Methods and compositions for modulating KRAS (G12D)

Abstract

Tumor-targeted protein degradation chimeras, referred to as chaperone-mediated protein degradation agents (CHAMP), are provided that include a first moiety capable of binding to one or more target proteins (e.g., KRAS (G12D)) and a second moiety capable of binding to a protein component of one or more chaperone proteins or chaperone complexes (e.g., HSP90). Also provided are pharmaceutical compositions comprising the disclosed CHAMPs and their use for therapy, which are useful for the treatment of cancer and related conditions.

Description

[0001] Related Applications

[0002] This application claims the priority benefit of international application No. PCT / CN2022 / 114635 filed on August 24, 2022, the entire contents of which are incorporated herein by reference. Background Art

[0003] Protein homeostasis or proteostasis refers to the ability of cells to regulate the synthesis, folding, transport and degradation of proteins. In particular, properly regulated protein degradation is necessary for the normal functioning of cells (including their proliferation, differentiation and death), and is often dysregulated in cancer and other diseases (Van Die, Chin J Cancer, 2011, 30: 124-137).

[0004] The ubiquitin-proteasome system (UPS) is one of the main pathways for mediating the disposal and metabolic cycle of proteins in cells (Yu and Matouschek, Annu Rev Biophys, 2017, 46: 149-173; Navon and Ciechanover, J Biol Chem, 2009, 284: 33713-33718). Ubiquitin is a ubiquitously expressed protein of 76 amino acid residues. Regarding protein degradation achieved by UPS, the process of ubiquitination occurs when 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 the E1 ubiquitin activating enzyme. Secondly, the activated ubiquitin is transferred from E1 to the E2 ubiquitin conjugating enzyme. And thirdly, one of hundreds of different E3 ubiquitin ligases connects ubiquitin to a lysine residue in a substrate protein. The repetition of this enzymatic process results in labeling the substrate protein with a polyubiquitin chain. 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 toward 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).

[0005] Chemically induced targeted protein degradation has become an important approach for drug development. Small molecules can be used to promote the interaction of one or more target proteins with one or more components of various cellular protein degradation pathways, thereby inducing the degradation of one or more target proteins as a way to treat diseases.

[0006] In particular, proteolysis targeting chimera (PROTAC) is an example of such a small molecule, which induces protein degradation of a specific protein by drawing in 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 one or more target proteins and E3 ubiquitin ligases to form a ternary complex between the target protein, PROTAC molecule and E3 ligase protein in the cell. The induction of one or more target proteins and E3 ligases approaches the ubiquitination of one or more target proteins and the subsequent degradation of the target protein by the proteasome. Although PROTACs incorporating target protein binders that promiscuously bind to multiple proteins can generally degrade multiple proteins, in some cases, protein-protein interactions between individual targets and E3 ligases can increase or decrease the observed degradation potency and selectivity, for example by inhibiting the formation of some ternary complexes due to charge repulsion and steric clashes between a given target protein and an 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).

[0007] Other chemically induced TPD methods have also been described, such as molecular glue (Che et al., Bioog Med Chem Lett, 2018, 28: 2585-2592), AUTAC, ATTEC and LYTAC (Ding et al., Trends Pharmacol Sci, 2020, 41: 464-474). For example, AUTAC technology follows a similar induced approach principle, but targets proteins to be degraded via autophagy (Daiki et al., Mol Cell, 2019, 76: 797-810).

[0008] In general, TPD technology has many 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 reagents work in a substoichiometric manner, and can usually mediate the sequential degradation of multiple molecules of one or more target proteins, which usually results in a higher efficacy than the separated target binding moieties and other biochemical inhibitors they incorporate. In addition, since the inhibition of the function of one or more target proteins by TPD reagents is mainly due to degradation rather than simple biochemical inhibition, the recovery of the function of one or more target proteins is usually slower than that observed for biochemical inhibitors. Compared with biochemical inhibitors, TPD reagents may also have improved target selectivity. Finally, TPD reagents can interact with the binding pocket that does not affect the biochemical activity of the target but still allows its degradation to target proteins that are not affected by biochemical inhibition.

[0009] However, current TPD technology is accompanied by some shortcomings. These shortcomings include the promiscuous degradation of one or more target proteins in many tissues and organs, not just in one or more tissues and one or more organs in which one or more target proteins participate in the disease process, which is expected to cause the adverse side effects of treatment. In addition, drug resistance to these technologies may occur by mutations or changes in the expression of UPS components such as E3 ligases (Ottis et al., ACS Chem Biol, 2019, 14: 2215-2223; Zhang et al., Mol Cancer Ther, 2019, 18: 1302-1311), thereby resulting in the loss of efficacy. Therefore, there is a demand for improvements / alternative methods and compositions for TPD.

[0010] Therefore, it is expected to develop improved / alternative TPD reagents that mediate the degradation of proteins involved in cancer and other diseases.HSP90 (heat shock protein 90-kDa) is a molecular chaperone that will interact with most of the signal transduction proteins expressed in cells.These proteins include kinases, transcription factors and many E3 ligases that guide protein degradation (Taipale et al., Cell, 2012, 150: 987-100).In addition, HSP90 folds and maintains the structure of many mutated or overexpressed oncoproteins, which drive tumor growth (Schwartz et al., Cell Stress Chaperones. 2015, 20: 729-41).Obviously, it is observed that the molecular inhibitors combined with the N-terminal of HSP90 accumulate in tumor cells (Kamal et al., Nature, 2003, 425: 407-102003; Moulick et al., Nat Chem Biol. 2011, 7: 818-26). HSP90 inhibitor binding induces HSP90-dependent oncogenic protein depletion through a process involving E3 ligases and UPS (Li et al., Cell Rep. 2017, 20; 19: 2515-2528; Xu et al., Proc Natl Acad Sci US A. 2002, 99: 12847-52). Therefore, targeted inhibition of HSP90 can lead to tumor cell cytotoxicity (Wang et al., Curr Opin Investig Drugs. 2010, 11: 1466-76; Trepel et al., Nat Rev Cancer. 2010, 10: 537-49).

[0011] Kirsten rat sarcoma virus homolog (KRAS) is a monomeric small 21kDa GTPase that has long been an elusive cancer drug target (Chang et al., PNAS, 1982, 79: 4848-52; McCoy et al., Nature, 1983, 302: 79-8). KRAS acts as a molecular switch that promotes cell growth by cycling between a GTP-bound state and a GDP-bound state. In the GTP-bound state, KRAS sends growth signals through the RAF-MAPK and PI3K-AKT-MTOR pathways. Subsequently, KRAS hydrolyzes GTP to GDP with the help of GTPase activating proteins (GAPs). This GDP-bound state "turns off" KRAS growth-promoting signaling. KRAS can then be "turned back on" by exchanging GDP for GTP with the help of guanine nucleotide exchange factors such as SOS1 (Cox and Der, Small GTPases, 2010, 1:2-27; Kerk et al., Nat Rev Cancer, 2021, 21:510-525). Preventing this exchange by locking KRAS in the GDP-bound state is a practical approach to inhibiting its oncogenic activity.

[0012] The human KRAS gene is encoded on chromosome 12p12.1 and is one of the most commonly mutated genes in human cancer (Pylayeva-Gupta et al., Nat Rev Cancer, 2011, 11: 761-774). Mutations that prevent GTP hydrolysis lock KRAS in an active GTP-bound state and reprogram cells to achieve permanent proliferation. As analyzed by next-generation sequencing, KRAS mutations from glycine (G) at the 12th codon to aspartic acid (D) were observed in 6.8% of cancer cases, resulting in a long-term active KRAS (G12D) oncogene (Zhou et al., Pathol Oncol Res, 2020, 26: 2835-2837). KRAS(G12D) is associated with poor clinical outcomes and has been observed in 4.9% of lung adenocarcinomas, 12.5% ​​of colorectal cancers, and 37% of pancreatic ductal adenocarcinomas (Hofman et al., Cancer Discov. 2022, 12:924-937). Notably, HSP90 is not known to accompany / associate with KRAS or its mutants.

[0013] Oncogenic KRAS mutants have historically been considered undruggable (McCormick F., Biochem J, 2019, 476: 356-74), however, the discovery of an allosteric pocket in GDP-bound KRAS allows people to look for small molecule inhibitors (Ostrem et al., Nature, 2013, 503: 548-51). In addition, the G12D mutation provides a unique partial binding space due to the encoding of an acidic amino acid residue (D) instead of a small flexible amino acid residue (G) with only a hydrogen side chain. This change in the KRAS protein structure provides a unique space that can be targeted with small molecule drugs that specifically bind to and inhibit the oncogenic activity of KRAS (G12D).

[0014] Therefore, it is desirable to design and develop agents that regulate KRAS (G12D). It is also desirable to design and develop agents that combine both HSP90 and KRAS (G12D) to induce new protein-protein interactions, thereby promoting TPD of KRAS (G12D) as a treatment for cancer and other diseases. It is also desirable to develop agents that inhibit and induce the degradation of KRAS (G12D) and one or more other proteins, particularly those involved in mediating resistance to KRAS (G12D) inhibitors. In addition, it is desirable to develop agents that accumulate in tumor cells. Summary of the invention

[0015] The present disclosure provides tumor-targeted protein degradation chimeras, termed chaperone-mediated protein degraders (CHAMPs), comprising a first portion capable of binding to one or more target proteins (e.g., KRAS(G12D)) and a second portion capable of binding to one or more chaperone proteins or protein components of a chaperone complex (e.g., HSP90).

[0016] Such CHAMP compounds include those having the formula KL-Hs, wherein K is a chemical entity that binds to KRAS(G12D), L is a linker, and Hs is a chemical entity that binds to the HSP90 protein.

[0017] Compositions comprising the disclosed CHAMP compounds and methods of making the same are also provided.In one aspect, the disclosed CHAMP compounds induce degradation of targeted oncogenic proteins in a tumor-selective manner and can be used to treat cancer and related conditions. DETAILED DESCRIPTION

[0018] 1. Compound Overview

[0019] In a first embodiment, the CHAMP compound described herein is of Formula I or II:

[0020]

[0021] or a pharmaceutically acceptable salt thereof, wherein

[0022] HET is an optionally substituted heterocyclic group;

[0023] Hs is the chemical moiety that binds to HSP90;

[0024] X is hydrogen or halogen;

[0025] L is the connector;

[0026] m is 0, 1, 2 or 3;

[0027] R 1 Selected from (C 1 -C 4 )alkylO(C 1 -C 4 )alkyl, -(C 1 -C 4 ) alkylNH(C 1 -C 4 )alkyl, -(C 1 -C 4 )alkylN[(C 1 -C 4 )alkyl] 2 , heterocyclyl and cycloalkyl, wherein the heterocyclyl and cycloalkyl are each optionally and independently substituted;

[0028] R 2 Selected from hydrogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, (C 1 -C 4 ) alkynyl, (C 1 -C 4 )alkenyl, halogen, (C 3 -C 6 )cycloalkyl, -O(C 3 -C 6 ) Cycloalkyl, cyano, NH 2 、-NH(C 1 -C 4 )alkyl, -N[(C 1 -C 4 )alkyl] 2 、-P(O)[(C 1 -C 4 )alkyl]2 and -S(C 1 -C 4 )alkyl;

[0029] R 3 Selected from

[0030] a 1 N or CHZ 1 ;

[0031] Z 1 is selected from hydrogen, halogen, (C 1 -C 4 ) alkyl, (C 2 -C 4 ) alkenyl, cyano, cyano (C 1 -C 4 )alkyl, -S[halo(C 1 -C 4 )alkyl] and (C 3 -C 6 )cycloalkyl;

[0032] R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are each independently selected from hydrogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) cyanoalkyl, (C 1 -C 4 )hydroxyalkyl, -(C 1 -C 4 )Alkyl NR a R b 、-(C 1 -C 4 )alkylC(O)NR a R b , (C 1 -C 4 )alkylO(C 1 -C 4 )alkyl, -(C 1 -C 4 )alkylC(O)OR a 、-(C 1 -C 4 )Alkyl NR a C(O)OR b 、-(C 1 -C4 )alkylC(O)R a 、-(C 1 -C 4 )alkyl heterocyclic group, -(C 1 -C 4 ) alkylaryl, -(C 1 -C 4 ) alkylheteroaryl, (C 2 -C 4 ) alkenyl, (C 2 -C 4 ) haloalkenyl, (C 2 -C 4 )cyanoalkenyl, (C 2 -C 4 )hydroxyalkenyl, -(C 2 -C 4 )Alkenyl NR a R b , (C 2 -C 4 ) alkynyl, (C 2 -C 4 ) haloalkynyl, (C 2 -C 4 ) cyanoalkynyl, (C 2 -C 4 ) hydroxyalkynyl, -(C 2 -C 4 ) NR a R b , (C 1 -C 4 ) alkoxy, (C 1 -C 4 )halogenated alkoxy, halogen, cyano, oxo, hydroxy, -S(C 1 -C 4 )alkyl, -S(C 1 -C 4 ) haloalkyl, -NR a R b 、-NR a C(O)R b 、-C(O)R a 、-C(O)OR a 、-SO 2 R a 、-S(O)R a 、-SO 2 NR a R b 、-NR a SO 2 R b , (C 3 -C 6)cycloalkyl, 5- or 6-membered heteroaryl and 4- to 6-membered heterocyclyl, wherein -(C 1 -C 4 )alkyl heterocyclic group, -(C 1 -C 4 ) alkylaryl and -(C 1 -C 4 ) alkyl heteroaryl said heterocyclic group, aryl and heteroaryl and said (C 3 -C 6 ) cycloalkyl, 5- or 6-membered heteroaryl and 4- to 6-membered heterocyclyl are each optionally and independently substituted by 1 to 3 members selected from R c substituted by a group;

[0033] R a and R b are each independently selected from hydrogen, (C 1 -C 4 ) alkyl and (C 1 -C 4 ) haloalkyl, or when on the same nitrogen atom, R a and R b may together form a heterocyclic group; and

[0034] R c Selected from halogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 )Haloalkoxy, cyano, hydroxy, oxo, -C(O)OR a 、-C(O)R a 、-SO 2 R a 、-S(O)R a 、-SO 2 NR a R b 、-NR a C(O)R b 、-NR a SO 2 R b 、-NR a R b and NO 2 .

[0035] 2. Definition

[0036] 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 used in the art. Unless otherwise defined, 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.

[0037] As used herein, the articles "a" and "an" refer to one or more than one (e.g., at least one) of the grammatical object of the article. When used in conjunction with the term "comprising" herein, the use of the words "a" or "an" may mean "one", but it is also consistent with the meaning of "one or more", "at least one", and "one or more than one".

[0038] In the claims and in the above description, all transitional terms such as "comprising," "including," "with," "having," "containing," "involving," "having," "consisting of," etc. shall be construed as open-ended, i.e., meaning including but not limited to. Only the transitional terms "consisting of" and "consisting essentially of" shall be closed or semi-closed transitional terms, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures Section 2111.03.

[0039] The term "IC 50 ” or “EC 50 ” refers to the amount, concentration or dose of a compound required to inhibit 50% of the maximal response in an assay measuring such response.

[0040] Unless otherwise indicated, as used herein, the term "compound" refers to any CHAMP compound disclosed herein. In some aspects, one or more hydrogen atoms on the 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 equivalent "non-deuterated" compounds.

[0041] As used herein, the term "alkyl" refers to a saturated straight or branched chain non-cyclic hydrocarbon having from 1 to 10 carbon atoms, unless otherwise specified, for example, (C 1 -C 6 ) alkyl or (C 1 -C 4Representative straight-chain alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl; while saturated branched alkyl groups 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, etc.

[0042] As used herein, the term "alkenyl" refers to a saturated straight or branched chain non-cyclic hydrocarbon having, unless otherwise specified, 2 to 10 carbon atoms (e.g., (C 2 -C 6 ) alkenyl or (C 2 -C 4 ) alkenyl), and having at least one carbon-carbon double bond. Representative straight and branched (C 2 -C 10 )Alkenyl includes vinyl, allyl, 1-butenyl, 2-butenyl, isobutenyl, 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, etc.

