KRAS G12D proteolysis targeting chimera

Abstract

Provided herein are KRAS G12D proteolysis targeting chimeras (PROTACs), compositions comprising the KRAS G12D PROTACs, and methods of making and using the KRAS G12D PROTACs, for example, to promote degradation of KRAS G12D and / or to treat cancers associated with KRAS G12D. KRAS G12D PROTAC has the structural formula: [KRAS G12Di]-L '-[Deron], or a pharmaceutically acceptable salt thereof, where KRAS G12Di is a KRAS G12D binding moiety, L' is a linker, and Deron is a selebron binding moiety. Preferably the compound is a compound of formula (VII). # imgabs0 #

Description

[0001] Related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 364,297, filed May 6, 2022, U.S. Provisional Application No. 63 / 382,959, filed November 9, 2022, U.S. Provisional Application No. 63 / 477,001, filed December 23, 2022, U.S. Provisional Application No. 63 / 485,640, filed February 17, 2023, and U.S. Provisional Application No. 63 / 489,281, filed March 9, 2023. The entire teachings of the above applications are incorporated herein by reference. Background Art

[0003] Kirsten rat sarcoma viral oncogene homolog (KRAS) is a group of genes responsible for producing the K-Ras protein, which is important for cell growth and proliferation. Many KRAS mutations are associated with many different types of cancer. In particular, a mutation in KRASG12D is a common oncogenic KRAS mutation and offers a promising target for treating solid tumors associated with the KRAS pathway. Much work has been done to identify binding pockets, such as the switch II pocket, for irreversibly inhibiting KRAS with the corresponding KRASG12C mutation (MA, Marx et al., Identification of the Clinical Development Candidate MRTX849, a Covalent KRASG12C Inhibitor for the Treatment of Cancer. J. Med. Chem. 2020, 63(13), 6679-6693; VJ, Cee et al., Discovery of a Covalent Inhibitor of KRASG12C (AMG 510) for the Treatment of Solid Tumors. J. Med. Chem. 2020, 63(1), 52-65; X. Lu et al., Small-Molecule Inhibitors Directly Targeting KRAS as Anticancer Therapeutics. J. Med. Chem. 2020, 63(23), 14404-14424). However, KRAS G12D lacks reactive residues adjacent to the switch II pocket present in KRAS G12C.Although some work has been done to try to develop new types of drugs that bind to the shallow pocket between switch I and switch II of KRAS G12D (G. Fang et al., Small-Molecule Ligands Bind to a Distinct Pocket in RAS and Inhibit SOS-Mediated Nucleotide Exchange Activity. Proc. Natl. Acad. Sci. USA, 2012, 109(14), 5299-5304; SW, Fesik et al., Discovery of Small Molecules that Bind to K-RAS and Inhibit SOS-Mediated Activation. Angew. Chem., Int. Ed. 2012, 51(25), 6140-6143), the observed cellular activity is limited. Recently, a small molecule called MRTX1133 was discovered that binds to the switch II pocket of KRAS G12D. MRTX1133 is a potent, selective, non-covalent inhibitor of KRAS G12D, exhibiting picomolar binding affinity, low nanomolar activity in cell-based assays, and in vivo efficacy in tumor models harboring KRAS G12D mutations (MA Marx et al., Identification of MRTX1133, a Noncovalent, Potent, and Selective KRASG12D Inhibitor. J. Med. Chem., 2022, 65(4), 3123-3133).

[0004] Proteolysis targeting chimeras (PROTACs) are bifunctional molecules containing two active domains, commonly known as "warheads," covalently linked to each other by a linker (Hodges et al., Next-Generation Drugs and Probes for Chromatin Biology: From Targeted Protein Degradation to Phase Separation. Molecules. 23(8), 1958). One such PROTAC targeting KRAS G12C is the molecule LC-2. LC-2 is based on the KRAS G12C inhibitor MRTX849 and can rapidly degrade KRASG12C in homozygous and heterozygous tumor cells (MJBond et al., Target degradation of oncogenic KRASG12C by VHL-recruitingPROTACs, ACS Cent. Sci., 2020, 6, 1367-1375; J.Halin et al., The KRAS (G12C) inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients. Cancer Discov. 10, 54-71). However, because LC-2 is a covalent inhibitor of KRAS G12C, it still binds to its target protein, which affects the catalytic cycle of the PROTAC molecule, thereby limiting its efficacy.

[0005] Therefore, there remains a need to develop PROTACs that can bind to KRAS G12D, preferably in a non-covalent manner, and induce the degradation of KRAS G12D. Summary of the Invention

[0006] Provided herein are compounds of structural formula A:

[0007] [KRAS G12Di]-L'-[Degron](A),

[0008] or a pharmaceutically acceptable salt thereof, wherein the values ​​of the variables (eg, KRAS G12Di, L', Degron) are as described herein.

[0009] Also provided herein are compounds of structural formula VII:

[0010]

[0011] or a pharmaceutically acceptable salt thereof, wherein the variables (eg, Ring A, X 4 , Y, R 2 、R 3 、R 4 The values ​​of L, L', and Degron are as described herein.

[0012] Also provided herein is a compound of structural formula VI:

[0013]

[0014] or a pharmaceutically acceptable salt thereof, wherein the variable (e.g., X 4 , Y, R 1 、R 2 、R 3 、R 4 The values ​​of L, L', and Degron are as described herein.

[0015] Also provided herein are compounds of structural formula I:

[0016]

[0017] or a pharmaceutically acceptable salt thereof, wherein the variables (e.g., Y, R 1 、R 2 、R 3 、R 4 The values ​​of L, L', and Degron are as described herein.

[0018] Also provided herein are pharmaceutical compositions comprising a compound of the present disclosure (eg, a compound of Structural Formula A and / or I and / or VI and / or VII, or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier.

[0019] Also provided herein are pharmaceutical combinations comprising a compound of the present disclosure (eg, a compound of Structural Formula A and / or I and / or VI and / or VII, or a pharmaceutically acceptable salt thereof) and at least one additional therapeutic agent.

[0020] Also provided herein are methods of reducing the level or activity of KRAS G12D in a cell expressing KRAS G12D, comprising contacting the cell with (e.g., an effective amount of) a compound of the present disclosure (e.g., a compound of Structural Formula A and / or I and / or VI and / or VII, or a pharmaceutically acceptable salt thereof) (e.g., in the form of a pharmaceutical composition).

[0021] Also provided herein are methods of reducing the level or activity of KRAS G12D in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound of Structural Formula A and / or I and / or VI and / or VII, or a pharmaceutically acceptable salt thereof), e.g., in the form of a pharmaceutical composition.

[0022] Also provided herein are methods of treating KRAS G12D-related cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Structural Formula A and / or I and / or VI and / or VII, or a pharmaceutically acceptable salt thereof), e.g., in the form of a pharmaceutical composition.

[0023] Also provided herein are compounds of the present disclosure (e.g., compounds of formula A and / or I and / or VI and / or VII, or pharmaceutically acceptable salts thereof) or pharmaceutical compositions comprising compounds of the present disclosure for use as described herein (e.g., reducing the level or activity of KRAS G12D; treating KRAS G12D-associated cancers, e.g., in a subject). Also provided herein are uses of compounds of the present disclosure (e.g., compounds of formula A and / or I and / or VI and / or VII, or pharmaceutically acceptable salts thereof) for the preparation of medicaments for use as described herein (e.g., reducing the level or activity of KRAS G12D; treating KRAS G12D-associated cancers, e.g., in a subject). DETAILED DESCRIPTION

[0024] The following is a description of example implementations.

[0025] definition

[0026] The compounds described herein include those generally described and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions apply unless otherwise indicated. For the purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements (CAS version) in the Handbook of Chemistry and Physics, 75th edition. In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999 and "March's Advanced Organic Chemistry", 5th edition, eds.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the relevant contents of which are incorporated herein by reference.

[0027] Unless otherwise specified in this specification, the nomenclature used in this specification generally follows the examples and rules set forth in Nomenclature of Organic Chemistry, Parts A, B, C, D, E, F, and H, Pergamon Press, Oxford, 1979, which is incorporated herein by reference for its chemical structure names and rules for naming chemical structures. Optionally, chemical nomenclature procedures (e.g., Version 17.0.0.206, PerkinElmer Informatics, Inc.) was used to generate compound names.

[0028] When introducing elements disclosed herein, the articles "a," "an," and "the" are intended to mean that there are one or more of the elements, unless explicitly stated or indicated otherwise by context, for example. Further, the one or more elements may be the same or different.

[0029] "Aliphatic" refers to a saturated or unsaturated branched or straight chain hydrocarbon group having a specified number of carbon atoms. Thus, a "C1-C5 aliphatic" refers to a group having 1 to 5 carbon atoms arranged in a branched or straight chain. In some embodiments, an aliphatic group is (C1-C5). 15 ) aliphatic groups, such as (C1-C 10 )aliphatic, (C1-C6)aliphatic, (C1-C5)aliphatic, (C1-C4)aliphatic, or (C1-C3)aliphatic. In some embodiments, the aliphatic group is methylene or ethylene. Examples of aliphatic groups include alkyl, alkenyl, and alkynyl. In some aspects, the aliphatic group is an alkyl or alkynyl group. In some aspects, the aliphatic group is an alkyl or alkenyl group.

[0030] "Alkenyl" refers to a branched or straight chain hydrocarbon radical having a specified number of carbon atoms and at least one carbon-carbon double bond. Thus, "(C2-C6)alkenyl" refers to a radical having 2-6 carbon atoms in a branched or straight chain arrangement and at least one carbon-carbon double bond. In some embodiments, alkenyl is (C2-C6) 15 )alkenyl, such as (C2-C 10 )alkenyl, (C2-C6)alkenyl, (C2-C5)alkenyl, (C2-C4)alkenyl or (C2-C3)alkenyl. Examples of the alkenyl group include vinyl and the like.

[0031] "Alkoxy" refers to an alkyl group attached through an oxygen linking atom, wherein alkyl is as described herein. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, and the like.

[0032] "Alkyl" refers to a saturated branched or straight chain hydrocarbon radical having a specified number of carbon atoms. Thus, "(C1-C6)alkyl" refers to a radical having 1 to 6 carbon atoms arranged in a branched or straight chain. In some embodiments, an alkyl radical is (C1-C6)alkyl. 15 )alkyl, such as (C1-C 10 Examples of the alkyl group include methyl, ethyl, propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, isobutyl, sec-butyl, tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl, 2-methylpentyl), hexyl (e.g., n-hexyl), and the like.

[0033] "Alkylene" refers to a divalent alkyl group, wherein alkyl is as described herein. Examples of alkylene include methylene, ethylene, propylene, and the like.

[0034] "Alkynyl" refers to a branched or straight chain hydrocarbon radical having the specified number of carbon atoms and at least one carbon-carbon triple bond. Thus, "(C2-C6)alkynyl" refers to a radical having 2-6 carbon atoms in a branched or straight chain arrangement and at least one carbon-carbon triple bond. In some embodiments, alkynyl is (C2-C6)alkynyl. 15 )alkynyl, such as (C2-C 10 )alkynyl, (C2-C6)alkynyl, (C2-C5)alkynyl, (C2-C4)alkynyl or (C2-C3)alkynyl. Examples of the alkynyl group include propargyl and the like.

[0035] "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic, tricyclic) aromatic hydrocarbon ring radical having the specified number of ring atoms. Thus, "(C6-C 14 ) aryl" means an aromatic ring group having 6-14 ring atoms. In some embodiments, aryl is (C6-C 14 ) aryl, such as (C6-C 12 )aryl, (C6-C 10 )aryl or (C6)aryl. Examples of aryl groups include phenyl, naphthyl, anthracenyl, and fluorenyl. In some embodiments, aryl is phenyl. "Aryl" includes bicyclic and tricyclic ring systems consisting of an aromatic ring fused to one or two non-aromatic rings or a non-aromatic ring system consisting of two non-aromatic rings. When an aromatic ring is fused to a non-aromatic ring system, the non-aromatic rings in the ring system may be fused to each other or spiro-linked.

[0036] "Arylalkyl" refers to an alkyl group in which one of the hydrogen atoms of the alkyl group is replaced by an aryl group, and the alkyl and aryl groups are as described herein. Examples of arylalkyl groups include benzyl, phenethyl, and naphthylmethyl.

[0037] "Cyano" refers to -C≡N.

[0038] "Cyanoalkyl" refers to an alkyl group in which one of the hydrogen atoms of the alkyl group is replaced by a cyano group, and the alkyl group and the cyano group are as described herein. Examples of cyanoalkyl groups include cyanomethyl, cyanoethyl, cyanopropyl, and the like.

[0039] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic (e.g., bicyclic, tricyclic) hydrocarbon ring group having a specified number of ring atoms. Thus, "(C3-C6)cycloalkyl" refers to a ring group having 3-6 ring atoms. Cycloalkyl can be monocyclic, fused bicyclic, bridged bicyclic, or polycyclic, but is typically monocyclic. In some embodiments, cycloalkyl is (C3-C6)cycloalkyl. 12 )cycloalkyl, for example (C3-C8)cycloalkyl or (C3-C6)cycloalkyl. In some embodiments, the cycloalkyl is saturated. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, bicyclo[1.1.1]pentanyl, and the like.

[0040] The suffixes "ene" or "enyl" are used herein to indicate that the group modified with the suffix has two or more points of attachment (i.e., divalent, trivalent, or multivalent) within the compound being described. For example, a divalent alkyl group is an alkylene group, a divalent heteroalkyl group is a heteroalkylene group, a divalent aryl group is an arylene group, a divalent heteroaryl group is a heteroarylene group, and so on. Substituted groups that have a single point of attachment to the compound being described are not referred to using the "ene" designation. Thus, for example, a trifluoromethyl substituent is not referred to herein as a trifluoromethylene group.

[0041] "Halogen" and "halo" are used interchangeably herein and refer to fluorine, chlorine, bromine, or iodine, respectively. In some embodiments, halogen is fluoro, chloro, or bromo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0042] "Haloalkyl" refers to an alkyl group in which at least one hydrogen of the alkyl group is replaced by a halo group, and the alkyl group and the halo group are as described herein.Haloalkyl includes monohaloalkyl, polyhaloalkyl and perhaloalkyl, wherein each halogen is independently selected. In some embodiments, haloalkyl is a perhaloalkyl group (e.g., perfluoroalkyl).Haloalkyl includes but is not limited to fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethylethyl, pentafluoroethyl, etc.

[0043] "Hetero" refers to an atom that is not carbon or hydrogen. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and the like. In some embodiments, hetero is independently selected from nitrogen, oxygen, or sulfur. In some embodiments, hetero is independently selected from nitrogen or oxygen.

[0044] "Heteroaryl" refers to a monocyclic or polycyclic (e.g., bicyclic, tricyclic) aromatic hydrocarbon ring group having a specified number of ring atoms, wherein at least one carbon atom in the ring has been replaced by a heteroatom (e.g., a heteroatom independently selected from N, O, or S). Thus, "(C5-C6)heteroaryl" refers to an aromatic ring group having 5 or 6 ring atoms consisting of carbon and one or more independently selected heteroatoms (e.g., selected from N, O, or S). In some embodiments, heteroaryl contains 1, 2, 3, or 4 (e.g., 1, 2, or 3; 1 or 2) heteroatoms independently selected from N, S, and O. In some embodiments, heteroaryl contains 1, 2, 3, or 4 (e.g., 1, 2, or 3; 1 or 2) independently selected heteroatoms, e.g., independently selected from N and O. In some embodiments, heteroaryl is (C5-C6)heteroaryl. 14 ) heteroaryl, such as (C5-C 10 )heteroaryl, (C5-C6)heteroaryl, (C6)heteroaryl, (C5)heteroaryl, (C9-C 10 )heteroaryl, (C9)heteroaryl, (C 10 )heteroaryl or (C 14) heteroaryl. Examples of heteroaryl groups include, but are not limited to, acridinyl, azinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H-indazole 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl), oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthrid ... pyridinyl, pyrrolinyl, phenazinyl, phenothiazinyl, phenoxathiazinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridoimidazole, pyridothiazole, pyridinyl (pyridinyl / pyridyl), pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl , tetrazolyl, 6H-1,2,5-thiadiazinyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl), thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, phenylthio, triazinyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl), and xanthenyl. “Heteroaryl” includes bicyclic ring systems consisting of a heteroaromatic ring fused to a non-aromatic ring.

[0045] "Heterocyclyl" or "heterocycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., bicyclic, tricyclic) hydrocarbon ring group having a specified number of ring atoms, wherein at least one carbon atom in the ring has been replaced by a heteroatom. Thus, "(C3-C6)heterocyclyl" means a heterocyclic ring system having 3-6 ring atoms consisting of carbon and one or more independently selected heteroatoms. A heterocyclyl group can be monocyclic, fused bicyclic, bridged bicyclic, or polycyclic, but is typically monocyclic. In some embodiments, the heterocyclyl group contains 1, 2, 3, or 4 (e.g., 1, 2, or 3; 1 or 2) heteroatoms independently selected from N, S, and O. In some embodiments, the heterocyclyl group contains 1, 2, 3, or 4 (e.g., 1, 2, or 3; 1 or 2) heteroatoms independently selected from N and O. When one heteroatom is S, it may optionally be monooxygenated or dioxygenated (i.e., -S(O)- or -S(O)2). In some embodiments, the heterocyclyl group is (C3-C 15 ) heterocyclic group, such as (C3-C 12 ) heterocyclyl, (C4-C8) heterocyclyl, (C3-C7) heterocyclyl or (C3-C6) heterocyclyl. Examples of monocyclic heterocyclyl groups include, but are not limited to, epoxy, azetidinyl, aziridine, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinone, decahydroquinolinyl, piperidonyl, 4-piperidonyl, quinuclidinyl, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, morpholinyl, azepanyl, oxazepanyl, azabicyclohexanyl, azabicycloheptanyl, azabicyclooctanyl, azabicyclononanyl (e.g.,

[0015] In some embodiments, the present invention further comprises the following: octahydroindolizinyl), azaspiroheptane, dihydro-1H,3H,5H-oxazolo[3,4-c]oxazolyl, tetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine], hexahydro-1H-pyrrolizinyl, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl, octahydroindolizinyl, oxazaspironanyl, oxazaspirooctane, diazaspironanyl, oxazabicycloheptanyl, hexahydropyrrolazinyl 4(1H)-oxide, tetrahydro-2H-thiopyranyl 1-oxide and tetrahydro-2H-thiopyranyl 1,1-dioxide.

[0046] "Hydroxyl" refers to -OH.

[0047] "Hydroxyalkyl" refers to an alkyl group in which one of the hydrogen atoms of the alkyl group is replaced by a hydroxy group, and the alkyl and hydroxy groups are as described herein. Examples of hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, and the like.

[0048] "Hydroxyalkynyl" means an alkynyl group wherein one of the hydrogens of the alkynyl group is replaced by a hydroxy group, and the alkynyl and hydroxy groups are as described herein.

[0049] "Oxo" refers to =0.

[0050] The term "substituted" refers to the replacement of a hydrogen atom with a suitable substituent. Typically, a suitable substituent replaces a hydrogen atom bound to a carbon atom, but a substituent may also replace a hydrogen bound to a heteroatom (such as a nitrogen atom). When two or more hydrogen atoms are each replaced by an independently selected substituent, the substituent may be the same or different. "Replacement" or "substituted by..." includes implicit restrictive conditions, i.e., such replacement conforms to the allowed valences of the substituted atom. It is also preferred that the substituent and the substitution produce stable compounds, e.g., they do not spontaneously undergo transformations such as by rearrangement, cyclization, elimination, etc.

[0051] As used herein, the term "optionally substituted" means that substitution is optional, and thus an atom or moiety designated as "optionally substituted" may be unsubstituted or substituted. In some embodiments, an optionally substituted group is unsubstituted. In some embodiments, an optionally substituted group is substituted. An "optionally substituted" group is, in some embodiments, substituted with 0-5 (e.g., 1-5, 0-3, 1-3, 0, 1, 2, 3, 4, 5) substituents. Unless otherwise indicated, for example, by the terms "substituted" or "optionally substituted," a group designated herein is unsubstituted.

[0052] When a bond to a substituent is shown as a bond connecting two atoms in a ring (e.g., to R in the formulas depicted herein), 1 、R 6 and R 8 A substituent group may be bonded to any substitutable atom in the ring. Further, when the ring into which the bond to the substituent group is shown to cross is polycyclic (e.g., bicyclic, such as the hexahydropyrrolazinyl ring system in Formula II), the substituent group may be bonded to any substitutable atom in the ring or ring system into which the bond to the substituent group is shown to cross.

[0053] When a substituent is listed or depicted without indicating the atom to which such substituent is bonded to the rest of the compound of a given formula, such substituent may be bonded via any atom in such substituent so long as the substitution results in a stable compound. Square brackets are used herein to depict substituents without indicating the atom to which such substituent is bonded to the rest of the compound of a given formula. Thus, for example, in the compound of the following formula:

[0054] The portion of the compound in square brackets that is bonded to -L'-[Degron] can be bonded via the nitrogen atom of the secondary amine of the diazabicyclooctanyl moiety to produce a compound of the following formula: Or bonded via the oxygen atom of the hydroxyl group to produce a compound of the following formula: Similarly, in the compound of the following formula: [KRAS G12Di]-L'-[Degron], wherein Degron is For example, Degron can be bonded to [KRAS G12Di]-L'- via the ortho-carbon atom of phthalimide, as in or via the meta-carbon atom of the phthalimide, as in These examples are for illustration only and are given without limitation to the portion of the compound in square brackets that is bonded to -L'-[Degron] and / or other binding sites in the Degron, all of which are contemplated by the present disclosure.

[0055] Suitable substituents for use herein include halogen, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl or acyl), thiocarbonyl (such as thioester, thioacetate or thioformate), alkyl, alkoxy, alkylthio, acyloxy, phosphoryl, phosphate, phosphonate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl. It will be understood by those skilled in the art that, where appropriate, the substituent itself may be substituted. Thus, the substituent may further include, for example, acetamide.

[0056] When a divalent substituent is listed without indicating the directionality of such substituent (e.g., variables L' and / or X), the divalent substituent may be bonded in either direction. Thus, for example, a compound of formula (I):

[0057] Where L' is -X-(CH2) q -, including the following structural formula: And the following structural formula: A compound of both.

[0058] As used herein, the term "compound of the present disclosure" refers to a compound of any formula depicted herein (e.g., a compound of Formula I or its subformulas, such as compounds of Formulas Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, Table 1), as well as isomers thereof, such as stereoisomers (including diastereomers, enantiomers, and racemates) and tautomers, isotopomers thereof, and inherently formed moieties thereof (e.g., polymorphs and / or solvates, such as hydrates). When a moiety capable of forming a salt is present, salts, particularly pharmaceutically acceptable salts, are also included.

[0059] The compounds of the present disclosure may possess asymmetric centers, axes of chirality, and planes of chirality (e.g., as described in E.L. Eliel and S.H. Wiley, Stereo-chemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pp. 1119-1190), and, unless otherwise indicated, exist as racemic mixtures, individual isomers (e.g., diastereomers, enantiomers, geometric isomers (including cis and trans double bond isomers), conformational isomers (including rotamers and atropisomers), tautomers, and intermediate mixtures, including all possible isomers and mixtures thereof.

[0060] Except where otherwise indicated herein, when a disclosed compound or moiety is depicted by structure without indicating stereochemistry, and the compound or moiety has one or more chiral centers, it is understood that the structure encompasses one enantiomer or diastereomer of the compound or moiety separated or substantially separated from the corresponding optical isomer, racemic mixtures, and mixtures enriched in one enantiomer or diastereomer relative to its corresponding optical isomer. Except where otherwise indicated herein, when a disclosed compound or moiety is depicted by structure using solid and / or dashed wedges to indicate stereochemistry, and the compound or moiety has one or more chiral centers, the stereochemistry indicates the absolute configuration of substituents around the one or more chiral centers. Except where otherwise indicated herein, when a disclosed compound or moiety is depicted by structure using solid bold lines and / or dashed bold lines to indicate stereochemistry, and the compound or moiety has one or more chiral centers, the stereochemistry indicates the relative stereochemistry of substituents around the one or more chiral centers without specifying the absolute configuration. "R" and "S" may also or alternatively be used to indicate the absolute configuration of substituents around one or more chiral centers (e.g., carbon atoms). D- and L- may also or alternatively be used to designate stereochemistry. Thus, for example, the conventional RS system may be used to designate a single stereoisomer whose relative and absolute configurations of two chiral centers are known (e.g., (1S,2S)); and the two-letter RS ​​system may be used to designate diastereomers in a racemic mixture (e.g., (1RS,2RS) is a racemic mixture of (1R,2R) and (1S,2S); and (1RS,2SR) is a racemic mixture of (1R,2S) and (1S,2R)).

[0061] "Enantiomers" are pairs of stereoisomers that are non-superimposable mirror images of one another, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center.

[0062] "Diastereomers" are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms.

[0063] As used herein, "racemate" or "racemic mixture" refers to a mixture containing equimolar amounts of the two enantiomers of a compound. Such mixtures do not exhibit optical activity (ie, they do not rotate the plane of polarized light).

[0064] The enantiomeric excess (ee) is defined as the absolute difference between the mole fractions of each enantiomer multiplied by 100% and can be expressed by the following formula: wherein R and S represent the respective fractions of each enantiomer in the mixture such that R + S = 1. In some embodiments, the enantiomers are present with an ee of at least or about 50%, for example, an ee of at least or about: 60%, 70%, 80%, 90%, 95%, 98%, 99%, or 99.9%.

[0065] The diastereomeric excess (de) is defined as the absolute difference between the mole fractions of each diastereomer multiplied by 100% and can be expressed by the following formula: wherein D1 and (D2+D3+D4...) represent the respective fractions of each diastereomer in the mixture such that D1+(D2+D3+D4...)=1. In some embodiments, the diastereomers are present with a de of at least or about 50%, for example, a de of at least or about: 60%, 70%, 80%, 90%, 95%, 98%, 99%, or 99.9%.

[0066] Tautomers are isomers of a compound that differ in the position of one or more hydrogen atoms.

[0067] Unless otherwise indicated, the present invention includes all possible isomers and mixtures thereof, including optical isomers, rotational isomers, tautomers, and cis- and trans-isomers.

[0068] The term "isotopologue" refers to a molecule that differs from a reference molecule only in its isotopic composition.

[0069] Certain atoms exist naturally in various isotopic forms. Natural isotopic abundance describes the relative abundance of various naturally occurring isotopes of a given atom. Therefore, it will be understood that a population of molecules represented by a particular chemical structure will typically contain isotopologues of that particular chemical structure. The relative amounts of such isotopologues will depend on many factors, such as relative natural isotopic abundance, the isotopic purity of the reagents used to prepare the compound, and the incorporation efficiency of the isotopic atoms in the various synthesis steps used to prepare the compound. In certain embodiments, the total amount of such isotopologues will be less than 49.9%, e.g., less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1% or less than 0.5%.

[0070] The structures depicted herein are intended to allow for such natural isotopic abundances, as well as for the replacement of one or more atoms in the structure with their isotopes or isotopically enriched counterparts, e.g., at non-natural isotopic abundances. For example, by replacing hydrogen with deuterium or tritium, or with 13 C or 14 Compounds resulting from the replacement of a carbon with C are within the scope of the present disclosure. In some embodiments, hydrogen atoms in the compounds of the present disclosure are replaced with or enriched with D. In some embodiments, methyl groups in the compounds of the present disclosure are replaced with or enriched with -CD3. Isotopologues can be used, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the present disclosure.

[0071] The phrase "pharmaceutically acceptable" means that the substance or composition modified by the phrase is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, etc., and is commensurate with a reasonable benefit / risk ratio.

[0072] As used herein, the term "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with mammalian tissues without excessive toxicity, irritation, allergic reaction, etc., and commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, the relevant teachings of which are incorporated herein by reference in their entirety. Pharmaceutically acceptable salts of the compounds described herein include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0073] Examples of pharmaceutically acceptable acid addition salts are salts formed with an amino group and inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by other methods used in the art such as ion exchange. Other pharmaceutically acceptable acid addition salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cinnamate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, glutarate, glycolate, hemisulfate, heptanoate, hexanoate, hydroiodide, hydroxybenzoate, 2-hydroxy-ethanesulfonate, hydroxy Maleate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 2-phenoxybenzoate, phenylacetate, 3-phenylpropionate, phosphate, pivalate, propionate, pyruvate, salicylate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Mono-, di-, or tri-basic acid salts can be formed, and such salts can exist in a hydrated, solvated, or substantially anhydrous form.

[0074] Pharmaceutically acceptable base addition salts include salts formed with inorganic bases (such as alkali metals, alkaline earth metals and ammonium bases) and salts formed with aliphatic, alicyclic or aromatic organic amines (such as methylamine, trimethylamine and picoline) or N + ((C1-C4) alkyl) 4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, barium, and the like. Where appropriate, further pharmaceutically acceptable base addition salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxyls, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0075] The compounds described herein may also exist as "solvates" or "hydrates." A "hydrate" is a compound present in a composition together with one or more water molecules. Hydrates may include a stoichiometric amount of water, such as a monohydrate or dihydrate, or may include a random amount of water. "Solvates" are similar to hydrates, except that a solvent other than water (e.g., methanol, ethanol, dimethylformamide, diethyl ether, etc.) is used in place of water. Mixtures of such solvates or hydrates may also be prepared. The source of such solvates or hydrates may be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or incidental to such solvent.

[0076] "Pharmaceutically acceptable carrier" refers to a non-toxic carrier or excipient that does not destroy the pharmacological activity of the medicament formulated therewith and is non-toxic when administered in a dose sufficient to deliver a therapeutic amount of the medicament. Pharmaceutically acceptable carriers that can be used in the compositions described herein include, but are not limited to, ion exchangers, aluminum oxide, 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.

[0077] As used herein, "treating" refers to taking steps to deliver a treatment to a subject (e.g., a mammal) in need thereof (e.g., by administering one or more therapeutic agents to the subject). "Treatment" includes inhibiting a disease or condition (e.g., by slowing or halting its progression or causing regression of the disease or condition) as well as alleviating symptoms caused by a disease or condition.

[0078] "KRAS G12D" refers to a mammalian KRAS protein containing a glycine to aspartic acid substitution at amino acid position 12. The assignment of amino acid codons and residue positions for human KRAS is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variantp.Gly12Asp.

[0079] "KRAS G12D-associated cancer" refers to a cancer that is associated with (e.g., mediated by) a KRAS G12D mutation or has a KRAS G12D mutation. One skilled in the art will know how to determine (e.g., diagnose) whether a cancer or a subject has a KRAS G12D mutation, for example, using a kit or assay approved by, for example, the U.S. Food and Drug Administration (FDA). Techniques that can be used to determine whether a cancer or a subject has a KRAS G12D mutation include next-generation sequencing, immunohistochemistry, fluorescence microscopy, break-through FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR).

[0080] A "binding moiety" is a portion of a compound that binds to a designated target with measurable affinity. In the context of the present disclosure, the target is typically a protein, e.g., KRAS G12D in a KRAS G12D binding moiety; a ubiquitin E3 ligase in a ubiquitin E3 ligase binding moiety. In the compounds of the present disclosure, binding of the compounds of the present disclosure to a designated target is typically mediated by a binding moiety for that target. For example, binding to KRAS G12D in a compound of the present disclosure is typically mediated by a KRAS G12D binding moiety. For example, binding to a ubiquitin E3 ligase is typically mediated by a ubiquitin E3 ligase binding moiety.

[0081] Binding of (binding moieties and / or compounds of the present disclosure) to a target can result in, for example, inhibition and / or agonism (complete or partial) of the target (e.g., a target protein). Thus, in some embodiments, the binding moieties and / or compounds of the present disclosure are inhibitors. In certain embodiments, the binding moieties and / or compounds of the present disclosure have an IC against their designated target. 50 , and / or has a binding constant to its designated target of less than about 50 μM, such as less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM. Measuring IC 50 and binding constants are described herein and / or are within the capabilities of those skilled in the art.

[0082] An "effective amount" is an amount effective, at dosages and for periods of time necessary, to achieve a desired result (eg, a desired therapeutic result, a desired in vitro result).

[0083] A "therapeutically effective amount" is an amount that is effective to achieve the desired therapeutic outcome (e.g., treatment, cure, inhibition or improvement of a physiological response or condition, etc.) at the necessary dosage and time period. A complete therapeutic effect may not necessarily be produced by administering one dose, and a complete therapeutic effect may only be produced after administering a series of doses. Therefore, a therapeutically effective amount may be administered in one or more administrations. A therapeutically effective amount may vary according to a variety of factors, such as the disease state, age, sex, and weight of the mammal; the mode of administration; and the ability of the therapeutic agent or combination of therapeutic agents to elicit the desired response in the individual. A clinician with ordinary skills can determine a therapeutically effective amount of the agent to be administered using the guidance provided herein and other methods known in the art.

[0084] As used herein, "subject" includes humans, domestic animals, such as laboratory animals (e.g., dogs, monkeys, pigs, rats, mice, etc.), household pets (e.g., cats, dogs, rabbits, etc.), and livestock (e.g., pigs, cattle, sheep, goats, horses, etc.), as well as non-domesticated animals. In some embodiments, the subject is a human.

[0085] Compound

[0086] Provided herein in the embodiments is a KRAS G12D PROTAC of structural formula (A):

[0087] [KRAS G12Di]-L'-[Degron](A),

[0088] or a pharmaceutically acceptable salt thereof, wherein:

[0089] KRAS G12Di is a KRAS G12D binding portion, preferably a KRAS G12D inhibitor;

[0090] L' is a divalent linker connecting KRAS G12Di to Degron; and

[0091] Degron is a degrader, preferably a ubiquitin E3 ligase binding moiety. Alternative values ​​for each variable in Structural Formula A are described in the following sections and throughout the disclosure. This disclosure contemplates all combinations of values ​​and alternative values ​​for the variables shown herein.

[0092] KRAS G12D binding site

[0093] International Publication Nos.: WO 2021 / 041671; WO 2022 / 031678; WO 2022 / 066646; and WO 2022 / 015375 disclose KRAS G12D binding portions and methods for their preparation, the entire contents of which are incorporated herein by reference. In some aspects, the KRAS G12D binding portion is a KRAS G12D inhibitor, such as a KRAS G12D inhibitor disclosed in WO 2021 / 041671; WO 2022 / 031678; WO 2022 / 066646; or WO 2022 / 015375. In some aspects, the KRAS G12D binding portion is a KRAS G12D inhibitor disclosed in WO 2021 / 041671 or WO 2022 / 015375.

[0094] KRAS G12D binding moieties and methods for preparing the same are also disclosed in Mao et al., "KRAS (G12D) can be targeted by potent inhibitors via formation of salt bridge," Cell Discovery, 2022, 8, the entire contents of which are incorporated herein by reference. See, in particular, Figures 1 and 2 therein. In some aspects, the KRAS G12D binding moiety is a KRAS G12D inhibitor disclosed by Mao et al.

[0095] International Publication No. WO 2022 / 105857 discloses KRAS G12D binding portions and methods for their preparation, the entire contents of which are incorporated herein by reference. In some aspects, the KRAS G12D binding portion is a KRAS G12D inhibitor disclosed in WO 2022 / 105857. International Publication No. WO 2022 / 105859 also discloses KRAS G12D binding portions and methods for their preparation, the entire contents of which are incorporated herein by reference. In some aspects, the KRASG12D binding portion is a KRAS G12D inhibitor disclosed in WO 2022 / 105859.

