethylamine (51 mg, 0.50 mmol, 70.71 uL, 2 eq) in a solution of 1,2-dichloroethane (4 mL) of carbonyl] phenyl] -3-fluoro-pyrrolidin-1-sulfonamide (155 mg, 0.25 mmol, 1 eq). Was added. The mixture was stirred at 30 ° C. for 0.5 hours. Sodium triacetoxyborohydride (161 mg, 0.76 mmol, 3 eq) was added to the mixture and the mixture was stirred at 30 ° C. for 1.5 hours. The residue was purified by preparative HPLC. The pH of the reaction mixture was adjusted to 8 using a saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate (20 mLx3). The combined organic layers were washed with brine (20 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Compound 4- [6- [[1- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] Pyridine-5-yl] Phenyl] -4-
Piperidine] Methyl] -2,6-diazaspiro [3.3] heptane-2-yl] -N- (2,6-dioxo-3-piperidyl) -2-methoxy-benzamide (71.8 mg, 0.074 mmol, yield 29%) , 98% purity) was obtained as a yellow solid. LC / MS (ESI) m / z: 954.3 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 1.20
--1.30 (m, 2 H) 1.47 (s, 1 H) 1.77 (d, J = 10.8 Hz, 2 H) 2.02 --2.17 (m, 3 H) 2.52 (s, 4 H) 2.69 --2.83 (m, 2) H) 3.24 --3.30 (m, 4 H) 3.34 --3.42 (m, 6 H) 3.47 (s, 1 H) 3.76 (d, J = 12.0 Hz, 2 H) 3.90 (s, 3 H) 3.99 (s, 1 H) 3 H) 4.69 (dt, J = 12.4, 6.0 Hz, 1 H) 5.20 --5.41 (m, 1 H) 6.01 (d, J = 1.6 Hz, 1 H) 6.07 (dd, J = 8.8, 1.6 Hz, 1 H) 7.05 (d, J = 8.8 Hz, 2 H) 7.25 (t, J = 8.4 Hz, 1 H) 7.54 --7.66 (m, 3 H) 7.76
(d, J = 8.4 Hz, 1 H) 8.06 (s, 1 H) 8.39 (d, J = 6.8 Hz, 1 H) 8.53 (s, 1 H) 8.64 (d, 1 H)
J = 2.0 Hz, 1 H) 10.85 (s, 1 H) 12.89 (s, 1 H).
4- (6-((1- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [2, 3-b] Pyridine-5-yl) phenyl) piperidine-4-yl) methyl) -2,6-diazaspiro [3.3] heptane-2-yl) -N- (2,6-dioxopiperidine-3-yl) )-2-Exemplary synthesis of fluorobenzamide (exemplary compound 792) Step 1: tert-butyl 6- (3-fluoro-4- (methoxycarbonyl) phenyl) -2,6-diazaspiro [3.3] heptane-2- Preparation of carboxylate.

Methyl 2,4-difluorobenzoate (500 mg, 2.90 mmol, 1 eq) and tert-butyl 2,6-diazaspiro [3.3] heptane-2-carboxylate; oxalic acid (706 mg, 1.45 mmol, 0.5 eq) Diisopropylethylamine (750 mg, 5.81 mmol, 1.01 mL, 2 eq) was added to a solution of dimethylsulfoxide (10 mL). The mixture was stirred at 120 ° C. for 2 hours. Pour water (50 mL) into the mixture, 1
Stir for minutes. The aqueous layer was extracted with ethyl acetate (20 mLx3). The combined organic layers were washed with brine (30 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 20/1 to 3/1). The compound tert-butyl 6- (3-fluoro-4-methoxycarbonyl-phenyl) -2,6-diazaspiro [3.3] heptane-2-carboxylate (350 mg, 0.99 mmol, 34% yield) is a white solid. Got as. LC / MS (ESI) m / z: 351.5 [M + 1] ⁺ .
Step 2: Preparation of 4- (6- (tert-butoxycarbonyl) -2,6-diazaspiro [3.3] heptane-2-yl) -2-fluorobenzoic acid.

tert-butyl 6- (3-fluoro-4-methoxycarbonyl-phenyl) -2,6-diazaspiro [3.3] heptane-2-carboxylate (350 mg, 0.99 mmol, 1 eq) in tetrahydrofuran (6 mL), methanol (6 mL) Sodium hydroxide (159 mg, 4.00 mmol, 4 eq) was added to the solution of 6 mL) and water (6 mL). The mixture was stirred at 40 ° C. for 3 hours. The reaction mixture was adjusted to pH 6 with sulfuric acid (2M). Water (30 mL) was poured into the mixture and stirred for 1 minute. The aqueous layer was extracted with dichloromethane (10 mLx3). The combined organic layers were washed with brine (10 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The compound 4- (2-tert-butoxycarbonyl-2,6-diazaspiro [3.3] heptane-6-yl) -2-fluoro-benzoic acid (300 mg, 0.89 mmol, 89% yield) was obtained as a white solid. rice field. LC / MS (ESI) m / z: 337.4 [M + 1] ⁺ .
Step 3: Of tert-butyl 6-(4-((2,6-dioxopiperidine-3-yl) carbamoyl) -3-fluorophenyl) -2,6-diazaspiro [3.3] heptane-2-carboxylate Preparation.

N, N-dimethylformamide (5 mL) of 4- (2-tert-butoxycarbonyl-2,6-diazaspiro [3.3] heptane-6-yl) -2-fluoro-benzoic acid (300 mg, 0.89 mmol, 1 eq) To the solution of, add o- (7-azabenzotriazole-1-yl) -n, n, n', n'-tetramethyluronium hexafluorophosphate (508 mg, 1.34 mmol, 1.5 eq) and mix. The solution was stirred at 20 ° C. for 0.5 hours. Diisopropylethylamine (230 mg, 1.78 mmol, 310.71 uL, 2 eq) and 3-aminopiperidine-2,6-dione (146 mg, 0.89 mmol, 1 eq, hydrochloride) were then added to the mixture. The mixture was stirred at 20 ° C. for 12 hours. Water (50 mL) was poured into the mixture and stirred for 1 minute. The aqueous layer was extracted with ethyl acetate (20 mLx3). The combined organic layers were washed with brine (20 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (dichloromethane: methanol = 200: 1 to 20: 1). The compound tert-butyl 6- [4-[(2,6-dioxo-3-piperidyl) carbamoyl] -3-fluoro-phenyl] -2,6-diazaspiro [3.3] heptane-2-carboxylate (250 mg, 0.55 mmol (yield 62%)) was obtained as a white solid. LC / MS (ESI) m / z: 447.2 [M + 1] ⁺ .
Step 4: Preparation of N- (2,6-dioxopiperidine-3-yl) -2-fluoro-4- (2,6-diazaspiro [3.3] heptane-2-yl) benzamide.

tert-butyl 6- [4-[(2,6-dioxo-3-piperidyl) carbamoyl] -3-fluoro-phenyl] -2,6-diazaspiro [3.3] heptane-2-carboxylate (250 mg, 0.55 mmol) , 1 eq) to a solution of dichloromethane (5 mL) was added trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 24.12 eq). The mixture was stirred at 20 ° C. for 12 hours. The reaction mixture was concentrated under reduced pressure. Compound 4- (2,6-
Diazaspiro [3.3] heptane-2-yl) -N- (2,6-dioxo-3-piperidyl) -2-fluoro-benzamide (250 mg, trifluoroacetate) was obtained as a brown oil. LC / MS (ESI) m / z: 347.2 [M + 1] ⁺ .
Step 5: 4-(6-((1- (4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) phenyl) piperidine-4-yl) methyl) -2,6-diazaspiro [3.3] heptane-2-yl) -N- (2,6-dioxopiperidine- 3-Il) -2-Preparation of fluorobenzamide.

4- (2,6-diazaspiro [3.3] heptane-2-yl) -N- (2,6-dioxo-3-piperidyl) -2-fluoro-benzamide (90 mg, 0.19 mmol, 1 equivalent, trifluoroacetate) ), And (3R) -N- [2,4-difluoro-3- [5- [4- (4-formyl-1-piperidyl) phenyl] -1H-pyrrolo [2,3-b] pyridine-3- Carbonyl] phenyl] -3-fluoro-pyrrolidin-1-sulfonamide (120 mg, 0.19 mmol, 1)
Equivalent) to a solution of 1,2-dichloroethane (3 mL) with triethylamine (39 mg, 0.39 mmol, 2 equivalents)
Was added, and the mixture was stirred at 30 ° C. for 0.5 hours. Sodium triacetoxyborohydride (124 mg, 0.58 mmol, 3 eq) was added to the mixture and the mixture was stirred at 30 ° C. for 1.5 hours. The residue was purified by preparative HPLC. The pH of the reaction mixture was adjusted to 8 using a saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate (20 mLx3). The combined organic layers were washed with brine (20 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Compound 4- [6- [[1- [4- [3- [2,6-difluoro-3-[[(3R) -3-fluoropyrrolidin-1-yl] sulfonylamino] benzoyl] -1H-pyrrolo [2,3-b] Pyridine-5-yl] Phenyl] -4-piperidyl] Methyl] -2,6-Diazaspiro [3.3] Heptane-2-yl] -N- (2,6-dioxo-3-piperidyl )-2-Fluoro-benzamide (37.7 mg, 0.038 mmol, yield 19%, purity 95%) was obtained as a yellow solid. LC / MS (ESI) m / z: 942.3 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 1.20 --1.30 (m, 2 H) 1.46 (s, 1 H) 1.76 (d, J) = 11.2 Hz, 2 H) 2.02 --2.17 (m, 3 H) 2.52 (s, 1 H) 2.64 --2.82 (m, 3 H) 3.26 --3.33 (m, 9 H) 3.39 (d, J = 3.2 Hz, 2 H) 3.47 (s, 1 H) 3.7
6 (d, J = 12.0 Hz, 2 H) 3.93 --4.06 (m, 4 H) 4.72 (dt, J = 12.8, 6.28 Hz, 1 H) 5.17 --5.41 (m, 1 H) 6.20 --6.31 (m, 2 H) 7.05 (d, J = 8.8 Hz, 2 H) 7.25 (t, J = 8.4 Hz, 1 H) 7.54 --7.66 (m, 4 H) 7.97 (t, J = 7.2 Hz, 1 H) 8.05 ( s, 1 H) 8.53 (s, 1 H) 8.64 (d, J = 2.0 Hz, 1 H) 10.82 (s, 1 H) 12.88 (s, 1 H).
General synthesis scheme for PEG prodrugs
Scheme Prodrug 1. A general synthetic scheme for PEG prodrugs linked via an alkoxy-acetic acid ester on the hydroxyproline of the VHL ligand.

Scheme Prodrug 2. A common synthetic scheme for PEG prodrugs linked via a succinic acid bisester on hydroxyproline, a VHL ligand.

Scheme Prodrug 3. A common synthetic scheme for PEG prodrugs linked via a 3-alkoxy-propionic acid ester on the hydroxyproline of the VHL ligand.

Scheme Prodrug 4. A common synthetic scheme for PEG prodrugs linked via a 3-alkoxy-butyrate ester on the hydroxyproline of the VHL ligand.

Scheme Prodrug 5. A common synthetic scheme for PEG prodrugs linked via a 2-alkoxy-propionic acid ester on the hydroxyproline of the VHL ligand.

Scheme Prodrug 6. A common synthetic scheme for PEG prodrugs linked via a 4-alkoxy-butyrate ester on the hydroxyproline of the VHL ligand.

Scheme Prodrug 7. A general synthetic scheme for PEG prodrugs linked via a succinic acid monoester mono- (secondary) -amide on hydroxyproline, a VHL ligand.

Scheme Prodrug 8. A general synthetic scheme for PEG prodrugs linked via a succinic acid monoester mono- (tertiary) -amide on hydroxyproline, a VHL ligand.

Scheme Prodrug 9. A general synthetic scheme for PEG prodrugs linked via a succinic acid mono-ester mono-amide on the benzylmethyl group of the VHL ligand.

Scheme Prodrug 10. A common synthetic scheme for PEG prodrugs linked via the bis-ester of 2,2'-oxydiacetic acid on the VHL ligand hydroxyproline.

Scheme Prodrug 11. A general synthetic scheme for PEG prodrugs linked via Click chemistry on the hydroxyproline VHL ligand.

Scheme Prodrug 12. A general synthetic scheme for PEG prodrugs linked via methylene carbonate on the imide N of the celebrone ligand.

Scheme Prodrug 13. A common synthetic scheme for PEG prodrugs linked via methylene 2-propionate from the parent drug indole.

Scheme Prodrug 14. General synthetic scheme for PEG prodrugs linked via methylene acetate from the parent drug indole

Scheme Prodrug 15. A common synthetic scheme for PEG prodrugs linked via methylene carbonate from the parent drug indole.

(3R, 5S) -1-((S) -2-(2-(3-(4-(4-(3-(2,6-difluoro-3-(((R) -3-fluoropyrrolidine)) -1-sulfonamide) benzoyl) -1H-pyrrolidine [2,3-b] pyridine-5-yl) phenyl) piperazine-1-yl) azetidine-1-yl) acetamide) -3,3-dimethylbutanoyl) -5-((4- (4-Methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidine-3-yl 2,5,8,11,14,17,20,23,26,29,32,35, 38,41,44,47,50-Exemplary synthesis of heptadecaoxadopentacontane-52-acid acid (exemplary compound 797) Step 1: tert-butyl 3- (4- (4-bromophenyl) piperazine- 1-Il) Preparation of azetidine-1-carboxylate.

1- (4-bromophenyl) piperazine (10.0 g, 36.2 mmol 1.0 eq), tert-butyl 3-oxoazetidine-1-carboxylate (7.0 g, 36.2 mmol, 1.0 eq), dichloromethane in a 500 mL round bottom flask. (300.0 mL), N, N-diisopropylethylamine (4.67 g, 36.2 mmol, 1.0 eq) and sodium triacetoxyborohydride (35.0 g, 0.16 mol, 4 eq) were added. The resulting mixture was stirred at room temperature for 24 hours and extracted with dichloromethane (500.0 mlx2). The organic layer was concentrated to give 12.0 g of tert-butyl 3- (4- (4-bromophenyl) piperazine-1-yl) azetidine-1-carboxylate as a solid. LC / MS (ESI) m / z: 396.25 [M + 1] ⁺ .
Step 2: Preparation of 1- (azetidine-3-yl) -4- (4-bromophenyl) piperazine.

In a 1 L round-bottom flask, place a 100 mL solution of tert-butyl 3- [4- (4-bromophenyl) piperazine-1-yl] azetidine-1-carboxylate (15.0 g, 1 eq) in dichloromethane. Then a 1,4-dioxane solution of hydrogen chloride (4.0 M, 100 mL) was added. The obtained mixture was stirred at room temperature for 2 hours. The solids were collected by filtration to give 10.0 g of 1- (azetidine-3-yl) -4- (4-bromophenyl) piperazine as solids. LC / MS (ESI) m / z: 296.20 [M + 1] ⁺ .
Step 3: Preparation of tert-butyl 2- (3- (4- (4-bromophenyl) piperazine-1-yl) azetidine-1-yl) acetate.

In a 1 L round-bottom flask purged and maintained in an inert nitrogen atmosphere, 1- (azetidine-3-yl) -4- (4-bromophenyl) piperazine (15.0 g, 50.68 mmol, 1.0 eq), oxolan ( 200.0 mL), aqueous sodium hydroxide solution (2.0 M, 100.0 mL) and tert-butyl 2-bromoacetate (10.0 g, 51.3 mmol 1.1 eq) were added. The resulting mixture was stirred for 2 hours in an ice / salt bath at 0 ° C. The resulting solution was extracted with ethyl acetate (500.0 mlx2), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated. As a result, 10.0 g of tert-butyl 2- [3- [4- (4-bromophenyl) piperazine-1-yl] azetidine-1-yl] acetate was obtained as a solid substance. LC / MS (ESI) m / z: 410.30 [M + 1] ⁺ .
Step 4: tert-Butyl 2- (3- (4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-1-yl) azetidine -1-yl) Preparation of acetate.

In a 250 mL round bottom flask purged and maintained in an inert nitrogen atmosphere, tert-butyl 2- [3- [4- (4-bromophenyl) piperazin-1-yl] azetidine-1-yl] acetate ( 10.4 g, 25.24 mmol 1.0 equivalent), 4,4,5,5-tetramethyl-2- (tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolan (12.8 g, 50.48 mmol 2.0 eq), potassium acetate (4.9 g 50.48 mmol 2.0 eq), Pd (dppf) Cl ₂ (2.0 g 2.52 mmol 0.1 eq), and dioxane (200.0 mL) were added. The resulting solution was stirred overnight in an oil bath at 80 ° C. The resulting mixture was concentrated. The residue was applied on a silica gel column and eluted with dichloromethane / methanol (10: 1). This resulted in 10.0 g of tert-butyl 2- (3- [4- [4- (tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine-1-yl] azetidine-1-yl). Acetate was obtained as a solid. LC / MS (ESI) m / z: 458.35 [M + 1] ⁺ .
Step 5: tert-butyl (R) -2- (3-(4- (4- (3- (2,6-difluoro-3-((3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H) -Preparation of pyrrolidine [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) azetidine-1-yl) acetate.

In a 30 mL closed tube purged and maintained in an inert nitrogen atmosphere, (3R) -N- [3-([5-bromo-1H-pyrrolo [2,3-b] pyridine-3-yl] carbonyl) -2,4-difluorophenyl] -3-fluoropyrrolidin-1-sulfonamide (1.0 g, 2.0 mmol 1.0 eq), tert-butyl 2- (3- [4- [4- (tetramethyl-1,3,) 2-Dioxaborolan-2-yl) phenyl] piperazin-1-yl] azetidine-1-yl) acetate (1.9 g 4.15 mmol 2.1 eq), Na ₂ CO ₃ (0.43 g, 4.0 mmol, 2.0 eq), Pd ( dppf) Cl ₂ (163.0 mg, 0.2 mmol, 0.1 eq), dioxane (10 mL) and H ₂ O (2 mL) were added. The obtained mixture was stirred at 105 ° C. for 3 hours in a microwave environment. The resulting mixture was concentrated, the residue was applied on a silica gel column and eluted with dichloromethane / methanol (10: 1). This resulted in 0.94 g (62.76%) of tert-butyl 2- [3- [4- (4- [3-[(2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1-). Sulfonyl] Amino] Phenyl) Carbonyl] -1H-Pyrrolidine [2,3-b] Pyridine-5-
Ill] phenyl) piperazine-1-yl] azetidine-1-yl] acetate was obtained as a solid. LC / MS (ESI) m / z: 754.45 [M + 1] ⁺ .
Step 6: (R) -2- (3- (4- (4- (3- (2,6-difluoro-3-((3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [ 2,3-b] Pyridine-5-yl) Phenyl) Piperazine-1-yl) Azetidine-1-yl) Preparation of acetic acid.

In a 100 mL round bottom flask, tert-butyl 2- [3- [4- (4- [3-[(2,6-difluoro-3-[[(3R) -3-]
Fluoropyrrolidine-1-sulfonyl] amino] phenyl) carbonyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazine-1-yl] azetidine-1-yl] acetate (1.0 g) , Dichloromethane (20 mL) and trifluoroacetic acid (10 mL) were added. The resulting solution was stirred at room temperature for 12 hours. The resulting mixture was concentrated. This resulted in 820.0 mg of 2- [3- [4- (4- [3-[(2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1-sulfonyl] amino] phenyl) carbonyl). ] -1H-Pyrrolidine [2,3-b] Pyridine-5-yl] Phenyl) Piperazine-1-yl] Azetidine-1-yl] Acetic acid was obtained as a brown solid. LC / MS (ESI) m / z: 698.05 [M + 1] ⁺ .
Step 7: (2S, 4R) -1-((S) -2- (2- (3- (4- (4- (3- (2,6-difluoro-3- (((R) -3-) -3-) Fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) azetidine-1-yl) acetamide) -3,3-dimethyl Preparation of butanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide.

2- [3- [4- (4- [3-[(2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine-1-sulfonyl] amino] phenyl) in a 100 mL round bottom flask) Carbonyl] -1H-pyrrolidine [2,3-b] pyridine-5-yl] phenyl) piperazin-1-yl] azetidine-1-yl] acetic acid (1.0 g), N, N-dimethylformamide (10 mL), ( 2S, 4R) -1-[(2S) -2-amino-3,3-dimethylbutanoyl] -4-hydroxy-N-[[4- (4-methyl-1,3-thiazole-5-yl)) Phenyl] methyl] pyrrolidine-2-carboxamide (0.61 g), N, N-diisopropylethylamine (0.55 g) and propanephosphonic acid cyclic anhydride (1.3 g) were added. The resulting solution was stirred at room temperature for 1 hour. The reaction was then quenched by the addition of 60 mL of water. The resulting solution was extracted with ethyl acetate (50 mLx2) and the organic layer was concentrated. The crude product was purified by preparative HPLC. This resulted in 251.7 mg of (2S, 4R) -1-[(2S) -2- (2- [3- [4- (4- [3- [(2,6-difluoro-3-] [(3R). ) -3-Fluoropyrrolidine-1-sulfonyl] amino] phenyl) carbonyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazine-1-yl] azetidine-1-yl] acetamide) -3,3-dimethyl was obtained as a solid. LC / MS (ESI) m / z: 1110.15 [M + 1] +;
1H-NMR (300MHz, DMSO-d6) δ 12.89 (s, 1H), 8.94 (s, 1H), 8.70-8.36 (m, 3H), 8.13 (s, 1H), 8.04 (s, 1H), 7.57 ( dd, J = 9.0, 5.1 Hz, 4H), 7.38 (s, 4H), 7.22 (td,
J = 8.8, 1.6 Hz, 1H), 7.03 (d, J = 8.7 Hz, 2H), 5.26 (d, J = 53.1 Hz, 2H), 4.54-4.16 (m, 5H), 3.68-3.50 (m, 3H) ), 3.42 (d, J = 19.4 Hz, 2H), 3.30 (dt, J = 25.7,
4.6 Hz, 2H), 3.15 (d, J = 18.7 Hz, 7H), 3.01 (s, 3H), 2.40 (d, J = 8.0 Hz, 7H),
2.16-1.78 (m, 4H), 1.37 (s, 1H), 0.91 (s, 9H).
Step 8: tert-Butyl 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50-Heptadecaoxadopentacontane-52-acid Preparation of salt.

In a 1 L round bottom flask purged and maintained in an inert nitrogen atmosphere, 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47- Hexadecaoxanonatetracontan-49-ol (40.00g)
, 54.28 mmol, 1 eq) in a solution of THF (400 mL). Cool the solution to 0 ° C in a water / ice bath,
Subsequently, NaH (3.20 g, 80.01 mmol, 1.47 eq) was added in several portions. The obtained mixed solution was stirred at 0 ° C. for 0.5 hours. Then tert-butyl 2-bromoacetate (15.60 g, 79.98 mmol, 1.47 eq) was added dropwise with stirring. The obtained mixed solution was reacted at room temperature for another 14 hours with stirring. The reaction was then stopped by the addition of water (300 mL). The resulting solution was extracted with ethyl acetate (130 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded into a silica gel column with dichloromethane / methanol (20: 1). This will result in 20g (43.29%) of tert-butyl 2,5,8,11,14,17,20,23,2.
6,29,32,35,38,41,44,47,50-heptadecaoxadopentacontane-52-acid salt was obtained as a colorless oil. 1H-NMR (300MHz, CDCl3) δ 4.02 (s, 2H), 3.71-3.56 (m, 75H), 3.38 (s, 3H), 1.48 (s, 9H).
Step 9: Preparation of 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50-heptadecaoxadopentacontane-52-acid.

In a 50 mL round bottom flask, tert-butyl 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50-heptadecaoxadopentacontane -52-The acid salt (500 mg), DCE (5.0 mL) and TFA (1.5 mL) were added. The resulting solution was stirred at room temperature for 4 hours. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC. This resulted in 126.1 mg (27.00%) of 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50-heptadecaoxadopentacontane. -52-Acid was obtained as a bright yellow oil. LC / MS (ESI) m / z: 398.35 [M / 2 + 1] ⁺ ; ¹ H-NMR (300MHz, D ₂ O) δ 4.8-4.15 (m, 2H), 3.70-3.55 (m, 77H), 3.30 (s, 3H).
Step 10: (3R, 5S) -1-((S) -2- (2- (3- (4- (4- (3- (2,6-difluoro-3- (((R) -3-) -3-) Fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) azetidine-1-yl) acetamide) -3,3-dimethyl Butanoyl) -5-((4- (4-Methylthiazole-5-yl) benzyl) carbamoyl) pyrrolidine-3-yl 2,5,8,11,14,17,20,23,26,29,32 , 35,38,41,44,47,50-Preparation of heptadecaoxadopentacontane-52-acid salt.