[0043] As used herein, the term "alkynyl" refers to a saturated straight or branched chain non-cyclic hydrocarbon having, unless otherwise specified, 2 to 10 carbon atoms (e.g., (C 2 -C 6 ) alkynyl or (C 2 -C 4) alkynyl), and having at least one carbon-carbon triple bond. Representative straight and branched alkynyl groups include ethynyl, 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, etc.

[0044] The term "aryl", used alone or as a larger moiety as in -(C 1 -C 4 ) is used as part of an alkylaryl group and refers to monocyclic and bicyclic carbocyclic 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, anthracenyl, and the like. It should be understood that when specified, optional substituents on the aryl group may be present in any substitutable position.

[0045] As used herein, the term "cycloalkyl" refers to a saturated, monocyclic alkyl group having, for example, 3 to 10 carbon atoms (e.g., 3 to 6 carbon atoms). Representative cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.

[0046] The term "oxo" refers to the group =0.

[0047] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more (including all) hydrogen groups are replaced with a halogen group, wherein each halogen 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.

[0048] "Alkoxy" refers to an alkyl group attached through an oxygen linking atom, represented by -O-alkyl. For example, "(C 1 -C 4 The term "alkoxy" includes methoxy, ethoxy, propoxy and butoxy.

[0049] "Haloalkoxy" is a haloalkyl group attached to another moiety through an oxygen atom, for example, -OCHF 2 or –OCF 3 .

[0050] As used herein, the term "halogen" or "halo" refers to F, Cl, Br or I.

[0051] As used herein, the term "heterocyclyl" refers to 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. As long as the valence permits, the heterocycle can be connected via any heteroatom or carbon atom. Representative heterocycles include morpholinyl, thiomorpholinyl, pyrrolidonyl, pyrrolidinyl, piperidinyl, piperazinyl, oxacyclopropyl, dioxanyl, oxetanyl, dihydrofuranyl, dihydropyranyl, isoindolyl, dihydropyridyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroindolyl, tetrahydropyrimidinyl, diazabicyclooctyl, hexahydropyrrolizinyl, 2-azaspiro[ 3.3]heptyl, 2,7-diazaspiro[3.5]nonyl, 2-azaspiro[3.5]nonyl, 3-azabicyclo[3.1.0]hexyl, 8-azabicyclo[3.2.1]octyl, 3,8-diazabicyclo[3.2.1]octyl, 3,6-diazabicyclo[3.1.1]heptyl, octahydro-1H-pyrrolo[2,3-c]pyridinyl, and the like. Optional substituents on the heterocyclyl group may be present at any substitutable position as valence permits and include, for example, the position at which the heterocyclyl is attached.

[0052] As used herein, the term "heteroaryl" refers to a 5- to 12-membered aromatic group containing 1-4 heteroatoms selected from N, O and S. The heteroaryl group may be monocyclic or bicyclic. As long as the valence permits, the heteroaryl group may be attached via any heteroatom or carbon atom. Representative heteroaryl groups include pyridyl, furanyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, thiadiazolyl, isoquinolinyl, indazolyl, benzoxazolyl, benzofuranyl, indolizinyl, imidazopyridinyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridinyl, quinazolinyl, purinyl, benzothienyl, and the like. Optional substituents on heteroaryl groups may be present at any substitutable position as valence permits and include, for example, the position of attachment of the heteroaryl group.

[0053] When used to describe a chemical group that may have multiple points of attachment, the hyphen (-) indicates the point of attachment of the group to the variable that defines it. For example, -(C 1 -C 4 )alkylaryl means that the point of attachment of these groups is on the alkyl group.

[0054] The term "alkylene" refers to a straight or branched chain saturated divalent hydrocarbon group. 1-6 The alkanediyl group refers to a straight-chain saturated divalent hydrocarbon group of 1 to 6 carbon atoms or a branched-chain saturated divalent hydrocarbon group of 3 to 6 carbon atoms.

[0055] 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, phenethyl (including all isomeric forms, e.g., 1-phenethyl and 2-phenethyl) and phenylpropyl (including all isomeric forms, e.g., 1-phenylpropyl, 2-phenylpropyl and 3-phenylpropyl).

[0056] Hash keys, as in , represents the point at which the drawn group is attached to the defined variable.

[0057] 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 at each position may be the same or different. Optional substituents include, but are not limited to, one or more groups selected from the following: cyano (-CN), halogen, imino (=NH), nitro (-NO 2 ), oxo (=O), –C(O)R i , –C(O)OR i , –C(O)NR ii R iii , –C(O)SR i , –C(NR i )NR ii R iii , –C(S)R i , –C(S)OR i , –C(S)NR ii R iii ,–OR i 、–OC(O)R i 、–OC(O)OR i 、–OC(O)NR ii R iii 、–OC(O)SR i 、–OC(NR i )NR ii R iii 、–OC(S)R i 、–OC(S)OR i 、–OC(S)NR ii R iii ,–OP(O)(OR ii )OR iii 、–OS(O)R i 、–OS(O) 2 R i 、–OS(O)NR ii R iii 、–OS(O) 2 NRii R iii ,–NR ii R iii ,–NR i C(O)R iv ,–NR i C(O)OR iv ,–NR i C(O)NR ii R iii ,–NR a C(O)SR iv ,–NR i C(NR iv )NR ii R iii ,–NR i C(S)R iv ,–NR i C(S)OR iv ,–NR i C(S)NR ii R iii ,–NR i S(O)R iv ,–NR i S(O) 2 R iv ,–NR i S(O)NR ii R iii ,–NR i S(O) 2 NR ii R iv ,–SR i , –S(O)R i , –S(O) 2 R i , –S(O)NR ii R iv , –S(O) 2 NR ii R iv alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is further optionally substituted by one or more (in one embodiment, one, two, three or four) substituents Q a is replaced by, where each R i , R ii , R iii and R iv is independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one or more (in one embodiment, one, two, three or four) substituents Qa Replaced by, or R ii and R iii Together with the N atom to which they are attached, they form a group Q optionally substituted by one or more (in one embodiment, one, two, three or four) a substituted heterocyclic group, wherein each Q a are independently selected from cyano, halogen, imino, nitro, oxo, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, C 6-14 Aryl, Heteroaryl, Heterocyclyl, –C(O)R v , –C(O)OR v , –C(O)NR vi R vii , –C(O)SR v , –C(NR v )NR vi R vii , –C(S)R v , –C(S)OR v , –C(S)NR vi R vii ,–OR v 、–OC(O)R v 、–OC(O)OR v 、–OC(O)NR vi R vii 、–OC(O)SR v 、–OC(NR v )NR vi R vii 、–OC(S)R v 、–OC(S)OR v 、–OC(S)NR vi R vii ,–OP(O)(OR v )OR vi 、–OS(O)R v 、–OS(O) 2 R v 、–OS(O)NR vi R vii 、–OS(O) 2 NR v R vii ,–NR vi R vii ,–NR v C(O)R viii ,–NR e C(O)OR vi ,–NR v C(O)NR vi R vii ,–NRv C(O)SR vi ,–NR v C(NR viii )NR vi R vii ,–NR v C(S)R viii ,–NR v C(S)OR vi ,–NR v C(S)NR vi R vii ,–NR v S(O)R viii ,–NR v S(O) 2 R viii ,–NR v S(O)NR vi R vii ,–NR v S(O) 2 NR vi R vii ,–SR v , –S(O)R v , –S(O) 2 R v , –S(O)NR vi R vii and –S(O) 2 NR vi R vii ; where each R v , R vi , R vii and R viii are independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl or heterocyclyl; or (iii) R vi and R viii Together with the N atom to which they are attached they form a heterocyclyl.

[0058] The terms "linker" or "tether" are used interchangeably and refer to a chemical moiety that connects two other parts (e.g., a first binding moiety and a second binding moiety). The linker can covalently connect the first binding moiety to the second binding moiety. In one aspect, the linker is not cleavable in vivo. In one aspect, the linker comprises a ring system of one or more rings. In another aspect, the linker comprises an alkyl chain that is optionally substituted and / or interrupted by one or more chemical groups. In one aspect, the linker comprises optimal spatial and chemical properties to achieve 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 to their respective targets (e.g., HSP90 and KRAS (G12D)). In one aspect, the linker changes the ability of the first binding moiety and / or the second binding moiety to bind to their respective targets (e.g., HSP90 and KRAS (G12D)).

[0059] The term "KRAS" refers to the protein product of the KRAS proto-oncogene GTPase gene.

[0060] 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 HSP90-α), HSP90AB1 (HSP90-beta or HSP90β), HSP90B1 (GRP94) and TRAP1.

[0061] The term "KRAS(G12D)" refers to the protein product of a KRAS gene carrying a mutation resulting in a substitution of the glycine amino acid at position 12 of KRAS with aspartic acid.

[0062] "A chemical entity that binds to KRAS(G12D)" refers to a small molecule or a different part of a larger molecule that binds to a portion of KRAS(G12D). In some aspects, the chemical entity that binds to KRAS(G12D) is a small molecule. In some aspects, the chemical entity that binds to KRAS(G12D) is a small molecule with a molecular weight of less than 2,000 g / mol. In some aspects, the chemical entity that binds to KRAS(G12D) induces a conformational change in KRAS(G12D).

[0063] The term "SOS1" refers to the protein product of the SOS1 gene, which acts as a guanine nucleotide exchange factor for RAS proteins.

[0064] When used to describe a chemical group that may have multiple points of attachment, the hyphen (-) indicates the point of attachment of the group to the variable that defines it. For example, -NR a R b and -C(O)NR a(C 1-4 Alkylene)NR a R refers to the fact that the points of attachment of these groups are located on the nitrogen atom and the carbon atom, respectively.

[0065] 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% pure by weight relative to all other stereoisomers. Weight percent purity relative to all other stereoisomers is the ratio of the weight of one stereoisomer to the weight of the other stereoisomers. For example, when a single enantiomer is named or depicted by structure, the enantiomer depicted or named is at least 60%, 70%, 80%, 90%, 99%, or 99.9% optically pure by weight. Weight percent optical purity is the ratio of the weight of an enantiomer to the weight of the enantiomer plus the weight of its optical isomers.

[0066] For use in medicine, 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, for example, salts of inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid and sulfuric acid) and organic acids (such as acetic acid, benzenesulfonic acid, benzoic acid, methanesulfonic acid and p-toluenesulfonic acid). The compounds of the present teachings having acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. Suitable pharmaceutically acceptable basic salts include, for example, ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts). Compounds having quaternary ammonium groups also contain counter anions such as chloride, bromide, iodide, acetate, perchlorate, etc. Other examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, benzoates, and salts with amino acids such as glutamic acid.

[0067] The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound formulated with it. Pharmaceutically acceptable carriers, adjuvants or vehicles that can 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 silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin.

[0068] Any composition or method provided herein can be combined with one or more of any other compositions and methods provided herein.

[0069] As used herein, the term "subject" refers to humans 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, dogs, cats, horses, cows, chickens, amphibians and reptiles. In a preferred embodiment, the subject is a human and can be referred to as a patient.

[0070] As used herein, the terms "treat," "treating," or "treatment" preferably refer 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, reduction in the extent of the disease, stabilization (i.e., non-exacerbation) of the state of the disease, improvement or palliation of the disease state, slowing of the rate or time of progression, and relief (whether partial or total), whether detectable or undetectable. "Treatment" may also refer to prolonging survival, such as compared to the expected survival in the absence of treatment. Treatment does not require a cure.

[0071] A "therapeutically effective amount" is an 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 about 0.01 to about 100 mg / kg body weight / day.

[0072] The terms "administer," "administering," or "administration" include any method of delivering a pharmaceutical composition or agent to a subject or a specific area in or on a subject. In certain embodiments of the invention, the agent is administered intravenously, intramuscularly, subcutaneously, intradermally, intranasally, orally, transdermally, or transmucosally. In a preferred embodiment, the agent is administered intravenously. In another preferred embodiment, the agent is administered orally. Administration of the agent can be accomplished by multiple people working in collaboration. Administration of the agent includes, for example, prescribing the agent to be administered to the subject and / or providing instructions for taking a particular agent directly or through another person, by self-delivery, such as oral delivery, subcutaneous delivery, intravenous delivery via a central catheter, etc.; or delivery by a trained professional, such as intravenous delivery, intramuscular delivery, intratumoral delivery, etc.

[0073] 3. Compounds

[0074] In a second embodiment, the CHAMP compound described herein is of Formula I:

[0075]

[0076] or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described above.

[0077] In a third embodiment, HET in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, is optionally substituted 3,8-diazabicyclo[3.2.1]octyl, wherein the remaining variables are as described above for Formula I and II. Alternatively, as part of the third embodiment, HET in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, is optionally substituted 3,8-diazabicyclo[3.2.1]octyl or 3,6-diazabicyclo[3.2.1]octyl, wherein the remaining variables are as described above for Formula I and II.

[0078] In a fourth embodiment, the CHAMP compounds described herein have Formula Ia or IIa:

[0079]

[0080] or a pharmaceutically acceptable salt thereof, wherein R 0 For halogen, (C 1 -C 4 ) alkyl, hydroxyl (C 1 -C 4 ) alkyl, cyano (C 1 -C 4 )alkyl, -C(O)H, -C(O) 2 H, -C(O) 2 (C 1 -C 4 )alkyl, -C(O)(C 1 -C 4 )alkyl, -C(O)(C 1 -C 4 ) haloalkyl, -C(O) 2 (C 1 -C 4 )Haloalkyl, C(O) 2 NH 2 、-C(O) 2 NH(C 1 -C 4 )alkyl, -C(O) 2 N[(C 1 -C 4 )alkyl] 2 、-S(O) 2 (C 1 -C 4 )alkyl and -S(O) 2 (C 1 -C 4) haloalkyl or 5- to 6-membered optionally substituted heteroaryl; k is 0, 1, 2 or 3, and wherein the remaining variables are as described above for Formulas I and II.

[0081] In a fifth embodiment, the CHAMP compounds described herein are of Formula Ib or lib:

[0082]

[0083] or a pharmaceutically acceptable salt thereof, wherein k is 0 or 1 and wherein the remaining variables are as described above for Formulas I and II or the fourth embodiment.

[0084] In a sixth embodiment, R in the compound of Formula Ia, IIa, Ib or IIb or a pharmaceutically acceptable salt thereof 0 -C(O)(C 1 -C 4 )alkyl or -C(O)(C 1 -C 4 ) haloalkyl, wherein the remaining variables are as described above for Formulas I and II or the fourth embodiment. Alternatively, as part of the sixth embodiment, R in the compound of Formula Ia, IIa, Ib or IIb or a pharmaceutically acceptable salt thereof is 0 is cyano (C1-C4) alkyl, -C(O)(C 1 -C 4 )alkyl or -C(O)(C 1 -C 4 )haloalkyl, wherein the remaining variables are as described above for Formulas I and II or the fourth embodiment.

[0085] In a seventh embodiment, k is 0 in the compound of Formula Ia, IIa, Ib or IIb, or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described above for Formulas I and II or any of the fourth or sixth embodiments.

[0086] In an eighth embodiment, a of the compound of Formula I, Ia or Ib 1 is N, wherein the remaining variables are as described above for Formula I, Ia or Ib, or any of the fourth, sixth or seventh embodiments.

[0087] In a ninth embodiment, X in a compound of Formula I, Ia or Ib, or a pharmaceutically acceptable salt thereof, is halogen, wherein the remaining variables are as described above for Formula I, Ia or Ib, or any one of the fourth or sixth through eighth embodiments. Alternatively, as part of the ninth embodiment, X in a compound of Formula I, Ia or Ib, or a pharmaceutically acceptable salt thereof, is fluoro, wherein the remaining variables are as described above for Formula I, Ia or Ib, or any one of the fourth or sixth through eighth embodiments.

[0088] In a tenth embodiment, R in the compound of Formula Ia, IIa, Ib or IIb or a pharmaceutically acceptable salt thereof is 2 is hydrogen or (C 1 -C 4 )alkoxy, wherein the remaining variables are as described above for Formula Ia, IIa, Ib or IIb or any one of the fourth or sixth through ninth embodiments. Alternatively, as part of the tenth embodiment, R in the compound of Formula Ia, IIa, Ib or IIb or a pharmaceutically acceptable salt thereof is 2 is hydrogen, wherein the remaining variables are as described above for Formula Ia, IIa, Ib or IIb or any one of the fourth or sixth through ninth embodiments.

