Methods and compositions for modulating SHP2

Abstract

Disclosed herein are compounds having the Formula I: SHP-L-Hs (I) and pharmaceutically acceptable salts thereof, wherein SHP is a chemical entity that binds to SHP2 protein, L is a linker, and Hs is chemical entity that binds HSP90 protein. Pharmaceutical compositions comprising the disclosed compounds and their uses for treating diseases responsive to modulation of SHP2 protein are also provided.

Description

[0001] METHODS AND COMPOSITIONS FOR MODULATING SHP2 Related Applications This application claims the benefit of priority to international application No. PCT / CN2023 / 108476, filed July 20, 2023, the entire contents of which are incorporated herein by reference. Field of Invention The present disclosure provides compounds and methods for modulating SHP2, as well as their use for the treatment of a variety of diseases and disorders. Background Protein homeostasis, or proteostasis, refers to the ability of cells to regulate the synthesis, folding, trafficking and degradation of proteins. In particular, properly regulated protein degradation is required for the normal functioning of cells, including their proliferation, differentiation and death, and is often dysregulated in cancers and other diseases (Van Die, Chin J Cancer, 2011, 30:124-137). The ubiquitin-proteasome system (UPS) is one of the major pathways in cells that mediates the disposal and metabolic recycling of proteins (Yu and Matouschek, Annu Rev Biophys, 2017, 46:149-173; Navon and Ciechanover, J Biol Chem, 2009, 284:33713-33718). Ubiquitin is a 76 amino acid-residue protein that is ubiquitously expressed. With respect to protein degradation by the UPS, the process of ubiquitination occurs when a ubiquitin is attached to a lysine amino acid residue in a substrate protein, which involves a series of enzymatic steps. First, ubiquitin is transferred to an E1 ubiquitin-activating enzyme. Second, activated ubiquitin is transferred from the E1 to an E2 ubiquitin-conjugating enzyme. And third, one of the several hundred different E3 ubiquitin ligase enzymes links the ubiquitin to a lysine residue in a substrate protein. Repetition of this enzymatic process results in tagging substrate proteins with polyubiquitin chains. Such ubiquitin-tagged proteins can then be delivered to the proteasome, a large multi-subunit complex that degrades proteins. The ability of some cellular chaperone proteins and chaperone complexes to direct proteins towards the UPS is facilitated by their direct interaction with E3 ubiquitin ligases (Amm et al., Biochim Biophys Acta, 2014, 1843:182-196; Taipale et al., Cell, 2012,150:987-1001). Chemically induced, targeted protein degradation (TPD) has emerged as an important for drug development. A small molecule can be used to promote the interaction of a target protein or proteins with a component or components of various cellular protein degradation pathways, thereby inducing the degradation of the targeted protein or proteins as a way to treat disease. In particular, proteolysis-targeting chimeras (PROTACs) are an example of such small molecules that induce protein degradation of specific proteins by coopting the UPS (Burslem and Crews, Cell, 2020, 181:102-114; Pettersson and Crews, Drug Discov Today Technol, 2019, 31:15-27). PROTAC molecules are bifunctional small molecules that simultaneously bind to a target protein or proteins and an E3 ubiquitin ligase, creating ternary complexes in cells between the target protein(s), the PROTAC molecule and an E3 ligase protein. The induced proximity of the target protein(s) and the E3 ligase causes the ubiquitination of the target protein(s) and subsequent degradation of the target protein(s) by the proteasome. Although PROTACs that incorporate target protein binders that promiscuously bind to multiple proteins can often degrade multiple proteins, in some cases protein-protein interactions between individual targets and an E3 ligase can increase or decrease the observed potency and selectivity of degradation, for example by inhibiting formation of some ternary complexes due to charge repulsion and steric clashing between a given target protein and E3 ligase pair (Pettersson and Crews, Drug Discov Today Technol, 2019, 31:15- 27; Bondeson et al., Cell Chem Biol, 2018, 25:78-87; Gadd et al., Nat Chem Biol, 2017, 13:514-521; Zengerle et al., ACS Chem Biol, 2015, 10:1770-1777). Other methods to chemically induce TPD have also been described, such as molecular glues (Che et al., Bioog Med Chem Lett, 2018, 28:2585-2592), AUTACs, ATTECs and LYTACs (Ding et al., Trends Pharmacol Sci, 2020, 41:464-474). For example, AUTAC technology follows a similar principle of induced proximity, but targets proteins for degradation via autophagy (Daiki et al., Mol Cell, 2019, 76:797- 810). Collectively, TPD technologies have a number of advantages over conventional biochemical inhibitors (Pettersson and Crews, Drug Discov Today Technol, 2019, 31:15-27; Ding et al., Trends Pharmacol Sci, 2020, 41:464-474). For example, unlike conventional inhibitors, TPD agents work sub-stoichiometrically and can typically mediate the sequential degradation of multiple molecules of the target protein(s), often leading to greater potency than the isolated target binding moiety that they incorporate and other biochemical inhibitors. Also, since inhibition of target protein(s) function by TPD agents is principally due to degradation rather than solely biochemical inhibition, recovery of the function of target protein(s) is typically slower than is observed for biochemical inhibitors. TPD agents may also have improved target selectivity over biochemical inhibitors. Finally, TPD agents can target proteins that are not amenable to biochemical inhibition by interacting with binding pockets that do not affect the biochemical activity of the target but still permit its degradation. However, some disadvantages are associated with current TPD technologies. These include the promiscuous degradation of the target protein(s) in many tissues and organs, not just the tissue(s) and organ(s) where the target protein(s) is involved in a disease process, which is expected to result in unwanted side effects of treatment. Also, resistance to these technologies can develop through mutations or alterations in expression of components of the UPS such as E3 ligases (Ottis et al., ACS Chem Biol, 2019, 14:2215-2223; Zhang et al., Mol Cancer Ther, 2019, 18:1302-1311), resulting in loss of therapeutic efficacy. As such, a need exists for improved / alternative methods and compositions for TPD. It is therefore desirable to develop improved / alternative TPD agents that mediate the degradation of proteins involved in cancer and other diseases. HSP90 (Heat Shock Protein 90-kDa) is a molecular machine that interacts with a significant portion of proteins expressed in cells. These proteins include numerous E3 ligases that direct proteins for degradation (Taipale et al., Cell, 2012, 150:987-100). Moreover, small molecules that target HSP90 are observed to accumulate in tumor cells and deplete oncogenic protein levels (Kamal et al., Nature, 2003, 425:407-102003; Moulick et al., Nat Chem Biol.2011, 7:818-26). Src homology 2 domain-containing phosphatase (SHP2) is a protein tyrosine phosphatase encoded by the PTPN11 gene. Mutations in SHP2 are prevalent in Noonan syndrome (50%) and LEOPARD syndrome (80%) (Tartaglia et al., Nat. Genet, 2001, 29: 465-468; Kontaridis et al., J Biol Chem, 2006, 281:6785-6792) and activated mutations of SHP2 have also been identified in juvenile myelomonocytic leukemia (JMML, 35%), myelodysplastic syndrome (10%), B-cell acute lymphoblastic leukemia (7%) and acute leukemia (AML, 4%) (Tartaglia et al., Nat. Genet 2003, 34:148-150). Somatic activating mutations in SHP2 have been associated with several types of solid tumors, including lung adenocarcinoma, colon cancer, neuroblastoma, glioblastoma, melanoma, hepatocellular carcinoma, prostate cancer and breast cancer (Bentires-Alj et al., Cancer Res, 2004, 64:8816-8820). SHP2, however, is not known to be chaperoned by HSP90. Accumulated evidence demonstrates that in cancer cells, SHP2 is involved in multiple signaling processes, such as the RAS-ERK, JAK-STAT, PI3K-AKT, NF-kB and mTOR pathways (Agazie et al., Mol Cell Biol, 2003, 23, 7875-7886). In the RAS-ERK pathway, SHP2 acts as a positive regulator upstream to promote RAS- RAF-ERK kinase cascade signal transduction. SHP2 inhibition thus leads to inactivation of ERK and suppression of the pro-oncogenic function of RAS-RAF- ERK pathway, resulting in cell growth inhibition and apoptosis induction in cancer cells (Bunda et al., Nat Commun 2015, 6:8859). SHP2 also participates in the programmed cell death pathway (PD-1 / PD-L1) and inhibits T cell activation, thus contributing to immune evasion (Chemnitz et al., J Immunol, 2004, 173:945-954). In summary, SHP2 is a promising therapeutic target for cancer and other diseases. Due to the highly conserved and positively charged nature of its proteintyrosine phosphatase (PTP) catalytic site, SHP2 has proved to be a difficult target for the discovery of small molecule inhibitors (Scott et al., Curr Pharm Des, 2010, 16: 1843-1862; Butterworth et al., Future Med Chem, 2014, 6: 1423-1437). Previously reported SHP2 inhibitors have not shown satisfactory selectivity and / or cellular activity, and this has prevented their development as useful therapeutic agents (Chen et al., Mol Pharmacol, 2006, 70:562-570). A breakthrough in this field was the discovery of SHP099, a potent allosteric SHP2 inhibitor, which was shown to selectively block SHP2 phosphatase activity and inhibit cancer cell growth in vitro and tumor growth in xenograft models in mice (Chen et al., Nature, 2016, 535: 148- 152; Garcia Fortanet et al., J Med Chem, 2016, 59:7773-7782). Subsequently, additional allosteric SHP2 inhibitors including SHP389 were reported and several have been advanced into clinical development for the treatment of human cancers (Xie et al., J Med Chem, 2017, 60: 10205-10219; Bagdanoff et al., J Med Chem, 2019, 62: 1781-1792; Sarver et al., J Med Chem, 2019, 62: 1793-1802).

[0002] Allosteric SHP2 inhibitors have been shown to be effective in preclinical models of Kirsten rat sarcoma (KRAS)-mutant human cancers. Depletion of SHP2 protein may provide an alternative and perhaps even more effective strategy for blocking SHP2 activity. Mainardi et al. demonstrated that SHP2 inactivation by CRISPR-Cas9 induced senescence and impaired tumor growth in xenograft models of KRAS-mutant tumors (Mainardi et al., Nat Med, 2018, 24:961-967). Ruess et al., disclosed that knockout of the PTPN11 gene, which encodes SHP2, in KRAS-mutant human ductal adenocarcinoma (PDAC) cells resulted in reduced in cell proliferation and PTPN11-knockout cells were uniquely susceptible to mitogen-activated protein kinase (MEK) inhibitors (Ruess et al., Nat Med, 2018, 24:954-960). Such findings provide evidence that depletion of SHP2 protein in tumor cells could be an effective therapeutic strategy for human cancers, particularly those carrying a KRAS-mutation.