[0096] In a first embodiment, a compound of the following formula is provided:

[0097]

[0098] or a pharmaceutically acceptable salt thereof, wherein:

[0099] Y is a bond, O or NR 5 ;

[0100] R 1 is hydrogen, hydroxy, halogen, (C1-C3) alkyl, (C1-C3) cyanoalkyl, (C1-C3) hydroxyalkyl, -C(O)H, -CO2R 5 、-CO2N(R 5 )2 or (C5-C6) heteroaryl;

[0101] R 2 is hydrogen, -N(R 5 )2、(C3-C 12 ) heterocyclic group, (C1-C6) alkyl group, -L-(C3-C 12 ) heterocyclic group, -L-(C6-C 14 )aryl, -L-(C5-C 14 )heteroaryl, -L-(C3-C 12 )cycloalkyl, -LN(R 5 )2, -LN(H)C(NH)NH2, -LC(O)N(R 5 )2, -L-(C1-C6) haloalkyl, -L-OR 5 、-L-NR 5 C(O)-(C6-C 14 )aryl, -L-COOH or -LC(O)O(C1-C6)alkyl, wherein (C3-C 12 ) heterocyclic group, -L-NR 5 C(O)-(C6-C 14) aryl (C6-C 14 )aryl, -L-(C3-C 12 ) heterocyclic (C3-C 12 ) heterocyclic group and -L-(C3-C 12 )cycloalkyl (C3-C 12 ) cycloalkyl is optionally substituted with one or more R 6 Substituted, and -L-(C6-C 14 ) aryl and -L-(C5-C 14 )heteroaryl(C5-C 14 ) heteroaryl is optionally substituted with one or more R 7 replace;

[0102] L is optionally substituted by hydroxy, (C1-C4)hydroxyalkyl or (C5-C 14 ) heteroaryl-substituted (C1-C4)alkylene;

[0103] R 3 Yes (C6-C 14 )aryl or (C5-C 14 ) heteroaryl, wherein (C6-C 14 )aryl or (C5-C 14 ) heteroaryl is optionally substituted with one or more R 8 replace;

[0104] R 4 is hydrogen, halogen or (C1-C3)alkyl;

[0105] Each R 5 are independently hydrogen or (C1-C3)alkyl;

[0106] Each R 6 are independently deuterated, halogen, hydroxy, (C1-C3) hydroxyalkyl, (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) alkoxy, cyano, -Q-phenyl, -Q-phenyl-SO2F, -N(H)C(O)-phenyl, -N(H)C(O)-phenyl-SO2F, (C1-C3) alkyl-substituted pyrazole, (C6-C 14 )aryl (C1-C3) alkyl, tert-butyldimethylsilyloxy-CH2-, -N(R 5 )2, (C1-C3) alkoxy (C1-C3) alkyl, (C1-C3) alkyl-C(O)-, oxo, (C1-C3) haloalkyl-C(O)-, -SO2F, (C1-C3) alkoxy (C1-C3) alkoxy, -CH2OC(O)N(R 5 )2、-CH2N(H)C(O)O-(C1-C6)alkyl、-CH2N(H)C(O)N(R 5)2, -CH2N(H)C(O)(C1-C6)alkyl, -CH2(pyrazolyl), -CH2N(H)S(O)2(C1-C6)alkyl, -CH2OC(O)(C3-C 12 ) heterocyclic group, -OC(O)N(R 5 )2, -OC(O)N(H)(C1-C3)alkyl-O-(C1-C3)alkyl, -OC(O)N(H)(C1-C3)alkyl-O-(C1-C3)alkyl-phenyl-(C1-C3)alkyl-N(CH3)2, -OC(O)N(H)(C1-C3)alkyl-O-(C1-C3)alkyl-phenyl, -OC(O)(C3-C 12 ) heterocyclic group or -CH2-(C3-C 12 ) heterocyclic group, wherein the phenyl group of -N(H)C(O)phenyl and -OC(O)N(H)(C1-C3)alkyl-O-(C1-C3)alkyl-phenyl is optionally substituted by -C(O)H or -OH, and -CH2-(C3-C 12 ) heterocyclic (C3-C 12 ) The heterocyclic group is optionally substituted with oxo;

[0107] Q is a bond or O;

[0108] Each R 7 are independently halogen, hydroxy, -C(O)H, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)hydroxyalkyl, or -N(R 5 )2;

[0109] Each R 8 are independently halogen, cyano, hydroxy, (C1-C4) alkyl, -S-(C1-C3) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C2-C4) hydroxyalkynyl, (C1-C3) cyanoalkyl, triazolyl, (C1-C3) haloalkyl, -O-(C1-C3) haloalkyl, -S-(C1-C3) haloalkyl, (C1-C3) alkoxy, (C1-C3) hydroxyalkyl, -CH2C(O)N(R 5 )2、(C3-C4)alkynyl-N(R 5 )2、N(R 5 )2, deuterated (C2-C4)alkynyl, (C1-C3)alkoxy, (C1-C3)haloalkyl or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl is optionally substituted with halogen or (C1-C3)alkyl;

[0110] L' is a divalent linker connected to the Degron; and

[0111] Degron is a degrader.

[0112] In a first aspect of the first embodiment, Y is O. The values ​​for the remaining variables are as described in the first embodiment.

[0113] In a second aspect of the first embodiment, R 1 The values ​​for the remaining variables are as described in the first embodiment, or first aspect thereof.

[0114] In a third aspect of the first embodiment, R 2 Yes-L-(C3-C 12 ) heterocyclic group, wherein -L-(C3-C 12 ) heterocyclic (C3-C 12 ) The heterocyclic group is optionally substituted with one or more R 6 The values ​​for the remaining variables are as described in the first embodiment, or first or second aspect thereof.

[0115] In a fourth aspect of the first embodiment, L is methylene.The values ​​for the remaining variables are as described in the first embodiment, or first through third aspects thereof.

[0116] In a fifth aspect of the first embodiment, R 3 is optionally replaced by one or more R 8 Substituted (C6-C 14 The values ​​for the remaining variables are as described in the first embodiment, or first through fourth aspects thereof.

[0117] In a sixth aspect of the first embodiment, R 4 The values ​​for the remaining variables are as described in the first embodiment, or first through fifth aspects thereof.

[0118] In a seventh aspect of the first embodiment, R 4 The values ​​for the remaining variables are as described in the first embodiment, or first through sixth aspects thereof.

[0119] In an eighth aspect of the first embodiment, each R 6 and (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, or cyano. The values ​​for the remaining variables are as described in the first embodiment, or first through seventh aspects thereof.

[0120] In a ninth aspect of the first embodiment, each R 8 and (C-C)alkyl, -S-(C-C)alkyl, (C-C)alkenyl, (C-C)alkynyl, (C-C)alkoxy, (C-C)hydroxyalkyl, or deuterated (C-C)alkynyl. The values ​​for the remaining variables are as described in the first embodiment, or first through eighth aspects thereof.

[0121] In a tenth aspect of the first embodiment, each R 8 is independently halogen, hydroxy, or (C2-C4)alkynyl.The values ​​for the remaining variables are as described in the first embodiment, or first through ninth aspects thereof.

[0122] In an eleventh aspect of the first embodiment, R 3 yes The values ​​for the remaining variables are as described in the first embodiment, or first through tenth aspects thereof.

[0123] In a twelfth aspect of the first embodiment, YR 2 yes *—H. The values ​​for the remaining variables are as described in the first embodiment, or first through eleventh aspects thereof.

[0124] In a thirteenth aspect of the first embodiment, R 3 yes The values ​​for the remaining variables are as described in the first embodiment, or first through twelfth aspects thereof.

[0125] In a fourteenth aspect of the first embodiment, each R 6 and (C1-C3)alkyl, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, or cyano. The values ​​for the remaining variables are as described in the first embodiment, or first through thirteenth aspects thereof.

[0126] In a fifteenth aspect of the first embodiment, each R 6 are independently halogen, hydroxy, (C1-C3) hydroxyalkyl, (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) alkoxy, cyano, -Q-phenyl, -Q-phenyl-SO2F, -N(H)C(O)-phenyl, -N(H)C(O)-phenyl-SO2F, (C1-C3) alkyl-substituted pyrazole, (C6-C 14 )aryl (C1-C3) alkyl, tert-butyldimethylsilyloxy-CH2-, -N(R 5 )2, (C1-C3) alkoxy (C1-C3) alkyl, (C1-C3) alkyl-C(O)-, oxo, (C1-C3) haloalkyl-C(O)-, -SO2F, (C1-C3) alkoxy (C1-C3) alkoxy, -CH2OC(O)N(R 5)2、-CH2N(H)C(O)O-(C1-C6)alkyl、-CH2N(H)C(O)N(R 5 )2, -CH2N(H)C(O)(C1-C6)alkyl, -CH2(pyrazolyl), -CH2N(H)S(O)2(C1-C6)alkyl, -CH2OC(O)(C3-C 12 ) heterocyclic group, -OC(O)N(R 5 )2, -OC(O)N(H)(C1-C3)alkyl-O-(C1-C3)alkyl, -OC(O)N(H)(C1-C3)alkyl-O-(C1-C3)alkyl-phenyl-(C1-C3)alkyl-N(CH3)2, -OC(O)N(H)(C1-C3)alkyl-O-(C1-C3)alkyl-phenyl, -OC(O)(C3-C 12 ) heterocyclic group or -CH2-(C3-C 12 ) heterocyclic group, wherein the phenyl group of -N(H)C(O)phenyl and -OC(O)N(H)(C1-C3)alkyl-O-(C1-C3)alkyl-phenyl is optionally substituted by -C(O)H or -OH, and -CH2-(C3-C 12 ) heterocyclic (C3-C 12 The values ​​for the remaining variables are as described in the first embodiment, or first through fourteenth aspects thereof.

[0127] A second embodiment provides a compound of the following formula:

[0128]

[0129] or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2 (and in some aspects is 1 or 2; in further aspects is 1), and the remaining variables (e.g., R 1 、R 3 、R 4 、R 6 The values ​​of L, L', Degron) are as described in the first embodiment or any aspect thereof.

[0130] In a first aspect of the second embodiment, the compound has the following structural formula:

[0131]

[0132] or a pharmaceutically acceptable salt thereof. 1 、R 3 、R 4 、R 6 , n, L', Degron) are as described in the first embodiment or any aspect thereof or in the second embodiment.

[0133] In a second aspect of the second embodiment, the compound has the following structural formula:

[0134]

[0135] or a pharmaceutically acceptable salt thereof. 1 、R 3 、R 4 、R 6 , n, L', Degron) are as described in the first embodiment or any aspect thereof or in the second embodiment.

[0136] The third embodiment is a compound of the following formula:

[0137]

[0138] or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3, 4, or 5 (and in some aspects is 1, 2, or 3; in further aspects is 2 or 3; in yet further aspects is 3), and the remaining variables (e.g., R 1 、R 4 、R 6 、R 8 The values ​​of L, n, L', Degron) are as described in the first or second embodiment or any aspect thereof.

[0139] In a first aspect of the third embodiment, the compound has the following structural formula:

[0140]

[0141] or a pharmaceutically acceptable salt thereof. 1 、R 4 、R 6 、R 8 , n, m, L', Degron) are as described in the first or second embodiment or any aspect thereof.

[0142] In a second aspect of the third embodiment, the compound has the following structural formula:

[0143]

[0144] or a pharmaceutically acceptable salt thereof. 1 、R 4 、R 6 、R 8 , n, m, L', Degron) are as described in the first or second embodiment or any aspect thereof.

[0145] A fourth embodiment is a compound of the following formula:

[0146]

[0147] or a pharmaceutically acceptable salt thereof. 1 、R 4 、R 6 The values ​​of L, n, L', Degron) are as described in the first or second embodiment or any aspect thereof.

[0148] In a first aspect of the fourth embodiment, the compound has the following structural formula:

[0149]

[0150] or a pharmaceutically acceptable salt thereof. 1 、R 4 、R 6 The values ​​of L, n, L', Degron) are as described in the first or second embodiment or any aspect thereof.

[0151] In a second aspect of the fourth embodiment, the compound has the following structural formula:

[0152]

[0153] or a pharmaceutically acceptable salt thereof. 1 、R 4 、R 6 The values ​​of L, n, L', Degron) are as described in the first or second embodiment or any aspect thereof.

[0154] A fifth embodiment is a compound of the following formula:

[0155]

[0156] or a pharmaceutically acceptable salt thereof, wherein n' is 0 or 1 (and in some aspects is 0), and the remaining variables (eg, R 1 、R 4 、R 6 The values ​​of L, L', Degron) are as described in the first embodiment or any aspect thereof.

[0157] In a first aspect of the fifth embodiment, the compound has the following structural formula:

[0158]

[0159] or a pharmaceutically acceptable salt thereof. 1 、R 4 、R 6, n', L', Degron) are as described in the first embodiment, or any aspect thereof, or in the fifth embodiment.

[0160] In a second aspect of the fifth embodiment, the compound has the following structural formula:

[0161]

[0162] or a pharmaceutically acceptable salt thereof. 1 、R 4 、R 6 , n', L', Degron) are as described in the first embodiment, or any aspect thereof, or in the fifth embodiment.

[0163] The sixth embodiment is a compound of the following formula:

[0164]

[0165] or a pharmaceutically acceptable salt thereof, wherein:

[0166] X 4 Is N or C (R 42 );

[0167] R 42 Selected from hydrogen, halogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Halogenated alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, oxo, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 Alkyl), -S(halogenated C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -C(=O)OH, -C(=O)(OC 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -OC(=O)O(C1-6 alkyl), -NHC(=O)(OC 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(OC 1-6 alkyl), -OC(=O)NH(C 1-6 alkyl), -OC(=O)N(C 1-6 alkyl)2、-NHC(=O)NH2、-NHC(=O)NH(C 1-6 alkyl), -NHC(=O)N(C 1-6 Alkyl)2, -N(C 1-6 alkyl) C(=O)NH2, -N(C 1-6 alkyl)C(=O)NH(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)N(C 1-6 alkyl)2, -S(=O)(OC 1-6 alkyl), -OS(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 Alkyl)2, -NHS(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)(C 1-6 alkyl), -S(=O)2(OC 1-6 alkyl), -OS(=O)2(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C 1-6 alkyl)2, -NHS(=O)2(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)2(C 1-6 alkyl), -OS(=O)2O(C 1-6 alkyl), -NHS(=O)2O(C 1-6 Alkyl), -N(C 1-6 Alkyl)S(=O)2O(C 1-6 alkyl), -OS(=O)2NH2, -OS(=O)2NH(C 1-6 alkyl), -OS(=O)2N(C 1-6 alkyl)2、-NHS(=O)2NH2、-NHS(=O)2NH(C 1-6 alkyl), -NHS(=O)2N(C 1-6 Alkyl)2, -N(C 1-6 alkyl)S(=O)2NH2, -N(C1-6 alkyl)S(=O)2NH(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)2N(C 1-6 Alkyl)2, -PH(C 1-6 alkyl), -P(C 1-6 alkyl)2, -P(=O)H(C 1-6 alkyl), -P(=O)(C 1-6 alkyl) 2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, wherein each of these groups is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from the group consisting of halogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Halogenated alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, oxo, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 Alkyl), -S(halogenated C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -C(=O)OH, -C(=O)(OC 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -OC(=O)O(C 1-6 alkyl), -NHC(=O)(OC 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(OC 1-6 alkyl), -OC(=O)NH(C 1-6 alkyl), -OC(=O)N(C 1-6 alkyl)2、-NHC(=O)NH2、-NHC(=O)NH(C 1-6 alkyl), -NHC(=O)N(C 1-6 Alkyl)2, -N(C 1-6alkyl) C(=O)NH2, -N(C 1-6 alkyl)C(=O)NH(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)N(C 1-6 alkyl)2, -S(=O)(OC 1-6 alkyl), -OS(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 Alkyl)2, -NHS(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)(C 1-6 alkyl), -S(=O)2(OC 1-6 alkyl), -OS(=O)2(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C 1-6 alkyl)2, -NHS(=O)2(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)2(C 1-6 alkyl), -OS(=O)2O(C 1-6 alkyl), -NHS(=O)2O(C 1-6 Alkyl), -N(C 1-6 Alkyl)S(=O)2O(C 1-6 alkyl), -OS(=O)2NH2, -OS(=O)2NH(C 1-6 alkyl), -OS(=O)2N(C 1-6 alkyl)2、-NHS(=O)2NH2、-NHS(=O)2NH(C 1-6 alkyl), -NHS(=O)2N(C 1-6 Alkyl)2, -N(C 1-6 alkyl)S(=O)2NH2, -N(C 1-6 alkyl)S(=O)2NH(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)2N(C 1-6 Alkyl)2, -PH(C 1-6 alkyl), -P(C 1-6 alkyl)2, -P(=O)H(C 1-6 alkyl), -P(=O)(C 1-6 alkyl) 2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; and

[0168] The remaining variables (e.g., Y, R 1 、R 2 、R 3 、R 4 The values ​​of L, L', and Degron are as described in the first to fifth embodiments or any aspect thereof.

[0169] In a first aspect of the sixth embodiment, X 4 It is C(R 42 ). The values ​​for the remaining variables are as described in the first to fifth embodiments, or any aspect of the foregoing, or the sixth embodiment.

[0170] In a second aspect of the sixth embodiment, R 42 wherein R is hydrogen, halogen, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, -CN, (Ci-C6)alkoxy, -S-(Ci-C6)alkyl, or -S-(Ci-C6)haloalkyl. The values ​​for the remaining variables are as described in the first through fifth embodiments, or any aspect of the foregoing, or the sixth embodiment, or its first aspect.

[0171] In a third aspect of the sixth embodiment, R 42 is hydrogen, fluoro, chloro, methyl, -CF3, -OCF3, -CN, -OCH3, -SCH3, or -SCF3. The values ​​for the remaining variables are as described in the first through fifth embodiments, or any aspect of the foregoing, or the sixth embodiment, or first or second aspect thereof.

[0172] The seventh embodiment is a compound of the following formula:

[0173]

[0174] or a pharmaceutically acceptable salt thereof, wherein:

[0175] yes

[0176] X 5 is O or CH2;

[0177] Two R's o Combined with the same carbon atom to form C 3-7wherein each (C3-C7)cycloalkyl or 4-7 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, oxo, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, hydroxy, cyano, -S(O)2(C1-C4)alkyl, =NH, =N(C1-C4)alkyl, -NH2, -N(H)(C1-C4)alkyl or -N((C1-C4)alkyl)2, and when p is 3 or 4, each remaining R o independently selected from hydroxy, halogen, oxo, cyano, -N((C1-C4)alkyl)2, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl or (C1-C4)haloalkoxy;

[0178] o is 2, 3, or 4;

[0179] p is 0, 1 or 2 (and in some preferred aspects is 1);

[0180] q is 0, 1 or 2 (and in some preferred aspects is 1); and

[0181] The remaining variables (e.g., X 4 , Y, R 1 、R 2 、R 3 、R 4 , L', Degron) are as described in the first to sixth embodiments or any aspect of the foregoing.

[0182] In a first aspect of the seventh embodiment, yes The values ​​for the remaining variables are as described in the first through sixth embodiments, or any aspect of the foregoing, or the seventh embodiment.

[0183] In a second aspect of the seventh embodiment, yes

[0184]

[0185] The values ​​for the remaining variables are as described in the first through sixth embodiments, or any aspect of the foregoing, or the seventh embodiment, or first aspect thereof.

[0186] In a third aspect of the seventh embodiment, yes The values ​​for the remaining variables are as described in the first through sixth embodiments, or any aspect of the foregoing, or the seventh embodiment, or first or second aspect thereof.

[0187] An eighth embodiment provides a compound of the following formula:

[0188]

[0189] or a pharmaceutically acceptable salt thereof, wherein R 21 and R 22 are each independently H, D, or F; n' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 (and in some aspects 0, 1, 2, 3, 4, 5, or 6; in further aspects 0, 1, 2, 3, or 4), and the remaining variables (e.g., Ring A, X 4 、R 3 、R 4 、R 6 The values ​​of L, L', and Degron are as described in the first to seventh embodiments, or any aspect thereof.

[0190] In a first aspect of the eighth embodiment, R 21 and R 22 Each is D. The values ​​for the remaining variables are as described in the first through seventh embodiments, or any aspect of the foregoing, or the eighth embodiment.

[0191] In a second aspect of the eighth embodiment, R 21 and R 22 Each is H. The values ​​for the remaining variables are as described in the first through seventh embodiments, or any aspect of the foregoing, or the eighth embodiment.

[0192] It will be understood that the moiety shown in square brackets in the compounds of Structural Formulas (I)-(VIII) corresponds to the KRAS G12D binding moiety in the compounds of Structural Formulas (I)-(VIII). In some embodiments, the KRAS G12D binding moiety is the moiety shown in square brackets in any one of Structural Formulas (I)-(VIII), wherein the variable (e.g., X) 4 、X 5 , Y, R o 、R 1 、R 2 、R 3 、R 4 、R 6 、R 8 , n, m, o, p, q) are as described in the first to seventh embodiments or any aspect thereof.

[0193] In some aspects of any of the above embodiments or aspects thereof, the KRAS G12D binding moiety is via a member corresponding to R in formula (I)-(VIII), for example, 2 or R 6 The atoms of the group are bonded to -L'-[Degron]: where R23 and R 24 are each independently H, D, or F, and the remaining variables (e.g., Ring A, X 4 、R 3 、R 4 、R 6 The values ​​of L, L', and Degron are as described in the first to eighth embodiments, or any aspect thereof.

[0194] Specific examples of KRAS G12D binding moieties include:

[0195] In some embodiments, the KRAS G12D binding portion is In some embodiments, the KRAS G12D binding portion is In some embodiments, the KRAS G12D binding portion is

[0196] Other specific examples of KRAS G12D binding moieties include:

[0197] In some embodiments, the KRAS G12D binding portion is In some embodiments, the KRAS G12D binding portion is In some embodiments, the KRAS G12D binding portion is

[0198] Other specific examples of KRAS G12D binding moieties include those disclosed by Mao et al. Thus, in some embodiments, the KRAS G12D binding moiety has the following structural formula: in yes

[0199] Still other specific examples of KRAS G12D binding moieties include those described by Wang et al. in "Ideation of MRTX1133, a Noncovalent, Potent, and Selective KRAS G12D Binding Moiety." G12DInhibitor," J. Med Chem., https: / / doi.org / 10.1021 / acs.jmedche m.1c01688, the entire contents of which are incorporated herein by reference. In some embodiments, the KRAS G12D binding portion is a KRAS G12D inhibitor disclosed by Wang et al. For example, in some embodiments, the KRAS G12D binding portion has the following structural formula: In some embodiments, the KRAS G12D binding portion has the following structural formula: In some embodiments, the KRAS G12D binding portion has the following structural formula: Where R4 is In some embodiments, the KRAS G12D binding portion has the following structural formula: Where R2 is In some embodiments, the KRAS G12D binding portion has the following structural formula: Where R7 is

[0200] In some embodiments, the KRAS G12D binding portion has the following structural formula:

[0201]

[0202] in:

[0203] X 1 is a bond or a C1-C4 alkylene group;

[0204] Y and Y 1 Each independently is a bond, O or NR 5 ;

[0205] R 1 is hydroxyl, N(R 5 )2、(C3-C 12 )cycloalkyl or (C3-C 12 ) heterocyclic group, wherein (C3-C 12 )cycloalkyl or (C3-C 12 ) The heterocyclic group is optionally substituted with one or more R X replace;

[0206] Each R X are independently (C1-C3)alkyl, hydroxy, -N(R 5 )2、-CH2N(R 5 )2、cyanomethyl or (C3-C12 ) heterocyclic group;

[0207] R 2 is hydrogen, -N(R 5 )2、(C3-C 12 ) heterocyclic group, (C1-C6) alkyl group, -L-(C3-C 12 ) heterocyclic group, -L-(C6-C 14 )aryl, -L-(C5-C 14 )heteroaryl, -L-(C3-C 12 )cycloalkyl, -LN(R 5 )2, -LN(H)C(NH)NH2, -LC(O)N(R 5 )2, -L-(C1-C6) haloalkyl, -L-OR 5 、-L-(CH2OR 5 )(CH2) 1-3 OR 5 、-L-NR 5 C(O)-(C6-C 14 )aryl or -L-COOH, wherein (C3-C 12 ) heterocyclic group, -L-NR 5 C(O)-(C6-C 14 ) aryl (C6-C 14 )aryl, -L-(C3-C 12 ) heterocyclic (C3-C 12 ) heterocyclic group and -L-(C3-C 12 )cycloalkyl (C3-C 12 ) cycloalkyl is optionally substituted with one or more R 6 Substituted, and -L-(C6-C 14 ) aryl and -L-(C5-C 14 )heteroaryl(C5-C 14 ) heteroaryl is optionally substituted with one or more R 7 replace;

[0208] Each L is independently optionally hydroxy, (C1-C4)hydroxyalkyl or (C5-C 14 ) heteroaryl-substituted (C1-C4)alkylene;

[0209] R 3 Yes (C6-C 14 )aryl or (C5-C 14 ) heteroaryl, wherein (C6-C 14 )aryl or (C5-C 14 ) heteroaryl is optionally substituted with one or more R 8 replace;

[0210] R 4 is hydrogen, halogen or (C1-C3)alkyl;

[0211] Each R 5 are independently hydrogen or (C1-C3)alkyl;

[0212] Each R 6 are independently halogen, hydroxy, (C1-C3) hydroxyalkyl, (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) alkoxy, -Q-phenyl, -Q-phenyl-SO2F, -N(H)C(O)-phenyl, -N(H)C(O)-phenyl-SO2F, (C1-C3) alkyl-substituted pyrazole, (C6-C 14 )aryl (C1-C3) alkyl, tert-butyldimethylsilyloxy-CH2-, -N(R 5 )2, (C1-C3) alkoxy (C1-C3) alkyl, (C1-C3) alkyl-C(O)-, oxo, (C1-C3) haloalkyl-C(O)-, -SO2F, (C1-C3) alkoxy (C1-C3) alkoxy, -L-OC(O)N(R 5 )2 or -L-OC(O)(C3-C 12 ) heterocyclic group;

[0213] Each Q is independently a bond or O;

[0214] Each R 7 are independently halogen, hydroxy, -C(O)H, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)hydroxyalkyl, or -N(R 5 )2; and

[0215] Each R 8 are independently halogen, cyano, hydroxy, (C3-C6)cycloalkyl, (C1-C3)alkyl, -S-(C1-C3)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C2-C4)hydroxyalkynyl, (C1-C3)cyanoalkyl, triazolyl, (C1-C3)haloalkyl, -O-(C1-C3)haloalkyl or -S-(C1-C3)haloalkyl.

[0216] Alternative values ​​for the variables are as described in the first, second or third embodiment, or any aspect thereof.

[0217] In some embodiments, the KRAS G12D binding portion is

[0218]

[0219]

[0220]

[0221]

[0222] In some embodiments, the KRAS G12D binding portion has the following structural formula:

[0223]

[0224] in:

[0225] X 2 is hydrogen, -C(O)-OC(H)(R 9 )-OC(O)-Z、-C(O)-O-(C6-C 14 )aryl or -C(O)(C1-C6)alkyl;

[0226] Y is a bond, O or NR 5 ;

[0227] Z is -(CH2) 0-20 -CH3 or (C1-C3) alkyl;

[0228] R 1 is hydrogen, hydroxy, halogen, (C1-C3) alkyl, (C1-C3) cyanoalkyl, (C1-C3) hydroxyalkyl, -C(O)H, -CO2R 5 、-CO2N(R 5 )2 or (C5-C6) heteroaryl;

[0229] R 2 is hydrogen, -N(R 5 )2,(C3-C 12 ) heterocyclic group, (C1-C6) alkyl group, -L-(C3-C 12 ) heterocyclic group, -L-(C6-C 14 )aryl, -L-(C5-C 14 )heteroaryl, -L-(C3-C 12 )cycloalkyl, -LN(R 5 )2, -LN(H)C(NH)NH2, -LC(O)N(R 5 )2, -L-(C1-C6) haloalkyl, -L-OR 5 、-L-(CH2OR 5 )(CH2) 1-3 OR 5 、-L-NR 5 C(O)-(C6-C 14)aryl, -L-COOH or -LC(O)O(C1-C6)alkyl, wherein (C3-C 12 ) heterocyclic group, -L-NR 5 C(O)-(C6-C 14 ) aryl (C6-C 14 )aryl, -L-(C3-C 12 ) heterocyclic (C3-C 12 ) heterocyclic group and -L-(C3-C 12 )cycloalkyl (C3-C 12 ) cycloalkyl is optionally substituted with one or more R 6 Substituted, and -L-(C6-C 14 ) aryl and -L-(C5-C 14 )heteroaryl(C5-C 14 ) heteroaryl is optionally substituted with one or more R 7 replace;

[0230] Each L is independently optionally hydroxy, (C1-C4) hydroxyalkyl (C5-C 14 ) heteroaryl or 1-2 deuterium-substituted (C1-C4) alkylene;

[0231] R 3 Yes (C6-C 14 )aryl or (C5-C 14 ) heteroaryl, wherein (C6-C 14 )aryl or (C5-C 14 ) heteroaryl is optionally substituted with one or more R 8 replace;

[0232] R 4 is hydrogen, halogen or (C1-C3)alkyl;

[0233] Each R 5 are independently hydrogen or (C1-C3)alkyl;

[0234] Each R 6 are independently halogen, hydroxy, (C1-C3) hydroxyalkyl, (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) alkoxy, cyano, -Q-phenyl, -Q-phenyl-SO2F, -N(H)C(O)-phenyl, -N(H)C(O)-phenyl-SO2F, (C1-C3) alkyl-substituted pyrazole, (C6-C 14 )aryl (C1-C3) alkyl, tert-butyldimethylsilyloxy-CH2-, -N(R 5)2, (C1-C3) alkoxy (C1-C3) alkyl, (C1-C3) alkyl-C(O)-, oxo, (C1-C3) haloalkyl-C(O)-, -SO2F, (C1-C3) alkoxy (C1-C3) alkoxy, -CH2OC(O)N(R 5 )2、-CH2N(H)C(O)O-(C1-C6)alkyl、-CH2N(H)C(O)N(R 5 )2, -CH2N(H)C(O)(C1-C6)alkyl, -CH2(pyrazolyl), -CH2N(H)S(O)2(C1-C6)alkyl, -CH2OC(O)(C3-C 12 ) heterocyclic group, -OC(O)N(R 5 )2, -OC(O)N(H)(C1-C3)alkyl-O-(C1-C3)alkyl, -OC(O)N(H)(C1-C3)alkyl-O-(C1-C3)alkyl-phenyl-(C1-C3)alkyl-N(CH3)2, -OC(O)N(H)(C1-C3)alkyl-O-(C1-C3)alkyl-phenyl, -OC(O)(C3-C 12 ) heterocyclic group, -CH2-(C3-C 12 ) heterocyclyl or deuterium, wherein the phenyl of -N(H)C(O)phenyl and -OC(O)N(H)(C1-C3)alkyl-O-(C1-C3)alkyl-phenyl is optionally substituted by -C(O)H or -OH, and -CH2-(C3-C 12 ) heterocyclic (C3-C 12 ) The heterocyclic group is optionally substituted with oxo;

[0235] Q is a bond or O;

[0236] Each R 7 are independently halogen, hydroxy, -C(O)H, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)hydroxyalkyl, or -N(R 5 )2;

[0237] Each R 8 are independently halogen, cyano, hydroxy, (C1-C4) alkyl, -S-(C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C2-C4) hydroxyalkynyl, (C1-C3) cyanoalkyl, triazolyl, (C1-C3) haloalkyl, -O-(C1-C3) haloalkyl, -S-(C1-C3) haloalkyl, (C1-C3) alkoxy, (C1-C3) hydroxyalkyl, -CH2C(O)N(R 5 )2、(C3-C4)alkynyl-N(R 5 )2、N(R5 )2, deuterated (C2-C4)alkynyl, (C1-C3)alkoxy (C1-C3)haloalkyl, -OC(O)-Z or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl is optionally substituted with halogen or (C1-C3)alkyl; and

[0238] R 9 is hydrogen or (C1-C3)alkyl.

[0239] Alternative values ​​for the variables are as described in the first, second or third embodiment, or any aspect thereof.

[0240] In some embodiments, the KRAS G12D binding portion is

[0241]

[0242]

[0243] In some embodiments, the KRAS G12D binding portion has the following structural formula:

[0244]

[0245] in:

[0246] X 3 Is N or CR 5 ;

[0247] Y is a bond, O or NR 5 ;

[0248] Z is -(CH2) 0-20 -CH3 or (C1-C3) alkyl;

[0249] Each R 1 are independently hydrogen, hydroxy, halogen, (C1-C3)haloalkyl, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)alkoxy(C1-C3)alkyl, (C1-C3)alkyl-N(R 5 )2, cyano, (C1-C3) cyanoalkyl, (C2-C4) cyanoalkenyl, (C1-C3) hydroxyalkyl, -C(O)H, -CO2R 5 or -CO2N(R 5 )2;

[0250] R 2 is hydrogen, -N(R 5 )2、(C3-C 12 ) heterocyclic group, (C1-C6) alkyl group, -L-(C3-C 12 ) heterocyclic group, -L-(C6-C 14)aryl, -L-(C5-C 14 )heteroaryl, -L-(C3-C 12 )cycloalkyl, -LN(R 5 )2, -LN(H)C(NH)NH2, -LC(O)N(R 5 )2, -L-(C1-C6) haloalkyl, -L-OR 5 、-L-(CH2OR 5 )(CH2) 1-3 OR 5 、-L-NR 5 C(O)-(C6-C 14 )aryl or -L-COOH, wherein (C3-C 12 ) heterocyclic group, -L-NR 5 C(O)-(C6-C 14 ) aryl (C6-C 14 )aryl, -L-(C3-C 12 ) heterocyclic (C3-C 12 ) heterocyclic group and -L-(C3-C 12 )cycloalkyl (C3-C 12 ) cycloalkyl is optionally substituted with one or more R 6 Substituted, and -L-(C6-C 14 ) aryl and -L-(C5-C 14 )heteroaryl(C5-C 14 ) heteroaryl is optionally substituted with one or more R 7 replace;

[0251] Each L is independently optionally hydroxy, (C1-C4)hydroxyalkyl or (C5-C 14 ) heteroaryl-substituted (C1-C4)alkylene;

[0252] R 3 Yes-L-(C6-C 14 )aryl, (C6-C 14 )aryl, -L-(C5-C 14 )heteroaryl or (C5-C 14 ) heteroaryl, wherein (C6-C 14 )aryl or (C5-C 14 ) heteroaryl is optionally substituted with one or more R 8 replace;

[0253] Each R 5 are independently hydrogen, (C1-C3)alkyl or (C1-C3)hydroxyalkyl, or two R 5 The atoms to which they are connected are joined together to form (C3-C 12) heterocyclic group, wherein two R 5 The formed (C3-C 12 )heterocyclyl is optionally substituted by one or more substituents independently selected from (C1-C3)alkyl, hydroxy or (C1-C3)alkoxy;

[0254] Each R 6 are independently halogen, hydroxy, (C1-C3) hydroxyalkyl, (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) alkoxy, -Q-phenyl, -Q-phenyl-SO2F, -N(H)C(O)-phenyl, -N(H)C(O)-phenyl-SO2F, (C1-C3) alkyl-substituted pyrazole, (C6-C 14 )aryl (C1-C3) alkyl, tert-butyldimethylsilyloxy-CH2-, -N(R 5 )2, (C1-C3) alkoxy (C1-C3) alkyl, (C1-C3) alkyl-C (O) -, oxo, (C1-C3) haloalkyl-C (O) -, -SO2F, (C1-C3) alkoxy (C1-C3) alkoxy, -(C1-C3) alkyl-OC (O) N (R 5 )2 or -(C1-C3)alkyl-OC(O)N(OR 5 )R 5 ;

[0255] Q is a bond or O;

[0256] Each R 7 are independently halogen, hydroxy, -C(O)H, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)hydroxyalkyl, or -N(R 5 )2;

[0257] Each R 8 are independently halogen, cyano, hydroxy, (C1-C4) alkyl, -S-(C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C2-C4) hydroxyalkynyl, (C1-C3) cyanoalkyl, triazolyl, (C1-C3) haloalkyl, -O-(C1-C3) haloalkyl, cyclopropyl, N(R 5 )2, (C1-C4)hydroxyalkyl, -S-(C1-C3)haloalkyl or (C1-C3)alkoxy; and

[0258] R 9 It is hydrogen or oxo.

[0259] Alternative values ​​for the variables are as described in the first, second or third embodiment, or any aspect thereof.