[0089] In an eleventh embodiment, R in the compound of Formula Ia, IIa, Ib or IIb or a pharmaceutically acceptable salt thereof 8 , R 9 , R 10 , R 11 , R 12 and R 13 are each independently selected from hydrogen, halogen, (C 2 -C 4 ) alkynyl, halo (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkyl, cyano, (C 1 -C 4 ) alkoxy and hydroxy, wherein the remaining variables are as described above for Formula Ia, IIa, Ib or IIb or any one of the fourth or sixth through tenth embodiments. Alternatively, as part of the eleventh embodiment, R in the compound of Formula Ia, IIa, Ib or IIb or a pharmaceutically acceptable salt thereof is 8 , R 9 , R 10 and R 11 each is hydrogen; or R 9 , R 10 and R 11 Each is hydrogen and R 8 Selected from halogen, cyano, hydroxyl, (C1 -C 4 ) alkoxy and (C 2 -C 4 ) alkynyl; or R 8 , R 9 and R 10 Each is hydrogen and R 11 is hydroxyl; or R 10 is hydrogen and R 8 , R 9 and R 11 are each independently selected from halogen, (C 2 -C 4 ) alkynyl, (C 1 -C 4 ) alkyl, cyano, (C 1 -C 4 ) alkoxy and hydroxy; or R 12 and R 13 each is hydrogen; or R 12 For halogenated (C 1 -C 4 ) alkyl and R 13 is hydrogen; or R 12 and R 13 Each independently selected from halogenated (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkyl and halogen, wherein the remaining variables are as described above for Formula Ia, IIa, Ib or IIb, or any one of the fourth or sixth through tenth embodiments.

[0090] In a twelfth embodiment, R in the compound of Formula Ia, IIa, Ib or IIb or a pharmaceutically acceptable salt thereof 3 Selected from wherein the remaining variables are as described above for Formula Ia, IIa, Ib or IIb or any one of the fourth or sixth through eleventh embodiments. Alternatively, as part of the twelfth embodiment, R in the compound of Formula Ia, IIa, Ib or IIb or a pharmaceutically acceptable salt thereof is 3 Selected from wherein the remaining variables are as described above for Formula Ia, IIa, Ib or lib or any one of the fourth or sixth through eleventh embodiments.

[0091] In a thirteenth embodiment, R in the compound of Formula Ia, IIa, Ib or IIb or a pharmaceutically acceptable salt thereof is 1is selected from optionally substituted heterocyclyl and optionally substituted cycloalkyl, wherein the remaining variables are as described above for Formula Ia, IIa, Ib or IIb or any one of the fourth or sixth through twelfth embodiments. Alternatively, as part of the thirteenth embodiment, R in the compound of Formula Ia, IIa, Ib or IIb or a pharmaceutically acceptable salt thereof is 1 is selected from an optionally substituted 4- to 6-membered nitrogen-containing heterocyclic group, an optionally substituted 8- to 10-membered fused bicyclic heterocyclic group, and an optionally substituted (C 3 -C 4 )cycloalkyl, wherein the remaining variables are as described above for Formula Ia, IIa, Ib or IIb or any one of the fourth or sixth through twelfth embodiments. In another alternative, as part of the thirteenth embodiment, R in the compound of Formula Ia, IIa, Ib or IIb or a pharmaceutically acceptable salt thereof is 1 is selected from azetidinyl, pyrrolidinyl, cyclopropyl, piperazinyl and hexahydro-1H-pyrrolizinyl, each of which is optionally substituted by 1 to 3 selected from (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, C 1 -C 4 ) haloalkoxy and halogen, wherein the remaining variables are as described above for Formula Ia, IIa, Ib or IIb or any one of the fourth or sixth through twelfth embodiments. In another alternative, as part of the thirteenth embodiment, R in the compound of Formula Ia, IIa, Ib or IIb or a pharmaceutically acceptable salt thereof is 1 is selected from pyrrolidinyl, cyclopropyl, piperazinyl and hexahydro-1H-pyrrolizinyl, each of which is optionally substituted by 1 to 3 selected from (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, C 1 -C 4 ) haloalkoxy and halogen, wherein the remaining variables are as described above for Formula Ia, IIa, Ib or IIb or any one of the fourth or sixth through twelfth embodiments. In yet another alternative, as part of the thirteenth embodiment, R in the compound of Formula Ia, IIa, Ib or IIb or a pharmaceutically acceptable salt thereof is 1 is selected from azetidinyl, pyrrolidinyl, cyclopropyl, piperazinyl and hexahydro-1H-pyrrolizinyl, each of which is optionally substituted by (C1 -C 4 ) alkyl, wherein the remaining variables are as described above for Formula Ia, IIa, Ib or IIb or any one of the fourth or sixth through twelfth embodiments. In yet another alternative, as part of the thirteenth embodiment, R in the compound of Formula Ia, IIa, Ib or IIb or a pharmaceutically acceptable salt thereof is 1 is selected from pyrrolidinyl, cyclopropyl, piperazinyl and hexahydro-1H-pyrrolizinyl, each of which is optionally substituted by (C 1 -C 4 ) alkyl, wherein the remaining variables are as described above for Formula Ia, IIa, Ib or IIb or any one of the fourth or sixth through twelfth embodiments. In yet another alternative, as part of the thirteenth embodiment, R in the compound of Formula Ia, IIa, Ib or IIb or a pharmaceutically acceptable salt thereof is 1 Selected from wherein the remaining variables are as described above for Formula Ia, IIa, Ib or IIb or any one of the fourth or sixth through twelfth embodiments. In yet another alternative, as part of the thirteenth embodiment, R in the compound of Formula Ia, IIa, Ib or IIb or a pharmaceutically acceptable salt thereof is 1 Selected from wherein the remaining variables are as described above for Formula Ia, IIa, Ib or IIb or any one of the fourth or sixth through twelfth embodiments. In yet another alternative, as part of the thirteenth embodiment, R in the compound of Formula Ia, IIa, Ib or IIb or a pharmaceutically acceptable salt thereof is 1 Selected from wherein * indicates the point of attachment to L and wherein the remaining variables are as described above for Formula Ia, IIa, Ib or IIb or any one of the fourth or sixth through twelfth embodiments.

[0092] In a fourteenth embodiment, m is 0, 1 or 2 in a compound of Formula Ia, IIa, Ib or IIb, or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described above for Formula Ia, IIa, Ib or IIb, or any one of the fourth or sixth to thirteenth embodiments.

[0093] In a fifteenth embodiment, Hs in the compound of Formula Ia, IIa, Ib or IIb or a pharmaceutically acceptable salt thereof is selected from in

[0094] Q and U are each independently selected from phenyl, heteroaryl, heterocyclyl and cycloalkyl, each of which is optionally substituted by 1 to 3 selected from R 14substituted by a group;

[0095] R 17 , R 18 , R 19 and R 20 are each independently selected from hydrogen, halogen, CN, (C 1 -C 4 ) alkyl, halogenated (C 1 -C 4 )alkyl and -C(O)NR a R b ;

[0096] R 21 , R 22 and R 23 are each independently hydrogen, (C 1 -C 4 ) alkyl or halogenated (C 1 -C 4 )alkyl;

[0097] W is optionally 1 to 3 selected from R 14 A 5- or 6-membered heteroaryl group substituted with a group of

[0098] V is optionally 1 to 3 selected from R 15 phenyl or 5- to 9-membered heteroaryl substituted with a group;

[0099] R 5 For halogen, (C 1 -C 4 ) alkyl, halogenated (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy or halogenated (C 1 -C 4 ) alkoxy;

[0100] R 14 For (C 1 -C 4 ) alkyl, halogenated (C 1 -C 4 ) alkyl, (C 2 -C 6 )alkenyl, halo (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, halo (C 2 -C 6 )alkynyl, CN, -C 1-4 Alkyl OR e 、-OR e 、-C(O)Re 、-C(O)OR e 、-C(O)NR e R f 、-C(O)NR e (C 1-4 Alkylene)OR e 、-C(O)NR e (C 1-4 Alkylene)NR e R f 、-C(O)NR e (C 1-4 Alkylene)OR, -NR e R f 、-O(C 1-4 Alkylene)NR e R f ,-SH,-S(C 1-4 Alkyl), -C 1-4 Alkyl NR e R f 、-SR e 、-S(O)R e 、-S(O) 2 R e 、-S(O)NR e R f 、-SO 2 NR e R f 、-NR e (C 1-4 alkyl)OR e 、-NR e (C 1-4 Alkyl)NR e R f , -C 1-6 Alkyl C(O)NR e R f , phenyl or 5- to 7-membered heteroaryl, wherein the phenyl and 5- to 7-membered heteroaryl are each optionally and independently substituted by 1 to 3 selected from R 16 substituted by a group;

[0101] R e and R f are each independently selected from hydrogen and (C 1 -C 4 )alkyl, wherein said (C 1 -C 4 )alkyl is optionally substituted with one or more halogen or 3- to 7-membered heterocyclyl or both; and

[0102] R 15 and R 16 are independently halogen, -NRe R f , (C 1 -C 4 ) alkyl, halogenated (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy or halogenated (C 1 -C 4 )alkoxy, wherein the remaining variables are as described above for Formula Ia, IIa, Ib or IIb, or any one of the fourth or sixth through fourteenth embodiments.

[0103] Alternatively, as part of the fifteenth embodiment, Hs in the compound of Formula Ia, IIa, Ib or IIb or a pharmaceutically acceptable salt thereof is selected from in

[0104] Q and U are each independently selected from phenyl, heteroaryl, heterocyclyl and cycloalkyl, each of which is optionally substituted by 1 to 3 selected from R 14 substituted by a group;

[0105] R 17 , R 18 , R 19 and R 20 are each independently selected from hydrogen, halogen, CN, (C 1 -C 4 ) alkyl, halogenated (C 1 -C 4 )alkyl, -NR a R b 、-OR e and -C(O)NR a R b ;

[0106] q is 0, 1, 2, or 3;

[0107] R 21 , R 22 and R 23 are each independently hydrogen, (C 1 -C 4 ) alkyl or halogenated (C 1 -C 4 )alkyl;

[0108] W is optionally 1 to 3 selected from R 14 A 5- or 6-membered heteroaryl group substituted with a group of

[0109] V is optionally 1 to 3 selected from R 15 phenyl or 5- to 9-membered heteroaryl substituted with a group;

[0110] R 5 For halogen, (C 1 -C 4 ) alkyl, halogenated (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy or halogenated (C 1 -C 4 ) alkoxy;

[0111] R 14 For (C 1 -C 4 ) alkyl, halogenated (C 1 -C 4 ) alkyl, (C 2 -C 6 )alkenyl, halo (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, halo (C 2 -C 6 )alkynyl, CN, -C 1-4 Alkyl OR e 、-OR e 、-C(O)R e 、-C(O)OR e 、-C(O)NR e R f 、-C(O)NR e (C 1-4 Alkylene)OR e 、-C(O)NR e (C 1-4 Alkylene)NR e R f 、-C(O)NR e (C 1-4 Alkylene)OR, -NR e R f 、-O(C 1-4 Alkylene)NR e R f ,-SH,-S(C 1-4 Alkyl), -C 1-4 Alkyl NR e R f 、-SR e 、-S(O)R e 、-S(O) 2 R e 、-S(O)NR e R f 、-SO2 NR e R f 、-NR e (C 1-4 alkyl)OR e 、-NR e (C 1-4 Alkyl)NR e R f , -C 1-6 Alkyl C(O)NR e R f , phenyl or 5- to 7-membered heteroaryl, wherein the phenyl and 5- to 7-membered heteroaryl are each optionally and independently substituted by 1 to 3 selected from R 16 substituted by a group;

[0112] R e and R f are each independently selected from hydrogen and (C 1 -C 4 )alkyl, wherein said (C 1 -C 4 )alkyl is optionally substituted with one or more halogen or 3- to 7-membered heterocyclyl or both; and

[0113] R 15 and R 16 are independently halogen, -NR e R f , (C 1 -C 4 ) alkyl, halogenated (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy or halogenated (C 1 -C 4 )alkoxy, wherein the remaining variables are as described above for Formula Ia, IIa, Ib or IIb, or any one of the fourth or sixth through fourteenth embodiments.

[0114] In a sixteenth embodiment, Hs in the compound of Formula Ia, IIa, Ib or IIb or a pharmaceutically acceptable salt thereof is wherein the remaining variables are as described above for Formula Ia, IIa, Ib or lib or any one of the fourth or sixth through fifteenth embodiments.

[0115] In the seventeenth embodiment, R as described in the preceding embodiments 20 For (C 1 -C 4 )alkyl.

[0116] In an eighteenth embodiment, R as described in the preceding embodiments22 and R 23 Each is hydrogen, R 22 is hydrogen and R 23 For (C 1 -C 4 ) alkyl, or R 23 is hydrogen and R 22 For (C 1 -C 4 ) alkyl. Alternatively, as part of the eighteenth embodiment, R as described in the previous embodiments 22 and R 23 Each is hydrogen, R 22 and R 23 Each is (C 1 -C 4 ) alkyl, R 22 is hydrogen and R 23 For (C 1 -C 4 ) alkyl, or R 23 is hydrogen and R 22 For (C 1 -C 4 )alkyl.

[0117] In a nineteenth embodiment, Hs in the compound of Formula Ia, IIa, Ib or IIb or a pharmaceutically acceptable salt thereof is selected from and

[0118] Z is N or CH (preferably CH), wherein the remaining variables are as described above for Formula Ia, IIa, Ib or IIb or any one of the fourth or sixth through fifteenth embodiments.

[0119] In a twelfth embodiment, R as described in the fifteenth to nineteenth embodiments 15 Independently (C 1 -C 4 ) alkyl or halogen.

[0120] In a twenty-first embodiment, Hs in the compound of Formula Ia, IIa, Ib or IIb or a pharmaceutically acceptable salt thereof is wherein the remaining variables are as described above for Formula Ia, IIa, Ib or IIb or any one of the fourth or sixth through twentieth embodiments. Alternatively, as part of the twenty-first embodiment, the compound of Formula Ia, IIa, Ib or IIb, or a pharmaceutically acceptable salt thereof, wherein Hs is wherein the remaining variables are as described above for Formula Ia, IIa, Ib or IIb or any one of the fourth or sixth through twentieth embodiments. In another alternative, as part of the twenty-first embodiment, Hs in the compound of Formula Ia, IIa, Ib or IIb or a pharmaceutically acceptable salt thereof is wherein the remaining variables are as described above for Formula Ia, IIa, Ib or IIb or any one of the fourth or sixth through twentieth embodiments. In yet another alternative, as part of the twenty-first embodiment, Hs in the compound of Formula Ia, IIa, Ib or IIb, or a pharmaceutically acceptable salt thereof, is wherein the remaining variables are as described above for Formula Ia, IIa, Ib or lib or any one of the fourth or sixth through twentieth embodiments.

[0121] In a twenty-second embodiment, R in any one of the fifteenth to twenty-first embodiments 5 is halogen or (C 1 -C 4 ) alkyl. Alternatively, as part of the twenty-second embodiment, R in any one of the fifteenth to twenty-first embodiments is 5 In another alternative, as part of the twenty-second embodiment, R in any one of the fifteenth to twenty-first embodiments is 5 is isopropyl or ethyl.

[0122] In a twenty-third embodiment, R in any one of the fifteenth to twenty-second embodiments 14 For –OR e 、-SR e 、-C(O)NR e R f or -C(O)NR e (C 1-4 Alkylene)NR e R f .

[0123] In a twenty-fourth embodiment, R in any one of the fifteenth to twenty-third embodiments e and R f are each independently selected from hydrogen and (C 1 -C 4 )alkyl, wherein said (C 1 -C 4 ) The alkyl group is optionally substituted with 1 to 3 halogen or 6-membered heterocyclic groups.