[0003] It is therefore desirable to design and develop agents that bind both HSP90 and SHP2 to induce TPD of SHP2 protein as a treatment for cancer and other diseases. It is also desirable to develop agents that induce degradation of both SHP2 protein and one or more other proteins, particularly those involved in mediating resistance to SHP2 inhibitors. Moreover, it is desirable to develop agents to inhibit SHP2 and HSP90 oncogenic signaling. Finally, it is desirable to develop agents that accumulate in tumor cells. SUMMARY Disclosed herein are compounds having the Formula I: SHP-L-Hs (I) and pharmaceutically acceptable salts thereof, wherein SHP is a chemical entity that binds to SHP2 protein, L is a linker, and Hs is chemical entity that binds HSP90 protein. In some aspects, the compounds of Formula I modulate SHP2 protein. For example, in some aspects the compounds of Formula I degrade SHP2 protein. In other aspects, the compounds of Formula I deplete SHP2 protein. In yet other aspects, the compounds of Formula I inhibit SHP2 protein. Also provided are pharmaceutically acceptable compositions comprising the compounds of Formula I and pharmaceutically acceptable salts, as well as methods for their manufacture. Also provided is the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition comprising a compound of Formula I or a pharmaceutically acceptable salt therefore, for treating one or more conditions responsive to the modulation (e.g., degradation) of SHP2 protein. DETAILED DESCRIPTION 1. General Description of Compounds In a first embodiment, the compounds described herein are of the Formula I: S-L-Hs (I) or a pharmaceutically acceptable salt thereof, wherein S is a chemical entity that binds to SHP2 protein, L is a linker, and Hs is chemical entity that binds HSP90 protein; 2. Definitions Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, biochemistry, biology, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. As used herein, the articles “a” and “an” refer to one or more than one, e.g., to at least one, of the grammatical object of the article. The use of the words "a" or "an" when used in conjunction with the term "comprising" herein may mean "one," but it is also consistent with the meaning of "one or more," "at least one," and "one or more than one." In the claims, as well as in the specification above, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," "composed of," and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases "consisting of' and "consisting essentially of' shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03. The terms “IC50”, “IC50”, “EC50”, “EC50”, “GI50” or “GI50”refers to an amount, concentration, or dosage of a compound that is required for 50% inhibition of a maximal response in an assay that measures such a response. The term “compound”, as used herein, unless otherwise indicated, refers to any compound disclosed herein. In some aspects one or more hydrogen atoms on a disclosed compound may be replaced with deuterium. Such deuterated compounds may have one or more improved pharmacokinetic or pharmacodynamic properties (e.g., longer half-life) compared to the equivalent “un-deuterated” compound. As used herein, the term "alkyl" means a saturated straight chain or branched non-cyclic hydrocarbon having, unless specified otherwise, from 1 to 10 carbon atom e.g., (C1-C6)alkyl or (C1-C4)alkyl. Representative straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4- methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3- dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4- dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylpentyl, 2,2-dimethylhexyl, 3,3- dimethylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3- ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2- methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, 3,3- diethylhexyl and the like. As used herein, the term "alkenyl" means a saturated straight chain or branched non-cyclic hydrocarbon having, unless specified otherwise, from 2 to 10 carbon atoms (e.g., (C2-C6)alkenyl or (C2-C4)alkenyl) and having at least one carbon- carbon double bond. Representative straight chain and branched (C2-C10)alkenyls include vinyl, allyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3- methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 1- nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl and the like. As used herein, the term "alkynyl" means a saturated straight chain or branched non-cyclic hydrocarbon having, unless specified otherwise, from 2 to 10 carbon atoms (e.g., (C2-C6)alkynyl or (C2-C4)alkynyl) and having at least one carbon- carbon triple bond. Representative straight chain and branched alkynyls include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1- butynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl, 6- heptynyl, 1-octynyl, 2-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl, 8-nonynyl, 1- decynyl, 2-decynyl, 9-decynyl, and the like. The term “aryl” used alone or as part of a larger moiety as in “-(C1- C4)alkylaryl”, refers to monocyclic and bicyclic carbon ring systems having a total of six to 10 ring members, wherein at least one ring in the system is aromatic. Examples include, but are not limited to phenyl, naphthyl, anthracyl and the like. It will be understood that when specified, optional substituents on an aryl group may be present on any substitutable position. As used herein, the term “cycloalkyl" means a saturated, monocyclic alkyl radical having from e.g., 3 to 10 carbon atoms (e.g., from 3 to 6 carbon atoms). Representative cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecanyl. The term “oxo” refers to the group =O. As used herein, the term "haloalkyl" means and alkyl group in which one or more (including all) the hydrogen radicals are replaced by a halo group, wherein each halo group is independently selected from -F, -Cl, -Br, and -I. Representative haloalkyl groups include trifluoromethyl, bromomethyl, 1,2-dichloroethyl, 4- iodobutyl, 2-fluoropentyl, and the like. “Alkoxy” means an alkyl radical attached through an oxygen linking atom, represented by –O-alkyl. For example, “(C1-C4)alkoxy” includes methoxy, ethoxy, proproxy, and butoxy. “Haloalkoxy” is a haloalkyl group which is attached to another moiety via an oxygen atom such as, e.g., –OCHF2or –OCF3. As used herein, the term "halogen" or "halo" means F, Cl, Br or I. As used herein, the term "heterocyclyl" means a 4- to 12-membered monocyclic or polycyclic saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S. The heterocycle may be attached via any heteroatom or carbon atom, as valency permits. Representative heterocycles include morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, oxiranyl, dioxanyl, oxetanyl, dihydrofuranyl, dihydropyranyl, isoindolinyl, dihydropyridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrindinyl, tetrahydropyrimidinyl, diazabicyclooctanyl, hexahydropyrrolizinyl, 2-azaspiro[3.3]heptanyl, 2,7-diazaspiro[3.5]nonanyl, 2- azaspiro[3.5]nonanyl, 3-azabicyclo[3.1.0]hexanyl, 8-azabicyclo[3.2.1]octanyl, 3,8- diazabicyclo[3.2.1]octanyl, 3,6-diazabicyclo[3.1.1]heptanyl, octahydro-1H- pyrrolo[2,3-c]pyridinyl, and the like. Optional substituents on a heterocyclyl group may be present on any substitutable position and, include, e.g., the position at which the heterocyclyl is attached, valence permitting. As used herein, the term "heteroaryl" means a 5- to 12-membered aromatic radical containing 1-4 heteroatoms selected from N, O, and S. A heteroaryl group may be mono- or bicyclic. The heteroaryl may be attached via any heteroatom or carbon atom, as valency permits. Representative heteroaryl groups include pyridyl, furanyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, thiadiazolyl, isoquinolinyl, indazolyl, benzoxazolyl, benzofuryl, indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl, quinazolinyl, purinyl, benzothienyl, and the like. Optional substituents on a heteroaryl group may be present on any substitutable position and, include, e.g., the position at which the heteroaryl is attached, valence permitting. When used in connection to describe a chemical group that may have multiple points of attachment, a hyphen (-) designates the point of attachment of that group to the variable to which it is defined. For example, -(C1-C4)alkylaryl and means that the point of attachment for these groups occurs on the alkyl group. The term “alkylene” refers to a linear or branched saturated divalent hydrocarbon radical. For example, C1-6alkanediyl refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms. The term “aralkyl” or “arylalkyl” refers to a monovalent alkyl group substituted with one or more aryl groups. Examples of aralkyl groups include, but are not limited to, benzyl, phenylethyl (including all isomeric forms, e.g., 1-phenylethyl and 2-phenylethyl), and phenylpropyl (including all isomeric forms, e.g., 1- phenylpropyl, 2-phenylpropyl, and 3-phenylpropyl). A hash bond as in “ ” represents the point at which the depicted group is attached to the defined variable. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position. Optional substituents include, but are not limited to, one or more groups selected from cyano (–CN), halo, imino (=NH), nitro (–NO2), oxo (=O), – C(O)Ri, –C(O)ORi, –C(O)NRiiRiii, –C(O)SRi, –C(NRi)NRiiRiii, –C(S)Ri, –C(S)ORi, – C(S)NRiiRiii, –ORi, –OC(O)Ri, –OC(O)ORi, –OC(O)NRiiRiii, –OC(O)SRi, – OC(NRi)NRiiRiii, –OC(S)Ri, –OC(S)ORi, –OC(S)NRiiRiii, –OP(O)(ORii)ORiii, – OS(O)Ri, –OS(O)2Ri, –OS(O)NRiiRiii, –OS(O)2NRiiRiii, –NRiiRiii, –NRiC(O)Riv, – NRiC(O)ORiv, –NRiC(O)NRiiRiii, –NRaC(O)SRiv, –NRiC(NRiv)NRiiRiii, –NRiC(S)Riv, –NRiC(S)ORiv, –NRiC(S)NRiiRiii, –NRiS(O)Riv, –NRiS(O)2Riv, –NRiS(O)NRiiRiii, – NRiS(O)2NRiiRiv, –SRi, –S(O)Ri, –S(O)2Ri, –S(O)NRiiRiv, –S(O)2NRiiRiv, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein said alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are each further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa, wherein each Ri, Rii, Riii, and Rivis independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qaor Riiand Riiitogether with the N atom to which they are attached form heterocyclyl optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa, wherein each Qais independently selected from cyano, halo, imino, nitro, oxo, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, C6-14aryl, heteroaryl, heterocyclyl, –C(O)Rv, –C(O)ORv, – C(O)NRviRvii, –C(O)SRv, –C(NRv)NRviRvii, –C(S)Rv, –C(S)ORv, –C(S)NRviRvii, – ORv, –OC(O)Rv, –OC(O)ORv, –OC(O)NRviRvii, –OC(O)SRv, –OC(NRv)NRviRvii, – OC(S)Rv, –OC(S)ORv, –OC(S)NRviRvii, –OP(O)(ORv)ORvi, –OS(O)Rv, –OS(O)2Rv, – OS(O)NRviRvii, –OS(O)2NRvRvii, –NRviRvii, –NRvC(O)Rviii, –NReC(O)ORvi, –NRvC(O)NRviRvii, –NRvC(O)SRvi, – NRvC(NRviii)NRviRvii, –NRvC(S)Rviii, –NRvC(S)ORvi, –NRvC(S)NRviRvii, – NRvS(O)Rviii, –NRvS(O)2Rviii, –NRvS(O)NRviRvii, –NRvS(O)2NRviRvii, –SRv, – S(O)Rv, –S(O)2Rv, –S(O)NRviRvii, and –S(O)2NRviRvii; wherein each Rv, Rvi, Rvii, and Rviiiis independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heterocyclyl; or (iii) Rviand Rviiitogether with the N atom to which they are attached form heterocyclyl. The term "linker" or "tether," used interchangeably, refers to a chemical moiety that joins two other moieties (e.g., a first binding moiety and a second binding moiety). A linker can covalently join a first binding moiety and a second binding moiety. In one aspect, the linker is uncleavable in vivo. In one aspect, the linker comprises one or more cyclic ring systems. In another aspect, the linker comprises an alkyl chain optionally substituted by and / or interrupted with one or more chemical groups. In one aspect, the linker comprises optimal spatial and chemical properties to effectuate optimal therapeutic activity. In one aspect, the linker does not interfere with the ability of the first binding moiety and / or the second binding moiety to bind their respective targets (e.g., HSP90 and SHP2). In one aspect, the linker alters the ability of the first binding moiety and / or the second binding moiety to bind their respective targets (e.g., HSP90 and SHP2). The term “SHP2” refers to the protein product of the Src homology 2 domain- containing tyrosine phosphatase “PTPN11” gene. The term “HSP90” refers collectively, individually or in various combinations to the protein products of members of the heat shock protein 90 (90 kDa) gene family, including: HSP90AA1 (HSP90-alpha or HSP90α), HSP90AB1 (HSP90-beta or HSP90β), HSP90B1 (GRP94) and TRAP1. The term KRAS refers to the protein product of the KRAS GTPase proto- oncogene. A “chemical entity which binds SHP2” refers to a small molecule or a distinct portion of a larger molecule which binds to a portion of SHP2. In some aspects, the chemical entity which binds SHP2 is a small molecule. In some aspects, the chemical entity which binds SHP2 is a small molecule having a molecular weight of less than 2,000 g / mol. In some aspects, the chemical entity which binds SHP2 induces a confirmation change in SHP2. When used in connection to describe a chemical group that may have multiple points of attachment, a hyphen (-) designates the point of attachment of that group to the variable to which it is defined. For example, -NRaRband -C(O)NRa(C1-4alkylene)NRaR mean that the point of attachment for these groups occur on the nitrogen atom and carbon atom respectively. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure relative to all of the other stereoisomers. Percent by weight pure relative to all of the other stereoisomers is the ratio of the weight of one stereoisomer over the weight of the other stereoisomers. For example, when a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight optically pure. Percent optical purity by weight is the ratio of the weight of the enantiomer over the weight of the enantiomer plus the weight of its optical isomer. For use in medicines, the pharmaceutically acceptable salts of the disclosed compounds refer to non-toxic “pharmaceutically acceptable salts.” Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic / anionic or basic / cationic salts. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include e.g., salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, nitric, and sulfuric acids) and of organic acids (such as, acetic acid, benzenesulfonic, benzoic, methanesulfonic, and p- toluenesulfonic acids). Compounds of the present teachings with acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include e.g., ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts). Compounds with a quaternary ammonium group also contain a counteranion such as chloride, bromide, iodide, acetate, perchlorate and the like. Other examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, benzoates and salts with amino acids such as glutamic acid. The term “pharmaceutically acceptable carrier” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Any compositions or methods provided herein can be combined with one or more of any of the other compositions and methods provided herein. As used herein, the term "subject" refers to human and non-human animals, including veterinary subjects. The term "non-human animal" includes all vertebrates, e.g., mammals and non-mammals, such as non-human primates, mice, rabbits, sheep, dog, cat, horse, cow, chickens, amphibians, and reptiles. In a preferred embodiment, the subject is a human and may be referred to as a patient. As used herein, the terms "treat," "treating" or "treatment" refer, preferably, to an action to obtain a beneficial or desired clinical result including, but not limited to, alleviation or amelioration of one or more signs or symptoms of a disease or condition, diminishing the extent of disease, stability (i.e., not worsening) of the state of disease, amelioration or palliation of the disease state, diminishing rate of or time to progression, and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival in the absence of treatment. Treatment does not need to be curative. A "therapeutically effective amount" is that amount sufficient to treat a disease in a subject. A therapeutically effective amount can be administered in one or more administrations. In one aspect, a therapeutically effective amount refers to a dosage of from about 0.01 to about 100 mg / kg body weight / day. The terms "administer," "administering" or "administration" include any method of delivery of a pharmaceutical composition or agent into a subject's system or to a particular region in or on a subject. In certain embodiments of the invention, an agent is administered intravenously, intramuscularly, subcutaneously, intradermally, intranasally, orally, transcutaneously, or mucosally. In a preferred embodiment, an agent is administered intravenously. In another preferred embodiment, an agent is administered orally. Administering an agent can be performed by a number of people working in concert. Administering an agent includes, for example, prescribing an agent to be administered to a subject and / or providing instructions, directly or through another, to take a specific agent, either by self-delivery, e.g., as by oral delivery, subcutaneous delivery, intravenous delivery through a central line, etc.; or for delivery by a trained professional, e.g., intravenous delivery, intramuscular delivery, intratumoral delivery, etc. 3. Compounds In a second embodiment, SHP in the compound of Formula I is of the formula: or a pharmaceutically acceptable salt thereof, wherein R1is selected from halo and C1-C3haloalkyl; R2is selected from NH2, H and D; R3is selected from R4is selected from C1-4alkyl and C3-C6cycloalkyl; R5is selected from H and C1-C4alkyl; and X is selected from -O- and -CH2-; and the wavy line designates the connection point to L, wherein the remaining variables are as described above for Formula I. Alternatively, as part of a second embodiment, SHP is of the Formula II-a: or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described above for Formula I. In another alternative, as part of a second embodiment, SHP is of the Formula II-b: or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described above for Formula I. In yet another alternative, as part of a second embodiment, SHP is of the Formula II-c: or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described above for Formula I. In yet another alternative, as part of a second embodiment, SHP is of the Formula II-d: or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described above for Formula I. In a third embodiment, SHP in the compound of Formula I or pharmaceutically acceptable salt thereof is selected from