In a 100 mL round bottom flask, (2S, 4R) -1-[(2S) -2- (2- [3- [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] azetidine-1-yl] acetamide )-3,3-dimethyl (300.0 mg, 270.51 mmol, 1.0 eq), 2- (2-methoxyethoxy) acetic acid (1.074 g, 1.35 mmol 5.0 eq), dichloromethane (20.0 mL), 4-dimethylaminopyridine (1.5) g, 2.7 mol 10 eq) and N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (5.71 g, 2.7 mol 10.0 eq) were added. The resulting solution was stirred at room temperature for 24 hours. The resulting mixture was washed with 300 x ml NH ₄ Cl. The resulting solution was extracted with 2x200 ml dichloromethane, dried over anhydrous sodium sulfate and concentrated. The resulting mixture was concentrated. The crude product was purified by preparative HPLC. This resulted in 31.6 mg of (3R, 5S) -1-((S) -2- (2- (3- (4- (4- (3- (2,6-difluoro-3- (((R)). -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridine-
5-yl) phenyl) piperazine-1-yl) azetidine-1-yl) acetamide) -3,3-dimethylbutanoyl) -5-((4- (4-methylthiazole-5-yl) benzyl) carbamoyl) Pyrrolidine-3-yl 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50-heptadecaoxadopentacontane-52-acid acid Was obtained as a solid substance. LC / MS (ESI) m / z: 1887.26 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 8.99 (s, 1H), 8.89 --8.44 (m, 2H), 8.17 (s, 3H) ), 7.62 (dd, J = 9.0, 6.8 Hz, 1H), 7.42 (s, 3H), 7.28 (t, J = 8.9 Hz, 4H), 7.08 (d, J = 8.4 Hz, 2H), 5.31 (d) , J = 52.8 Hz, 2H), 4.58 --4.23 (m, 5H), 4.29 --3.68 (m, 6H), 3.78 --3.51 (m, 12H), 3.47 --2.77 (m, 66H), 2.47 (s, 7H) ), 2.42 --1.88 (m, 5H), 0.97 (s, 9H).
(3R, 5S) -1-((S) -2-(2-(3-(4-(4-(3-(2,6-difluoro-3-(((R) -3-fluoropyrrolidine)) -1-sulfonamide) benzoyl) -1H-pyrrolidine [2,3-b] pyridin-5-yl) phenyl) piperazin-1-yl) azetidine-1-yl) acetamide) -3,3-dimethylbutanoyl) -5-((4- (4-Methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidine-3-yl (65-hydroxy-3,6,9,12,15,18,21,24,27,30) , 33,36,39,42,45,48,51,54,57,60,63-Henicosoxaoxapentahexacontyl) Exemplary synthesis of succinate (exemplary compound 799) Step 1: 4-((() (3R, 5S) -1-((S) -2-(2-(3-(4-(4-(3-(2,6-difluoro-3-(((R) -3-fluoropyrrolidine)) -1-sulfonamide) benzoyl) -1H-pyrrolidine [2,3-b] pyridin-5-yl) phenyl) piperazin-1-yl) azetidine-1-yl) acetamide) -3,3-dimethylbutanoyl) Preparation of -5-((4- (4-methylthiazole-5-yl) benzyl) carbamoyl) pyrrolidine-3-yl) oxy) -4-oxobutanoic acid.

In a 100 mL round bottom flask, (2S, 4R) -1-[(2S) -2- (2- [3- [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] azetidine-1-yl] acetamide )-3,3-dimethylbutanoyl] -4-hydroxy-N-[[4- (4-methyl-1,3-thiazole-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (250.0 mg, 0.23) mmol, 1.00 equivalent), dichloromethane (10 mL), 4-dimethylaminopyridine (82.50 mg, 0.68 mmol, 3.00 equivalent), triethylamine (45.53 mg, 0.45 mmol, 2.00 equivalent), stirred for 10 minutes, and then oxolan-2. , 5-Dione (45.08 mg, 0.45 mmol, 2.00 equivalents) was added. The resulting solution was stirred at room temperature overnight. The resulting solution was extracted with dichloromethane (100 mL) and the organic layers were combined into one. The obtained mixture was washed with NH ₄ Cl aqueous solution (50 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by preparative HPLC. This resulted in 38 mg (14%) of 4-[[(3R, 5S) -1-[(2S) -2- (2- [3- [4- (4- [3- [(2,6-difluoro). -3-[[(3R) -3-fluoropyrrolidine-1-sulfonyl] amino] phenyl) carbonyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazine-1-yl] azetidine -1-yl] acetamide) -3,3-dimethylbutanoyl] -5-([[4- (4-methyl-1,3-thiazole-5-yl) phenyl] methyl] carbamoyl) pyrrolidine-3-yl ] Oxy] -4-oxobutanoic acid was obtained as a bright yellow solid. LC / MS (ESI) m / z: 1210.10 [M + 1] +; 1H-NMR (
400MHz, CD3OD) δ 8.85 (s, 1H), 8.67 (s, 1H), 8.58 (d, J = 2.0Hz, 1H), 7.88 (s, 1H), 7.75-7.74 (m, 1H), 7.58 (d) , J = 8.8Hz, 2H), 7.47-7.40 (m, 4H), 7.16-7.07 (m, 3H), 5.35-5.15 (m, 2H), 4.57-4.53 (m, 3H), 4.38-4.34 (m) , 1H), 4.16-4.13 (m, 1H), 4.00-3.87 (m, 3H), 3.59-3.39 (m, 7H), 3.30-3.24 (m, 6H), 2.55-2.44 (m, 12H), 2.20 -2.00 (m, 3H), 1.04 (s, 9H).
Step 2: (3R, 5S) -1-((S) -2- (2- (3- (4- (4- (3- (2,6-difluoro-3- (((R) -3-) -3-) Fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) azetidine-1-yl) acetamide) -3,3-dimethyl Preparation of butanoyl) -5-((4- (4-methylthiazole-5-yl) benzyl) carbamoyl) pyrrolidine-3-yl (2,5-dioxopyrrolidine-1-yl) succinate.

In a 50 mL round bottom flask, 4-[[(3R, 5S) -1-[(2S) -2- (2- [3- [4- (4- [3- [(2,6-difluoro-3) -[[(3R) -3-fluoropyrrolidine-1-sulfonyl] amino] phenyl) carbonyl] -1H-pyrrolo [2,3-b] pyridine-5-yl] phenyl) piperazine-1-yl] azetidine-1 -Il] acetamide) -3,3-dimethylbutanoyl] -5-([[4- (4-methyl-1,3-thiazole-5-yl) phenyl] methyl] carbamoyl) pyrrolidine-3-yl] oxy ] -4-oxobutanoic acid (250.0 mg, 0.21 mmol, 1.00 equivalent), dichloromethane (10 mL), 1-hydroxypyrrolidine-2,5-dione (47.55 mg, 0.41 mmol, 2.00 equivalent), DCC (85.19 mg, 0.41 mmol) , 2.00 equivalents). The resulting solution was stirred at room temperature overnight. The solids were filtered off. This resulted in 270.0 mg (100%) of (3R, 5S) -1-[(2S) -2- (2- [3- [4- (4- [3- [(2,6-difluoro-3-]). [[(3R) -3-fluoropyrrolidin-1-sulfonyl] amino] phenyl) carbonyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazine-1-yl] azetidine-1- Il] acetamide) -3,3-dimethylbutanoyl] -5-([[4- (4-methyl-1,3-thiazole-5-yl) phenyl] methyl] carbamoyl) pyrrolidine-3-yl 2,5 -Dioxopyrrolidine-1-ylbutane diate was obtained as a bright yellow solid.

Step 3: (3R, 5S) -1-((S) -2- (2- (3- (4- (4- (3- (2,6-difluoro-3- (((R) -3-) -3-) Fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) azetidine-1-yl) acetamide) -3,3-dimethyl Butanoyl) -5-((4- (4-Methylthiazole-5-yl) benzyl) carbamoyl) pyrrolidine-3-yl (65-hydroxy-3,6,9,12,15,18,21,24, Preparation of 27,30,33,36,39,42,45,48,51,54,57,60,63-henicosoxapentapentahexacontyl) succinate.

In a 50 mL round bottom flask purged and maintained in an inert nitrogen atmosphere, (3R, 5S) -1-[(2S) -2- (2- [3- [4- (4- [3- [() 2,6-difluoro-3- [[(3R) -3-fluoropyrrolidin-1-sulfonyl] amino] phenyl) carbonyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazine- 1-yl] azetidine-1-yl] acetamide) -3,3-dimethylbutanoyl] -5-([[4- (4-methyl-1,3-thiazole-5-yl) phenyl] methyl] carbamoyl) Pyrrolidine-3-yl 2,5-dioxopyrrolidine-1-yl butane phosphate (290.0 mg, 0.22 mmol, 1.00 equivalent), dichloromethane (5.0 mL), PEG 1000 (666.0 mg, 3.00 equivalent), triethylamine (67.28) mg, 0.66 mmol, 3.00 equivalent)
I put in. The resulting solution was stirred at room temperature overnight. The resulting solution was extracted with dichloromethane (50 mLx2) and the organic layers were combined into one. The obtained mixed solution was _{washed with NH 4} Cl aqueous solution (50 mLx2). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by preparative HPLC. This resulted in 59.6 mg (21%) of (3R, 5S) -1-((S) -2- (2- (3- (4- (4- (3- (2,6-difluoro-3-). ((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) azetidine-1-yl) acetamide )-3,3-dimethylbutanoyl) -5-((4- (4-Methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidine-3-yl (65-hydroxy-3,6,9,12,15) , 18,21,24,27,30,33,36,39,42,45,48,51,54,57,60,63-Henicosoxapentahexacontyl) Obtain succinate as a bright yellow oil. rice field. LC / MS (ESI) m / z: 2179.44 [M + 1] +; 1H-NMR (400MHz, CD3OD) δ 8.86 (s, 1H), 8.67 (s, 1H), 8.59-8.58 (d, J = 2.0) Hz, 1H), 7.89 (s, 1H), 7.75- 7.74 (m, 1H), 7.60-7.58 (d, J = 8.8Hz, 2H), 7.48-7.41 (m, 4H), 7.10-7.08 (m, 3H), 5.35-5.15 (m, 2H), 4.54-4.53 (m, 3H), 4.38-4.34 (m, 1H), 4.23-4.13 (m, 3H), 3.90-3.80 (m, 2H),
3.70-3.53 (m, 99H), 3.47-3.31 (m, 3H), 3.29-3.26 (m, 4H), 3.17-3.10 (m, 3H), 2.64 (s, 4H), 2.56 (s, 4H), 2.48 (s, 4H), 2.47-2.35 (m, 1H), 2.25-2.10 (m, 3H), 1.05 (s, 9H)
(3R, 5S) -1-((S) -2-(2-(2-(4-(4-(3-(2,6-difluoro-3-(((R) -3-fluoropyrrolidin)) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) ethoxy) acetamide) -3,3-dimethylbutanoyl) -5-( (4- (4-Methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidine-3-yl 2,5,8,11,14,17,20,23,26,29,32,35,38,41, 44,47,50,53,56,59,62,65,68-Exemplary synthesis of tricosaoxahenheptacontane-71-acid salt (exemplary compound 800) Step 1: tert-butyl 2- (2-) Preparation of (benzyloxy) ethoxy) acetate.

2- (benzyloxy) ethane-1-ol (10.0 g, 65.71 mmol, 1.00 eq), tert-butyl 2-bromoacetate (19.2 g, 98.43 mmol, 1.50 eq), 37% in a 1000 mL round bottom flask. A solution of sodium hydroxide (150 mL) and tetrabutylammonium chloride (18.3 g, 65.83 mmol, 1.00 eq) in dichloromethane (150 mL) was added. The solution obtained in a water / ice tank was stirred at room temperature for 4 hours. The resulting solution was extracted with dichloromethane (100 mLx3), the organic layers were combined and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1/15). This gave 15.0 g (86%) of tert-butyl 2- [2- (benzyloxy) ethoxy] acetate as a yellow oil.

Step 2: Preparation of tert-butyl 2- (2-hydroxyethoxy) acetate.

Palladium on carbon (15.0 g, 92.02 mmol, 10.00 eq) at room temperature in a 500 mL round bottom flask, tert-butyl 2- [2- (benzyloxy) ethoxy] acetate (20.9 g, 78.47 mmol,) 1.00 eq) was added to a solution of methanol (250 mL). The reaction flask was evacuated and filled with a hydrogen balloon. The resulting solution was stirred at room temperature for 16 hours. Palladium on carbon was removed. The resulting mixture was concentrated under vacuum. This gave 9.9 g (72%) of tert-butyl 2- (2-hydroxyethoxy) acetate as a bright yellow solid.

Step 3: Preparation of tert-butyl 2- (2- (tosyloxy) ethoxy) acetate.

In a 250 mL round bottom flask, tert-butyl 2- (2-hydroxyethoxy) acetate (4.5 g, 25.54 mmol, 1.00 eq), triethylamine (5.2 g, 51.39 mmol, 2.01 eq), 4-methylbenzene-1- A solution of sulfonyl chloride (5.8 g, 30.42 mmol, 1.20 eq) in dichloromethane (50 mL) was added. The resulting solution was stirred at room temperature for 8 hours. The reaction was then stopped by the addition of water (100 mL). The resulting solution was extracted with dichloromethane (30 mLx3) and the organic layers were combined into one. The resulting mixture was washed with brine (20 mLx1). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1: 3). This gave 6.1 g (72%) of tert-butyl 2-(2-[[(4-methylbenzene) sulfonyl] oxy] ethoxy) acetate as a colorless oil. LC / MS (ESI) m / z: 275.06 [M-55] ⁺ .
Step 4: Preparation of tert-butyl 2- (2- (4- (4-bromophenyl) piperazine-1-yl) ethoxy) acetate.

In a 500 mL round bottom flask, 1- (4-bromophenyl) piperazine hydrochloride (10.0 g, 36.02 mmol, 1.00 eq), tert-butyl 2-2-[(4-methylbenzenesulfonyl) oxy] ethoxyacetate ( 14.2 g, 42.98 mmol, 1.20 eq), acetonitrile (200 mL), potassium iodide (6.0 g, 1.00 eq), and potassium carbonate (14.9 g, 107.81 mmol, 3.00 eq) were added. The resulting solution was stirred for 10 hours in an oil bath at 70 ° C. The solid was filtered. The filtrate was concentrated under reduced pressure. The residue was applied on a silica gel column and eluted with ethyl acetate / petroleum ether (V: V = 1: 1). This gave 9.6 g (67%) of tert-butyl 2- [2- [4- (4-bromophenyl) piperazine-1-yl] ethoxy] acetate as a light brown solid. LC / MS (ESI) m / z: 399.10 [M + 1] ⁺ .
Step 5: tert-Butyl 2- (2- (4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-1-yl) ethoxy ) Preparation of acetate.

In a 500 mL round bottom flask purged and maintained in an inert nitrogen atmosphere, tert-butyl 2- [2- [4- (4-bromophenyl) piperazin-1-yl] ethoxy] acetate (9.6 g, 24.04). mmol, 1 equivalent), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2- dioxaborolane (12.2g, 48.08mmol, 2 eq), potassium acetate (7.1g, 72.12mmol, 3 _{eq), Pd (dppf) Cl 2} . CH 2 Cl 2 (3.9g, 4.81mmol, 0.2 eq), and 100mL dioxane I put in. The obtained solution was stirred for 5 hours in an oil tank under a nitrogen atmosphere at 85 ° C. The reaction was then quenched with water (100 mL) and extracted with dichloromethane (100 mLx3). The combined organic layers were washed with brine (100 mL) and water (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied on a silica gel column and eluted with ethyl acetate / petroleum ether (V: V = 1: 1). This resulted in 8.2 g (76.41%) of tert-butyl 2- (2- [4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl]]. Piperazine-1-yl] ethoxy) acetate was obtained as a light brown solid. LC / MS (ESI) m / z: 447.30 [M + 1] ⁺ .
Step 6: tert-butyl (R) -2- (2-(4- (4- (3- (2,6-difluoro-3-((3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H) -Preparation of pyrrolidine [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) ethoxy) acetate.

In a 100 mL round-bottom flask purged and maintained in an inert nitrogen atmosphere, (3R) -N- (3- [5-bromo-1H-pyrrolo [2,3-b] pyridine-3-carbonyl]- 2,4-Difluorophenyl) -3-fluoropyrrolidin-1-sulfonamide (5.8 g, 11.52 mmol, 1 equivalent), tert-butyl 2- (2- [4- [4- (4,4,, 4), 1 equivalent)
5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine-1-yl] ethoxy) acetate (6.2 g, 13.83 mmol, 1.2 eq), sodium carbonate (3.7 g, 34.57 mmol) , 3 _{eq), Pd (dppf) Cl 2} . CH 2 Cl 2 (1.9g, 2.30mmol, 0.2 eq), dioxane (50 mL), and containing water (5 mL). The resulting solution was stirred for 2 hours in an oil bath at 105 ° C. The resulting solution was diluted with dichloromethane (100 mL) and extracted with dichloromethane (100 mLx3). The combined organic layers were washed with brine (100 mL) and water (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied on a silica gel column and eluted with dichloromethane / methanol (10: 1). This resulted in 4.8 g (56.07%) of tert-butyl 2- [2- [4- (4- [3- [2,6-difluoro-3- ([[(3R) -3-fluoropyrrolidine-1-). Il] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazine-1-yl] ethoxy] acetate was obtained as a yellow oil. LC / MS (ESI) m / z: 743.15 [M + 1] ⁺ .
Step 7: (R) -2- (2- (4- (4- (3- (2,6-difluoro-3-((3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [ 2,3-b] Pyridine-5-yl) Phenyl) Piperazine-1-yl) ethoxy) Preparation of acetic acid.

In a 250 mL round bottom flask, tert-butyl 2- [2- [4- (4- [3- [2,6-difluoro-3- ([[(3R) -3-)
Fluoropyrrolidine-1-yl] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazine-1-yl] ethoxy] acetate (4.8 g, 6.46 mmol, 1 Equivalent), dichloromethane (50 mL, 786.50 mmol, 121.71 equivalent), and TFA (10 mL) were added. The resulting solution was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure. This resulted in 3.8 g (85.64%) of 2- [2- [4- (4- [3- [2,6-difluoro-3- ([[(3R) -3-fluoropyrrolidine-1-yl]].
Sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazine-1-yl] ethoxy] acetic acid was obtained as a yellow oil. LC / MS (ESI) m / z: 687.35 [M + 1] ⁺ .
Step 8: (2S, 4R) -1-((S) -2- (2- (2- (4- (4- (3- (2,6-difluoro-3- (((R) -3-) -3-) Fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) ethoxy) acetamide) -3,3-dimethylbutanoyl)- Preparation of 4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide.

2- [2- [4- (4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) in a 100 mL round bottom flask) Benzoyl] -1H-pyrrolo [2,3-b] pyridine-5-yl] phenyl) piperazin-1-yl] ethoxy] acetic acid (1.1 g, 1.60 mmol, 1 eq), N, N-dimethylformamide (20 mL) , (2S, 4R) -1-[(2S) -2-amino-3,3-dimethylbutanoyl] -4-hydroxy-N-[[4- (4-methyl-1,3-thiazole-5- Il) phenyl] methyl] pyrrolidine-2-carboxamide hydrochloride (748.1 mg, 1.60 mmol, 1 eq), N, N-diisopropylethylamine (621.1 mg, 4.81 mmol, 3 eq), and T ₃ P (1.526 g, acetate). A 50% solution, 2.40 mmol, 1.5 eq) was added in ethyl. The resulting solution was stirred at room temperature for 2 hours. The reaction was then quenched with water (50 mL) and extracted with dichloromethane (50 mLx3). The combined organic layers were washed with brine (50 mL) and water (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied to a silica gel column eluting with dichloromethane / methanol (v: v = 10: 1). This resulted in 256.3 mg (14.56%) of (2S, 4R) -1-[(2S) -2- (2- [2- [4- (4- [3- [2,6-difluoro-3- ( [[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazine-1-yl] ethoxy] acetamide) -3,3-dimethylbutanoyl] -4-hydroxy-N-[[4- (4-methyl-1,3-thiazole-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide obtained as a yellow solid rice field. LC / MS (ESI) m / z: 1099.60 [M + 1] +; 1H-NMR (300MHz, DMSO-d6) δ 12.94 (s, 1H), 9.81 (s, 1H), 8.96 (s, 1H), 8.74-8.60 (m, 2H), 8.60-8.49 (m, 1H), 8.08 (s, 1H), 7.72-7.53 (m, 3H), 7.51-7.33 (m, 5H), 7.32-7.22 (m, 1H) ), 7.04 (d, J = 8.5 Hz, 2H), 5.48-5.11 (m, 2H), 4.71-4.08 (m, 6H), 4.08-3.89 (m, 2H), 3.77-3.48 (m, 4H), 3.30-3.11 (m, 6H), 2.72-2.58 (m, 6H), 2.42 (s, 3H), 2.26-1.84 (m, 5H), 0.97 (s, 9H).
Step 9: tert-butyl 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65, Preparation of 68-tricosaoxahen heptacontane-71-acid salt.

2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65-docosaoxaheptahexacontan- A solution of 67-ol (1.00 g, 1.00 mmol, 1 eq) in THF (10 mL), Na (5.8 mg, 0.25 mmol, 0.253 eq), and tert-butyl propa-2-enolate (640.9 mg, 5.00) mmol, 5.606 eq) was added. The reaction mixture was stirred at room temperature for 26 hours. The reaction was then stopped by the addition of water (30 mL). THF was removed under vacuum. The residue was extracted with ethyl acetate (80 mLx4). The combined organic layers were washed with brine (30 mLx1). The organic layer was dried over anhydrous sodium sulfate. The residue was loaded into a silica gel column with dichloromethane / methanol (15: 1). This resulted in 453.3 mg (40.19%) of tert-butyl 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56. , 59,62,65,68-tricosaoxahenheptacontane-71-ate was obtained as a light brown semi-solid.

Process 10: 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68-Toriko Preparation of saoxahenheptacontane-71-acid.

tert-butyl 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68-Toriko Trifluoroacetic acid (1.2 mL) was added to a solution of 1,2-dichloroethane (4 mL) of saoxahenheptacontane-71-acid salt (400 mg, 0.35 mmol, 1 eq). The reaction solution was stirred at room temperature for 4 hours. The obtained solution was evaporated to dryness, then 1,2-dichloroethane was added, and the evaporation to dryness was carried out several times to remove trifluoroacetic acid. As a result, 380 mg (99.97%) of 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62 , 65,68-tricosaoxahenheptacontane-71-acid was obtained as a bright yellow oil.

Step 11: (3R, 5S) -1-((S) -2- (2- (2- (4- (4- (3- (2,6-difluoro-3- (((R) -3-) -3-) Fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) ethoxy) acetamide) -3,3-dimethylbutanoyl)- 5-((4- (4-Methylthiazole-5-yl) benzyl) carbamoyl) pyrrolidine-3-yl 2,5,8,11,14,17,20,23,26,29,32,35,38 , 41,44,47,50,53,56,59,62,65,68-Preparation of tricosaoxahenheptacontane-71-acid.