[0124] In a twenty-fifth embodiment, R in any one of the fifteenth to twenty-fourth embodiments 14 OH, -C(O)NHCH2 CF 3 、-C(O)NHCH 2 CH 3 、-C(O)NHCH(CH 3 ) 2 、-C(O)NH(CH 2 CH 3 ) 2 、-C(O)NHCH(CH 3 )CF 3 , -C(O)NH cyclopropyl, -C(O)NH methylcyclopropyl, C(O)NH 2 or -C(O)NH(CH 2 ) 2 Alternatively, as part of the twenty-fifth embodiment, R in any one of the fifteenth to twenty-fourth embodiments is 14 -C(O)NHCH 2 CF 3 In another alternative, as part of the twenty-fifth embodiment, R in any one of the fifteenth to twenty-fourth embodiments is 14 For OH.

[0125] In a twenty-sixth embodiment, Hs in the compound of Formula Ia, IIa, Ib or IIb or a pharmaceutically acceptable salt thereof is selected from wherein the remaining variables are as described above for Formula Ia, IIa, Ib or IIb or any one of the fourth or sixth through fourteenth embodiments. Alternatively, as part of the twenty-sixth embodiment, Hs in the compound of Formula Ia, IIa, Ib or IIb or a pharmaceutically acceptable salt thereof is selected from

[0126] wherein the remaining variables are as described above for Formula Ia, IIa, Ib or lib or any one of the fourth or sixth through fourteenth embodiments.

[0127] In a twenty-seventh embodiment, L in the compound of Formula Ia, IIa, Ib or IIb or a pharmaceutically acceptable salt thereof is selected from (C 1 -C 6 )alkyl, (CH 2 CH 2 O) v , (C 1 -C 6 )Alkyl NR q , (C 1 -C6 ) alkyl C(O), (C 1 -C 6 ) alkyl C(O)O, (C 1 -C 6 ) alkyl OC(O), (C 1 -C 6 ) alkyl C(O)NR q , (C 1 -C 6 ) alkyl NR q C(O), X 1 -Het 1 -X 2 , X 1 -Het 1 -X 2 -X 3 , X 1 -Het 1 -X 2 -Het 2 -X 3 -, X 1 -Het 1 -X 2 -Het 2 -X 3 -Het 3 -X 4 -, (CH 2 CH 2 O) v -X 1 -Het 1 -X 2 , (CH 2 CH 2 O) v -X 1 -Het 1 -X 2 -X 3 , (CH 2 CH 2 O) v -X 1 -Het 1 -X 2 -Het 2 -X 3 , (CH 2 CH 2 O) v -X 1 -Het 1 -X 2 -Het 2 -X 3 -Het 3 -X 4 , (C1 -C 6 )Alkyl NR q -X 1 -Het 1 -X 2 , (C 1 -C 6 )Alkyl NR q -X 1 -Het 1 -X 2 -X 3 , (C 1 -C 6 )Alkyl NR q -X 1 -Het 1 -X 2 -Het 2 -X 3 -、(C 1 -C 6 )Alkyl NR q -X 1 -Het 1 -X 2 -Het 2 -X 3 -Het 3 -X 4 -、(C 1 -C 6 )alkylC(O)-X 1 -Het 1 -X 2 , (C 1 -C 6 )alkylC(O)-X 1 -Het 1 -X 2 -X 3 , (C 1 -C 6 )alkylC(O)-X 1 -Het 1 -X 2 -Het 2 -X 3 -、(C 1 -C 6 )alkylC(O)-X 1 -Het 1 -X 2 -Het 2 -X 3 -Het 3 -X 4 -、(C 1 -C 6 )alkylC(O)NR q -X1 -Het 1 -X 2 , (C 1 -C 6 )alkyl lC(O)NR q -X 1 -Het 1 -X 2 -X 3 , (C 1 -C 6 )alkylC(O)NR q -X 1 -Het 1 -X 2 -Het 2 -X 3 - and (C 1 -C 6 )alkylC(O)NR q -X 1 -Het 1 -X 2 -Het 2 -X 3 -Het 3 -X 4 -;

[0128] Each X 1 , X 2 , X 3 and X 4 Independently absent or selected from (C 1 -C 4 ) alkylene, O, NR q and C(O);

[0129] v is 1, 2, 3, 4, 5, or 6

[0130] R q is hydrogen or (C 1 -C 4 )alkyl; and

[0131] Each Het 1 、Het 2 and Het 3 are independently selected from 4- to 6-membered heterocyclic groups and (C 3 -C 6 )cycloalkyl, each optionally substituted by 1 to 3 groups selected from halogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy and (C 1 -C4 ) haloalkoxy radical, wherein the remaining variables are as described above for Formula Ia, IIa, Ib or IIb or any one of the fourth or sixth through twenty-sixth embodiments. Alternatively, as part of the twenty-seventh embodiment, L in the compound of Formula Ia, IIa, Ib or IIb or a pharmaceutically acceptable salt thereof is selected from (C 1 -C 6 )alkyl, (CH 2 CH 2 O) v , (C 1 -C 6 )Alkyl NR q , (C 1 -C 6 )alkylC(O),(C 1 -C 6 )alkylC(O)O,(C 1 -C 6 ) alkyl OC(O), (C 1 -C 6 )alkylC(O)NR q , (C 1 -C 6 )Alkyl NR q C(O),X 1 -Het 1 -X 2 , X 1 -Het 1 -X 2 -X 3 , X 1 -Het 1 -X 2 -X 3 -X 4 , X 1 -Het 1 -X 2 -X 3 -X 4 -X 5 , X 1 -Het 1 -X 2 -Het 2 -X 3 -、X 1 -Het 1 -X 2 -Het 2 -X 3 -Het 3 -X 4 -、(CH 2 CH 2 O) v -X1 -Het 1 -X 2 、(CH 2 CH 2 O) v -X 1 -Het 1 -X 2 -X 3 、(CH 2 CH 2 O) v -X 1 -Het 1 -X 2 -Het 2 -X 3 -、(CH 2 CH 2 O) v -X 1 -Het 1 -X 2 -Het 2 -X 3 -Het 3 -X 4 -、(C 1 -C 6 )alkylNR q -X 1 -Het 1 -X 2 、(C 1 -C 6 )alkylNR q -X 1 -Het 1 -X 2 -X 3 、(C 1 -C 6 )alkylNR q -X 1 -Het 1 -X 2 -Het 2 -X 3 -、(C 1 -C 6 )alkylNR q -X 1 -Het 1 -X 2 -Het 2 -X 3 -Het 3 -X 4 -、(C 1 -C 6 )alkylC(O)-X 1 -Het1 -X 2 , (C 1 -C 6 )alkylC(O)-X 1 -Het 1 -X 2 -X 3 , (C 1 -C 6 )alkylC(O)-X 1 -Het 1 -X 2 -Het 2 -X 3 -、(C 1 -C 6 )alkylC(O)-X 1 -Het 1 -X 2 -Het 2 -X 3 -Het 3 -X 4 -、(C 1 -C 6 )alkylC(O)NR q -X 1 -Het 1 -X 2 , (C 1 -C 6 )alkylC(O)NR q -X 1 -Het 1 -X 2 -X 3 , (C 1 -C 6 )alkylC(O)NR q -X 1 -Het 1 -X 2 -Het 2 -X 3 - and (C 1 -C 6 )alkylC(O)NR q -X 1 -Het 1 -X 2 -Het 2 -X 3 -Het 3 -X 4 -;

[0132] Each X 1 , X 2 , X 3 , X 4 and X5 Independently absent or selected from (C 1 -C 4 ) alkylene, O, NR q and C(O);

[0133] v is 1, 2, 3, 4, 5, or 6

[0134] R q is hydrogen or (C 1 -C 4 )alkyl; and

[0135] Each Het 1 、Het 2 and Het 3 are independently selected from 4- to 6-membered heterocyclic groups and (C 3 -C 6 )cycloalkyl, each optionally substituted by 1 to 3 groups selected from halogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy and (C 1 -C 4 ) haloalkoxy radical, wherein the remaining variables are as described above for Formula Ia, IIa, Ib or IIb, or any one of the fourth or sixth through twenty-sixth embodiments.

[0136] In a twenty-eighth embodiment, L in the compound of Formula Ia, IIa, Ib or IIb or a pharmaceutically acceptable salt thereof is selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 )Alkyl NR q , X 1 -Het 1 -X 2 , X 1 -Het 1 -X 2 -X 3 , X 1 -Het 1 -X 2 -Het 2 -X 3 - and X 1 -Het 1 -X 2 -Het 2 -X 3 -Het 3 -X 4-, wherein the remaining variables are as described above for Formula Ia, IIa, Ib or IIb or any one of the fourth or sixth through twenty-sixth embodiments. Alternatively, as part of the twenty-eighth embodiment, L in the compound of Formula Ia, IIa, Ib or IIb or a pharmaceutically acceptable salt thereof is selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 )Alkyl NR q , X 1 -Het 1 -X 2 , X 1 -Het 1 -X 2 -X 3 , X 1 -Het 1 -X 2 -X 3 -X 4 , X 1 -Het 1 -X 2 -X 3 -X 4 -X 5 , X 1 -Het 1 -X 2 -Het 2 -X 3 - and X 1 -Het 1 -X 2 -Het 2 -X 3 -Het 3 -X 4 -, wherein the remaining variables are as described above for Formula Ia, IIa, Ib or lib or any one of the fourth or sixth through twenty-sixth embodiments.

[0137] In the twenty-ninth embodiment, each Het as described in the twenty-seventh or twenty-eighth embodiment 1 、Het 2 and Het 3 are independently absent or selected from piperidinyl, piperazinyl, cyclohexyl, cyclobutyl, azetidinyl and pyrrolidinyl, each optionally substituted by 1 to 3 groups selected from halogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy and (C 1 -C 4) is substituted with a haloalkoxy group. Alternatively, as part of the twenty-ninth embodiment, each Het 1 、Het 2 and Het 3 In yet another alternative, as part of the twenty-ninth embodiment, each Het as described in the twenty-seventh or twenty-eighth embodiment is absent or selected from piperidinyl, piperazinyl and pyrrolidinyl. 1 、Het 2 and Het 3 are independently absent or selected from piperidinyl, piperazinyl, cyclohexyl, cyclopropyl, cyclobutyl, azetidinyl and pyrrolidinyl, each optionally substituted by 1 to 3 groups selected from halogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy and (C 1 -C 4 ) is substituted with a haloalkoxy group.

[0138] In a thirtieth embodiment, L in the compound of Formula Ia, IIa, Ib or IIb or a pharmaceutically acceptable salt thereof is selected from -CH 2 -、CH 2 N(CH 3 ), wherein the remaining variables are as described above for Formula Ia, IIa, Ib or IIb or any one of the fourth or sixth through twenty-sixth embodiments. Alternatively, as part of the thirtieth embodiment, L in the compound of Formula Ia, IIa, Ib or IIb or a pharmaceutically acceptable salt thereof is selected from -CH 2 -、*CH 2 N(CH 3 ), wherein * indicates the point of attachment to Hs, and wherein the remaining variables are as described above for Formula Ia, IIa, Ib or IIb, or any one of the fourth or sixth through twenty-sixth embodiments. In yet another alternative, as part of the thirtieth embodiment, L in the compound of Formula Ia, IIa, Ib or IIb, or a pharmaceutically acceptable salt thereof, is selected from -CH 2 -、*CH 2 N(CH 3 ), wherein * indicates the point of attachment to Hs and wherein the remaining variables are as described above for Formula Ia, IIa, Ib or IIb or any one of the fourth or sixth through twenty-sixth embodiments.

[0139] Additional compounds are further disclosed in the examples and are included in the present disclosure, including pharmaceutically acceptable salts and neutral forms thereof.

[0140] 4. Use, preparation and administration

[0141] The compounds and compositions described herein are generally useful as anticancer therapies. In one aspect, the disclosed compounds and compositions are expressed as chaperone-mediated protein degraders (CHAMPs), wherein a portion of the compound is responsible for binding to KRAS (G12D), while another 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 mechanism of action includes, but is not limited to, degrading KRAS (G12D) and thereby hindering downstream signals that may lead to inhibition of cancer cell growth and / or induction of cancer cell death or other KRAS or KRAS (G12D) functions. In one aspect, the disclosed compounds achieve degradation of KRAS (G12D).

[0142] In one aspect, disclosed compounds and compositions include chaperones or chaperone complex binders with a series of different binding affinities. In different embodiments, it is desirable to use high affinity binders, medium affinity binders or low affinity binders. Since the HSP90 binding moiety interacting 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 can not only induce the degradation of one or more specific target proteins (which may or may not be HSP90 client proteins), but also induce the degradation of HSP90 client proteins simultaneously. EGFR and ERBB2 (HER2) are two such HSP90 client proteins (Xu et al., J Biol Chem, 2001, 276: 3702-3708). Such a combination of degradation activities can increase the biological activity of CHAMP molecules compared to other TPD technologies targeting the same target and can evade resistance mechanisms to KRAS(G12D) inhibitors and degraders, such as those mediated by the EGFR pathway.

[0143] In one aspect, the disclosed compounds and compositions are shown as tumor-targeted CHAMPs, wherein a portion of the compound is responsible for binding to KRAS (G12D), while another 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, relative to normal cells, tissues and organs, the disclosed compounds and compositions have extended pharmacokinetic exposure in cancer cells and tumors (Kamal et al., Nature, 2003, 425: 407-410; Vilenchik et al., Chem Biol, 2004, 11: 787-797). In one aspect, the disclosed compounds have an increased therapeutic index relative to other KRAS (G12D) degraders and inhibitors.

[0144] Therefore, provided herein is a method for treating a condition responsive to degradation or inhibition of KRAS (G12D), comprising administering a therapeutically effective amount of one or more compounds or compositions described herein to a subject in need thereof. Also provided is the use of one or more compounds or compositions described herein in the manufacture of a medicament for treating a condition responsive to degradation or inhibition of KRAS (G12D). In addition, provided is the use of a compound or composition described herein for treating a condition responsive to degradation or inhibition of KRAS (G12D).

[0145] In one aspect, the condition treated by the compounds and compositions of the present invention is cancer. The term "cancer" or "tumor" is well known in the art and refers to, for example, the presence of cells in a subject having characteristics typical of a cancer cell, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, reduced cell death / apoptosis, and certain characteristic morphological features. Cancer cells are generally in the form of solid tumors. However, cancer also includes non-solid tumors, such as blood tumors, such as leukemias, in which cancer cells are derived from the bone marrow. As used herein, the term "cancer" includes pre-malignant cancers as well as malignant cancers. Cancers include, but are not limited to, acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, granulocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenoma, diffuse large B-cell lymphoma, Burkitt's lymphoma, dysproliferative changes (dysproliferative changes) (dysplasia and metaplasia), embryonal carcinoma, endometrial carcinoma, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal carcinoma, estrogen receptor-positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, heavy chain disease hormone-insensitive prostate cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphangioendotheliosarcoma, lymphangiosarcoma, lymphatic leukemia, lymphoma (Hodgkin and non-Hodgkin), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin, and uterus, T-cell or B-cell Lymphoid malignancies of cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myxosarcoma, neuroblastoma, non-small cell lung cancer, oligodendroglioma, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinomas and sarcomas), small cell lung cancer, gastric 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, gallbladder cancer, bile duct cancer, small intestine cancer, urinary tract cancer, kidney cancer, urothelial 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 cancer, hemangioma, sarcoma arising from bone and soft tissue, Kaposi's sarcoma, neural cancer, eye cancer, meningeal cancer, glioblastoma, neuroma, neuroblastoma, schwannoma, solid tumors arising from hematopoietic malignancies such as leukemia, metastatic melanoma, recurrent or persistent epithelial ovarian 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 carcinoma, metastatic liver cancer, neuroendocrine cancer, refractory malignancies, triple-negative breast cancer, HER2-amplified breast cancer, nasopharyngeal cancer, oral cancer, biliary tract cancer, hepatocellular carcinoma, squamous cell carcinoma of the head and neck (SCCHN), non-medullary thyroid cancer, recurrent glioblastoma multiforme, neurofibromatosis type 1, CNS cancers, liposarcoma, leiomyosarcoma, salivary gland cancer, mucosal melanoma, acral / lentiginous melanoma, paraganglioma, pheochromocytoma, advanced metastatic cancer, solid tumors, triple-negative breast cancer, colorectal cancer, sarcoma, melanoma, renal cancer, endometrial cancer, thyroid cancer, rhabdomyosarcoma, multiple myeloma, ovarian cancer, glioblastoma, gastrointestinal stromal tumor, mantle cell lymphoma, and refractory malignancies.