[0004] , wherein the remaining variables are as described above for Formula I or the second embodiment. In a fourth embodiment, Hs in the compound of Formula I or pharmaceutically acceptable salt thereof is selected from ,

[0005] Q and U are each independently selected from phenyl, heteroaryl, heterocyclyl, and cycloalkyl, each of which being optionally substituted with 1 to 3 groups selected from R14; R17, R18, R19and R20are each independently selected from hydrogen, halo, CN, (C1-C4)alkyl, halo(C1-C4)alkyl, and -C(O)NRaRb; R21and R22are each independently hydrogen, (C1-C4)alkyl, or halo(C1- C4)alkyl; R23is hydrogen, (C1-C4)alkyl, OH, -O(C1-C4)alkyl, or -O[halo(C1-C4)alkyl], W is 5- or 6-membered heteroaryl optionally substituted with 1 to 3 groups selected from R14; V is phenyl or 5- to 9-membered heteroaryl optionally substituted with 1 to 3 groups selected from R15; R6is halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, or halo(C1- C4)alkoxy; R14is (C1-C4)alkyl, halo(C1-C4)alkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, (C2- C6)alkynyl, halo(C2-C6)alkynyl, CN, -C1-4alkylORe, -ORe, -C(O)Re, -C(O)ORe, - C(O)NReRf, -C(O)NRe(C1-4alkylene)ORe, -C(O)NRe(C1-4alkylene)NReRf, -C(O)NRe(C1-4alkylene)OR, -NReRf, -O(C1-4alkylene)NReRf, -SH, - S(C1-4alkyl), -C1-4alkylNReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -SO2NReRf, - NRe(C1-4alkyl)ORe, -NRe(C1-4alkyl)NReRf, -C1-6alkylC(O)NReRf, phenyl or 5- to 7- membered heteroaryl, wherein said phenyl and 5- to 7-membered heteroaryl are each optionally and independently substituted with 1 to 3 groups selected from R16; Reand Rfare each independently selected from hydrogen and (C1-C4)alkyl, wherein said (C1-C4)alkyl is optionally substituted with one or more halo or a 3- to 7- membered heterocyclyl, or both; R15and R16are each independently halo, -NReRf, (C1-C4)alkyl, halo(C1- C4)alkyl, (C1-C4)alkoxy, or halo(C1-C4)alkoxy; and the wavy line designates the connection point to L, wherein the remaining variables are as described above for Formula I or any one of the second or third embodiment. Alternatively, as part of a fourth embodiment, Hs is selected from wherein the remaining variables are as described above for Formula I or any one of the second or third embodiment. In another alternative, as part of a fourth embodiment, Hs is selected from wherein the remaining variables are as described above for Formula I or any one of the second or third embodiment. In a fifth embodiment, R6is (C1-C4)alkyl, wherein the remaining variables are as described above for Formula I or any one of the second to fourth embodiments. In a sixth embodiment, R14is -C(O)NReRfand Reand Rfare each independently selected from hydrogen and (C1-C4)alkyl, wherein said (C1-C4)alkyl is optionally substituted with one or more halo, wherein the remaining variables are as described above for Formula I or any one of the second to fifth embodiments. In a seventh embodiment, R15is hydrogen, wherein the remaining variables are as described above for Formula I or any one of the second to sixth embodiments. In an eighth embodiment, R20is hydrogen, halo or (C1-C4)alkyl, wherein the remaining variables are as described above for Formula I or any one of the second to seventh embodiments. In a ninth embodiment, R23is hydrogen, (C1-C4)alkyl, or OH, wherein the remaining variables are as described above for Formula I or any one of the second to eighth embodiments. In a tenth embodiment, R22is hydrogen, wherein the remaining variables are as described above for Formula I or any one of the second to ninth embodiments.

[0006] In an eleventh embodiment, Hs is selected from: , variables are as described above for Formula I or any one of the second to tenth embodiments. In a twelfth embodiment, L in the compound of Formula I or pharmaceutically acceptable salt thereof is selected from (C1-C6)alkyl, (CH2CH2O)v, (C1-C6)alkylNRq, (C1-C6)alkylC(O), (C1-C6)alkylC(O)O, (C1-C6)alkylOC(O), (C1-C6)alkylC(O)NRq, (C1-C6)alkylNRqC(O), X1-Het1-X2, X1-Het1-X2-X3, X1-Het1-X2-Het2-X3-, X1-Het1-X2- Het2-X3-Het3-X4-, (CH2CH2O)v-X1-Het1-X2, (CH2CH2O)v-X1-Het1-X2-X3, (CH2CH2O)v-X1-Het1-X2-Het2-X3-, (CH2CH2O)v-X1-Het1-X2-Het2-X3-Het3-X4-, (C1- C6)alkylNRq-X1-Het1-X2, (C1-C6)alkylNRq-X1-Het1-X2-X3, (C1-C6)alkylNRq-X1-Het1- X2-Het2-X3-, (C1-C6)alkylNRq-X1-Het1-X2-Het2-X3-Het3-X4-, (C1-C6)alkylC(O)-X1- Het1-X2, (C1-C6)alkylC(O)-X1-Het1-X2-X3, (C1-C6)alkylC(O)-X1-Het1-X2-Het2-X3-, (C1-C6)alkylC(O)-X1-Het1-X2-Het2-X3-Het3-X4-, (C1-C6)alkylC(O)NRq-X1-Het1-X2, (C1-C6)alkylC(O)NRq-X1-Het1-X2-X3, (C1-C6)alkylC(O)NRq-X1-Het1-X2-Het2-X3-, and (C1-C6)alkylC(O)NRq-X1-Het1-X2-Het2-X3-Het3-X4-; each X1, X2, X3, and X4are independently absent or selected from (C1- C4)alkylene, O, NRq, and C(O); v is 1, 2, 3, 4, 5, or 6 Rqis hydrogen or (C1-C4)alkyl; and each Het1, Het2, and Het3are independently selected from a 4- to 6-membered heterocyclyl and (C3-C6)cycloalkyl, each optionally substituted with 1 to 3 groups selected from halo, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, and (C1- C4)haloalkoxy, wherein the remaining variables are as described above for Formula I or any one of the second to eleventh embodiments. Alternatively, as part of a twelfth embodiment, L is selected from (C1-C6)alkyl, (C1-C6)alkylNRq, X1-Het1-X2, X1-Het1- X2-X3, X1-Het1-X2-Het2-X3-, and X1-Het1-X2-Het2-X3-Het3-X4-, wherein the remaining variables are as described above for Formula I or any one of the second to eleventh embodiments. In a thirteenth embodiment, X1, X2, X3, and X4is independently absent or selected from piperidinyl, piperazinyl, cyclohexyl, cyclobutyl, azetidinyl, and pyrrolidinyl, each optionally substituted with 1 to 3 groups selected from halo, (C1- C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, and (C1-C4)haloalkoxy, wherein the remaining variables are as described above for Formula I or any one of the second to twelfth embodiments. Alternatively, as part of a thirteenth embodiment, each X1, X2, X3, and X4is independently absent or selected from piperidinyl, piperazinyl, cyclohexyl, cyclobutyl, azetidinyl, and pyrrolidinyl, each optionally substituted with 1 to 3 groups selected from halo, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, and (C1-C4)haloalkoxy, wherein the remaining variables are as described above for Formula I or any one of the second to twelfth embodiments. In another alternative, as part of a thirteenth embodiment, each X1, X2, X3, and X4is independently absent or selected from piperidinyl, piperazinyl, and pyrrolidinyl, wherein the remaining variables are as described above for Formula I or any one of the second to twelfth embodiments. In a fourteenth embodiment, L is , wherein the * indicates the point of attachment to Hs, wherein the remaining variables are as described above for Formula I or any one of the second to thirteenth embodiments Additional compounds are further disclosed in the Exemplification and are included in the present disclosure. Pharmaceutically acceptable salts thereof as well as the neutral forms are included. 4. Uses, Formulation and Administration Compounds and compositions described herein are generally useful as anticancer therapies. In one aspect, the disclosed compounds and compositions behave as chaperone-mediated protein degraders / depleters (CHAMPs) in which one portion of the compounds is responsible for binding SHP2 and the other portion is responsible for binding to HSP90 or other chaperone proteins or protein components of chaperone complexes (e.g., members of the HSP70 family). Their mechanisms of action include, but are not limited to, degrading SHP2 and thereby impeding down- stream signals that may result in inhibition of cancer cell growth and / or induction of cancer cell death or other SHP2 functions. In one aspect, the disclosed compounds effectuate the degradation of SHP2. In one aspect, the disclosed compounds and compositions include chaperone or chaperone complex binders that have a range of different binding affinities. In different embodiments, it is desirable to use a high-affinity binder, a moderate-affinity binder or a low-affinity binder. Since a HSP90-binding moiety that interacts with the N-terminal ATP-binding pocket of HSP90 may inhibit HSP90 activity and induce the degradation of HSP90 client proteins (Schopf et al., Nat Rev Mol Cell Biol, 2017, 18:345-360), some CHAMP molecules may not only induce the degradation of the desired target protein or proteins (which may or may not be HSP90 client proteins), but also simultaneously induce the degradation of HSP90 client proteins. EGFR and ERBB2 (HER2) are two such HSP90 client proteins (Xu et al., J Biol Chem, 2001, 276:3702-3708). Such combinations of degradation activities may increase the biological activity of CHAMP molecules over that of other TPD technologies directed towards the same target(s) and may evade mechanisms of resistance to SHP2 inhibitors and degraders such as that mediated by the EGFR pathway. In one aspect, the disclosed compounds and compositions behave as tumor- targeted CHAMPs in which one portion of the compounds is responsible for binding SHP2 and the other portion is responsible for binding to HSP90 or other chaperone proteins or protein components of chaperone complexes (e.g., members of the HSP70 family). In one aspect, the disclosed compounds and compositions have prolonged pharmacokinetic exposures in cancer cells and tumors relative to normal cells, tissues and organs (Kamal et al., Nature, 2003, 425:407-410; Vilenchik et al., Chem Biol, 2004, 11:787-797). In one aspect, the disclosed compounds have increased therapeutic indexes relative to other SHP2 degraders and inhibitors. Thus, provided herein are methods of treating conditions which are responsive to the modulation (e.g., degradation or depletion) of SHP2 comprising administering to a subject in need thereof, a therapeutically effective amount of one or more compounds or compositions described herein. Also provided is the use of one or more compounds or compositions described herein in the manufacture of a medicament for treating conditions which are responsive to the modulation (e.g., degradation or depletion) of SHP2. Further provided is the use of a compound or composition described herein for treating conditions which are responsive to the modulation (e.g., degradation or depletion) of SHP2. In one aspect, the condition treated by the present compounds and compositions is a cancer. The terms "cancer" or "tumor" are well known in the art and refer to the presence, e.g., in a subject, of cells possessing characteristics typical of cancer-causing cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, decreased cell death / apoptosis, and certain characteristic morphological features. Cancer cells are often in the form of a solid tumor. However, cancer also includes non-solid tumors, e.g., blood tumors, e.g., leukemia, wherein the cancer cells are derived from bone marrow. As used herein, the term "cancer" includes pre-malignant as well as malignant cancers. Cancers include, but are not limited to, acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, Burkitt's lymphoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen- receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin and non-Hodgkin), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin, and uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor. Other cancers include primary cancer, metastatic cancer, oropharyngeal cancer, hypopharyngeal cancer, liver cancer, gall bladder cancer, bile duct cancer, small intestine cancer, urinary tract cancer, kidney cancer, urothelium cancer, female genital tract cancer, uterine cancer, gestational trophoblastic disease, male genital tract cancer, seminal vesicle cancer, testicular cancer, germ cell tumors, endocrine gland tumors, thyroid cancer, adrenal cancer, pituitary gland cancer, hemangioma, sarcoma arising from bone and soft tissues, Kaposi's sarcoma, nerve cancer, ocular cancer, meningial cancer, glioblastomas, neuromas, neuroblastomas, Schwannomas, solid tumors arising from hematopoietic malignancies such as leukemias, metastatic melanoma, recurrent or persistent ovarian epithelial cancer, fallopian tube cancer, primary peritoneal cancer, gastrointestinal stromal tumors, colorectal cancer, gastric cancer, melanoma, glioblastoma multiforme, non-squamous non-small-cell lung cancer, malignant glioma, epithelial ovarian cancer, primary peritoneal serous cancer, metastatic liver cancer, neuroendocrine carcinoma, refractory malignancy, triple negative breast cancer, HER2-amplified breast cancer, nasopharageal cancer, oral cancer, biliary tract, hepatocellular carcinoma, squamous cell carcinomas of the head and neck (SCCHN), non-medullary thyroid carcinoma, recurrent glioblastoma multiforme, neurofibromatosis type 1, CNS cancer, liposarcoma, leiomyosarcoma, salivary gland cancer, mucosal melanoma, acral / lentiginous melanoma, paraganglioma, pheochromocytoma, advanced metastatic cancer, solid tumor, triple negative breast cancer, colorectal cancer, sarcoma, melanoma, renal carcinoma, endometrial cancer, thyroid cancer, rhabdomysarcoma, multiple myeloma, ovarian cancer, glioblastoma, gastrointestinal stromal tumor, mantle cell lymphoma, and refractory malignancy. "Solid tumor," as used herein, is understood as any pathogenic tumor that can be palpated or detected using imaging methods as an abnormal growth having three dimensions. A solid tumor is differentiated from a blood tumor such as leukemia. However, cells of a blood tumor are derived from bone marrow; therefore, the tissue producing the cancer cells is a solid tissue that can be hypoxic. "Tumor tissue” or “tumorous tissue" are understood as cells, extracellular matrix, and other naturally occurring components associated with the solid tumor. A specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound described herein in the composition will also depend upon the particular compound in the composition. Abbreviations: DMF: dimethylformaldehyde CH2Cl2: dichloromethane EtOAc: ethyl acetate PE: petroleum ether THF: Tetrahydrofuran MeOH: Methanol CDI: 1,1'-Carbonylbis-1H-imidazole DIEA: N,N-Diisopropylethylamine HOBt: 1-Hydroxybenzotriazole hydrate EDCI: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- oxide hexafluorophosphate TFA: Trifluoroacetic Acid BINAP: 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl XantPhos: 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene Pd2(dba)3:Tris(dibenzylideneacetone)dipalladium(0) DEA: Diethanolamine SEM-Cl: (2-Chloromethoxyethyl)trimethylsilane Pd(dppf)Cl2:1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) chloride DMAP: 4-Dimethylaminopyridine T3P: Propyl phosphate tricyclic anhydride solution STAB: Sodium triacetoxyborohydride MTBE: Methyl tert-butyl ether EXEMPLIFICATION Chemical Synthesis The representative examples that follow are intended to help illustrate the present disclosure, and are not intended to, nor should they be construed to, limit the scope of the invention. General starting materials were obtained from commercial sources or prepared in other examples, unless otherwise noted. Preparation of Intermediates Scheme 1 to Scheme 7 illustrate the synthetic procedures of some intermediates which was used in the synthesis of claimed compounds. Other intermediates can be prepared in a similar manner. Scheme 1 Step 1: Methyl 1-(4-nitrobenzyl)piperidine-4-carboxylate (1-2) To the mixture of 1-(bromomethyl)-4-nitrobenzene (40 g, 185.16 mmol) and methyl piperidine-4-carboxylate (26.51 g, 185.16 mmol) in DMF (300 mL) was added K2CO3(51.18 g, 370.22 mmol). The mixture was stirred at r.t. overnight. The mixture was poured into 500 mL of H2O. It was extracted with ethyl acetate (500 mL*2). Combined organic phase was washed with H2O and brine, and was dried (Na2SO4), filtered and concentrated to give desired 1-2 as yellow solid (49 g). Step 2: methyl 1-(4-aminobenzyl)piperidine-4-carboxylate (1-3) To the mixture of methyl 1-(4-nitrobenzyl) piperidine-4-carboxylate (5.0 g, 17.97 mmol) and NH4Cl (4.81 g, 89.83 mmol) in MeOH / H2O (25 mL / 25 mL) was added Fe powder (5.02 g, 89.83 mmol). The mixture was refluxed overnight. After cooled to r.t., the mixture was filtered and the filtrate was concentrated followed by extraction with ethyl acetate (50 mL*2). Combined organic phase was washed with H2O and brine, then dried under Na2SO4, filtered and concentrated under vacuum to give 1-3 as brown oil (3.8 g) Step3: Methyl 1-(4-(2,4-dihydroxy-5-isopropylphenylthioamido)benzyl) piperidine-4-carboxylate (1-4) To a solution of compound (1-3-1) (20.69 g, 90.61 mmol), ClCH2COONa (10.55 g, 90.61 mmol) and NaHCO3(15.22 g, 181.22 mmol) in DMF (100 mL) was stirred at 40°C for 3 hours. Compound 1-3 (15.0 g, 60.41 mmol) in DMF (50 mL) was added to the mixture. After the resulting mixture was heated to 80°C and stirred overnight, the mixture was poured into water and precipitated solid was collected by filtration. The mother liquid was extracted with ethyl acetate (200 mL*2). Combined organic phase was washed with H2O and brine, then was dried (Na2SO4), filtered and concentrated. It was combined with the solid filtered and purified by silica gel column to give 1-4 (22.1 g) as a yellow solid. Step 4: methyl 1-(4-(7-hydroxy-6-isopropyl-2-oxo-4-thioxo-2H-benzo[e][1,3] oxazin-3(4H)-yl)benzyl)piperidine-4-carboxylate (1-5) The solution of compound 1-4 (8.0 g, 18.08 mmol) and CDI (11.72 g, 72.3 mmol) in THF (80 mL) was stirred for 2 hours at room temperature. The reaction solution was poured into brine (1 L) and extracted with EtOAc (200 mL*3). The combine organic layers were washed with brine, dried over Na2SO4and concentrated to give the 1-5 (crude) which was used for next step reaction without purification. Step 5: Methyl-1-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4- triazol-4-yl)benzyl)piperidine-4-carboxylate (1-6) To a solution of compound 1-5 (8.0 g, 17.07 mmol) in EtOH (80 mL) was added NH2NH2H2O (1.11 g, 22.2 mmol). Then the resulting mixture was stirred at room temperature overnight. The precipitated solid was filtered and dried to give 1-6 (4 g) as a white solid. Step 6: 1-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4- yl)benzyl)piperidine-4-carboxylic acid; Intermediate (1) To a solution of compound 1-6 (4.0 g, 8.57 mmol) in MeOH / THF (1:1, 30 mL) was added the solution (15 mL) of LiOH H2O (1.8 g, 42.87 mmol). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was added 2N HCl to adjust pH to 5-6. The precipitated solid was filtered and dried to give intermediate (1) (2.5 g) as a white solid. Scheme 2