In a 100 mL round bottom flask, (2S, 4R) -1-[(2S) -2- (2- [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) piperazine-1-yl] ethoxy] acetamide) -3, 3-dimethylbutanoyl] -4-hydroxy-N-[[4- (4-methyl-1,3-thiazole-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (330 mg, 0.30 mmol, 1 equivalent) , DCM (25 mL) was added. 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68-Tricosaoxahen Henheptacontane-71-acid (2.42 g, 2.25 mmol, 7.511 eq), DMAP (550 mg, 4.50 mmol, 14.996 eq) and EDCI (863 mg, 4.50 mmol, 14.996 eq) were added in 5 batches over 3 hours. The resulting solution was stirred at room temperature for 48 hours. The resulting solution was concentrated and the residue _{was diluted with saturated NH 4} Cl (200 mL). The obtained mixed solution was extracted with ethyl acetate (180 mLx2), and the organic layers were combined into one. The combined organic layers were _{washed with saturated NH 4} Cl (200 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by preparative HPLC. This resulted in 162.0 mg (25.05%) of (3R, 5S) -1-((S) -2- (2- (2- (4- (4- (3- (2,6-difluoro-3- (). ((R) -3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) ethoxy) acetamide) -3, 3-Dimethylbutanoyl) -5-((4- (4-Methylthiazole-5-yl) benzyl) carbamoyl) pyrrolidine-3-yl 2,5,8,11,14,17,20,23,26, 29,32,35,38,41,44,47,50,53,56,59,62,65,68-tricosaoxahenheptacontane-71-acid acid was obtained as a yellow oil. LC / MS (ESI) m / z: 2154.45 [M + 1] +; 1H-NMR (300MHz, CDCl3) δ 11.70 (s, 1H), 8.83 (s, 1H), 8.66 (s, 1H), 8.57 ( s, 1H), 7.76-7.68 (m, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.41-7.32 (m, 5H), 7.23-7.20 (m, 1H), 7.06-6.96 (m, 3H), 5.42 (s, 1H), 5.23 (d, J = 51.0 Hz, 1H), 4.74-4.69 (m, 1H), 4.58-4.51 (m, 2H), 4.37-4.31 (m, 1H), 4.08 -3.94 (m, 3H), 3.87-3.73 (m, 2H), 3.70-3.61 (m, 93H), 3.57-3.48 (m, 2)
H), 3.37 (s, 3H), 3.29 (m, 4H), 2.73-2.53 (m, 9H), 2.49 (s, 3H), 2.27-2.11 (m, 4H), 0.95 (s, 9H).
(3R, 5S) -1-((S) -2-(2-(2-(4-(4-(3-(2,6-difluoro-3-(((R) -3-fluoropyrrolidin)) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) ethoxy) acetamide) -3,3-dimethylbutanoyl) -5-( (4- (4-Methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidine-3-yl 69-methyl-2,5,8,11,14,17,20,23,26,29,32,35, Illustrative Synthesis of 38,41,44,47,50,53,56,59,62,65,68-tricosaoxahen heptacontane-71-acetate (exemplary compound 801) Step 1: tert-butyl 69 -Methyl-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68-Trico Preparation of saoxahenheptacontane-71-acid salt.

2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65-Docosaoxaheptahexacontane- Na (236.6 mg, 10.29 mmol, 0.515 eq) was added to a solution of 67-ol (20 g, 19.98 mmol, 1 eq) in THF (200 mL). Then tert-butyl porcine-3-enolate (65 mL, 400.89 mmol, 20.069 eq) was added. The resulting solution was stirred at room temperature for 14 hours. The reaction was then quenched by the addition of water (20 mL). THF was removed under vacuum. The residue was extracted with ethyl acetate (80 mLx4). The organic layer was washed with brine (20 mL x 4) and dried over anhydrous sodium sulfate. The crude product was applied to a silica gel column with dichloromethane / methanol (15: 1). This resulted in 14.64g (64.10%) of tert-butyl 69-methyl-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50. , 53,56,59,62,65,68-tricosaoxahenheptacontane-71-ate was obtained as a white semi-solid. 1H-NMR (300MHz, CDCl3) δ 3.90-3.84 (m, 1H), 3.80-3.53 (m, 90H), 3.38 (m, 3H), 2.56-2.48 (m, 1H), 2.33-2.24 (m, 2H) ), 1.45 (s, 9H), 1.21-1.19 (m, 3H).
Step 2: 69-Methyl-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65 , 68-Preparation of tricosaoxahenheptacontane-71-acid.

tert-butyl 69-methyl-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65 TFA (30 mL, 403.89 mmol, 46.181 eq) was added to a solution of DCE (100 mL) of 68-tricosaoxahenheptacontane-71-acid salt (10 g, 8.75 mmol, 1 eq). The resulting solution was stirred at room temperature for 5 hours. Then, the obtained mixed solution was evaporated to dryness. DCE was added and the solution was evaporated to dryness again. This process was repeated 3 times and then dried under vacuum to give a light brown oil. This resulted in 9.6g (100%) of 69-methyl-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53, 56,59,62,65,68-tricosaoxahenheptacontane-71-acid was obtained as a light brown oil.

Step 3: (3R, 5S) -1-((S) -2- (2- (2- (4- (4- (3- (2,6-difluoro-3- (((R) -3-) -3-) Fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) ethoxy) acetamide) -3,3-dimethylbutanoyl)- 5-((4- (4-Methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidine-3-yl 69-methyl-2,5,8,11,14,17,20,23,26,29,32 , 35,38,41,44,47,50,53,56,59,62,65,68-Preparation of tricosaoxahenheptacontane-71-acid.

In a 100 mL round bottom flask, (2S, 4R) -1-[(2S) -2- (2- [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) piperazine-1-yl] ethoxy] acetamide) -3, 3-dimethylbutanoyl] -4-hydroxy-N-[[4- (4-methyl-1,3-thiazole-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (330 mg, 0.30 mmol, 1 equivalent) , Dichloromethane (25 mL) was added. 69-Methyl-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68- Tricosaoxahen heptacontane-71-acid (2.45 g, 2.25 mmol, 7.506 eq), DMAP (550 mg, 4.50 mmol, 14.996 eq), and EDCI (863 mg, 4.50 mmol, 14.996 eq) 5 times in 3 hours Added separately. The resulting solution was stirred at room temperature for 48 hours. The resulting solution was concentrated and the residue _{was diluted with saturated NH 4} Cl (200 mL). The obtained mixed solution was extracted with ethyl acetate (200 mLx2), and the organic layers were combined into one. The organic layer was _{washed with saturated NH 4} Cl (200 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by preparative HPLC. This resulted in 189.9 mg (29.17%) of (3R, 5S) -1-((S) -2- (2- (2- (4- (4- (3- (2,6-difluoro-3-)). ((R) -3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) ethoxy) acetamide) -3, 3-dimethylbutanoyl) -5-((4- (4-methylthiazole-5-yl) benzyl) carbamoyl) pyrrolidine-3-yl 69-methyl-2,5,8,11,14,17,20, 23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68-tricosaoxahenheptacontane-71-acid acid was obtained as a yellow oil. .. LC / MS (ESI) m / z: 2168.46 [M + 1] +; 1H-NMR (300MHz, CDCl3) δ 11.67 (s, 1H), 8.82 (s, 1H), 8.66 (s, 1H), 8.58 ( s, 1H), 7.75-7.67 (m, 2H), 7.54 (d, J = 8.7 Hz, 2H), 7.40-7.29 (m, 5H), 7.25-7.23 (m, 1H), 7.05-6.96 (m, 3H), 5.40 (s, 1H), 5.21 (d, J = 52.2 Hz, 1H), 4.70 (m, 1H), 4.59-4.50 (m, 2H), 4.37-4.30 (m, 1H), 4.07-3.98 (m, 3H), 3.93-3.81 (m, 3H), 3.70-3.42 (m, 92H), 3.37 (s, 3H), 3.27 (m, 4H), 2.73 (m, 6H), 2.62-2.50 (m) , 2H), 2.48 (s, 3H), 2.42-2.35 (m, 1H), 2.26-2.09 (m, 4H), 1.98-1.93 (m, 1H), 1.19 (d, J = 6.3 Hz, 3H), 0.96 (s, 9H).
(3R, 5S) -1-((S) -2-(2-(3-(4-(4-(3-(2,6-difluoro-3-(((R) -3-fluoropyrrolidin)) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazin-1-yl) azetidine-1-yl) acetamide) -3,3-dimethylbutanoyl) -5-((4- (4-Methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidine-3-yl 69-methyl-2,5,8,11,14,17,20,23,26,29, Illustrative Synthesis of 32,35,38,41,44,47,50,53,56,59,62,65,68-tricosaoxaheptacontane-70-acid acid (exemplary compound 802) Step 1: tert -Butyl 69-Methyl-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65, Preparation of 68-tricosaoxaheptacontane-70-acid salt.

PEG1000 (10 g, 10.00 mmol, 1.00 eq), tetrahydrofuran (100 mL) was placed in a 100 mL round bottom flask purged and maintained in an inert nitrogen atmosphere. Subsequently, sodium hydride (1.6 g, 66.67 mmol, 4.00 eq) was added in several portions at 0 ° C., and after stirring for 1 hour, tert-butyl 2-bromopropaneate (4.16 g, 19.90 mmol) was added thereto. , 2.00 eq) was added dropwise with stirring. The resulting solution was stirred at room temperature overnight. The reaction was then quenched by the addition of water / ice (100 mL). The resulting solution was extracted with ethyl acetate (200 mLx2) and the organic layers were combined into one. The residue was loaded into a silica gel column with dichloromethane / methanol (10/1). This resulted in 4.63 g of tert-butyl 69-methyl-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56. , 59,62,65,68-tricosaoxaheptacontane-70-acid salt was obtained as a colorless oil.

Step 2: 69-Methyl-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65 Preparation of 68-tricosaoxaheptacontane-70-acid.

A 250 mL round-bottom flask was charged with tert-butyl 2- (2-methoxyethoxy) propanoate (4.63 g, 4.10 mmol, 1.00 eq), dioxane (50 mL), hydrogen chloride (4M) (20 mL). The resulting solution was stirred at room temperature for 16 hours. The resulting mixture was concentrated under vacuum. This results in 4.0g (91%)
69-Methyl-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68 -Tricosaoxaheptacontan-70-acid was obtained as a bright yellow oil.

Step 3: (3R, 5S) -1-((S) -2- (2- (3- (4- (4- (3- (2,6-difluoro-3- (((R) -3-) -3-) Fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) azetidine-1-yl) acetamide) -3,3-dimethyl Butanoyl) -5-((4- (4-methylthiazole-5-yl) benzyl) carbamoyl) pyrrolidine-3-yl 69-methyl-2,5,8,11,14,17,20,23,26 , 29,32,35,38,41,44,47,50,53,56,59,62,65,68-Preparation of tricosaoxaheptacontane-70-acid salt.

In a 100 mL round bottom flask, (2S, 4R) -1-[(2S) -2- (2- [3- [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] azetidine-1-yl] acetamide )-3,3-dimethylbutanoyl] -4-hydroxy-N-[[4- (4-methyl-1,3-thiazole-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (300.0 mg, 0.27) mmol, 1.00 equivalent), dichloromethane (10 mL), 4-dimethylaminopyridine (165 mg, 1.35 mmol, 5.00 equivalent), 2- (2-methoxyethoxy) propanoic acid (581.0 mg, 0.54 mmol, 2.00 equivalent), 10 After stirring for minutes, EDCI (259.0 mg, 1.35 mmol, 5.00 equivalent) was added. The resulting solution was stirred at room temperature for 16 hours. Then DMAP was added and the mixture was further stirred for 16 hours. The resulting mixture was concentrated under vacuum. The resulting solution was extracted with ethyl acetate (150 mLx2) and the organic layers were combined into one. The resulting mixture was washed with brine (50 mLx2). The crude product was purified by preparative HPLC. This resulted in 122.8 mg (37%) of (3R, 5S) -1-((S) -2- (2- (3- (4- (4- (3- (2,6-difluoro-3- (). ((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) azetidine-1-yl) acetamide )-3,3-dimethylbutanoyl) -5-((4- (4-methylthiazole-5-yl) benzyl) carbamoyl) pyrrolidine-3-yl 69-methyl-2,5,8,11,14, 17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68-tricosaoxaheptacontane-70-acid salt yellow solid Got as. LC / MS (ESI) m / z: 2165.45 [M + 1] +; 1H-NMR (400MHz, CD3OD) δ 8.86 (s, 1H), 8.67 (s, 1H), 8.59 (d, J = 2.0Hz, 1H), 7.89 (s, 1H), 7.75-7.74 (m, 1H), 7.59 (d, J = 8.8Hz, 2H), 7.46-7.43 (m, 4H), 7.10-7.08 (m, 3H), 5.35 -5.15 (m, 2H), 4.56-4.54 (m, 3H), 4.38-4.34 (m, 1H), 4.23-4.13 (m, 2H), 3.90-3.80 (m, 2H), 3.63-3.44 (m, 3H) 89H), 3.34-3.31 (m, 6H), 3.29-3.16 (m, 11H), 2.56 (s, 4H), 2.48 (s, 3H), 2.30-2.25 (m, 1H), 2.20-2.10 (m, 2H), 1.36-1.34 (m, 3H), 1.05 (s, 9H).
(3R, 5S) -1-((S) -2-(2-(2-(4-(4-(3-(2,6-difluoro-3-(((R) -3-fluoropyrrolidine)) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) ethoxy) acetamide) -3,3-dimethylbutanoyl) -5-( (4- (4-Methylthiazole-5-yl) benzyl) carbamoyl) pyrrolidine-3-yl 2,5,8,11,14,17,20,23,26,29,32,35,38,41, Illustrative Synthesis of 44,47,50,53,56,59,62,65,68-Tricosaoxadoheptacontane-72-Atage (Exemplary Compound 803) Step 1: Preparation of 4-bromobutanoyl chloride.

A 250 mL round bottom flask was charged with 4-bromobutane acid (10.0 g, 59.88 mmol, 1.00 eq), dichloromethane (100 mL) and N, N-dimethylformamide (0.15 mL). Subsequently, thionyl chloride (8.5 mL) was added dropwise at 0 ° C. with stirring. The resulting solution was stirred at room temperature for 4 hours. The resulting mixture was concentrated under vacuum. This gave 11.08 g (100%) of 4-bromobutanoyl chloride as a bright yellow oil.

Step 2: Preparation of (3-methyloxetane-3-yl) methyl4-bromobutaneate.

A 250 mL round-bottom flask was charged with (3-methyloxetane-3-yl) methanol (6.14 g, 60.12 mmol, 1.00 eq), dichloromethane (100 mL), pyridine (5.70 g, 72.06 mmol, 1.20 eq). Subsequently, a solution of 4-bromobutanoyl chloride (11.08 g, 59.75 mmol, 0.99 eq) in dichloromethane (100 mL) was added dropwise at 0 ° C. with stirring. The resulting solution was stirred at room temperature for 16 hours. The resulting solution was extracted with dichloromethane (50 mLx2) and the organic layers were combined into one. The resulting mixture was washed with brine (10 mLx2). The mixture was dried over anhydrous sodium sulfate. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1/3). This gave 11.4 g (72%) of 5-bromo-1- [(3-methyloxetane-3-yl) methoxy] pentane-2-one as a bright yellow oil.

Step 3: Preparation of 1- (3-bromopropyl) -4-methyl-2,6,7-trioxabicyclo [2.2.2] octane.

5-bromo-1 ^-. [(3-methyl-oxetane-3-yl) methoxy] pentan-2-one (9.46g, 35.68mmol, 1 eq) in a solution of dichloromethane (40 mL) of, BF ₃ Et ₂ O ( 1.2 mL, 9.47 mmol, 0.265 equivalent)
Was added at 0 ° C. The reaction mixture was then stirred at 0 ° C. for 4 hours. The reaction was then quenched by the addition of _{5.7 mL Et 3 N.} The resulting mixture was stirred at room temperature for 15 minutes and then concentrated. The residue _{was dissolved in Et 2} O (100 mL), filtered and concentrated. The residue was applied on a _{basic Al 2} O ₃ column with dichloromethane / petroleum ether (1: 2). This gave 4.68 g (52.2%) of 1- (3-bromopropyl) -4-methyl-2,6,7-trioxabicyclo [2.2.2] octane as a colorless oil. 1H-NMR (300MHz, CDCl3) δ 3.89 (s, 6H), 3.48-3.42 (m, 2H), 2.06-1.99 (m, 2H), 1.83-1.80 (m, 2H), 0.80 (s, 3H).
Process 4: 1- (2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65, 68-Tricosaoxahen Henheptacontane-71-yl) -4-Methyl-2,6,7-Trioxabicyclo [2.2.2] Preparation of octane.

In a 30 mL closed tube, 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65- Docosaoxaheptahexacontan-67-ol (1.1967 g, 1.20 mmol, 1.500 eq), toluene (2 mL), t-BuOH (1.3 mL), t-BuOK (143.6 mg, 1.28 mmol, 1.606 eq), 1- ( 3-Bromopropyl) -4-methyl-2,6,7-trioxabicyclo [2.2.2] octane (200.1 mg, 0.80 mmol, 1 eq) was added. The obtained mixed solution was placed in an N2 atmosphere and stirred at 70 ° C. for 12 hours. The reaction mixture was cooled to room temperature. The mixture was filtered and the solvent was distilled under reduced pressure. The resulting solution was extracted with ethyl acetate (10 mLx4) and the organic layers were combined into one. The combined organic layers were washed with brine (10 mL x 2) and dried over anhydrous sodium sulfate. The obtained mixture was concentrated under vacuum and dried. This resulted in 657.5 mg (70.4%) of 4-methyl-1- (2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50). , 53,56,59,62,65,68-tricosaoxahenheptacontane-71-yl) -2,6,7-trioxabicyclo [2.2.2] Octane was obtained as a bright yellow semi-solid. ..

Process 5: 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68-Toriko Preparation of saoxadheptacontan-72-acid.

4-Methyl-1- (2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65 , 68-Tricosaoxahenheptacontane-71-yl) -2,6,7-Trioxavicyclo [2.2.2] Octane (657.5 mg, 0.56 mmol, 1 eq) in an aqueous solution (2 mL) with a pH of 1 H ₃ PO ₄ was added until. The reaction solution was stirred for 1 hour at room temperature. Then KOH was added to adjust the pH to 12. The resulting solution was stirred at room temperature for 17 hours and H ₃ PO ₄ was added again to adjust the pH to 3. The resulting mixture was extracted with dichloromethane (20 mLx4), the organic layers were combined and dried over anhydrous sodium sulfate. The residue was loaded into a silica gel column with dichloromethane / methanol (10: 1). As a result, 555.4mg (91.0%) of 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59, 62,65,68-tricosaoxadoheptacontan-72-acid was obtained as a bright yellow semi-solid.

Step 6: (3R, 5S) -1-((S) -2- (2- (2- (4- (4- (3- (2,6-difluoro-3- (((R) -3-) -3-) Fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) ethoxy) acetamide) -3,3-dimethylbutanoyl)- 5-((4- (4-Methylthiazole-5-yl) benzyl) carbamoyl) pyrrolidine-3-yl 2,5,8,11,14,17,20,23,26,29,32,35,38 , 41,44,47,50,53,56,59,62,65,68-Preparation of tricosaoxadoheptacontane-72-acid salt.

(2S, 4R) -1-[(2S) -2- (2- [2- [4- (4- [3-[(2,6-difluoro-3-[[(3R) -3-fluoropyrrolidine) -1-sulfonyl] amino] phenyl) carbonyl] -1H-pyrrolo [2,3-b] pyridine-5-yl] phenyl) piperazine-1-yl] ethoxy] acetamide) -3,3-dimethylbutanoyl (50.3) 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50 in a solution of dichloromethane (4 mL) in mg, 0.05 mmol, 1 equivalent) , 53,56,59,62,65,68-tricosaoxadoheptacontan-72-acid (74.6 mg, 0.07 mmol, 1.4 eq) and DMAP (17.0 mg, 0.14 mmol, 2.80 eq) were added. The mixture was stirred at room temperature for 10 minutes. EDCI (28.8 mg, 0.15 mmol, 3.0 eq) was then added to this. The reaction solution was stirred at room temperature for 1 hour. Additional 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68-Trico Saoki The above process was divided into three parts: sadheptacontan-72-acid (225 mg, 0.21 mmol, 4.1 eq), DMAP (55.1 mg, 0.45 mmol, 9.0 eq), and EDCI (87 mg, 0.45 mmol, 9.1 eq). Repeated three more times. Then DMAP (58.6 mg, 0.48 mmol, 9.6 eq) was added to this. The reaction solution was stirred for an additional 2 hours. Dichloromethane was removed under vacuum. The residue was extracted with ethyl acetate (30 mLx3). The resulting mixture was washed with saturated NH ₄ Cl (10 mL x 2). The mixture was dried over anhydrous sodium sulfate. The crude product was purified by preparative HPLC. This resulted in 16.6 mg (16.7%) of (3R, 5S) -1-((S) -2- (2- (2- (4- (4- (3- (2,6-difluoro-3-). ((R) -3-fluoropyrrolidine) -1-sulfonamide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-
Ill) phenyl) piperazine-1-yl) ethoxy) acetamide) -3,3-dimethylbutanoyl) -5-((4- (4-methylthiazole-5-yl) benzyl) carbamoyl) pyrrolidine-3-yl 2 , 5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68-tricosaoxadoheptacontane -72-Anate was obtained as a bright yellow oil. LC / MS (ESI) m / z: 2168.45 [M + 1] +; 1H-NMR (400MHz, CDCl3) δ 0.95 (s, 9H), 1.85-1.89 (m, 2H), 1.92-2.01 (m, 1H) ), 2.03-2.28 (m, 3H), 2.36-2.38 (m, 2H), 2.48 (s, 4H), 2.66-2.71 (m, 8H), 3.21-3.28 (m, 4H), 3.37 (s, 3H) ), 3.44-3.49 (m, 4H), 3.53-3.72 (m, 91H), 3.81-3.88 (m, 1H), 3.94-4.12 (m, 3H), 4.25-4.38 (m, 1H), 4.47-4.58 (m, 2H), 4.65-4.73 (m, 1H), 5.08-5.35 (m, 1H), 5.39 (s, 1H), 6.96-7.06 (m, 3H), 7.19-7.24 (m, 1H), 7.32 -7.39 (m, 5H), 7.52-7.55 (m, 2H), 7.65-7.79 (m, 2H), 8.57-8.58 (m, 1H), 8.66 (s, 1H), 8.81 (s, 1H).
(3R, 5S) -1-((S) -2- (2- (4- (4- (4- (4- (3- (2,6-difluoro-3- (((R) -3-fluoropyrrolidin)) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) piperidine-1-yl) acetamide) -3,3-dimethylbutanoyl) -5-(((S) -1- (4- (4-Methylthiazol-5-yl) phenyl) ethyl) carbamoyl) piperidine-3-yl 69-oxo-2,5,8,11,14,17 , 20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65-docosaoxa-68-azadoheptacontane-72-acid acid (exemplary compound 828) ) Exemplary Synthesis Step 1: Preparation of tert-butyl 4- (4- (4-bromophenyl) piperazine-1-yl) piperidine-1-carboxylate.

In a 250 mL round bottom flask, a solution of 1- (4-bromophenyl) piperazine hydrochloride (5.0 g, 18.0 mmol, 1.0 equivalent) in dichloromethane (10 ml), tert-butyl 4-oxopiperidine-1-carboxylate (4.9). g, 24.9 mmol, 1.4 equivalents), acetyl ethaneperoxoate; sodioboranyl acetate (13.2 g, 62.3 mmol, 3.5 equivalents) was added. The resulting solution was stirred at room temperature overnight. The reaction was then stopped by adding 1 mL of water / ice. The resulting solution was extracted with dichloromethane (20 mLx2), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1: 0). This gave 4.2 g (54%) of tert-butyl 4- [4- (4-bromophenyl) piperazin-1-yl] piperidine-1-carboxylate as a white solid. LC / MS (ESI) m / z: 426.10 [M + 1] ⁺ .
Step 2: Preparation of 1- (4-bromophenyl) -4- (piperidine-4-yl) piperazine hydrochloride.

A solution of tert-butyl 4- [4- (4-bromophenyl) piperazine-1-yl] piperidine-1-carboxylate (4.2 g, 9.8 mmol, 1.0 equivalent) in dichloromethane (10 ml) in a 100 mL round bottom flask. , Hydrogen chloride (5 ml) was added. The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum. This gave 3.0 g (85%) of 1- (4-bromophenyl) -4- (piperidine-4-yl) piperazine hydrochloride as a white solid. LC / MS (ESI) m / z: 325.95 [M + 1] ⁺ .
Step 3: Preparation of tert-butyl 2- (4- (4- (4-bromophenyl) piperazine-1-yl) piperidine-1-yl) acetate.

In a 100 mL round bottom flask, a solution of 1- (4-bromophenyl) -4- (piperidine-4-yl) piperazine hydrochloride (3.0 g, 8.3 mmol, 1.0 eq) in dichloromethane (10 ml), triethylamine (2.0 g, 19.8 mmol (2.4 eq), tert-butyl 2-bromoacetate (2.3 g, 11.8 mmol, 1.4 eq) were added. The resulting solution was stirred at room temperature overnight. The reaction was then stopped by adding 1 mL of water / ice. The resulting solution was extracted with dichloromethane (20 mLx2), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1: 0). This gave 2.0 g (53%) of tert-butyl 2- [4- [4- (4-bromophenyl) piperazin-1-yl] piperidine-1-yl] acetate as a white solid. LC / MS (ESI) m / z: 440.30 [M + 1] ⁺ .
Step 4: tert-butyl 2- (4- (4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-)
Preparation of yl) phenyl) piperazine-1-yl) piperidine-1-yl) acetate.