[0146] As used herein, "solid tumor" is understood to mean any pathogenic tumor that can be palpated or detected using imaging methods as having three-dimensional abnormal growth. Solid tumors are different from blood tumors such as leukemia. However, the cells of blood tumors are derived from the bone marrow; therefore, the tissue that produces cancer cells is a solid tissue that may be hypoxic.

[0147] "Tumor tissue" or "tumorous tissue" is understood to refer to cells, extracellular matrix and other naturally occurring components associated with a solid tumor.

[0148] The specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, rate of excretion, co-administration, the judgment of the treating physician, and the severity of the specific disease being treated. The amount of the compound described herein in the composition will also depend on the specific compound in the composition.

[0149] Example

[0150] Chemical synthesis

[0151] The following representative examples are intended to help illustrate the present disclosure and are not intended to, and should not be construed to, limit the scope of the invention. Unless otherwise noted, general starting materials were obtained from commercial sources or prepared in other examples.

[0152] Preparation of intermediates

[0153] The following schemes and synthetic procedures illustrate the synthesis of intermediates used in the synthesis of the claimed compounds. Other intermediates can be prepared in a similar manner.

[0154] Solution 1

[0155]

[0156] Step 1: 1-(4-nitrobenzyl)piperidine-4-carboxylic acid methyl ester (1-2)

[0157] To a 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 K 2 CO 3 (51.18 g, 370.22 mmol). The mixture was stirred at room temperature overnight. The mixture was poured into 500 mL of H2O. It was extracted with ethyl acetate (500 mL*2). The organic phases were combined and washed with H 2 O and washed with brine. 2 SO 4 ), filtered and concentrated to give the desired 1-2 (49 g) as a yellow solid.

[0158] Step 2: 1-(4-aminobenzyl)piperidine-4-carboxylic acid methyl ester (1-3)

[0159] To 1-(4-nitrobenzyl)piperidine-4-carboxylic acid methyl ester (5.0 g, 17.97 mmol) and NH 4 Cl (4.81 g, 89.83 mmol) in MeOH / H 2 To the mixture in 4% 4-nitropropene (2% 4-nitropropene) was added Fe powder (5.02 g 89.83 mmol). The mixture was stirred under reflux overnight. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated. It was extracted with ethyl acetate (50 mL*2). The organic phases were combined, washed with H2O and brine. Drying (Na2SO4), filtering and concentrating gave 1-3 (3.8 g) as a brown oil.

[0160] Step 3: 1-(4-(2,4-dihydroxy-5-isopropylphenylthioamido)benzyl)piperidine-4-carboxylic acid methyl ester (1-4)

[0161] Compound 3a (20.69 g, 90.61 mmol), ClCH 2 COONa (10.55 g, 90.61 mmol) and NaHCO 3 A solution of (15.22 g, 181.22 mmol) in DMF (100 mL) was stirred at 40 ° C for 3 hours. To the mixture was added compound 1-3 (15.0 g, 60.41 mmol) in DMF (50 mL). The resulting mixture was then heated at 80 ° C overnight. The reaction mixture was poured into water and the precipitated solid was collected by filtration. The mother liquor was extracted with ethyl acetate (200 mL*2). The organic phases were combined and washed with H2O and brine. Dry (Na 2 SO 4 ), filtered and concentrated. It was combined with the filtered solid and purified by SGC to give 1-4 (22.1 g) as a yellow solid.

[0162] Step 4: 1-(4-(7-hydroxy-6-isopropyl-2-oxo-4-thioxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)benzyl)piperidine-4-carboxylic acid methyl ester (1-5)

[0163] A 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 at room temperature for 2 hours. The reaction solution was poured into brine (1 L) and extracted with EtOAc (200 mL*3). The organic layers were combined, washed with brine, and purified by Na 2 SO 4 Drying and concentration gave 1-5 (crude), which was used for further reaction without purification.

[0164] Step 5: 1-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperidine-4-carboxylic acid methyl ester (1-6)

[0165] To a solution of compound 1-5 (8.0 g, 17.07 mmol) in EtOH (80 mL) was added NH 2 NH 2 H 2 O (1.11 g, 22.2 mmol). The resulting mixture was then stirred at room temperature overnight. The precipitated solid was filtered and dried to obtain 1-6 (4 g) as a white solid.

[0166] 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)

[0167] To a solution of compound 1-6 (4.0 g 8.57 mmol) in MeOH / THF (1:1, 30 mL) was added LiOH H 2 O (1.8 g, 42.87 mmol) in a solution (15 mL). The resulting mixture was then stirred at room temperature for 3 hours. The pH was adjusted to 5-6 with 2N HCl. The precipitated solid was filtered and dried to give intermediate (1) (2.5 g) as a white solid.

[0168] Solution 2

[0169]

[0170] Preparation of compound 1-3-1

[0171] Compound O-ethyl dithiocarbonate potassium (137 g, 855 mmol) was added to a solution of 4-isopropylbenzene-1,3-diphenol (100 g, 658 mmol) in DMF (500 mL). The resulting mixture was stirred at 100 ° C for 14 hours under argon. It was poured into ice water (2 L), the pH was adjusted to 2 with 2N HCl solution and a yellow solid was formed. The solid was washed with water and brine and dried to obtain compound 1-3-1 (120 g, yield 80%) as a yellow solid.

[0172] Preparation of compound 2-2-1

[0173] At 0°C, triethylamine (7.78 g, 76.9 mmol) and ethylamine hydrochloride (2.98 g, 36.6 mmol) were dissolved in dichloromethane (100 mL). Ethyl oxalyl chloride (5.0 g, 36.6 mmol) was slowly added dropwise to the reaction system at 0°C for 2 hours. After the reaction, the mixture was filtered, the reaction solution was diluted with dichloromethane, and then washed with saturated sodium bicarbonate solution and brine in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 2-2-1 (5 g).

[0174] Step 1: Compound 2-5

[0175] Compound 1-3-1 (10 g, 44 mmol), ClCH 2 COONa (7 g, 60 mmol) and NaHCO 3A solution of (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 then heated at 80 ° C overnight. The reaction mixture was poured into ice water and the precipitated solid was collected by filtration to obtain compound 2-5 (7.0 g, yield 50%) as a yellow solid. MS-ESI (m / z) 346.2 [M+H] + .

[0176] Step 2: Compound 2-6

[0177] Compound 2-5 (7 g, 20 mmol) and NH 2 NH 2 H 2 A solution of O (2 g, 40 mmol) in dioxane (70 mL) was stirred at 30 °C for 6 h or overnight. The reaction solution was poured into H 2 O and extracted with EtOAc (200 mL*3). The organic layers were combined, washed with brine, and purified by Na 2 SO 4 Drying and concentration gave compound 2-6 (7 g, crude product), which was used for further reaction without purification. MS-ESI (m / z) 344.1 [M+H] + .

[0178] Step 3: Compound 2-7

[0179] Compound 2-2-1 (4.35 g, 30 mmol) and AcOH (0.5 mL) were added to a solution of compound 2-6 (7 g, 20 mmol) in i-PrOH (100 mL). The resulting mixture was then stirred overnight under reflux. Concentrated and purified by silica gel chromatography (DCM: MeOH = 20: 1) to give compound 2-7 (6 g) as a yellow solid. MS-ESI (m / z) 425.2 [M + H] + .

[0180] Step 4: Compound 2-8

[0181] To a 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, 50 mL). The mixture was stirred at room temperature overnight. THF and MeOH were concentrated to remove. 1N HCl was added to adjust the pH to 3. The precipitated solid was collected by filtration and dried to give compound 2-8 (4.4 g) as a yellow solid. MS-ESI (m / z) 411.3 [M+H] + .

[0182] Step 5: Compound 2-9

[0183] 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). HOBt (1.75 g, 12.95 mmol) and EDCI (2.48 g, 12.95 mmol) were added. The mixture was stirred at room temperature overnight. The reaction solution was poured into H 2 O and extracted with EtOAc (200 mL*3). The organic layers were combined, washed with brine, and purified by Na 2 SO 4 After drying and concentration, the product was purified by silica gel chromatography (DCM: MeOH = 20: 1) to obtain compound 2-9 (1.8 g) as a yellow solid. MS-ESI (m / z) 454.2 [M+H] + .

[0184] Step 6: Intermediate (2)

[0185] To a solution of compound 2-9 (5.1 g, 12.8 mmol) in THF (50 mL) was added LiAlH 4 (2.5 M in THF, 13.8 mL) and stirred at room temperature for 1 hour. 2 O (1 g), 10% NaOH (1 mL) and H 2 O (3 mL) to quench the reaction solution. Add brine and extract with THF (40 mL*3). Combine the organic phases and dry (Na 2 SO 4 ) and concentrated to give intermediate (2) (1.7 g) as a white solid. MS-ESI (m / z) 395.2 [M+H] + .

[0186] Solution 3

[0187]

[0188] Step 1: Compound 3-1

[0189] To a solution of compound 3-0 (93 g, 353 mmol) in DMF (1 L) were 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 room temperature overnight. The reaction solution was poured into H 2 O and extracted with EtOAc (1L×3). The organic layers were combined, washed with brine, and purified by Na2 SO 4 After drying and concentration, it was purified by SGC (PE:EA=3:1) to obtain compound 3-1 (70 g) as a yellow solid.

[0190] MS-ESI(m / z)307.1[M+H] + .

[0191] Step 2: Compound 3-2

[0192] To a solution of compound 3-1 (70 g, 228.5 mmol) in DCM (560 mL) was slowly added TFA (140 mL). It was stirred at room temperature overnight. Concentration gave compound 3-2 (70 g) as a yellow solid.

[0193] MS-ESI(m / z)207.1[M+H] + .

[0194] Step 3: Compound 3-3

[0195] Compound 3-2-1 (35.6 g, 181.3 mmol), DIEA (198.2 g, 1.53 mol) and HATU (70 g, 181 mmol) were added to a solution of compound 3-2 (52.8 g, 165 mmol) in DMF (400 mL). The mixture was stirred at room temperature overnight. The reaction solution was poured into H 2 O and extracted with EtOAc (1 L * 3). The organic layers were combined, washed with brine, and purified by Na 2 SO 4 After drying and concentration, it was purified by SGC (PE:EA=2:1) ​​to obtain compound 3-3 (23 g) as a yellow solid. MS-ESI (m / z) 384.9 [M+H] + .

[0196] Step 4: Intermediate (3)

[0197] 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 -78 °C and stirred at this temperature for 4 hours. The reaction solution was carefully quenched with HCl (1N, aq) and extracted with ethyl acetate (400 mL*3). The organic phases were combined and dried (Na 2 SO 4 ) and concentrated, and then purified by SGC (PE:EA=2:1) ​​to give intermediate (3) (13 g) as a white solid. MS-ESI (m / z) 326.0 [M+H] + .

[0198] Solution 4

[0199]

[0200] Step 1: 4,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine; 4-1:

[0201] To a solution of 7-chloro-8-fluoro-2-methylsulfanyl-pyrido[4,3-d]pyrimidin-4-ol (SM 567.0 g, 273 mmol, 1 eq) in Tol. (350 mL) was added POCl at 25°C. 3 (209 g, 1.36 mol, 127 mL, 5 eq), then DIEA (77.6 g, 600 mmol, 105 mL, 2.2 eq) was added to the mixture at below 40 °C and stirred at 110 °C for 2 hours. LCMS showed that the desired MS was detected. The residue was slowly poured into saturated NaHCO 3 The mixture was stirred for 2 h (maintaining pH = 8) and extracted with EtOAc (500 mL*2), washed with saturated NaCl (400 mL), and then purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure to obtain a brown solid compound (67.3 g, 255 mmol, yield 93.5%). LCMS: m / z 264.0 [M+H] + .

[0202] Step 2: tert-butyl 3-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate;

[0203] To a solution of compound 4-1 (67.3 g, 255 mmol, 1 eq) in DCM (600 mL) was added a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (48.7 g, 229 mmol, 0.9 eq) in DCM (100 mL) at -40°C. Then DIEA (98.9 g, 765 mmol, 133 mL, 3 eq) was added at -40°C and stirred for 0.5 hours. TLC (SiO 2 , petroleum ether:ethyl acetate=5:1,R1 R f =0.46,P1 R f =0.22) shows that a new spot has formed. 2 The mixture was quenched with O (1000 mL) and extracted with DCM (600 mL*2), washed with saturated NaCl (600 mL), and 2 SO 4The residue was dried, filtered and concentrated under reduced pressure to obtain a residue. The solid was stirred in EtOAc (100 mL) and filtered to obtain compound 4-2 (92.2 g, 209 mmol, yield 82.2%) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 )δ8.72(s,1H),4.57-4.33(m,4H),3.76-3.54(m,2H),2.62(s,3H),2.01-1.89(m,2H),1.69(d,J=7.4Hz,2H),1.52(s,9H). LCMS:m / z441.0[M+H] + .

[0204] Step 3: tert-butyl 3-(8-fluoro-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate; 4-3:

[0205] To a solution of compound 4-2 (3.77 g, 5.92 mmol, 1.3 eq) in THF (20 mL) was added K 3 PO 4 (1.5M, 9.10mL, 3eq) and [2-(2-aminophenyl)phenyl]palladium (1+) bis(1-adamantyl)-butyl-phosphine methanesulfonate (497mg, 683umol, 0.15eq), then stirred at 65°C for 10 hours. LCMS showed that the desired MS was detected. The reaction mixture was concentrated to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether: ethyl acetate = 10:1 to 0:1, SiO 2 , petroleum ether:ethyl acetate=3:1,P1 R f =0.3) to obtain compound 4-3 (4.2 g, crude product) as brown oil. LCMS: m / z 772.3 [M+H] + .

[0206] Step 4: 3-[8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]-2-methylsulfonyl-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester; intermediate (4)

[0207] To a solution of compound 4-3 (11.5 g, 14.5 mmol, 1.00 eq) in DCM (100 mL) was added m-CPBA (6.50 g, 32.0 mmol, purity 85%, 2.20 eq). The mixture was stirred at 0°C for 1 hour. TLC (PE:EA=3:1R1 R f =0.3P1 R f =0.2) indicated that reactant 1 was completely consumed and the reaction was clean according to TLC. 2 SO 3 The reaction mixture was quenched with H 2 The reaction mixture was diluted with 200 mL of 1% O and extracted with 200 mL of DCM (100 mL*2). The organic layers were combined, washed with 200 mL of NaCl (100 mL*2) aqueous solution, and then purified by Na 2 SO 4 Drying, filtration and concentration under reduced pressure gave a residue. The crude product was purified by flash silica gel column chromatography (PE:EA=5:1-3:1) to give intermediate (4) as a brown oil.

[0208] Solution 5

[0209]

[0210] Scheme 5 shows the synthesis of the linker intermediate (5). The following are the details of the synthetic procedure:

[0211] Step 1: (2S,4S)-4-{4-[(benzyloxy)carbonyl]piperazin-1-yl}pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester; 5-1

[0212] To a stirred solution of (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester (30 g, 122.312 mmol, 1 eq) and DIEA (79.04 g, 611.560 mmol, 5 eq) in DCM (600 mL) was added Tf dropwise at -78 °C under nitrogen atmosphere. 2 O (51.76 g, 183.462 mmol, 1.50 equiv). The mixture was stirred at -78 °C for 30 min, then piperazine-1-carboxylic acid benzyl ester (40.41 g, 183.468 mmol, 1.5 equiv) was added at -40 °C. The mixture was stirred at room temperature for 3 h. The reaction was quenched by adding water (500 mL) at room temperature. CH 2 Cl 2 The resulting mixture was extracted with 1% paraformaldehyde (2 x 300 mL). The organic layers were combined, washed with brine (1 x 500 mL), and purified by anhydrous Na 2 SO 4After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (2:1) to obtain compound 5-1 (26 g, 47.50%) as a colorless oil.