[0007] Preparation of compound 1-3-1 To a solution of 4-isopropylbenzene-1,3-diol (100 g, 658 mmol) in DMF (500 mL) was added potassium O-ethyl carbonodithioate (137 g, 855 mmol). The resulting mixture was stirred at 100℃ for 14 h under argon. The reaction mixture was poured into ice water (2 L), adjusted the pH to 2 with 2 N HCl solution. The precipitated yellow solid was filtered and washed with water and brine, dried to give compound 1-3-1 as yellow solid (120 g, 80% yield) Preparation of compound 2-2-1 Triethylamine (7.78 g, 76.9 mmol) and ethylamine hydrochloride (2.98 g, 36.6 mmol) were dissolved in dichloromethane (100 mL) at 0℃. Oxalyl chloride monoethyl ester (5.0 g, 36.6 mmol) was added dropwise to the reaction system at 0 °C for 2 hours. The reaction mixture was filtered and diluted with methylene chloride, and then washed successively with saturated sodium bicarbonate solution and brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to give compound 2-2- 1 (5 g). Step 1: Compound 2-5 A solution of compound 1-3-1 (10 g, 44 mmol), ClCH2COONa (7 g, 60 mmol) and NaHCO3(10.1 g, 120 mmol) in DMF (80 mL) was stirred at 40°C for 3 hours. Compound 2-4 (6.0 g, 40 mmol) was added to the reaction. The resulting mixture was heated at 80ºC and stirred overnight. The reaction mixture was poured into ice-water, the solid precipitated was collected by filtration to give compound 2-5 (7.0 g, 50% yield) as a yellow solid. MS-ESI (m / z) 346.2 [M+H]+. Step 2: Compound 2-6 The solution of compound 2-5 (7 g, 20 mmol) and NH2NH2H2O (2 g, 40 mmol) in dioxane (70 mL) was stirred for 6 hours or overnight at 30ºC. The reaction solution was poured into H2O and extracted with EtOAc (200 mL*3). The combine organic layers were washed with brine, dried over Na2SO4and concentrated to give the Compound 2-6 (7 g, crude) which was used for next step reaction without further purification. MS-ESI (m / z) 344.1 [M+H]+. Step 3: Compound 2-7 To a solution of compound 2-6 (7 g, 20 mmol) in i-PrOH (100 mL) was added compound 2-2-1 (4.35 g, 30 mmol) and AcOH (0.5 mL). Then the resulting mixture was refluxed overnight. The reaction mixture was concentrated and purified by silica gel chromatography (DCM:MeOH=20:1) to give compound 2-7 (6 g) as yellow solid. MS-ESI (m / z) 425.2 [M+H]+. Step 4: Compound 2-8 The solution of compound 2-7 (7.3 g, 17.2 mmol) in THF / MeOH (1:1, 100 mL) was added NaOH solution (3.4 g NaON in 50 mL water). The mixture was stirred at room temperature overnight. The mixture was concentrated to remove THF and MeOH and 1 N HCl was added to adjust the pH to 3. The solid precipitated was collected by filtration and dried to give compound 2-8 (4.4 g) as yellow solid. MS-ESI (m / z) 411.3 [M+H]+. Step 5: Compound 2-9 To a solution of compound 2-8 (4.43 g, 10.79 mmol) in DMF (36 mL) was added N, O-dimethylhydroxylamine HCl salt (1.16 g, 11.87 mmol) and DIEA (4.19 g, 32.38 mmol), followed by HOBt (1.75 g, 12.95 mmol) and EDCI (2.48 g, 12.95 mmol) . The mixture was stirred at r.t. overnight. The reaction solution was poured into H2O and extracted with EtOAc (200 mL*3). The combine organic layers were washed with brine, dried over Na2SO4and concentrated then purified by silica gel chromatography (DCM:MeOH=20:1) to give compound 2-9 (1.8 g) as yellow solid. MS-ESI (m / z) 454.2 [M+H]+. Step 6: Intermediate (2) To a solution of compound 2-9 (5.1 g, 12.8 mmol) in THF (50 mL) was added LiAlH4(2.5 M in THF, 13.8 mL) at 0ºC and stirred at room temperature for 1 hour. The reaction solution was quenched with H2O (1 g) 10% NaOH (1 mL) and H2O (3 mL). Brine was added and extracted with THF (40 mL*3). The combined organic phase was dried (Na2SO4) and concentrated to give intermediate (2) (1.7 g) as a white solid. MS- ESI (m / z) 395.2 [M+H]+. Scheme 3