[0260] In some embodiments, the KRAS G12D binding portion is

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276] In some embodiments, the KRAS G12D binding portion has the following structural formula:

[0277]

[0278] in:

[0279] Y is selected from a bond, O, NR 55 , S, S=O or S(=O)2;

[0280] R 1 and R 2Together with the nitrogen atom to which they are all attached, they form a 5-20 membered spiro heterocyclic ring, a 5-20 membered fused heterocyclic ring, a 5-20 membered bridged heterocyclic ring, a 4 membered monocyclic heterocyclic ring, a 7 membered monocyclic heterocyclic ring or an 8-20 membered monocyclic heterocyclic ring, wherein the 5-20 membered spiro heterocyclic ring, the 5-20 membered fused heterocyclic ring, the 5-20 membered bridged heterocyclic ring, the 4 membered monocyclic heterocyclic ring, the 7 membered monocyclic heterocyclic ring or the 8-20 membered monocyclic heterocyclic ring optionally further contains a radical selected from -O-, -S-, -S(=O)-, -S(=O)2- R8 is a ring member of -C(=O)-, -NH-, -CH2-, -CHF-, -CF2-, -C(=O)NH-, -NHC(=O)-, -S(=O)NH-, -NHS(=O)-, -S(=O)2NH- or -NHS(=O)2-, and the 5-20 membered spiro heterocyclic ring, 5-20 membered fused heterocyclic ring, 5-20 membered bridged heterocyclic ring, 4 membered monocyclic heterocyclic ring, 7 membered monocyclic heterocyclic ring or 8-15 membered monocyclic heterocyclic ring is independently optionally substituted with one or more R8;

[0281] R8 is independently selected at each occurrence from halogen-C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Halogenated alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, oxo, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 Alkyl), -S(halogenated C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -C(=O)OH, -C(=O)(OC 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -OC(=O)O(C 1-6 alkyl), -NHC(=O)(OC 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(OC 1-6alkyl), -OC(=O)NH(C 1-6 alkyl), -OC(=O)N(C 1-6 alkyl)2、-NHC(=O)NH2、-NHC(=O)NH(C 1-6 alkyl), -NHC(=O)N(C 1-6 Alkyl)2, -N(C 1-6 alkyl) C(=O)NH2, -N(C 1-6 alkyl)C(=O)NH(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)N(C 1-6 alkyl)2, -S(=O)(OC 1-6 alkyl), -OS(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 Alkyl)2, -NHS(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)(C 1-6 alkyl), -S(=O)2(OC 1-6 alkyl), -OS(=O)2(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C 1-6 alkyl)2, -NHS(=O)2(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)2(C 1-6 alkyl), -OS(=O)2O(C 1-6 alkyl), -NHS(=O)2O(C 1-6 Alkyl), -N(C 1-6 Alkyl)S(=O)2O(C 1-6 alkyl), -OS(=O)2NH2, -OS(=O)2NH(C 1-6 alkyl), -OS(=O)2N(C 1-6 alkyl)2、-NHS(=O)2NH2、-NHS(=O)2NH(C 1-6 alkyl), -NHS(=O)2N(C 1-6 Alkyl)2, -N(C 1-6 alkyl)S(=O)2NH2, -N(C 1-6 alkyl)S(=O)2NH(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)2N(C 1-6Alkyl)2, -PH(C 1-6 alkyl), -P(C 1-6 alkyl)2, -P(=O)H(C 1-6 alkyl), -P(=O)(C 1-6 alkyl) 2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, wherein the -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Halogenated alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl are independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from the group consisting of: -F, -Cl, -Br, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Halogenated alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, oxo, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 Alkyl), -S(halogenated C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -C(=O)OH, -C(=O)(OC 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -OC(=O)O(C 1-6 alkyl), -NHC(=O)(OC 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(OC 1-6 alkyl), -OC(=O)NH(C 1-6 alkyl), -OC(=O)N(C 1-6 alkyl)2、-NHC(=O)NH2、-NHC(=O)NH(C 1-6alkyl), -NHC(=O)N(C 1-6 Alkyl)2, -N(C 1-6 alkyl) C(=O)NH2, -N(C 1-6 alkyl)C(=O)NH(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)N(C 1-6 alkyl)2, -S(=O)(OC 1-6 alkyl), -OS(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 Alkyl)2, -NHS(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)(C 1-6 alkyl), -S(=O)2(OC 1-6 alkyl), -OS(=O)2(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C 1-6 alkyl)2, -NHS(=O)2(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)2(C 1-6 alkyl), -OS(=O)2O(C 1-6 alkyl), -NHS(=O)2O(C 1-6 Alkyl), -N(C 1-6 Alkyl)S(=O)2O(C 1-6 alkyl), -OS(=O)2NH2, -OS(=O)2NH(C 1-6 alkyl), -OS(=O)2N(C 1-6 alkyl)2、-NHS(=O)2NH2、-NHS(=O)2NH(C 1-6 alkyl), -NHS(=O)2N(C 1-6 Alkyl)2, -N(C 1-6 alkyl)S(=O)2NH2, -N(C 1-6 alkyl)S(=O)2NH(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)2N(C 1-6 Alkyl)2, -PH(C 1-6 alkyl), -P(C 1-6 alkyl)2, -P(=O)H(C 1-6 alkyl), -P(=O)(C 1-6alkyl) 2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;

[0282] R 3 is selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl or 10-membered heteroaryl; each of the above is independently optionally replaced by one or more R 31 replace;

[0283] R 31 is independently selected at each occurrence from halogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Halogenated alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, oxo, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 Alkyl), -S(halogenated C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -C(=O)OH, -C(=O)(OC 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -OC(=O)O(C 1-6 alkyl), -NHC(=O)(OC 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(OC 1-6 alkyl), -OC(=O)NH(C 1-6 alkyl), -OC(=O)N(C 1-6 alkyl)2、-NHC(=O)NH2、-NHC(=O)NH(C 1-6 alkyl), -NHC(=O)N(C 1-6 Alkyl)2, -N(C 1-6 alkyl) C(=O)NH2, -N(C 1-6 alkyl)C(=O)NH(C 1-6Alkyl), -N(C 1-6 alkyl)C(=O)N(C 1-6 alkyl)2, -S(=O)(OC 1-6 alkyl), -OS(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 Alkyl)2, -NHS(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)(C 1-6 alkyl), -S(=O)2(OC 1-6 alkyl), -OS(=O)2(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C 1-6 alkyl)2, -NHS(=O)2(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)2(C 1-6 alkyl), -OS(=O)2O(C 1-6 alkyl), -NHS(=O)2O(C 1-6 Alkyl), -N(C 1-6 Alkyl)S(=O)2O(C 1-6 alkyl), -OS(=O)2NH2, -OS(=O)2NH(C 1-6 alkyl), -OS(=O)2N(C 1-6 alkyl)2、-NHS(=O)2NH2、-NHS(=O)2NH(C 1-6 alkyl), -NHS(=O)2N(C 1-6 Alkyl)2, -N(C 1-6 alkyl)S(=O)2NH2, -N(C 1-6 alkyl)S(=O)2NH(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)2N(C 1-6 Alkyl)2, -PH(C 1-6 alkyl), -P(C 1-6 alkyl)2, -P(=O)H(C 1-6 alkyl), -P(=O)(C 1-6 alkyl) 2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, wherein each of these groups is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from the group consisting of halogen, -C 1-6 Alkyl, -C1-6 Haloalkyl, -C 1-6 Halogenated alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, oxo, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 Alkyl), -S(halogenated C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -C(=O)OH, -C(=O)(OC 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -OC(=O)O(C 1-6 alkyl), -NHC(=O)(OC 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(OC 1-6 alkyl), -OC(=O)NH(C 1-6 alkyl), -OC(=O)N(C 1-6 alkyl)2、-NHC(=O)NH2、-NHC(=O)NH(C 1-6 alkyl), -NHC(=O)N(C 1-6 Alkyl)2, -N(C 1-6 alkyl) C(=O)NH2, -N(C 1-6 alkyl)C(=O)NH(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)N(C 1-6 alkyl)2, -S(=O)(OC 1-6 alkyl), -OS(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 Alkyl)2, -NHS(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)(C1-6 alkyl), -S(=O)2(OC 1-6 alkyl), -OS(=O)2(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C 1-6 alkyl)2, -NHS(=O)2(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)2(C 1-6 alkyl), -OS(=O)2O(C 1-6 alkyl), -NHS(=O)2O(C 1-6 Alkyl), -N(C 1-6 Alkyl)S(=O)2O(C 1-6 alkyl), -OS(=O)2NH2, -OS(=O)2NH(C 1-6 alkyl), -OS(=O)2N(C 1-6 alkyl)2、-NHS(=O)2NH2、-NHS(=O)2NH(C 1-6 alkyl), -NHS(=O)2N(C 1-6 Alkyl)2, -N(C 1-6 alkyl)S(=O)2NH2, -N(C 1-6 alkyl)S(=O)2NH(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)2N(C 1-6 Alkyl)2, -PH(C 1-6 alkyl), -P(C 1-6 alkyl)2, -P(=O)H(C 1-6 alkyl), -P(=O)(C 1-6 alkyl) 2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;

[0284] R 41 、R 42 or R 43 is independently selected at each occurrence from hydrogen, halogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Halogenated alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, oxo, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 Alkyl), -S(halogenated C1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -C(=O)OH, -C(=O)(OC 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -OC(=O)O(C 1-6 alkyl), -NHC(=O)(OC 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(OC 1-6 alkyl), -OC(=O)NH(C 1-6 alkyl), -OC(=O)N(C 1-6 alkyl)2、-NHC(=O)NH2、-NHC(=O)NH(C 1-6 alkyl), -NHC(=O)N(C 1-6 Alkyl)2, -N(C 1-6 alkyl) C(=O)NH2, -N(C 1-6 alkyl)C(=O)NH(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)N(C 1-6 alkyl)2, -S(=O)(OC 1-6 alkyl), -OS(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 Alkyl)2, -NHS(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)(C 1-6 alkyl), -S(=O)2(OC 1-6 alkyl), -OS(=O)2(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C 1-6 alkyl)2, -NHS(=O)2(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)2(C1-6 alkyl), OS(=O)2O(C 1-6 alkyl), -NHS(=O)2O(C 1-6 Alkyl), -N(C 1-6 Alkyl)S(=O)2O(C 1-6 alkyl), -OS(=O)2NH2, -OS(=O)2NH(C 1-6 alkyl), -OS(=O)2N(C 1-6 alkyl)2、-NHS(=O)2NH2、-NHS(=O)2NH(C 1-6 alkyl), -NHS(=O)2N(C 1-6 Alkyl)2, -N(C 1-6 alkyl)S(=O)2NH2, -N(C 1-6 alkyl)S(=O)2NH(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)2N(C 1-6 Alkyl)2, -PH(C 1-6 alkyl), -P(C 1-6 alkyl)2, -P(=O)H(C 1-6 alkyl), -P(=O)(C 1-6 alkyl) 2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, wherein each of these groups is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from the group consisting of halogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Halogenated alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, oxo, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 Alkyl), -S(halogenated C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -C(=O)OH, -C(=O)(OC 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -NHC(=O)(C1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -OC(=O)O(C 1-6 alkyl), -NHC(=O)(OC 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(OC 1-6 alkyl), -OC(=O)NH(C 1-6 alkyl), -OC(=O)N(C 1-6 alkyl)2、-NHC(=O)NH2、-NHC(=O)NH(C 1-6 alkyl), -NHC(=O)N(C 1-6 Alkyl)2, -N(C 1-6 alkyl) C(=O)NH2, -N(C 1-6 alkyl)C(=O)NH(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)N(C 1-6 alkyl)2, -S(=O)(OC 1-6 alkyl), -OS(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 Alkyl)2, -NHS(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)(C 1-6 alkyl), -S(=O)2(OC 1-6 alkyl), -OS(=O)2(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C 1-6 alkyl)2, -NHS(=O)2(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)2(C 1-6 alkyl), -OS(=O)2O(C 1-6 alkyl), -NHS(=O)2O(C 1-6 Alkyl), -N(C 1-6 Alkyl)S(=O)2O(C 1-6 alkyl), -OS(=O)2NH2, -OS(=O)2NH(C 1-6 alkyl), -OS(=O)2N(C 1-6 alkyl)2、-NHS(=O)2NH2、-NHS(=O)2NH(C 1-6alkyl), -NHS(=O)2N(C 1-6 Alkyl)2, -N(C 1-6 alkyl)S(=O)2NH2, -N(C 1-6 alkyl)S(=O)2NH(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)2N(C 1-6 Alkyl)2, -PH(C 1-6 alkyl), -P(C 1-6 alkyl)2, -P(=O)H(C 1-6 alkyl), -P(=O)(C 1-6 alkyl) 2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;

[0285] R 51 、R 52 、R 53 、R 54 or R 55 is independently selected at each occurrence from hydrogen, halogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Halogenated alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, oxo, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 Alkyl), -S(halogenated C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -C(=O)OH, -C(=O)(OC 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -OC(=O)O(C 1-6 alkyl), -NHC(=O)(OC 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(OC 1-6alkyl), -OC(=O)NH(C 1-6 alkyl), -OC(=O)N(C 1-6 alkyl)2、-NHC(=O)NH2、-NHC(=O)NH(C 1-6 alkyl), -NHC(=O)N(C 1-6 Alkyl)2, -N(C 1-6 alkyl) C(=O)NH2, -N(C 1-6 alkyl)C(=O)NH(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)N(C 1-6 alkyl)2, -S(=O)(OC 1-6 alkyl), -OS(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 Alkyl)2, -NHS(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)(C 1-6 alkyl), -S(=O)2(OC 1-6 alkyl), -OS(=O)2(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C 1-6 alkyl)2, -NHS(=O)2(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)2(C 1-6 alkyl), -OS(=O)2O(C 1-6 alkyl), -NHS(=O)2O(C 1-6 Alkyl), -N(C 1-6 Alkyl)S(=O)2O(C 1-6 alkyl), -OS(=O)2NH2, -OS(=O)2NH(C 1-6 alkyl), -OS(=O)2N(C 1-6 alkyl)2、-NHS(=O)2NH2、-NHS(=O)2NH(C 1-6 alkyl), -NHS(=O)2N(C 1-6 Alkyl)2, -N(C 1-6 alkyl)S(=O)2NH2, -N(C 1-6 alkyl)S(=O)2NH(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)2N(C 1-6Alkyl)2, -PH(C 1-6 alkyl), -P(C 1-6 alkyl)2, -P(=O)H(C 1-6 alkyl), -P(=O)(C 1-6 alkyl) 2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, wherein each of these groups is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from the group consisting of halogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Halogenated alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, oxo, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 Alkyl), -S(halogenated C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -C(=O)OH, -C(=O)(OC 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -OC(=O)O(C 1-6 alkyl), -NHC(=O)(OC 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(OC 1-6 alkyl), -OC(=O)NH(C 1-6 alkyl), -OC(=O)N(C 1-6 alkyl)2、-NHC(=O)NH2、-NHC(=O)NH(C 1-6 alkyl), -NHC(=O)N(C 1-6 Alkyl)2, -N(C 1-6 alkyl) C(=O)NH2, -N(C 1-6 alkyl)C(=O)NH(C 1-6 Alkyl), -N(C 1-6alkyl)C(=O)N(C 1-6 alkyl)2, -S(=O)(OC 1-6 alkyl), -OS(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 Alkyl)2, -NHS(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)(C 1-6 alkyl), -S(=O)2(OC 1-6 alkyl), -OS(=O)2(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C 1-6 alkyl)2, -NHS(=O)2(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)2(C 1-6 alkyl), -OS(=O)2O(C 1-6 alkyl), -NHS(=O)2O(C 1-6 Alkyl), -N(C 1-6 Alkyl)S(=O)2O(C 1-6 alkyl), -OS(=O)2NH2, -OS(=O)2NH(C 1-6 alkyl), -OS(=O)2N(C 1-6 alkyl)2、-NHS(=O)2NH2、-NHS(=O)2NH(C 1-6 alkyl), -NHS(=O)2N(C 1-6 Alkyl)2, -N(C 1-6 alkyl)S(=O)2NH2, -N(C 1-6 alkyl)S(=O)2NH(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)2N(C 1-6 Alkyl)2, -PH(C 1-6 alkyl), -P(C 1-6 alkyl)2, -P(=O)H(C 1-6 alkyl), -P(=O)(C 1-6 alkyl) 2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;

[0286] R 6 is independently selected at each occurrence from halogen, -C 1-6 Alkyl, -C 1-6Haloalkyl, -C 1-6 Halogenated alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, oxo, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 Alkyl), -S(halogenated C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -C(=O)OH, -C(=O)(OC 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -OC(=O)O(C 1-6 alkyl), -NHC(=O)(OC 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(OC 1-6 alkyl), -OC(=O)NH(C 1-6 alkyl), -OC(=O)N(C 1-6 alkyl)2、-NHC(=O)NH2、-NHC(=O)NH(C 1-6 alkyl), -NHC(=O)N(C 1-6 Alkyl)2, -N(C 1-6 alkyl) C(=O)NH2, -N(C 1-6 alkyl)C(=O)NH(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)N(C 1-6 alkyl)2, -S(=O)(OC 1-6 alkyl), -OS(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 Alkyl)2, -NHS(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)(C 1-6alkyl), -S(=O)2(OC 1-6 alkyl), -OS(=O)2(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C 1-6 alkyl)2, -NHS(=O)2(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)2(C 1-6 alkyl), -OS(=O)2O(C 1-6 alkyl), -NHS(=O)2O(C 1-6 Alkyl), -N(C 1-6 Alkyl)S(=O)2O(C 1-6 alkyl), -OS(=O)2NH2, -OS(=O)2NH(C 1-6 alkyl), -OS(=O)2N(C 1-6 alkyl)2、-NHS(=O)2NH2、-NHS(=O)2NH(C 1-6 alkyl), -NHS(=O)2N(C 1-6 Alkyl)2, -N(C 1-6 alkyl)S(=O)2NH2, -N(C 1-6 alkyl)S(=O)2NH(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)2N(C 1-6 Alkyl)2, -PH(C 1-6 alkyl), -P(C 1-6 alkyl)2, -P(=O)H(C 1-6 alkyl), -P(=O)(C 1-6 alkyl) 2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, wherein each of these groups is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from the group consisting of halogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Halogenated alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, oxo, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 Alkyl), -S(halogenated C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C1-6 alkyl), -C(=O)(C 1-6 alkyl), -C(=O)OH, -C(=O)(OC 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -OC(=O)O(C 1-6 alkyl), -NHC(=O)(OC 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(OC 1-6 alkyl), -OC(=O)NH(C 1-6 alkyl), -OC(=O)N(C 1-6 alkyl)2、-NHC(=O)NH2、-NHC(=O)NH(C 1-6 alkyl), -NHC(=O)N(C 1-6 Alkyl)2, -N(C 1-6 alkyl) C(=O)NH2, -N(C 1-6 alkyl)C(=O)NH(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)N(C 1-6 alkyl)2, -S(=O)(OC 1-6 alkyl), -OS(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 Alkyl)2, -NHS(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)(C 1-6 alkyl), -S(=O)2(OC 1-6 alkyl), -OS(=O)2(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C 1-6 alkyl)2, -NHS(=O)2(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)2(C 1-6 alkyl), -OS(=O)2O(C 1-6alkyl), -NHS(=O)2O(C 1-6 Alkyl), -N(C 1-6 Alkyl)S(=O)2O(C 1-6 alkyl), -OS(=O)2NH2, -OS(=O)2NH(C 1-6 alkyl), -OS(=O)2N(C 1-6 alkyl)2、-NHS(=O)2NH2、-NHS(=O)2NH(C 1-6 alkyl), -NHS(=O)2N(C 1-6 Alkyl)2, -N(C 1-6 alkyl)S(=O)2NH2, -N(C 1-6 alkyl)S(=O)2NH(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)2N(C 1-6 Alkyl)2, -PH(C 1-6 alkyl), -P(C 1-6 alkyl)2, -P(=O)H(C 1-6 alkyl), -P(=O)(C 1-6 alkyl) 2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;

[0287] R 7 is independently selected at each occurrence from halogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Halogenated alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, oxo, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 Alkyl), -S(halogenated C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -C(=O)OH, -C(=O)(OC 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -NHC(=O)(C 1-6 Alkyl), -N(C 1-6alkyl)C(=O)(C 1-6 alkyl), -OC(=O)O(C 1-6 alkyl), -NHC(=O)(OC 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(OC 1-6 alkyl), -OC(=O)NH(C 1-6 alkyl), -OC(=O)N(C 1-6 alkyl)2、-NHC(=O)NH2、-NHC(=O)NH(C 1-6 alkyl), -NHC(=O)N(C 1-6 Alkyl)2, -N(C 1-6 alkyl) C(=O)NH2, -N(C 1-6 alkyl)C(=O)NH(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)N(C 1-6 alkyl)2, -S(=O)(OC 1-6 alkyl), -OS(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 Alkyl)2, -NHS(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)(C 1-6 alkyl), -S(=O)2(OC 1-6 alkyl), -OS(=O)2(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C 1-6 alkyl)2, -NHS(=O)2(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)2(C 1-6 alkyl), -OS(=O)2O(C 1-6 alkyl), -NHS(=O)2O(C 1-6 Alkyl), -N(C 1-6 Alkyl)S(=O)2O(C 1-6 alkyl), -OS(=O)2NH2, -OS(=O)2NH(C 1-6 alkyl), -OS(=O)2N(C 1-6 alkyl)2、-NHS(=O)2NH2、-NHS(=O)2NH(C 1-6 alkyl), -NHS(=O)2N(C 1-6Alkyl)2, -N(C 1-6 alkyl)S(=O)2NH2, -N(C 1-6 alkyl)S(=O)2NH(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)2N(C 1-6 Alkyl)2, -PH(C 1-6 alkyl), -P(C 1-6 alkyl)2, -P(=O)H(C 1-6 alkyl), -P(=O)(C 1-6 alkyl) 2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, wherein each of these groups is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from the group consisting of halogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Halogenated alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, oxo, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 Alkyl), -S(halogenated C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -C(=O)OH, -C(=O)(OC 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -OC(=O)O(C 1-6 alkyl), -NHC(=O)(OC 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(OC 1-6 alkyl), -OC(=O)NH(C 1-6 alkyl), -OC(=O)N(C 1-6 alkyl)2、-NHC(=O)NH2、-NHC(=O)NH(C 1-6alkyl), -NHC(=O)N(C 1-6 Alkyl)2, -N(C 1-6 alkyl) C(=O)NH2, -N(C 1-6 alkyl)C(=O)NH(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)N(C 1-6 alkyl)2, -S(=O)(OC 1-6 alkyl), -OS(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 Alkyl)2, -NHS(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)(C 1-6 alkyl), -S(=O)2(OC 1-6 alkyl), -OS(=O)2(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C 1-6 alkyl)2, -NHS(=O)2(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)2(C 1-6 alkyl), -OS(=O)2O(C 1-6 alkyl), -NHS(=O)2O(C 1-6 Alkyl), -N(C 1-6 Alkyl)S(=O)2O(C 1-6 alkyl), -OS(=O)2NH2, -OS(=O)2NH(C 1-6 alkyl), -OS(=O)2N(C 1-6 alkyl)2、-NHS(=O)2NH2、-NHS(=O)2NH(C 1-6 alkyl), -NHS(=O)2N(C 1-6 Alkyl)2, -N(C 1-6 alkyl)S(=O)2NH2, -N(C 1-6 alkyl)S(=O)2NH(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)2N(C 1-6 Alkyl)2, -PH(C 1-6 alkyl), -P(C 1-6 alkyl)2, -P(=O)H(C 1-6 alkyl), -P(=O)(C 1-6alkyl) 2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;

[0288] m, n, p and q are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and the heterocyclyl, heterocycle or heteroaryl contains, in each occurrence, 1, 2, 3, 4 or 5 ring members selected from N, O, S, S(=O) or S(=O)2.

[0289] In some embodiments, the KRAS G12D binding moiety is:

[0290]

[0291]

[0292]

[0293]

[0294]

[0295] In some embodiments, the KRAS G12D binding portion has the following structural formula:

[0296]

[0297] in:

[0298] n1 is selected from 0, 1, 2, 3, 4, 5 or 6;

[0299] n2 is selected from 0, 1, 2, 3, 4, 5 or 6;

[0300] n3 is selected from 0, 1, 2, 3, 4, 5 or 6;

[0301] n4 is selected from 0, 1, 2, 3, 4, 5 or 6;

[0302] n5 is selected from 0, 1, 2, 3, 4, 5 or 6;

[0303] Every R S1 is independently selected at each occurrence from halogen, -C 1-10 Alkyl, halogenated C 1-10 Alkyl, halogenated C 1-10 Alkoxy, -C 2-10 Alkenyl, halogenated C 2-10 Alkenyl, -C 2-10 Alkynyl, halo C 2-10 Alkynyl, -CN, oxo, -N(R 61 )2、-OR 61 、-SR 61 、-S(=O)R62 、-S(=O)2R 62 、-C(=O)R 62 、-C(=O)OR 61 、-OC(=O)R 62 、-C(=O)N(R 61 )2、-NR 61 C(=O)R 62 、-OC(=O)OR 61 、-NR 61 C(=O)OR 61 、-OC(=O)N(R 61 )2、-NR 61 C(=O)N(R 61 )2、-S(=O)OR 61 、-OS(=O)R 62 、-S(=O)N(R 61 )2、-NR 61 S(=O)R 62 、-S(=O)2OR 61 、-OS(=O)2R 62 、-S(=O)2N(R 61 )2、-NR 61 S(=O)2R 62 、-OS(=O)2OR 61 、-NR 61 S(=O)2OR 61 、-OS(=O)2N(R 61 )2、-NR 61 S(=O)2N(R 61 )2、-P(R 61 )2、-P(=O)(R 62 )2, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein, the -C 1-10 Alkyl, halogenated C 1-10 Alkyl, halogenated C 1-10 Alkoxy, -C 2-10 Alkenyl, halogenated C 2-10 Alkenyl, -C 2-10 Alkynyl, halo C 2-10 Alkynyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl are optionally substituted independently with one or more substituents selected from the group consisting of halogen, -C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -C2-6 Alkenyl, halogenated C 2-6 Alkenyl, -C 2-6 Alkynyl, halo C 2-6 Alkynyl, -CN, -N(R 63 )2、-OR 63 、-SR 63 、-S(=O)R 64 、-S(=O)2R 64 、-C(=O)R 64 、-C(=O)OR 63 、-OC(=O)R 64 、-C(=O)N(R 63 )2、-NR 63 C(=O)R 64 、-OC(=O)OR 63 、-NR 63 C(=O)OR 63 、-OC(=O)N(R 63 )2、-NR 63 C(=O)N(R 63 )2、-S(=O)OR 63 、-OS(=O)R 64 、-S(=O)N(R 63 )2、-NR 63 S(=O)R 64 、-S(=O)2OR 63 、-OS(=O)2R 64 、-S(=O)2N(R 63 )2、-NR 63 S(=O)2R 64 、-OS(=O)2OR 63 、-NR 63 S(=O)2OR 63 、-OS(=O)2N(R 63 )2、-NR 63 S(=O)2N(R 63 )2、-P(R 63 )2、-P(=O)(R 64 )2, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;

[0304] Optionally, two R S1 Together with the carbon atoms to which they are attached, they form a 3-10 membered carbocyclic ring or a 3-10 membered heterocyclic ring; wherein the 3-10 membered carbocyclic ring or the 3-10 membered heterocyclic ring is optionally replaced by one or more R 6b replace;

[0305] Optionally, two adjacent R S1 Together with the carbon atoms to which they are attached, they form a 3-10 membered carbocyclic ring, a 3-10 membered heterocyclic ring, a 6-10 membered aryl ring or a 5-10 membered heteroaryl ring, wherein each ring is independently optionally substituted with one or more R 6c replace;

[0306] Each q1 is independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0307] L1 is a bond, O, S, S(=O), S(=O)2 or NR 6a ;

[0308] R1 is selected from

[0309] L2 is selected from a bond or optionally replaced by one or more R 6d Substituted C 1-10 alkylene;

[0310] L3 is selected from a bond or optionally substituted by one or more R 6e Substituted C 1-10 alkylene;

[0311] L4 is selected from a bond or optionally replaced by one or more R 6f Substituted C 1-10 alkylene;

[0312] Ring A or Ring B is independently selected from a 3-10 membered heterocyclic ring, which optionally further contains 1, 2 or 3 heteroatoms selected from N, O or S;

[0313] Ring C is selected from a 3-10 membered carbocyclic ring or a 3-10 membered heterocyclic ring; wherein -L3- and -L4X1 moieties are attached to the same atom or different atoms of Ring C;

[0314] X1 is selected from -N(R 65 )2、-OR 65 、-SR 65 , 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the 3-10 membered heterocyclyl or 5-10 membered heteroaryl is optionally independently replaced by one or more R S3 replace;

[0315] (R S2 and R S3 ) is independently selected at each occurrence from halogen, -C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -C 2-6 Alkenyl, halogenated C 2-6 Alkenyl, -C2-6 Alkynyl, halo C 2-6 Alkynyl, -CN, oxo, -N(R 66 )2、-OR 66 、-SR 66 、-S(=O)R 67 、-S(=O)2R 67 、-C(=O)R 67 、-C(=O)OR 66 、-OC(=O)R 67 、-C(=O)N(R 66 )2、-NR 66 C(=O)R 67 、-OC(=O)OR 66 、-NR 66 C(=O)OR 66 、-NR 66 C(=S)OR 66 、-OC(=O)N(R 66 )2、-NR 66 C(=O)N(R 66 )2、-S(=O)OR 66 、-OS(=O)R 67 、-S(=O)N(R 66 )2、-NR 66 S(=O)R 67 、-S(=O)2OR 66 、-OS(=O)2R 67 、-S(=O)2N(R 66 )2、-NR 66 S(=O)2R 67 、-OS(=O)2OR 66 、-NR 66 S(=O)2OR 66 、-OS(=O)2N(R 66 )2、-NR 66 S(=O)2N(R 66 )2、-P(R 66 )2、-P(=O)(R 67 )2, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered cycloalkynyl, 4-8 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl; wherein the -C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -C 2-6 Alkenyl, halogenated C 2-6 Alkenyl, -C 2-6 Alkynyl, halo C 2-6Alkynyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered cycloalkynyl, 3-8 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl are optionally substituted independently with one or more substituents selected from the group consisting of halogen, -C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -C 2-6 Alkenyl, halogenated C 2-6 Alkenyl, -C 2-6 Alkynyl, halo C 2-6 Alkynyl, -CN, -N(R 68 )2、-OR 68 、-SR 68 、-S(=O)R 69 、-S(=O)2R 69 、-C(=O)R 69 、-C(=O)OR 68 、-OC(=O)R 69 、-C(=O)N(R 68 )2、-NR 68 C(=O)R 69 、-OC(=O)OR 68 、-NR 68 C(=O)OR 68 、-NR 68 C(=S)OR 68 、-OC(=O)N(R 68 )2、-NR 68 C(=O)N(R 68 )2、-S(=O)OR 68 、-OS(=O)R 69 、-S(=O)N(R 68 )2、-NR 68 S(=O)R 69 、-S(=O)2OR 68 、-OS(=O)2R 69 、-S(=O)2N(R 68 )2、-NR 68 S(=O)2R 69 、-OS(=O)2OR 68 、-NR 68 S(=O)2OR 68 、-OS(=O)2N(R 68 )2、-NR 68 S(=O)2N(R 68 )2、-P(R 68 )2、-P(=O)(R 69)2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;

[0316] Optionally, two R S2 Together with the carbon atoms to which they are attached or two R S3 Together with the carbon atoms to which they are attached, they form a 3-10 membered carbocyclic ring or a 3-10 membered heterocyclic ring; wherein the 3-10 membered carbocyclic ring or the 3-10 membered heterocyclic ring is optionally replaced by one or more R 6h replace;

[0317] Optionally, two adjacent R S2 The carbon atoms to which they are attached or two adjacent R S3 Together with the carbon atoms to which they are attached, they form a 3-10 membered carbocyclic ring, a 3-10 membered heterocyclic ring, a 6-10 membered aryl ring or a 5-10 membered heteroaryl ring, wherein each ring is independently optionally substituted with one or more R 6i replace;

[0318] Optionally, two non-adjacent R S2 or two non-adjacent R S3 are linked together to form a bridge containing 0, 1, 2, 3, 4, 5 or 6 carbon atoms, wherein each carbon atom in the bridge is optionally replaced by 1 or 2 heteroatoms selected from N, O, S, S=O or S(=O)2; the hydrogen on each carbon atom or N atom is optionally independently replaced by R 6j replace;

[0319] q2 is selected from 0, 1, 2, 3, 4, 5 or 6;

[0320] Every R S4 is independently selected at each occurrence from halogen, -C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -C 2-6 Alkenyl, halogenated C 2-6 Alkenyl, -C 2-6 Alkynyl, halo C 2-6 Alkynyl, -CN, oxo, -N(R 71 )2、-OR 71 、-SR 71 、-S(=O)R 72 、-S(=O)2R 71 、-C(=O)R 72 、-C(=O)OR 71 、-OC(=O)R 72 、-C(=O)N(R 71 )2、-NR71 C(=O)R 72 、-OC(=O)OR 71 、-NR 71 C(=O)OR 71 、-OC(=O)N(R 71 )2、-NR 71 C(=O)N(R 71 )2、-S(=O)OR 71 、-OS(=O)R 72 、-S(=O)N(R 71 )2、-NR 71 S(=O)R 72 、-S(=O)2OR 71 、-OS(=O)2R 72 、-S(=O)2N(R 71 )2、-NR 71 S(=O)2R 72 、-OS(=O)2OR 71 、-NR 71 S(=O)2OR 72 、-OS(=O)2N(R 71 )2、-NR 71 S(=O)2N(R 71 )2、-P(R 71 )2、-P(=O)(R 72 )2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein the -C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -C 2-6 Alkenyl, halogenated C 2-6 Alkenyl, -C 2-6 Alkynyl, halo C 2-6 Alkynyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl are optionally substituted independently with one or more substituents selected from the group consisting of halogen, -C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -C 2-6 Alkenyl, halogenated C 2-6 Alkenyl, -C 2-6 Alkynyl, halo C 2-6 Alkynyl, -CN, -N(R 73 )2、-OR 73 、-SR 73 、-S(=O)R74 、-S(=O)2R 73 、-C(=O)R 74 、-C(=O)OR 73 、-OC(=O)R 74 、-C(=O)N(R 73 )2、-NR 73 C(=O)R 74 、-OC(=O)OR 73 、-NR 73 C(=O)OR 73 、-OC(=O)N(R 73 )2、-NR 73 C(=O)N(R 73 )2、-S(=O)OR 73 、-OS(=O)R 74 、-S(=O)N(R 73 )2、-NR 73 S(=O)R 74 、-S(=O)2OR 73 、-OS(=O)2R 74 、-S(=O)2N(R 73 )2、-NR 73 S(=O)2R 74 、-OS(=O)2OR 73 、-NR 73 S(=O)2OR 74 、-OS(=O)2N(R 73 )2、-NR 73 S(=O)2N(R 73 )2、-P(R 73 )2、-P(=O)(R 74 )2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;

[0321] q4 is selected from 0, 1, 2, 3, 4, 5 or 6;

[0322] R3 is selected from 6-10 membered aryl or 5-10 membered heteroaryl, wherein said 6-10 membered aryl or 5-10 membered heteroaryl is optionally independently replaced by one or more R 31 replace;

[0323] R 31 is independently selected at each occurrence from halogen, -C 1-10 Alkyl, halogenated C 1-10 Alkyl, halogenated C 1-10 Alkoxy, -C 2-10 Alkenyl, halogenated C2-10 Alkenyl, -C 2-10 Alkynyl, halo C 2-10 Alkynyl, -CN, oxo, -N(R 75 )2、-OR 75 、-SR 75 、-S(=O)R 76 、-S(=O)2R 76 、-C(=O)R 76 、-C(=O)OR 75 、-OC(=O)R 76 、-C(=O)N(R 75 )2、-NR 75 C(=O)R 76 、-OC(=O)OR 75 、-NR 75 C(=O)OR 75 、-OC(=O)N(R 75 )2、-NR 75 C(=O)N(R 75 )2、-S(=O)OR 75 、-OS(=O)R 76 、-S(=O)N(R 75 )2、-NR 75 S(=O)R 76 、-S(=O)2OR 75 、-OS(=O)2R 76 、-S(=O)2N(R 75 )2、-NR 75 S(=O)2R 76 、-OS(=O)2OR 75 、-NR 75 S(=O)2OR 75 、-OS(=O)2N(R 75 )2、-NR 75 S(=O)2N(R 75 )2、-P(R 75 )2、-P(=O)(R 75 )2, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, wherein the -C 1-10 Alkyl, halogenated C 1-10 Alkyl, halogenated C 1-10 Alkoxy, -C 2-10 Alkenyl, halogenated C 2-10 Alkenyl, -C 2-10 Alkynyl, halo C 2-10Alkynyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl are optionally substituted independently with one or more substituents selected from the group consisting of halogen, -C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -C 2-6 Alkenyl, halogenated C 2-6 Alkenyl, -C 2-6 Alkynyl, halo C 2-6 Alkynyl, -CN, -N(R 77 )2、-OR 77 、-SR 77 、-S(=O)R 78 、-S(=O)2R 78 、-C(=O)R 78 、-C(=O)OR 77 、-OC(=O)R 78 、-C(=O)N(R 77 )2、-NR 77 C(=O)R 78 、-OC(=O)OR 77 、-NR 77 C(=O)OR 77 、-OC(=O)N(R 77 )2、-NR 77 C(=O)N(R 77 )2、-S(=O)OR 77 、-OS(=O)R 78 、-S(=O)N(R 77 )2、-NR 77 S(=O)R 78 、-S(=O)2OR 77 、-OS(=O)2R 78 、-S(=O)2N(R 77 )2、-NR 77 S(=O)2R 78 、-OS(=O)2OR 77 、-NR 77 S(=O)2OR 77 、-OS(=O)2N(R 77 )2、-NR 77 S(=O)2N(R 77 )2、-P(R 77 )2、-P(=O)(R 78 )2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;