[0213] Step 2: 4-[(3S,5S)-1-(tert-butoxycarbonyl)-5-(hydroxymethyl)pyrrolidin-3-yl]piperazine-1-carboxylic acid benzyl ester; 5-2

[0214] To a stirred solution of compound 5-1 (26 g, 58.096 mmol, 1 eq.) and LiCl (4.93 g, 116.192 mmol, 2 eq.) in THF (250 mL, 3085.692 mmol) and EtOH (250 mL, 4303.328 mmol) was added NaBH4 (4.40 g, 116.192 mmol, 2 eq.) in portions at room temperature under nitrogen atmosphere. The mixture was stirred at room temperature for 3 hours. The reaction was quenched with water (500 mL) at room temperature. The resulting mixture was extracted with CH2Cl2 (3 x 400 mL). The organic layers were combined, washed with brine (1 x 500 mL), and washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1) to obtain compound 5-2 (14.4 g, 59.08%) as a colorless oil.

[0215] Step 3: 4-[(3S,5S)-5-(hydroxymethyl)pyrrolidin-3-yl]piperazine-1-carboxylic acid benzyl ester; 5-3

[0216] To a stirred solution of compound 5-2 (14.4 g, 34.325 mmol, 1 eq.) in DCM (150 mL) was added TFA (80 mL, 1077.046 mmol, 31.38 eq.) at room temperature under nitrogen atmosphere. The mixture was stirred at room temperature. The resulting mixture was concentrated in vacuo. The crude product was used directly in the next step without further purification.

[0217] Step 4: Benzyl 4-[(3S,5S)-5-(hydroxymethyl)-1-methylpyrrolidin-3-yl]piperazine-1-carboxylate; intermediate (5)

[0218] To a stirred solution of compound 5-3 (12 g, 37.570 mmol, 1 eq.) and HCHO (60 mL, 37%) in water in MeOH (250 mL, 6174.708 mmol) was added STAB (31.85 g, 150.280 mmol, 4 eq.) in portions at room temperature under nitrogen atmosphere. The mixture was stirred at room temperature for 3 hours. The reaction was quenched with water (300 mL) at room temperature. The resulting mixture was extracted with CH2Cl2 (3 x 200 mL). The organic layers were combined, washed with brine (1 x 200 mL), and 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 (10:1) to give intermediate 5 (5.5 g, 93.91%) as a colorless oil. 1H NMR (400MHz, DMSO-d6) δ7.43–7.24(m,5H),5.07(s,2H),4.42(s,1H),3.46(dd,J=10.8,4.4Hz,1H),3.36-3.32(m,6H),2.96(dd,J=1 0.1,3.5Hz,1H),2.89-2.86(m,1H),2.34(m,4H),2.29–2.14(m,4H),1.97-1.92(m,1H),1.52–1.40(m,1H); LCMS(ES,m / z):334[M+H] +

[0219] Solution 6

[0220]

[0221] Step 1: 4-[1-(tert-butoxycarbonyl)piperidine-4-carbonyl]piperazine-1-carboxylic acid benzyl ester; 6-1

[0222] To a stirred mixture of benzyl piperazine-1-carboxylate (10 g, 45.398 mmol, 1 eq) and 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (10.41 g, 45.398 mmol, 1 eq) in DCM (100 mL) at room temperature under nitrogen atmosphere was added DIEA (17.60 g, 136.194 mmol, 3 eq), EDC.HCl (11.31 g, 59.017 mmol, 1.3 eq) and HOBT (7.97 g, 59.017 mmol, 1.3 eq) portionwise. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction was quenched with water at room temperature. The mixture was heated to 40 ℃ and dried over medium temperature. The reaction mixture was stirred for 2 hours at room temperature under nitrogen atmosphere. The reaction mixture was heated to 40 ℃ and dried over medium temperature. The mixture was heated to 40 ℃ and dried over medium temperature. The reaction ... 2 Cl 2 The resulting mixture was extracted with 4% paraformaldehyde (3 x 50 mL). The organic layers were combined, washed with brine (2 x 30 mL), and purified by anhydrous Na 2 SO 4After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to obtain compound 6-1 (8.2 g, 41.86%) as a yellow solid. LCMS (ES, m / z): 432 [M+H] +

[0223] Step 2: Compound 6-2

[0224] To a stirred solution of compound 6-1 (8.2 g, 19.002 mmol, 1 eq.) in DCM (80 mL) was added dropwise HCl (gas) (40.00 mL, 1316.511 mmol, 69.28 eq.) in 1,4-dioxane at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for 2 hours under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS (ES, m / z): 332 [M+H] +

[0225] Step 2: Compound 6-3

[0226] To a stirred mixture of compound 6-2 (10.5 g, 31.682 mmol, 1 eq.) and 1-{[(tert-butyldimethylsilyl)oxy]methyl}cyclopropane-1-carbaldehyde (compound 6-2-1, 8.15 g, 38.018 mmol, 1.2 eq.) in DCM (100 mL) was added STAB (20.14 g, 95.046 mmol, 3 eq.) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 hours under nitrogen atmosphere. The mixture was treated with saturated NaHCO at 0°C. 3 (aq.) to quench the reaction. 2 Cl 2 The resulting mixture was extracted with 4% paraformaldehyde (3 x 50 mL). The organic layers were combined, washed with brine (2 x 20 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and purified by CH 2 Cl 2 / MeOH (10:1) to obtain compound 6-3 (4 g) as a yellow oil. LCMS (ES, m / z): 530 [M+H] +

[0227] Step 3: Benzyl 4-(1-{[1-(hydroxymethyl)cyclopropyl]methyl}piperidine-4-carbonyl)piperazine-1-carboxylate; Intermediate (6)

[0228] A solution of compound 6-3 (4 g, 7.550 mmol, 1 eq.) in DCM (40 mL) was stirred with TBAF (2.96 g, 11.325 mmol, 1.5 eq.) in THF (11 mL) at room temperature under nitrogen atmosphere for 2 hours. The reaction was quenched with water at room temperature. 2 Cl 2 The resulting mixture was extracted with 1x 30 mL. The organic layers were combined, washed with water (3x20 mL), and purified by anhydrous Na 2 SO 4 After drying, the filtrate was concentrated under reduced pressure. The crude intermediate (6) (1.6 g) was used directly in the next step without further purification. LCMS (ES, m / z): 416 [M+H] +

[0229] Preparation of compounds

[0230] The compounds claimed herein were prepared according to the procedures illustrated by the following examples.

[0231] Example 1

[0232]

[0233] Step 1: Compound 7-2

[0234] To a stirred solution of tert-butyl 3-(8-fluoro-7-(3-(methoxymethoxy)-8-methylnaphthalen-1-yl)-2-(methylsulfonyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Compound 7-1, 1 g, 1.174 mmol, 1 eq) and benzyl 4-[(3S,5S)-5-(hydroxymethyl)-1-methylpyrrolidin-3-yl]piperazine-1-carboxylate (0.71 g, 1.761 mmol, 1.5 eq) in THF (20 mL, 246.855 mmol) was added t-BuONa (0.34 g, 3.522 mmol, 3 eq) at 0°C under nitrogen atmosphere. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, NH 4 The solution was quenched with aqueous Cl solution. 2 Cl 2 The resulting mixture was extracted with 4% paraformaldehyde (3 x 10 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and purified by CH 2 Cl 2 / MeOH (10:1) to obtain compound 7-2 (1 g, 72.61%) as a yellow solid.

[0235] Step 2: Compound 7-3

[0236] Compound 7-3 and Et 3 To a stirred solution of SiH (148.63 mg, 1.280 mmol, 5 eq.) in DCM (6 mL) was added TEA (206.95 mg, 2.048 mmol, 8 eq.) and PdCl 2 (9.07 mg, 0.051 mmol, 0.2 eq.). The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the resulting mixture was filtered and the filter cake was washed with DCM (2 x 10 mL). The filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0237] Step 3: Compound 7-4

[0238] To a stirred solution of compound 7-3 (60 mg, 0.086 mmol, 1 eq.) and 2-(2,4-dihydroxy-5-isopropylbenzoyl)-1,3-dihydroisoindole-5-carbaldehyde (42.02 mg, 0.129 mmol, 1.5 eq.) in DMF (1.5 mL) at room temperature under nitrogen atmosphere was added STAB (54.74 mg, 0.258 mmol, 3 eq.). The mixture was stirred at room temperature for 16 hours. The product was precipitated by the addition of brine. The crude product mixture was used directly in the next step without further purification.

[0239] Step 4: Example 1

[0240] To a stirred solution of compound 7-4 (70 mg, 0.070 mmol, 1 eq.) in DCM (1.5 mL) was added HCl (gas) in 1,4-dioxane (0.3 mL, 9.874 mmol, 141.93 eq.) at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 1 hour. The reaction was detected by LC-MS. After the reaction was completed, the crude product was purified by preparative HPLC under the following conditions to give the compound of Example 1 (9.65 mg, 15.02%) as a white solid. LCMS-PH-RNS-2021-1228-0 (ES, m / z): 906 [M+H] + ; 1 H-NMR-PH-RNS-2021-1228-0(400MHz,DMSO-d 6,ppm)δ10.07(br,1H),9.60(s,1H),9.10(s,1H),8.07(dd,J=8.2Hz,1H),7.91(d,J=8.2Hz,1H),7.63–7.55(m, 1H),7.50–7.41(m,2H),7.35–7.12(m,4H),7.04(s,1H),6.39(s,1H),4.75(s,4H),4.55–4.25(m,4H),3.67-3. 54(m,4H),3.44–3.39(m,2H),3.32–3.24(m,4H),3.13–3.05(m,1H),2.99(d,J=10.2Hz,1H),2.88(s,1H),2.6 2(s,1H),2.49–2.43(m,3H),2.42-2.25(m,5H),2.06(s,1H),1.95(s,3H),1.64(s,5H),1.13(d,J=6.8Hz,6H).

[0241] Example 2

[0242]

[0243] Step 1: Compound 8-2; tert-butyl 3-{8-fluoro-7-[3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-yl]-2-[({1-[(4-{[1-(2,2,2-trifluoroacetyl)piperidin-4-yl]methyl}piperazin-1-yl)methyl]cyclopropyl}methoxy)methyl]pyrido[4,3-d]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0244] A solution of tert-butyl 3-{8-fluoro-2-methanesulfonyl-7-[3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-yl]pyrido[4,3-d]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (IM 4, 500 mg, 0.622 mmol, 1 eq) and 2,2,2-trifluoro-1-{4-[(4-{[1-(hydroxymethyl)cyclopropyl]methyl}piperazin-1-yl)methyl]piperidin-1-yl}ethanone (Compound 8-1, 338.99 mg, 0.933 mmol, 1.5 eq) and t-BuONa (179.28 mg, 1.866 mmol, 3 eq) in THF was stirred at room temperature under nitrogen atmosphere for 2 hours. The desired product could be detected by LCMS. The resulting mixture was washed with 20 mL of water. The resulting mixture was extracted with EtOAc (3 x 20 mL). The organic layers were combined and purified by anhydrous Na 2 SO 4After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and purified by CH 2 Cl 2 / MeOH (10:1) to obtain compound 8-2 as a yellow solid. LCMS-PH-RNS-2021-1606-1: (ES, m / z): 1087 [M+H] +

[0245] Step 2: Compound 8-3; tert-butyl 3-{8-fluoro-7-[3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-yl]-2-[(1-{[4-(piperidin-4-ylmethyl)piperazin-1-yl]methyl}cyclopropyl)methoxy]pyrido[4,3-d]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0246] Intermediate 8-2 (400 mg, 0.147 mmol, 1 eq., 40%) and K 2 CO 3 A solution of (61.01 mg, 0.441 mmol, 3 equiv) in MeOH and water was stirred at room temperature under air atmosphere for 2 hours. The desired product was detected by LCMS. 2 Cl 2 The resulting mixture was extracted with 1% ethanol (3 x 20 mL). The organic layers were combined and washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to obtain compound 8-3 (366 mg, 250.90%) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS-PH-RNS-2021-1606-2: (ES, m / z): 991 [M+H] +

[0247] Step 3: Compound 8-4; tert-butyl 3-[2-({1-[(4-{[1-({4-[3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylcarbamoyl)-1,2,4-triazol-4-yl]phenyl}methyl)piperidin-4-yl]methyl}piperazin-1-yl)methyl]cyclopropyl}methoxy)-8-fluoro-7-[3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-yl]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0248] To a stirred solution of compound 8-3 (59.68 mg, 0.152 mmol, 1.5 eq.) in DMF was added STAB (85.51 mg, 0.404 mmol, 4 eq.) in portions at room temperature under air atmosphere. The resulting mixture was stirred at room temperature overnight. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18; mobile phase, MeCN / water (0.1% NH 3 .H 2 O), 10% to 100% gradient in 10 minutes; detector, UV 254nm. This produced compound 8-4 (106 mg, 76.72%) as a yellow solid. LCMS-PH-RNS-2021-1606-3: (ES, m / z): 1369 [M+H] +

[0249] Step 4: Compound 8-5; tert-butyl 3-[2-({1-[(4-{[1-({4-[3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylcarbamoyl)-1,2,4-triazol-4-yl]phenyl}methyl)piperidin-4-yl]methyl}piperazin-1-yl)methyl]cyclopropyl}methoxy)-7-[8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0250] A mixture of compound 8-4 (106 mg, 0.077 mmol, 1 eq.) and CsF (58.77 mg, 0.385 mmol, 5 eq.) in DMF was stirred at room temperature under air atmosphere for 40 minutes. The resulting mixture was extracted with EtOAc (4 x 10 mL). The organic layers were combined and purified by anhydrous Na 2 SO 4 After drying, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS-PH-RNS-2021-1606-4: (ES, m / z): 1213 [M+H] +

[0251] Step 5: Example 2; 4-(4-{[4-({4-[(1-{[(4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-7-(8-ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy]methyl}cyclopropyl)methyl]piperazin-1-yl}methyl)piperidin-1-yl]methyl}phenyl)-5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-1,2,4-triazole-3-carboxamide

[0252] A solution of compound 8-5 (80 mg, 0.066 mmol, 1 eq.) and HCl (gas) in 1,4-dioxane (0.99 mL, 3.960 mmol, 60 eq.) in MeCN was stirred at room temperature under air atmosphere for 1.5 hours. The desired product could be detected by LCMS. The mixture was cooled to 0°C. NH 3 ·H 2 The mixture was basified to pH 8 with CH 2 Cl 2 The resulting mixture was extracted with 1 mL (3 x 15 mL). The organic layers were combined and washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography using the following conditions: column, C18; mobile phase, MeCN / water (10 mmol / L NH 4 HCO 3 ), 10% to 100% gradient in 10 minutes; detector, UV 254nm. The crude product was purified by preparative HPLC to give Example 2 (4.08 mg, 5.25%) as a yellow solid. LCMS-PH-RNS-2021-1606-0: (ES, m / z): 1069 [M+H] + ; 1 HNMR-PH-RNS-2021-1606-0:(400MHz,DMSO-d 6)δ10.62(s,1H),10.15(s,1H),9.77(s,1H),9.02(s,1H),8.96(t,J=5.8 Hz,1H),7.88(dd,J=8.0,1.8Hz,1H),7.49–7.39(m,2H),7.38–7.32(m,3H ),7.28(d,J=8.2Hz,2H),7.11(d,J=2.6Hz,1H),6.57(s,1H),6.34(s,1H ),4.50(d,J=12.0Hz,1H),4.33–4.21(m,3H),3.65(d,J=12.2Hz,2H),3.5 9–3.54(m,4H),3.52(s,1H),3.46(s,2H),3.16(p,J=7.0Hz,2H),2.90(p ,J=6.8Hz,1H),2.83–2.63(m,2H),2.42–2.16(m,7H),2.06(d,J=7.0Hz,2 H),1.91(t,J=11.2Hz,2H),1.64(d,J=2.6Hz,6H),1.45(s,2H),1.23(s, 2H), 1.14–0.98 (m, 4H), 0.80 (d, J = 6.8Hz, 6H), 0.63 (s, 2H), 0.40 (s, 2H).