In a 20-30 mL closed tube, tert-butyl 2- [4- [4- (4-bromophenyl) piperazine-1-yl] piperidine-1-yl] acetate (2.0 g, 4.5 mmol, 1.0 eq) Dioxane (10 ml) solution, 4,4,5,5-
Tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolan (2.3 g, 9.1 mmol, 2.0 eq), KOAc ( 874.6 mg, 8.9 mmol, 2.0 eq) and Pd (dppf) Cl ₂ (700.6 mg, 0.9 mmol, 0.2 eq) were added. The resulting solution was stirred overnight in an oil bath at 85 ° C. The reaction was then stopped by adding 1 mL of water / ice. The resulting solution was extracted with ethyl acetate (20 mlx2), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1: 0). This resulted in 630.0 mg (29%) of tert-butyl 2- (4- [4- [4- (4, 4, 5, 5-)
Tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl] piperazine-1-yl] piperidine-1-yl) Acetate was obtained as a black solid. LC / MS (ESI) m / z: 486.25 [M + 1] ⁺ .
Step 5: tert--butyl (R) -2- (4- (4- (4- (3- (2,6-difluoro-3-((3-fluoropyrrolidin) -1-sulfonamide) benzoyl)-)- Preparation of 1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) piperidine-1-yl) acetate.

In a 20-30 mL closed tube, tert-butyl 2- (4- [4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine- 1-Il] piperidine-1-yl) acetate (630.0 mg, 1.3 mmol, 1.0 eq) in dioxane / H2O (4: 1 ml) solution, (3R) -N- (3-5-bromo-1H-pyrrolo [ 2,3-b]
Pyridine-3-carbonyl-2,4-difluorophenyl) -3-fluoropyrrolidin-1-sulfonamide (300.0 mg, 0.6 mmol, 0.5 eq), Pd (dppf) Cl ₂ (46.9 mg), sodium carbonate (99.2 mg) , 0.9 mmol, 0.7 eq). The resulting solution was stirred at 105 ° C. for 2 hours. The reaction was then quenched by the addition of 1 mL of water / ice. The resulting solution was extracted with ethyl acetate (20 mLx2), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded into a silica gel column with dichloromethane / methanol (10: 1). This resulted in 256.0 mg (25%) of tert-butyl 2- [4- [4- (4- [3- [2,6-difluoro-3- ([[(3R) -3-fluoropyrrolidine-1-). Ill] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazine-1-yl] piperidine-1-yl] acetate was obtained as a yellow solid. LC / MS (ESI) m / z: 782.05 [M + 1] ⁺ .
Step 6: (R) -2- (4- (4- (4- (3- (2,6-difluoro-3-((3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [ 2,3-b] Pyridine-5-yl) Phenyl) Piperazine-1-yl) Piperidine-1-yl) Preparation of acetic acid.

In a 100 mL round bottom flask, tert-butyl 2- [4- [4- (4- [3- [2,6-difluoro-3- ([[(3R) -3-)
Fluoropyrrolidine-1-yl] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazine-1-yl] piperidine-1-yl] acetate (256.0 mg, A solution of 0.3 mmol (1.0 eq) in dichloromethane (10 ml) and trifluoroacetic acid (2 ml) were added. The resulting solution was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum. This resulted in 120.0 mg (50%) of 2- [4- [4- (4- [3- [2,6-difluoro-3- ([[(3R) -3-fluoropyrrolidine-1-yl] sulfonyl] sulfonyl). ] <Amino) Benzoyl] -1H-pyrrolo [2,3-b] Pyridine-5-yl] Phenyl) Piperazine-1-yl] Piperidine-1-yl] Acetic acid was obtained as a yellow solid. LC / MS (ESI) m / z: 726.15 [M + 1] ⁺ .
Step 7: (2S, 4R) -1-((S) -2- (2- (4- (4- (4- (3- (2,6-difluoro-3- (((R) -3-) -3-) Fluoropyrrolidine) -1-sulfonamide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperazine-1-yl) Piperidine-1-yl) Acetamide) -3,3-dimethyl Preparation of butanoyl) -4-hydroxy-N-((S) -1-(4- (4-methylthiazole-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide.

2- [4- [4- (4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) in a 100 mL round bottom flask) Benzoyl] -1H-pyrrolidine [2,3-b] pyridine-5-yl] phenyl) piperazine-1-yl] piperidine-1-yl] N, N-dimethyl of acetic acid (120.0 mg, 0.3 mmol, 1.0 equivalent) Formamide (5 ml) solution, (2S, 4R) -1-[(2S) -2-amino-3,3-dimethylbutanoyl] -4-hydroxy-N-[(1S) -1- [4- (4) -Methyl-1,3-thiazol-5-yl) phenyl] ethyl] pyrrolidine-2-carboxamide (88.2 mg, 0.4 mmol, 1.2 equivalent), N, N-diisopropylethylamine (64.1 mg, 1.0 mmol, 3.0 equivalent), (Benzotriazole-1-yloxy) Tris (dimethylamino) phosphonium hexafluorophosphate (87.8 mg) was added. The resulting solution was stirred at room temperature for 1 hour. The reaction was then stopped by adding 1 mL of water / ice. The resulting solution was extracted with ethyl acetate (20 mLx2), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by preparative HPLC and 42.9 mg (23%) of (2S, 4R) -1-[(2S) -2- (2- [4- [4- (4- [3- [). 2,6-difluoro-3-([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazine -1-yl] piperidine-1-yl] acetamide) -3,3-dimethylbutanoyl] -4-hydroxy-N-[(1S) -1- [4- (4-methyl-1,3-thiazole-) 5-Il) Phenyl] ethyl] pyrrolidine-2-carboxamide was obtained as an off-white solid. LC / MS (ESI) m / z: 1152.20 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 12.87 (brs, 1H), 9.96 (brs, 1H), 8.96 (d, J = 2.1) Hz, 1H), 8.63 (d, J = 2.3 Hz, 1H), 8.51 (s, 1H), 8.40 (d, J = 7.6 Hz, 1H), 8.04 (s, 1H), 7.74 (d, J = 9.6) Hz, 1H), 7.70-7.60 (m, 3H), 7.47-7.42 (m, 2H), 7.40-7.31 (m, 2H), 7.23 (t, J = 8.9 Hz, 1H), 7.05 (d, J = 8.5 Hz, 2H), 5.36-5.15 (m, 1H), 5.19 (s, 1H), 4.88 (t, J = 7.1 Hz, 1H), 4.54-4.38 (m, 2H), 4.27-4.21 (m, 1H) ), 3.60-3.52 (m, 2H), 3.47-3.41 (m, 1H), 3.37-3.31 (m, 2H), 3.30-3.24 (m, 5H), 3.03 (d, J = 16.1 Hz, 1H), 2.89-2.80 (m, 3H), 2.70-2.55 (m, 5H), 2.34-2.03 (m, 7H), 1.87-1.72 (m, 3H), 1.47-1.37 (m, 6H), 0.93 (s, 9H) ).
Step 8: 4-(((3R, 5S) -1-((S) -2- (2- (4- (4- (4- (3- (2,6-difluoro-3- (((R) ) -3-Fluoropyrrolidine) -1-sulfonamide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperazine-1-yl) Piperidine-1-yl) Acetamide) -3 , 3-dimethylbutanoyl) -5-(((S) -1-(4- (4-methylthiazole-5-yl) phenyl) ethyl) carbamoyl) pyrrolidine-3-
Il) Oxy) Preparation of -4-oxobutanoic acid.

In a 50 mL round bottom flask purged and maintained in an inert nitrogen atmosphere, (2S, 4R) -1-[(2S) -2- (2- [4- [4- (4- [3- [2] , 6-difluoro-3-([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazine- 1-Il] piperidine-1-yl] acetamide) -3,3-dimethylbutanoyl] -4-hydroxy-N-[(1S) -1- [4- (4-methyl-1,3-thiazole-5) -Il) phenyl] ethyl] pyrrolidine-2-carboxamide (467 mg, 0.405 mmol, 1 equivalent), Et ₃ N (123.02 mg, 1.216 mmol, 3 equivalents), DMAP (148.53 mg, 1.216 mmol, 3 equivalents), oxorane- A solution of 2,5-dione (202.77 mg, 2.026 mmol, 5 equivalents) in dichloromethane (20 mL) was added. The resulting solution was stirred for 16 hours in an oil bath at 25 ° C. The reaction was then quenched by the addition of water / ice (10 mL). The resulting mixture was extracted with dichloromethane (40 mLx3), the organic layers were combined, _{washed with saturated NH 4} Cl solution (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. did. This resulted in 353 mg (69.55%) of 4-[[(3R, 5S) -1-[(2S) -2- (2- [4- [4- (4- [3- [2,6-difluoro- 3-([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazine-1-yl] piperidine -1-yl] acetamide) -3,3-dimethylbutanoyl] -5-[[(1S) -1- [4- (4-methyl-1,3-thiazole-5-yl) phenyl] ethyl] carbamoyl ] Pyrrolidine-3-yl] Oxy] -4-oxobutanoic acid was obtained as a yellow solid.

Step 9: 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65-docosaoxahepta Preparation of hexacontan-67-yl 4-methylbenzenesulfonate.

PEG1000-OMe (5.0 g, 5.00 mmol, 1.00 eq), TsCl (1.9 g, 9.97 mmol, 2.00 eq), triethylamine (1.01 g, 9.98 mmol, 2.00 eq), 4-dimethylaminopyridine in a 250 mL round bottom flask. (61.0 mg, 0.50 mmol, 0.10 eq) was added. The resulting solution was stirred at room temperature for 5 hours.
The resulting mixture was concentrated under vacuum. The residue was loaded into a silica gel column with dichloromethane / methanol (15/1). As a result, 7.47g of 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65- Docosaoxa Heptahexacontan -67-Il 4-
Methylbenzene sulfonate was obtained as a bright yellow solid.

Step 10: tert-butyl (tert-butoxycarbonyl) (2,5,8,11,14,17,20,23,26,29,32,35
, 38,41,44,47,50,53,56,59,62,65-docosaoxaheptahexacontan-67-yl) Preparation of carbamate.

In a 250 mL round bottom flask, 2-methoxyethyl 4-methylbenzene-1-sulfonate (7.47 g, 6.47 mmol, 1.00 eq), acetonitrile (150 mL), tert-butyl N-[(tert-butoxy) carbonyl] Carbamate (1.40 g, 6.44 mmol, 1.00 eq) and Cs ₂ CO ₃ (4.20 g, 12.89 mmol, 2.00 eq) were added. The resulting solution was stirred in an oil bath overnight at 50 ° C. The solids were filtered off. The resulting mixture was concentrated under vacuum. The residue was loaded into a silica gel column with dichloromethane / methanol (10/1). This resulted in 6.6 g (371%) of tert-butyl (tert-butoxycarbonyl) (2,5,8,11,14,17,20,23,26,29,32,35,38,41,44, 47,50,53,56,59,62,65-docosaoxaheptahexacontan-67-yl) carbamate was obtained as a bright yellow solid.

Step 11: 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65-docosaoxahepta Preparation of hexacontan-67-amine.

In a 250 mL round bottom flask, tert-butyl N-[(tert-butoxy) carbonyl] -N- (2-methoxyethyl) carbamate (6.6 g, 5.50 mmol, 1.00 eq), dioxane (60.0 mL), chloride. Hydrogen (4M) (60 mL) was added. The resulting solution was stirred at room temperature for 16 hours. The resulting mixture was concentrated under vacuum. As a result, 5.5g of 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65- Docosaoxaheptahexacontan-67-amine hydrochloride was obtained as a bright yellow solid.

Step 12: (3R, 5S) -1-((S) -2- (2- (4- (4- (4- (3- (2,6-difluoro-3- (((R) -3-) -3-) Fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) piperidine-1-yl) acetamide) -3,3-dimethyl Butanoyl) -5-(((S) -1- (4- (4-methylthiazole-5-yl) phenyl) ethyl) carbamoyl) pyrrolidine-3-yl 69-oxo-2,5,8,11, Preparation of 14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65-docosaoxa-68-azadoheptacontane-72-acid acid ..

In a 50 mL round bottom flask, 4-[[(3R, 5S) -1-[(2S) -2- (2- [4- [4- (4- [3- [2,6-difluoro-3-] ([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridine-5-yl] phenyl) piperazine-1-yl] piperidine-1 -Il] acetamide) -3,3-dimethylbutanoyl] -5-[[(1S) -1- [4- (4-methyl-1,3-thiazole-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine Add a solution of DMF (25 mL) of -3-yl] oxy] -4-oxobutanoic acid (333 mg, 0.266 mmol, 1 equivalent) to DIPEA (137.45 mg, 1.064 mmol, 4 equivalents), 2,5,8. , 11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65-docosaoxaheptahexacontan-67-amine (531.88) mg, 0.532 mmol, 2.00 equivalents) and BOP (176.39 mg, 0.399 mmol, 1.5 equivalents) were added. The resulting solution was stirred for 3 hours in an oil bath at 25 ° C. The reaction was then quenched by the addition of water / ice (30 mL). The resulting mixture was extracted with ethyl acetate (40 mLx3), the organic layers were combined, washed with brine (40 mLx2), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by preparative HPLC. This resulted in 207 mg (34.84%) of (3R, 5S) -1-[(2S) -2- (2- [4- [4- (4- [3- [2,6-difluoro-3- ([ [(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazine-1-yl] piperidine-1-yl ] Acetamide) -3,3-dimethylbutanoyl] -5-[[(1S) -1- [4- (4-methyl-1,3-thiazole-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-3 -Il 3-[(2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65- Docosaoxaheptahexacontan-67-yl) carbamoyl] propanoate was obtained as a yellow oil. LC / MS (ESI) m / z: 2234.68 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 9.01 (s, 1H), 8.75 (s, 1H), 8.65 (s, 1H), 7.95 (s, 1H), 7.78-7.70 (m, 3H), 7.50-7.44 (m, 4H), 7.24-7.17 (m, 3H), 5.32 (s, 2H), 5.19 (s, 1H), 5.06- 5.04 (m, 1H), 4.89 (s, 1H), 4.60-4.58 (m, 1H), 4.41-4.32 (m, 2H), 4.30 (s, 5H), 4.14-4.10 (m, 91H), 3.83- 3.81 (m, 7H), 3.64-3.63 (m, 5H), 3.56-3.33 (m, 4H), 2.76 (s, 1H), 2.67-2.42 (m, 4H), 2.37-2.34 (m, 4H), 2.21 (m, 3H), 2.16-2.13 (m, 3H), 1.55-1.53 (m, 3H), 1.11-1.08 (m, 9H).
(3R, 5S) -1-((S) -2- (2- (4-((1- (4- (3- (2,6-difluoro-3- (((R) -3-fluoropyrolidin) ) -1-sulfonamide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperidine-4-yl) Methyl) Piperazine-1-yl) Acetamide) -3,3-dimethyl Butanoyl) -5-((4- (4-methylthiazole-5-yl) benzyl) carbamoyl) piperidine-3-yl 68-methyl-69-oxo-2,5,8,11,14,17,20 , 23,26,29,32,35,38,41,44,47,50,53,56,59,62,65-docosaoxa-68-azadoheptacontane-72-acid acid (exemplary compound 816) Exemplary Synthesis Step 1: (2S, 4R) -1-((S) -2- (2- (4-((1- (4- (3- (2,6-difluoro-3- (((R) ) -3-Fluoropyrrolidin) -1-sulfonamide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperidine-4-yl) Methyl) Piperazin-1-yl) Acetamide) Preparation of -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) piperidine-2-carboxamide.

2-(4-[[1- (4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidine-1-yl] sulfonyl] amino] in a 100 mL round bottom flask ) Benzoyl] -1H-pyrrolidine [2,3-b] pyridine-5-yl] phenyl) piperidine-4-yl] methyl] piperazine-1-yl) acetic acid (500.0 mg, 0.67 mmol, 1 equivalent), (2S) , 4R) -1-[(2S) -2-amino-3,3-dimethylbutanoyl] -4-hydroxy-N-[[4- (4-methyl-1,3-thiazole-5-yl) phenyl ] Methyl] Pyrrolidine-2-carboxamide (290.0 mg, 0.67 mmol, 1.00 equivalent), DIEA (345.0 mg, 2.68 mmol, 4.0 equivalent), BOP (450.0 mg, 1.01 mmol, 1.51 equivalent) in DMF (15 mL) solution. I put it in. The reaction was stirred at room temperature for 3 hours and then quenched by the addition of 50 mL of water. The resulting mixture was extracted with ethyl acetate (50 mLx2). The mixed organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by preparative HPLC. This resulted in 193 mg of (2S, 4R) -1-[(2S) -2- [2- (4-[[1- (4- [3- [2,6-difluoro-3- ([[(3R). ) -3-Fluoropyrrolidin-1-yl] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperidine-4-yl] methyl] piperazin-1-yl) Acetamide] -3,3-dimethylbutanoyl] -4-hydroxy-N-[[4- (4-methyl-1,3-thiazole-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide off-white Obtained as a solid substance. LC / MS (ESI) m / z: 1152.45 [M + 1] +; 1H-NMR (300MHz, CD3OD) δ 12.90 (brs, 1H), 9.85 (brs, 1H), 8.98 (s, 1H), 8.67- 8.60 (m, 2H), 8.60-8.48 (m, 1H), 8.07 (s, 1H), 7.85-7.76 (m, 1H), 7.68-7.56 (m, 3H), 7.50-7.38 (m, 4H), 7.30-7.22 (m, 1H), 7.12-7.00 (m, 2H), 5.40-5.20 (m, 1H), 5.14 (s, 1H), 4.57-4.47 (m, 1H), 4.47-4.32 (m, 3H) ), 4.31-4.22 (m, 1H), 3.83-3.70 (m, 2H), 3.70-3.57 (m, 2H), 3.52-3.45 (m, 1H), 3.44-3.35 (m, 2H), 3.31-3.23 (m, 1H), 3.14-2.87 (m, 2H), 2.87-2.67 (m, 2H), 2.63-2.52 (m, 4H), 2.49-2.38 (m, 7H), 2.23-2.14 (m, 2H) , 2.14-1.89 (m, 4H), 1.83-1.62 (m, 3H), 1.87-1.12 (m, 2H), 1.00-0.92 (m, 9H).
Step 2: 4-(((3R, 5S) -1-((S) -2- (2- (4-((1- (4- (3- (2,6-difluoro-3- (((() R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperidine-4-yl) methyl) piperazin-1-yl) acetamide )-3,3-Dimethylbutanoyl) -5-((4- (4-Methylthiazole-5-yl) benzyl) carbamoyl) pyrrolidine-3-yl) oxy) -4-oxobutanoic acid preparation.

In a 30 mL closed tube, (2S, 4R) -1-[(2S) -2- [2- (4-[[1- (4- [3- [2,6-difluoro-3- ([[( 3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperidine-4-yl] methyl] piperazin-1-yl ) Acetamide] -3,3-dimethylbutanoyl] -4-hydroxy-N-[[4- (4-methyl-1,3-thiazole-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (576.2 mg) , 0.50 mmol, 1 equivalent), Et ₃ N (0.14 mL, 1.01 mmol, 2.01 equivalent), DMAP (183.3 mg, 1.50 mmol, 3.00 equivalent), dichloromethane (16 mL), tetrahydrofuran (4 mL). The mixture was stirred at room temperature for 10 minutes, followed by the addition of oxolane-2,5-dione (250.3 mg, 2.50 mmol, 5.00 eq). The obtained mixed solution was reacted with stirring for another 16 hours while maintaining the temperature at 35 ° C. in an oil tank. The resulting mixture was diluted with dichloromethane (300 mL _{) and washed with NH 4} Cl (200 mlx2). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting mixture was concentrated under vacuum. This resulted in 620 mg (99.00%) of 4-[[(3R, 5S) -1-[(2S) -2- [2- (4- [[1- (4- [3- [2,6-difluoro). -3-([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperidine-4-yl] Methyl] piperazine-1-yl) acetamide] -3,3-dimethylbutanoyl] -5-([[4- (4-methyl-1,3-thiazole-5-yl) phenyl] methyl] carbamoyl) pyrrolidine- 3-Il] oxy] -4-oxobutanoic acid was obtained as a dark yellow solid. LC / MS (ESI) m / z: 1252.20 [M + 1] ⁺ .
Step 3: 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65-docosaoxahepta Preparation of hexacontan-67-yl 4-methylbenzenesulfonate.

In a 250 mL round bottom flask, 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65 -Docosaoxaheptahexacontan-67-ol (5 g, 4.99 mmol, 1 eq), Et ₃ N (1.39 mL, 10.00 mmol, 2.00 eq), DMAP (61 mg, 0.50 mmol, 0.10 eq), DCM (50 mL), TsCl (1.91 g, 10.02 mmol, 2.01 eq) was added. The resulting solution was stirred for 4 hours in an oil bath at 35 ° C. The resulting mixture was concentrated under vacuum. The residue was loaded into a silica gel column with dichloromethane / methanol (23: 2). As a result, 5.73g (99.31%) of 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59, 62,65-docosaoxaheptahexacontan-67-yl 4-methylbenzene-1-sulfonate was obtained as a white semi-solid. LC / MS (ESI) m / z: 578.30 [M / 2 + 1] ⁺ .
Step 4: N-Methyl-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65 -Preparation of docosaoxaheptahexacontan-67-amine.

2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50 in a 30 mL closed tube purged and maintained in an inert nitrogen atmosphere , 53,56,59,62,65-docosaoxaheptahexacontan-67-yl 4-methylbenzene-1-sulfonate (1.155 g, 1.00 mmol, 1 equivalent), methaneamine hydrochloride (337.5 mg, 5.00 mmol) , 5.00 eq), K ₂ CO ₃ (552.8 mg, 4.00 mmol, 4.00 eq), dioxane (20 mL) was added. The obtained mixed solution was stirred in an oil tank at 70 ° C. for 16 hours. The reaction mixture was cooled to room temperature and combined into one. The mixture was diluted with water (200 mL). The resulting solution was extracted with dichloromethane (200 mLx2), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. As a result, 2.02g (99.61%) of 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59, 62,65-docosaoxa-68-Azanonahexacontane was obtained as a bright yellow semi-solid. LC / MS (ESI) m / z: 507.70 [M / 2 + 1] ⁺ .
Step 5: (3R, 5S) -1-((S) -2- (2-(4-((1- (4- (3- (2,6-difluoro-3- (((R) -3) -3) -Fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperidine-4-yl) methyl) piperazin-1-yl) acetamide) -3, 3-dimethylbutanoyl) -5-((4- (4-methylthiazole-5-yl) benzyl) carbamoyl) pyrrolidine-3-yl 68-methyl-69-oxo-2,5,8,11,14, Preparation of 17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65-docosaoxa-68-azadoheptacontane-72-acid.

In a 100 mL round bottom flask, 4-[[(3R, 5S) -1-[(2S) -2- [2- (4- [[1- (4- [3- [2,6-difluoro-3) -([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridine-5-yl] phenyl) piperidine-4-yl] methyl] Piperazine-1-yl) acetamide] -3,3-dimethylbutanoyl] -5-([[4- (4-methyl-1,3-thiazole-5-yl) phenyl] methyl] carbamoyl) pyrrolidine-3- Il] Oxy] -4-oxobutanoic acid (300 mg, 0.24 mmol, 1 equivalent), 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47 , 50,53,56,59,62,65-docosaoxa-68-azanonahexacontane (971.8 mg, 0.96 mmol, 4.00 equivalent), DIEA (123.8 mg, 0.96 mmol, 4.00 equivalent), BOP (211.8 mg, 0.48 equivalent) A solution of mmol, 2.00 equivalents) and DMF (8 mL) was added. The resulting solution was stirred at room temperature for 2 hours. The resulting solution was diluted with water (400 mL) and extracted with EtOAc / THF (10/1, 400 mLx3) to combine the organic layers into one. The organic layer was washed with brine (400 mLx2), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by preparative HPLC. This resulted in 87.7 mg (16.28%) of (3R, 5S) -1-[(2S) -2- [2- (4- [[1- (4- [3- [2,6-difluoro-3-]. ([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperidine-4-yl] methyl] piperazine -1-yl) acetamide] -3,3-dimethylbutanoyl] -5-([[4- (4-methyl-1,3-thiazole-5-yl) phenyl] methyl
] Carbamoyl) Pyrrolidine-3-yl 3-[(2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56, 59,62,65-docosaoxaheptahexacontan-67-yl) (methyl) carbamoyl] propanoate was obtained as a yellow semi-solid. LC / MS (ESI) m / z: 2248.5 [M + 1] +; 1H-NMR (400MHz, D2O) δ 9.69 (s, 1H), 8.44-8.36 (m, 2H), 7.79 (s, 1H), 7.59-7.55 (m, 5H), 7.42-7.37 (m, 4H), 7.05-7.00 (m, 1H), 5.34 (s, 1H), 5.20 (d, J = 52.4 Hz, 1H), 4.55-4.51 ( m, 1H), 4.41-4.38 (m, 3H), 4.11-4.03 (m, 3H), 3.90-3.88 (m, 1H), 3.37-3.46 (m, 102H), 3.40-3.27 (m, 6H), 3.01-2.99 (m, 2H), 2.84-2.57 (m, 6H), 2.47-2.41 (m, 6H), 2.22-2.06 (m, 5H), 1.98-1.83 (m, 3H), 0.92 (s, 9H) ).
(R) -2-((2S, 4R) -1-((S) -2- (2-(4-((4- (3- (2,6-difluoro-3- (((() R) -3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridine-5-yl) phenyl) piperidine-1-yl) methyl) piperidin-1-yl) acetamide ) -3,3-Dimethylbutanoyl) -4-Hydroxypyridine-2-carboxamide) -2- (4- (4-Methylthiazole-5-yl) phenyl) Ethyl 69-oxo-2,5,8,11 , 14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65-docosaoxa-68-azadoheptacontan-72-acid acid ( Exemplary Synthesis of Exemplary Compound 827) Step 1: benzyl (2S, 4R) -1-[(2S) -2-[[(tert-butoxy) carbonyl] amino] -3,3-dimethylbutanoyl] -4 -Preparation of hydroxypyrrolidin-2-carboxylate.