[0008] Step 1: Compound 3-1 To a solution of compound 3-0 (93 g, 353 mmol) in DMF (1 L) was added N,O- dimethylhydroxylamine HCl salt (37.9 g, 388.5 mmol), DIEA (137 g, 1.06 mol) and HATU (147.7 g, 388.5 mmol). The mixture was stirred at r.t. overnight. The reaction solution was poured into H2O and extracted with EtOAc (1 LX3). The combine organic layers were washed with brine, dried over Na2SO4and concentrated then purified by silica gel column (PE:EtOAc=3:1) to give compound 3-1 (70 g) as yellow solid MS-ESI (m / z) 307.1 [M+H]+. Step 2: Compound 3- 2 To a solution of compound 3-1 (70 g, 228.5 mmol) in DCM (560 mL) was added TFA (140 mL) slowly. The mixture was stirred at r.t. overnight and concentrated to give compound 3- 2 (70 g) as yellow solid. MS-ESI (m / z) 207.1 [M+H]+. Step 3: Compound 3-3 To a solution of compound 3-2 (52.8 g, 165 mmol) in DMF (400 mL) was added compound 3-2-1 (35.6 g, 181.3 mmol), DIEA (198.2 g, 1.53 mol) and HATU (70 g, 181 mmol). The mixture was stirred at r.t. overnight. The reaction solution was poured into H2O and extracted with EtOAc (1 L*3). The combine organic layers were washed with brine, dried over Na2SO4and concentrated then purified by silica gel column (PE:EtOAc=2:1) to give compound 3-3 (23 g) as yellow solid. MS-ESI (m / z) 384.9 [M+H]+. Step 4: Intermediate (3) To a solution of compound 3-3 (23 g, 50.8 mmol) in THF (400 mL) was added DIBAL-H (1.5 M in THF, 135.6 mL) at -78ºC and stirred at this temperature for 4 hours. The reaction solution was quenched with HCl (1N) carefully and extracted with ethyl acetate (400 mL*3). The combined organic phase was dried (Na2SO4) and concentrated then purified by silica gel column (PE:EtOAc=2:1) to give intermediate (3) (13 g) as white solid MS-ESI (m / z) 326.0 [M+H]+. Scheme 4 Step 1: 5-bromo-2-[5-isopropyl-2,4-bis(methoxymethoxy)benzoyl]-1,3- dihydroisoindole) (4-2) To a stirred solution of 5-isopropyl-2,4-bis(methoxymethoxy)benzoic acid (3 g, 10.552 mmol, 1.00 equiv), 5-bromo-2,3-dihydro-1H-isoindole (3.13 g, 15.828 mmol, 1.5 equiv) in DMF (30 mL) was added HOBt (0.14 g, 1.054 mmol, 1.50 equiv), EDCI (0.20 g, 1.054 mmol, 1.50 equiv) and DIEA (0.45 g, 3.515 mmol, 5.00 equiv). The resulting mixture was stirred for 16 hrs at room temperature under nitrogen atmosphere. The reaction mixture was poured into H2O and extracted with EtOAc (2 x50 mL). The combined organic layers were washed with water (4 x 150 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column, eluted with PE / EtOAc (5:1) to afford compound 4-2 (3.7g, 75.51%) as a yellow solid. LC-MS: m / z 464 [M+H]+. Step 2: 5-bromo-2-[5-isopropyl-2,4-bis(methoxymethoxy)benzoyl]-1,3- dihydroisoindole) (4-3) To a stirred solution of 5-bromo-2-[5-isopropyl-2,4- bis(methoxymethoxy)benzoyl]-1,3-dihydroisoindole (3.7 g, 7.968 mmol, 1.00 equiv) and methyl piperidine-4-carboxylate (1.71 g, 11.952 mmol, 1.50 equiv) in 1,4-dioxane (37 mL) was added Cs2CO3(7.79 g, 23.904 mmol, 3.00 equiv) and RuPhos Palladacycle Gen.3 (2.00 g, 2.390 mmol, 0.30 equiv). The resulting mixture was stirred for 16 hrs at 100°C under nitrogen atmosphere and cooled to room temperature. The mixture was extracted with EtOAc (3 x50 mL). The combined organic layers were washed with water (3 x 150 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column, eluted with PE / EtOAc (1:1) to afford compound 4-3 (2.2 g, 52.28%) as a yellow solid. LC-MS: m / z 527 [M+H]+. Step 3: 1-{2-[5-isopropyl-2,4-bis(methoxymethoxy)benzoyl]-1,3-dihydroisoindol - 5-yl}piperidine-4-carboxylic acid) (Intermediate (4)) To a stirred solution of methyl 1-{2-[5-isopropyl-2,4- bis(methoxymethoxy)benzoyl]-1,3-dihydroisoindol -5-yl} piperidine-4-carboxylate (2.2 g, 4.178 mmol, 1.00 equiv) in THF (17.6 mL) / H2O (4.4mL) was added LiOH (500.26 mg, 20.890 mmol, 5.00 equiv). The resulting mixture was stirred for 1h at room temperature. The resulting mixture was adjusted pH to 5 with 1N HCl, extracted with EtOAc (3 x30 mL). The combined organic layers were washed with water (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (20:1) to afford Intermediate (4) (1.4 g, 65.38%) as a light yellow solid. LC-MS: m / z 513 [M+H]+. Scheme 5 Step 1: N-(3 -{[3 –amino -5 -(4 –amino -4 -methylpiperidin-1-yl)pyrazin-2- yl]sulfanyl} -2-chlorophenyl)-4-[4-({4-[3-(2,4-dihydroxy-5-isopropylphenyl)-5- hydroxy-1,2,4-triazol-4-yl]phenyl}methyl)piperazin-1-yl]-4-oxobutanamide (Intermediate (5)) To a stirred solution of tert-butyl N-(1-{6 –amino -5 -[(2 -chloro-3 -{4 -[4 -({4 -[3 - (2,4 -dihydroxy-5 -isopropylphenyl)-5-hydroxy-1,2,4-triazol-4- yl]phenyl}methyl)piperazin-1-yl]-4-oxobutanamido}phenyl)sulfanyl]pyrazin-2-yl}-4- methylpiperidin-4-yl)carbamate (150 mg, 0.157 mmol, 1 equiv) in DCM (3 mL) was added TFA (1.5 mL, 20.195 mmol, 128.78 equiv) and the mixture was stirred 16 h at 100ºC. The resulting mixture was dried to give the crude product. Then it was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 50% B to 85% B in 10 min, 85% B; Wave Length: 220 nm; RT1(min): 10.35; Number Of Runs: 0) to afford Intermediate (5) (10.35 mg, 7.40%) as an off-white solid. LC-MS: m / z 565 [M+H]+Scheme 6

[0009] Step 1: tert-butyl 4-[3-(tert-butylsulfanyl) -2-chlorophenyl]piperazine-1- carboxylate (6-2) A mixture of 1-(tert-butylsulfanyl)-2-chloro-3-iodobenzene (1.3 g, 3.980 mmol, 1 equiv), tert-butyl piperazine-1-carboxylate (1.11 g, 5.970 mmol, 1.5 equiv), Pd2(dba)3(0.36 g, 0.398 mmol, 0.1 equiv), BINAP (0.50 g, 0.796 mmol, 0.2 equiv), Cs2CO3(3.89 g, 11.940 mmol, 3.0 equiv) in methylbenzene (20 mL) was heated to 100°C under N2atmosphere and stirred for additional 16 hrs. The reaction mixture was cooled to room temperature and quenched with saturated NH4Cl. Extraction with ethyl acetate and the organic phase was concentrated, and the residue was purified to afford 6-2 (1.4 g, 91.37%) as a white solid. LC-MS: m / z 385 [M+H]+. Step 2: 1-[3-(tert-butylsulfanyl)-2-chlorophenyl]piperazine (6-3) A mixture of tert-butyl 4-[3-(tert-butylsulfanyl)-2-chlorophenyl]piperazine-1- carboxylate (1.44 g, 3.741 mmol, 1 equiv) in 6N HCl in 1,4-dioxane (20 mL) was stirred for 1h at room temperature. The resulting mixture was concentrated under reduced pressure to provide 6-3 (930 mg, crude) as a yellow solid. LC-MS: m / z 285 [M+H]+. Step 3: 9H-fluoren-9-ylmethyl 4-[3-(tert-butylsulfanyl)-2-chlorophenyl] piperazine-1-carboxylate (6-4) A mixture of 1-[3-(tert-butylsulfanyl)-2-chlorophenyl]piperazine (1.44 g, 5.055 mmol, 1 equiv), fluorenylmethyloxycarbonyl chloride (1.44 g, 5.561 mmol, 1.1 equiv) and sodium methaneperoxoate (1.27 g, 15.165 mmol, 3 equiv), in dioxane (10 mL) / H2O (10 mL) was stirred at room temperature for 16 hrs. The reaction mixture was concentrated and the residue was purified by silica gel column, eluted with PE / EtOAc to afford 6-4 (0.937 g, 36.55%) as a yellow solid. LC-MS: m / z 507 [M+H]+. Step 4: 9H-fluoren-9-ylmethyl 4-(2-chloro-3-sulfanylphenyl)piperazine-1- carboxylate (6-5) A mixture of 9H-fluoren-9-ylmethyl 4-[3-(tert-butylsulfanyl)-2- chlorophenyl]piperazine-1-carboxylate (930 mg, 1.834 mmol, 1 equiv) in concentrated HCl (20 mL) was heated to 55°C. The resulting mixture was stirred for additional 16 hrs at 55°C and quenched with sat. NaHCO3. The mixture was extracted with ethyl acetate (30 ml*3) and the combined organic phases were dried over Na2SO4, and then concentrated. The residue was purified by silica gel column, eluted with PE / EtOAc to afford 6-5 (720 mg, 87.1%) as a yellow oil. LC-MS: m / z 451 [M+H]+. Step 5: 9H-fluoren-9-ylmethyl 4-{3-[(3-amino-5-chloropyrazin-2-yl)sulfanyl] -2- chlorophenyl}piperazine-1-carboxylate (6-6) To a mixture of 9H-fluoren-9-ylmethyl 4-(2-chloro-3- sulfanylphenyl)piperazine-1-carboxylate (370 mg, 0.820 mmol, 1 equiv), l, 3-bromo- 6-chloropyrazin-2-amine (188.11 mg, 0.902 mmol, 1.10 equiv), XantPhos (94.95 mg, 0.164 mmol, 0.2 equiv), Pd2(dba)3(75.13 mg, 0.082 mmol, 0.1 equiv) in dioxane (20 mL) was added DIEA (265.10 mg, 2.050 mmol, 2.5 equiv) dropwise at 100°C under N2atmosphere. The residue was purified by silica gel column, eluted with PE / EtOAc to afford 6-6 (365 mg, 74.80%) as a yellow solid. LC-MS: m / z 578 [M+H]+. Step 6: 6-chloro-3-{[2-chloro-3-(piperazin -1-yl)phenyl]sulfanyl}pyrazin-2-amine (intermediate (6)) To a solution of 9H-fluoren-9-ylmethyl 4-{3-[(3-amino-5-chloropyrazin-2- yl)sulfanyl]-2-chlorophenyl} piperazine-1-carboxylate (358 mg, 0.619 mmol, 1 equiv) in DCM (8 mL) was added DEA (8 mL). The resulting mixture was stirred for 4 h at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, 30% MeCN in Water (10mmol / L NH4HCO3); detector, UV 254 nm. This resulted in intermediate (6) (100.9 mg, 45.77%) as a yellow solid. LC-MS: m / z 356 [M+H]+. Scheme 7 Step 1: tert-butyl N-[1-(3-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl} pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl]carbamate (7-2) To a stirred solution of tert-butyl N-(1-{3-bromo-1H-pyrazolo[3,4-b]pyrazin- 6-yl}-4-methylpiperidin-4-yl) carbamate (1 g, 2.431 mmol, 1 equiv) in THF (10 mL) was added NaH (87.52 mg, 3.647 mmol, 1.5 equiv) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 0°C under nitrogen atmosphere. To the above mixture was added SEM-Cl (0.52 mL, 2.917 mmol, 1.2 equiv) dropwise over 5 min at 0°C. The resulting mixture was stirred for additional 2 h at room temperature and quenched with saturated NH4Cl. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (3 x 60 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column, eluted with PE / EtOAc (3:1) to afford 7-2 (760 mg, 57.72%) as a white solid. LC- MS: m / z 541 [M+H]+. Step 2: tert-butyl N-{1-[3-(3-amino-2-chlorophenyl)-1-{[2-(trimethylsilyl)ethoxy] methyl}pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidin-4-yl}carbamate (intermediate (7) A solution of tert-butyl N-[1-(3-bromo-1-{[2- (trimethylsilyl)ethoxy]methyl}pyrazolo[3,4-b]pyrazin-6-yl) -4-methylpiperidin-4- yl]carbamate (340 mg, 0.628 mmol, 1 equiv), 2-chloro-3-(4,4,5,5-tetramethyl -1,3,2- dioxaborolan-2-yl)aniline (238.75 mg, 0.942 mmol, 1.5 equiv), Pd(dppf)Cl2(102.29 mg, 0.126 mmol, 0.2 equiv) and K3PO4(399.79 mg, 1.884 mmol, 3 equiv) in dioxane (3 mL) and H2O (0.3 mL) was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was poured into water and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (5 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column, eluted with PE / EtOAc (3:1) to afford intermediate (7) (326 mg, 88.28%) as a yellow solid. LC-MS: m / z 588 [M+H]+. Scheme 8 Step 1: 4-chloro-5-iodo-2,3-dihydro-1H-isoindole (8-2) To a solution of 4-chloro-5-iodo-2,3-dihydroisoindol-1-one (400 mg, 1.363 mmol, 1 equiv)) in THF (12 mL) was added NaBH4(515.59 mg, 13.630 mmol, 10 equiv), then cooled to -10 °C, BF3.Et2O (1.73 mL, 13.630 mmol, 10 equiv) was added dropwise over 10 min at -10 °C. The resulting mixture was stirred for additional 4 h at -10 °C. The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was quenched by the addition of saturated aqueous NaHCO3 (20 mL) at -5 °C, extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to provide 8-2 (302 mg, crude) as a pink solid. LCMS: m / z 280 [M+H]+. Step 2: tert-butyl 4-chloro-5-iodo-1,3-dihydroisoindole-2-carboxylate (8-3) To a stirred solution of 4-chloro-5-iodo-2,3-dihydro-1H-isoindole (302 mg, 1.080 mmol, 1 equiv) and NaHCO3(453.83 mg, 5.400 mmol, 5 equiv) in THF (3 mL) and H2O (3 mL) was added (Boc)2O (353.71 mg, 1.620 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred overnight at room temperature. The resulting mixture was extracted with EtOAc (4 x 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (50:1) to afford 8-3 (379 mg, 92.40%) as a pink solid. LCMS: m / z 380 [M+H]+. Step 3: 2-(tert-butoxycarbonyl)-4-chloro-1,3-dihydroisoindol-5-ylboronic acid (intermediate (8) A solution of tert-butyl 4-chloro-5-iodo-1,3-dihydroisoindole-2-carboxylate (450 mg, 1.185 mmol, 1 equiv) and Mg (31.69 mg, 1.304 mmol, 1.1 equiv) in 1M BH3. THF complex (6 mL) was stirred for 2 h at 50 °C under nitrogen atmosphere. To the above mixture was added H2O (2 mL) dropwise over 10min at room temperature. The resulting mixture was stirred for additional 1 h at 100 °C. The resulting mixture was acidified to pH 3 with 1M HCl and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions (column, C18; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 35% to 50% gradient in 15 min; detector, UV 254 nm) to afford intermediate (8) (190 mg, 53.87%) as a yellow solid. LC-MS: m / z 298 [M+H]+. Preparation of Compounds The compounds claimed herein were prepared following the procedures which were exemplified by following examples. Compound 1 Step 1: tris(tert-butyl N-[1-(6-amino-5-{[2-chloro-3-(1-{2-[5-isopropyl-2,4- bis(methoxymethoxy) benzoyl]-1,3-dihydroisoindol-5-yl}piperidine-4- amido)phenyl]sulfanyl}pyrazin-2-yl)-4-methylpiperidin-4-yl]carbamate) (9-1) To a stirred solution of 1-{2-[5-isopropyl-2,4-bis(methoxymethoxy)benzoyl]- 1,3-dihydroisoindol -5-yl}piperidine-4-carboxylic acid (250 mg, 0.488 mmol, 1.00 equiv) and tert-butyl N-(1-{6-amino-5-[(3-amino-2-chlorophenyl)sulfanyl]pyrazin-2- yl}-4-methylpiperidin-4-yl)carbamate (226.79 mg, 0.488 mmol, 1.00 equiv) in Pyridine (2.50 mL) were added T3P (232.77 mg, 0.732 mmol, 1.50 equiv) and DMAP (178.75 mg, 1.464 mmol, 3.00 equiv). The resulting mixture was stirred at r.t. for 2h. The resulting mixture was poured into water and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product 9-1 was used in the next step directly without further purification. LC- MS: m / z 959 [M+H]+. Step 2: tris(N-(3-{[3-amino-5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2- yl]sulfanyl}-2-chlorophenyl) -1-[2-(2,4-dihydroxy-5-isopropylbenzoyl)-1,3- dihydroisoindol-5-yl]piperidine-4-carboxamide (Compound 1) A solution of tris(tert-butyl N-[1-(6-amino-5-{[2-chloro-3-(1-{2-[5-isopropyl- 2,4-bis(methoxymethoxy) benzoyl]-1,3-dihydroisoindol-5-yl}piperidine-4- amido)phenyl]sulfanyl}pyrazin-2-yl)-4-methylpiperidin-4-yl]carbamate) (581 mg, 0.202 mmol, 1 equiv) in 6N HCl in 1,4-dioxane (5 mL) was stirred for 1 h at room temperature. The residue was concentrated and purified by Prep-HPLC (Column: XBridge BEH C18 OBD Prep Column, 19*250 mm, 5μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 20% B to 65% B in 8 min, 65% B; Wave Length: UV 220 nm; RT1(min): 7.67; Number Of Runs: 0) to afford Compound 1 (26.82 mg, 5.32%) as a white solid. LC- MS: m / z 771.2 [M+H]+.1H NMR (DMSO-d6, 400 MHz): δ 10.11 (br, 1H), 9.60 (br, 1H), 9.52 (s, 1H), 8.30 (s, 1H), 7.64 (s, 1H), 7.40 (dd, J = 8.0, 1.2 Hz, 1H), 7.16 (t, J = 8.0 Hz, 2H), 7.05 (s, 1H), 6.92-6.90 (m, 2H), 6.44 (dd, J = 8.0, 1.2 Hz, 1H), 6.39 (s, 1H), 6.10 (br, 2H), 4.72-4.68 (m, 4H), 3.75-3.72 (m, 4H), 3.57-3.53 (m, 2H), 3.15- 3.06 (m, 2H), 2.76-2.69 (m, 2H), 1.90-1.88 (m, 2H), 1.79-1.73 (m, 2H), 1.55-1.54 (m, 4H), 1.21 (s, 3H), 1.14 (d, J = 7.2 Hz, 6H). Compound 2 Step 1: tert-butyl N-(1 -{6 –amino -5-[(2 –chloro -3-{4 -[4 -({4 -[3 -(2,4 – dihydroxy-5-isopropylphenyl)-5-hydroxy-1,2,4-triazol-4- yl]phenyl}methyl)piperazin-1-yl]-4-oxobutanamido}phenyl)sulfanyl]pyrazin-2- yl}-4-methylpiperidin-4-yl)carbamate (10-2) To a stirred solution of 3 -({3 -[(3 –amino -5 -{4 -[(tert-butoxycarbonyl)amino] -4 - methylpiperidin-1-yl}pyrazine-2-yl)sulfanyl]-2-chlorophenyl}carbamoyl)propanoic acid (100 mg, 0.177 mmol, 1 equiv) and 4-{5-hydroxy-4-[4-(piperazin-1- ylmethyl)phenyl]-1,2,4-triazol-3-yl}-6-isopropylbenzene-1,3-diol (72.46 mg, 0.177 mmol, 1 equiv), HATU (2 mL, 1.5 equiv), DIEA (68.62 mg, 0.531 mmol, 3 equiv) in DMF (2 mL) at room temperature. The mixture was stirred 16h at room temperature. The crude product was concentrated to afford 10-2 (165 mg, 77.98%) as an off-white solid. LC-MS: m / z 956.0 [M+H]+ Step 2: N-(3 -{[3 –amino -5 -(4 –amino -4 –methylpiperidin-1-yl)pyrazin-2- yl]sulfanyl}-2-chlorophenyl)-4-[4-({4-[3-(2,4-dihydroxy-5-isopropylphenyl)-5- hydroxy-1,2,4-triazol-4-yl]phenyl}methyl)piperazin-1-yl]-4-oxobutanamide (Compound 2) To a stirred solution of tert-butyl N -(1 -{6 –amino -5 -[(2-chloro -3-{4 -[4 -({4 -[3- (2,4 –dihydroxy -5-isopropylphenyl)-5-hydroxy-1,2,4-triazol-4- yl]phenyl}methyl)piperazin-1-yl]-4-oxobutanamido}phenyl)sulfanyl]pyrazin-2-yl}-4- methylpiperidin-4-yl)carbamate (150 mg, 0.157 mmol, 1 equiv) in DCM (3 mL) and TFA (1.5 mL, 20.195 mmol, 128.78 equiv) at room temperature. The mixture was stirred 0.5 h at room temperature. The crude product was concentrated and purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 50% B to 85% B in 10 min, 85% B; Wave Length: 220 nm; RT1(min): 10.35; Number Of Runs: 0) to afford Compound 2 (10.35 mg, 7.40%) as an off-white solid. LC-MS: m / z 856.0 [M+H]+.1H NMR (DMSO-d6, 400 MHz): δ 9.51 (s, 2H), 9.41 (s, 1H), 8.30 (s, 1H), 7.63 (s, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 8.2 Hz, 2H), 7.18 – 7.10 (m, 3H), 6.77 (s, 1H), 6.44-6.40 (m, 1H), 6.26 (s, 1H), 6.10 (s, 2H), 3.73 (s, 2H), 3.45-3.58 (m, 8H), 3.01 – 2.93 (m, 1H), 2.62 (s, 4H), 2.37 (s, 2H), 2.29 (s, 2H), 1.55 (s, 4H), 1.21 (s, 3H), 0.95 (d, J = 6.8 Hz, 6H). Compound 25