[0324] Each of R2, R4 and R5 is independently selected from hydrogen, halogen, -C 1-10 Alkyl, halogenated C 1-10 Alkyl, halogenated C 1-10 Alkoxy, -C 2-10 Alkenyl, halogenated C 2-10 Alkenyl, -C 2-10 Alkynyl, halo C 2-10 Alkynyl, -CN, oxo, -N(R 81 )2、-OR 81 、-SR 81 、-S(=O)R 82 、-S(=O)2R 82 、-C(=O)R 82 、-C(=O)OR 81 、-OC(=O)R 82 、-C(=O)N(R 81 )2、-NR 81 C(=O)R 82 、-OC(=O)OR 81 、-NR 81 C(=O)OR 81 、-OC(=O)N(R 81 )2、-NR 81 C(=O)NR 81 )2、-S(=O)OR 81 、-OS(=O)R 82 、-S(=O)N(R 81 )2、-NR 81 S(=O)R 82 、-S(=O)2OR 81 、-OS(=O)2R 82 、-S(=O)2N(R 81 )2、-NR 81 S(=O)2R 82 、-OS(=O)2OR 81 、-NR 81 S(=O)2OR 81 、-OS(=O)2N(R 81 )2、-NR 81 S(=O)2N(R 81 )2、-P(R 81 )2、-P(=O)(R 82 )2, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein the -C 1-10 Alkyl, halogenated C1-10 Alkyl, halogenated C 1-10 Alkoxy, -C 2-10 Alkenyl, halogenated C 2-10 Alkenyl, -C 2-10 Alkynyl, halo C 2-10 Alkynyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl are optionally substituted independently with one or more substituents selected from the group consisting of halogen, -C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -C 2-6 Alkenyl, halogenated C 2-6 Alkenyl, -C 2-6 Alkynyl, halo C 2-6 Alkynyl, -CN, -N(R 83 )2、-OR 83 、-SR 83 、-S(=O)R 84 、-S(=O)2R 84 、-C(=O)R 84 、-C(=O)OR 83 、-OC(=O)R 83 、-C(=O)N(R 83 )2、-NR 83 C(=O)R 84 、-OC(=O)OR 83 、-NR 83 C(=O)OR 83 、-OC(=O)N(R 83 )2、-NR 83 C(=O)N(R 84 )2、-S(=O)OR 83 、-OS(=O)R 84 、-S(=O)N(R 83 )2、-NR 83 S(=O)R 84 、-S(=O)2OR 83 、-OS(=O)2R 84 、-S(=O)2N(R 83 )2、-NR 83 S(=O)2R 84 、-OS(=O)2OR 83 、-NR 83 S(=O)2OR 83 、-OS(=O)2N(R 83 )2、-NR 83 S(=O)2N(R83 )2、-P(R 83 )2、-P(=O)(R 84 )2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;

[0325] R 6a 、R 61 、R 63 、R 65 、R 66 、R 68 、R 71 、R 73 、R 75 、R 77 、R 81 and R 83 Each of which, at each occurrence, is independently selected from hydrogen, halogen, -C 1-10 Alkyl, halogenated C 1-10 Alkyl, -C 2-10 Alkenyl, -C 2-10 Alkynyl, -S(=O)R a 、-S(=O)2R a 、-C(=O)R a 、-C(=O)OR a 、-C(=O)NR a )2、-S(=O)OR a 、-S(=O)N(R a )2、-S(=O)2OR a 、-S(=O)2N(R a )2、-P(=O)(R a )2, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein the -C 1-10 Alkyl, halogenated C 1-10 Alkyl, -C 2-10 Alkenyl, -C 2-10 Alkynyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl are optionally substituted independently with one or more substituents selected from the group consisting of halogen, -C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, -N(R c )2、-OR c 、-SR c 、-S(=O)Rd 、-S(=O)2R d 、-C(=O)R d 、-C(=O)OR c 、-OC(=O)R d 、-C(=O)N(R c )2、-NR c C(=O)R d 、-OC(=O)OR c 、-NR c C(=O)OR d 、-OC(=O)N(R c )2、-NR c C(=O)N(R c )2、-S(=O)OR c 、-OS(=O)R d 、-S(=O)N(R c )2、-NR c S(=O)R d 、-S(=O)2OR c 、-OS(=O)2R d 、-S(=O)2N(R c )2、-NR c S(=O)2R d 、-OS(=O)2OR c 、-NR c S(=O)2OR c 、-OS(=O)2NR c 、-NR c S(=O)2N(R c )2、-P(R c )2、-P(=O)(R d )2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;

[0326] Optionally, two R 61 , two R 63 , two R 65 , two R 66 , two R 68 , two R 71 , two R 73 , two R 75 , two R 77 , two R 81 and two R 83) are independently taken together with the nitrogen atom to which they are attached to form a 3-20 membered heterocyclic ring or a 5-10 membered heteroaryl ring, wherein the 3-20 membered heterocyclic ring or the 5-10 membered heteroaryl ring is optionally independently replaced by one or more R 6k replace;

[0327] R 62 、R 64 、R 67 、R 69 、R 72 、R 74 、R 76 、R 78 、R 82 and R 84 Each of which, at each occurrence, is independently selected from hydrogen, -C 1-10 Alkyl, halogenated C 1-10 Alkyl, halogenated C 1-10 Alkoxy, -C 2-10 Alkenyl, halogenated C 2-10 Alkenyl, -C 2-10 Alkynyl, halo C 2-10 Alkynyl, -N(R b )2、-OR b 、-SR b , 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein said -C 1-10 Alkyl, halogenated C 1-10 Alkyl, halogenated C 1-10 Alkoxy, -C 2-10 Alkenyl, -C 2-10 Alkynyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl are optionally substituted independently with one or more substituents selected from the group consisting of halogen, -C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, -N(R c )2、-OR c 、-SR c 、-S(=O)R d 、-S(=O)2R d 、-C(=O)R d 、-C(=O)OR c 、-OC(=O)R d 、-C(=O)N(R c )2、-NR cC(=O)R d 、-OC(=O)OR c 、-NR c C(=O)OR d 、-OC(=O)N(R c )2、-NR c C(=O)N(R c )2、-S(=O)OR c 、-OS(=O)R d 、-S(=O)N(R c )2、-NR c S(=O)R d 、-S(=O)2OR c 、-OS(=O)2R d 、-S(=O)2N(R c )2、-NR c S(=O)2R d 、-OS(=O)2OR c 、-NR c S(=O)2OR c 、-OS(=O)2NR c 、-NR c S(=O)2N(R c )2、-P(R c )2、-P(=O)(R d )2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;

[0328] R a 、R b 、R c and R d Each of which, at each occurrence, is independently selected from hydrogen, -C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein the -C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl are optionally independently substituted with one or more R 6l replace;

[0329] Optionally, two R a , two R b and two R c Each of the Rs independently together with the atoms to which they are attached form a 3-6 membered heterocyclic ring, wherein the 3-6 membered heterocyclic ring is independently optionally replaced by one or more Rs. 6m replace;

[0330] R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6h 、R 6i 、R 6j 、R 6k 、R 6l and R 6m Each of the following is independently selected at each occurrence from halogen, -C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, oxo, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -C(=O)OH, -C(=O)(OC 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -OC(=O)O(C 1-6 alkyl), -NHC(=O)(OC 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(OC 1-6 alkyl), -OC(=O)NH(C 1-6 alkyl), -OC(=O)N(C 1-6alkyl)2、-NHC(=O)NH2、-NHC(=O)NH(C 1-6 alkyl), -NHC(=O)N(C 1-6 Alkyl)2, -N(C 1-6 alkyl) C(=O)NH2, -N(C 1-6 alkyl)C(=O)NH(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)N(C 1-6 alkyl)2, -S(=O)(OC 1-6 alkyl), -OS(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 Alkyl)2, -NHS(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)(C 1-6 alkyl), -S(=O)2(OC 1-6 alkyl), -OS(=O)2(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C 1-6 alkyl)2, -NHS(=O)2(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)2(C 1-6 alkyl), -OS(=O)2O(C 1-6 alkyl), -NHS(=O)2O(C 1-6 Alkyl), -N(C 1-6 Alkyl)S(=O)2O(C 1-6 alkyl), -OS(=O)2NH2, -OS(=O)2NH(C 1-6 alkyl), -OS(=O)2N(C 1-6 alkyl)2、-NHS(=O)2NH2、-NHS(=O)2NH(C 1-6 alkyl), -NHS(=O)2N(C 1-6 Alkyl)2, -N(C 1-6 alkyl)S(=O)2NH2, -N(C 1-6 alkyl)S(=O)2NH(C 1-6 Alkyl), -N(C 1-6 alkyl)S(=O)2N(C 1-6 Alkyl)2, -PH(C 1-6 alkyl), -P(C 1-6 alkyl)2, -P(=O)H(C1-6 alkyl), -P(=O)(C 1-6 alkyl) 2,3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein, the -C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, -C 1-3 Alkyl, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -C 2-3 Alkenyl, -C 2-3 Alkynyl, -CN, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, -OH, -O(C 1-3 alkyl), -SH, -S(C 1-3 alkyl), -S(=O)(C 1-3 alkyl), -S(=O)2(C 1-3 alkyl), -C(=O)(C 1-3 alkyl), -C(=O)OH, -C(=O)(OC 1-3 alkyl), -OC(=O)(C 1-3 alkyl), -C(=O)NH2, -C(=O)NH(C 1-3 alkyl), -C(=O)N(C 1-3 alkyl)2, -NHC(=O)(C 1-3 Alkyl), -N(C 1-3 alkyl)C(=O)(C 1-3 alkyl), -OC(=O)O(C 1-3 alkyl), -NHC(=O)(OC 1-3 Alkyl), -N(C 1-3 alkyl)C(=O)(OC 1-3 alkyl), -OC(=O)NH(C 1-3 alkyl), -OC(=O)N(C 1-3 alkyl)2、-NHC(=O)NH2、-NHC(=O)NH(C 1-3 alkyl), -NHC(=O)N(C 1-3 Alkyl)2, -N(C 1-3 alkyl) C(=O)NH2, -N(C 1-3alkyl)C(=O)NH(C 1-3 Alkyl), -N(C 1-3 alkyl)C(=O)N(C 1-3 alkyl)2, -S(=O)(OC 1-3 alkyl), -OS(=O)(C 1-3 alkyl), -S(=O)NH2, -S(=O)NH(C 1-3 alkyl), -S(=O)N(C 1-3 Alkyl)2, -NHS(=O)(C 1-3 Alkyl), -N(C 1-3 alkyl)S(=O)(C 1-3 alkyl), -S(=O)2(OC 1-3 alkyl), -OS(=O)2(C 1-3 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-3 alkyl), -S(=O)2N(C 1-3 alkyl)2, -NHS(=O)2(C 1-3 Alkyl), -N(C 1-3 alkyl)S(=O)2(C 1-3 alkyl), -OS(=O)2O(C 1-3 alkyl), -NHS(=O)2O(C 1-3 Alkyl), -N(C 1-3 Alkyl)S(=O)2O(C 1-3 alkyl), -OS(=O)2NH2, -OS(=O)2NH(C 1-3 alkyl), -OS(=O)2N(C 1-3 alkyl)2、-NHS(=O)2NH2、-NHS(=O)2NH(C 1-3 alkyl), -NHS(=O)2N(C 1-3 Alkyl)2, -N(C 1-3 alkyl)S(=O)2NH2, -N(C 1-3 alkyl)S(=O)2NH(C 1-3 Alkyl), -N(C 1-3 alkyl)S(=O)2N(C 1-3 Alkyl)2, -PH(C 1-3 alkyl), -P(C 1-3 alkyl)2, -P(=O)H(C 1-3 alkyl), -P(=O)(C 1-3 alkyl) 2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6 membered aryl or 5-6 membered heteroaryl;

[0331] Each heterocyclyl and heteroaryl group independently contains 1, 2, 3 or 4 heteroatoms selected from N, O, S, S(=O) or S(=O)2 at each occurrence.

[0332] In some embodiments, the KRAS G12D binding moiety is:

[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] Yet other specific examples of KRAS G12D binding moieties are disclosed in International Publication No. WO 2021 / 249519, the entire contents of which are incorporated herein by reference. In some embodiments, the KRAS G12 binding moiety is a KRAS G12D inhibitor binding moiety (e.g., an inhibitor) disclosed in WO 2021 / 249519. For example, in some embodiments, the KRAS G12D binding moiety has the following structural formula:

[0380]

[0381] in:

[0382] Ring A is an aryl group or a heteroaryl group;

[0383] R 1 Selected from hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyloxy, heterocyclyloxy, alkenyl, alkynyl, hydroxy, cyano, amino, -NR 5 R 6 , nitro, cycloalkyl, heterocycle, aryloxy, heteroaryloxy, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryloxy, heteroaryloxy, aryl and heteroaryl are each optionally and independently substituted by one or more independently selected from halogen, alkyl, alkoxy, haloalkoxy, hydroxy, amino, oxo, -C(O)(CH2) q OR 7 、-NHC(O)R 8 、-C(O)R 8 、-NR 9 R 10 、-C(O)(CH2) p NR 9 R 10 , nitro, cyano, cycloalkyl, heterocyclic, aryl or heteroaryl substituents;

[0384] R 2 is selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, amino or cycloalkyl;

[0385] R 3 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, hydroxy, cyano, amino, -(CH2) r NR 5 R 6, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally and independently substituted by one or more independently selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, amino, -(CH2) s NR 9 R 10 , cyano, cycloalkyl or heterocyclic substituents;

[0386] R 4 is selected from hydrogen, alkyl or cycloalkyl; wherein the alkyl and cycloalkyl are each optionally and independently substituted with one or more substituents independently selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, amino, cyano, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0387] R 5 and R 6 are the same or different and are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, hydroxy, amino, cycloalkyl or heterocyclyl;

[0388] R 7 is selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl or heterocyclyl;

[0389] R 8 are the same or different and are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, hydroxy, amino, cycloalkyl, or heterocyclyl; wherein each of the alkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally and independently substituted with one or more substituents independently selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, amino, cyano, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0390] R 9 and R 10 are the same or different and are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, hydroxy, amino, cycloalkyl or heterocyclyl;

[0391] n is 1, 2, 3, or 4;

[0392] p is 0, 1, 2, or 3;

[0393] q is 0, 1, 2, or 3;

[0394] r is 0, 1, 2, or 3; and

[0395] s is 0, 1, 2, or 3.

[0396] In some embodiments, the KRAS G12D binding moiety is:

[0397]

[0398]

[0399]

[0400] Yet other specific examples of KRAS G12D binding moieties are disclosed in International Publication No. WO 2022 / 221739, the entire contents of which are incorporated herein by reference. In some embodiments, the KRAS G12 binding moiety is a KRAS G12D inhibitor binding moiety (e.g., an inhibitor) disclosed in WO 2022 / 221739. For example, in some embodiments, the KRAS G12D binding moiety has the following structural formula:

[0401]

[0402] in:

[0403] Ring A is a saturated or partially unsaturated 8- to 10-membered N-bridged ring containing at least one further heteroatom selected from the group consisting of N, S and O;

[0404] wherein Ring A is unsubstituted or substituted by 1 to 3 R independently selected from the group consisting of A Substituents: C1-C3 alkyl, C2-C4 alkenyl, C1-C3 alkoxy, C1-C3 alkoxy(C1-C3)alkyl, halo, C1-C3 fluoroalkyl, hydroxy, C1-C3 hydroxyalkyl, CF3-C(H)(OH)-, C(H)(F2)-C(H)(OH)-, cyano and C1-C3 cyanoalkyl;

[0405] Ring B is a 5- or 6-membered partially unsaturated ring or aromatic ring having 0, 1 or 2 heteroatoms,

[0406] The heteroatom is selected from the group consisting of N, S and O, and wherein Ring B is fused to the pyrimidine ring as shown;

[0407] wherein ring B is unsubstituted or substituted by 1 to 2 R groups independently selected from the group consisting of halo, hydroxy, oxo, cyano, C1-C3 alkyl, C1-C3 fluoroalkyl and C1-C3 alkoxy B Substituent substitution;

[0408] Ring Y is a 6-membered monocyclic, 9- to 10-membered bicyclic, or 13- to 14-membered tricyclic ring system, wherein the ring system is partially unsaturated or aromatic, and wherein Ring Y contains 0 to 3 heteroatoms selected from the group consisting of N, S, and O;

[0409] wherein ring Y is unsubstituted or substituted with 1 to 4 R independently selected from the group consisting of YSubstituents: halo, hydroxy, oxo, C1-C3 alkyl, C2-C3 alkynyl, C1-C3 fluoroalkyl, C1-C3 alkoxy, C1-C3 fluoroalkoxy, C1-C3 alkylthio, C1-C3 fluoroalkylthio, amino, C1-C3 alkylamino, C1-C3 dialkylamino, C3-C 12 Cycloalkyl, tri(C1-C3 alkyl)silyl and cyano;

[0410] Ring Z is

[0411] (i) a 3- to 10-membered monocyclic or bicyclic cycloalkyl group;

[0412] (ii) a 3- to 10-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heterocycloalkyl group is saturated and contains 1 to 2 heteroatoms selected from the group consisting of N, S and O; or

[0413] (iii) a 3- to 8-membered spiroheterocycloalkyl group, wherein the spiroheterocycloalkyl group is saturated and contains 1 to 2 heteroatoms selected from the group consisting of N, S, and O;

[0414] wherein ring Z is unsubstituted or substituted by 1 to 4 R independently selected from the group consisting of Z Substituents: halo, hydroxy, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, C1-C6 fluoroalkyl, carboxyl, carbamoyl, methoxy (C1-C3) alkyl, amino (C1-C3) alkyl, C1-C3 alkylamino (C1-C3) alkyl, C1-C3 dialkylamino and C1-C3 dialkylamino (C1-C3) alkyl;

[0415] Ring Z is optionally replaced by 1 -MR ZC Replace, where

[0416] M is -CH2- or absent; and

[0417] R ZC is a 5- to 6-membered monocyclic or 9- to 10-membered bicyclic saturated heterocycloalkyl group containing 1 to 3 heteroatoms selected from the group consisting of N, S and O, wherein R ZC is unsubstituted or substituted with a substituent selected from the group consisting of C1-C3 alkyl, C1-C3 alkylcarbonylalkyl, C1-C3 hydroxyalkyl, fluoro, cyano, amino, C1-C3 alkylamino, C1-C3 dialkylamino, C1-C3 alkoxyalkyl and C1-C3 cyanoalkyl;

[0418] L is O or absent; and

[0419] m is 0, 1, or 2.

[0420] In some embodiments, the KRAS G12D binding moiety is:

[0421]

[0422]

[0423]

[0424] Yet other specific examples of KRAS G12D binding moieties are disclosed in International Publication No. WO 2023 / 018810, the entire contents of which are incorporated herein by reference. In some embodiments, the KRAS G12D binding moiety is a KRAS G12D binding moiety (e.g., an inhibitor) disclosed in WO 2023 / 018810. For example, in some embodiments, the KRAS G12D moiety has the following structural formula:

[0425]

[0426] in:

[0427] Is a single bond or a double bond;

[0428] W is C, CH or N, wherein when W is CH or N, It is a single bond;

[0429] X is O, S, S(O), S(O)(NR z ), S(O)2, CH2 or CH=CH;

[0430] n is 0, 1, or 2;

[0431] m is 0, 1, or 2;

[0432] p is 2, 3, or 4;

[0433] Two R's x Combined with the same carbon atom to form C 3-7 Cycloalkyl or 4-7 membered heterocycloalkyl, wherein each C 3-7 Cycloalkyl or 4-7 membered heterocycloalkyl is further supported by 0-3 occurrences of R y and when p is 3 or 4, each remaining R x is hydroxy, halogen, oxo, cyano, -N(R z )2、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, 5-7 membered heteroaryl;

[0434] L is C 1-6Alkylene, -OC 1-6 Alkylene, -SC 1-6 Alkylene, NR z , O or S, where each C 1-6 Alkylene, -OC 1-6 Alkylene and -SC 1-6 The alkylene chain is composed of 0-2 occurrences of R 2 replace;

[0435] R 1 is hydroxyl, aryl, heteroaryl, C 3-8 Cycloalkyl or 0-3 occurrences of R 5 substituted heterocycloalkyl;

[0436] R 2 Halogen, hydroxyl, C 1-4 Alkyl, or two R on the same or adjacent carbon atoms 2 Can be combined to form C 3-7 Cycloalkyl;

[0437] R 3 Is 0-3 R 6 substituted aryl or heteroaryl;

[0438] R 4 It is hydrogen, hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-7 Cycloalkyl or cyano;

[0439] Each R 5 is halogen, oxo, hydroxy, cyano, amino or C 1-4 alkyl;

[0440] Each R 6 Is halogen, hydroxyl, cyano, -N(R z )2、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 2-4 Alkynyl or C 3-6 Cycloalkyl;

[0441] T is C 1-4 Alkylene, -S(O)2-, -C(O)-, -C 1-4 Alkylene-C(O)-, -N(H)-C(O)-, -N(H)-S(O)2-, C 1-4 Alkylene-S(O)2- or -S-;

[0442] R y Is halogen, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, hydroxy, cyano, -S(O)2-C 1-4 Alkyl, =NR z or -N(R z )2; and

[0443] R z is hydrogen or C 1-4 alkyl.

[0444] In some embodiments, the KRAS G12D binding moiety is:

[0445] 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;

[0446] 6-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol;

[0447] 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one;

[0448] 6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one;

[0449] 3-chloro-4-cyclopropyl-5-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)phenol;

[0450] 6-(7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol;

[0451] 6-(7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol;

[0452] 7-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one;

[0453] 6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-methyl-6-azaspiro[3.5]nonan-2-ol;

[0454] 6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,6-diazaspiro[3.5]nonan-1-one;

[0455] 6-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol;

[0456] 9-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-oxa-1,9-diazaspiro[3.6]decan-2-one;

[0457] 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;

[0458] 7-(7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one;

[0459] 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,7-diazaspiro[4.5]decan-2-one;

[0460] 7-(7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decan-3-one;

[0461] 7-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decan-3-one;

[0462] 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-7-azaspiro[4.5]decane 2,2-dioxide;

[0463] 6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-methyl-1,6-diazaspiro[3.5]nonan-2-one;

[0464] 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-imino-2l6-thia-7-azaspiro[4.5]decane 2-oxide;

[0465] 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-oxa-1,7-diazaspiro[4.5]decan-2-one;

[0466] 8-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one;

[0467] 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;

[0468] 6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol; or

[0469] 5-ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol.

[0470] Yet other specific examples of KRAS G12D binding moieties are disclosed in International Publication No. WO 2022 / 194191, the entire contents of which are incorporated herein by reference. In some embodiments, the KRAS G12D binding moiety is a KRAS G12D binding moiety (e.g., an inhibitor) disclosed in WO 2022 / 194191. For example, in some embodiments, the KRAS G12D moiety has the following structural formula:

[0471]

[0472] Provided that the compound does not have the following structural formula:

[0473]

[0474] in:

[0475] yes

[0476] Is a single bond or a double bond;

[0477] X and X 1 independently selected from a bond, O, S, S(O)2, CH2, CHF, CF2 or NR x , provided that X and X 1 At least one of them is NR x ;

[0478] X 2 It is CH2 or not present;

[0479] W is C, CH, C(C 1-6 alkyl) or N;

[0480] Select one of the following:

[0481]

[0482]

[0483]

[0484] R x It is H, C 1-3 Alkyl, cyclopropyl;

[0485] R 1 It is H, NR a R b 、C 1-3 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-3 Alkoxy, NH-C 1-3 Alkyl, N(C 1-3 Alkyl)2, CO2R 8 、CONR a R b or a 5-6 membered heteroaryl group;

[0486] R 2 Is halogenated, C 1-6 Alkyl, C 1-6Halogenated alkyl, C 1-6 Alkoxy, -Y-heterocyclyl, -Y-aryl, -Y-heteroaryl, -Y-cycloalkyl, -Y-NR a R b 、-YC(O)NR a R b , -Y-haloalkyl, -Y-OR a 、-Y-NR a C(O)aryl, -Y-CO2R a or -Y-NR c C(O)NR a R b 、-YS(O)2aryl、-YS(O)2C 1-6 Alkyl, S(O)2NR a R b , where whenever the valence rules allow, R 2 The part can be optionally replaced by 0-3 occurrences of R 10 replace;

[0487] Y is independently C0-C4 alkylene, C0-C4 alkylene-O, C0-C4 alkylene-S-, C0-C4 alkylene-NR c -、(Z)-CR 11 =CR 12 -C0-C4 alkylene, (E)-CR 11 =CR 12 -C0-C4 alkylene, -C≡C-C0-C4 alkylene, S, (Z)-CR 11 =CR 12 -C0-C4 alkylene, (E)-CR 11 =CR 12 -C0-C4 alkylene, -C≡C-C0-C4 alkylene,

[0488]

[0489] Z is a bond, O, S or NR c ;

[0490] R 3 is aryl or heteroaryl, wherein said aryl or heteroaryl is optionally replaced by 0-4 occurrences of R 10 replace;

[0491] R 4 、R 5 、R 6 and R 7 independently selected from H, halogen, -CN, C1-C3 alkyl, C 3-6 Cycloalkyl, C 3-6Halogenated cycloalkyl or C1-C3 haloalkyl;

[0492] R 8 and R 9 Independently selected from H, C1-C3 alkyl, C 3-6 Cycloalkyl;

[0493] R a 、R b and R c are independently hydrogen or C 1-6 Alkyl, -C 0-6 Alkylene-C 6-10 Aryl, -C 0-6 Alkylene-5-10 membered heteroaryl or 5-10 membered heterocyclic group (preferably hydrogen or C 1-6 Alkyl, C 6-10 aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclyl); or R a and R b Together with the atoms to which they are attached, they form an optionally substituted 5-10 membered carbocyclyl or heterocyclyl, which is optionally replaced by 0-5 occurrences of R 10 Replacement; R b 、R c and R e Independently by 0-5 occurrences of R 10 replace;

[0494] R 10 Independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, halo, hydroxy, oxo, amino, N(C 1-6 Alkyl)2, cyano, C 0-6 Alkylene-NR b R a 、C 0-6 Alkylene-NR b R a 、C 0-6 Alkylene-C(O)NR b R a 、C 0-6 Alkylene-NR a C(O)R b 、C 0-6 Alkylene-S(O)2R b 、C 0-6 Alkylene-S(O)2NR a R b 、C 0-6 Alkylene-NR c S(O)2R b 、C 0-6 Alkylene-NR c S(O)2NR aR b 、C 0-6 Alkylene-P(O)R a R b 、C 0-6 Alkylene-P(O)(OR c )(OR b ), C 0-6 Alkylene-cyano, C 0-6 Alkylene-C 3-8 Cycloalkyl and 5-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl (preferably selected from C 1-6 Alkyl, C 1-6 Alkoxy, halo, hydroxy, oxo, amino, C 0-6 Alkylene-NR b R a 、C 0-6 Alkylene-NR b R a 、C 0-6 Alkylene-C(O)NR b R a 、C 0-6 Alkylene-NR a C(O)R b 、C 0-6 Alkylene-S(O)2R b 、C 0-6 Alkylene-S(O)2NR a R b 、C 0-6 Alkylene-NR a S(O)2R b 、C 0-6 Alkylene-NR c S(O)2NR a R b 、C 0-6 Alkylene-P(O)R a R b 、C 0-6 Alkylene-P(O)(OR c )(OR b ), C 0-6 Alkylene-cyano, C 0-6 Alkylene-C 3-8 Cycloalkyl and 5-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl; two adjacent R 10 , such as two R connected to two adjacent atoms (two atoms connected to each other only by a bond) 10 or two R attached to the same atom 10, together with the atoms to which they are attached, form an optionally substituted 5-10 membered cyclic group or a 5-10 membered heterocyclic group containing 0-3 heteroatoms;

[0495] R 11 and R 12 Independently selected from H, F, C1-C3 alkyl, C 3-6 Cycloalkyl, C1-C3 haloalkyl or cyclopropyl;

[0496] Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group may be substituted with one or more substituents.

[0497] In some embodiments, the KRAS G12D binding moiety is:

[0498]

[0499]

[0500] Yet other specific examples of KRAS G12D binding moieties are disclosed in International Publication No. WO 2022 / 194066, the entire contents of which are incorporated herein by reference. In some embodiments, the KRAS G12D binding moiety is a KRAS G12D binding moiety (e.g., an inhibitor) disclosed in WO 2022 / 194066. For example, in some embodiments, the KRAS G12D binding moiety has the following structural formula:

[0501]

[0502] in:

[0503] Ring A is selected from C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0504] L1 is selected from -O-(CH2) 0-3 、-S-(CH2) 0-3 、-NH-(CH2) 0-3 or C 1-3 alkylene;

[0505] L2 is selected from a bond or C 1-3 alkylene;

[0506] R1 is independently selected from H, halogen, alkyl, alkoxy, haloalkyl, hydroxy and hydroxyalkyl;

[0507] R2 is selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, the C 3-14 Cycloalkyl, 3-14 membered heteroaryl, C6-14 Aryl and 5-14 membered heteroaryl are optionally further substituted by 1-4 groups selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, cyano, amino, nitro, hydroxyl, C 1-6 Hydroxyalkyl, C 0-3 Alkylene-N(R a ) 2, cycloalkyl, heterocyclic, aryl and heteroaryl substituents, and the R a Independently selected from H or C 1-6 alkyl;

[0508] R3 is selected from H, halogen, C 1-6 Alkyl or -OR 2a , and R 2a Selected from C 1-6 Alkyl, C 3-8 Cycloalkyl or haloalkyl;

[0509] R4 is selected from the group consisting of one or more R 3a substituted cycloalkyl, heterocyclyl, aryl or heteroaryl; each R 3a independently selected from H, =O, =S, acyl, hydroxy, cyano, halogen, nitro, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, -C 0-3 Alkylene-OR b 、-OC(=O)C 1-6 Alkyl, -C 0-3 Alkylene-SR b 、-C 0-3 Alkylene-N(R b )2. -C 0-3 Alkylene-S(=O)R b 、-C 0-3 Alkylene-S(=O)2R b 、-C 0-3 Alkylene-SR b 、-C 0-3 Alkylene-S(R b )5. -C 0-3 Alkylene-C(=O)R b 、-C 0-3 Alkylene-C(=O)OR b 、-C 0-3 Alkylene-C(=O)N(R b )2. Substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted -C 0-3 Alkylene-C3-14 Cycloalkyl, substituted or unsubstituted -C 0-3 Alkylene-(3-14 membered heterocycloalkyl), substituted or unsubstituted-C 0-3 Alkylene-C 6-14 Aryl or substituted or unsubstituted -C 0-3 Alkylene-(5-14 membered heteroaryl, each R b Independently H, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 alkyl halide;

[0510] R5 is selected from H, amino, substituted amino, C 1-6 Alkyl, substituted C 1-6 Alkyl, halogen, C 2-6 Alkenyl, substituted C 2-6 Alkenyl, C 3-6 Cycloalkyl or substituted C 3-6 Cycloalkyl;

[0511] R6 is selected from H, halogen or C 1-6 alkyl; and

[0512] m is selected from 0, 1, 2, 3 or 4.