In a 250 mL round-bottom flask, N, N-dimethylformamide (8.5 g, 36.75 mmol, 1.00 eq) of (2S) -2-{[(tert-butoxy) carbonyl] amino} -3,3-dimethylbutanoic acid (8.5 g, 36.75 mmol, 1.00 eq) 100 mL) of solution was added. Following this, HATU (15.5 g, 40.76 mmol, 1.10 eq) was added in several batches at 0 ° C.
DIEA (14.24 g, 110.40 mmol, 3.00 eq) was then added. The resulting mixture was stirred at 0 ° C. for 20 minutes, then N, N- of benzyl (2S, 4R) -4-hydroxypyrrolidin-2-carboxylate hydrochloride (9.5 g, 36.86 mmol, 1.00 eq). A solution of dimethylformamide (20 mL) was added dropwise at 0 ° C. The reaction mixture was stirred at room temperature for 1 hour and then quenched by the addition of water (500 mL). The obtained mixture was extracted with ethyl acetate (100 mLx3). The organic layers were combined into one, washed with water (100 mLx2) and brine (100 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied on a silica gel column and eluted with ethyl acetate / petroleum ether (1: 2). This resulted in 11.6 g (72%) of benzyl (2S, 4R) -1-[(2S) -2-[[(tert-butoxy) carbonyl] amino] -3,3-dimethylbutanoyl] -4-hydroxy. Pyrrolidine-2-carboxylate was obtained as a bright yellow solid. LC / MS (ESI) m / z: 435.15 [M + 1] ⁺ .
Step 2: Benzyl (2S, 4R) -1-[(2S) -2-[[(tert-butoxy) carbonyl] amino] -3,3-dimethylbutanoyl] -4-[(tert-butyldimethylsilyl) Preparation of oxy] pyrrolidine-2-carboxylate.

In a 150 mL round bottom flask, benzyl (2S, 4R) -1-[(2S) -2-[[(tert-butoxy) carbonyl] amino] -3,3-dimethylbutanoyl] -4-hydroxypyrrolidin-2 -Carboxylate (7 g, 16.11 mmol, 1.00 eq), imidazole (1.6 g, 23.51 mmol, 1.46 eq) dichloromethane (80 mL)
The solution was added at 0 ° C. This was followed by the addition of TBDMSCl (3.6 g, 23.89 mmol, 1.48 eq) at 0 ° C. in several batches. The resulting solution was stirred at room temperature for 6 hours. The reaction was then quenched by the addition of water (60 mL). The resulting mixture was extracted with dichloromethane (50 mL x 3), the organic layers were combined, washed with brine (100 mL x 2), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied on a silica gel column and eluted with ethyl acetate / petroleum ether (1: 9). This resulted in 5.8 g (66%) of benzyl (2S, 4R) -1-[(2S) -2-[[(tert-butoxy) carbonyl] amino] -3,3-dimethylbutanoyl] -4- [ (tert-Butyldimethylsilyl) oxy] pyrrolidine-2-carboxylate was obtained as a bright yellow oil. LC / MS (ESI) m / z: 549.20 [M + 1] ⁺ .
Step 3: (2S, 4R) -1-[(2S) -2-[[(tert-butoxy) carbonyl] amino] -3,3-dimethylbutanoyl] -4-[(tert-butyldimethylsilyl) oxy ] Preparation of pyrrolidine-2-carboxylic acid.

In a 50 ml round bottom flask, benzyl (2S, 4R) -1-[(2S) -2-[[(tert-butoxy) carbonyl] amino] -3,3-dimethylbutanoyl] -4-[(tert- Pd / C (10%, 100 mg) was added to a solution of butyldimethylsilyl) oxy] pyrrolidine-2-carboxylate (500 mg, 0.91 mmol, 1.00 eq) in methanol (15 mL) under a nitrogen atmosphere. The flask was then evacuated and flushed with hydrogen. The reaction mixture was hydrogenated at room temperature for 16 hours in a hydrogen atmosphere using a hydrogen balloon, then filtered through a Celite bed and concentrated under reduced pressure. This resulted in 273 mg (65%) of (2S, 4R) -1-[(2S) -2-[[(tert-butoxy) carbonyl] amino] -3,3-dimethylbutanoyl] -4-[(tert). -Butyldimethylsilyl) oxy] Pyrrolidine-2-carboxylic acid was obtained as a colorless oil. LC / MS (ESI) m / z: 459.30 [M + 1] ⁺ .
Step 4: tert-butyl N-[(2S) -1-[(2S, 4R) -4-[(tert-butyldimethylsilyl) oxy] -2-[[(1R) -2-hydroxy-1-[ Preparation of 4- (4-methyl-1,3-thiazole-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-yl] -3,3-dimethyl-1-oxobutan-2-yl] carbamate.

In a 25 mL round bottom flask, (2S, 4R) -1-[(2S) -2-[[(tert-butoxy) carbonyl] amino] -3,
3-Dimethylbutanoyl] -4-[(tert-butyldimethylsilyl) oxy] pyrrolidine-2-carboxylic acid (930 mg, 1 equivalent), (2R) -2-amino-2- [4- (4-methyl-) A solution of 1,3-thiazole-5-yl) phenyl] ethane-1-ol hydrochloride (550 mg), HATU (930 mg) and DIEA (1 g) in DMF (5 mL) was added. The resulting solution was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (50 mLx3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was applied on a silica gel column and eluted with ethyl acetate / petroleum ether (1: 0). This resulted in 460 mg of tert-butyl N-[(2S) -1-[(2S, 4R) -4-[(tert-butyldimethylsilyl) oxy] -2-[[(1R) -2-hydroxy-1). -[4- (4-Methyl-1,3-thiazole-5-yl) phenyl]
Ethyl] carbamoyl] pyrrolidine-1-yl] -3,3-dimethyl-1-oxobutane-2-yl] carbamate was obtained as a bright yellow oil. LC / MS (ESI) m / z: 675.20 [M + 1] ⁺ .
Step 5: 4-[(2R) -2-[[(2S, 4R) -1-[(2S) -2-[[(tert-butoxy) carbonyl] amino] -3,3-
Dimethylbutanoyl] -4-[(tert-butyldimethylsilyl) oxy] pyrrolidine-2-yl] formamide] -2- [4- (4-methyl-1,3-thiazole-5-yl) phenyl] ethoxy] Preparation of -4-oxobutanoic acid.

In a 50 mL round bottom flask, tert-butyl N-[(2S) -1-[(2S, 4R) -4-[(tert-butyldimethylsilyl) oxy] -2-[[(1R) -2-hydroxy) -1- [4- (4-Methyl-1,3-thiazole-5-yl) phenyl] ethyl] carbamoyl] pyrrolidine-1-yl] -3,3-dimethyl-1-oxobutane-2-yl] carbamic acid A solution of salt (840 mg, 1.24 mmol, 1 equivalent), oxorane-2,5-dione (623 mg, 6.23 mmol, 5.00 equivalent) and triethylamine (380 mg, 3.76 mmol, 3.02 equivalent) in dichloromethane (20 mL) was added. This was followed by the addition of DMAP (460 mg, 3.77 mmol, 3.03 eq) in several batches at room temperature. The resulting solution was stirred at room temperature for 16 hours. The mixture was diluted with water (30 mL) and extracted with dichloromethane (25 mLx3). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate and concentrated. The residue was loaded into a silica gel column with dichloromethane / methanol (10: 1). This resulted in 800 mg (82.94%) of 4-[(2R) -2-[[(2S, 4R) -1-[(2S) -2-[[(tert-butoxy) carbonyl] amino] -3,3. -Dimethylbutanoyl] -4-[(tert-butyldimethylsilyl) oxy] pyrrolidine-2-yl] formamide] -2- [4- (4-methyl-1,3-thiazole-5-yl) phenyl] ethoxy ] -4-oxobutanoic acid was obtained as a bright yellow oil. LC / MS (ESI) m / z: 775.25 [M + 1] ⁺ .
Step 6: (2R) -2-[[(2S, 4R) -1-[(2S) -2-[[(tert-butoxy) carbonyl] amino] -3,3-dimethylbutanoyl] -4- [ (tert-Butyldimethylsilyl) Oxy] Pyrrolidine-2-yl] Formamide] -2- [4- (4-Methyl-1,3-thiazole-5-yl) Phenyl] Ethyl 3-[(2,5,8) , 11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65-docosaoxaheptahexacontan-67-yl) carbamoyl ] Preparation of propanoate.

In a 50 mL round bottom flask, 4-[(2R) -2-[[(2S, 4R) -1-[(2S) -2-[[(tert-butoxy) carbonyl] amino] -3,3-dimethyl Butanoyl] -4-[(tert-butyldimethylsilyl) oxy] pyrrolidine-2-yl] formamide] -2- [4- (4-methyl-1,3-thiazole-5-yl) phenyl] ethoxy]- 4-oxobutanoic acid (800 mg, 1.03 mmol, 1 equivalent), 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53, 56,59,62,65-docosaoxaheptahexacontan-67-amine hydrochloride (2.1 g)
, 2.03 mmol, 1.96 eq), DIEA (540 mg, 4.18 mmol, 4.05 eq) in a solution of DMF (10 mL). This was followed by the addition of BOP (900 mg, 2.03 mmol, 1.97 eq) at room temperature. The resulting solution was stirred at room temperature for 2 hours. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mLx3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated. The residue was loaded into a silica gel column with dichloromethane / methanol (10: 1). This resulted in 1.8 g (99.24%) of (2R) -2-[[(2S, 4R) -1-[(2S) -2-[[(tert-butoxy) carbonyl] amino] -3,3-dimethyl. Butanoyl] -4-[(tert-butyldimethylsilyl) oxy] pyrrolidine-2-yl] formamide] -2- [4- (4-methyl-1,3-thiazole-5-yl) phenyl] ethyl 3- [(2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65-docosaoxaheptahexacon Tan-67-yl) carbamoyl] propanoate was obtained as a yellow oil.

Step 7: (2R) -2-[[(2S, 4R) -1-[(2S) -2-amino-3,3-dimethylbutanoyl] -4-hydroxypyrrolidine-2-yl] formamide] -2 -[4- (4-Methyl-1,3-thiazole-5-yl) phenyl] ethyl 3-[(2,5,8,11,14,17,20,23,26,29,32,35, 38,41,44,47,50,53,56,59,62,65-docosaoxaheptahexacontan-67-yl) Carbamoyl] Preparation of propanoate.

In a 100 mL round bottom flask, (2R) -2-[[(2S, 4R) -1-[(2S) -2-[[(tert-butoxy) carbonyl] amino] -3,3-dimethylbutanoyl] -4-[(tert-butyldimethylsilyl) oxy] pyrrolidine-2-yl] formamide] -2- [4- (4-methyl-1,3-thiazole-5-yl) phenyl] ethyl 3-[(2) , 5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65-docosaoxaheptahexacontan-67 -Il) Carbamoyl] A solution of dioxane (20 mL) of propanoate (1.8 g, 1.02 mmol, 1 equivalent) was added. To the above, HCl / dioxane (20 mL, 4 mol / L) was added. The obtained solution was stirred at room temperature for 1 hour in a hydrochloric acid gas atmosphere. The mixture was concentrated. As a result, 1.6 g (98.90%) of (2R) -2-[[(2S, 4R) -1-[(2S) -2-amino-3,3-dimethylbutanoyl] -4-hydroxypyrrolidine-2) -Il] formamide] -2- [4- (4-methyl-1,3-thiazole-5-yl) phenyl] ethyl 3-[(2,5,8,11,14,17,20,23,26) , 29,32,35,38,41,44,47,50,53,56,59,62,65-docosaoxaheptahexacontan-67-yl) carbamoyl] Proanoate was obtained as a yellow oil. LC / MS (ESI) m / z: 772.30 [M / 2 + 1] ⁺ .
Step 8: (R) -2-((2S, 4R) -1-((S) -2- (2- (4-((4- (4- (3- (2,6-difluoro-3-) (((R) -3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) methyl) piperidine-1- Il) Acetamide) -3,3-dimethylbutanoyl) -4-hydroxypyridine-2-carboxamide) -2- (4- (4-Methylthiazole-5-yl) phenyl) ethyl 69-oxo-2,5, 8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65-docosaoxa-68-azadoheptacontan-72- Preparation of acid salt.

In a 25 mL round bottom flask, 2- (4-[[4- (4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino] ) Benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazine-1-yl] methyl] piperidine-1-yl) acetic acid (280 mg, 0.378 mmol, 1 equivalent), (2R) -2-[[(2S, 4R) -1-[(2S) -2-amino-3,3-dimethylbutanoyl] -4-hydroxypyrridine-2-yl] formamide] -2- [4- (4) -Methyl-1,3-thiazole-5-yl) phenyl] ethyl 3-[(2,5,8,11,14,17,20,23,26,29,32,35,38,41,44, 47,50,53,56,59,62,65-docosaoxaheptahexacontane-67-yl) carbamoyl] propanoate hydrochloride (600 mg, 0.380 mmol, 1.00 equivalent), DIEA (200 mg, 1.547 mmol, 4.09 equivalent) ) DMF (6 mL) solution was added. This was followed by the addition of BOP (330 mg, 0.746 mmol, 1.97 eq) at room temperature. The resulting solution was stirred at room temperature for 2 hours and then concentrated. The crude product was purified by preparative HPLC and 114.6 mg (13.37%) of (R) -2-((2S, 4R) -1-((S) -2- (2- (4-((4)). -(4- (3- (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridine-5- Il) phenyl) piperazine-1-yl) methyl) piperidine-1-yl) acetamide) -3,3-dimethylbutanoyl) -4-hydroxypyrrolidine-2-carboxamide) -2- (4- (4-methylthiazole) -5-yl) phenyl) ethyl 69-oxo-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56, 59,62,65-docosaoxa-68-azadoheptacontane-72-ate was obtained as a yellow oil. LC / MS (ESI) m / z: 2264.7 [M + 1] +; 1H-NMR (300MHz, CD3OD) δ 8.89 (s, 1H), 8.69 (s, 1H), 8.60 (s, 1H),
7.89 (s, 1H), 7.76-7.74 (m, 1H), 7.62 (d, J = 9Hz, 2H), 7.48-7.45 (m, 4H), 7.14-7.11 (m, 3H), 5.32-5.14 (m) , 2H), 4.64-4.63 (m, 2H), 4.46-4.44 (m, 2H), 4.37-4.32 (m, 1H), 3.88-3.84 (m, 3H), 3.68-3.51 (m, 109H), 3.47 -3.36 (m, 5H), 3.14 (s, 2H), 3.01-2.97 (m, 2H), 2.75-2.66 (m, 7H), 2.54-2.42 (m, 7H), 2.37-2.10 (m, 5H) , 1.96-1.85 (m, 4H), 1.75-1.70 (m, 1H), 1.46-1.33 (m, 2H), 1.06-1.04 (m, 9H).
(R) -2-((2S, 4R) -1-((S) -2- (2-(4-((4- (3- (2,6-difluoro-3- (((() R) -3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperidine-1-yl) methyl) piperidine-1-yl) acetamide ) -3,3-dimethylbutanoyl) -4-hydroxypyrrolidin-2-carboxamide) -2- (4- (4-methylthiazole-5-yl) phenyl) ethyl 68-methyl-69-oxo-2,5 , 8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65-docosaoxa-68-azadoheptacontan-72 -Exemplary synthesis of acid acid (exemplary compound 842).

Step 1: (2R) -2-[[(2S, 4R) -1-[(2S) -2-[[(tert-butoxy) carbonyl] amino] -3,3-dimethylbutanoyl] -4- [ (tert-butyldimethylsilyl) oxy] pyrrolidine-2-yl] formamide] -2- [4- (4-methyl-1,3-thiazole-5-yl) phenyl] ethyl 3-[(2,5,8) , 11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59, 62,65-docosaoxaheptahexacontan-67-yl) ( Preparation of methyl) carbamoyl] propanoate.

In a 100 mL round bottom flask, 4-[(2R) -2-[[(2S, 4R) -1-[(2S) -2-[[(tert-butoxy) carbonyl] amino] -3,3-dimethyl Butanoyl] -4-[(tert-butyldimethylsilyl) oxy] pyrrolidine-2-yl] formamide] -2- [4- (4-methyl-1,3-thiazole-5-yl) phenyl] ethoxy]- 4-oxobutanoic acid (1.11 g, 1.432 mmol, 1.00 eq), 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53 , 56,59,62,65-docosaoxa-68-azanonahexacontane (1.45 g, 1.430 mmol, 1 eq), DIEA (0.37 g, 2.863 mmol, 2.00 eq), BOP (0.76 g, 1.718 mmol, 1.20 eq) ) DMF (50 mL) solution was added. The obtained mixture was stirred at room temperature for 1 hour. The mixture was then diluted with 50 mL of water and extracted with dichloromethane (100 mLx2). The organic layers were combined and concentrated under reduced pressure. The residue was applied on a silica gel column and eluted with dichloromethane / methanol (10: 1). As a result, 1.56 g (61.60%) of (2R) -2-[[(2S, 4R) -1-[(2S) -2-[[(tert-butoxy) carbonyl] amino] -3,3-dimethyl Butanoyl] -4-[(tert-butyldimethylsilyl) oxy] pyrrolidine-2-yl] formamide] -2- [4- (4-methyl-1,3-thiazole-5-yl) phenyl] ethyl 3- [(2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59, 62,65-docosaoxaheptahexacon Tan-67-yl) (methyl) carbamoyl] propanoate was obtained as a white solid.

Step 2: (2R) -2-[[(2S, 4R) -1-[(2S) -2-amino-3,3-dimethylbutanoyl] -4-hydroxypyrrolidine-2-yl] formamide] -2 -[4- (4-Methyl-1,3-thiazole-5-yl) phenyl] ethyl 3-[(2,5,8,11,14,17,20,23,26,29,32,35, 38,41,44,47,50,53,56,59,62,65-docosaoxaheptahexacontan-67-yl) (methyl) carbamoyl] Preparation of hydrochloride hydrochloride.

In a 100 mL round bottom flask, (2R) -2-[[(2S, 4R) -1-[(2S) -2-[[(tert-butoxy) carbonyl] amino] -3,3-dimethylbutanoyl] -4-[(tert-butyldimethylsilyl) oxy] pyrrolidine-2-yl] formamide] -2- [4- (4-methyl-1,3-thiazole-5-yl) phenyl] ethyl 3-[(2) , 5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65-docosaoxaheptahexacontan-67 -Il) (methyl) carbamoyl] A solution of 50 mL of dioxane of propanoate (1.0 g, 0.565 mmol, 1 equivalent) was added. This was followed by the addition of a 1,4-dioxane solution of hydrogen chloride (4.0 M, 10 mL). The resulting mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. This resulted in 850.0 mg (94.49%) of (2R) -2-[[(2S, 4R) -1-[(2S) -2-amino-3,3-dimethylbutanoyl] -4-hydroxypyrrolidin-2). -Il] formamide] -2- [4- (4-methyl-1,3-thiazole-5-yl) phenyl] ethyl 3-[(2,5,8,11,14,17,20,23,26) , 29,32,35,38,41,44,47,50,53,56,59,62,65-docosaoxaheptahexacontan-67-yl) (methyl) carbamoyl] Propanate hydrochloride is colorless Obtained as an oil.

Step 3: (R) -2-((2S, 4R) -1-((S) -2- (2- (4-((4- (4- (3- (2,6-difluoro-3-) (((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) methyl) piperidine-1- Il) Acetamide) -3,3-dimethylbutanoyl) -4-hydroxypyrrolidine-2-carboxamide) -2- (4- (4-Methylthiazole-5-yl) phenyl) ethyl 68-methyl-69-oxo- 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65-docosaoxa-68-azadohepta Preparation of Contan-72-acid salt.

2- (4-[[4- (4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino] in a 100 mL round bottom flask ) Benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazin-1-yl] methyl] piperidin-1-yl) acetic acid (417.9 mg, 0.565 mmol, 1.00 equivalent), (2R) ) -2- [[(2S, 4R) -1- [(2S) -2-amino-3,3-dimethylbutanoyl] -4-hydroxypyrrolidin-2-yl] formamide] -2- [4-( 4-Methyl-1,3-thiazole-5-yl) phenyl] ethyl 3-[(2,5,8,11,14,17,20,23,26,29,32,35,38,41,44) , 47,50,53,56,59,62,65-docosaoxaheptahexacontane-67-yl) (methyl) carbamoyl] propanoate hydrochloride (900.0 mg, 0.565 mmol, 1 equivalent), DIEA (146.0 mg) , 1.130 mmol, 2.00 equivalents), BOP (299.8 mg, 0.678 mmol, 1.20 equivalents) in a solution of DMF (30 mL). The obtained mixture was stirred at room temperature for 1 hour. The mixture was then diluted with 50 mL of water and extracted with dichloromethane (100 mLx2). The organic layers were combined and concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions: Column: X select CSH OBD Column 30 * 150mm 5um n; Mobile phase A: Water (0.1% FA), Mobile phase B: ACN;
Flow rate: 60 mL / min; Gradient: 15% B-38% B in 11 minutes; 254/220 nm; Rt: 10.27 min. As a result, 200.3 mg (7.23%) of (R) -2-((2S, 4R) -1-((S) -2- (2- (4-((4- (4- (3- (2)) , 6-difluoro-3-(((R) -3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl ) Methyl) piperidine-1-yl) acetamide) -3,3-dimethylbutanoyl) -4-hydroxypyrrolidin-2-carboxamide) -2- (4- (4-methylthiazole-5-yl) phenyl) ethyl 68 -Methyl-69-oxo-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65 -Docosaoxa-68-azadoheptacontane-72-acid salt was obtained as a solid. LC / MS (ESI) m / z: 2278.71 [M + 1] +; 1H-NMR (400MHz, DMSO-d6) δ 12.91 (s, 1H), 9.85 (brs, 1H), 8.99 (s, 1H), 8.65 (d, J = 2.2 Hz, 1H), 6.60-8.53 (m, 2H), 8.07 (s, 1H), 7.88-7.80 (m, 1H), 7.69-7.54 (m, 3H), 7.52-7.45 ( m, 4H), 7.31-7.25 (m, 1H), 7.07 (d, J = 8.4 Hz, 2H), 5.36-5.23 (m, 1H), 5.21-5.13 (m, 2H), 4.55-4.43 (m, 4H) 2H), 4.29-4.22 (m, 3H), 3.72-3.38 (m, 105H), 3.26-3.15 (m, 7H), 3.02-2.95 (m, 2H), 2.85-2.76 (m, 2H), 2.48- 2.39 (m, 4H), 2.34-1.91 (m, 6H), 1.77-1.60 (m, 4H), 1.31-1.19 (m, 2H), 0.95 (s, 9H).
(3R, 5S) -1-((S) -2- (2- (4-((1- (4- (3- (2,6-difluoro-3- (((R) -3-fluoropyrolidin) ) -1-sulfonamide) Benzoyl) -1H-pyrrolo [2,3-b] Pyridine-5-yl) Phenyl) Piperidine-4-yl) Methyl) Piperazine-1-yl) Acetamide) -3,3-dimethyl Butanoyl) -5-((4- (4-Methylthiazole-5-yl) benzyl) carbamoyl) piperidine-3-yl 2-((69-oxo-2,5,8,11,14,17,20) , 23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68-tricosaoxaheptacontan-70-yl) oxy) acetate (exemplary) Exemplary Synthesis of Compound 815) Step 1: (2S, 4R) -1-((S) -2- (2- (4-((1- (4- (3- (2,6-difluoro-3-)) (((R) -3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperidine-4-yl) methyl) piperazine-1- Il) Acetamide) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazole-5-yl) benzyl) pyrridin-2-carboxamide
Preparation of (Exemplary Compound 227).