[0253] Example 3

[0254]

[0255] Step 1: Compound 9-1; tert-butyl 3-(2-((1-((4-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoro-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0256] A solution of tert-butyl 3-{8-fluoro-2-methanesulfonyl-7-[3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-yl]pyrido[4,3-d]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 0.622 mmol, 1 eq) and benzyl 4-(1-{[1-(hydroxymethyl)cyclopropyl]methyl}piperidine-4-carbonyl)piperazine-1-carboxylate (350 mg, 0.933 mmol, 1.5 eq) and t-BuONa (179.28 mg, 1.866 mmol, 3 eq) in THF was stirred at room temperature under nitrogen atmosphere for 2 hours. The desired product can be detected by LCMS. The resulting mixture was washed with 20 mL of water. The resulting mixture was extracted with EtOAc (3 x 20 mL). The organic layers were combined and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and purified by CH 2 Cl 2 / MeOH (10:1) to obtain compound 9-1 as a yellow solid.

[0257] Step 2: Compound 9-2; tert-butyl 3-{8-fluoro-7-[3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-yl]-2-[(1-{[4-(piperazine-1-carbonyl)piperidin-1-yl]methyl}cyclopropyl)methoxy]pyrido[4,3-d]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0258] Compound 9-1 and Et 3 To a stirred solution of SiH (120 mg, 1.10 mmol, 5 eq.) in DCM (6 mL) was added TEA (180 mg, 1.80 mmol, 8 eq.) and PdCl 2 (9.07 mg, 0.051 mmol, 0.2 eq.). The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the resulting mixture was filtered and the filter cake was washed with DCM (2 x 10 mL). The filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0259] Step 3: Compound 9-3; tert-butyl 3-{2-[(1-{[4-(4-{[2-(2,4-dihydroxy-5-isopropylbenzoyl)-1,3-dihydroisoindol-5-yl]methyl}piperazine-1-carbonyl)piperidin-1-yl]methyl}cyclopropyl)methoxy]-8-fluoro-7-[3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-yl]pyrido[4,3-d]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0260] STAB (69.57 mg, 0.327 mmol, 3 equiv) was added in batches to a stirred solution of compound 9-3 and 2-(2,4-dihydroxy-5-isopropylbenzoyl)-1,3-dihydroisoindole-5-carbaldehyde (42.72 mg, 0.131 mmol, 1.2 equiv) in DMF at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3x10 mL). The organic layers were combined and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 minutes; detector, UV 254 nm. This produced compound 9-3 (90 mg, 62.57%) as a yellow solid. LCMS-PH-RNS-2022-1013-4(ES,m / z):1315[M+H] +

[0261] Step 4: Compound 9-4; tert-butyl 3-{2-[(1-{[4-(4-{[2-(2,4-dihydroxy-5-isopropylbenzoyl)-1,3-dihydroisoindol-5-yl]methyl}piperazine-1-carbonyl)piperidin-1-yl]methyl}cyclopropyl)methoxy]-8-fluoro-7-[3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-yl]pyrido[4,3-d]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0262] To a stirred solution of compound 9-3 (110 mg, 0.084 mmol, 1 eq.) in DMF was added CsF (127.09 mg, 0.840 mmol, 10 eq.) in portions at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 10 mL). The organic layers were combined and washed with anhydrous Na 2 SO 4After drying, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS-PH-RNS-2022-1013-5 (ES, m / z): 1158 [M+H] +

[0263] Step 5: Example 3; 4-{5-[(4-{1-[(1-{[(4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-7-(8-ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy]methyl}cyclopropyl)methyl]piperidine-4-carbonyl}piperazin-1-yl)methyl]-1,3-dihydroisoindole-2-carbonyl}-6-isopropylbenzene-1,3-diol

[0264] To a stirred solution of compound 9-4 (90 mg, 0.068 mmol, 1 eq) in DMF was added HCl (gas) in 1,4-dioxane (1 mL, 32.913 mmol, 480.79 eq) in portions at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with aqueous ammonia at room temperature. The resulting mixture was extracted with EtOAc (3 x 10 mL). The organic layers were combined and purified by anhydrous Na 2 SO 4 After drying, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain the compound of Example 3 (20.59 mg, 27.05%) as a yellow solid. LCMS-PH-RNS-2022-1013-0 (ES, m / z): 1014 [M+H] + ; 1 H NMR-PH-RNS-2022-1013-0NMR(400MHz,DMSO-d 6)δ10.23–10.08(m,2H),9.61(s,1H),9.01(s,1H),7.88(dd,J=8.2,1.6Hz,1H),7.49–7.37(m,2H),7.33(d,J=2.6Hz,1H),7. 22(s,3H),7.12(d,J=2.4Hz,1H),7.04(s,1H),6.39(s,1H),4.76(s,4H),4.49(d,J=11.8Hz,1H),4.25(q,J=11.4,9.0Hz,3H) ,3.64(d,J=12.2Hz,1H),3.60(s,1H),3.54(s,2H),3.48(d,J=13.4Hz,7H),3.49–3.37(s,1H),3.09(p,J=7.0Hz,1H),2.96(t ,J=12.2Hz,2H),2.39–2.16(m,6H),1.88(s,2H),1.65(s,4H),1.52(s,4H),1.13(d,J=6.8Hz,6H),0.63(s,2H),0.39(s,2H).

[0265] The following compounds in Table 1 were prepared according to the above methods using appropriate starting materials.

[0266] Table 1

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395] result

[0396] Cell lines

[0397] The following cancer cell lines were used: AGS gastric cancer [heterozygous G12D] (ATCC, CRL-1739); A-427 lung cancer [heterozygous G12D] (ATCC, HTB-53); ASPC1 pancreatic adenocarcinoma [heterozygous G12D] (ATCC, CRL-1682) and SW1990 pancreatic adenocarcinoma [heterozygous G12D] (ATCC CRL-2172). The cell lines were cultured essentially according to ATCC recommendations.

[0398] KRAS(G12D) / SOS1 Homogeneous Time-Resolved Fluorescence (HTRF) Assay

[0399] Unless otherwise indicated, the binding of the test compound to the KRAS (G12D) target protein was measured by homogeneous time-resolved fluorescence in the absence of GTP using the KRAS-G12D / SOS1 binding assay kit (Cisbio, 63ADK000CB17PEH) according to the manufacturer's instructions, which in turn blocked the interaction of KRAS (G12D) with the SOS1 protein. A 3-fold serial dilution of each test compound was prepared, ranging from 20 μM to 1.02 nM. The test compound was mixed and incubated with the reaction components, incubated at 4 ° C for 3 hours in a sealed plate, and then the fluorescence was measured using a PerkinElmer Envision plate reader. KRAS (G12D) -SOS1 IC50 values ​​(50% concentration of maximum inhibition) were calculated using GraphPad Prism 7 software. The results are listed in Table 2.

[0400] Cancer cell line proliferation ( Determination)

[0401] AGS, A-427, ASPC1, SW1990, and GP2D cells were seeded at 4,000 cells / well in 96-well tissue culture plates and incubated in 100 μl of culture medium at 37°C / 5% CO2 for 72 hours. Three-fold serial dilutions of each test compound were prepared, ranging from 20 μM to 1.02 nM. Each cell line was then treated with various concentrations of the test compound at a final concentration of 0.5% DMSO / well and then incubated at 37°C / 5% CO2 for 72 hours. 100 μl of Reagents (Promega Corporation, Madison, WI) were used and processed according to the manufacturer's operating procedures. The results were analyzed using GraphPad 7 software and the EC50 values ​​were calculated. The results are listed in Table 2.

[0402] Table 2: Biochemistry and cell-based assays of compounds

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412] KRAS(G12D) / SOS1 HTRF assay: A. IC50 < 100 nM; B. IC50 = 100-1000 nM;

[0413] C. IC50>1000nM; AGS proliferation assay: A. EC50<100nM; B. EC50=100-1000nM;

[0414] C.EC50>1000nM; A427 proliferation assay: A.EC50<100nM; B.EC50=100-1000nM;

[0415] C.EC50>1000nM; ASPC proliferation assay: A.EC50<100nM; B.EC50=100-1000nM;

[0416] C.EC50>1000nM; SW1990 proliferation assay: A.EC50<100nM; B.EC50=100-1000nM; C.EC50>1000nM

[0417] Without departing from the scope and spirit of the present disclosure, modifications and variations of the methods and compositions described in the present disclosure will be apparent to those skilled in the art. Although the present disclosure has been described in conjunction with specific embodiments, it should be understood that the disclosure claimed should not be unduly limited to such specific embodiments. In fact, it is contemplated and understood by those skilled in the relevant art to which the present disclosure belongs that various modifications to the described modes of implementing the present disclosure are within the scope of the present disclosure as represented by the following claims.

[0418] Incorporated by Reference

[0419] All patents and publications mentioned in this specification are herein incorporated by reference as if each independent patent and publication was specifically and individually indicated to be incorporated by reference.

Claims

1. A compound having formula I or II: or a pharmaceutically acceptable salt thereof, wherein HET is an optionally substituted heterocyclic group; Hs is the chemical moiety that binds to HSP90; X is hydrogen or halogen; L is the connector; m is 0, 1, 2 or 3; R 1 Selected from (C1-C4)alkylO(C1-C4)alkyl, -(C1-C4)alkylNH(C1-C4)alkyl, -(C1-C4)alkylN[(C1-C4)alkyl]2, heterocyclyl and cycloalkyl, wherein the heterocyclyl and cycloalkyl are each optionally and independently substituted; R 2 is selected from hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C1-C4)alkynyl, (C1-C4)alkenyl, halogen, (C3-C6)cycloalkyl, -O(C3-C6)cycloalkyl, cyano, NH2, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -P(O)[(C1-C4)alkyl]2 and -S(C1-C4)alkyl; R 3 Selected from a 1 N or CHZ 1 ; Z 1 is selected from hydrogen, halogen, (C1-C4)alkyl, (C2-C4)alkenyl, cyano, cyano(C1-C4)alkyl, -S[halo(C1-C4)alkyl] and (C3-C6)cycloalkyl; R 8 , R 9 , R 10 , R 11 , R 12 and R 13 each independently selected from hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)cyanoalkyl, (C1-C4)hydroxyalkyl, -(C1-C4)alkylNR a R b 、-(C1-C4)alkylC(O)NR a R b 、(C1-C4)alkylO(C1-C4)alkyl、-(C1-C4)alkylC(O)OR a 、-(C1-C4)alkylNR a C(O)OR b 、-(C1-C4)alkylC(O)R a , -(C1-C4) alkylheterocyclyl, -(C1-C4) alkylaryl, -(C1-C4) alkylheteroaryl, (C2-C4) alkenyl, (C2-C4) haloalkenyl, (C2-C4) cyanoalkenyl, (C2-C4) hydroxyalkenyl, -(C2-C4) alkenyl NR a R b , (C2-C4)alkynyl, (C2-C4)haloalkynyl, (C2-C4)cyanoalkynyl, (C2-C4)hydroxyalkynyl, -(C2-C4)alkynylNR a R b , (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, cyano, oxo, hydroxy, -S(C1-C4) alkyl, -S(C1-C4) haloalkyl, -NR a R b 、-NR a C(O)R b 、-C(O)R a 、-C(O)OR a 、-SO2R a 、-S(O)R a 、-SO2NR a R b 、-NR a S02R b , (C3-C6) cycloalkyl, 5- or 6-membered heteroaryl and 4- to 6-membered heterocyclyl, wherein the heterocyclyl, aryl and heteroaryl of -(C1-C4) alkylheterocyclyl, -(C1-C4) alkylaryl and -(C1-C4) alkylheteroaryl and the (C3-C6) cycloalkyl, 5- or 6-membered heteroaryl and 4- to 6-membered heterocyclyl are each optionally and independently replaced by 1 to 3 selected from R c substituted by a group; R a and R b are each independently selected from hydrogen, (C1-C4)alkyl and (C1-C4)haloalkyl, or when on the same nitrogen atom, R a and R b may together form a heterocyclic group; and R c is selected from halogen, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, cyano, hydroxy, oxo, -C(O)OR a 、-C(O)R a 、-SO2R a 、-S(O)R a 、-SO2NR a R b 、-NR a C(O)R b 、-NR a S02R b 、-NR a R b and NO2.

2. The compound of claim 1, wherein the compound is of formula I: or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein HET is an optionally substituted 3,8-diazabicyclo[3.2.1]octyl group or 3,6-diazabicyclo[3.2.1]octyl group. 4 . The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein HET is an optionally substituted 3,8-diazabicyclo[3.2.1]octyl group.

5. The compound of any one of claims 1 to 4, wherein the compound is of formula Ia or IIa: or a pharmaceutically acceptable salt thereof, wherein R 0 is halogen, (C1-C4)alkyl, hydroxy(C1-C4)alkyl, cyano(C1-C4)alkyl, -C(O)H, -C(O)2H, -C(O)2(C1-C4)alkyl, -C(O)(C1-C4)alkyl, -C(O)(C1-C4)haloalkyl, -C(O)2(C1-C4)haloalkyl, C(O)2NH2, -C(O)2NH(C1-C4)alkyl, -C(O)2N[(C1-C4)alkyl]2, -S(O)2(C1-C4)alkyl and -S(O)2(C1-C4)haloalkyl or 5- to 6-membered optionally substituted heteroaryl; and k is 0, 1, 2 or 3.

6. The compound of any one of claims 1 to 5, wherein the compound is of formula Ia: or a pharmaceutically acceptable salt thereof.

7. The compound of claim 5, wherein the compound is of formula Ib or IIb: or a pharmaceutically acceptable salt thereof, wherein k is 0 or 1.

8. The compound of claim 5 or 6, wherein the compound is of formula Ib: or a pharmaceutically acceptable salt thereof, wherein k is 0 or 1.

9. The compound or pharmaceutically acceptable salt thereof according to any one of claims 5 to 8, wherein R 0 is cyano(C1-C4)alkyl, -C(O)(C1-C4)alkyl or -C(O)(C1-C4)haloalkyl.

10. The compound or pharmaceutically acceptable salt thereof according to any one of claims 5 to 8, wherein R 0 It is -C(O)(C1-C4)alkyl or -C(O)(C1-C4)haloalkyl. 11 . The compound or pharmaceutically acceptable salt thereof according to claim 5 , wherein k is 0.

12. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein a 1 is N.

13. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein X is a halogen.

14. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein X is fluorine.

15. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein R 2 is hydrogen or (C1-C4)alkoxy.

16. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, wherein R 2 For hydrogen.

17. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, wherein R 8 , R 9 , R 10 , R 11 , R 12 and R 13 Each is independently selected from hydrogen, halogen, (C2-C4)alkynyl, halo(C1-C4)alkyl, (C1-C4)alkyl, cyano, (C1-C4)alkoxy and hydroxy.

18. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, wherein R 8 , R 9 , R 10 and R 11 are each hydrogen; or R 9 , R 10 and R 11 Each is hydrogen and R 8 is selected from halogen, cyano, hydroxy, (C1-C4)alkoxy and (C2-C4)alkynyl; or R 8 , R 9 and R 10 Each is hydrogen and R 11 is hydroxyl; or R 10 is hydrogen and R 8 , R 9 and R 11 are each independently selected from halogen, (C2-C4)alkynyl, (C1-C4)alkyl, cyano, (C1-C4)alkoxy and hydroxy; or R 12 and R 13 each is hydrogen; or R 12 is a halogenated (C1-C4) alkyl group and R 13 is hydrogen; or R 12 and R 13 Each is independently selected from halo(C1-C4)alkyl, (C1-C4)alkyl and halogen.

19. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein R 3 Selected from 20. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, wherein R 3 Selected from 21. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 20, wherein R 1 is selected from optionally substituted heterocyclyl and optionally substituted cycloalkyl.

22. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 21, wherein R 1 The group consisting of an optionally substituted 4- to 6-membered nitrogen-containing heterocyclic group, an optionally substituted 8- to 10-membered condensed bicyclic heterocyclic group and an optionally substituted (C3-C4)cycloalkyl group.

23. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 22, wherein R 1 is selected from azetidinyl, pyrrolidinyl, cyclopropyl, piperazinyl and hexahydro-1H-pyrrolizinyl, each of which is optionally substituted by 1 to 3 groups selected from (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy and halogen.

24. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 22, wherein R 1 is selected from pyrrolidinyl, cyclopropyl, piperazinyl and hexahydro-1H-pyrrolizinyl, each of which is optionally substituted by 1 to 3 groups selected from (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy and halogen.

25. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 23, wherein R 1 is selected from azetidinyl, pyrrolidinyl, cyclopropyl, piperazinyl and hexahydro-1H-pyrrolizinyl, each of which is optionally substituted with (C1-C4)alkyl.

26. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 24, wherein R 1 is selected from pyrrolidinyl, cyclopropyl, piperazinyl and hexahydro-1H-pyrrolizinyl, each of which is optionally substituted by (C1-C4)alkyl.

27. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 25, wherein R 1 Selected from Where * indicates the connection point with L.

28. A compound according to any one of claims 1 to 26 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from Where * indicates the connection point with L.

29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2.

30. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 29, wherein Hs is selected from in Q and U are each independently selected from phenyl, heteroaryl, heterocyclyl and cycloalkyl, each of which is optionally substituted by 1 to 3 selected from R 14 substituted by a group; R 17 , R 18 , R 19 and R 20 Each is independently selected from hydrogen, halogen, CN, (C1-C4) alkyl, halo (C1-C4) alkyl, -NR a R b 、-OR e and -C(O)NR a R b ; q is 0, 1, 2, or 3; R 21 , R 22 and R 23 are each independently hydrogen, (C1-C4)alkyl or halogenated (C1-C4)alkyl; W is optionally 1 to 3 selected from R 14 A 5- or 6-membered heteroaryl group substituted with a group of V is optionally 1 to 3 selected from R 15 phenyl or 5- to 9-membered heteroaryl substituted with a group; R 5 is halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy or halo(C1-C4)alkoxy; R 14 is (C1-C4)alkyl, halogenated (C1-C4)alkyl, (C2-C6)alkenyl, halogenated (C2-C6)alkenyl, (C2-C6)alkynyl, halogenated (C2-C6)alkynyl, CN, -C 1-4 Alkyl OR e 、-OR e 、-C(O)R e 、-C(O)OR e 、-C(O)NR e R f 、-C(O)NR e (C 1-4 Alkylene)OR e 、-C(O)NR e (C 1-4 Alkylene)NR e R f 、-C(O)NR e (C 1-4 Alkylene)OR, -NR e R f 、-O(C 1-4 Alkylene)NR e R f ,-SH,-S(C 1-4 Alkyl), -C 1-4 Alkyl NR e R f 、-SR e 、-S(O)R e 、-S(O)2R e 、-S(O)NR e R f 、-SO2NR e R f 、-NR e (C 1-4 alkyl)OR e 、-NR e (C 1-4 Alkyl)NR e R f , -C 1-6 Alkyl C(O)NR e R f , phenyl or 5- to 7-membered heteroaryl, wherein the phenyl and 5- to 7-membered heteroaryl are each optionally and independently substituted by 1 to 3 selected from R 16 substituted by a group; R e and R f are each independently selected from hydrogen and (C1-C4)alkyl, wherein the (C1-C4)alkyl is optionally substituted with one or more halogen or 3- to 7-membered heterocyclyl, or both; and R 15 and R 16 are independently halogen, -NR e R f , (C1-C4)alkyl, halogenated (C1-C4)alkyl, (C1-C4)alkoxy or halogenated (C1-C4)alkoxy.

31. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 29, wherein Hs is selected from in Q and U are each independently selected from phenyl, heteroaryl, heterocyclyl and cycloalkyl, each of which is optionally substituted by 1 to 3 selected from R 14 substituted by a group; R 17 , R 18 , R 19 and R 20 are each independently selected from hydrogen, halogen, CN, (C1-C4)alkyl, halo(C1-C4)alkyl and -C(O)NR a R b ; R 21 , R 22 and R 23 are each independently hydrogen, (C1-C4)alkyl or halogenated (C1-C4)alkyl; W is optionally 1 to 3 selected from R 14 A 5- or 6-membered heteroaryl group substituted with a group of V is optionally 1 to 3 selected from R 15 phenyl or 5- to 9-membered heteroaryl substituted with a group; R 5 is halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy or halo(C1-C4)alkoxy; R 14 is (C1-C4)alkyl, halogenated (C1-C4)alkyl, (C2-C6)alkenyl, halogenated (C2-C6)alkenyl, (C2-C6)alkynyl, halogenated (C2-C6)alkynyl, CN, -C 1-4 Alkyl OR e 、-OR e 、-C(O)R e 、-C(O)OR e 、-C(O)NR e R f 、-C(O)NR e (C 1-4 Alkylene)OR e 、-C(O)NR e (C 1-4 Alkylene)NR e R f 、-C(O)NR e (C 1-4 Alkylene)OR, -NR e R f 、-O(C 1-4 Alkylene)NR e R f ,-SH,-S(C 1-4 Alkyl), -C 1-4 Alkyl NR e R f 、-SR e 、-S(O)R e 、-S(O)2R e 、-S(O)NR e R f 、-SO2NR e R f 、-NR e (C 1-4 alkyl)OR e 、-NR e (C 1-4 Alkyl)NR e R f , -C 1-6 Alkyl C(O)NR e R f , phenyl or 5- to 7-membered heteroaryl, wherein the phenyl and 5- to 7-membered heteroaryl are each optionally and independently substituted by 1 to 3 selected from R 16 substituted by a group; R e and R f are each independently selected from hydrogen and (C1-C4)alkyl, wherein the (C1-C4)alkyl is optionally substituted with one or more halogen or 3- to 7-membered heterocyclyl, or both; and R 15 and R 16 are independently halogen, -NR e R f , (C1-C4)alkyl, halogenated (C1-C4)alkyl, (C1-C4)alkoxy or halogenated (C1-C4)alkoxy.

32. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 31, wherein Hs is 33. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 30 to 32, wherein R 20 It is (C1-C4) alkyl.

34. The compound or pharmaceutically acceptable salt thereof of any one of claims 30 to 33, wherein R 22 and R 23 Each is hydrogen, R 22 and R 23 Each is (C1-C4) alkyl, R 22 is hydrogen and R 23 is (C1-C4) alkyl, or R 23 is hydrogen and R 22 It is (C1-C4) alkyl.

35. The compound or pharmaceutically acceptable salt thereof of any one of claims 30 to 33, wherein R 22 and R 23 Each is hydrogen, R 22 is hydrogen and R 23 is (C1-C4) alkyl, or R 23 is hydrogen and R 22 It is (C1-C4) alkyl.

36. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 32, wherein Hs is selected from and Z is N or CH.

37. The compound of claim 36 or a pharmaceutically acceptable salt thereof, wherein Z is CH.

38. The compound of claim 36 or 37, wherein each R 15 are independently (C1-C4)alkyl or halogen.

39. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 32, wherein Hs is 40. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 32, wherein Hs is 41. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 32, wherein Hs is 42. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 32, wherein Hs is 43. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 30 to 42, wherein R 5 It is halogen or (C1-C4) alkyl.

44. The compound of any one of claims 30 to 43, or a pharmaceutically acceptable salt thereof, wherein R 5 is chloro, isopropyl, methyl, propyl or ethyl.

45. The compound of any one of claims 30 to 44, or a pharmaceutically acceptable salt thereof, wherein R 5 is isopropyl or ethyl.

46. ​​The compound of any one of claims 30 to 45, or a pharmaceutically acceptable salt thereof, wherein R 14 For –OR e 、-SR e 、-C(O)NR e R f or -C(O)NR e (C 1-4 Alkylene)NR e R f .

47. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 30 to 46, wherein R e and R f Each is independently selected from hydrogen and (C1-C4)alkyl, wherein the (C1-C4)alkyl is optionally substituted with 1 to 3 halogens or 6-membered heterocyclyl.

48. A compound according to any one of claims 30 to 47, or a pharmaceutically acceptable salt thereof, wherein R 14 It is OH, -C(O)NHCH2CF3, -C(O)NHCH2CH3, -C(O)NHCH(CH3)2, -C(O)NH(CH2CH3)2, -C(O)NHCH(CH3)CF3, -C(O)NHcyclopropyl, -C(O)NHmethylcyclopropyl, C(O)NH2 or -C(O)NH(CH2)2piperidinyl.

49. The compound or pharmaceutically acceptable salt thereof of any one of claims 30 to 48, wherein R 14 It is -C(O)NHCH2CF3 or OH.

50. The compound of any one of claims 30 to 49 or a pharmaceutically acceptable salt thereof, wherein R 14 For OH.

51. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 30, wherein Hs is selected from 52. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 31, wherein Hs is selected from 53. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 52, wherein L is selected from (C1-C6) alkyl, (CH2CH2O) v 、(C1-C6) alkyl NR q 、(C1-C6)alkylC(O),(C1-C6)alkylC(O)O,(C1-C6)alkylOC(O),(C1-C6)alkylC(O)NR q 、(C1-C6) alkyl NR q C(O),X 1 -Het 1 -X 2 , X 1 -Het 1 -X 2 -X 3 , X 1 -Het 1 -X 2 -X 3 -X 4 , X 1 -Het 1 -X 2 -X 3 -X 4 -X 5 , X 1 -Het 1 -X 2 -Het 2 -X 3 -、X 1 -Het 1 -X 2 -Het 2 -X 3 -Het 3 -X 4 -、(CH2CH2O) v -X 1 -Het 1 -X 2 、(CH2CH2O) v -X 1 -Het 1 -X 2 -X 3 、(CH2CH2O) v -X 1 -Het 1 -X 2 -Het 2 -X 3 -、(CH2CH2O) v -X 1 -Het 1 -X 2 -Het 2 -X 3 -Het 3 -X 4 -, (C1-C6) alkyl NR q -X 1 -Het 1 -X 2 、(C1-C6) alkyl NR q -X 1 -Het 1 -X 2 -X 3 、(C1-C6) alkyl NR q -X 1 -Het 1 -X 2 -Het 2 -X 3 -, (C1-C6) alkyl NR q -X 1 -Het 1 -X 2 -Het 2 -X 3 -Het 3 -X 4 -, (C1-C6) alkyl C(O)-X 1 -Het 1 -X 2 、(C1-C6)alkylC(O)-X 1 -Het 1 -X 2 -X 3 、(C1-C6)alkylC(O)-X 1 -Het 1 -X 2 -Het 2 -X 3 -, (C1-C6) alkyl C(O)-X 1 -Het 1 -X 2 -Het 2 -X 3 -Het 3 -X 4 -, (C1-C6) alkyl C(O)NR q -X 1 -Het 1 -X 2 、(C1-C6)alkylC(O)NR q -X 1 -Het 1 -X 2 -X 3 、(C1-C6)alkylC(O)NR q -X 1 -Het 1 -X 2 -Het 2 -X 3 - and (C1-C6)alkyl C(O)NR q -X 1 -Het 1 -X 2 -Het 2 -X 3 -Het 3 -X 4 -; Each X 1 , X 2 , X 3 , X 4 and X 5 are independently absent or selected from (C1-C4)alkylene, O, NR q and C(O); v is 1, 2, 3, 4, 5, or 6; R q is hydrogen or (C1-C4)alkyl; and Each Het 1 、Het 2 and Het 3 Independently selected from 4- to 6-membered heterocyclyl and (C3-C6)cycloalkyl, each optionally substituted by 1 to 3 groups selected from halogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy and (C1-C4)haloalkoxy.

54. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 52, wherein L is selected from (C1-C6) alkyl, (CH2CH2O) v 、(C1-C6) alkyl NR q 、(C1-C6)alkylC(O),(C1-C6)alkylC(O)O,(C1-C6)alkylOC(O),(C1-C6)alkylC(O)NR q 、(C1-C6) alkyl NR q C(O),X 1 -Het 1 -X 2 , X 1 -Het 1 -X 2 -X 3 , X 1 -Het 1 -X 2 -Het 2 -X 3 -、X 1 -Het 1 -X 2 -Het 2 -X 3 -Het 3 -X 4 -、(CH2CH2O) v -X 1 -Het 1 -X 2 、(CH2CH2O) v -X 1 -Het 1 -X 2 -X 3 、(CH2CH2O) v -X 1 -Het 1 -X 2 -Het 2 -X 3 -、(CH2CH2O) v -X 1 -Het 1 -X 2 -Het 2 -X 3 -Het 3 -X 4 -, (C1-C6) alkyl NR q -X 1 -Het 1 -X 2 、(C1-C6) alkyl NR q -X 1 -Het 1 -X 2 -X 3 、(C1-C6) alkyl NR q -X 1 -Het 1 -X 2 -Het 2 -X 3 -, (C1-C6) alkyl NR q -X 1 -Het 1 -X 2 -Het 2 -X 3 -Het 3 -X 4 -, (C1-C6) alkyl C(O)-X 1 -Het 1 -X 2 、(C1-C6)alkylC(O)-X 1 -Het 1 -X 2 -X 3 、(C1-C6)alkylC(O)-X 1 -Het 1 -X 2 -Het 2 -X 3 -, (C1-C6) alkyl C(O)-X 1 -Het 1 -X 2 -Het 2 -X 3 -Het 3 -X 4 -, (C1-C6) alkyl C(O)NR q -X 1 -Het 1 -X 2 、(C1-C6)alkylC(O)NR q -X 1 -Het 1 -X 2 -X 3 、(C1-C6)alkylC(O)NR q -X 1 -Het 1 -X 2 -Het 2 -X 3 - and (C1-C6)alkyl C(O)NR q -X 1 -Het 1 -X 2 -Het 2 -X 3 -It 3 -X 4 -; Each X 1 , X 2 , X 3 and X 4 are independently absent or selected from (C1-C4)alkylene, O, NR q and C(O); v is 1, 2, 3, 4, 5, or 6 R q is hydrogen or (C1-C4)alkyl; and Each Het 1 、Het 2 and Het 3 Independently selected from 4- to 6-membered heterocyclyl and (C3-C6)cycloalkyl, each optionally substituted by 1 to 3 groups selected from halogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy and (C1-C4)haloalkoxy.

55. The compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, wherein L is selected from (C1-C6) alkyl, (C1-C6) alkylNR q , X 1 -Het 1 -X 2 , X 1 -Het 1 -X 2 -X 3 , X 1 -Het 1 -X 2 -X 3 -X 4 , X 1 -Het 1 -X 2 -X 3 -X 4 -X 5 , X 1 -Het 1 -X 2 -Het 2 -X 3 - and X 1 -Het 1 -X 2 -Het 2 -X 3 -Het 3 -X 4 -.

56. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 54, wherein L is selected from (C1-C6) alkyl, (C1-C6) alkylNR q , X 1 -Het 1 -X 2 , X 1 -Het 1 -X 2 -X 3 , X 1 -Het 1 -X 2 -Het 2 -X 3 - and X 1 -Het 1 -X 2 -Het 2 -X 3 -Het 3 -X 4 -.

57. A compound as described in any one of claims 53 to 56, or a pharmaceutically acceptable salt thereof, wherein each Het 1 、Het 2 and Het 3 independently absent or selected from piperidinyl, piperazinyl, cyclohexyl, cyclopropyl, cyclobutyl, azetidinyl and pyrrolidinyl, each optionally substituted with 1 to 3 groups selected from halogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy and (C1-C4)haloalkoxy.

58. A compound as described in any one of claims 53 to 57, or a pharmaceutically acceptable salt thereof, wherein each Het 1 、Het 2 and Het 3 and independently absent or selected from piperidinyl, piperazinyl and pyrrolidinyl.

59. The compound of any one of claims 1 to 58, or a pharmaceutically acceptable salt thereof, wherein L is selected from -CH2-, *CH2N(CH3), where * indicates the point of connection to Hs.

60. The compound of claim 1, wherein the compound is selected from any one of Examples 1 to 3 and those in Table 1; or a pharmaceutically acceptable salt thereof.

61. A pharmaceutical composition comprising a compound according to any one of claims 1 to 60 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

62. A method for treating cancer in a subject, the method comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 60, or a pharmaceutically acceptable composition according to claim 61.

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