[0513] In some embodiments, the KRAS G12D binding moiety is:

[0514]

[0515] Other specific examples of KRAS G12D binding moieties are disclosed in International Publication No. WO 2022 / 148421, the entire contents of which are incorporated herein by reference. In some embodiments, the KRAS G12D binding moiety is a KRAS G12D binding moiety (e.g., an inhibitor) disclosed in WO 2022 / 148421. For example, in some embodiments, the KRASG12D binding moiety has the following structural formula:

[0516]

[0517] in:

[0518] Ring A is aryl or 5- to 7-membered monocyclic heteroaryl or 8- to 12-membered bicyclic heteroaryl;

[0519] are each independently a single bond or a double bond;

[0520] Y1 is -NH- or -C(R Y1a )(NHR Y1b )-;

[0521] Y2 is N or CR Y2 ,if If it is a single bond; or Y2 is C, and R 1b Does not exist if If it is a double bond;

[0522] n1, n2, n3, m1, m2 and m3 are each independently 0 or 1, provided that at least one of n1, n2 and n3 is 1; and at least one of m1, m2 and m3 is 1;

[0523] p is 0, 1, 2, 3, 4, 5, or 6;

[0524] q is 0, 1, 2, 3, 4, 5, 6, or 7, provided that the valence theory is satisfied;

[0525] R 1a 、R 1b 、R 2a 、R 2b 、R 3a 、R 3b 、R 1c 、R 1d 、R 2c 、R 2d 、R 3c 、R 3d 、R Y1a 、R Y1b and R Y2 If present, each is independently hydrogen, halogen, -C 1-8 Alkyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -OR 1e 、-NR 1e R 1f ; where -C 1-8 Alkyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one substituent R 1g replace;

[0526] (R 1a and R 1c )、(R 1a and R 2c )、(R 1a and R 3c )、(R 2a and R 1c )、(R 2a and R 2c )、(R 2a and R 3c )、(R 3a and R1c )、(R 3a and R 2c )、(R 3a and R 3c )、(R Y1a and R Y2 )、(R Y1a and R 1a )、(R Y1a and R 2a )、(R Y1a and R 1c )、(R Y1a and R 2c )、(R Y1b and R 1a )、(R Y1b and R 2a )、(R Y1b and R 1c )、(R Y1b and R 2c ) and (R Y1b and R Y2 ) form a bridge containing, in addition to the two bridgeheads, one, two, three or four -CH2- moieties, wherein one of the -CH2- moieties is optionally replaced by -O-, -S- or -NH-, and wherein the bridge is optionally substituted by at least one substituent R 1g replace;

[0527] Optionally, (R Y1a and R Y1b )、(R Y1a and R 3a )、(R Y1a and R 3c )、(R Y1b and R 3a ) or (R Y1b and R 3c ) form a 3 to 12 membered ring containing 0 to 3 heteroatoms selected from nitrogen, sulfur and oxygen, and the bridge is optionally substituted by at least one substituent R 1g replace;

[0528] R 1e and R 1f are each independently selected from hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 1-8 Alkoxy-C 1-8 Alkyl-, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12 aryl or 5- to 12-membered heteroaryl;

[0529] R 1gis independently at each occurrence halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, -C6-C 12 Aryl or 5- to 12-membered heteroaryl, -C 1-8 Halogenated alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-、-CN、-OH、-NH2、-C 1-8 Alkoxy, -COOH or CO-C 1-8 alkyl;

[0530] R6 is hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, oxo, -OR 6a 、-SR 6a 、-SO2R 6a 、-SO2NR 6a R 6b 、-COR 6a 、-CO2R 6a 、-CONR 6a R 6b 、-NR 6a R 6b 、-NR 6a COR 6b 、-NR 6a CO2R 6b or -NR 6a SO2R 6b ;-C 1-8 Alkyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one substituent R 6c replace;

[0531] R 6a and R 6b are each independently selected from hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 1-8 Alkoxy-C 1-8 Alkyl-, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12 Aryl or 5- to 12-membered heteroaryl, -C 1-8 Alkyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one substituent R 6d replace;

[0532] R 6c is independently at each occurrence halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, -C6-C 12 aryl or 5 to 12 membered heteroaryl; or two R6 together with the atoms to which they are attached form a 5, 6, 7 or 8 membered unsaturated (preferably aromatic) or saturated ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the ring is optionally substituted with at least one substituent R 6d replace;

[0533] R 6d It is hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, oxo, -OR 6e 、-SO2R 6e 、-SO2NR 6e R 6f 、-COR 6e 、-CO2R 6e 、-CONR 6e R 6f 、-NR 6e R 6f 、-NR 6e COR 6f 、-NR 6e CO2R 6f or -NR 6e SO2R 6f ; C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one substituent R 6g replace,

[0534] R 6e and R 6f are each independently selected from hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 1-8 Alkoxy-C1-8 Alkyl-, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12 aryl or 5- to 12-membered heteroaryl;

[0535] R 6g is independently at each occurrence halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, -C6-C 12 aryl or 5- to 12-membered heteroaryl;

[0536] R4 is hydrogen, halogen, -C 1-8 Alkyl, C3-C8 cycloalkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, 3 to 8 membered heterocyclic group, C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, oxo, -OR 4a 、-SR 4a 、-SO2R 4a 、-SO2NR 4a R 4b 、-COR 4a 、-CO2R 4a 、-CONR 4a R 4b 、-NR 4a R 4b 、-NR 4a COR 4b 、-NR 4a CO2R 4b or -NR 4a SO2R 4b ;-C 1-8 Alkyl, C3-C8 cycloalkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, 3 to 8 membered heterocyclic group, C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one substituent R 4c or two R4 are joined to form a spiro ring or a bicyclic ring;

[0537] R 4a and R 4b are each independently selected from hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 1-8 Alkoxy-C 1-8 Alkyl-, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12 Aryl or 5- to 12-membered heteroaryl, -C1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 1-8 Alkoxy-C 1-8 Alkyl-, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one substituent R 4d replace;

[0538] R 4c and R 4d Each occurrence is independently halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, -C6-C 12 aryl or 5- to 12-membered heteroaryl;

[0539] L1 is selected from a single bond, -O-, -NR L1a -、-C(O)-、-C 1-8 Alkylene-,* L1 -OC 1-8 Alkylene-** L1 、-C3-C8 cycloalkylene-、* L1 -O-C3-C8 cycloalkylene-** L1 、* L1 -OC 1-8 Alkylene-NR L1a -** L1 、* L1 -OC 1-8 Alkylene-CO-** L1 、* L1 -C 1-8 Alkylene-O-** L1 、* L1 -C(O)-C 1-8 Alkylene-** L1 、* L1 -C 1-8 Alkylene-C(O)-** L1 、* L1 -NR L1a -C 1-8 Alkylene-** L1 、* L1 -C 1-8 Alkylene-NR L1a -** L1 、

[0540]

[0541] Said-C 1-8 Alkylene-,* L1 -OC 1-8 Alkylene-** L1 、-C3-C8 cycloalkylene-、* L1 -O-C3-C8 cycloalkylene-** L1 、* L1 -OC 1-8 Alkylene-NR L1a -** L1 、* L1 -OC 1-8 Alkylene-CO-** L1 、* L1 -C 1-8 Alkylene-O-** L1 、* L1 -C(O)-C 1-8 Alkylene-** L1 、* L1 -C 1-8 Alkylene-C(O)-** L1 、* L1 -NR L1a -C 1-8 Alkylene-** L1 、* L1 -C 1-8 Alkylene-NR L1a -**L1, Each of which is optionally replaced by at least one R L1b replace;

[0542] in** L1 refers to Partially connected locations, and* L1 Refers to the location where it connects to the other side;

[0543] R L1a Selected from hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 Aryl or 5 to 12 membered heteroaryl, the C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one substituent R L1c replace;

[0544] The R L1b and R L1cEach of which is independently halogen, hydroxy, -C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 aryl or 5- to 12-membered heteroaryl; or

[0545] Two R's L1b or two R L1c Together with the atoms to which they are attached, they form a 3- to 6-membered unsaturated or saturated ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the ring is optionally substituted with at least one substituted group: halogen, hydroxyl, -C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 substituted with aryl or 5- to 12-membered heteroaryl;

[0546] Each of X5 and X6 is selected from CH or N;

[0547] n4 and n5 are each independently 0, 1 or 2;

[0548] R5 is hydrogen, halogen, -C 1-8 Alkyl, C3-C8 cycloalkyl, 3 to 12 membered heterocyclic group, C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo, -CN, -OR 5a 、-COR 5a 、-CO2R 5a 、-CONR 5a R 5b 、-NR 5a R 5b 、-NR 5a COR 5b or -NR 5a CO2R 5b ; where -C 1-8 Alkyl, C3-C8 cycloalkyl, 3 to 12 membered heterocyclic group, C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one substituent R 5c replace;

[0549] R 5a and R 5b are each independently selected from hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 1-8 Alkoxy-C1-8 Alkyl-, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12 aryl, 5 to 12 membered heteroaryl or oxo, wherein the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 1-8 Alkoxy-C 1-8 Alkyl-, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12 Each of the aryl group and the 5- to 12-membered heteroaryl group is optionally substituted with at least one substituent R 5d Replace; or

[0550] R 5a and R 5b Together with the carbon atoms to which they are attached, they form a 3- to 8-membered unsaturated or saturated ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the ring is optionally substituted with at least one substituent R 5c replace;

[0551] R 5c is independently at each occurrence halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo, -CN, -OR 5e 、-COR 5e 、-CO2R 5e 、-CONR 5e R 5f 、-NR 5e R 5f 、-NR 5e COR 5f or -NR 5e CO2R 5f , wherein the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, -C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one substituent R 5d Replace; or

[0552] Two R's 5c Together with the carbon atoms to which they are attached, they form a 3- to 8-membered unsaturated or saturated ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the ring is optionally substituted with at least one substituent R 5d Replacement; R 5dIt is hydrogen, halogen, -C 1-8 Alkyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo, -CN, -OR 5g 、-COR 5g 、-CO2R 5g 、-CONR 5g R 5h 、-NR 5g R 5h 、-NR 5g COR 5h or -NR 5g CO2R 5h ; where -C 1-8 Alkyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one substituent R 5i Replacement; R 5e 、R 5f 、R 5g 、R 5h and R 5i are each independently selected from hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 1-8 Alkoxy-C 1-8 Alkyl-, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12 aryl or 5- to 12-membered heteroaryl.

[0553] In some embodiments, the KRAS G12D binding moiety is:

[0554]

[0555]

[0556]

[0557] Other specific examples of KRAS G12D binding moieties are disclosed in International Publication No. WO 2023 / 284537, the entire contents of which are incorporated herein by reference. In some embodiments, the KRAS G12D binding moiety is a KRAS G12D binding moiety (e.g., an inhibitor) disclosed in WO 2023 / 284537. For example, in some embodiments, the KRASG12D binding moiety has one of the following structural formulas:

[0558]

[0559] in:

[0560] Ring A is a heterocyclic group or a heteroaryl group, wherein represents N-linked ring A, and represents C-linked ring A;

[0561] Each R 1 are independently selected from oxo, hydroxy, halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, -C(O)OR a 、-C(O)N(R a )2、-N(R a )2 or heteroaryl, wherein the alkyl, alkenyl, alkynyl and heteroaryl are optionally substituted by one or more independently selected from cyano, hydroxy, halogen, -OR b or -N(R b )2 group substitution;

[0562] Each R a and R b are independently hydrogen, alkyl, alkenyl or alkynyl;

[0563] Ring B is optionally substituted with one or more R c substituted cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0564] Each R c independently selected from the group consisting of oxo, hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl and heteroaryl are optionally substituted by one or more independently selected from the group consisting of hydroxy, halogen, cyano, -OR a 、-N(R a )2 and a heteroaryl group;

[0565] Ring W is cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0566] R' is selected from hydrogen, hydroxy, halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, -C(O)OR a 、-C(O)N(R a )2、-N(R a )2 or heteroaryl, wherein the alkyl, alkenyl, alkynyl and heteroaryl are optionally substituted by one or more independently selected from cyano, hydroxy, halogen, -OR b or -N(R b )2 group substitution;

[0567] Each R 2independently selected from the group consisting of hydrogen, oxo, hydroxy, halo, cyano, amino, nitro, alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently consisting of hydroxy, halo, cyano, amino, nitro, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0568] X is O or S;

[0569] M is O or S;

[0570] Y is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more R c replace;

[0571] L is a bond, -O-, -S-, -N(R a )-, alkenyl, cycloalkyl or alkynyl;

[0572] L' is a bond, -S-, -N(R a )-, alkenyl, cycloalkyl or alkynyl, provided that when ring B is When L' is alkenyl, cycloalkyl or alkynyl; and when B is not When L' is a bond, -S-, -N(R a )-, alkenyl or cycloalkyl;

[0573] Optionally substituted with hydroxy, halogen, cyano or amino;

[0574] Q is a bond, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from hydroxy, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl;

[0575] Z is selected from hydrogen, -N(R a )2, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -COOH, -NHC(=NH)NH2, -C(O)N(R a )2、-OR a 、-(CH2OR a )(CH2) p OR a 、-N(R a )C(O)-aryl and -(CH2) p -heterocyclyl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more R d Substituted, and -N(R a)C(O)-aryl and -(CH2) p - The heterocyclic group in the heterocyclic group is optionally replaced by one or more R e replace;

[0576] Each R d are independently selected from hydroxy, halogen, -C(O)H, alkyl, alkoxy, haloalkyl, hydroxyalkyl or -N(R a )2;

[0577] Each R e are independently selected from oxo, hydroxy, halogen, alkyl, heteroalkyl, hydroxyalkyl, haloalkyl, alkoxy, -T-phenyl, -T-phenylSO2F, -N(R a )2, -SO2F, -C(O)(alkyl), or -C(O)(haloalkyl), wherein the alkyl, heteroalkyl, hydroxyalkyl, haloalkyl, and alkoxy groups are optionally substituted with one or more groups independently selected from aryl, heteroaryl, or tert-butyldimethylsiloxy;

[0578] T is a bond, -O-, or -NHC(O)-;

[0579] m is 0 or 1;

[0580] n is 0 or 1;

[0581] s is an integer from 0 to 5;

[0582] t is an integer from 0 to 4; and

[0583] p is an integer from 0 to 4.

[0584] In some embodiments, the KRAS G12D binding moiety is:

[0585]

[0586]

[0587]

[0588]

[0589] Other specific examples of KRAS G12D binding moieties are disclosed in International Publication No. WO 2023 / 001141, the entire contents of which are incorporated herein by reference. In some embodiments, the KRAS G12D binding moiety is a KRAS G12D binding moiety (e.g., an inhibitor) disclosed in WO 2023 / 001141. For example, in some embodiments, the KRASG12D binding moiety has one of the following structural formulas:

[0590]

[0591] in:

[0592] Y is O or S;

[0593] Ring A is a heterocyclic group or a heteroaryl group,

[0594] Each R 1 are independently selected from the group consisting of oxo, hydroxy, halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroaryl, -C(O)R * 、-C(O)OR * 、-C(O)N(R a )2、-N(R a )2、-P(O)OR * OR ** and -C(O)OC(R a )2-Z 1 -Z 2 The group consisting of wherein the alkyl, alkenyl, alkynyl and heteroaryl are optionally substituted by one or more independently selected from cyano, hydroxy, halogen, -OR b or -N(R b )2 group substitution;

[0595] Each R a and R b are independently hydrogen, alkyl, alkenyl or alkynyl;

[0596] R * is selected from hydrogen, alkyl, alkylaryl or aryl;

[0597] R ** is selected from hydrogen, alkyl, alkenyl or alkynyl; or

[0598] R * and R ** Together with the oxygen atom to which they are attached, they form a heterocyclic group optionally substituted with an aryl group or a haloaryl group;

[0599] Z 1 Is -OC(O)-#, -OP(=O)(OR *** )O-#OR-OP(=O)(OR * )N(R a )-#, where the # end is connected to Z 2 connect;

[0600] Z 2 is hydrogen or optionally substituted by aryl or -C(O)OR a substituted alkyl groups;

[0601] R *** are independently selected from hydrogen, alkyl, alkenyl or alkynyl; or

[0602] R *** and Z 2 Together with the oxygen atom to which they are attached, they form a heterocyclic group optionally substituted with an aryl group or a haloaryl group;

[0603] Ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted with one or more R';

[0604] Each R' is independently selected from the group consisting of oxo, hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl and heteroaryl are optionally substituted by one or more independently substituted by hydroxy, halogen, cyano, -OR a 、-N(R a )2 and a heteroaryl group;

[0605] Ring Q is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0606] Each R 2 independently selected from the group consisting of hydrogen, oxo, hydroxy, halogen, cyano, amino, nitro, alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -C(O)R * , wherein alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently consisting of hydroxy, halo, cyano, amino, nitro, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0607] Ring W is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0608] Each R 3 independently selected from the group consisting of hydrogen, oxo, hydroxy, halo, cyano, amino, nitro, alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently consisting of hydroxy, halo, cyano, amino, nitro, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0609] G 1 is a bond, -O-, -S(O) p -、-SS-、-N(R c )-or-C(R d )=C(Rd )-;

[0610] G 2 is a key, -[C(R d )2] u -、-C(O)- or -C(O)C(R d )2-;

[0611] R c is selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, and heterocyclyl;

[0612] Each R d is independently selected from the group consisting of hydrogen, hydroxy, halogen, cyano, amino, nitro, alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl, wherein alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more groups independently consisting of hydroxy, halogen, cyano, amino, nitro, alkyl, alkoxy, haloalkyl, and hydroxyalkyl; or

[0613] Two R's d Together with the carbon atom to which they are both attached, they form a cycloalkyl or heterocyclyl group, wherein the cycloalkyl and heterocyclyl groups are optionally substituted with cyano, halogen, hydroxy, amino, nitro, alkoxy, haloalkyl, hydroxyalkyl and alkyl;

[0614] Z is C(R e ) or N;

[0615] R e Absent or hydrogen;

[0616] L 1 Selected from bond, -O-, -S-, -N(R a )-、-C(O)N(R a )-, alkenyl, alkynyl or cycloalkyl Optionally substituted with hydroxy, halogen, cyano or amino;

[0617] L 2 is a bond, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from hydroxy, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl;

[0618] E is selected from the group consisting of hydrogen, hydroxy, halogen, -N(R a )2, alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -COOH, -CH2OC(O)-heterocyclyl, -CH2OC(O)N(R a)2, -NHC(=NH)NH2, -C(O)N(R a )2、-OR a 、-(CH2OR a )(CH2) p OR a 、-N(R a )C(O)-aryl and -(CH2) u -heterocyclyl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more R", and -N(R a )C(O)-aryl and the aryl portion of -(CH2) u -heterocyclyl and the heterocyclyl portion of -CH2OC(O)-heterocyclyl are optionally substituted with one or more R"';

[0619] Each R" is independently selected from hydroxy, halogen, -C(O)H, alkyl, alkoxy, haloalkyl, hydroxyalkyl, or -N(R a )2;

[0620] Each R'' is independently selected from oxo, hydroxy, halogen, alkyl, heteroalkyl, hydroxyalkyl, haloalkyl, alkoxy, -T-phenyl, -T-phenylSO2F, -N(R a )2, -SO2F, -C(O)(alkyl), or -C(O)(haloalkyl), wherein the alkyl, heteroalkyl, hydroxyalkyl, haloalkyl, and alkoxy groups are optionally substituted with one or more groups independently selected from aryl, heteroaryl, or tert-butyldimethylsiloxy;

[0621] T is a bond, -O-, or -NHC(O)-;

[0622] m is an integer from 0 to 6;

[0623] n is an integer from 0 to 5;

[0624] r is an integer from 0 to 4;

[0625] s is an integer from 0 to 5;

[0626] p is an integer from 0 to 2; and

[0627] u is an integer from 0 to 4.

[0628] In some embodiments, the KRAS G12D binding moiety is:

[0629]

[0630] Yet other specific examples of KRAS G12D binding moieties are disclosed in International Publication No. WO 2022 / 262838, the entire contents of which are incorporated herein by reference. In some embodiments, the KRAS G12D binding moiety is a KRAS G12D binding moiety (e.g., an inhibitor) disclosed in WO 2022 / 262838. For example, in some embodiments, the KRAS G12D binding moiety has the following structural formula:

[0631]

[0632] X 0 It is H, deuterium, halogenated, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Hydroxyalkyl or C 1-6 Alkoxy, each of these groups may independently be unsubstituted or substituted with a 3 to 7 membered heterocycle having one or more heteroatoms independently selected from N, O or S, and at least one of the heteroatoms is N, which is C 1-6 Alkyl or C 1-6 One of the C atoms of the hydroxyalkyl group is directly attached; the 3- to 7-membered heterocyclic ring is further optionally substituted with -CH3 or -N(CH3)2;

[0633] R 1 and R 2 Each of which is independently selected from H, deuterium, halogen, -NH2, -CN, -OH, -C 1-6 Alkyl or -C 1-6 Alkoxy, each of these groups is independently optionally unsubstituted or substituted with deuterium, halogen, -NH2, -CN, -OH, -C 1-6 Alkyl or -C 1-6 Alkoxy substitution;

[0634] R 3 and R 4 Each of which is independently selected from H, deuterium, halogen, -NH2, -CN, -OH, -C 1-4 Alkyl or -C 1-4 Alkoxy, and each of these groups is independently optionally unsubstituted or substituted with deuterium, halogen, -NH2, -CN, -OH, -NHC(O)NHC 1-6 Alkyl, -NHC(O)N(C 1-6 Alkyl)2, -OH, -OC(O)NHC 1-6 Alkyl, -OC(O)N(C 1-6 Alkyl)2, -C 1-6 Alkyl or -C 1-6 Alkoxy substitution;

[0635] R 5 and R 6 Each of which is independently selected from H, deuterium, halogen, -NH2, -CN, -OH, -C 1-6 Alkyl or -C 1-6 Alkoxy, each of these groups is independently optionally unsubstituted or substituted with deuterium, halogen, -NH2, -CN, -OH, -C 1-6 Alkyl or -C 1-6 Alkoxy substituted; and R 1 、R 2 、R 3 、R 4 、R 5 and R 6 At least one of is deuterium;

[0636] R is independently:

[0637]

[0638] in:

[0639] n is 0, 1, 2, or 3;

[0640] q is 0, 1, 2, or 3;

[0641] X 1 It is H, -CH2CN, C 1-6 Alkyl or C 1-6 alkoxy;

[0642] X 2 is 6 to 10 membered aryl or 5 to 10 membered heteroaryl; and each of said 6 to 10 membered aryl or 5 to 10 membered heteroaryl is independently optionally unsubstituted or replaced by one or more R 2x replace;

[0643] Every R 2x independently selected from halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Deuterated alkynyl, cyano, (C 1-6 Alkoxy) C 1-6 Alkyl, (C 1-6 Alkoxy) C 1-6 Alkoxy, (C 1-6 Hydroxyalkoxy)C 1-6Alkoxy, 3 to 7 membered cycloalkyl or 3 to 7 membered heterocycloalkyl, each of which is independently optionally unsubstituted or substituted with one or more -NH2, halogen, deuterium, -CN, -OH, -C 1-6 Alkyl or -C 1-6 Alkoxy substitution;

[0644] X 3 independently selected from H, halogen, C 1-6 Alkyl or C 1-6 alkoxy;

[0645] Is a single bond or a double bond;

[0646] 5 X is N or CR 7 ,in:

[0647] when 5 X is N or 5 X is CR 7 hour, is a double bond; and

[0648] when 5 X is C(R 7 )2 or 5 X is NR 7 When , "---" is a single key;

[0649] Every R 7 are independently H, halogen, -C 1-6 Alkyl or -C substituted by one or more halogen, deuterium, -OH or NH2 1-6 Alkyl; or

[0650] Two R's 7 With two R 7 The C atoms connected together form an oxo group (=O), and the oxo group and X 2 The attached N atoms together form a lactam; or

[0651] R 7 and R 7 Together with the C atoms to which they are respectively attached, they form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclic ring; or

[0652] W is O or NR w , and R w Is H, deuterium or C 1-6 alkyl.

[0653] In some embodiments, the KRAS G12D binding moiety is:

[0654]

[0655]

[0656]

[0657] Connector (L')

[0658] The linker is a divalent moiety that connects KRAS G12Di to Degron. Linkers are disclosed, for example, in International Publication No. WO 2021 / 127278, the entire contents of which are incorporated herein by reference, and are referred to as variable L therein. See, in particular, paragraphs

[00491] -

[00501] and Table B therein. In some aspects (e.g., of any of the foregoing embodiments, aspects, or combinations thereof), L' is a linker disclosed in WO 2021 / 127278. U.S. Patent No. US11,352,350 also discloses, for example, a linker, the entire contents of which are incorporated herein by reference, and are referred to as variable L therein. See, in particular, columns 408-409 and 2573-2574 therein. In some aspects (e.g., of any of the foregoing embodiments, aspects, or combinations thereof), L' is a linker disclosed in US11,352,350.

[0659] Linkers are also disclosed in U.S. Patent Application Publication No. US2020 / 0140456, the entire contents of which are incorporated herein by reference. See, in particular, paragraphs

[0491] -

[0508] thereof. In some aspects (e.g., of any of the foregoing embodiments, aspects, or combinations of aspects), L' is a linker disclosed in US2020 / 0140456.

[0660] In some aspects (eg, of any preceding embodiment, aspect, or combination of aspects), L' is a covalent bond or a divalent saturated or unsaturated linear or branched C 1-50 A hydrocarbon chain wherein 0-10 methylene units of L' are independently replaced by X, wherein:

[0661] Each X is independently -C(D)(H)-, -C(D)2-, -C(H)(F)-, -C(F)2-, -Cy-, -O-, -N(R)-, -Si(R)2-, -Si(OH)(R)-, -Si(OH)2-, -P(O)(OR)-, -P(O)(R)-, -P(O)(NR2)-, -S-, -OC(O)-, -C(O)-, -S(O)-, -S(O)2-, -N(R)S(O)2-, -N(R)C(O)-, -OC(O)N(R)-, -N(R)C(O)N(R)-,

[0662] each -Cy- is independently an optionally substituted bivalent ring selected from phenylene, an 8-10 membered bicyclic arylene, a 4-7 membered saturated or partially unsaturated carbocyclo ...

[0663] Each R is independently hydrogen, deuterium, or an optionally substituted group selected from: C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or

[0664] Two R on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; and

[0665] r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0666] In some aspects (eg, of any preceding embodiment, aspect, or combination of aspects), L' is a covalent bond or a divalent saturated or unsaturated linear or branched C1-C 25 A hydrocarbon chain wherein 0-10 methylene groups of L' are replaced by X, wherein: each X is independently -O-, -N(R)-, -S-, -OC(O)-, -C(O)-, -C(H)(F)-, -C(F)2-, -Cy-, -S(O)-, -S(O)2-, -N(R)S(O)2-, -N(R)C(O)-, -OC(O)N(R)-, -N(R)C(O)N(R-, (and in some further aspects, -O-, -N(R)-, -S-, -OC(O)-, -C(O)-, -C(H)(F)-, -C(F)2-, -Cy-, -S(O)-, -S(O)2-, -N(R)S(O)2-, -N(R)C(O)-, -OC(O)N(R)-, or -N(R)C(O)N(R)-);

[0667] each -Cy- is independently an optionally substituted bivalent ring selected from: phenylene, 8-10 membered bicyclic arylene, 4-7 membered saturated or partially unsaturated carbocycloylene, 4-11 membered saturated or partially unsaturated spirocarbocycloylene, 8-10 membered bicyclic saturated or partially unsaturated carbocycloylene, 4-7 membered saturated or partially unsaturated heterocycloylene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 4-11 membered saturated or partially unsaturated spiroheterocycloylene having 1-3 (and in some aspects 1-2) heteroatoms independently selected from nitrogen, oxygen and sulfur, 8-10 membered bicyclic saturated or partially unsaturated heterocycloylene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 8-10 membered bicyclic heteroarylene having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0668] Each R is independently hydrogen or (C1-C3)alkyl.

[0669] In a further aspect, L' is a divalent saturated or unsaturated linear or branched C1-C 25 A hydrocarbon chain wherein 0-10 methylene groups of L' are replaced by X. In a further aspect, L' is a divalent saturated or unsaturated linear or branched C1-C 15 A hydrocarbon chain in which 0 to 10 methylene groups of L' are replaced by X.

[0670] In some aspects (eg, of any preceding embodiment, aspect, or combination of aspects), L' is a covalent bond or a divalent saturated or unsaturated linear or branched

[0671] C1-C 25 A hydrocarbon chain in which 0-10 methylene groups of L' are replaced by X, wherein:

[0672] Each -Cy- is independently an optionally substituted bivalent ring selected from the group consisting of a 4-7 membered saturated or partially unsaturated carbocycloalkylene, a 4-11 membered saturated or partially unsaturated spirocarbocycloalkylene, an 8-10 membered bicyclic saturated or partially unsaturated carbocycloalkylene, a 4-7 membered saturated or partially unsaturated heterocycloalkylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-11 membered saturated or partially unsaturated spiroheterocycloalkylene having 1-3 (and in some aspects 1-2) heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 8-10 membered bicyclic saturated or partially unsaturated carbocycloalkylene, a 4-7 membered saturated or partially unsaturated heterocycloalkylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein -Cy- is an 8-10 membered bicyclic saturated or partially unsaturated heterocycloalkylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (and in some further aspects, each -Cy- is independently an optionally substituted (e.g., unsubstituted) bivalent ring selected from: a 4-7 membered saturated or partially unsaturated heterocycloalkylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-11 membered saturated or partially unsaturated spiroheterocycloalkylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic saturated or partially unsaturated heterocycloalkylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur);

[0673] each X is independently -O-, -N(R)-, -S-, -OC(O)-, -C(O)-, -C(H)(F)-, -C(F)2-, -S(O)-, -S(O)2-, -N(R)S(O)2-, -N(R)C(O)-, -OC(O)N(R)-, or -N(R)C(O)N(R)-; and

[0674] Each R is independently hydrogen or (C1-C3)alkyl.

[0675] In a further aspect, L' is a divalent saturated or unsaturated linear or branched C1-C 25 A hydrocarbon chain wherein 0-10 methylene groups of L' are replaced by X. In a further aspect, L' is a divalent saturated or unsaturated linear or branched C1-C 15 A hydrocarbon chain in which 0 to 10 methylene groups of L' are replaced by X.

[0676] In some aspects (eg, of any of the preceding embodiments, aspects, or combinations of aspects), L' is a divalent saturated or unsaturated linear or branched C1-C 15 A hydrocarbon chain wherein 1, 2, or 3 (e.g., 1 or 2; 1; 2) methylene groups of L' are replaced by Cy, and 0-5 (e.g., 0-3, 1-3, 1, or 2) methylene groups of L' are replaced by X, wherein Cy, X, and R are as described in any aspect herein. In some further aspects, 1 or 2 methylene groups of L' are replaced by Cy. In some further aspects, 1 methylene group of L' is replaced by Cy. In some further aspects, 2 methylene groups of L' are replaced by Cy.

[0677] In some aspects, L' is saturated. In some aspects, L' is linear. In some aspects, L' is saturated and linear.

[0678] In some aspects, 0-8 methylene groups of L' are replaced with X, eg, 0-7, 1-8, 2-8, or 1-5 methylene groups of L' are replaced with X.

[0679] In some aspects, each -Cy- is independently an optionally substituted bivalent ring selected from: a 4-7 membered saturated or partially unsaturated carbocycloalkylene, a 4-11 membered saturated or partially unsaturated spirocarbocycloalkylene, an 8-10 membered bicyclic saturated or partially unsaturated carbocycloalkylene, a 4-7 membered saturated or partially unsaturated heterocycloalkylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-11 membered saturated or partially unsaturated spiroheterocycloalkylene having 1-3 (and in some aspects 1-2) heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic saturated or partially unsaturated heterocycloalkylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some aspects, each -Cy- is independently an optionally substituted (e.g., unsubstituted) divalent ring selected from: a 4-7 membered saturated or partially unsaturated heterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-11 membered saturated or partially unsaturated spiroheterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic saturated or partially unsaturated heterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In further aspects, each -Cy- is independently an optionally substituted (e.g., unsubstituted) divalent 4-7 membered saturated or partially unsaturated (e.g., saturated) heterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4-11 membered saturated or partially unsaturated (e.g., saturated) spiroheterocycloalkylene group having 1-3 (and in some aspects 1-2) heteroatoms independently selected from nitrogen, oxygen, and sulfur. In yet further aspects, each -Cy- is independently an optionally substituted (e.g., unsubstituted) divalent 4-7 membered saturated or partially unsaturated (e.g., saturated) heterocycloalkyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some aspects, each -Cy- is independently selected from cyclohexylene, piperidinylene, azetidinylene, pyrrolidinylene, piperazinylene, morpholinylene, 1-oxa-4,9-diazaspiro[5.5]undecylene, 3-azaspiro[5.5]undecylene, 2-azaspiro[3.3]heptylene, 7-azaspiro[3.5]nonylene, 3-azabicyclo[3.2.1]octylene, 2,7-diazaspiro[3.5]nonylene, 3,9-diazaspiro[5.5]undecylene, or triazinylene.

[0680] In some aspects, each -Cy- is independently optionally substituted with halo, alkyl, or haloalkyl.

[0681] In some aspects (e.g., of any preceding embodiment, aspect, or combination of aspects), L' is -X-(C1-C5)aliphatic-X-, -X-(C1-C5)aliphatic-, -XX-(C1-C5)aliphatic-X-, -XXX-(C1-C5)aliphatic-, -XX-(C1-C5)aliphatic-, -XX-(C1-C5)aliphatic-, -XX-(C1-C5)aliphatic-X-(C1-C5)aliphatic- , -XXXX-(C1-C5)aliphatic-, -XXX-(C1-C5)aliphatic-X-(C1-C5)aliphatic-, -XX-(C1-C5)aliphatic-XX-(C1-C5)aliphatic-, -XX-(C1-C5)aliphatic-XX-, -XXX-(C1-C5)aliphatic-X-, -XXXX-, -XXX- or -XX-, where X is as defined herein. For example, in some aspects, L' is -X-(C1-C5)aliphatic-X-, -X-(C1-C5)aliphatic-*, -XX-(C1-C5)aliphatic-X-*, *-XX-(C1-C5)aliphatic-X-, -XXX-(C1-C5)aliphatic-*, -XX-(C1-C5)aliphatic-*, -XX-(C1-C5)aliphatic-X-, -XXXX-(C1-C5)aliphatic-*, -XX-(C1-C5)aliphatic-*, -XX-(C1-C5)aliphatic-X-(C1-C5)aliphatic-*, -XXXX-(C1-C5)aliphatic- -C5)aliphatic-*, -XXX-(C1-C5)aliphatic-X-(C1-C5)aliphatic-*, -XX-(C1-C5)aliphatic-XX-(C1-C5)aliphatic-*, -XX-(C1-C5)aliphatic-XX-, -XXX-(C1-C5)aliphatic-X-*, -XXXX-, -XXX- or -XX-, wherein X is as defined herein and * represents the point of attachment of L' to the Degron.

[0682] In some aspects (e.g., of any preceding embodiment, aspect, or combination of aspects):

[0683] L' is -X-(C1-C 15 ) aliphatic-X-*, -X-(C1-C 15 )aliphatic-*, -X-Cy-(C1-C5)aliphatic-Cy-*, -X-Cy-(C1-C5)aliphatic-Cy-(C1-C5)aliphatic-*, -X-Cy-X-(C1-C 10)aliphatic-*, -X-Cy-Cy-(C1-C5)aliphatic-*, -X-(C1-C5)aliphatic-X-Cy-*, -X-Cy-(C1-C5)aliphatic-*, -X-Cy-(C1-C5)aliphatic-Cy-(C1-C5)aliphatic-*, -X-Cy-X-Cy-(C1-C5)aliphatic-*, -X-Cy-X-(C1-C5)aliphatic-Cy-*, -X-Cy-Cy-(C1-C5)aliphatic-X-(C1-C5)aliphatic-*, -X-Cy-X-(C1-C5)aliphatic-Cy-*, -X-Cy-Cy-(C1-C5)aliphatic-X-(C1-C5)aliphatic-*, -X-Cy-X-(C1-C5)aliphatic-Cy-(C1-C5)aliphatic-*, -X-Cy-X-(C1-C5)aliphatic -*, -X-(C1-C5)aliphatic-X-Cy-*, -X-Cy-(C1-C5)aliphatic-X-Cy-(C1-C5)aliphatic-*, -X-Cy-(C1-C5)aliphatic-X-(C1-C5)aliphatic-*, -X-Cy-(C1-C5)aliphatic-Cy-X-*, -X-(C1-C5)aliphatic-X-(C1-C5)aliphatic-Cy-*, -X-(C1-C5)aliphatic-Cy-(C1-C5)aliphatic-*, -X-Cy-Cy-X-*, -X-Cy-X-Cy-*, -X-Cy-Cy-*, or -X-Cy-*, where * represents the point of attachment of L' to the Degron;

[0684] each X is independently -O-, -C(O)-, -N(R)-, or -N(R)C(O)-; and

[0685] Each -Cy- is independently selected from any value of -Cy- described herein, e.g., cyclohexylene, piperidinylene, azetidinylene, pyrrolidinylene, piperazinylene, morpholinylene, 1-oxa-4,9-diazaspiro[5.5]undecylene, 3-azaspiro[5.5]undecylene, 2-azaspiro[3.3]heptylene, 7-azaspiro[3.5]nonanylene, 3-azabicyclo[3.2.1]octanylene, 2,7-diazaspiro[3.5]nonanylene, 3,9-diazaspiro[5.5]undecylene, or triazinylene.

[0686] In some further aspects, L' is -X-Cy-(C1-C5)aliphatic-Cy-*, -X-Cy-(C1-C5)aliphatic-Cy-(C1-C5)aliphatic-*, -X-Cy-X-(C1-C 10)aliphatic-*, -X-Cy-Cy-(C1-C5)aliphatic-*, -X-(C1-C5)aliphatic-X-Cy-*, -X-Cy-(C1-C5)aliphatic-*, -X-Cy-(C1-C5)aliphatic-Cy-(C1-C5)aliphatic-*, -X-Cy-X-Cy-(C1-C5)aliphatic-*, -X-Cy-X-(C1-C5)aliphatic-Cy-*, -X-Cy-Cy-(C1-C5)aliphatic-X-(C1-C5)aliphatic-*, -X-Cy-X-(C1-C5)aliphatic-Cy-*, -X-Cy-Cy-(C1-C5)aliphatic-X-(C1-C5)aliphatic-*, -X-Cy-X-(C1-C5)aliphatic-Cy-(C1-C5)aliphatic-*, -X-Cy-X-(C1-C5)aliphatic 5) aliphatic-X-Cy-*, -X-(C1-C5)aliphatic-X-Cy-*, -X-Cy-(C1-C5)aliphatic-X-Cy-(C1-C5)aliphatic-*, -X-Cy-(C1-C5)aliphatic-X-(C1-C5)aliphatic-*, -X-Cy-(C1-C5)aliphatic-Cy-X-*, -X-(C1-C5)aliphatic-X-(C1-C5)aliphatic-Cy-*, -X-(C1-C5)aliphatic-Cy-(C1-C5)aliphatic-*, -X-Cy-Cy-X-*, -X-Cy-X-Cy-*, -X-Cy-Cy-*, or -X-Cy-*. In some further aspects, L' is -X-Cy-(C1-C5)aliphatic-Cy-*, -X-Cy-(C1-C5)aliphatic-Cy-(C1-C5)aliphatic-*, -X-Cy-X-(C1-C 10 )aliphatic-*, -X-Cy-Cy-(C1-C5)aliphatic-*, -X-(C1-C5)aliphatic-X-Cy-*, -X-Cy-(C1-C5)aliphatic-*, -X-Cy-(C1-C5)aliphatic-Cy-(C1-C5)aliphatic-*, -X-Cy-X-Cy-(C1-C5)aliphatic-*, -X-Cy-X-(C1-C5)aliphatic-Cy-*, -X-Cy-Cy-(C1-C5)aliphatic-X-(C1-C5)aliphatic-*, -X-Cy -X-(C1-C5)aliphatic-Cy-(C1-C5)aliphatic-*, -X-Cy-(C1-C5)aliphatic-X-Cy-*, -X-Cy-(C1-C5)aliphatic-X-Cy-(C1-C5)aliphatic-*, -X-Cy-(C1-C5)aliphatic-X-Cy-(C1-C5)aliphatic-*, -X-Cy-(C1-C5)aliphatic-X-(C1-C5)aliphatic-*, -X-Cy-(C1-C5)aliphatic-Cy-X-*, -X-Cy-Cy-X-*, -X-Cy-X-Cy-*, -X-Cy-Cy-* or -X-Cy-*.