In an 8 mL tube, 2- (4-[[1- (4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) benzoyl) ] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperidine-4-yl] methyl] piperazine-1-yl) acetic acid (111 mg, 0.15 mmol, 1 equivalent), (2S, 4R) -1- [(2S) -2-amino-3,3-dimethylbutanoyl] -4-hydroxy-N-[[4- (4-methyl-1,3-thiazole-5-yl) phenyl] methyl] Piperidine-2-carboxamide hydrochloride (84 mg, 0.18 mmol, 1.20 equivalents), DIEA (77.5 mg, 0.60 mmol, 4.00 equivalents), DMF (2 mL), BOP (79.6 mg, 0.18 mmol, 1.20 equivalents) were added. The resulting solution was stirred at room temperature for 1 hour. Dilute the resulting solution with water (30 mL) and
Extracted with dichloromethane / methanol (10/1, 50 mLx2) and combined into one organic layer. The organic layer was washed with brine (50 mLx2), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by preparative HPLC and 81.9 mg (47.37%) of (2S, 4R) -1-((S) -2- (2- (4-((1- (4- (3- (3- ( 2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-
Pyrrolidine [2,3-b] Pyridine-5-yl) Phenyl) Piperidine-4-yl) Methyl) Piperazin-1-yl) Acetamide) -3,3-dimethylbutanoyl) -4-Hydroxy-N- (4) -(4-Methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide was obtained. LC / MS (ESI) m / z: 1152.20 [M + 1] +; 1H-NMR (300MHz, CD3OD) δ 8.87 (s, 1H), 8.67 (s, 1H), 8.58 (s, 1H), 7.88 ( s, 1H), 7.78-7.70 (m, 1H), 7.56 (d, J = 8.7 Hz, 2H), 7.48-7.38 (m, 4H), 7.16-7.06 (m, 3H), 5.21 (d, J = 53.7 Hz, 1H), 4.63-4.50 (m, 4H), 4.37-4.32 (m, 1H), 3.91-3.70 (m, 4H), 4.63-3.35 (m, 4H), 3.05 (s, 2H), 2.72 -2.46 (m, 13H), 2.27-1.95 (m, 6H), 1.84-1.80 (m, 2H), 1.65 (m, 1H), 1.35-1.24 (m, 2H), 1.04 (m, 9H).
Step 2: 69-oxo-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65 , 68,71-Preparation of tetracosaoxatriheptacontane-73-acid.

In a 1L round bottom flask, 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65 -Docosaoxaheptahexacontan-67-ol (8 g, 7.99 mmol, 1 eq), TEA (2.22 mL, 15.97 mmol, 2.00 eq), DMAP (2.93 g, 23.98 mmol, 3.00 eq), dichloromethane (250 mL), tetrahydrofuran (30 mL) was added and the mixture was stirred for 10 minutes. This was followed by the addition of 1,4-dioxane-2,6-dione (4.64 g, 39.98 mmol, 5.00 eq) with stirring. The resulting solution was stirred for 16 hours in an oil bath at 35 ° C. The resulting solution was diluted with dichloromethane (800 mL) and washed with NH4Cl (800 mLx2). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 8.90g (99.69%) of 69-oxo-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53, 56,59,62,65,68,71-Tetracosaoxatriheptacontane-73-acid was obtained as a yellow semi-solid. LC / MS (ESI) m / z: 559.30 [M / 2 + 1] ⁺ .
Step 3: (3R, 5S) -1-((S) -2- (2-(4-((1- (4- (3- (2,6-difluoro-3- (((R) -3) -3) -Fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperidine-4-yl) methyl) piperazin-1-yl) acetamide) -3, 3-dimethylbutanoyl) -5-((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidine-3-yl 2-((69-69-)
Oxo-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68-Torikosa Oxaheptacontan-70-yl) Oxy) Preparation of acetate.

In a 100 mL round bottom flask, (2S, 4R) -1-((S) -2- (2- (4-((1- (4- (3- (2,6-difluoro-3- (((() R) -3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperidine-4-yl) methyl) piperazin-1-yl) acetamide )-3,3-dimethylbutanoyl) -4-hydroxy-N-(4- (4-methylthiazole-5-yl) benzyl) pyrrolidine-2-carboxamide (300 mg, 0.26 mmol, 1 equivalent), dichloromethane (20 mL) ) Was put in. In the mixture, 69-oxo-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62, 65,68,71-Tetracosaoxatriheptacontane-73-acid (1.31 g, 1.17 mmol, 4.50 eq), DMAP (285.9 mg, 2.34 mmol, 9.00 eq), and EDCI (449 mg, 2.34 mmol, 9.00 eq) Was added in 3 divided doses over 3 hours. The resulting solution was stirred at room temperature for 16 hours. This was followed by the rest of DMAP (636.6 mg, 5.21 mmol, 20.01 eq) added in 4 divided doses over 4 hours. The resulting solution was reacted at room temperature for an additional 2 hours with stirring. The resulting solution was concentrated and the residue was diluted with NH4Cl (300 mL). The mixture was extracted with EtOAc / THF (10/1, 300 mLx2) and the organic layers were combined into one. The organic layer was washed with NH4Cl (300 mLx2), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by preparative HPLC and 125.8 mg (21.46%) of (3R, 5S) -1-((S) -2- (2- (4-((1- (4- (3- (3- (3-)3-). (2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperidine-4 -Il) Methyl) Piperazine-1-yl) Acetamide) -3,3-dimethylbutanoyl) -5-((4- (4-Methylthiazole-5-yl) benzyl) Carbamoyl) Pyrrolidine-3-yl 2- ((69-oxo-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65, 68-Tricosaoxaheptacontan-70-yl) oxy) acetate was obtained as a dark yellow semi-solid. LC / MS (ESI) m / z: 2251.46 [M + 1] +; 1H-NMR (300MHz, CDCl3) δ 11.49 (s, 1H), 8.84 (s, 1H), 8.69 (s, 1H), 8.60 ( s, 1H), 7.74-7.66 (m, 3H), 7.56 (d, J = 8.4 Hz, 2H), 7.45-7.41 (m, 1H), 7.37-7.30 (m, 4H), 7.04-6.99 (m, 3H), 5.43 (s, 1H), 5.21 (d, J = 52.5 Hz, 1H), 4.76-4.71 (m, 1H), 4.59-4.52 (m, 1H), 4.35-4.18 (m, 9H), 3.86 -3.68 (m, 7H), 3.64-3.62 (m, 78H), 3.55-3.44 (m, 7H), 3.37 (s, 3H), 2.96 (s, 2H), 2.81-2.68 (m, 4H), 2.51 -2.43 (m, 11H), 2.26-2.19 (m, 5H), 2.02-1.95 (m, 1H), 1.86-1.82 (m, 2H), 1.61 (m, 1H), 1.35-1.30 (m, 2H) , 0.93 (s, 9H).
(3R, 5S) -1-((S) -2- (2- (4-((1- (4- (3- (2,6-difluoro-3- (((R) -3-fluoropyrrolidine) ) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperidine-4-yl) methyl) piperazine-1-yl) acetamide) -3,3-dimethyl Butanoyl) -5-((4- (4-methylthiazole-5-yl) benzyl) carbamoyl) pyrrolidine-3-yl 69-oxo-2,5,8,11,14,17,20,23,26 , 29,32,35,38,41,44,47,50,53,56,59,62,65,71-Tricosaoxa-68-Azatriheptacone-73-Anate (exemplary compound 814) Synthetic step 1: 2- (2-[[(3R, 5S) -1-[(2S) -2- [2- (4- [[1- (4- [3- [2,6-difluoro- 3-([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperidine-4-yl] methyl ] Piperazine-1-yl) acetamide] -3,3-dimethylbutanoyl] -5-([[4- (4-methyl-1,3-thiazole-5-yl) phenyl] methyl] carbamoyl) pyrrolidine-3 -Il] oxy] -2-oxoethoxy) Preparation of acetic acid.

In a 30 mL closed tube, (2S, 4R) -1-[(2S) -2- [2- (4-[[1- (4- [3- [2,6-difluoro-3- ([[( 3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperidine-4-yl] methyl] piperazin-1-yl ) Acetamide] -3,3-dimethylbutanoyl] -4-hydroxy-N-[[4- (4-methyl-1,3-thiazole-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (230 mg, 0.20 mmol (1 equivalent), Et ₃ N (40.4 mg, 0.40 mmol, 2.00 equivalent), DMAP (73 mg, 0.60 mmol, 2.99 equivalent), dichloromethane (8 mL), tetrahydrofuran (2 mL) and stir the mixture for 10 minutes. did. This was followed by the addition of 1,4-dioxane-2,6-dione (116.1 mg, 1.00 mmol, 5.01 eq) with stirring. The resulting solution was stirred for 16 hours in an oil bath at 35 ° C. The resulting solution was diluted with dichloromethane / methanol (10/1, 200 mL) and washed with saturated NH4Cl aqueous solution (100 mLx2). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC and 79.6 mg (31.44%) of 2- (2-[[(3R, 5S) -1-[(2S) -2- [2- (4-[1). -(4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridine -5-yl] phenyl) piperidine-4-yl] methyl] piperazine-1-yl) acetamide] -3,3-dimethylbutanoyl] -5-([[4- (4-methyl-1,3-thiazole) -5-yl) phenyl] methyl] carbamoyl) pyrrolidine-3-yl] oxy] -2-oxoethoxy) acetic acid was obtained as a bright yellow solid. LC / MS (ESI) m / z: 1268.20 [M + 1] +; 1H-NMR (300MHz, CD3OD) δ 8.90 (s, 1H), 8.69 (s, 1H), 8.62 (m, 1H), 7.94 ( s, 1H), 7.82-7.74 (m, 1H), 7.63-7.60 (m, 2H), 7.49-7.42 (m, 4H), 7.22-7.14 (m, 3H), 5.50 (s, 1H), 5.26 ( m, 1H), 4.66-4.56 (m, 7H), 4.42-4.29 (m, 4H), 4.13-4.00 (m, 2H), 3.92-3.79 (m, 3H), 3.61-3.44 (m, 6H), 3.17 (m, 3H), 3.03 (s, 3H), 2.90-2.79 (m, 4H), 2.50 (s, 3H), 2.28-2.22 (m, 2H), 2.07-1.96 (m, 3H), 1.49- 1.45 (m, 2H), 1.07 (s, 9H).
Step 2 (3R, 5S) -1-((S) -2- (2-(4-((1- (4- (3- (2,6-difluoro-3- (((R) -3-) -3- Fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperidine-4-yl) methyl) piperazin-1-yl) acetamide) -3,3 -Dimethylbutanoyl) -5-((4- (4-Methylthiazol-5-yl) benzyl) Carbamoyl) Pyrrolidine-3-yl 69-oxo-2,5,8,11,14,17,20,23 , 26,29,32,35,38,41,44,47,50,53,56,59,62,65,71-Preparation of tricosaoxa-68-azatriheptacontane-73-acid.

In a 50 mL round bottom flask, 2- (2-[[(3R, 5S) -1-[(2S) -2- [2- (4- [[1- (4- [3- [2,6-,6-,6- Difluoro-3-([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino) benzoyl] -1H-pyrrolo [2,3-b] pyridine-5-yl] phenyl) piperidine-4-yl ] Methyl] piperazine-1-yl) acetamide] -3,3-dimethylbutanoyl] -5-([[4- (4-methyl-1,3-thiazole-5-yl) phenyl] methyl] carbamoyl) pyrrolidine -3-yl] oxy] -2-oxoethoxy) acetic acid (761 mg, 0.60 mmol, 1 equivalent), 2,5,8,11,14,17,20,23,26,29,32,35,38, 41,44,47,50,53,56,59,62,65-docosaoxaheptahexacontan-67-amine hydrochloride (1.244 g, 1.20 mmol, 2.00 equivalents), DIEA (310 mg, 2.40 mmol, 4.00 equivalents) , DMF (15 mL), BOP (398 mg, 0.90 mmol, 1.50 equivalents) were added. The resulting solution was stirred at room temperature for 2 hours. The resulting solution was diluted with water (200 mL) and extracted with ethyl acetate / THF (10/1, 300 mLx2) to combine the organic layers into one. The organic layer was washed with NH4Cl (300 mL x 2). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by preparative HPLC and 238.0 mg (17.63%) of 3R, 5S) -1-((S) -2- (2- (4-((1- (4- (3- (3- ( 2,6-difluoro-3-(((R) -3-fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperidine-4- Il) Methyl) Piperazine-1-yl) Acetamide) -3,3-dimethylbutanoyl) -5-((4- (4-Methylthiazol-5-yl) benzyl) Carbamoyl) Pyrrolidine-3-yl 69-oxo -2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,71-Triheptacontane-68 -Azatriheptacontane-73-acid acid was obtained as a yellow solid. LC / MS (ESI) m / z: 2250.47 [M + 1] +; 1H-NMR (400MHz, CDCl3) δ 11.22 (s, 1H), 8.86 (s, 1H), 8.70 (s, 1H), 8.64 ( s, 1H), 7.75-7.71 (m, 3H), 7.57 (d, J = 8.0 Hz, 2H), 7.47 (m, 1H), 7.338-7.33 (m, 4H), 7.13 (m, 1H), 7.06 -7.02 (m, 3H), 5.44 (s, 1H), 5.23 (d, J = 54.2 Hz, 1H), 4.9-4.75 (m, 1H), 4.60-4.55 (m, 1H), 4.37-4.27 (m) , 4H), 4.19-4.07 (m, 3H), 3.82-3.48 (m, 91H), 3.39 (s, 3H), 2.98 (m, 2H), 2.77-2.71 (m, 4H), 2.55-2.46 (m) , 11H), 2.27-2.22 (m, 4H), 2.12-2.00 (m, 2H), 1.88-1.85 (m, 3H), 1.64 (m, 1H), 1.36-1.27 (m, 4H), 0.94 (s) , 9H).
2-(((2S, 4R) -1-((S) -2- (4-((4- (4- (3- (2,6-difluoro-3-(((R)-)- 3-Fluoropyrrolidine) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) methyl) piperidine-1-yl) acetamide) -3 , 3-Dimethylbutanoyl) -4-
Hydroxypyrrolidine-2-carboxamide) Methyl) -5- (4-Methylthiazole-5-yl) benzyl 2,5,8,11,14,17,20,23,26,29,32,35,38,41 , 44,47,50,53,56,59,62,65,68-Illustrated synthesis of tricosoxaxaheptacontane-70-acid acid (exemplary compound 813) Step 1: Methyl 2-([bis [() Preparation of tert-butoxy) carbonyl] amino] methyl) -5-bromobenzoate.

Methyl 5-bromo-2- (bromomethyl) benzoate (3.5 g, 11.36 mmol, 1 eq), tert-butyl N-[(tert-butoxy) carbonyl] carbamate (2.65 g) in a 250 mL round bottom flask. , 12.20 mmol, 1.07 eq) and methyl ethyl ketone (120 mL) were added at room temperature. Cesium carbonate (3.7 g, 11.36 mmol, 1.00 eq) was added to the stirred mixture in several batches at room temperature. The resulting mixture was stirred for 16 hours at 70 ° C. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The resulting mixture was diluted with water (200 mL). The aqueous layer was extracted with ethyl acetate (60 mLx3).
The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with ethyl acetate / petroleum ether (1:10) and methyl 2-([bis [(tert-butoxy) carbonyl] amino] methyl) -5-bromobenzoic acid. Salt (4.25 g, 84.16%) was obtained as a yellow oil. LC / MS (ESI) m / z: 465.90 [M + 23] ⁺ .
Step 2: Preparation of methyl 2-([bis [(tert-butoxy) carbonyl] amino] methyl) -5- (4-methyl-1,3-thiazole-5-yl) benzoate.

In a 250 mL round-bottom flask, methyl 2-([bis [(tert-butoxy) carbonyl] amino] methyl) -5-bromobenzoate (25 g, 56.27 mol, 1 eq), 4-methyl-1,3- Thiazol (12 g, 120 mmol), DMF (50 mL), and potassium acetate (25 g, 254.73 mmol, 4.53 eq) were added at room temperature. Pd (OAc) 2 (2.5 g, 0.01 mmol) was added to the mixture at room temperature under a nitrogen atmosphere. The obtained mixed solution was stirred at 100 ° C. for 2 hours under a nitrogen atmosphere. The resulting mixture was diluted with water (50 mL). The aqueous layer was extracted with ethyl acetate (60 mLx4). The obtained solid matter was dried. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleum ether (3: 1), and methyl 2-([bis [(tert-butoxy) carbonyl] amino] methyl) -5- (4-. Methyl-1,3-thiazole-5-yl) benzoate (15 g, 57.63%) was obtained as a yellow solid. LC / MS (ESI) m / z: 463.10 [M + 1] ⁺ .
Step 3: tert-butyl N-[(tert-butoxy) carbonyl] -N-[[2- (hydroxymethyl) -4- (4-methyl-1,3-thiazole-5-yl) phenyl] methyl] carbamine Preparation of acid salt.

In a 250 mL round-bottom flask, methyl 2-([bis [(tert-butoxy) carbonyl] amino] methyl) -5- (4-methyl-1,3-thiazole-5-yl) benzoate (360 mg, 0.78) mmol (1 eq) and dichloromethane (20 mL, 314.60 mol, 404.23 eq) were added at room temperature. DIBAl-H (3.3 mL, 19.68 mmol, 25.28 eq) was added to the above mixture in several batches over 10 minutes at -70 ° C. The resulting mixture was stirred for an additional hour at -70 ° C. The reaction solution was quenched with an aqueous ammonium chloride solution at room temperature. The resulting mixture was extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with brine (20 mLx1) and dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with ethyl acetate / petroleum ether (2: 1) to tert-butyl N-[(tert-butoxy) carbonyl] -N-[[2- (hydroxymethyl). ) -4- (4-Methyl-1,3-thiazole-5-yl) phenyl] methyl] carbamate (120 mg, 35.48%) was obtained as a yellow oil. LC / MS (ESI) m / z: 335.00 [M-100] ⁺ .
Step 4: Preparation of [2- (aminomethyl) -5- (4-methyl-1,3-thiazole-5-yl) phenyl] methanol hydrochloride.

In a 250 mL round bottom flask, tert-butyl N-[(tert-butoxy) carbonyl] -N-[[2- (hydroxymethyl) -4- (4-methyl-1,3-thiazole-5-yl) phenyl) ] Methyl] carbamate (150 mg, 0.35 mmol, 1 eq) and a dioxane solution of HCl (4M) (10.0 mL, 329.12 mmol, 953.46 eq) were added at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum. As a result, [2- (aminomethyl) -5- (4-methyl-1,3-thiazole-5-yl) phenyl] methanol hydrochloride (132 mg, crude) was obtained as a brown solid. LC / MS (ESI) m / z: 234.95 [M + 1] ⁺ .
Step 5: tert-butyl N-[(2S) -1-[(2S, 4R) -4-[(tert-butyldimethylsilyl) oxy] -2-([[2- (hydroxymethyl) -4-( Preparation of 4-methyl-1,3-thiazole-5-yl) phenyl] methyl] carbamoyl) pyrrolidine-1-yl] -3,3-dimethyl-1-oxobutan-2-yl] carbamate.

In a 50 mL round bottom flask, (2S, 4R) -1-[(2S) -2-[[(tert-butoxy) carbonyl] amino] -3,3-dimethylbutanoyl] -4-[(tert-butyl) Dimethylsilyl) oxy] pyrrolidine-2-carboxylic acid (750 mg, 1.64 mmol, 1 equivalent), DMF (10 mL, 0.14 mmol, 0.08 equivalent), HATU (750 mg, 1.97 mmol)
, 1.21 eq), DIEA (840 mg, 6.50 mmol, 3.97 eq), and [2- (aminomethyl) -5- (4-methyl-1,3-thiazole-5-yl) phenyl] methanol hydrochloride (440 mg, 1.62 mmol (0.99 eq) was added at room temperature. The obtained mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with water (60 mL). The resulting mixture was extracted with ethyl acetate (25 mLx3). The combined organic layers were washed with brine (15 mL) and dried over anhydrous Na2SO4. After filtering, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with ethyl acetate / petroleum ether (1: 0) to provide 1.34 g (121.41%) of tert-butyl N-[(2S) -1-[(2S,,). 4R) -4-[(tert-butyldimethylsilyl) oxy]-2-([[2- (hydroxymethyl) -4- (4-methyl-1,3-)
Thiazole-5-yl) phenyl] methyl] carbamoyl) pyrrolidine-1-yl] -3,3-dimethyl-1-oxobutan-2-yl] carbamate was obtained as an orange oil. LC / MS (ESI) m / z: 675.15 [M + 1] ⁺ .
Step 6: [2-([[(2S, 4R) -1-[(2S) -2-[[(tert-butoxy) carbonyl] amino] -3,3-dimethylbutanoyl] -4-[(tert -Butyldimethylsilyl) Oxy] Pyrrolidine-2-yl] Formamide] Methyl) -5- (4-Methyl-1,3-thiazole-5-yl) Phenyl] Methyl 2,5,8,11,14,17, 20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68-Tricosaoxaheptacontan-70-
Preparation of acid salt.

In a 50 mL round bottom flask, tert-butyl N-[(2S) -1-[(2S, 4R) -4-[(tert-butyldimethylsilyl) oxy] -2-([[2- (hydroxymethyl)) -4- (4-Methyl-1,3-thiazole-5-yl) phenyl] methyl] carbamoyl) pyrrolidine-1-yl] -3,3-dimethyl-1-oxobutan-2-yl] carbamate (570 mg) , 0.84 mmol, 1 equivalent), dichloromethane (20 mL). 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68-Tricosaoxahepta Contan-70-acid (1.34 g, 1.27 mmol, 1.50 eq), DMAP (309.6 mg, 2.53 mmol, 3.00 eq), and EDCI (485.6 mg, 2.53 mmol, 3.00 eq) were added. The resulting solution was stirred at room temperature for 2 hours. The resulting solution was concentrated and the residue was diluted with NH4Cl (400 mL). The mixture was extracted with ethyl acetate / THF (10/1, 300 mLx2) and the organic layers were combined into one. The organic layer was washed with saturated aqueous NH4Cl solution (300 mLx2), dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 910 mg (62.79%) of [2-([[(2S, 4R) -1-[(2S) -2-[[(tert-butoxy) carbonyl] amino] -3,3-dimethylbutanoyl]]. -4-[(tert-butyldimethylsilyl) oxy] pyrrolidine-2-yl] formamide] methyl) -5- (4-methyl-1,3-thiazole-5-yl) phenyl] methyl 2,5,8, 11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68-tricosaoxaheptacontane-70-acid salt Was obtained as a yellow oil.

Step 7: [2-([[(2S, 4R) -1-[(2S) -2-amino-3,3-dimethylbutanoyl] -4-hydroxypyrrolidine-2-yl] formamide] methyl) -5 -(4-Methyl-1,3-thiazole-5-yl) phenyl] Methyl 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47 , 50,53,56,59,62,65,68-Preparation of hydrochloride of tricosaoxaheptacontane-70-acid salt.

In a 100 mL round bottom flask, [2-([[(2S, 4R) -1-[(2S) -2-[[(tert-butoxy) carbonyl] amino] -3,3-dimethylbutanoyl] -4 -[(tert-Butyldimethylsilyl) oxy] pyrrolidine-2-yl] formamide] methyl) -5- (4-methyl-1,3-thiazole-5-yl) phenyl] methyl 2,5,8,11, 14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68-tricosaoxaheptacontane-70-acid salt (950 mg) , 0.55 mmol, 1 equivalent), dioxane / HCl (10 mL), (4M dioxane solution). The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum. This resulted in 850 mg (99.82%) of [2-([[(2S, 4R) -1-[(2S) -2-amino-3,3-dimethylbutanoyl] -4-hydroxypyrrolidine-2-yl]]. Formamide] Methyl) -5- (4-Methyl-1,3-
Thiazole-5-yl) phenyl] methyl 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62 A hydrochloride of 65,68-tricosaoxaheptacontane-70-acid salt was obtained as a yellow oil.