[0010] Step 1: tert-butyl N-(1-{6-amino-5-[(2-chloro-3-{4-oxo-4-[4-(2,2,2- trifluoroacetyl)piperazin-1-yl]butanamido}phenyl)sulfanyl]pyrazin-2-yl}-4- methylpiperidin-4-yl)carbamate (11-1) A solution of 3-({3-[(3-amino-5-{4-[(tert-butoxycarbonyl)amino]-4-methylpiperidin- 1-yl}pyrazin-2-yl) sulfanyl]-2-chlorophenyl}carbamoyl)propanoic acid (2 g, 3.539 mmol, 1 equiv), 2,2,2-trifluoro-1-(piper azin-1-yl)ethanone hydrochloride (1.08 g, 4.955 mmol, 1.4 equiv), HATU (2.02 g, 5.309 mmol, 1.5 equiv) and DIEA (1.85 mL, 10.617 mmol, 3 equiv) in DMF (20 mL) was stirred for overnight at room temperature under nitrogen atmosphere. The crude solution was directly purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 10% to 80% gradient in 10 min; detector, UV 254 nm. This resulted in 11-1 (1.1 g, 42.62%) as a white solid. LC-MS: m / z 729 [M+H]+. Step 2: tert-butyl N-{1-[6-amino-5-({2-chloro-3-[4-oxo-4-(piperazin-1- yl)butanamido]phenyl} sulfanyl)pyrazin-2-yl]-4-methylpiperidin-4-yl}carbamate (11-2) A solution of tert-butyl N-(1-{6-amino-5-[(2-chloro-3-{4-oxo-4-[4-(2,2,2- trifluoroacetyl)piperazin-1-yl] butanamido}phenyl)sulfanyl]pyrazin-2-yl}-4- methylpiperidin-4-yl)carbamate (1.1 g, 1.508 mmol, 1 equiv) and K2CO3(1.04 g, 7.540 mmol, 5 equiv) in MeOH (10 mL) and H2O (5 mL) was stirred for 5 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 10% to 80% gradient in 10 min; detector, UV 254 nm. This resulted in 11-2 (400 mg, 41.88%) as a white solid. LC-MS: m / z 633 [M+H]+. Step 3: tert-butyl N-{1-[6-amino-5-({2-chloro-3-[4-oxo-4-(4-{[1-(2,2,2-trifluo roacetyl)piperidin-4-yl]methyl}piperazin-1- yl)butanamido]phenyl}sulfanyl)pyrazin-2-yl]-4-methylpiperidin-4-yl}carbamate (11-3) A solution of tert-butyl N-{1-[6-amino-5-({2-chloro-3-[4-oxo-4-(piperazin-1- yl)butanamido] phenyl}sulfanyl)pyrazin-2-yl]-4-methylpiperidin-4-yl}carbamate (250 mg, 0.395 mmol, 1 equiv), 1-(2,2,2-trifluoroacetyl)piperidine-4-carbaldehyde (99.10 mg, 0.474 mmol, 1.2 equiv) and STAB (251.03 mg, 1.185 mmol, 3 equiv) in DMF (3 mL) was stirred for overnight at room temperature under nitrogen atmosphere. The crude solution was directly purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 40% to 60% gradient in 15 min; detector, UV 254 nm. This resulted in 11-3 (320 mg, 98.08%) as a white solid. LC-MS: m / z 826 [M+H]+. Step 4: tert-butyl N-(1-{6-amino-5-[(2-chloro-3-{4-oxo-4-[4-(piperidin-4- ylmethyl)piperazin-1-yl]butanamido}phen yl)sulfanyl]pyrazin-2-yl}-4- methylpiperidin-4-yl)carbamate (11-4) A solution of tert-butyl N-{1-[6-amino-5-({2-chloro-3-[4-oxo-4-(4-{[1-(2,2,2- trifluoroacetyl)piperidin-4-yl]methyl}piperazin-1- yl)butanamido]phenyl}sulfanyl)pyrazin-2-yl]-4-methylpiperidin-4-yl}carbamate (300 mg, 0.363 mmol, 1 equiv) and K2CO3(250.86 mg, 1.815 mmol, 5 equiv) in MeOH (3 mL) and H2O (1.5 mL) was stirred for 5h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 10% to 50% gradient in 20 min; detector, UV 254 nm. This resulted in 11-4 (79 mg, 29.79%) as a light yellow solid. LC-MS: m / z 730 [M+H]+. Step 5: tert-butyl N-[1-(6-amino-5-{[2-chloro-3-(4-{4-[(1-{[2-(2,4-dihydroxy-5- isopropylbenzoyl)-1,3-dihydroisoindol-5-yl]methyl}piperidin-4- yl)methyl]piperazin-1-yl}-4-oxobutanamido)phenyl]sulfanyl}pyrazin-2-yl)-4- methylpiperidin-4-yl]carbamate (11-5) A solution of tert-butyl N-(1-{6-amino-5-[(2-chloro-3-{4-oxo-4-[4-(piperidin- 4-ylmethyl)piper azin-1-yl]butanamido}phenyl)sulfanyl]pyrazin-2-yl}-4- methylpiperidin-4-yl)carbamate (36 mg, 0.049 mmol, 1 equiv), 2-(2,4-dihydroxy-5- isopropylbenzoyl)-1,3-dihydroisoindole-5-carbaldehyde (19.24 mg, 0.059 mmol, 1.2 equiv) and STAB (52.23 mg, 0.245 mmol, 5 equiv) in DMF (1 mL) was stirred for overnight at room temperature under nitrogen atmosphere. The crude solution was directly purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 10% to 80% gradient in 10 min; detector, UV 254 nm. This resulted in 11-5 (18 mg, 35.12%) as a light yellow solid. LC-MS: m / z 1039 [M+H]+. Step 6: N-(3-{[3-amino-5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2- yl]sulfanyl}-2-chlorophenyl)-4-{4-[(1-{[2-(2,4-dihydroxy-5-isopropylbenzoyl)-1,3- dihydroisoindol-5-yl]methyl}piperidin-4-yl)methyl]piperazin-1-yl}-4- oxobutanamide (Compound 25) A solution of tert-butyl N-[1-(6-amino-5-{[2-chloro-3-(4-{4-[(1-{[2-(2,4- dihydroxy-5-isopropyl benzoyl) -1,3-dihydroisoindol-5-yl]methyl}piperidin-4- yl)methyl]piperazin-1-yl}-4-oxobutanamido)phenyl]sulfanyl}pyrazin-2-yl)-4- methylpiperidin-4-yl]carbamate (39 mg, 0.038 mmol, 1 equiv) and TFA (1 mL, 13.463 mmol) in DCM (2 mL) was stirred for 0.5 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 19*150 mm, 5μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 15% B to 55% B in 8 min, 55% B; Wave Length: 220 nm; RT1(min): 7.5; Number Of Runs: 0) to afford Compound 25 (10.65 mg, 29.80%) as a white solid. LC-MS: m / z 939.1 [M+H]+.1H NMR (DMSO-d6, 400 MHz): δ 10.07 (s, 2H), 9.50 (s, 1H), 7.62 (s, 1H), 7.48 (dd, J = 8.2, 1.4 Hz, 1H), 7.34 – 7.08 (m, 3H), 7.14 (t, J = 8.0 Hz, 1H),7.05 (s, 1H), 6.42 (dd, J = 8.0, 1.4 Hz, 1H), 6.39 (s, 1H), 6.08 (s, 2H), 4.76 (s, 4H), 3.63 (s, 4H), 3.42 (s, 6H), 3.09 (p, J = 6.8 Hz, 1H), 2.77 (d, J = 10.8 Hz, 2H), 2.62 (s, 4H), 2.31 (s, 2H), 2.25 (s, 2H), 2.11 (d, J = 7.2 Hz, 2H), 1.89 (t, J = 11.2 Hz, 2H), 1.64 (d, J = 12.4 Hz, 2H), 1.49 (s, 5H), 1.24 (s, 2H), 1.14 (d, J = 7.0 Hz, 6H), 1.07 (s, 3H). Compound 28