[0687] In some aspects of L', L' is linked to KRAS G12Di via -X-Cy-. In some aspects, when -X-Cy- links L' to KRAS G12Di, -X-Cy- is -C(O)-Cy-, wherein Cy is a 4-7 membered saturated or partially unsaturated heterocycloalkylene having 1 nitrogen atom and optionally one additional heteroatom selected from nitrogen, oxygen, and sulfur, a 4-11 membered saturated or partially unsaturated spiroheterocycloalkylene having 1 nitrogen atom and optionally 1-2 (and in some aspects 1) additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic saturated or partially unsaturated heterocycloalkylene having 1 nitrogen atom and optionally 1 additional heteroatom independently selected from nitrogen, oxygen, and sulfur. In some further aspects, when -X-Cy- connects L' to KRASG12Di, -X-Cy- is In some still further aspects, when -X-Cy- links L' to KRAS G12Di, -X-Cy- is

[0688] In some aspects of L', L' comprises -Cy 1 -(CH2) 0-1 -X-(CH2) 0-1 -Cy 2 -, where: Cy 1 and Cy 2 is independently selected from any value of Cy described herein; and X is absent or selected from any value of X described herein. For example, in some aspects, Cy 1 is a 4-7 membered saturated or partially unsaturated heterocycloalkylene having 1 nitrogen atom and optionally 1 additional heteroatom selected from nitrogen, oxygen and sulfur, a 4-11 membered saturated or partially unsaturated spiroheterocycloalkylene having 1 nitrogen atom and optionally 1-2 (and in some aspects 1) additional heteroatoms independently selected from nitrogen, oxygen and sulfur, or an 8-10 membered bicyclic saturated or partially unsaturated heterocycloalkylene having 1 nitrogen atom and optionally 1 additional heteroatom independently selected from nitrogen, oxygen and sulfur, and is attached via the nitrogen atom (e.g., to the remainder of L', if present, KRAS G12Di or Degron), e.g., Cy 1In some further aspects, Cy is piperidinylene, azetidinylene, pyrrolidinylene, piperazinylene, morpholinylene, 1-oxa-4,9-diazaspiro[5.5]undecylene, 3-azaspiro[5.5]undecylene, 2-azaspiro[3.3]heptylene, 7-azaspiro[3.5]nonylene, 3-azabicyclo[3.2.1]octylene, 2,7-diazaspiro[3.5]nonylene or 3,9-diazaspiro[5.5]undecylene. 1 yes In some further aspects, Cy 1 yes In some preferred aspects, Cy 1 Represents the -Cy closer to KRAS G12Di in the compounds disclosed herein 1 -(CH2) 0-1 -X-(CH2) 0-1 -Cy 2 -terminal. In some further or alternative aspects, Cy 2 is cyclohexylene, piperidinylene, azetidinylene, pyrrolidinylene, piperazinylene, morpholinylene, 1-oxa-4,9-diazaspiro[5.5]undecylene, 3-azaspiro[5.5]undecylene, 2-azaspiro[3.3]heptylene, 7-azaspiro[3.5]nonylene, 3-azabicyclo[3.2.1]octanylene, 2,7-diazaspiro[3.5]nonylene, 3,9-diazaspiro[5.5]undecylene or triazinylene. In some preferred aspects, Cy 2 Represents the -Cy closer to Degron in the compounds disclosed herein 1 -(CH2) 0-1 -X-(CH2) 0-1 -Cy 2 -terminal. In some aspects, X is C(O), O or N(R), wherein R is as described herein. In some further aspects, X is O or N(R). In some aspects, Cy 1 is linked to KRAS G12Di via X, wherein X is as described herein, for example, -C(O)- or -C(O)O-. 1 In certain aspects of KRAS G12Di linked via -C(O)- or -C(O)O-, Cy 1 Via Cy 1 The nitrogen atom is connected to the carbonyl carbon of -C(O)- or -C(O)O-.

[0689] In some aspects (eg, of any preceding embodiment, aspect, or combination of aspects), L' is -X-(CO-C 15 ) aliphatic group -X-, -X-(C0-C15 ) aliphatic-, -XX-(C0-C 15 ) aliphatic-X-, -XXX-(C1-C 15 ) aliphatic- or -XX-(C1-C 15 )aliphatic-. For example, in some aspects, L' is -X-(CO-C 15 ) aliphatic group-X-*, -X-(C0-C 15 ) aliphatic-*, -XX-(C0-C 15 ) aliphatic-X-*, -XXX-(C1-C 15 ) aliphatic-* or -XX-(C1-C 15 )aliphatic-*, wherein * represents the point of attachment of L' to Degron. In some aspects, L' is -X-(C1-C 15 ) aliphatic-X-, -X-(C1-C 15 ) aliphatic-, -XX-(C1-C 15 ) aliphatic-X-, -XXX-(C1-C 15 ) aliphatic- or -XX-(C1-C 15 ) aliphatic-. In some aspects, L' is -X-(C1-C 15 ) aliphatic-X-*, -X-(C1-C 15 ) aliphatic-*, -XX-(C1-C 15 ) aliphatic-X-*, -XXX-(C1-C 15 ) aliphatic-* or -XX-(C1-C 15 )aliphatic-*, wherein * represents the point of attachment of L' to Degron. In some aspects, L' is -C(O)-Cy-O-(C1-C 10 ) aliphatic or -C(O)-Cy-(C1-C 10 ) aliphatic groups, such as -C(O)-Cy-O-(C1-C 10 ) aliphatic* or -C(O)-Cy-(C1-C 10 ) aliphatic group*, wherein * represents the point of attachment of L' to Degron.

[0690] In some aspects (eg, of any preceding embodiment, aspect, or combination of aspects), L' is -X-(CH2) p -X-, -X-(CH2) q -or-X-(CH2CH2O) r CH2CH2-X-, wherein p is an integer from 0 to 15; q is an integer from 0 to 15; and r is an integer from 1 to 5. For example, in some aspects, L' is -X-(CH2) p-X-*, -X-(CH2) q -* or -X-(CH2CH2O) r CH2CH2-X-*, wherein * represents the point of attachment of L' to Degron. In some aspects, L' is -C(O)N(H)-(CH2) p -N(H)-, -C(O)N(H)-(CH2) p -or-C(O)N(H)-(CH2CH2O) r CH2CH2-N(H)-. In a further aspect, L' is -C(O)N(H)-(CH2) p -N(H)-*、-C(O)N(H)-(CH2) p -*or-C(O)N(H)-(CH2CH2O) r CH2CH2-N(H)-*, where * represents the connection point between L' and Degron.

[0691] In some aspects, p is an integer from 2 to 10, eg, from 3 to 10; from 6 to 10; or 9 or 10.

[0692] In some aspects, q is an integer from 2 to 11, such as from 3 to 11; from 5 to 11; or from 9, 10, or 11. In some aspects, q is an integer from 6 to 15, such as from 8 to 12.

[0693] In some aspects, r is 1, 2, 3, 4, or 5. In some aspects, r is 1, 2, or 3, such as 2 or 3; 2; or 3.

[0694] In some aspects, each X is independently -O-, -N(R)-, -S-, -OC(O)-, -C(O)-, -C(H)(F)-, -C(F)2-, -Cy-, -S(O)-, -S(O)2-, -N(R)S(O)2-, -N(R)C(O)-, -OC(O)N(R)-, -N(R)C(O)N(R)-, In some aspects, each X is independently -O-, -C(O)-, -N(R)-, -S-, -OC(O)-, -Cy-, -N(R)C(O)-, -OC(O)N(R)-, or -N(R)C(O)N(R)-. In some aspects, each X is independently -O-, -N(R)-, -S-, -OC(O), -N(R)C(O)-, -OC(O)N(R)-, or -N(R)C(O)N(R)-. In some aspects, each X is independently -O-, -N(R)-, -S-, -OC(O), -N(R)C(O)-, or -OC(O)N(R)-. In some aspects, each X is independently -O-, -C(O)-, -N(R)-, -Cy-, or -N(R)C(O)-. In some aspects, each X is independently -O-, -C(O)-, -N(R)-, or -N(R)C(O)-. In some aspects, each X is independently -O-, -N(R)-, or -N(R)C(O)-.

[0695] In some aspects, each R is independently hydrogen or methyl. In further aspects, each R is hydrogen.

[0696] Specific examples of L' include -C(O)N(H)-(CH2) 3,4,6,8,9,10 -N(H)-*、-C(O)N(H)-(CH2) 2,3,4,5,8,9,10,11 -* and -C(O)N(H)-(CH2CH2O) 2,3 CH2CH2-N(H)-*, wherein * represents the connection point between L' and Degron. Other specific examples of L' include in indicates the point of attachment to KRAS G12Di, and * indicates the point of attachment of L' to Degron.

[0697] Other specific examples of L' include the linkers depicted in Table A. In some aspects, L' is a linker in Table A.

[0698] Table A. Connector (L')

[0699]

[0700]

[0701]

[0702]

[0703]

[0704]

[0705]

[0706]

[0707]

[0708]

[0709]

[0710]

[0711]

[0712]

[0713]

[0714]

[0715]

[0716]

[0717]

[0718]

[0719]

[0720]

[0721]

[0722]

[0723]

[0724] From the above, it will be understood that, except as indicated by, for example, "*", when the value of L' is asymmetric (e.g., -C(O)N(H)-, -C(O)N(H)-(CH2) 3,4,6,8,9,10 -N(H)-, -C(O)N(H)-(CH2) 2,3,4,5,9,10,11 -、-C(O)N(H)-(CH2CH2O) 2,3In some embodiments, -C(O)N(H)- may be oriented in any direction between KRASG12Di and Degron. Thus, for example, unless otherwise specified, -C(O)N(H)- may be oriented to produce any of the following compounds: [KRASG12Di]-C(O)N(H)-[Degron] or [KRASG12Di]-N(H)C(O)-[Degron]. Alternatively, the notation -C(O)N(H)-* (where * indicates the point of attachment of L' to Degron) may be used to describe a compound of the following formula: [KRASG12Di]-C(O)N(H)-[Degron].

[0725] Degron

[0726] Degron brings the ligase into close contact with the target protein, enabling the protein to be tagged with a ubiquitin tag and targeted for degradation via the ubiquitin-proteasome system.

[0727] As used herein, "Degron" refers to a portion that can promote the degradation of a target protein (such as KRAS G12D) via the ubiquitin proteasome pathway (UPP) under suitable conditions (e.g., in vitro, in vivo). Typically, in PROTAC, such as the compounds of the present disclosure, degron can bind to ubiquitin E3 ligases, thereby recruiting ubiquitin E3 ligases to enter the vicinity of PROTAC, and by extension recruiting into the target protein, which binds to KRAS G12Di in the compounds of the present disclosure under suitable conditions. The formation of a ternary ligase-PROTAC-target protein complex leads to ubiquitination and degradation of the target protein, for example, by the 26S proteasome as a component of the UPP. Therefore, examples of degron include ubiquitin E3 ligase binding moieties that bind to ubiquitin E3 ligases. Examples of E3 ligases include cereblon (CRBN), von Hippel-Lindau (VHL), inhibitor of apoptosis protein (IAP), mouse double minute 2 homolog (MDM2), DDB1 and CUL4-associated factor 16 (DCAF16), and ring finger protein 114 (RNF114). Other examples of degraders include hydrogen atoms and lysine mimetics, both of which are disclosed in International Publication No. WO 2021 / 127278, the entire contents of which are incorporated herein.

[0728] In some aspects (e.g., of any preceding embodiment, aspect, or combination of aspects), Degron is a ubiquitin E3 ligase binding moiety (e.g., a celebron binding moiety). In further aspects, the ubiquitin E3 ligase is CRBN, VHL, IAP, MDM2, DCAF16, or RNF114. In yet further aspects, the ubiquitin E3 ligase is CRBN, such as when the ubiquitin E3 ligase binding moiety is a celebron binding moiety. Thus, in some aspects, Degron is a celebron binding moiety.

[0729] International Publication No. WO 2021 / 127278 discloses ubiquitin E3 ligase binding moieties, including celebron binding moieties. See, e.g., Table A therein. In some aspects (e.g., of any of the foregoing embodiments, aspects, or combinations of aspects), Degron is a ubiquitin E3 ligase binding moiety (e.g., a celebron binding moiety) disclosed in WO 2021 / 127278.

[0730] Celebron-binding moieties are also disclosed in U.S. Patent No. 10,849,982; and U.S. Patent Application Publication Nos. US 2020 / 0140456 and US 2020 / 0377469. In some aspects (e.g., of any of the foregoing embodiments, aspects, or combinations of aspects), Degron is a Celebron-binding moiety disclosed in U.S. Patent No. 10,849,982 or U.S. Patent Application Publication Nos. US 2020 / 0140456 or US 2020 / 0377469.

[0731] In some aspects (e.g., of any preceding embodiment, aspect, or combination of aspects), Degron is (For example, ), (For example, ), (For example, )or (For example, ).

[0732] In some aspects (e.g., of any preceding embodiment, aspect, or combination of aspects), Degron is In a further aspect, Degron is

[0733] In some aspects (e.g., of any preceding embodiment, aspect, or combination of aspects), Degron is In a further aspect, Degron is In a still further aspect, Degron is In other respects, Degron is In a further aspect, Degron is

[0734] In some aspects (e.g., of any preceding embodiment, aspect, or combination of aspects), Degron is In a further aspect, Degron is In a still further aspect, Degron is In other respects, Degron is In a further aspect, Degron is

[0735] In any Degron structure containing a benzene ring (e.g., any of the aforementioned Degron structures), it will be understood that one or more hydrogen atoms of the benzene ring may be substituted, such as in the following formula: Where indicated, the present disclosure encompasses such substitutions. Thus, in some aspects, one or more hydrogen atoms (e.g., 1-4; 1-3; 1 or 2) on the phenyl ring of Degron are optionally replaced by fluorine atoms. In some aspects, one hydrogen atom on the phenyl ring of Degron is replaced by a fluorine atom. In some aspects, two hydrogen atoms on the phenyl ring of Degron are replaced by fluorine atoms. In some aspects, three fluorine atoms on the phenyl ring of Degron are replaced by fluorine atoms. In some aspects, the phenyl ring of Degron is perfluorinated. In some aspects, the phenyl ring of Degron is unsubstituted.

[0736] Other specific examples of ubiquitin E3 ligase binding moieties include those depicted in Table B. In some aspects, Degron is a ubiquitin E3 ligase binding moiety in Table B.

[0737] Table B. Ubiquitin E3 ligase binding moieties

[0738]

[0739]

[0740]

[0741]

[0742]

[0743] In some aspects (e.g., of any preceding embodiment, aspect, or combination of aspects), Degron is In some aspects (e.g., of any preceding embodiment, aspect, or combination of aspects), Degron is not

[0744] Specific examples of compounds of the present disclosure are listed in Table 1. One embodiment provides a compound of Table 1 or a pharmaceutically acceptable salt thereof.

[0745] In some aspects (eg, of any preceding embodiment, aspect, or combination of aspects), the compound is not:

[0746]

[0747]

[0748]

[0749]

[0750] or a salt thereof. In some aspects, the compound is not:

[0751]

[0752]

[0753]

[0754] or a salt thereof.

[0755] Table 1. Exemplary compounds of the present disclosure

[0756]

[0757]

[0758]

[0759]

[0760]

[0761]

[0762]

[0763]

[0764]

[0765]

[0766]

[0767]

[0768]

[0769]

[0770]

[0771]

[0772]

[0773]

[0774]

[0775]

[0776]

[0777]

[0778]

[0779]

[0780]

[0781]

[0782]

[0783]

[0784]

[0785]

[0786] Methods of preparing compounds of the present disclosure are described herein in the Examples.

[0787] Composition, combination, kit

[0788] Typically, in order to administer to a subject, the compounds of the present disclosure are formulated together with one or more pharmaceutically acceptable carriers. The present disclosure provides such compositions, including pharmaceutical compositions. Therefore, one embodiment is a composition (e.g., a pharmaceutical composition) comprising a compound of the present disclosure and a pharmaceutically acceptable carrier. The compositions described herein can be used according to the purposes and / or methods described herein, for example, to provide a compound of the present disclosure for administration to a subject.

[0789] Can be orally, parenterally (including subcutaneous, intramuscular, intravenous and intradermal), by inhalation spray, topically, rectal, nasal, buccal, vaginal or via implanted reservoir administration composition as described herein and (therefore) compound of the present disclosure.Term " parenteral " as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraocular, intravitreal, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, intrahepatic, intraperitoneal, intralesional and intracranial injection or infusion technology.In some aspects, composition as described herein can be administered intravenously and / or intraperitoneally.In some aspects, composition as described herein can be administered orally.Preferably, composition as described herein is administered orally, subcutaneously, intraperitoneally or intravenously.

[0790] The compositions provided herein can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, dispersions, and solutions. In the case of oral tablets, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions and / or emulsions for oral use are desired, the active ingredient can be suspended or dissolved in an oil phase and combined with an emulsifier and / or suspending agent. If desired, certain sweeteners, flavorings, or coloring agents can also be added.

[0791] In some aspects, oral formulations are formulated for immediate release or sustained / delayed release.

[0792] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or (a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) humectants, such as glycerol, (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents, such as paraffin, (f) absorption promoters, such as quaternary ammonium salts, (g) wetting agents, such as acetyl alcohol and glycerol monostearate, (h) absorbents, such as kaolin and bentonite, and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain a buffer.

[0793] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the disclosed compound, liquid dosage forms can also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol (ethyl alcohol / ethanol), isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oil (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuran methanol, polyethylene glycol and the fatty acid ester of sorbitan, or a mixture thereof. In addition to inert diluents, oral compositions can also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings, coloring agents, aromatics and preservatives.

[0794] Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.

[0795] Solid compositions of similar types can also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the art of pharmaceutical formulation. They may optionally contain opacifiers and may also be compositions that release the active ingredient only or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0796] As noted above, the compounds of the present disclosure may also be in microencapsulated form with one or more excipients. In such solid dosage forms, the compounds may be admixed with at least one inert diluent, such as sucrose, lactose, or starch. Conventionally, such dosage forms may also contain additional substances in addition to the inert diluent, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose.

[0797] Compositions for oral administration can be designed to protect the active ingredient from degradation as it passes through the digestive tract, for example, by external coatings of the formulation on tablets or capsules.

[0798] On the other hand, the compound of the present disclosure can be provided in the form of an extended (or "delayed" or "sustained") release composition. This delayed release composition comprises a compound of the present disclosure and a delayed release component. This composition allows the compound to be released in a targeted manner, for example, into the lower gastrointestinal tract, for example, into the small intestine, large intestine, colon and / or rectum. In some aspects, the delayed release composition further comprises an enteric or pH-dependent coating, such as cellulose acetate phthalate and other phthalates (e.g., polyvinyl acetate phthalate, methacrylate (Eudragits)). Alternatively, the delayed release composition can provide controlled release to the small intestine and / or colon by providing a pH-sensitive methacrylate coating, a pH-sensitive polymer microsphere or a polymer that is degraded by hydrolysis. The delayed release composition can be formulated with a hydrophobic or gelling excipient or coating. Colonic delivery can be further provided by coatings that are digested by bacterial enzymes (such as amylose or pectin), by pH-dependent polymers, by hydrogel plugs that swell over time (Pulsincap), by time-dependent hydrogel coatings, and / or by acrylic acid coatings linked to azoaromatic linkages.

[0799] The compositions described herein can also be administered subcutaneously, intraperitoneally, or intravenously, for example in the form of sterile injectable preparations, for example, as sterile injectable aqueous or oily suspensions. Such suspensions can be prepared using suitable dispersants or wetting agents (e.g., Tween 80) and suspending agents according to techniques known in the art. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used include mannitol, dextrose, water, Ringer's solution, lactated Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, can be used to prepare injections, such as oils acceptable to natural medicines, such as olive oil or castor oil, particularly their polyoxyethylated forms. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersants, which are commonly used to formulate pharmaceutically acceptable dosage forms, such as emulsions and or suspensions. Other commonly used surfactants (such as Tween or Span and / or other similar emulsifiers or bioavailability enhancers) commonly used in the preparation of pharmaceutically acceptable solid, liquid or other dosage forms may also be used for formulation purposes.

[0800] The compositions described herein can also be administered in the form of suppositories for rectal administration. These can be prepared by mixing the compounds of the present disclosure with suitable non-irritating excipients that are solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such substances include cocoa butter, beeswax, and polyethylene glycol.

[0801] The compositions described herein can also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0802] Topical application to the lower intestinal tract can be accomplished in a rectal suppository formulation (see above) or in a suitable enema formulation.Topical transdermal patches may also be used.

[0803] For other topical applications, the composition can be formulated into a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical application of the compounds described herein include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, water, and a penetration enhancer. Alternatively, the composition can be formulated into a suitable lotion or cream containing the active compound suspended or dissolved in one or more pharmaceutically acceptable carriers. Alternatively, the composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier and a suitable emulsifier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. Suitable carriers also include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetyl alcohol, 2-octyldodecanol, benzyl alcohol, water, and a penetration enhancer.

[0804] For ophthalmic use, the composition can be formulated as a micronized suspension in isotonic pH-adjusted sterile saline, or preferably, as a solution in isotonic pH-adjusted sterile saline, with or without a preservative such as benzalkonium chloride. Alternatively, for ophthalmic use, the composition can be formulated as an ointment such as petrolatum.

[0805] The compositions can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, absorption promoters to improve bioavailability, fluorocarbons, and / or other conventional solubilizing agents or dispersants. Without wishing to be bound by any particular theory, it is believed that local delivery of the compositions described herein, such as can be achieved by nasal aerosol or inhalation, can reduce the risk of systemic consequences (e.g., consequences on red blood cells) of the compositions.

[0806] Other pharmaceutically acceptable carriers that can be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopheryl polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tween or other similar polymeric delivery matrices, 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 materials, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin. Cyclodextrins, such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives, such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrin, or other solubilized derivatives, may also be advantageously used to enhance delivery of the agents described herein.

[0807] In some aspects, the compositions described herein further include one or more additional therapeutic agents, eg, for use in combination with the compounds of the present disclosure.

[0808] Some embodiments provide combinations (e.g., pharmaceutical combinations) comprising a compound of the present disclosure (e.g., a composition comprising a compound of the present disclosure as described herein) and one or more additional therapeutic agents (e.g., one or more compositions comprising one or more additional therapeutic agents). Such combinations are particularly useful, for example, when the compound of the present disclosure and the one or more additional therapeutic agents are to be administered separately. In the combinations provided herein, the compound of the present disclosure and the one or more additional therapeutic agents can be administered by the same route of administration or by different routes of administration.

[0809] Some embodiments provide kits comprising a compound of the present disclosure (e.g., a composition comprising a compound of the present disclosure as described herein) and an additional therapeutic agent (e.g., a composition comprising an additional therapeutic agent). In one embodiment, the kit comprises a therapeutically effective amount of a compound of the present disclosure for treating a disease, disorder, or condition as described herein and one or more additional therapeutic agents for treating the disease, disorder, or condition as described herein. In some aspects, the kit further comprises written instructions for administering a compound of the present disclosure and / or an additional agent to a subject to treat a disease, disorder, or condition as described herein.

[0810] Additional therapeutic agents for use in the compositions, combinations and / or kits provided herein include any of the therapeutic agents discussed herein with respect to combination therapy.

[0811] In some aspects, the compositions described herein are provided in unit dosage form. Therefore, some embodiments provide a unit dosage form comprising, for example, a compound of the present disclosure and a pharmaceutically acceptable carrier. The amount of the compound of the present disclosure or other therapeutic agent that can be combined with a carrier substance to produce a composition of a unit dosage form will vary according to, for example, the subject being treated, the specific mode of administration, and the activity of the medicament used. Preferably, the composition and / or unit dosage form should be formulated so that the compound of the present disclosure or other therapeutic agent can be administered to the subject receiving the composition and / or unit dosage form with a dosage and / or frequency consistent with those described herein. Typically, the unit dosage form will contain an active ingredient of about 1 mg to about 5,000 mg, about 10 mg to about 2,500 mg, about 100 mg to about 1,000 mg, about 1 mg to about 1000 mg, about 1 mg to about 500 mg, about 1 mg to about 250 mg, about 1 mg to about 150 mg, about 0.5 mg to about 100 mg, or about 1 mg to about 50 mg.

[0812] In some embodiments, the concentration of the therapeutic agent (e.g., a compound of the present disclosure) in the composition is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% w / w, w / v, or v / v; and / or greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% w / w, w / v, or v / v. In some embodiments, the concentration of the therapeutic agent (e.g., a compound of the present disclosure) in the composition is in the range of about 0.001% to about 50%, about 0.001% to about 25%, about 0.01% to about 20%, about 0.05% to about 15%, about 0.1% to about 10%, or about 1% to about 10% w / w, w / v, or v / v. In some embodiments, the concentration of the therapeutic agent (e.g., a compound of the present disclosure) in the composition is in the range of about 0.001% to about 10%, about 0.01% to about 5%, or about 0.1% to about 1% w / w, w / v, or v / v.

[0813] use

[0814] It has been found that various compounds of the present disclosure exhibit effects consistent with the degradation of KRAS G12D. Therefore, provided herein in one embodiment is a method for reducing the level or activity of KRAS G12D in a cell (e.g., a cell expressing KRAS G12D), comprising contacting the cell with (e.g., an effective amount of) a compound of the present disclosure or a composition comprising a compound of the present disclosure. In some aspects, the method is performed in vitro. In some aspects, the method is performed ex vivo. In some aspects, the method is performed in vivo. In some aspects, the cell is in a subject, such as a subject suffering from a KRAS G12D-related cancer.

[0815] Thus, provided herein, in another embodiment, are methods of reducing the level or activity of KRAS G12D in a subject in need thereof, comprising administering to the subject an effective amount (eg, a therapeutically effective amount) of a disclosed compound or a composition comprising a disclosed compound.

[0816] KRASG12D levels or activity can be reduced according to the methods described herein by, for example, promoting degradation of KRASG12D and / or inhibiting the activity of KRASG12D via UPP. In some aspects, the method for reducing the level or activity of KRASG12D is a method for promoting (e.g., inducing) degradation of KRASG12D. Additionally or alternatively, in some aspects, the method for reducing the level or activity of KRASG12D is a method for inhibiting the activity of KRASG12D.

[0817] Also provided herein in the embodiments is a method for treating a cancer (e.g., a KRAS G12D-related cancer) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a composition comprising a compound of the present disclosure. The cancer can be a solid tumor cancer or a hematological cancer (e.g., a leukemia, a lymphoma, or a myeloma). In some aspects, the cancer is a solid tumor cancer. In some aspects, the cancer is a hematological cancer.

[0818] Cancers that can be treated according to the methods described herein (e.g., KRAS G12D cancers) include, but are not limited to, astrocytic carcinoma, breast cancer, cervical cancer, skin cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, testicular cancer, and prostate cancer, thyroid cancer, and sarcoma. For example, the following cancers (e.g., KRAS G12D cancer) G12D cancers) can be treated according to the methods described herein: cardiac cancers, such as sarcomas (e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyomas, fibromas, lipomas, and teratomas; lung cancers, such as bronchogenic carcinomas (e.g., squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, enchondromatous hamartoma, mesothelioma; gastrointestinal cancers, such as esophageal cancer (e.g., squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (e.g., carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (e.g., Cancers of the genitourinary tract, such as renal cancer (e.g., adenocarcinoma, Wilms' tumor (Nephroblastoma), lymphoma, leukemia), bladder and urethral cancer (e.g., squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (e.g., adenocarcinoma, myxoma), and colorectal cancer (e.g., adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma). Cancers of the liver, such as hepatoma (e.g., hepatocellular carcinoma), bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; cancers of the biliary tract, such as gallbladder cancer, ampullary carcinoma, and bile duct cancer; bone cancers, such as osteogenic sarcomas (e.g., osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphomas (e.g., reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, and osteochondroma (e.g., osteochondroma). bone exostoses), benign enchondromas, chondroblastomas, chondromyxofibromas, osteoid osteomas, and giant cell tumors; nervous system cancers, such as skull cancers (e.g., osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meningeal cancers (e.g., meningiomas, meningosarcomas, gliomatosis), brain cancers (e.g., astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors (e.g., pinealoma), glioblastoma multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors), spinal cord cancers (e.g., neurofibromas, meningiomas, gliomas, sarcomas);Gynecological cancers, such as uterine cancer (e.g., endometrial cancer), cervical cancer (e.g., cervical carcinoma, preneoplastic cervical dysplasia), ovarian cancer (e.g., ovarian carcinoma (e.g., serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa cell-thecoma, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulvar cancer (e.g., squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (e.g., clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (e.g., embryonal rhabdomyosarcoma), Fallopian tube cancer (e.g., carcinoma); hematological cancers, such as blood cancers (e.g., myeloid leukemia (e.g., acute, chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (e.g., malignant lymphoma); skin cancers, such as malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal cancers, such as neuroblastoma.

[0819] Other examples of cancers that can be treated according to the methods described herein include acute lymphoblastic leukemia (ALL); acute myeloid leukemia (AML); adrenocortical carcinoma; childhood adrenocortical carcinoma; AIDS-related cancers (e.g., Kaposi's sarcoma, AIDS-related lymphoma, primary CNS lymphoma); anal cancer; appendix cancer; childhood astrocytoma; childhood atypical teratoid / rhabdoid tumors, central nervous system; basal cell carcinoma of the skin; bile duct cancer; bladder cancer; childhood bladder cancer; bone cancer (including Ewing's sarcoma, osteosarcoma, and malignant fibrous histiocytoma); brain tumors / cancer; breast cancer; Burkitt's lymphoma; carcinoid tumors (gastrointestinal); childhood carcinoid tumors; childhood cardiac (heart) tumors; childhood embryonal tumors; childhood Germ cell tumors; primary CNS lymphoma; cervical cancer; childhood cervical cancer; bile duct cancer; childhood chordoma; chronic lymphocytic leukemia (CLL); chronic myeloid leukemia (CML); chronic myeloproliferative neoplasms; colorectal cancer; childhood colorectal cancer; childhood craniopharyngioma; cutaneous T-cell lymphoma (e.g., mycosis fungoides and Sézary syndrome); ductal carcinoma in situ (DCIS); childhood CNS embryonal tumor; endometrial cancer (uterine cancer); childhood ependymoma; esophageal cancer; childhood esophageal cancer; olfactory neuroblastoma; Ewing's sarcoma; extracranial germ cell tumors in children; extragonadal germ cell tumors; eye cancer; intraocular melanoma in children; intraocular melanoma; retinoblastoma; fallopian tube cancer; malignant bone Fibrous histiocytoma and osteosarcoma; gallbladder cancer; stomach (gastric) cancer; childhood stomach (gastric) cancer; gastrointestinal carcinoid tumors; gastrointestinal stromal tumors (GIST); childhood gastrointestinal stromal tumors; germ cell tumors; childhood central nervous system germ cell tumors (e.g., extracranial germ cell tumors, extragonadal germ cell tumors, ovarian germ cell tumors, testicular cancer); gestational trophoblastic disease; hairy cell leukemia; head and neck cancer; childhood heart tumors; hepatocellular (liver) cancer; Langerhans cell histiocytosis; Hodgkin lymphoma; hypopharyngeal cancer; intraocular melanoma; intraocular melanoma in children; islet cell tumors, pancreatic neuroendocrine tumors; Kaposi sarcoma; kidney (renal cell) cancer; Langerhans cell histiocytosis; laryngeal cancer; leukemia; Lip and oral cancer; liver cancer; lung cancer (non-small cell and small cell); childhood lung cancer; lymphoma; male breast cancer; malignant fibrous histiocytoma and osteosarcoma of bone; melanoma; childhood melanoma; intraocular (eye) melanoma; childhood intraocular melanoma; Merkel cell carcinoma; malignant mesothelioma; childhood mesothelioma; metastatic cancer; metastatic squamous cell carcinoma of the neck with occult primary; median mediastinal cancer with NUT gene alterations; oral cancer; multiple endocrine neoplasia syndrome; multiple myeloma / plasma cell neoplasms; mycosis fungoides; myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasms; chronic myeloid leukemia (CML); acute myeloid leukemia (AML); chronic myeloproliferative neoplasms; nasal cavity and paranasal sinus cancer; nasopharyngeal cancer;Neuroblastoma; non-Hodgkin lymphoma; non-small cell lung cancer; cancer of the oral cavity, lip, and oral cavity, and oropharyngeal cancer; osteosarcoma and malignant fibrous histiocytoma of bone; ovarian cancer; childhood ovarian cancer; pancreatic cancer; childhood pancreatic cancer; pancreatic neuroendocrine tumors; papillomatosis (laryngeal cancer in children); paraganglioma; childhood paraganglioma; paranasal sinus and nasal cavity cancer; parathyroid cancer; penile cancer; pharyngeal cancer; pheochromocytoma; childhood pheochromocytoma; pituitary tumor; plasma cell neoplasms / multiple myeloma; pleuropulmonary blastoma; pregnancy and breast cancer; primary central nervous system (CNS) lymphoma; primary peritoneal cancer; prostate cancer; rectal cancer; recurrent cancer; renal cell (kidney) cancer; retinoblastoma; childhood rhabdomyosarcoma; salivary gland cancer; sarcomas (e.g., childhood rhabdomyosarcoma, childhood pheochromocytoma); Hemangioma, Ewing's sarcoma, Kaposi's sarcoma, osteosarcoma (bone cancer), soft tissue sarcoma, uterine sarcoma); Sézary syndrome; skin cancer; childhood skin cancer; small cell lung cancer; small bowel cancer; soft tissue sarcoma; squamous cell carcinoma of the skin; metastatic squamous cell carcinoma of the neck with occult primary; stomach (gastric) cancer; childhood stomach (gastric) cancer; cutaneous T-cell lymphomas (e.g., mycosis fungoides and Sèzary syndrome); testicular cancer; childhood testicular cancer; laryngeal cancer (e.g., nasopharyngeal, oropharyngeal, hypopharyngeal); thymoma and thymic carcinoma; thyroid cancer; transitional cell carcinoma of the renal pelvis and ureter; transitional cell carcinoma of the ureter and renal pelvis; urethral cancer; endometrial cancer; uterine sarcoma; vaginal cancer; vaginal cancer in children; hemangioma; vulvar cancer; and Wilms' tumor and other childhood kidney tumors.

[0820] Metastasis of the above cancers can also be treated according to the methods described herein. In some aspects, the cancer is a metastatic cancer.

[0821] In some aspects, the cancer is cardiac cancer, gastrointestinal cancer, genitourinary tract cancer, liver cancer, biliary tract cancer, bone cancer, nervous system cancer, gynecological cancer, hematological cancer, skin cancer or adrenal cancer. In some aspects, the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer.

[0822] In some aspects, the method further includes determining whether the cell and / or subject has a KRAS G12D mutation. In some aspects, the method includes determining whether the subject (e.g., a subject in need, such as a subject with cancer) suffers from a KRAS G12D-related cancer, and administering a therapeutically effective amount of a compound of the present disclosure or a composition comprising a compound of the present disclosure to a subject with a KRAS G12D-related cancer. Common KRAS G12D-related cancers are known in the art. Methods for determining whether a subject has a KRAS G12D mutation and therefore whether it suffers from a KRAS G12D-related cancer are known in the art and are described herein.

[0823] The compounds of the present disclosure can also be administered in combination with one or more other therapies (e.g., radiotherapy, chemotherapy, such as chemotherapeutic agents; immunotherapy, such as immunotherapeutic agents) to treat diseases, disorders or patients (e.g., cancer, autoimmune diseases) as described herein. When "combined" is administered, the compounds of the present disclosure can be administered before, after or in parallel with other therapies (e.g., radiotherapy, other therapeutic agents). When administered simultaneously (e.g., in parallel), the compounds of the present disclosure and another therapeutic agent can be in separate preparations or in the same preparation. Alternatively, the compounds of the present disclosure and another therapeutic agent can be administered as separate compositions at approximately the same time or in different time sequences. When the compounds of the present disclosure and other therapies (e.g., therapeutic agents) are administered as separate preparations or compositions, the compounds of the present disclosure and other therapies can be administered by the same route of administration or by different routes of administration. A skilled clinician can determine the appropriate timing of administration of each therapy used in combination (e.g., timing sufficient to allow the pharmacodynamics of the therapy to overlap).