Step 8: 2-(((2S, 4R) -1-((S) -2- (2- (4-((4- (4- (3- (2,6-difluoro-3- (((() R) -3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl) piperazine-1-yl) methyl) piperidin-1-yl) acetamide ) -3,3-Dimethylbutanoyl) -4-Hydroxypyridine-2-carboxamide) Methyl) -5- (4-Methylthiazole-5-yl) benzyl 2,5,8,11,14,17,20, Preparation of 23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68-tricosaoxaheptacontane-70-acid.

2- (4-[[4- (4- [3- [2,6-difluoro-3-([[(3R) -3-fluoropyrrolidin-1-yl] sulfonyl] amino] in a 100 mL round bottom flask ) Benzoyl] -1H-pyrrolo [2,3-b] pyridin-5-yl] phenyl) piperazin-1-yl] methyl] piperidine-1-yl) acetic acid (408.8 mg, 0.55 mmol, 1 equivalent), [2 -([[(2S, 4R) -1-[(2S) -2-amino-3,3-dimethylbutanoyl] -4-hydroxypyrrolidin-2-yl] formamide] methyl) -5- (4-methyl) -1,3-thiazole-5-yl) phenyl] methyl 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53, 56,59,62,65,68-Tricosaoxaheptacontane-70-acid hydrochloride hydrochloride (850 mg, 0.55 mmol, 1.00 equivalent), DIEA (283.4 mg, 2.19 mmol, 3.97 equivalent), BOP (293 mg, 0.66) mmol, 1.20 equivalents), DMF (15 mL) were added. The resulting solution was stirred at room temperature for 2 hours. The resulting solution was diluted with ethyl acetate / THF (10/1, 500 mL) and washed with water (200 mL) and NH4Cl (saturated aqueous solution, 200 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by preparative HPLC to 280.0 mg (22.79%) of 2-(((2S, 4R) -1-((S) -2- (2- (4-((4- (4)). -(3-(2,6-difluoro-3-(((R) -3-fluoropyrrolidin) -1-sulfonamide) benzoyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) phenyl ) Piperazine-1-yl) Methyl) Piperidine-1-yl) Acetamide) -3,3-dimethylbutanoyl) -4-Hydroxypyrrolidin-2-carboxamide) Methyl) -5- (4-Methylthiazole-5-yl) ) Benzyl 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68-Tricosa Oxaheptacontane-70-acid salt was obtained as a light brown solid. .LC / MS (ESI) m / z: 2223.44 [M + 1] +; 1H-NMR (400MHz, CDCl3) δ 11.61 (s, 1H), 8.84 (s, 1H), 8.70 (s, 1H), 8.59 (s, 1H), 7.90 (m, 1H), 7.76 (s, 1H), 7.73-7.68 (m, 1H), 7.57-7.55 (m, 2H), 7.44-7.33 (m, 1H)
4H), 7.04-6.97 (m, 3H), 5.27-5.15 (m, 3H), 4.74 (m, 1H), 4.61-4.44 (m, 4H), 4.20-4.13 (m, 4H), 3.81-3.66 ( m, 4H), 3.64-3.62 (m, 81H), 3.58-3.54 (m, 4H), 3.50-3.46 (m, 2H), 3.38 (s, 3H), 3.24 (m, 3H), 2.95-2.77 ( m, 4H), 2.55-2.46 (m, 8H), 2.28-1.98 (m, 8H), 1.80-1.72 (m, 2H), 1.52 (m, 1H), 1.27 (s, 1H), 1.17 (m, 2H), 0.97 (s, 9H), 0.88-0.82 (m, 1H).
Controlling Protein Levels The present specification further provides methods for controlling protein levels using cells. This method is based on the use of compounds described herein that are known to interact with a particular target protein, whereby in vivo degradation of the target protein is preferably to a particular therapeutic benefit. On the other hand, it brings about the control of the amount of protein in the biological system.

The following examples are used to supplement the description of this disclosure, but are by no means considered limiting this disclosure.

The following examples are used to supplement the statements in this disclosure, but are by no means considered limiting this disclosure.

Assay and Degradation Data Cell assay protocol for degradation of target proteins (A375 cells). A375 cells were cultured in ATCC DMEM + 10% FBS in a 12-well plate and treated with the compounds indicated in Table 1-41 or 0.1% DMSO solvent control group for 16 hours. Roche protease inhibitor tablets (Cat # 11873580001) were added and recovered in Cell Signaling lysis buffer (Cat # 9803), and the lysate was clarified by microcentrifugation. Proteins were separated by SDS-PAGE and transferred onto a nitrocellulose membrane using the Invitrogen iBlot system. Immunoblotting was performed on BRAF (Santa Cruz Cat # 9002), CRAF (BD Cat # 610151), and Perk (Cell Signaling Cat # 9106). GAPDH (Cat #) was used as load control. Quantification was performed using BiOrad Image Lab 5 software.

In-Cell Western Cell Assay Protocol for Target Protein Degradation (A375 cells). A375 cells were cultured in ATCC DMEM + 10% FBS in 96-well plates and treated with the compounds indicated in Table 43 or 0.1% DMSO solvent control group for 72 hours. The cells were washed once with PBS and pasted onto a plate in phosphate buffered saline for 15 minutes using 4% PFA; once in PBS using 0.1% Triton-X-100. It was permeabilized for 5 minutes; washed once with a LICOR blocker (Cat. No. 927-50000) and blocked for 1 hour. The cells were then cultured in LICOR blockers with B-Raf antibody (Santa Cruz Cat # 9002) and tubulin antibody (Sigma # T6074) for 18 hours. Cells were washed 3 times and cultured for 1 hour before adding secondary antibodies (LICOR cat # 926-32210 and 926-68071). Cells were washed 3 times and imaged using LICOR Odyssey software.

The bifunctional compounds in Tables 1A, 1B, 1C, and 1D (FIGS. 2A, 2B, 2C, and 2D, respectively) are examples of the bifunctional compounds described in the claims of this application. Some of them have been validated to see if they show intracellular BRAF protein degradation activity, and the results are shown in Tables 2A, 2B and 2D (Figures 3A, 3B and 3D) in column _{DC 50 and} It is listed in the D _{max column.} As used herein, DC ₅₀ has maximum and minimum levels of BRAF concentration in a dosing response curve in which intracellular BRAF protein concentration is measured as a function of compound concentration added to the medium in which the cells are cultured with the compound. The compound concentration that reaches the midpoint of, and D _max is the maximum protein degradation level that can be achieved by varying the compound concentration. Many compounds in these tables _{do not list the values or ranges of DC 50} and D _max at all, either because they have not been tested or synthesized, or because they are hypothetical examples. Isuzu.

Protocol for half-life and release rate of prodrugs. The chain length isomers differ slightly in retention time during chromatographic separation, thereby providing a mixture enriched with the desired PEG chain length. Chromatographic separations therefore do not provide the separation of homogeneous chain length products. In addition, analysis of pegged samples by LCMS shows a mixture of slightly different chain lengths, depending on the time point within the HPLC peak where the MS signal is reported or the interval at which the mass signal is averaged. ..

For pegged compounds that are a mixture of chain length isomers, the MS data in Table 2C report signals that closely match the calculated mass for the chain length of a particular compound (eg, n = 22). There is.

Due to the natural abundance of carbon-13 and deuterium (in the order of magnitude of about 1% each), organic molecules of prodrug size (MW is about 2000) can contain 13 carbon or deuterium atoms in them. High in sex. Therefore, the strongest mass spectral signal for these molecules is one unit heavier than the calculated mass of [M + H] + ions assumed to be carbon-12 and H-1. The lightest isotope peaks (all carbon-12 and H-1) are observable in all samples and are reported in the data table.

Larger molecules, such as the prodrugs of the present disclosure, typically and, as predicted by those of skill in the art, exhibit m / z signals for single-protonated, double-protonated, and triple-protonated ions. .. [M + H] +, [M + 2H] 2+, and [M + 3H] 3+. The MS signal of a single charge [M + H] + ion is often weaker than a double charge ion and a triple charge ion.

The names of the PEGylated prodrugs in Table 1C were generated by Chemdraw Pro (version 18.0). The name is for the chain length type of n = 22, and does not represent a mixture of chain lengths. It is in Table 2C.

The PEG-prodrugs of the present disclosure were treated with multiple heparin-stabilized plasmas and the release rate of the parent drug was tested.

Protocol for determining the rate of release of the parent drug from the PEG prodrug of the invention: A stock solution of the test compound was prepared in DMSO and diluted to a final concentration of 1 mM. Working solutions of 1 mM lovastatin and propantheline were prepared in DMSO and acetonitrile, respectively. Propantheline and lovastatin were used as positive controls. 2.5 μL of this 1 mM stock solution was added to 497.5 μL of crystals to give a final concentration of 5 μM. The final concentration of the organic solvent was 0.5%. The assay was performed in duplicate. Place the reaction sample in a water bath at about 60 rpm, 37.
Incubated at ° C. For prodrug samples, 50 μL dispenses were taken from reaction samples at 0, 2, 5, 15, 30, 120, 300 and 1440 minutes. For intermediate or parental standards, 50 μL of a dispense was taken from the 0 minute reaction sample. The pH value was measured before and after the incubation.

The reaction was stopped by the addition of 7 volumes of cold acetonitrile containing an internal standard (IS, 200 ng / mL). Alternatively, methanol containing 0.1% formic acid was used for the compound precipitated from acetonitrile.

All samples were vortexed for 2 minutes and then centrifuged at 3220 g for 30 minutes to precipitate the protein. 100 μL of supernatant was transferred to a new plate. The supernatant was diluted with ultrapure water according to the response and peak shape of the LC-MS signal. Samples were analyzed by LC-MS / MS.

LC system: Shimadzu Triple Quad 6500+ Low Mass from AB Inc (Canada) with ESI interface, column temperature: 40 ° C, injection volume: 10 μL, column: XSelect Hss T3 2.5 μ (2.1 ×) coupled with pre-guard column 30 mm) Column XP, mobile phase: acetonitrile solution of 0.1% formic acid (B), and aqueous solution of 0.1% formic acid (A).

All calculations were done using Microsoft Excel. The residual percentage of the prodrug at each time point was determined by the peak area ratio from the extracted ion chromatograms. The appearance of intermediates or parents (μM) was calculated by the intermediate or parent of the prodrug sample and the peak area ratio of the intermediate standard or parent standard, respectively.

Overview of Figures 4, 5, 6A, 6B, 6C, 7, 8A, 8B, 9A, 9B, and 10. Bifunctional compounds containing PTM-IIa and PTM-IIb, such as compound 512, are sensitive to vemurafenib (class 1).
) And insensitive (class 2 and class 3) BRAF mutants induce targeted degradation. By degrading mutant BRAF, MAPK can be suppressed and the growth of cancer cells can be stopped. Wild-type BRAF escapes degradation despite its ability to engage with the bifunctional compounds of the present disclosure to form triple complexes. Inefficient recruitment of Cullin2 may be the cause of this experimental result. Inducible degradation can be a strategy for overcoming bemuragenib resistance.
Table 1A. Exemplary protein targeting moieties and compounds of the present disclosure (see Figure 2A).
Table 1B. Exemplary protein targeting moieties and compounds of the present disclosure (see Figure 2B).
Table 1C. Exemplary protein targeting moieties and compounds of the present disclosure (see Figure 2C).
Table 1D. Exemplary protein targeting moieties and compounds of the present disclosure (see Figure 2D).
Table 2A. Degradation data of exemplary compounds in Table 1A (see Figure 3A).
Table 2B. Degradation data of exemplary compounds in Table 1B (see Figure 3B).
Table 2C. Degradation data of exemplary compounds in Table 1C (see Figure 3C).
Table 2D. Degradation data of exemplary compounds in Table 1D (see Figure 3D).

Specific Embodiments of the present disclosure The present disclosure includes the following specific embodiments. These embodiments below may include all of the properties listed in subsequent embodiments as defined. Where appropriate, the following embodiments may further include, inclusively or alternatively, the properties listed in any of the following embodiments.

In any embodiment or embodiment, the present specification describes the following exemplary RAF bifunctional molecules (
The compounds of Tables 1A, 1B, 1C, ie any one of the compounds of Tables 1A, 1B, 1C, or combinations thereof), with their salts, prodrugs, polyforms, analogs, derivatives, and deuterated forms. It includes and provides.

Thus, the present specification is a compound comprising the structure of any one of the compounds of Tables 1A-1C (ie, any one of the compounds of Tables 1A, 1B, 1C or a combination thereof), therapeutically comprising such compounds. It provides the composition and the methods of use described herein.

Claims (42)

A bifunctional compound having the following chemical structure, or a pharmaceutically acceptable salt thereof, a mirror image isomer, a stereoisomer, a solvate, a polymorph or a prodrug:
ULM-L-PTM,
During the ceremony:
The ULM is a small molecule E3 ubiquitin ligase binding moiety that binds to E3 ubiquitin ligase.
The PTM is a small molecule containing a rapidly accelerated fibrosarcoma (RAF) protein targeting moiety, and the L is a binding or chemical binding moiety that binds the ULM to the PTM. Bifunctional compound. The E3 ubiquitin ligase binding moiety targets E3 ubiquitin ligase selected from the group consisting of von Hippel-Lindow (VLM), cereblon (CLM), mouse double-minute homolog2 (MLM), and IAP (ILM). The bifunctional compound according to claim 1. The PTM is represented by the following chemical structure PTM-Ia or PTM-Ib:

During the ceremony:
The double dashed line bond is an aromatic bond,
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; C, O , C, CH, C; 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 selected independently of CH and N;
R _PTM1 is ULM, chemical linker group (L), CLM, ILM, VLM, MLM, ULM', CLM', ILM', VLM.
Covalently combined to', 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 _PTM2a and R _PTM2b are hydrogen, OH, halogen;
R _PTM3 is absent or hydrogen, aryl, methyl, ethyl, other alkyl, cyclic alkyl, OCH _3, NHCH ₃ or M1-CH ₂ -CH ₂ -M2,, wherein, M1 is CH ₂ , O and NH, 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
The bifunctional compound according to claim 1 or 2, wherein _{R PTM5 is selected from the group consisting of the following.}

The PTM is represented by the following chemical structure PTM-IIa or PTM-IIb:

During the ceremony:
X _PTM1 , X _PTM2 , X _PTM3 , X _PTM4 , X _PTM5 and X _PTM6 are selected independently of CH or N;
R _PTM5a is H, an optionally substituted amide (eg, optionally substituted with an alkyl group, a methyl group, an ethyl group, a propyl group, or a butyl group), an optionally substituted amine,

R _PTM5b is hydrogen, or linear or branched C1-C4 alkyl (eg, methyl or ethyl);
R _PTM6a and R _PTM6b are independently selected from hydrogen, halogen, or optionally substituted linear or branched C _1- C ₆ alkyl;
R _PTM6 is either of the following groups: absent, hydrogen, halogen, aryl, methyl, ethyl, OCH _3, NHCH ₃ or _{M1-CH 2 -CH 2 -M2,} , wherein, M1 is CH ₂ , O and NH, where M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle;
R _PTM6c is hydrogen, or linear or branched C1-C4 alkyl (eg, methyl or ethyl);
R _PTM7 is absent or hydrogen, halogen, aryl, methyl, ethyl, OCH _3, NHCH ₃ or _{M1-CH 2 -CH 2 -M2,} , wherein, M1 is CH _2, O and NH Yes, M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle;
R _PTM8 , R _PTM9 or R _PTM10 are independently absent or hydrogen, halogen, aryl, heteroaryl, alkyl, cycloalkyl, heterocycle, methyl, ethyl, OCH ₃ , NHCH ₃ or M1-CH _2- Selected from the group consisting of CH ₂ -M2, in the equation M1 is CH ₂ , O and NH, M2
Is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle; and
R _PTM11 is absent or hydrogen, halogen, methyl, ethyl, OCH _3, NHCH ₃ or _{M1-CH 2 -CH 2 -M2,} , wherein, M1 is CH _2, O and NH, M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle;
At _{least one of R PTM8} , R _PTM9 , or R _PTM10 is ULM, chemical linker group (L), CLM, ILM, VLM, MLM, ULM', CLM', ILM', VLM', MLM', or Modified to be covalently attached to their combination, or two of R _PTM8 , R _PTM9 , and R _PTM10 are modified to form polycyclic (eg, bicyclic) fused rings with chemical linker groups. The bifunctional compound according to claim 1 or 2.
When R _PTM9 is a covalent bond position, R _PTM7 and R _PTM8 are in such a way as to form a bicyclic group having a ring that R _PTM7 and R _PTM8 are attached, are joined to one another via a covalent bond, or
When R _PTM8 is a covalent bond position, R _PTM9 and R _PTM10 are in such a way as to form a bicyclic group having a ring that R _PTM9 and R _PTM10 are attached, are joined to one another via a covalent bond, or
4. According to claim 4, when RPTM10 is in a covalent bond position, RPTM8 and RPTM9 are bonded to each other via a covalent bond in such a way as to form a bicyclic group having a ring to which RPTM8 and RPTM9 attach. Bifunctional compound. The PTM is represented by the following chemical structure PTM-III:

During the ceremony:
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 in CH or N can be;
R _PTM12 , R _PTM13 , R _PTM14 , R _PTM15 , R _PTM16 , R _PTM17 , R _PTM18 , R _PTM19 are independent or absent, or hydrogen, halogen, aryl, heteroaryl, cycloalkyl, heterocycle, methyl, ethyl, other alkyl, selected from the group consisting of OCH _3, NHCH ₃ or M1-CH ₂ -CH ₂ -M2, wherein, M1 is CH _2, O and NH, M2 is hydrogen, alkyl, cycloalkyl , Aryl or heterocycle;
R _PTM20 is a small group containing less than four non-hydrogen atoms.
R _PTM21 is trifluoromethyl, chloro, bromo, fluoro, methyl, ethyl, propyl, isopropyl, tert-butyl, butyl, iso-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, OCH ₃ , NHCH ₃ , dimethylamino or is selected from the group consisting of M1-CH ₂ -CH ₂ -M2, wherein, M1 is CH _2, O or NH, M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocyclic; and
At _{least one of R PTM12} , R _PTM13 and R _PTM16 is ULM, chemical linker group (L), CLM, ILM, VLM, MLM, ULM', CLM', ILM', VLM', MLM', or a combination thereof. The bifunctional compound according to claim 1 or 2, which is modified to be covalently attached to. When R _PTM12 is in a covalent bond position, R _PTM13 and R _PTM14 are bonded to each other via a covalent bond in such a way as to form a bicyclic group with a ring to which R _PTM13 and R _{PTM14 attach.} / Or R _PTM15 and R _PTM16 are bonded together via a covalent bond in such a way as to form a bicyclic group with a ring to which _{R PTM15} and R _{PTM16 attach.}
When R _PTM13 is a covalent bond position, R _PTM12 and R _PTM16 are in such a way as to form a bicyclic group having a ring that R _PTM12 and R _PTM16 are attached, are connected to one another via a covalent bond, and / Or R _PTM15 and R _PTM16 are bonded to each other via covalent bonds in such a way as to form a bicyclic group with a ring to which R _PTM15 and R _{PTM16 attach.}
When R _PTM16 is in a covalent bond position, R _PTM12 and R _PTM13 are bonded to each other via a covalent bond in such a way as to form a bicyclic group with a ring to which R _PTM12 and R _{PTM13 attach.} / or R _PTM13 and R _PTM14 are in such a way as to form a bicyclic group having a ring that R _PTM13 and R _PTM14 are attached, are joined to one another via a covalent bond, a compound according to claim 6. The PTM is represented by the following chemical structure PTM-IVa or PTM-IVb:

During the ceremony:
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 independently in CH or N can be;
R _PTM22 is selected from the following group:

R _PTM25a and R _PTM25b are 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 bonded, hydrogen, halogen, aryl (optionally substituted), heteroaryl (optionally). Substituted), cycloalkyl (optionally substituted), heterocycle (optionally substituted), methyl, ethyl (optionally substituted), other alkyl (straight, branched, optional substituted) ), OCH ₃ , NHCH ₃ or M1-CH ₂ -CH ₂ -M2, in the formula M1 is CH ₂ , O and NH, M2 is hydrogen, alkyl (straight chain, minute). Branch chains, optionally substituted), cyclic alkyl (optionally substituted), aryl (optionally substituted) or heterocyclic (optionally substituted); and
R _PTM25 is absent or selected from hydrogen, halogen, C _1- C ₆ alkyl (straight chain, branched chain, optionally substituted), OCH ₃ , NHCH ₃ or SCH ₃ ;
R _PTM26 is absent or selected from hydrogen, halogen, C _1- C ₆ alkyl (straight chain, branched chain, optionally substituted), OCH ₃ , NHCH 3 or SCH ₃ ;
R _PTM27 is absent or selected from the group consisting of hydrogen, halogen, C _1- C ₆ alkyl (straight chain, branched chain, optionally substituted), OCH ₃ , NHCH 3 or SCH _{3; and}
At _{least one of R PTM24} , R _PTM29 and R _PTM32 is ULM, chemical linker group (L), CLM.
, ILM, VLM, MLM, ULM', CLM', ILM', VLM', MLM', or a combination thereof, which is a bifunctional compound according to claim 1 or 2. When R _PTM24 is in a covalent bond position, R _PTM31 and R _PTM32 are bonded to each other via a covalent bond or bonded together in such a way as to form a bicyclic group with a ring to which R _PTM31 and R _{PTM32 attach.} R _PTM29 and R _PTM30 are bonded to each other via a covalent bond or bonded to each other in such a way as to form a bicyclic group with a ring to which R _PTM29 and R _{PTM30 attach.}
When R _PTM29 is a covalent bond position, R _PTM24 and R _PTM32 are in such a way as to form a bicyclic group having a ring that R _PTM24 and R _PTM32 are attached, are connected to one another via a covalent bond,
And / or R _PTM31 and R _PTM32 are bonded to each other via covalent bonds in such a way as to form bicyclic groups with rings to which R _PTM31 and R _{PTM32 attach.}
When R _PTM32 is in a covalent bond position, R _PTM24 and R _PTM29 are bonded to each other via a covalent bond in such a way as to form a bicyclic group with a ring to which R _PTM24 and R _{PTM29 attach.} / or R _PTM29 and R _PTM30 are in such a way as to form a bicyclic group having a ring that R _PTM29 and R _PTM30 are attached, they are joined to one another via a covalent bond, difunctional claim 8 Sex compound. The PTM is represented by the following chemical structure PTM-Va:

During the ceremony:
X _PTM35 , X _PTM36 , X _PTM37 , X _PTM38 , and X _PTM39 are independently CH or N;
R _PTM33 is a halogen or linear or branched C1-C4 haloalkyl;
R _PTM34 , R _PTM35 , R _PTM36 , R _PTM37 , and R _PTM38 are independently hydrogen, halogen, or linear or branched C _1- C ₄ alkyl (eg, methyl, ethyl, propyl, etc.). Or butyl);
R _PTM39 is an optionally substituted C4-C7 heterocycloalkyl (eg, optionally substituted C5 or C6 heterocycloalkyl); and

ULM, Chemical Linker Group (L), CLM, ILM, VLM, MLM, ULM', CLM', ILM', VLM', MLM
'Or the bifunctional compound according to claim 1 or 2, which is a binding point with a combination thereof. The PTMs are PTM-1, PTM-2, PTM-3, PTM-4, PTM-5, PTM-6, PTM-7, PTM-8, PTM-9, PTM-10, PTM-11, PTM- 12. The bifunctional compound of claims 1-10, selected from the group consisting of PTM-13.