[0011] Step 1: tert-butyl N-(1-{6-amino-5-[(3-azido-2-chlorophenyl)sulfan yl]pyrazin-2- yl}-4-methylpiperidin-4-yl)carbamate (12-1) To a stirred solution of tert-butyl N-(1-{6-amino-5-[(3-amino-2- chlorophenyl)sulfanyl] pyrazin-2-yl}-4-meth ylpiperidin-4-yl)carbamate (1 g, 2.150 mmol, 1 equiv) in DMF (15 mL) was added N-diazosulfamoyl fluoride solution (12.900 mmol, 6 equiv, approximately 0.89 mM in MTBE, containing 14.5 mL) and aqueous KHCO3(0.86 g, 8.600 mmol, 4 equiv). The reaction mixture was stirred for 16h at room temperature. After monitoring by LC-MS, EtOAc (100 ml) was added and the mixture was washed sequentially with brine (2 x 20 ml), dried over Na2SO4, concentrated by rotary evaporation and dried in vacuo. The residue was purified by flashchromatography, eluted with EA / PE (40%) to afford 12-1 (190 mg, 17.99%) as a yellow solid. LC-MS: m / z 491 [M+H]+. Step 2: tert-butyl N-[1-(6-amino-5-{[2-chloro-3-(4-{[4- ({4-[3-(2,4-dihydroxy-5- isopropylphenyl)-5-(ethylcarbamoyl)-1,2,4-triazol-4-yl]phenyl}methyl)piperazin- 1-yl]methyl}-1,2,3-triazol-1-yl)phenyl]sulfanyl}pyrazin-2-yl)-4-methylpiperidin- 4-yl]carbamate (12-3) To a stirred mixture of tert-butyl N-(1-{6-amino-5-[(3-azido-2-chlorophenyl) sulfanyl]pyrazin-2-yl}-4-meth ylpiperidin-4-yl)carbamate (39 mg, 0.079 mmol, 1 equiv) and 5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-4-(4-{[4-(prop-2-yn-1- yl)piperazin-1-yl]methyl}phenyl)-1,2,4-triazole-3-carboxamide (79.84 mg, 0.158 mmol, 2 equiv) in 2-methylpropan-2-ol (6 mL) and H2O (2 mL) was added CuSO4.5H2O (6.34 mg, 0.040 mmol, 0.5 equiv) and sodium (2S)-2-[(1S)-1,2- dihydroxyethyl] -4-hydroxy-5-oxooxolan-3-olate (7.91 mg, 0.040 mmol, 0.5 equiv), the mixture was stirred for 16 h at 25°C, filtered through a Celite pad and concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% NH4HCO3), 10% to 67% gradient in 22 min; detector, UV 220 nm. This resulted in 12-3 (12 mg, 15.21%) as a yellow solid. LC-MS: m / z 993 [M+H]+. Step 3: 4-{4-[(4-{[1-(3-{[3-am ino-5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2- yl]sulfanyl}-2-chlorophenyl)-1,2,3-triazol-4-yl]methyl}piperazin-1- yl)methyl]phenyl}-5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-1,2,4-triazole-3- carboxamide (Compound 28) To a stirred solution of tert-butyl N-[1-(6-amino-5-{[2-chloro-3-(4-{[4- ({4- [3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylcarbamoyl)-1,2,4-triazol-4- yl]phenyl}methyl)piperazin-1-yl]methyl}-1,2,3-triazol-1-yl)phenyl]sulfanyl}pyrazin- 2-yl)-4-methylpiperidin-4-yl]carbamate (12 mg, 0.012 mmol, 1 equiv) in DCM (0.5 mL) and TFA (0.15 mL, 2.02 mmol, 168.33 equiv) at room temperature. The mixture was stirred 0.5 h at room temperature. The crude product was concentrated and purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 50% B to 85% B in 10 min, 85% B; Wave Length: 220 nm) to afford Compound 28 (3.5 mg, 32.5%) as an off-white solid. LC-MS: m / z 893.1 [M+H]+.1H NMR (DMSO-d6, 400 MHz): δ 10.59 (s, 1H), 10.53 – 9.01 (m, 1H), 8.95 (t, J = 5.8 Hz, 1H), 8.40 (s, 1H), 7.66 (s, 1H), 7.46 – 7.44 (m, 2H), 7.40 – 7.34 (m, 2H), 7.29 (d, J = 8.2 Hz, 2H), 6.82 (dd, J = 5.8, 3.8 Hz, 1H), 6.58 (s, 1H), 6.34 (s, 1H), 6.19 (s, 2H), 3.77 – 3.66 (m, 4H), 3.64 – 3.54 (m, 2H), 3.50 (s, 2H), 3.22 – 3.10 (m, 2H), 2.90 (p, J = 6.8 Hz, 1H), 2.46 – 2.35 (m, 8H), 1.53 – 1.41 (m, 4H), 1.13 (s, 3H), 1.03 (t, J = 7.2 Hz, 3H), 0.80 (d, J = 6.8 Hz, 6H). Compound 104 Step 1: tert-butyl 5-(6-{4-[(tert-butoxycarbonyl)amino]-4-methylpiperidin-1-yl}-1- {[2-(trimethylsilyl)ethoxy]methyl}pyrazolo[3,4-b]pyrazin-3-yl)-4-chloro-1,3- dihydroisoindole-2-carboxylate (13-1) To a solution of 2-(tert-butoxycarbonyl)-4-chloro-1,3-dihydroisoindol-5- ylboronic acid (190 mg, 0.639 mmol, 1.5 equiv), tert-butyl N-[1-(3-bromo-1-{[2- (trimethylsilyl)ethoxy]methyl}pyrazolo [3,4-b]pyrazin-6-yl)-4-methylpiperidin-4- yl]carbamate (230.55 mg, 0.426 mmol, 1 equiv) in dioxane (2 mL) were added K3PO4 (271.09 mg, 1.278 mmol, 3 equiv) and H2O (0.2 mL), followed by Pd(dppf)Cl2.CH2Cl2(69.36 mg, 0.085 mmol, 0.2 equiv). The mixture was purged and degassed with nitrogen, then heated to 100 °C and stirred for 2 h. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 13-1 (240 mg, 78.92%) as a yellow solid. LC-MS: m / z 714.0 [M+H]+. Step 2: 1-[3-(4-chloro-2,3-dihydro-1H-isoindol-5-yl)-1H-pyrazolo[3,4-b]pyrazin- 6-yl]-4-methylpiperidin-4-amine (13-2) 5-(6-{4-[(tert-butoxycarbonyl) amino]-4-methylpiperidin-1-yl}-1-{[2- (trimethylsilyl)ethoxy]methyl}pyrazolo[3,4-b]pyrazin-3-yl)-4-chloro-1,3- dihydroisoindole-2-carboxylate (110 mg, 0.154 mmol, 1 equiv) in 4M HCl (gas) in 1,4-dioxane (1 mL) was stirred for 1h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 13-2 (104 mg, crude) as a yellow solid. The crude product was used in the next step directly without further purification. LC- MS: m / z 384.0 [M+H]+. Step 3: 4-{5-[6-(4-amino-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3- yl]-4-chloro-1,3-dihydroisoindole-2-carbonyl}-6-isopropylbenzene-1,3-diol (Compound 104) To a stirred solution of 1-[3-(4-chloro-2,3-dihydro-1H-isoindol-5-yl)-1H- pyrazolo[3,4-b]pyrazin-6-yl] -4-methylpiperidin-4-amine (52 mg, 0.135 mmol, 1 equiv), 2,4-dihydroxy-5-isopropylbenzoic acid (23.92 mg, 0.122 mmol, 0.9 equiv) and PyBOP (105.74 mg, 0.203 mmol, 1.5 equiv) in DMF (1 mL) was added DIEA (52.52 mg, 0.405 mmol, 3 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature. The mixture was filtered and purified directly by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 23% B to 50% B in 8 min, 50% B; Wave Length: UV 220 nm; RT1(min): 6.68; Number Of Runs: 0) to afford Compound 104 (12.47 mg, 15.01%) as a white solid. LC-MS: m / z 562.0 [M+H]+.1H NMR (DMSO-d6, 400 MHz): δ 13.29 (br, 1H), 10.04 (br, 1H), 9.60 (s, 1H), 8.41 (s, 1H), 7.73 (s, 1H), 7.47 – 7.40 (m, 1H), 7.06 (s, 1H), 6.40 (s, 1H), 4.92 (s, 2H), 4.83 (s, 2H), 3.87 – 3.83 (m, 2H), 3.70 – 3.63 (m, 2H), 3.12 – 3.07 (m, 1H), 2.20 – 1.70 (br, 2H), 1.53 – 1.44 (m, 4H), 1.14 (d, J = 8.0 Hz, 6H), 1.10 (s, 3H). The following compounds in Table 1 were prepared according to the methods described above using the appropriate starting materials. Table 1 Cell lines The following cancer cell lines were employed: MV-4-11 Myelomonocytic Leukemia (ATCC, CRL-1739); NCI-H2122 Adenocarcinoma, (ATCC, CRL-5985); and KYSE- 520 esophageal squamous cell carcinoma (Cobioer, CBP60658). Cell lines were cultured essentially according to ATCC and Cobioer supplier recommendations. HSP90 Surface Plasmon Resonance (SPR) assay SPR experiments were carried out using a Biacore 8K+ with a CAP chip at 25 ℃ (GE Healthcare). SPR assays were performed in running buffer (10 mM HEPES (pH7.4), 150 mM NaCl, 3 mM EDTA, 0.05% P20, 2% DMSO). SPR assays for small molecule binding used biotinylated HSP90a(M1-E236) protein captured on a CAP chip. The protein was diluted to 50 μg / ml in running buffer. Before immobilization of protein, the sensor surface was conditioned with a two-minute injection of 6 M guanidine-HCl in 0.25 M NaOH at a rate of 30 μl / min. The biotin captured reagent was then injected over the sensor surface at the rate of 2 μl / min for 360s. Next, the protein was injected over the chip at the rate of 5 μl / min for 420s. Immobilization levels were typically 1300–1800 RU. Solvent correction solutions (10 mM HEPES (pH 7.4), 150 mM NaCl, 3 mM EDTA, 0.05% P20 with 1% ~ 3% DMSO) were injected over the sensor surface and the sensorgrams were recorded to obtain the solvent correction curve. Analytes were serially diluted to various concentrations with running buffer and injected for 240 s contact time and dissociated for 2400 s. The flow rate was 30 ul / min. Binding sensorgrams were processed, solvent-corrected, and double-referenced using Biacore software. 1:1 binding kinetic model was used to fit the single-cycle kinetic curves to determine binding data (Ka, Kd, KD values). Results are listed in Table 2. SHP2 Surface Plasmon Resonance (SPR) assay SPR experiments were carried out using a Biacore 8K+ with a SA chip at 16 ℃ (GE Healthcare). SPR assays were performed in running buffer containing 50 mM Bis-Tris (pH 7.0), 150 mM NaCl, 2 mM DTT, 0.05% Tween 20 and 3% DMSO. SPR assays of small molecule binding used biotinylated SHP2(M1-L525) protein captured on a SA chip. The protein was diluted to 20 μg / ml in running buffer. Before immobilization of the protein, the sensor surface was conditioned with three one- minute injections of 1 M NaCl in 50 mM NaOH at the rate of 10 μl / min. The protein was then injected over the chip at the rate of 5 μl / min for 80 s. Next, the sensor surface was blocked with 50 µM biocytin at the flow rate of 10 μl / min for 120 s. Immobilization levels were typically 4000–6000 RU. Solvent correction solutions (10 mM HEPES (pH 7.4), 150 mM NaCl, 3 mM EDTA, 0.05% P20 with 2% to ~ 4% DMSO) were injected over the sensor surface and the sensorgrams were recorded to obtain the solvent correction curve. Analytes were serially diluted to various concentrations with running buffer and injected for 400 s contact time and dissociated for 1800 s. The flow rate was 30 ul / min. Binding sensorgrams were processed, solvent-corrected, and double-referenced using Biacore software. A 1:1 binding kinetic model was used to fit the single-cycle kinetic curves to determine binding data (Ka, Kd, KD values). Results are listed in Table 2. Cancer cell line proliferation (CellTiter-Glo assays) MV-4-11, NCI-H2122 and KYSE-520 cells were plated in 384-well tissue culture plates at 1,000 cells / well and incubated at 37°C / 5% CO2 for 24, 48 or 72 hr in 30 μl of media.3-fold serial dilutions of each test compound were prepared ranging from 10 μM to 0.51 nM. Each cell line was then treated with test compounds at various concentrations with a final concentration of 0.1% DMSO / well, and then incubated at 37°C / 5% CO2 for 24, 48 or 72 hr.30 μl of CellTiter-Glo Reagent (Promega Corporation, G9243) was added to each well and processed according to manufacturer’s protocol. Results were analyzed and IC50 values were calculated using XLfit software. Results are listed in Table 2. Western blot experiments MV-4-11 and NCI-H2122 cells were incubated with test compounds and assayed for SHP2 levels. Suspension MV-4-11 cells were seeded at 1x106cells per well (6-well plate) with over 90% viability and incubated with serial diluted compounds simultaneously. Adherent NCI-H2122 cells were seeded at 2.5x105cells per well (12-well plate) with over 90% viability and cultured for 24h prior to compound testing. Cells were treated with compounds for 24, 48 or 72h at 37°C / 5% CO2. Treated cells were then washed with cold PBS buffer and harvested with addition of lysis buffer (20 mM Tris-HCl (pH 7.5), 150 mM NaCl, 1 mM Na2EDTA, 1 mM EGTA, 1% Triton, 2.5 mM sodium pyrophosphate, 1 mM beta- glycerophosphate, 1 mM Na3VO4, 1 µg / ml leupeptin) followed by mixing for 30min at 4°C. Next, the lysed cell supernatants were centrifuged at 20000 x g and BCA assayed for protein concentration. Protein concentrations of the supernatant were adjusted to the same protein concentration level, combined with loading buffer, and denatured at 95°C for 10min. Western blot analysis of samples was carried out through the following process: (1) load denatured samples into SDS-PAGE gel and run the gel for 20 minutes at 80 V, then increase voltage to 120 V for 1.5 hours; (2) electro-transfer proteins from gel to nitrocellulose membrane using wet-transfer method at 250 mA for 1.5 hours; (3) block the membrane with LI-COR blocking buffer for 1 hour. (4) incubate the membrane with primary anti-SHP2 antibody (ThermoFisher A301-544A, rabbit) and anti-β-Actin antibody (CST#3700, mouse) prepared in LI-COR blocking buffer at 4ºC overnight; (5) wash the membrane 3 times with TBST, 5 mins per wash. (6) incubate with LI-COR secondary antibodies (IR- Dye 680 CW Goat anti-Mouse IgG (H+L), IR-Dye 800 CW Goat anti Rabbit IgG (H+L)) for 1 hour at room temperature; (7) wash 3 times in TBST, 5 mins per wash; (8) scan the membrane via Odyssey CLx System; (9) analyze data with LI-COR Image Studio and GraphPad software. Results are listed in Table 2. Results A number of synthetic schemes have been developed to construct various CHAMP molecules designed to degrade SHP2, which are termed SHP2-CHAMP molecules. Representative examples are shown, each consisting of a HSP90-binder linked to a SHP2-binder. Similar chemistry can be applied to other CHAMP molecules not limited to these specific HSP90- and SHP2-binding moieties. Binding by a variety of CHAMP molecules to SHP2 was assessed by SPR assay, as listed in Table 2. CHAMP molecules containing SHP2-binding moieties documented in the literature were generally in agreement with the published SAR. As listed in Table 2, various SHP2-CHAMP molecules also inhibited the growth and / or survival of a panel of cancer cell lines as measured by CellTiter-Glo viability assay. Furthermore, as listed in Table 2, various SHP2-CHAMP molecules depleted SHP2 protein levels in cultured cell as determined by western blot analysis. Table 2: Biochemical and Cell-based Assays of Compounds HSP90 SPR assay: A. Kd<100 nM; B. Kd=100-1000 nM; C. Kd>1000 nM; SHP2 SPR assay: A. Kd<100 nM; B. Kd=100-1000 nM; C. Kd>1000 nM; MV411 western blot assay: A. DC50<100 nM; B. DC50=100-1000 nM; C. DC50>1000 nM; MV411 proliferation assay: A. GI50<100 nM; B. GI50=100-1000 nM; C. GI50>1000 nM; H2122; Western blot assay: A. DC50<100 nM; B. DC50=100-1000 nM; C. DC50>1000 nM; H2122 proliferation assay: A. GI50<100 nM; B. GI50=100-1000 nM; C. GI50>1000 nM; KYSE520 proliferation assay: A. GI50<100 nM; B. GI50=100-1000 nM; C. GI50>1000 nM. Modifications and variations of the described methods and compositions of the present disclosure will be apparent to those skilled in the art without departing from the scope and spirit of the disclosure. Although the disclosure has been described in connection with specific embodiments, it should be understood that the disclosure as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the disclosure are intended and understood by those skilled in the relevant field in which this disclosure resides to be within the scope of the disclosure as represented by the following claims. INCORPORATION BY REFERENCE All patents and publications mentioned in this specification are herein incorporated by reference to the same extent as if each independent patent and publication was specifically and individually indicated to be incorporated by reference.