[0824] In some aspects, the methods described herein further include administering to the subject (e.g., a therapeutically effective amount) another therapy (e.g., radiotherapy; another therapeutic agent, such as a chemotherapeutic agent, an immunotherapeutic agent, an antibody, such as a monoclonal antibody; a vaccine), for example, in combination with the compounds of the present disclosure. In some aspects, the compounds of the present disclosure are administered before the other therapy. In some aspects, the compounds of the present disclosure are administered after the other therapy. In some aspects, the compounds of the present disclosure are administered concurrently with the other therapy.

[0825] In some aspects, a method further comprises administering radiation therapy (eg, a therapeutically effective amount of radiation therapy), such as proton beam therapy, to the subject.

[0826] In some aspects, a method further comprises administering to the subject hormone therapy (e.g., a therapeutically effective amount of hormone therapy), such as an antiestrogen therapy, androgen deprivation therapy (ADT), such as flutamide, nilutamide, bicalutamide, leuprolide, or goserelin, a luteinizing hormone-releasing hormone (LHRH) agonist, an aromatase inhibitor (AI), such as anastrozole, exemestane, or letrozole, an estrogen receptor modulator, such as tamoxifen, raloxifene, or toremifene.

[0827] In some aspects, a method further comprises administering to the subject an epidermal growth factor receptor (EGFR) inhibitor (e.g., a therapeutically effective amount of an EGFR inhibitor), such as cetuximab. Other examples of EGFR inhibitors include the pan-EGFR inhibitors dacomitinib and mefatinib.

[0828] In some aspects, a method further comprises administering (e.g., a therapeutically effective amount of) a cyclin-dependent kinase (CDK) inhibitor (e.g., a CDK4 / 6 inhibitor) to the subject. Examples of CDK inhibitors include abemaciclib, alvocidib, palbociclib, and ribociclib.

[0829] In some aspects, a method further comprises administering to the subject (e.g., a therapeutically effective amount) a seven-spotted septin (SOS) inhibitor, such as an SOS1 inhibitor. SOS1 inhibitors are disclosed, for example, in International Publication No. WO 2021 / 173524.

[0830] In some aspects, a method further comprises administering to the subject (e.g., a therapeutically effective amount of) a small heterodimer partner (SHP) inhibitor, such as a SHP2 inhibitor. Examples of SHP2 inhibitors include SHP-099, RMC-4550, RMC4360, and TNO155.

[0831] In some aspects, a method further includes administering immunotherapy (e.g., a therapeutically effective amount of immunotherapy) to the subject. Immunotherapeutics include antibodies, vaccines, and immune cell (e.g., T cell) infusions that suppress proteins expressed by cancer cells. Antibody agents that can be used to promote anti-tumor reactions include anti-CTLA-4 antibodies (e.g., ipilimumab, tremelimumab), anti-PD-1 antibodies (e.g., pembrolizumab, nivolumab, cemiplizumab), anti-PD-L1 antibodies (e.g., atezolizumab, avelumab, durvalumab), anti-PD-L2 antibodies, anti-TIM-3 antibodies, anti-LAG-3 antibodies (e.g., rilatinib monoclonal antibody), anti-OX40 antibodies, and anti-GITR antibodies. In some aspects, immunotherapy is, for example, an immune checkpoint inhibitor (e.g., a therapeutically effective amount of an immune checkpoint inhibitor) for the treatment of solid tumor cancers. Examples of immune checkpoint inhibitors include CTLA-4 (e.g., ipilimumab, tremelimumab), PD-1 (e.g., nivolumab, pembrolizumab), PD-L1 (e.g., avelumab), PD-L2, TIM-3, LAG-3 (e.g., rilatinib), OX40 and GITR inhibitors. In some aspects, immune checkpoint inhibitors (e.g., for treating solid tumor cancers) are inhibitors of CTLA-4, PD-1, PD-L1 or LAG-3. In some aspects, immune checkpoint inhibitors (e.g., for treating solid tumor cancers) are inhibitors of PD-1 or PD-L1. In some aspects, immune checkpoint inhibitors (e.g., for treating solid tumor cancers) are inhibitors of PD-1, such as pembrolizumab.

[0832] In some aspects, a method further comprises administering chemotherapy (e.g., a therapeutically effective amount of chemotherapy) to the subject, e.g., comprising one or more chemotherapeutic agents. Examples of chemotherapeutic agents include, for example, antimetabolites (e.g., folic acid, nucleotide analogs, particularly purine and pyrimidine derivatives); alkylating agents (e.g., cyclophosphamide, mechlorethamine, chlorambucil, melphalan, dacarbazine, temozolomide, thiotepa); anthracyclines (e.g., daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, valrubicin); taxanes (e.g., paclitaxel, docetaxel, albumin-bound paclitaxel (abraxane), taxotere); epothilones; histone deacetylase inhibitors (e.g., vorinostat, romidepsin); topoisomerase inhibitors (e.g., irinotecan, topotecan, etoposide, teniposide, tafluroside); tafluposide); kinase inhibitors (e.g., bortezomib, erlotinib, gefitinib, imatinib, vemurafenib, vesmodesmus); nucleotide analogs (e.g., azacitidine, azathioprine, capecitabine, cytarabine, doxifluridine, fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, thioguanine); peptide antibiotics (e.g., bleomycin, actinomycin); platinum-based agents (e.g., carboplatin, cisplatin, oxaliplatin); retinoids (e.g., tretinoin, alitretinoin, bexarotene); and vinca alkaloids (e.g., vinblastine, vincristine, vindesine, vinorelbine), and pharmaceutically acceptable salts thereof. Further examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN TM); alkyl sulfonates, such as busulfan, improsulfan, and piposulfan; aziridines, such as benzodopa, carboquinone, meturedopa, and uredopa; ethyleneimines and methylmelamines, such as hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trihydroxymethylmelamine; acetyltoxins, such as bratacin and bratacinone; camptothecins, including the synthetic analogue topotecan; bryostatin; callystatin; CC-1065, including its adolesin, carzelesin, and biszelesin analogues; nostocs, such as nostoc 1 and nostoc 8; Aplysia caudatum chlorambucil, chlorpheniramine, chlorambucil, chlorpheniramine, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nembicidin, phenylephrine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics, such as enediyne antibiotics (e.g., calicheamicins, particularly calicheamicin gamma 1 and calicheamicin theta 1, see, e.g., Angew Chem. Intl. Ed. Engl.33:183-186 (1994); dynamin, such as dynamin A; esperamicin; and neostatin chromophores and related chromoprotein enediyne antibiotic chromophores), aclarubicin, dactinomycin, authramycin, azaserine, bleomycin, actinomycin, karatomycin, caminomycin, oncophilin, chromomycin, dactinomycin, daunomycin, detoxorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholinodoxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolineodoxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, mesilomycin, mycophenolic acid, nogamycin, oleocycin, peplomycin, potasein firomycin), puromycin, quelamycin, rhodorubicin, streptozotocin, streptozotocin, tuberculin, ubenimex, zoloft, and doxycycline; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs, such as leucovorin, methotrexate, pteropterin, and trimetrexate; purine analogs, such as fludarabine, 6-mercaptopurine , thioimidazole, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, and 5-FU; androgens such as captestosterone, drostanolone propionate, cyclothiocarbamate, melastane, and testolactone; antiadrenal drugs such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as folinic acid acid); acetylglucuronolactone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatrexate; defofamine; demeclocycline; diacrylamide; eflornithine; elliptonium acetate; epothilone; etoglucagon; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansine alkaloids, such as maytansine and ansamitocin; mitoguanidine; mitoxantrone; mopidarol; diamine nitrazepam; pentostatin; methambucil; pirarubicin; podophyllic acid; 2-ethylhydrazide; procarbazine; Razoxane; rhizoxin; sizofuran; spirogermanamine; tricholomanic acid; triazoline; 2,2',2"-trichlorotriethylamine; trichothecenes, such as T-2 toxin, vobraxone A, baculocin A, and anguidine; urethanes; vindesine; dacarbazine; mannitol mustard; dibromomannitol; dibromodulcitol; pipobroman; gadocytosine; cytarabine ("Ara-C"); cyclophosphamide; thiotepa; taxanes, such as paclitaxel (e.g., TAXOL TM, Bristol-Myers Squibb Oncology, Princeton, NJ; nab-paclitaxel, such as Nanoparticle albumin-bound forms of paclitaxel) and docetaxel ( Rhone-Poulenc Rorer, Antony, France); chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; folinic acid; platinum analogs such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunorubicin; aminopterin; xeloda; ibandronate; CPT-11; topoisomerase inhibitors such as irinotecan and RFS2000; difluoromethylornithine (DFMO); retinoic acid; and capecitabine; and pharmaceutically acceptable salts thereof.

[0833] Specific examples of chemotherapeutic agents include aclarubicin, dactinomycin, alitidine, hexamethylmelamine, aminopterin, aminolevulinic acid, amrubicin, amsacrine, anagrelide, arsenic trioxide, asparaginase, atrasentan, belotecan, bexarotene, bendamustine, bleomycin, bortezomib, busulfan, camptothecin, capecitabine, carboplatin, carboquinone, carmofur, carmustine, celecoxib, chlorambucil, nitrogen mustard, thine), cisplatin, cladribine, clofarabine, clerase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, decitabine, demeclomol, docetaxel, doxorubicin, efaproxiral, elesclomol, elsamitrucin, enocitabine, epirubicin, estramustine, etogluconol, etoposide, floxuridine, fludarabine, fluorouracil ( 5FU), fotemustine, gemcitabine, Glida implant, hydroxycarbamide, hydroxyurea, idarubicin, ifosfamide, irinotecan, ilofufen, ixabepilone, larotaxel, folinic acid, liposomal doxorubicin, liposomal daunomycin, lonidamine, lomustine, thiocanone, mannosulfamethoxazole, masopropol, melphalan, mercaptopurine, mesna, methotrexate, methyl aminolevulinate, Bromomannitol, mitoguanidine, mitotane, mitomycin, mitoxantrone, nedaplatin, nimustine, obermersen, omacetin, ortasel, oxaliplatin, paclitaxel, pegaspargase, pemetrexed, pentostatin, pirarubicin, pixentron, plicamycin, porfimer sodium, prednimustine, procarbazine, raltitrexed, ranimustine, rubitecan, sapacitabine, semustine, sitimagenone, and siranovich.

[00145] The present invention relates to a pharmaceutically acceptable salt of a pharmaceutically acceptable salt of vinblastine, vinblastine, vindesine, vinflunine, vinorelbine, or a pharmaceutically acceptable salt thereof.

[0834] Many other therapies may also be administered during treatment (e.g., cancer treatment, treatment of autoimmune diseases) to alleviate the effects of the disease and / or the side effects of treatment, including therapies to control pain (e.g., anesthetics, acupuncture), stomach discomfort (e.g., antacids), dizziness (e.g., anti-vertigo medications), nausea (e.g., antiemetics), infection (e.g., medications to increase red / white blood cell counts), etc., which are readily apparent to those skilled in the art.

[0835] The compounds of the present invention or other therapeutic agents described herein can be administered via a variety of routes of administration, including, for example, oral, dietary, topical, transdermal, rectal, parenteral (e.g., intraarterial, intravenous, intramuscular, subcutaneous injection, intradermal injection), intravenous infusion, and inhalation (e.g., intrabronchial, intranasal or oral inhalation, intranasal drops) routes of administration, depending on the compound and the specific disease to be treated. As shown, administration can be local or systemic. In some aspects, oral administration (e.g., compounds of the present invention). In some aspects, intravenous administration (e.g., compounds of the present invention). In some aspects, administration (e.g., compounds of the present invention) is by injection or infusion. The preferred mode of administration can vary depending on the specific compound or agent.

[0836] Typically, the compounds of the present disclosure or other therapeutic agents will be administered about 1 to about 6 times per day (e.g., 1, 2, 3, 4, 5, or 6 times), and may also or alternatively be infused (e.g., continuously). In some embodiments, the compounds of the present disclosure or other therapeutic agents are administered once daily (QD) or twice daily (BID). In some embodiments, the compounds of the present disclosure or other therapeutic agents are administered BID.

[0837] The dosage range of the compound of the present disclosure or other therapeutic agent used can be about 0.001mg / kg to about 100mg / kg body weight, or alternatively, the dosage range is about 1mg / agent to about 5,000mg / agent, once every 4 to 120 hours, or according to the requirements of a specific agent. For example, a suitable dosage can be about 0.001mg / kg to about 100mg / kg, about 0.01mg / kg to about 10mg / kg, about 0.01mg / kg to about 10mg / kg, about 0.01mg / kg to about 1mg / kg body weight per treatment. A suitable dosage can be about 1mg / agent to about 5,000mg / agent, about 10mg / agent to about 2,500mg / agent or about 100mg / agent to about 1,000mg / agent.

[0838] Doses lower or higher than those recited above may be necessary. The specific dosage and treatment regimen for any particular patient will depend, for example, on a variety of factors, such as the activity of the specific agent used, age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination; the severity and course of the disease, condition, or symptom, the subject's predisposition to the disease, condition, or symptom, and the judgment of the treating physician. Determining the dosage for a particular agent, subject, and disease, condition, or symptom is within the ability of those skilled in the art.

[0839] Example

[0840] According to the methods, reaction schemes and examples provided herein, the compounds of the present disclosure can be prepared in a variety of ways known to those skilled in the art. As will be appreciated by those skilled in the art, the compounds disclosed herein can be synthesized using the following methods and synthetic methods known in the field of synthetic organic chemistry or by variations thereof. Preferred methods include, but are not limited to, the methods described below. The reaction is carried out in a solvent or solvent mixture that is suitable for the reagents and substances used and suitable for the transformation being performed. It will be understood by those skilled in the art of organic synthesis that the functional groups present on the molecule should conform to the proposed transformation. This will sometimes require making a judgment to change the order of the synthesis steps, or selecting a specific process scheme rather than another process scheme, in order to obtain the desired compound.

[0841] Starting materials are generally available from commercial sources such as Sigma Aldrich or other commercial suppliers, or prepared as described herein, or readily prepared by methods well known to those skilled in the art (e.g., by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, New York (1967-1999 ed.); Larock, RC, Comprehensive Organic Transformations, 2nd ed., Wiley-VCH Weinheim, Germany (1999); or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database).

[0842] For illustrative purposes, the reaction scheme described below provides the possible route for synthesizing compounds disclosed herein and intermediates. It will be appreciated by those skilled in the art that other synthetic routes may also be used for synthesizing compounds disclosed herein. Although specific starting materials and reagents have been described in the scheme and discussed below, other starting materials and reagents may be easily substituted to provide various derivatives and / or reaction conditions. In addition, according to this disclosure, conventional chemical means well known to those skilled in the art may be further modified by many compounds prepared by the following methods.

[0843] In the preparation of compounds of the present invention, it may be necessary to protect the distal functional groups of the intermediates. The need for such protection will vary according to the properties of the distal functional groups and the conditions of the preparation method. It is easy for those skilled in the art to determine whether such protection is needed. For a general description of protecting groups and their uses, see Greene, TW et al., Protecting Groups in Organic Synthesis, 4th edition, Wiley (2007). The protecting groups (such as trityl protecting groups) introduced in the preparation of compounds of the present invention can be shown as a regioisomer, but can also exist as a mixture of regioisomers.

[0844] The following abbreviations used below have the corresponding meanings:

[0845] ACN acetonitrile;

[0846] Boc tert-butyloxycarbonyl;

[0847] C Celsius;

[0848] d doublet;

[0849] dd doublet;

[0850] DCM dichloromethane;

[0851] DMAP 4-dimethylaminopyridine;

[0852] DIEA N,N-diisopropylethylamine;

[0853] DMSO dimethyl sulfoxide;

[0854] Dtbbpy 4,4'-di-tert-butyl-2,2'-bipyridine;

[0855] DME dimethoxyethane;

[0856] EtOAc / EA ethyl acetate;

[0857] EtOH ethanol;

[0858] FA formic acid;

[0859] g gram;

[0860] h / hr hour;

[0861] HPLC high-pressure liquid chromatography;

[0862] HCl

[0863] L liter;

[0864] LC liquid chromatography;

[0865] LCMS liquid chromatography and mass spectrometry;

[0866] LiAlH4 lithium aluminum hydride;

[0867] LiHMDS lithium bis(trimethylsilyl)amide;

[0868] MeOH methanol;

[0869] MS mass spectrometry;

[0870] M. Moore;

[0871] m multiplet;

[0872] Me methyl;

[0873] min / min. minutes;

[0874] mL milliliter;

[0875] μM micromolar;

[0876] m / z mass-to-charge ratio;

[0877] nM nanomolar;

[0878] NMP N-methylpyrrolidone;

[0879] NMR nuclear magnetic resonance;

[0880] NaH sodium hydride;

[0881] NaHCO3 sodium bicarbonate;

[0882] Pd / C palladium on carbon;

[0883] PG protecting group;

[0884] PE petroleum ether;

[0885] POCl3 phosphorus oxychloride;

[0886] rt room temperature

[0887] s unimodal;

[0888] sat. saturated;

[0889] SFC supercritical fluid chromatography;

[0890] t triplet;

[0891] t-Bu tert-butyl;

[0892] TEA triethylamine;

[0893] TBAF tetra-n-butylammonium fluoride;

[0894] TTMSS tris(trimethylsilyl)silane;

[0895] TFA trifluoroacetic acid;

[0896] THF tetrahydrofuran;

[0897] TLC thin layer chromatography;

[0898] Example 1. Synthesis of Intermediate B

[0899] a) Synthesis of 2-But-3-enylpyrrolidine-1,2-dicarboxylic acid O1-benzyl O2-methyl ester

[0900]

[0901] A solution of (2S)-pyrrolidine-1,2-dicarboxylic acid O1-benzyl ester O2-methyl ester (120 g, 455 mmol, CAS#182210-00-0) in THF (200 mL) was added dropwise to a solution of LiHMDS (1 M, 546 mL) for 1 hour at -78 ° C. 4-bromobut-1-ene (123 g, 911 mmol, CAS#5162-44-7) was added to the mixture and stirred at 25 ° C. under N2 atmosphere for 16 hours. After completion, the reaction mixture was concentrated in vacuo to obtain a residue. The residue was purified by column chromatography (SiO2, PE: EA = 0: 1 to 5: 1) to give the title compound (120 g, 66% yield) as a white oil. LC-MS (ESI + )m / z 318.0(M+H) + .

[0902] b) Synthesis of 2-[2-(oxiran-2-yl)ethyl]pyrrolidine-1,2-dicarboxylic acid O1-benzyl O2-methyl ester

[0903]

[0904] A solution of 2-but-3-enylpyrrolidine-1,2-dicarboxylic acid O1-benzyl ester O2-methyl ester (146g, 460mmol) and m-CPBA (233g, 1.15mol, 85% purity) in DCM (1500mL) was stirred at 20°C for 16 hours. After completion, the reaction mixture was extracted with EA (3X400mL). The combined organic layer was washed with brine (300mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo to obtain a residue. The residue was purified by column chromatography (SiO2, PE:EA=0:1 to 3:1) to obtain the title compound (110g, 45% yield) as a white oil. 1 H NMR (400MHz, CDCl3) δ7.40-7.27(m,5H),5.18-5.07(m,2H),3.78-3.70(m,3H),3.50-3.46(m ,2H),2.73-2.71(m,2H),2.43-2.42(m,2H),2.13-1.85(m,5H),1.53-1.45(m,2H); LC-MS(ESI + )m / z 334.1(M+H) + .

[0905] c) Synthesis of methyl 3-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolizine-8-carboxylate

[0906]

[0907] To a solution of 2-[2-(oxiran-2-yl)ethyl]pyrrolidine-1,2-dicarboxylic acid O1-benzyl ester O2-methyl ester (110 g, 329 mmol) in MeOH (1000 mL) was added Pd / C (10.0 g, 330 mmol, 10% purity) under N2 atmosphere. The suspension was degassed and purged with hydrogen 3 times. The reaction mixture was stirred under hydrogen (50 psi) and 20 ° C for 16 hours. After completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (62.0 g, 94% yield) as a yellow oil. It was a yellow oil. LC-MS (ESI + )m / z 200.0(M+H) + .

[0908] d) Synthesis of methyl 3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizine-8-carboxylate

[0909]

[0910] A solution of 3-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolazine-8-carboxylic acid methyl ester (54.0 g, 271 mmol), tert-butyl-chloro-diphenyl-silane (111 g, 406 mmol) and imidazole (55.3 g, 813 mmol) in DCM (500 mL) was stirred at 20 ° C for 16 hours. After completion, the mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, PE: EA = 0: 1 to 3: 1) to give the title compound (trans racemic) (61.0 g, 41% yield) as a yellow oil. LC-MS (ESI + )m / z 438.7(M+H) + .

[0911] e) Synthesis of [3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol

[0912]

[0913] To a solution of 3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizine-8-carboxylic acid methyl ester (10.4 g, 23.0 mmol) in THF (100 mL) was added LiAlH4 (1.80 g, 47.0 mmol). The mixture was stirred at -20 ° C for 2 hours. After completion, H2O (2.2 mL) and 15% NaOH (2.2 mL) were added to the mixture. The mixture was then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA conditions) to give the title compound (trans racemic) (7.10 g, 73% yield) as a white solid. LC-MS (ESI + )m / z 410.3(M+H) + .

[0914] [(3S,8S)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizine-8-yl]methanol (40.0 g, 97.6 mmol) was separated by SFC (column: REGIS (s,s) WHELK-O1 (250 mm*50 mm, 10 μm); mobile phase: [0.1% NH3-H2OEtOH]; B%: 50%-50%, B2.95; 300 min) to give intermediate A (15.0 g, 37% yield) (retention time: 2.088 min) as a yellow oil, and intermediate B (15.0 g, 37% yield) (retention time: 1.823 min) as a yellow oil.

[0915] Intermediate A: 1 H NMR (400MHz, CDCl3) δ8.38 (s, 1H), 7.58-7.53 (m, 4H), 7.41-7.30 (m, 6H), 3.93-3.88 (m, 1H), 3.81 (d, J = 13.2Hz, 1H), 3.76-3.64 (m, 2H) ,3.57-3.48(m,2H),3.39(s,1H),3.22-3.12(m,1H),2.32-2.22(m,1H),2.08-1.83(m,5H),1.75-1.61(m,2H),1.00(s,9H); LC-MS(ESI) + )m / z 410.6(M+H) + .

[0916] Intermediate B: 1 H NMR (400MHz, CDCl3) δ7.70-7.65(m,4H),7.46-7.37(m,6H),3.95-3.88(m,1H),3.81-3.75(m,1H),3.48(s,1H),3.31(s,2H),3.26-3 .16(m,1H),2.93-2.84(m,1H),2.81-2.68(m,1H),2.02-1.93(m,1H),1.80-1.62(m,6H),1.59-1.51(m,1H),1.07(s,9H); LC-MS(ESI) + )m / z 410.6(M+H) + .

[0917] Initially, intermediate A and intermediate B were randomly assigned absolute structures, intermediate A was designated as [(3R,8R)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol, and intermediate B was designated as [(3S,8S)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol.

[0918] Subsequently, X-ray crystallographic analysis showed that intermediate A corresponds to [(3S,8S)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol, and intermediate B corresponds to [(3R,8R)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol. Briefly, 10 mg of intermediate A and 25 μL of HCl (1 mol / L) were dissolved in 600 μL of heptane and stored in a sealed 4-mL vial. In a separate sealed 4-mL vial, 10 mg of intermediate B and 25 μL of HCl (1 mol / L) were dissolved in 600 μL of heptane and stored. The solution was slowly evaporated at room temperature. The resulting crystals were analyzed using a Rigaku Oxford DiffractionXtaLAB Synergy-S four-circle diffractometer equipped with a HyPix-6000HE area detector and the following equipment:

[0919] Cryogenic system: Oxford Cryostream 800

[0920] Cu: 50W, microfocus source with multilayer mirrors (μ-CMF).

[0921] Distance from crystal to CCD detector: d = 35 mm

[0922] Tube voltage: 50kV

[0923] Tube current: 1mA.

[0924] The intermediate AHCl crystals were obtained as colorless masses with the following dimensions: 0.30 × 0.30 × 0.20 mm 3 The symmetry of the crystal structure is assigned to the monoclinic space group P21 with the following parameters: α=90°, β=103.4170(10)°, γ=90°, Z=2, Dc=1.188g / cm3, F(000)=480.0, μ(Cu Kα)=1.966mm -1 , and T = 293 (2) K. The obtained intermediate B HCl crystals were colorless blocks with the following dimensions: 0.30 × 0.30 × 0.20 mm 3 The symmetry of the crystal structure is assigned to the monoclinic space group P21 with the following parameters: α=90°, β=103.489(2)°, γ=90°, Z=2, Dc=1.181g / cm3, F(000)=480.0, μ(Cu Kα)=1.955mm-1 , and T=293(2)K.

[0925] Initially, the randomly assigned absolute configurations of Intermediate A and Intermediate B were revised based on these and other collected data and analyzed in conjunction with x-ray crystallographic analysis of Intermediate A and Intermediate B.

[0926] Example 2. Synthesis of Intermediate C

[0927] a) Synthesis of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine

[0928]

[0929] To a solution of 7-chloro-8-fluoro-pyrido[4,3-d]pyrimidine-2,4-diol (5.00 g, 23.2 mmol, CAS# 2454397-75-0) in toluene (300 mL) was added DIEA (14.9 g, 115 mmol) and POCl₃ (10.6 g, 69.5 mmol) at 0°C. The mixture was stirred at 110°C for 2 hours. Upon completion, the mixture was concentrated in vacuo to obtain a residue. The residue was then diluted with EA (200 mL) and added dropwise to H₂O (300 mL). The pH was then adjusted to 7-8 with saturated NaHCO₃, and the mixture was extracted with EA (3 x 200 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated in vacuo to obtain a residue. The residue was purified by column chromatography (SiO 2 , PE:EA=50:1 to 5:1) to give the title compound (8.00 g, 68% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ8.91 (s, 1H).

[0930] b) Synthesis of tert-butyl 3-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0931]

[0932] To a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (2.1 g, 8.32 mmol) in DCM (120 mL) was added DIEA (7.53 g, 58.2 mmol) at 25 ° C. A solution of (1S, 5R)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.24 g, 5.82 mmol, CAS#149771-44-8) in DCM (120 mL) was then added to the mixture and stirred at -40 ° C. The mixture was stirred at -40 ° C for 1 hour. After completion, the reaction mixture was diluted with H2O (100 mL) at 25 ° C and then extracted with DCM (3 × 100 mL). The combined organic layers were washed with brine (2 × 200 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO 2 , PE:EA=20:1 to 4:1) to give the title compound (4.40 g, 62% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ8.85 (s, 1H), 4.70-4.27 (m, 4H), 3.90-3.54 (m, 2H), 2.04-1.94 (m, 2H), 1.68 (d, J = 7.2Hz, 2H), 1.53 (s, 9H); LC-MS (ESI) + )m / z 428.0(M+H) + .

[0933] c) Synthesis of tert-butyl 3-[2-[[(3S,8S)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-chloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0934]

[0935] To a solution of intermediate A (1.4 g, 3.42 mmol) in THF (60 mL) was added NaH (410 mg, 10.2 mmol, 60% purity) at 0 ° C. The mixture was stirred at 0 ° C for 0.5 hours. Then 3- (2,7-dichloro-8-fluoro-pyrido [4,3-d] pyrimidin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (1.61 g, 3.76 mmol) was added to the mixture. The mixture was stirred at 25 ° C for 12 hours. After completion, the residue was quenched by H2O (30 mL) and extracted with EA (2 × 100 mL). The combined organic layer was washed with brine (80 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to obtain a residue. The residue was purified by preparative HPLC (column: Welch Ultimate XB-SiOH 250*50*10 μm; mobile phase: [hexane-EtOH]; B%: 0%-26%, 25 min) to give the title compound (1.50 g, 55% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ8.72(s,1H),7.75-7.58(m,4H),7.53-7.34(m,6H),4.62-4.30(m,4H),4.29-4.08(m,2H),3.99(dd,J= 4.8,10.4Hz,1H),3.81(dd,J=7.2,10.0Hz,1H),3.77-3.34(m,3H),3.29(s,1H),2.89-2.73(m,2H),2.25-2.15(m,1H),2.00

[0936] -1.89(m,4H),1.88-1.73(m,4H),1.69(d,J=7.6Hz,2H),1.52(s,9H),1.06(s,9H); LC-MS(ESI + )m / z 801.4(M+H) + .

[0937] d) Synthesis of tert-butyl 3-[2-[[(3S,8S)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0938]

[0939] 3-[2-[[(3S,8S)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-chloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (569 mg, 709 μmol), 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)-1-naphthyl] ethynyl-triisopropyl-silane (727 mg, 1.42 mmol, CAS# 2621932-37-2), di-tert-butyl(cyclopentyl)phosphine; palladium dichloride; a solution of iron (92.5 mg, 141 μmol) and Cs2CO3 (693 mg, 2.13 mmol) in dioxane (24 mL) and H2O (4.8 mL) was degassed and purged with N2 atmosphere 3 times. The mixture was stirred at 100 ° C under N2 atmosphere for 0.5 hours. After completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, PE:EA=1:0 to 0:1) to give the title compound (562 mg, 69% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ9.08-9.03(m,1H),7.79(dd,J=5.6,9.2Hz,1H),7.70-7.67(m,3H),7.64(d,J=4.0Hz,1H),7.51(d ,J=2.4Hz,1H),7.41(d,J=7.2Hz,6H),7.30(d,J=10.4Hz,2H),5.32-5.28(m,2H),4.87-4.83(m,1H),4.49-4.34(m,2H) ,4.28-4.06(m,4H),4.01(dd,J=4.4,10.0Hz,1H),3.82(s,2H),3.51(s,3H),3.46-3.17(m,2H),2.93-2.73(m,2H),2.3 2-2.16(m,2H),2.05-1.71(m,12H),1.65-1.60(m,6H),1.53(s,9H),1.47-1.15(m,9H),1.15-1.00(m,12H); LC-MS(ESI + )m / z 1151.6(M+H) + .

[0940] e) Synthesis of tert-butyl 3-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(3S,8S)-3-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0941]

[0942] To a solution of tert-butyl 3-[2-[[(3S,8S)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizine-8-yl]methoxy]-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (560 mg, 486 μmol) in THF (5 mL) at 0 ° C was added TBAF (1 M, 1.46 mL). The mixture was stirred at 25 ° C under N2 atmosphere for 16 hours. After completion, the mixture was concentrated in vacuo to give a residue. The residue was diluted with H2O (15 mL) and then extracted with EA (3×15 mL). The combined organics were washed with brine (2×15 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO 2 , PE:EA=50:1 to 1:1) to give the title compound (220 mg, 59% yield) as a yellow solid. LC-MS (ESI + )m / z757.4(M+H) + .

[0943] f) Synthesis of tert-butyl 3-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(3S,8S)-3-[(4-nitrophenoxy)carbonyloxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate C)

[0944]

[0945] To a solution of tert-butyl 3-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(3S,8S)-3-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolizine-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20.0 mg, 26.4 μmol) in DCM (2 mL) was added DMAP (322 ug, 2.64 μmol) and TEA (8.02 mg, 79.2 μmol) at 25 ° C. Then, (4-nitrophenyl) chloroformate (15.9 mg, 79.2 μmol) was added to the mixture. The mixture was stirred at 25 ° C for 2 hours. After completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was diluted with H2O (5 mL) and extracted with DCM (2×10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the title compound (24 mg, 98% yield) as a yellow oil. LC-MS (ESI + )m / z 922.3(M+H) + .

[0946] Example 3. Synthesis of Compound 028

[0947] a) Synthesis of tert-butyl N-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]carbamate.

[0948]

[0949] To a solution of tert-butyl N-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethyl]carbamate (2.00 g, 6.84 mmol, CAS#101187-40-0) and 2-(2,6-dioxo-3-piperidinyl)-4-fluoro-isoindoline-1,3-dione (1.70 g, 6.16 mmol, CAS#835616-60-9) in NMP (2 mL) was added DIEA (1.77 g, 13.6 mmol). The mixture was stirred at 90 ° C for 16 hours. After completion, the reaction mixture was extracted with EA (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo to give a residue. The crude product was purified by reverse phase (0.1% FA conditions) to give the title compound (1.5 g, 39% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ11.09 (s, 1H), 7.62-7.54 (m, 1H), 7.15 (d, J = 8.4Hz, 1H), 7.04 ( d,J=7.2Hz,1H),6.78-6.69(m,1H),6.61-6.58(m,1H),5.05(dd,J=5.2,12.8Hz,1H),3. 64-3.60(m,2H),3.56-3.46(m,10H),3.37-3.33(m,2H),3.29(s,1H),3.06-3.02(m,2H ),2.93-2.83(m,1H),2.55(d,J=9.2Hz,1H),2.06-1.99(m,1H),1.36(s,9H); LC-MS(ESI + )m / z 549.1(M+H) + .

[0950] b) Synthesis of 4-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione.

[0951]

[0952] To a solution of tert-butyl N-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]carbamate (150 mg, 273 μmol) in DCM (1.5 mL) was added HCl / dioxane (4 M, 0.75 mL). The mixture was stirred at 25 ° C for 4 hours. Upon completion, the reaction mixture was concentrated in vacuo to give the title compound (130 mg, 95% yield, HCl salt) as a green solid. LC-MS (ESI + )m / z 449.0(M+H) + .

[0953] c) Synthesis of tert-butyl 3-[2-[[(3S,8S)-3-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethylcarbamoyloxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0954]

[0955] To a solution of 4-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (18.9 mg, 39.0 μmol, HCl salt) and intermediate C (24.0 mg, 26.0 μmol) in THF (1 mL) was added TEA (7.90 mg, 78.1 μmol). The mixture was stirred at 25 ° C for 1 hour. After completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (FA)-ACN]; B%: 28%-58%, 15min) to give the title compound (20 mg, 62% yield) as a yellow solid. LC-MS (ESI + )m / z 1231.2(M+H) + .

[0956] d) Synthesis of [(3S,8S)-8-[[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-3-yl]methyl N-[2-[2-[2-[2-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]carbamate (028).

[0957]

[0958] To a solution of tert-butyl 3-[2-[[(3S,8S)-3-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethylcarbamoyloxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20.0 mg, 16.2 μmol) in DCM (1 mL) was added HCl / dioxane (4 M, 0.25 mL). The reaction mixture was stirred at 25° C. for 0.5 h. After completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (FA)-ACN]; B%: 9%-38%, 15min) to give the title compound (6.80 mg, 38% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ11.20-10.99(m,1H),9.03(s,1H),8.23(s,1H),7.9 7(dd,J=6.0,9.2Hz,1H),7.61-7.53(m,1H),7.46(t,J=9.2Hz,1H),7.38(d, J=2.4Hz,1H),7.17(d,J=2.4Hz,2H),7.13(d,J=8.4Hz,1H),7.03(d,J=7.2H z,1H),6.60-6.57(m,1H),5.05(dd,J=5.2,12.8Hz,1H),4.47(d,J=11.2Hz, 1H),4.30(d,J=11.2Hz,1H),4.19-4.00(m,4H),3.93(s,1H),3.66-3.59(m, 4H),3.58-3.51(m,8H),3.50-3.46(m,9H),3.11-3.07(m,2H),2.94-2.81(m ,2H),2.76-2.71(m,1H),2.63-2.54(m,2H),2.07-1.99(m,2H),1.78-1.69( m,4H),1.68-1.64(m,4H),1.63-1.56(m,1H),1.53-1.45(m,1H); LC-MS(ESI + )m / z 1087.3(M+H) + .