The ULM is selected from the group consisting of:

The bifunctional compound according to any one of claims 1 to 11, wherein R _{14a is methyl or hydroxymethyl in the formula.} ULM is a von Hippel-Lindow (VHL) ligase binding moiety (VLM) with the chemical structure represented by:

During the ceremony:
X ¹ and X ² are independently selected from the group of binding, O, NR ^Y3 , CR ^Y3 R ^Y4 , C = O, C = S, SO, and SO _2;
R ^Y3 and R ^Y4 are independently H, linear or branched C _1-6 alkyl (optionally substituted with one or more halos), optionally substituted C _1-6. alkoxyl (e.g., optionally substituted with a 0-3 R ^P groups) selected from the group of;
R ^P is 0, 1, 2 or 3 groups, each independently selected from H, halo, -OH, C _1-3 alkyl, C = O;
W ³ is optionally substituted T, optionally substituted-TN (R ^1a R ^1b ) X ³ , optionally substituted-TN (R ^1a R ^1b ), optionally substituted-T-aryl , Arbitrarily substituted-T-heteroaryl, optionally substituted T-diheteroaryl, optionally substituted-T-heterocycle, optionally substituted-T-diheteroaryl, optionally substituted -NR ¹ -T-aryl, optionally substituted-NR ¹ -T-heteroaryl, or optionally substituted-NR ¹ -T-selected from the group of heterocycles;
^{X 3} of the equation ULM-a is C = O, R ¹ , R ^1a , R ^1b ;
R ¹ , R ^1a , and R ^1b _{are H, linear or branched C 1-} C ₆ alkyl groups optionally substituted by one or more halo or -OH groups, R ^{Y 3} C = O, R, respectively. ^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 ) Selected independently from the group consisting of _{SO 2;}
T is selected from the group of optionally substituted alkyl,-(CH ₂ ) _n- groups, where each one of the methylene groups is halogen, methyl, optionally substituted alkoxy, one or more. Halogen, C (O) NR ¹ R ^1a , or NR ¹ R ^1a , or a linear or branched chain optionally substituted by ^{R 1} and R ^1a coupled to form an optionally substituted heterocycle. C ₁ -C ₆ alkyl group, or -OH
A group, or optionally substituted with one or two substituents selected from the group of amino acid side chains optionally substituted, and
n is 0 to 6 and
W ⁴

And
R _{14a and} R _14b are independently H, haloalkyl, optionally substituted alkoxy, optionally substituted hydroxylalkyl,-(CH ₂ ) _m'C (= O) (CH ₂ ) _m'C ( = O) (OH), ( CH 2) m 'OCOCH 2 (CH 2) m' OCH 2 (CH 2) m 'CO (CH 2) m' OH, (CH 2) m 'OCOCH 2 (CH 2) _{m 'CO (CH 2) m} ' OH or selected oxygen one or more carbons that is substituted with from the group of straight or branched alkyl optionally substituted with having optionally;
R ¹ is H, a linear or branched C _1- C ₆ alkyl group, or -OH group, optionally substituted with one or more halos;
Each m'is an integer from 1 to 4 (eg, 1, 2, 3, or 4);
W ⁵ is selected from the group of optionally substituted phenyls, optionally substituted 5-10 membered heteroaryls;
W ⁶ is an optionally substituted 8--14 member bicyclic heterocycle;
R ₁₅ can be replaced with 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. Alkyl substituted, haloalkyl optionally substituted, haloalkoxy optionally substituted, aryl optionally substituted, heteroaryl optionally substituted, cycloalkyl optionally substituted, or cyclohetero optionally substituted Selected from the group of alkyl; and dashed lines indicate the binding site of the chemical linker moiety that binds at least one PTM, another ULM (ULM'), or at least one PTM and / or ULM' to ULM. Item 1
The bifunctional compound according to any one of 11 to 11. ULM is a von Hippel-Lindow (VHL) ligase binding moiety (VLM) with the chemical structure represented by:

During the ceremony:
W ³ is optionally substituted aryl, optionally substituted heteroaryl, or

Selected from the group of;
R ₉ and R ₁₀ 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 atoms they bond to form cycloalkyls that are optionally substituted;
R ₁₁ is an optionally substituted heterocyclic, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl,

Selected from the group of;
R ₁₂ is selected from the group of H or optionally substituted alkyl;
R ₁₃ is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl) alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally. Selected from the group of (heterocyclyl) carbonyls substituted with, or optionally substituted aralkyl;
R ¹ is H, a linear or branched C _1- C ₆ alkyl group, or -OH group, optionally substituted with one or more halos;
R _{14a and} R _14b are independently H, haloalkyl, optionally substituted alkoxy, (CH ₂ ) _{m.
'OCOCH 2 (CH 2) m} ' OCH 2 (CH 2) m 'CO (CH 2) m' OH, (CH 2) m 'OCOCH 2 (CH 2) m' CO (CH 2) m 'OH, optionally Hydroxylalkyl substituted with,-(CH ₂ ) _m'C (= O) (CH ₂ ) _m'C (= O) (OH), or optionally with one or more carbons substituted with oxygen Selected from the group of alkyl substituted;
Each m'is an integer from 1 to 4 (eg, 1, 2, 3, or 4);
W ⁵ is selected from the group of optionally substituted phenyls or optionally substituted 5-10 membered heteroaryls;
R ₁₅ can be replaced with 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. Alkyl substituted, haloalkyl optionally substituted, haloalkoxy optionally substituted, aryl optionally substituted, heteroaryl optionally substituted, cycloalkyl optionally substituted, or cyclohetero substituted arbitrarily Selected from the group of alkyl;
Each R ₁₆ is independently substituted with an optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, or optionally substituted with one or more carbon atoms substituted with H, CN, halo, oxygen atoms. Selected from the group of haloalkoxy;
o is 0, 1, 2, 3, or 4;
R ₁₈ is independently selected from the group of H, halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy or linker; and
p is 0, 1, 2, 3, or 4, and in the equation, the dashed line indicates at least one PTM, another ULM (ULM'), or at least one PTM and / or ULM'to ULM. The bifunctional compound according to any one of claims 1 to 11, which indicates the binding site of the chemical linker moiety to be bound. The ULM has a chemical structure selected from the following groups:

During the ceremony:
R ₁ is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; optionally substituted alkyl, optionally substituted hydroxyalkyl, optionally substituted. Heteroaryl, or haloalkyl;
R _14a is, H, haloalkyl, alkyl substituted with optionally, methyl, fluoromethyl, hydroxymethyl, ethyl, _{isopropyl, (CH 2) m 'OCOCH} 2 (CH 2) m' OCH 2 (CH 2) m 'CO _{(CH 2) m 'OH,} (CH 2) m' be _{OCOCH 2 (CH 2) m '} CO (CH 2) m' OH or cyclopropyl;
Each m'is an integer from 1 to 4 (eg, 1, 2, 3, or 4);
R ₁₅ is H, halogen, CN, OH, NO ₂ , optionally substituted heteroaryl, optionally substituted aryl, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted halo. Selected from the group consisting of alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl;
X is C, CH ₂ , or C = O,
R ₃ is a 5- or 6-membered heteroaryl bound or optionally substituted, and in the formula, the dashed line is at least one PTM, another ULM (ULM'), or at least one PTM or ULM. 'The bifunctional compound according to any one of claims 1 to 11, which indicates the binding site of the chemical linker moiety that binds / or both of them to the ULM. The ULM contains a group according to the following chemical structure:

During the ceremony:
R _14a is, H, haloalkyl, alkyl substituted with optionally, methyl, fluoromethyl, hydroxymethyl, ethyl, _{isopropyl, (CH 2) m 'OCOCH} 2 (CH 2) m' OCH 2 (CH 2) m 'CO _{(CH 2) m 'OH,} (CH 2) m' be _{OCOCH 2 (CH 2) m '} CO (CH 2) m' OH or cyclopropyl;
Each m'is an integer from 1 to 4 (eg, 1, 2, 3, or 4);
R ₉ is H;
R ₁₀ is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
R ₁₁ is

Heteroaryl, optionally substituted

p is 0, 1, 2, 3, or 4; and each R ₁₈ is independently halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy or linker. can be;
R ₁₂ is H, C = O,
R ₁₃ is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl) alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally. It is a (heterocyclyl) carbonyl substituted with, or an aralkyl optionally substituted;
R ₁₅ is H, halogen, Cl, CN, OH, NO ₂ , optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloheteroalkyl,

The dashed line indicates any of claims 1-11, indicating the binding site of a chemical linker moiety that binds at least one PTM, another ULM (ULM'), or at least one PTM and / or ULM' to said ULM. The bifunctional compound according to item 1. 2. According to any one of claims 1 to 11, wherein the ULM is a cereblon E3 ligase binding moiety (CLM) selected from the group consisting of thalidomide, lenalidomide, pomalidomide, an analog thereof, an isostar thereof, or a derivative thereof. Functional compound. The ULM is a CLM having the chemical structure represented by:

During the ceremony:
W is _{selected from the group consisting of CH 2} , O, CHR, C = O, SO ₂ , NH, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and N-alkyl;
W ₃ is selected from C or N;
Each X either does not exist or is selected independently from the group consisting of _{O, S and CH 2;}
Y is selected from the group consisting of CH2, -C = CR', NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O and S;
Z does not exist or is selected from the group consisting of _{O, S and CH 2;}
G and G'are independently H, linear or branched-chain alkyl optionally substituted, OH,-(CH ₂ ) _n'- OP (= O) (OC _1-6 alkyl) ( OH),-(CH ₂ ) _n'- OP (= O) (OC _1-6 alkyl) ₂ ,-(CH ₂ ) _n'- OP (= O) (OH) ₂ , -CH ₂ OCOO (CH ₂₎ CH ₂ O) _{selected from the group consisting of n "} CH ₃ , R'OCOOR, R'OCONRR", CH ₂ -heterocyclyl optionally substituted with R', and benzyl optionally substituted with R';
n ”is an integer from 8 to 35 (eg 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 or 35);
Q ₁ , Q ₂ , Q ₃ and Q ₄ each independently represent carbon C substituted with a group independently selected from H, R, N or N-oxides;
A is independently selected from the group of H, optionally substituted linear or branched alkyl, cycloalkyl, Cl and F;
R is halogen, -CONR'R ", -OR', -NR'R", -SR', -SO ₂ R', -SO ₂ NR'R ", -CR'R"-, -CR'NR 'R'-, (-CR'O) n'R _' , optionally substituted aryl (eg, optionally substituted C5-C7 aryl), optionally substituted alkyl-aryl (eg, optionally substituted) C1-C6 alkyl to be optionally substituted C5-C7aryl, or alkyl-aryl comprising at least one of their combinations, optionally substituted heteroaryl (eg, optionally substituted C5). -C7 heteroaryl), optionally substituted linear or branched alkyl (eg, one or more halogens, cycloalkyl (eg, C3-C6 cycloalkyl), or aryl (eg, C5-C7). C1-C6 linear or branched alkyl optionally substituted with aryl), alkoxyl groups optionally substituted (eg, methoxy, ethoxy, butoxy, propoxy, pentoxy or hexoxy; where said alkoxyl). Can be substituted with one or more halogens, alkyls, haloalkyls, fluoroalkyls, cycloalkyls (eg, C3-C6cycloalkyl) or aryls (eg, C5-C7aryl), optionally.

(For example, optionally substituted with one or more halogens, alkyls, haloalkyls, fluoroalkyls, cycloalkyls (eg, C3-C6cycloalkyl) or aryls (eg, C5-C7aryl)), optionally substituted.

(For example, optionally substituted with one or more halogens, alkyls, haloalkyls, fluoroalkyls, cycloalkyls (eg, C3-C6cycloalkyl) or aryls (eg, C5-C7aryl)), optionally substituted. Cycloalkyl (eg, optionally substituted C3-C7)
Cycloalkyl), optionally substituted heterocyclyl (eg, optionally substituted C3-C7)
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 = NR'
) R ”, _{-SF 5} and -OCF ₃ , where at least one R is PTM, chemical linker group (L), ULM, CLM'(eg, CLM'is the same as or the first CLM. Additional CLM with different structure
), Or modified to be covalently bonded to a combination thereof;
Each of x, y, and z is independently 0, 1, 2, 3, 4, 5, or 6;
N'and n in equations (a) to (f) are independently 1 to 10 (for example, 1 to 4, 1, 2, 3, 4).
, 5, 6, 7, 8, 9, or 10);
R'and R'are independently H, optionally substituted linear or branched alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl , Optionally substituted heterocycle, -C (= O) R, optionally substituted heterocyclyl selected from the group;

The bifunctional compound according to any one of claims 1 to 11, wherein represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific. The ULM is a CLM having the chemical structure represented by:

During the ceremony:
W was selected independently from the group of CH2, C = O, NH and N-alkyl;
A is independently selected from H, methyl, or optionally substituted alkyl (eg, C1-C6 alkyl (optionally substituted straight chain, branched chain));
R in formula (g) is independently H, O, OH, N, NH, NH ₂ , halogen, methyl, optionally substituted linear or branched alkyl (eg, optionally substituted). Linear or branched C1-C6 alkyl), optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl (eg, optionally substituted C3-C7 cycloalkyl), optionally Includes at least one of a substituted heterocyclyl (eg, optionally substituted C3-C7 heterocyclyl), an optionally substituted alkyl-aryl (eg, C1-C6 alkyl, C4-C7 aryl, or a combination thereof). -Alkyl-aryl), optionally substituted aryl (eg C5-C7 aryl)
, Amine, amide, or carboxy;
N in equation (g) represents an integer from 1 to 4 (eg, 1, 2, 3, or 4) and at least one R (eg, O, OH, N, NH, NH ₂ , C1) in the equation. -C6 alkyl, C1-C6 alkoxy, -alkyl-aryl (eg, including at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof-alkyl-aryl), aryl (eg, C5-). At least one of C7aryl), amine, amide, or carboxy) has been modified to be covalently attached to PTM, chemical linker group (L), ULM, CLM (or CLM') or a combination thereof; and

The bifunctional compound according to any one of claims 1 to 11, wherein represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific. The ULM is a CLM having the chemical structure represented by:

During the ceremony:
W is independently selected from CH ₂ , O, CHR, C = O, SO ₂ , NH, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and N-alkyl;
Q ₁ , Q ₂ , Q ₃ , Q ₄ , and Q ₅ each independently represent carbon C or N substituted with a group independently selected from H, R', N or N-oxides;
R ¹ is absent or selected from H, OH, CN, C1-C3 alkyl, C = O;
R ² is absent or selected from the group of H, OH, CN, C1-C3 alkyl, CHF ₂ , CF ₃ , CHO, C (= O) NH _2;
R ³ is H, alkyl (eg C1-C6 alkyl or C1-C3 alkyl), substituted alkyl (eg substituted C1-C6 alkyl or C1-C3 alkyl), alkoxy (eg C1-C6 alkoxyl or C1-C3 alkoxyl). ), Substituted alkoxy (eg substituted C1-C6 alkoxyl or C1-C3 alkoxyl);
R ⁴ is selected from H, alkyl, substituted alkyl;
R ⁵ and R ⁶ are independently H, halogen, C (= O) R', CN, OH, CF ₃ ;
X is C, CH, C = O or N;
X ₁ is C = O, N, CH or CH ₂ ;
R'is H, OH, halogen, amine, cyano, alkyl (eg C1-C3 alkyl), substituted alkyl (eg substituted C1-C3 alkyl), alkoxy (eg C1-C3 alkoxyl), substituted alkoxy (eg C1-C3 alkoxy). For example, C1-C3 alkoxyl to be substituted), NR ² R ³ , C (= O) OR ² , optionally substituted phenyl;
n is 0-4;

Is a single bond or a double bond; and the CLM is covalently attached to a PTM, a chemical linker group (L), ULM, CLM (or CLM') or a combination thereof, any of claims 1-11. The bifunctional compound described in Crab. The ULM is selected from the group consisting of substituted imidazoline, substituted spiro-indolinone, substituted pyrrolidine, substituted piperidinone, substituted morpholinone, substituted pyrolopyrimidine, substituted imidazolopyridine, substituted thiazolomidazoline, substituted pyrrolopyrolidinone, and substituted isoquinolinone. It is a (MDM2) binding moiety (MLM) with a chemical moiety; or said ULM is the amino acids alanine (A), valine (V), proline (P), and isoleucine (I) or an unnatural mimetic thereof. The bifunctional compound according to any one of claims 1 to 11, which is an IAP E3 ubiquitin ligase binding moiety (ILM) comprising. The bifunctional compound according to any one of claims 1 to 11, wherein the ULM is an IAP E3 ubiquitin ligase binding moiety (ILM) containing an AVPI tetrapeptide fragment or a derivative thereof. (i) the chemical linker group (L) is selected from the linker of compound 307-873, (ii) the ULM is selected from the ULM of compound 307-873, and (iii) the PTM is compound 307-873. (Iv) the compound further comprises a prodrug chemical moiety selected from the PTM of compound 796-873, or (v) at least one of a combination thereof, claim. The bifunctional compound according to 1. The linker (L) contains a chemical structural unit represented by the following formula:
-( ^AL ) _q- ,
During the ceremony:
(A ^L) _q, the ULM, there the PTM or at least one coupled to the base of its combinations;
q is an integer greater than or equal to 1;
Each A ^L is independently coupled, 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 , optionally 0-6 R ^L1 and / or substituted with ^{R L2} _{C 3-11} cycloalkyl, optionally 0-6 R ^L1 and / or _{C 3-11} heterocyclyl substituted with R ^L2 groups, optionally 0-6 R ^L1 groups and / or ^{aryl substituted with R L2} groups, optionally 0-6 R ^L1 groups and / or R ^L2 Selected from the group consisting of heteroaryls substituted with groups, R ^L1 or R ^L2 are each independently optionally attached to another group and optionally ^{substituted with 0-4 R L5} groups. Forming moieties and / or heterocyclyl moieties; and
R ^L1 , R ^L2 , R ^L3 , R ^L4 and R ^L5 are independent, H, halo, 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, OC _3-8 cycloalkyl, SC _3-8 cycloalkyl, NHC _3-8 cycloalkyl, N ( C _3-8 cycloalkyl) ₂ , N (C _3-8 cycloalkyl) (C _1-8 alkyl), OH, NH ₂ , SH, SO ₂ C _1-8 alkyl, P (O) (OC _1-8) Alkyl) (C _1-8 alkyl), P (O) (OC _1-8 alkyl) ₂ , CC-C _1-8 alkyl, CCH, CH = CH (C _1-8 alkyl), C (C _{1-8 alkyl)} 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 , COC _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 (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 , NH SO _{2 The} bifunctional compound according to any one of claims 1 to 23, which is NH _2. The linker (L) comprises 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-;

In the equation, m, n, o, p, q, and r are independently 0, 1, 2, 3, 4, 5, 6, but the number is zero and NO or OO bonds. The bifunctional compound according to any one of claims 1 to 24, wherein R is selected from the group of H, methyl and ethyl and X is selected from the group of H and F.

The linker (L) is selected from the group consisting of:

The linker (L) is selected from the group consisting of:

The bifunctional compound according to any one of claims 1 to 24, wherein each m and n are independently 0, 1, 2, 3, 4, 5 or 6. The bifunctional compound according to any one of claims 1 to 24, wherein the linker (L) is selected from the group consisting of the following.

The linker (L) contains the following chemical structure:

Is a bifunctional compound according to any one of claims 1 to 23, which indicates a binding point to a PTM moiety or an ULM moiety. The linker (L) contains the following chemical structure:

During the ceremony
W ^L1 and W ^L2 are independent and absent, or aryl, heteroaryl, cyclic, heterocyclic, optionally one or more C atoms substituted with O, C _1-6 alkyl, optionally one. C _1-6 alkene in which one or more C atoms are substituted with O, C _1-6 alkyne in which one or more C atoms are optionally substituted with O, bicyclic, diaryl, biheteroaryl, or two They are heterocyclic, each of which is optionally ^{substituted with R Q} , and each R ^Q is independently H, halo, OH, CN, CF ₃ , hydroxyl, nitro, C ≡ CH, C _2-6 alkoxy, C _2-6 alkynyl, optionally substituted linear or branched C _1- C ₆ alkyl, optionally substituted linear or branched C ₁ -C ₆ alkoxy, optionally _{The OC 1-3} alkyl to be substituted (eg, optionally substituted with one or more -Fs), OH, NH ₂ , NR ^Y1 R ^Y2 , CN, or two R ^Q groups are them. Together with the atom to which it is bonded, it forms a 4- to 8-membered ring system containing 0 to 4 heteroatoms;
Y ^L1 is independently coupled, NR ^YL1 , O, S, NR ^YL2 , C ^YL1 R ^YL2 , C = O, C = S, SO, SO ₂ , optionally substituted linear or branched chain C _1- C ₆ alkyl in the form, optionally one or more C atoms substituted with O; optionally substituted linear or branched C _1- C ₆ alkoxy;
Q ^L is a 3- to 6-membered alicyclic or aromatic ring with 0 to 4 heteroatoms, optionally crosslinked, optionally ^{replaced with 0 to 6 R Q} , and each R ^Q. Is an independently H, a linear or branched C _1-6 alkyl optionally substituted (eg, optionally substituted with one or more halos, or a C _1-6 alkoxyl)? , Or two R ^Q groups form a 3- to 8-membered ring system containing 0 to 2 heteroatoms with the atom to which they are attached;
R ^YL1 and R ^YL2 are independently H, OH, and optionally substituted linear or branched C _1-6 alkyl (eg, one or more halos, or C _1-6 alkoxyls). (Optionally substituted), or R ¹ , R ² contains 0 to 2 heteroatoms along with the atom to which they are attached 3
Forming a ring system of ~ 8 members;
n is 0 to 10; and

Is a bifunctional compound according to any one of claims 1 to 23, which indicates a binding point to a PTM moiety or an ULM moiety. The linker (L)

The bifunctional compound according to claim 29 or 30, selected from the group consisting of. The linker (L) _{contains an optionally substituted C 1-} C ₁₀₀ alkyl, and in the formula,
Each carbon is optional, 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 , optionally substituted with 0-6 R ^L1 and / or R ^L2 _{groups, C 3-11} cycloalkyl, optionally substituted with 0-9 R ^L1 and / or R ^L2 groups C _5-13 spirocycloalkyl, optionally substituted with 0-6 R ^L1 and / or R ^L2 _{groups, C 3-11} heterocyclyl, ^{optionally with 0-8 R L1} and / or R ^L2 groups C _5-13 spiro heterocyclyl substituted, is substituted optionally with 0-6 aryl optionally substituted with at R ^L1 and / or R ^L2 groups, 0-6 R ^L1 and / or R ^L2 group In the formula, R ^L1 or R ^L2 is substituted with a heteroaryl, each independently bonded to another group, optionally with a cycloalkyl and / or heterocyclyl moiety substituted ^{with 0-4 R L5 groups.} Formed; and
R ^L1 , R ^L2 , R ^L3 , R ^L4 and R ^L5 are independent, H, halo, 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, OC _3-8 cycloalkyl, SC _3-8 cycloalkyl, NHC _3-8 cycloalkyl, N ( C _3-8 cycloalkyl) ₂ , N (C _3-8 cycloalkyl) (C _1-8 alkyl), OH, NH ₂ , SH, SO ₂ C _1-8 alkyl, P (O) (OC _1-8) Alkyl) (C _1-8 alkyl), P (O) (OC _1-8 alkyl) ₂ , CC-C _1-8 alkyl, CCH, CH = CH (C _1-8 alkyl), C (C _{1-8 alkyl)} 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 , COC _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 (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 , NH SO _{2 The} bifunctional compound according to any one of claims 1 to 23, which is NH _2. The linker

The bifunctional compound according to any one of claims 1 to 24 and 32, which is selected from the group consisting of. The bifunctional compound according to claim 1, wherein the compound is selected from Tables 1A to 1C. The bifunctional compound according to any one of claims 1 to 34, further comprising at least one polyethylene glycol chain. A composition comprising an effective amount of the bifunctional compound according to any one of claims 1 to 35 and a pharmaceutically acceptable carrier. 35. The composition of claim 35, wherein said composition further comprises an additional bioactive agent, or at least one of the other bifunctional compounds of any of claims 1-34. 36. The composition of claim 36, wherein the additional bioactive agent is an anticancer agent. A pharmaceutically acceptable carrier for treating a disease or disorder in a subject, and claim 1.
A composition comprising an effective amount of at least one of the compounds according to any one of 35 to 35, wherein the method comprises administering the composition to a subject in need thereof, wherein the compound is said to be said. A composition that is effective in treating or ameliorating at least one symptom of a disease or disorder. 38. The composition of claim 38, wherein the disease or disorder is associated with BRaf accumulation and aggregation. The disease or disorder is cancer; heart / face / skin (cardiofaciocutaneous) syndrome; neurofibromatosis type 1; Costello syndrome; Noonan syndrome; or kuroko, electrocardiogram abnormality, hypertelorism, pulmonary valve stenosis, genital abnormality, The composition according to claim 38 or 39, which is a LEOPARD syndrome associated with growth retardation, RAF accumulation and aggregation. 39. The cancer is renal cell carcinoma; pancreatic cancer, colorectal cancer; lung cancer; ovarian cancer; thyroid cancer; hairy cell stellate cell carcinoma; prostate cancer; gastric cancer; hepatocellular carcinoma; or melanoma. The composition described.

Images