Claims

Listing of Claims:

1. A compound having the Formula I: SHP-L-Hs (I) or a pharmaceutically acceptable salt thereof, wherein SHP is a chemical entity that binds to SHP2 protein, L is a linker, and Hs is chemical entity that binds HSP90 protein.

2. The compound of Claim 1, wherein SHP is of the formula:or a pharmaceutically acceptable salt thereof, wherein R1is selected from halo and C1-C3haloalkyl; R2is selected from NH2, H and D; R3is selected fromR4is selected from C1-4alkyl and C3-C6cycloalkyl; R5is selected from H and C1-C4alkyl; and X is selected from -O- and -CH2-; and the wavy line designates the connection point to L.

3. The compound of Claim 1 or 2, wherein SHP is of the Formula II-a:or a pharmaceutically acceptable salt thereof.

4. The compound of Claim 1 or 2, wherein SHP is of the Formula II-b:or a pharmaceutically acceptable salt thereof.

5. The compound of Claim 1 or 2, wherein SHP is of the Formula II-c:or a pharmaceutically acceptable salt thereof.

6. The compound of Claim 1 or 2, wherein SHP is of the Formula II-d:or a pharmaceutically acceptable salt thereof.

7. The compound of any one of Claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein SHP is selected from,.

8. The compound of any one of Claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Hs is selected from,Q and U are each independently selected from phenyl, heteroaryl, heterocyclyl, and cycloalkyl, each of which being optionally substituted with 1 to 3 groups selected from R14; R17, R18, R19and R20are each independently selected from hydrogen, halo, CN, (C1-C4)alkyl, halo(C1-C4)alkyl, and -C(O)NRaRb; R21and R22are each independently hydrogen, (C1-C4)alkyl, or halo(C1- C4)alkyl; R23is hydrogen, (C1-C4)alkyl, OH, -O(C1-C4)alkyl, or -O[halo(C1-C4)alkyl], W is 5- or 6-membered heteroaryl optionally substituted with 1 to 3 groups selected from R14;V is phenyl or 5- to 9-membered heteroaryl optionally substituted with 1 to 3 groups selected from R15; R6is halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, or halo(C1- C4)alkoxy; R14is (C1-C4)alkyl, halo(C1-C4)alkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, (C2- C6)alkynyl, halo(C2-C6)alkynyl, CN, -C1-4alkylORe, -ORe, -C(O)Re, -C(O)ORe, - C(O)NReRf, -C(O)NRe(C1-4alkylene)ORe, -C(O)NRe(C1-4alkylene)NReRf, -C(O)NRe(C1-4alkylene)OR, -NReRf, -O(C1-4alkylene)NReRf, -SH, - S(C1-4alkyl), -C1-4alkylNReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -SO2NReRf, - NRe(C1-4alkyl)ORe, -NRe(C1-4alkyl)NReRf, -C1-6alkylC(O)NReRf, phenyl or 5- to 7- membered heteroaryl, wherein said phenyl and 5- to 7-membered heteroaryl are each optionally and independently substituted with 1 to 3 groups selected from R16; Reand Rfare each independently selected from hydrogen and (C1-C4)alkyl, wherein said (C1-C4)alkyl is optionally substituted with one or more halo or a 3- to 7- membered heterocyclyl, or both; R15and R16are each independently halo, -NReRf, (C1-C4)alkyl, halo(C1- C4)alkyl, (C1-C4)alkoxy, or halo(C1-C4)alkoxy; and the wavy line designates the connection point to L.

9. The compound of any one of Claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein Hs is selected from.

10. The compound of any one of Claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein Hs is selected from.

11. The compound of any one of Claims 8 to 10, or a pharmaceutically acceptable salt thereof, wherein R6is (C1-C4)alkyl.

12. The compound of any one of Claims 8 to 11, or a pharmaceutically acceptable salt thereof, wherein R14is -C(O)NReRfand Reand Rfare each independently selected from hydrogen and (C1-C4)alkyl, wherein said (C1-C4)alkyl is optionally substituted with one or more halo.

13. The compound of any one of Claims 8 to 12, or a pharmaceutically acceptable salt thereof, wherein R15is hydrogen.

14. The compound of any one of Claims 8 to 13, or a pharmaceutically acceptable salt thereof, wherein R20is hydrogen, halo or (C1-C4)alkyl.

15. The compound of any one of Claims 8 to 14, or a pharmaceutically acceptable salt thereof, wherein R23is hydrogen, (C1-C4)alkyl, or OH.

16. The compound of any one of Claims 8 to 15, or a pharmaceutically acceptable salt thereof, wherein R22is hydrogen.

17. The compound of any one of Claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein Hs is selected from:,18. The compound of any one of Claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein L is selected from (C1-C6)alkyl, (CH2CH2O)v, (C1-C6)alkylNRq, (C1-C6)alkylC(O), (C1-C6)alkylC(O)O, (C1-C6)alkylOC(O), (C1-C6)alkylC(O)NRq, (C1-C6)alkylNRqC(O), X1-Het1-X2, X1-Het1-X2-X3, X1-Het1-X2-Het2-X3-, X1-Het1-X2-Het2-X3-Het3-X4-, (CH2CH2O)v-X1-Het1-X2, (CH2CH2O)v-X1-Het1-X2-X3, (CH2CH2O)v-X1-Het1-X2-Het2-X3-, (CH2CH2O)v-X1-Het1-X2-Het2-X3-Het3-X4-, (C1- C6)alkylNRq-X1-Het1-X2, (C1-C6)alkylNRq-X1-Het1-X2-X3, (C1-C6)alkylNRq-X1-Het1- X2-Het2-X3-, (C1-C6)alkylNRq-X1-Het1-X2-Het2-X3-Het3-X4-, (C1-C6)alkylC(O)-X1- Het1-X2, (C1-C6)alkylC(O)-X1-Het1-X2-X3, (C1-C6)alkylC(O)-X1-Het1-X2-Het2-X3-, (C1-C6)alkylC(O)-X1-Het1-X2-Het2-X3-Het3-X4-, (C1-C6)alkylC(O)NRq-X1-Het1-X2, (C1-C6)alkylC(O)NRq-X1-Het1-X2-X3, (C1-C6)alkylC(O)NRq-X1-Het1-X2-Het2-X3-, and (C1-C6)alkylC(O)NRq-X1-Het1-X2-Het2-X3-Het3-X4-; each X1, X2, X3, and X4are independently absent or selected from (C1- C4)alkylene, O, NRq, and C(O); v is 1, 2, 3, 4, 5, or 6 Rqis hydrogen or (C1-C4)alkyl; and each Het1, Het2, and Het3are independently selected from a 4- to 6-membered heterocyclyl and (C3-C6)cycloalkyl, each optionally substituted with 1 to 3 groups selected from halo, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, and (C1- C4)haloalkoxy.

19. The compound of any one of Claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein L is selected from (C1-C6)alkyl, (C1-C6)alkylNRq, X1-Het1-X2, X1-Het1-X2-X3, X1-Het1-X2-Het2-X3-, and X1-Het1-X2-Het2-X3-Het3-X4-.

20. The compound of Claim 18 or 19, or a pharmaceutically acceptable salt thereof, wherein each X1, X2, X3, and X4is independently absent or selected from piperidinyl, piperazinyl, cyclohexyl, cyclobutyl, azetidinyl, and pyrrolidinyl, each optionally substituted with 1 to 3 groups selected from halo, (C1-C4)alkyl, (C1- C4)haloalkyl, (C1-C4)alkoxy, and (C1-C4)haloalkoxy.

21. The compound of any one of Claims 18 to 20, or a pharmaceutically acceptable salt thereof, wherein each X1, X2, X3, and X4is independently absent or selected from piperidinyl, piperazinyl, cyclohexyl, cyclobutyl, azetidinyl, and pyrrolidinyl, each optionally substituted with 1 to 3 groups selected from halo, (C1- C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, and (C1-C4)haloalkoxy.

22. The compound of any one of Claims 18 to 21, or a pharmaceutically acceptable salt thereof, wherein each X1, X2, X3, and X4is independently absent or selected from piperidinyl, piperazinyl, and pyrrolidinyl.

23. The compound of any one of Claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein L is selected from, wherein the * indicates the point of attachment to Hs.

24. The compound of Claim 1, wherein the compound is selected from:

25. A pharmaceutical composition comprising a compound of any one of Claims 1 to 24, or a pharmaceutically acceptable salt thereof.

26. A method of treating cancer in a subject comprising administering to the subject an effective amount of a compound of any one of Claims 1 to 24, or a pharmaceutically acceptable salt thereof

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