[0959] Example 4. Synthesis of Intermediate D

[0960] a) Synthesis of tert-butyl 3-[2-[[(3R,8R)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-chloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0961]

[0962] To a solution of intermediate B (300 mg, 732 μmol) in THF (20 mL) was added NaH (87.8 mg, 2.20 mmol, 60% purity) at 0 ° C. The mixture was stirred at 25 ° C for 0.5 hours, and then 3- (2,7- dichloro -8- fluoro - pyrido [4,3-d] pyrimidin-4-yl) -3,8- diazabicyclo [3.2.1] octane -8- carboxylic acid tert-butyl ester (345 mg, 805 μmol) was added to the mixture at 25 ° C. The mixture was stirred at 25 ° C and N2 atmosphere for 15.5 hours. After completion, the reactant was quenched with H2O (10 mL) and dissolved in DCM (30 mL). The aqueous layer was separated and extracted with DCM (2 × 30 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to obtain a residue. The residue was purified by column chromatography (SiO 2 , DCM:MeOH=10:1). The residue was purified by preparative NPLC (column: Welch Ultimate XB-CN 250*50*10 μm; mobile phase: [hexane-EtOH]; B%: 5%-35%, 30 min) to give the title compound (320 mg, 51% yield) as a yellow solid. 1 H NMR(400MHz, CDCl3)δ8.72(s,1H),7.73-7.60(m,4H),7.49-7.35(m,6H),4.56-4.3 2(m,4H),4.29-4.12(m,2H),4.03-3.95(m,1H),3.87-3.78(m,1H),3.77-3.46(m,3 H),3.38-3.21(m,1H),2.95-2.71(m,2H),2.24-2.17(m,1H),2.00-1.91(m,4H),1. 89-1.79(m,4H),1.69(d,J=7.6Hz,2H),1.52(s,8H),1.11-1.01(m,9H); LC-MS(ESI + )m / z801.3(M+H) + .

[0963] b) Synthesis of tert-butyl 3-[2-[[(3R,8R)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0964]

[0965] 3-[2-[[(3R,8R)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-chloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (200 mg, 249 μmol), 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxadiazole]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-chloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (200 mg, 249 μmol),

[0366] A solution of 1,2-pentaborane-2-yl)-1-naphthyl]ethynyl-triisopropyl-silane (255 mg, 499 μmol, CAS# 2621932-37-2), di-tert-butyl(cyclopentyl)phosphine; palladium dichloride; iron (32.5 mg, 49.9 μmol) and Cs2CO3 (243 mg, 748 μmol) in dioxane (8 mL) and H2O (1.6 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 100 ° C. under N2 atmosphere for 0.5 hours. After completion, the reactants were concentrated in vacuo to give a residue. The residue was purified by preparative TLC (SiO2, DCM:MeOH=10:1) to give the title compound (270 mg, 88% yield) as a brown solid. 1H NMR (400MHz, CDCl3) δ9.12-8.99(m,1H),7.78(dd,J=5.6,9.2Hz,1H),7.69(t,J=6.4Hz,2H),7.62(s,2H),7.51(d,J=2.4Hz ,1H),7.45-7.37(m,6H),7.32-7.31(m,2H),5.31(s,2H),4.93-4.80(m,1H),4.59-4.30(m,3H),4.28-4.22(m,1H),4.22-4. 13(m,2H),4.40(dd,J=4.8,10.8Hz,1H),3.87-3.78(m,2H),3.76-3.52(m,2H),3.51(s,3H),3.48-3.37(m,1H),3.34-3.26( m,1H),2.84-2.83(m,2H),2.42-2.03(m,4H),2.02-1.66(m,14H),1.53(s,9H),1.25(s,9H),1.15-0.99(m,12H); LC-MS(ESI + )m / z 1152.2(M+H) + .

[0966] c) Synthesis of tert-butyl 3-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(3R,8R)-3-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0967]

[0968] To a solution of tert-butyl 3-[2-[[(3R,8R)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (270 mg, 234 μmol) in THF (3 mL) was added TBAF (1.00 M, 703 uL) at 0 ° C. The mixture was stirred at 25 ° C under N2 atmosphere for 2 hours. Upon completion, the reaction mixture was diluted with H2O (5 mL) and extracted with EA (3×5 mL). The combined organic layers were washed with brine (2 × 5 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated in vacuo to afford a residue. The residue was purified by column chromatography (SiO, DCM:MeOH = 100: 1 to 10: 1) to afford the title compound (110 mg, 60% yield) as a brown solid. 1 H NMR (400MHz, CDCl3) δ9.01 (s, 1H), 7.80-7.84 (m, 1H), 7.57-7.51 (m, 1H), 7.38 (dd, J = 2.4, 8.0Hz, 1H), 7.32-7.28(m,1H),5.35-5.30(m,2H),4.77-4.69(m,1H),4.66-4.56(m,2H),4.42-4.41(m,1H),4.40- 3.97(m,1H),3.88-3.60(m,5H),3.53(s,3H),3.25-3.01(m,2H),2.51-2.41(m,1H),2.39-2.30(m,1H) ,2.26-2.19(m,1H),2.12-2.10(m,2H),2.05-1.94(m,4H),1.93-1.71(m,6H),1.53(s,9H); LC-MS(ESI + )m / z 757.0(M+H) + .

[0969] d) Synthesis of tert-butyl 3-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(3R,8R)-3-[(4-nitrophenoxy)carbonyloxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate D)

[0970]

[0971] To a solution of tert-butyl 3-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(3R,8R)-3-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10.0 mg, 13.2 μmol), TEA (4.01 mg, 39.6 μmol) and DMAP (161 ug, 1.32 μmol) in DCM (2 mL) was added 4-nitrophenyl chloroformate (7.99 mg, 39.6 μmol, CAS#7693-46-1). The mixture was stirred at 25° C. under N atmosphere for 12 hours. After completion, the mixture was diluted with DCM (10 mL) and extracted with H2O (3×10 mL). The organic layer was washed with brine (2×10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo to give the title compound (12.0 mg, 57% yield) as a brown solid. LC-MS (ESI + )m / z 922.3(M+H) + .

[0972] Example 5. Synthesis of Compound 027

[0973] a) Synthesis of tert-butyl 3-[2-[[(3S,8S)-3-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethylcarbamoyloxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0974]

[0975] To a solution of intermediate D (12.0 mg, 13.0 μmol) and 4-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (9.47 mg, 19.5 μmol, HCl salt, from Example 3) in THF (1 mL) was added TEA (3.95 mg, 39.0 μmol). The mixture was stirred at 25 ° C for 2 hours. After completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18150*25mm*10μm; mobile phase: [water (FA)-ACN]; B%: 31%-61%, 10 min) to give the title compound (7.00 mg, 43% yield) as a yellow solid. LC-MS (ESI + )m / z 1232.0(M+H) + .

[0976] b) Synthesis of [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-3-yl]methyl N-[2-[2-[2-[2-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]carbamate (027).

[0977]

[0978] To a solution of tert-butyl 3-[2-[[(3R,8R)-3-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethylcarbamoyloxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (7.00 mg, 5.69 μmol) in DCM (1 mL) was added HCl / dioxane (4.00 M, 0.500 mL). The mixture was stirred at 25° C. for 0.5 h. After completion, the mixture was concentrated in vacuo to give a residue, which was purified by preparative HPLC (column: Welch Xtimate C18 150*25mm*5μm; mobile phase: [water(HCl)-ACN]; B%: 11%-41%, 8 min) to give the title compound (720 μg, 11% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ11.09(s,1H),10.59-10.48(m,1H),10.24(s,1H),9 .76-9.65(m,1H),9.38-9.29(m,1H),9.16(s,1H),7.99(dd,J=6.0,9.2Hz,1 H),7.60-7.55(m,1H),7.47(t,J=9.2Hz,1H),7.41(d,J=2.4Hz,1H),7.26-7 .17(m,2H),7.13(d,J=8.4Hz,1H),7.04(d,J=6.8Hz,1H),6.62-6.55(m,1H) ,5.05(dd,J=5.2,12.8Hz,1H),4.68(d,J=13.2Hz,1H),4.64-4.52(m,3H),4 .32(d,J=5.6Hz,2H),4.21(s,2H),3.99-3.88(m,4H),3.62-3.59(m,2H),3. 56-3.53(m,2H),3.53-3.51(m,2H),3.50-3.46(m,7H),3.17-3.12(m,2H),2 .95-2.79(m,3H),2.60(s,2H),2.15(m,2H),2.05-1.90(m,10H); LC-MS(ESI + )m / z 1187.2(M+H) + .

[0979] Example 6. Synthesis of Compound 025

[0980] a) Synthesis of tert-butyl N-[2-[2-[2-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-5-yl]amino]ethoxy]ethoxy]ethyl]carbamate.

[0981]

[0982] To a solution of tert-butyl N-[2-[2-(2-aminoethoxy)ethoxy]ethyl]carbamate (2.00 g, 8.05 mmol, CAS#153086-78-3) and 2-(2,6-dioxo-3-piperidinyl)-5-fluoro-isoindoline-1,3-dione (2.22 g, 8.05 mmol, CAS#835616-60-9) in NMP (30 mL) was added DIEA (2.08 g, 16.1 mmol). The mixture was stirred at 135 ° C for 4 hours. After completion, H2O (50 mL) was added to the reaction mixture and extracted with EA (3×60 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by reverse phase HPLC (0.1% FA conditions) to give the title compound (1.00 g, 24% yield) as a yellow solid. 1 HNMR (400MHz, DMSO-d6) δ11.05(s,1H),7.56(d,J=8.4Hz,1H),7.15(t,J=5.2Hz,1 H),7.00(d,J=2.0Hz,1H),6.90(dd,J=2.0,8.4Hz,1H),6.74(t,J=5.6z,1H),5.03 (J=5.2,12.8Hz,1H),3.59(t,J=5.6Hz,2H),3.55-3.53(m,2H),3.53-3.50(m,2H) ,3.38-3.34(m,4H),3.05(q,J=6.0Hz,2H),2.55(s,4H),1.36(s,10H); LC-MS(ESI + )m / z 504.9(M+H) + .

[0983] b) Synthesis of 4-[2-[2-(2-aminoethoxy)ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione.

[0984]

[0985] To a solution of tert-butyl N-[2-[2-[2-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethyl]carbamate (200 mg, 396 μmol) in DCM (2 mL) was added HCl / dioxane (4.00 M, 1.00 mL). The mixture was stirred at 25 ° C for 3 hours. Upon completion, the reaction mixture was concentrated in vacuo to give the title compound (174 mg, 99% yield, HCl salt) as a yellow solid. LC-MS (ESI + )m / z405.0(M+H) + .

[0986] c) Synthesis of tert-butyl 3-[2-[[(3R,8R)-3-[2-[2-[2-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethylcarbamoyloxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0987]

[0988] To a solution of intermediate D (120 mg, 130 μmol) and 4-[2-[2-(2-aminoethoxy)ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (86.1 mg, 195 μmol, HCl salt) in THF (12 mL) was added TEA (39.5 mg, 390 μmol). The mixture was stirred at 25 ° C for 2 hours. After completion, the reaction mixture was concentrated in vacuo to give the title compound (154 mg, 64% yield) as a yellow oil. LC-MS (ESI + )m / z 1187.3(M+H) + .

[0989] d) Synthesis of tert-butyl 3-[2-[[(3R,8R)-3-[2-[2-[2-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethylcarbamoyloxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (025).

[0990]

[0991] To a solution of tert-butyl 3-[2-[[(3R,8R)-3-[2-[2-[2-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethylcarbamoyloxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (154 mg, 83.0 μmol) in DCM (2 mL) was added HCl / dioxane (4.00 M, 1.00 mL). The mixture was stirred at 25° C. for 0.5 h. After completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (FA)-ACN]; B%: 17%-47%, 15min) to give the title compound (4.71 mg, 5.3% yield) as a brown solid. 1H NMR (400MHz, DMSO-d6) δ11.15-11.07(m,1H),9.03(s,1H),8.21(s,1H),7.97(dd,J=6.0,9.6Hz,1H ),7.57(t,J=8Hz,1H),7.46(t,J=9.2Hz,1H),7.38(d,J=2.0Hz,1H),7.17(d,J=2.4Hz,1H),7.13(br d,J=8.0Hz,1H),7.02(d,J=7.2Hz,1H),6.62-6.56(m,1H),5.09-5.00(m,1H),4.51-4.43(m,1H),4.34-4.26(m, 1H),4.16-4.07(m,3H),4.04-3.98(m,1H),3.92(s,1H),3.67-3.64(m,1H),3.61(m,2H),3.57(m,2H),3.55-3.54 (m,2H),3.52-3.50(m,2H),3.45(s,2H),3.41-3.38(m,4H),3.13-3.10(m,2H),2.95-2.81(m,2H),2.77-2.72(m, 1H),2.61-2.55(m,2H),2.03(m,3H),1.76-1.70(m,4H),1.66(s,6H),1.62(m,1H),1.54-1.47(m,1H); LC-MS(ESI + )m / z 1043.7(M+H) + .

[0992] Example 7. Synthesis of Compound 020

[0993] a) Synthesis of N-[3-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-4-yl]amino]propyl]carbamate.

[0994]

[0995] To a solution of 2-(2,6-dioxo-3-piperidinyl)-4-fluoro-isoindoline-1,3-dione (713 mg, 2.58 mmol, CAS#835616-60-9) and tert-butyl N-(3-aminopropyl)carbamate (500 mg, 2.87 mmol, CAS#75178-96-0) in NMP (12 mL) was added DIEA (741 mg, 5.74 mmol). The mixture was stirred at 135 ° C for 2 hours. After completion, the reaction mixture was filtered and concentrated in vacuo to obtain a residue. The residue was diluted with H2O (50 mL) and extracted with EA (2×100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to obtain a residue. The residue was purified by preparative HPLC (column: UniSil 10-120C18 50x250 mm; mobile phase: [water(FA)-ACN]; B%: 30%-60%, 22 min) to give the title compound (760 mg, 61% yield) as a yellow solid. 1 HNMR(400MHz, DMSO-d6)δ11.08(s,1H),7.57(dd,J=7.2,8.4Hz,1H),7.08(d,J=8 .8Hz,1H),7.02(d,J=7.2Hz,1H),6.93-6.90(m,1H),6.67-6.64(m,1H),5.05(dd ,J=5.2,12.8Hz,1H),3.32-3.26(m,2H),3.02-2.97(m,2H),2.94-2.82(m,1H),2 .62-2.54(m,2H),2.07-1.97(m,1H),1.68-1.62(m,2H),1.38(s,9H); LC-MS(ESI + )m / z 330.8(M+H-100) + .

[0996] a) Synthesis of 4-(3-aminopropylamino)-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione.

[0997]

[0998] To a solution of tert-butyl N-[3-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-4-yl]amino]propyl]carbamate (100 mg, 232 μmol) in DCM (1 mL) was added HCl / dioxane (4 M, 0.5 mL). The mixture was stirred at 25 ° C for 0.5 hours. After completion, the reaction mixture was concentrated in vacuo to give the title compound (85 mg, 99% yield, HCl salt) as a yellow solid. LC-MS (ESI + )m / z 330.8(M+H) + .

[0999] a) Synthesis of tert-butyl 3-[2-[[(3S,8S)-3-[3-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-4-yl]amino]propylcarbamoyloxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[1000]

[1001] To a solution of intermediate C (60.0 mg, 65.0 μmol) and 4-(3-aminopropylamino)-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (35.8 mg, 97.6 μmol, HCl salt) in THF (2 mL) was added TEA (19.7 mg, 195 μmol). The mixture was stirred at 25 ° C for 1.5 hours. After completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Waters xbridge 150*25mm 10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 30%-60%, 8 min) to give the title compound (55.0 mg, 75% yield) as a yellow solid. LC-MS (ESI + )m / z 1113.4(M+H) + .

[1002] a) Synthesis of [(3S,8S)-8-[[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-3-yl]methyl N-[3-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-4-yl]amino]propyl]carbamate (020).

[1003]

[1004] To a solution of tert-butyl 3-[2-[[(3S,8S)-3-[3-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-4-yl]amino]propylcarbamoyloxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (55.0 mg, 49.4 μmol) in DCM (1 mL) was added HCl / dioxane (4 M, 550 uL). The mixture was stirred at 25° C. for 0.5 hours. Upon completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Waters xbridge 150*25mm 10μm; mobile phase: [water(TFA)-ACN]; B%: 10%-40%, 8min) to give the title compound (12.5 mg, 22% yield, TFA salt) as a yellow solid. 1HNMR(400MHz,DMSO-d6)δ11.09(s,1H),10.48-10.31(m,1H),10.23(s,1H),9. 41-9.30(m,1H),9.17(s,1H),9.11-9.01(m,1H),8.00(dd,J=5.6,9.2Hz,1H),7 .59-7.55(m,1H),7.50-7.45(m,1H),7.42(d,J=2.4Hz,1H),7.33(d,J=6.0Hz, 1H),7.18(d,J=2.0Hz,1H),7.10-7.07(m,1H),7.03(d,J=7.2Hz,1H),6.65(t,J =5.2Hz,1H),5.04(dd,J=5.2,12.8Hz,1H),4.70(d,J=15.6Hz,1H),4.64-4.52 (m,3H),4.38-4.29(m,2H),4.25-4.21(m,2H),3.97-3.83(m,4H),3.33(d,J=6. 0Hz,2H),3.10-3.08(m,2H),2.95-2.81(m,2H),2.61(d,J=2.4Hz,2H),2.31-2. 25(m,1H),2.12-2.00(m,6H),1.98-1.90(m,6H),1.75-1.67(m,2H); LC-MS(ESI + )m / z969.4(M+H) + .

[1005] Example 8. Synthesis of Compound 019

[1006] a) Synthesis of tert-butyl N-[4-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-4-yl]amino]butyl]carbamate.

[1007]

[1008] To a solution of 2-(2,6-dioxo-3-piperidinyl)-4-fluoro-isoindoline-1,3-dione (660 mg, 2.39 mmol, CAS#835616-60-9) and tert-butyl N-(4-aminobutyl)carbamate (500 mg, 2.66 mmol, CAS#33545-98-1) in NMP (12 mL) was added DIEA (686 mg, 5.31 mmol). The mixture was stirred at 135 ° C for 1.5 hours. After completion, the reaction mixture was filtered and concentrated in vacuo to obtain a residue. The residue was diluted with H2O (50 mL) and extracted with EA (2×100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to obtain a residue. The residue was purified by preparative HPLC (column: UniSil 10-120C18 50x250 mm; mobile phase: [water(FA)-ACN]; B%: 32%-62%, 25 min) to give the title compound (812 mg, 68% yield) as a yellow solid. 1 HNMR(400MHz,DMSO-d6)δ11.08(s,1H),7.57(dd,J=7.2,8.4Hz,1H),7.10(d,J=8.8Hz,1H), 7.02(d,J=7.2Hz,1H),6.84-6.81(m,1H),6.56-6.53(m,1H),5.05(dd,J=5.6,12.8Hz,1H),3 .31-3.25(m,2H),2.96-2.92(m,2H),2.90-2.82(m,1H),2.60(d,J=2.8Hz,1H),2.55(d,J=10 .0Hz,1H),2.07-1.97(m,1H),1.59-1.50(m,2H),1.49-1.41(m,2H),1.36(s,9H); LC-MS(ESI + )m / z345.1(M+H-100) + .

[1009] b) Synthesis of 4-(4-aminobutylamino)-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione.

[1010]

[1011] To a solution of tert-butyl N-[4-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-4-yl]amino]butyl]carbamate (100 mg, 224 μmol) in DCM (1 mL) was added HCl / dioxane (4 M, 0.5 mL). The mixture was stirred at 25 ° C for 0.5 hours. After completion, the reaction mixture was concentrated in vacuo to give the title compound (85.0 mg, 99% yield, HCl salt) as a yellow solid. LC-MS (ESI + )m / z 344.8(M+H) + .

[1012] c) Synthesis of tert-butyl 3-[2-[[(3S,8S)-3-[4-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-4-yl]amino]butylcarbamoyloxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[1013]

[1014] To a solution of intermediate C (60.0 mg, 65.0 μmol) and 4-(4-aminobutylamino)-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (37.1 mg, 97.6 μmol, HCl salt) in THF (2 mL) was added TEA (19.7 mg, 195 μmol). The mixture was stirred at 25 ° C for 1.5 hours. After completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Waters xbridge 150*25mm 10 μm; mobile phase: [water (FA)-ACN]; B%: 30%-60%, 8 min) to give the title compound (52.0 mg, 70% yield) as a yellow solid. LC-MS (ESI + )m / z 1127.5(M+H) + .

[1015] d) Synthesis of [(3S,8S)-8-[[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-3-yl]methyl-N-[4-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-4-yl]amino]butyl]carbamate (019).

[1016]

[1017] To a solution of tert-butyl 3-[2-[[(3S,8S)-3-[4-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-4-yl]amino]butylcarbamoyloxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50.0 mg, 44.3 μmol) in DCM (1 mL) was added HCl / dioxane (4 M, 0.5 mL). The mixture was stirred at 25° C. for 0.5 h. Upon completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Waters xbridge 150*25mm 10μm; mobile phase: [water(TFA)-ACN]; B%: 12%-42%, 10min) to give the title compound (14.8mg, 29% yield, TFA salt) as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ11.13-11.03(m,1H),10.46-10.33(m,1H),10.29- 10.14(m,1H),9.45-9.26(m,1H),9.17(s,1H),9.11-9.01(m,1H),8.00(dd, J=6.0,9.2Hz,1H),7.61-7.53(m,1H),7.50-7.45(m,1H),7.42(d,J=2.4Hz, 1H),7.26(d,J=1.6Hz,1H),7.18(s,1H),7.12-7.05(m,1H),7.02(d,J=7.2H z,1H),6.60-6.47(m,1H),5.04(dd,J=5.6,12.8Hz,1H),4.75-4.66(m,1H), 4.64-4.49(m,3H),4.37-4.27(m,2H),4.25-4.21(m,2H),3.95-3.83(m,4H) ,3.30(d,J=6.0Hz,2H),3.09-2.99(m,2H),2.95-2.79(m,2H),2.65-2.58(m ,2H),2.32-2.25(m,1H),2.15-1.86(m,12H),1.63-1.42(m,4H); LC-MS(ESI + )m / z 983.1(M+H) + .

[1018] Example 9. Synthesis of Compound 024

[1019] a) Synthesis of N-[6-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-4-yl]amino]hexyl]carbamate.

[1020]

[1021] To a solution of tert-butyl N-(6-aminohexyl)carbamate (2.00g, 9.25mmol, CAS#51857-17-1) and 2-(2,6-dioxo-3-piperidinyl)-4-fluoro-isoindoline-1,3-dione (2.30g, 8.32mmol, CAS#835616-60-9) in NMP (30mL) was added DIEA (2.39g, 18.4mmol). The mixture was stirred at 135°C for 4 hours. After completion, the reaction mixture was extracted with EA (3X20mL). The combined organic layer was washed with brine (20mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo to obtain a residue. The residue was purified by reversed-phase HPLC (0.1% FA condition) to obtain the title compound (1.50g, 34% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),7.58(t,J=7.6Hz,1H),7.08(d,J=8.4Hz,1H),7.02(d,J=7.2Hz,1H),6.76(t,J=5.2Hz,1H),6.53(t,J=5. 6Hz, 1H), 5.05 (J=5.2, 12.8Hz, 1H), 3.28 (d, J=6.4Hz, 2H), 2.83 (s, 4H) ,2.63-2.51(m,2H),1.59-1.52(m,2H),1.36(s,9H),1.35-1.18(m,6H). LC-MS(ESI + )m / z 373.1(M-100+H) + .

[1022] b) Synthesis of 4-(6-aminohexylamino)-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione.

[1023]

[1024] To a solution of tert-butyl N-[6-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-4-yl]amino]hexyl]carbamate (200 mg, 423 μmol) in DCM (4 mL) was added HCl / dioxane (4.00 M, 2.00 mL). The mixture was stirred at 25 ° C for 2 hours. After completion, the mixture was concentrated in vacuo to give the title compound (150 mg, 86% yield, HCl salt) as a yellow solid. LC-MS (ESI + )m / z 373.1(M+H) + .

[1025] c) Synthesis of tert-butyl 3-[2-[[(3RS,8RS)-3-[6-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-4-yl]amino]hexylcarbamoyloxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[1026]

[1027] To a solution of 4-(6-aminohexylamino)-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (43.9 mg, 85.9 μmol, HCl salt) and intermediate E (trans racemic) (80.0 mg, 57.2 μmol) in THF (4 mL) was added TEA (17.3 mg, 171 μmol). The mixture was stirred at 25 ° C. under N2 atmosphere for 2 hours. After completion, the mixture was concentrated in vacuo to give the title compound (trans racemic) (100 mg, 74% yield) as a yellow oil. LC-MS (ESI + )m / z1155.8(M+H) + .

[1028] d) Synthesis of (3RS,8RS)-[8-[[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-3-yl]methyl N-[6-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-4-yl]amino]hexyl]carbamate (024).

[1029]

[1030] To a solution of tert-butyl 3-[2-[[3-[6-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-4-yl]amino]hexylcarbamoyloxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (trans-rac) (100 mg, 42.4 μmol) in DCM (5 mL) was added HCl / dioxane (4.00 M, 3.00 mL). The mixture was stirred at 25 ° C for 1 hour. Upon completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18150*25mm*10μm; mobile phase: [water (FA)-ACN]; B%: 14%-44%, 10min) to give the title compound (trans racemic) (22.05mg, 50% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),10.29-10.02(m,1H),9.06(s,1H),8.15(s,1H),8.00-7.94(m,1H),7.60-7.52(m,1H),7.46(t,J=8.8Hz,1H ),7.39(d,J=2.4Hz,1H),7.20-7.14(m,2H),7.07(d,J=8.6Hz,1H),7.00 (d,J=7.2Hz,1H),6.55-6.48(m,1H),5.08-5.01(m,1H),4.59-4.51(m,1H ),4.42-4.34(m,1H),4.19-4.04(m,4H),3.93(s,1H),3.84(s,2H),3.76 -3.65(m,2H),3.29-3.25(m,4H),2.99-2.93(m,2H),2.89-2.83(m,1H),2 .81-2.68(m,2H),2.61-2.53(m,2H),2.08-2.00(m,2H),1.81-1.65(m,1 0H),1.57-1.53(m,2H),1.42-1.35(m,2H),1.33-1.22(m,4H); LC-MS(ESI + )m / z 1011.7(M+H) + .

[1031] Example 10. Synthesis of Compound 022

[1032] a) Synthesis of tert-butyl 3-[2-[[(3R,8R)-3-[6-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-4-yl]amino]hexylcarbamoyloxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[1033]

[1034] To a solution of 4-(6-aminohexylamino)-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (39.9 mg, 97.6 μmol, HCl salt) and intermediate D (60.0 mg, 65.0 μmol) in THF (6 mL) was added TEA (19.7 mg, 195 μmol). The mixture was stirred at 25 ° C for 3 hours. After completion, the mixture was concentrated in vacuo to obtain a residue. The residue was purified by preparative HPLC (column: Welch Ultimate C18 150*25mm*5μm; mobile phase: [water (TFA)-ACN]; B%: 38%-68%, 10 min) to give the title compound (40.0 mg, 50% yield) as a brown solid. 1 H NMR (400MHz, DMSO-d6) δ11.09(s,1H),10.32(s,1H),9.16(s,1H),8.12(J=6.0,9.2Hz,1H),7.77(d,J=2.8Hz,1H),7.62-7.54(m, 2H),7.37(s,1H),7.22(s,1H),7.10-7.06(m,1H),7.02(d,J=6.8Hz,1H),6.58-6.48(m,1H),5.38(s,2H),5.09-5.00(m,1H),4.7 1-4.42(m,4H),4.39-4.26(m,4H),3.97-3.88(m,2H),3.45(s,3H),3.41-3.32(m,4H),3.31-3.27(m,2H),3.04-2.96(m,2H),2.9 0-2.83(m,1H),2.61-2.56(m,2H),2.16-2.00(m,6H),1.96-1.83(m,4H),1.76-1.68(m,2H),1.59-1.54(m,2H),1.47(s,9H),1.44

[1035] -1.40(m,2H),1.35-1.29(m,4H); LC-MS(ESI + )m / z 1155.5(M+H) + .

[1036] b) Synthesis of [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-3-yl]methyl N-[6-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-4-yl]amino]hexyl]carbamate (022).

[1037]

[1038] To a solution of tert-butyl 3-[2-[[(3R,8R)-3-[6-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-4-yl]amino]hexylcarbamoyloxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40.0 mg, 34.6 μmol) in DCM (0.5 mL) was added HCl / dioxane (4.00 M, 0.100 mL). The mixture was stirred at 25° C. for 0.5 h. Upon completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Welch Ultimate C18 150*25mm*5μm; mobile phase: [water(TFA)-ACN]; B%: 20%-50%, 10 min) to give the t...

Claims

1. A compound of the formula: [KRAS G12Di]-L'-[Degron](A), or a pharmaceutically acceptable salt thereof, wherein: KRAS G12Di is the KRAS G12D binding portion; L' is a covalent bond or a divalent saturated or unsaturated straight or branched chain C 1-50 A hydrocarbon chain, wherein 0-10 methylene units of L' are independently replaced by X; Each X is independently -C(D)(H)-, -C(D)2-, -C(H)(F)-, -C(F)2-, -Cy-, -O-, -N(R)-, -Si(R)2-, -Si(OH)(R)-, -Si(OH)2-, -P(O)(OR)-, -P(O)(R)-, -P(O)(NR2)-, -S-, -OC(O)-, -C(O)-, -S(O)-, -S(O)2-, -N(R)S(O)2-, -N(R)C(O)-, -OC(O)N(R)-, -N(R)C(O)N(R-, each -Cy- is independently an optionally substituted divalent ring selected from the group consisting of phenylene, 8-10 membered bicyclic arylene, 4-7 membered saturated or partially unsaturated carbocyclolene, 4-11 membered saturated or partially unsaturated spirocarbocyclolene, 8-10 membered bicyclic saturated or partially unsaturated carbocyclolene, 4-7 membered saturated or partially unsaturated heterocyclolene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 4-11 membered saturated or partially unsaturated spiroheterocyclolene having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, 8-10 membered bicyclic saturated or partially unsaturated heterocyclolene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 8-10 membered bicyclic heteroarylene having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R is independently hydrogen, deuterium, or an optionally substituted group selected from: C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or Two R on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and Degron is the combined part of Celerbron. Provided that the compound is not: or a salt thereof.

2. The compound of claim 1, wherein KRAS G12Di is a KRAS G12D inhibitor.

3. The compound of claim 1, wherein the KRAS G12Di is:

4. The compound of claim 1, 2 or 3, wherein: L' is a covalent bond or a divalent saturated or unsaturated straight or branched C1-C 25 A hydrocarbon chain in which 0 to 10 methylene groups of L' are replaced by X, Each X is independently -O-, -N(R)-, -S-, -OC(O)-, -C(O)-, -C(H)(F)-, -C(F)2-, -Cy-, -S(O)-, -S(O)2-, -N(R)S(O)2-, -N(R)C(O)-, -OC(O)N(R)-, -N(R)C(O)N(R-, each -Cy- is independently an optionally substituted bivalent ring selected from: a 4-7 membered saturated or partially unsaturated carbocyclopropylene, a 4-11 membered saturated or partially unsaturated spirocarbocyclopropylene, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclopropylene, a 4-7 membered saturated or partially unsaturated heterocyclopropylene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 4-11 membered saturated or partially unsaturated spiroheterocyclopropylene having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an 8-10 membered bicyclic saturated or partially unsaturated heterocyclopropylene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and Each R is independently hydrogen or (C1-C3)alkyl.

5. A compound of the formula: or a pharmaceutically acceptable salt thereof, wherein: yes X 5 is O or CH2; Two R's o Combined with the same carbon atom to form C 3-7 wherein each (C3-C7)cycloalkyl or 4-7 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, oxo, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, hydroxy, cyano, -S(O)2(C1-C4)alkyl, =NH, =N(C1-C4)alkyl, -NH2, -N(H)(C1-C4)alkyl or -N((C1-C4)alkyl)2, and when p is 3 or 4, each remaining R o independently selected from hydroxy, halogen, oxo, cyano, -N((C1-C4)alkyl)2, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl or (C1-C4)haloalkoxy; o is 2, 3, or 4; p is 0, 1, or 2; q is 0, 1, or 2; X 4 is N or C (R 42 ); R 42 is hydrogen, halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, -CN, (C1-C6)alkoxy, -S-(C1-C6)alkyl or -S-(C1-C6)haloalkyl; Y is a bond, O or NR 5 ; R 1 is hydrogen, hydroxyl, halogen, (C1-C3)alkyl, (C1-C3)cyanoalkyl, (C1-C3)hydroxyalkyl, -C(O)H, -CO2R 5 、-CO2N(R 5 )2 or (C5-C6) heteroaryl; R 2 is hydrogen, -N(R 5 )2、(C3-C 12 ) heterocyclic group, (C1-C6) alkyl group, -L-(C3-C 12 ) heterocyclic group, -L-(C6-C 14 )aryl, -L-(C5-C 14 )heteroaryl, -L-(C3-C 12 )cycloalkyl, -LN(R 5 )2, -LN(H)C(NH)NH2, -LC(O)N(R 5 )2, -L-(C1-C6) haloalkyl, -L-OR 5 、-L-NR 5 C(O)-(C6-C 14 )aryl, -L-COOH or -LC(O)O(C1-C6)alkyl, wherein the (C3-C 12 ) heterocyclic group, -L-NR 5 C(O)-(C6-C 14 ) aryl group 14 )aryl, -L-(C3-C 12 )heterocyclic group (C3-C 12 ) heterocyclic group and -L-(C3-C 12 )cycloalkyl 12 ) Cycloalkyl is optionally substituted with one or more R 6 Substituted, and -L-(C6-C 14 ) aryl and -L-(C5-C 14 ) heteroaryl (C5-C 14 ) heteroaryl is optionally substituted with one or more R 7 replace; L is optionally substituted by hydroxy, (C1-C4)hydroxyalkyl or (C5-C 14 )heteroaryl-substituted (C1-C4)alkylene; R 3 Yes (C6-C 14 )aryl or (C5-C 14 ) heteroaryl, wherein the (C6-C 14 )aryl or (C5-C 14 ) heteroaryl is optionally substituted with one or more R 8 replace; R 4 is hydrogen, halogen or (C1-C3)alkyl; Each R 5 are independently hydrogen or (C1-C3)alkyl; Each R 6 are independently halogen, hydroxy, (C1-C3) hydroxyalkyl, (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) alkoxy, cyano, -Q-phenyl, -Q-phenyl-SO2F, -N(H)C(O)-phenyl, -N(H)C(O)-phenyl-SO2F, (C1-C3) alkyl-substituted pyrazole, (C6-C 14 )aryl (C1-C3) alkyl, tert-butyldimethylsilyloxy-CH2-, -N(R 5 )2, (C1-C3) alkoxy (C1-C3) alkyl, (C1-C3) alkyl-C(O)-, oxo, (C1-C3) haloalkyl-C(O)-, -SO2F, (C1-C3) alkoxy (C1-C3) alkoxy, -CH2OC(O)N(R 5 )2, -CH2N(H)C(O)O-(C1-C6)alkyl, -CH2N(H)C(O)N(R 5 )2, -CH2N(H)C(O)(C1-C6)alkyl, -CH2(pyrazolyl), -CH2N(H)S(O)2(C1-C6)alkyl, -CH2OC(O)(C3-C 12 ) heterocyclic group, -OC(O)N(R 5 )2, -OC(O)N(H)(C1-C3)alkyl-O-(C1-C3)alkyl, -OC(O)N(H)(C1-C3)alkyl-O-(C1-C3)alkyl-phenyl-(C1-C3)alkyl-N(CH3)2, -OC(O)N(H)(C1-C3)alkyl-O-(C1-C3)alkyl-phenyl, -OC(O)(C3-C 12 ) heterocyclic group or -CH2-(C3-C 12 ) heterocyclic group, wherein the phenyl group of -N(H)C(O)phenyl and -OC(O)N(H)(C1-C3)alkyl-O-(C1-C3)alkyl-phenyl is optionally substituted by -C(O)H or -OH, and -CH2-(C3-C 12 )heterocyclic group (C3-C 12 ) The heterocyclic group is optionally substituted with oxo; Q is a bond or O; Each R 7 are independently halogen, hydroxy, -C(O)H, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)hydroxyalkyl or -N(R 5 )2; Each R 8 are independently halogen, cyano, hydroxy, (C1-C4) alkyl, -S-(C1-C3) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C2-C4) hydroxyalkynyl, (C1-C3) cyanoalkyl, triazolyl, (C1-C3) haloalkyl, -O-(C1-C3) haloalkyl, -S-(C1-C3) haloalkyl, (C1-C3) alkoxy, (C1-C3) hydroxyalkyl, -CH2C(O)N(R 5 )2、(C3-C4)alkynyl-N(R 5 )2、N(R 5 )2, deuterated (C2-C4)alkynyl, (C1-C3)alkoxy, (C1-C3)haloalkyl or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl is optionally substituted with halogen or (C1-C3)alkyl; L' is a covalent bond or a divalent saturated or unsaturated straight or branched C1-C 25 A hydrocarbon chain in which 0 to 10 methylene groups of L' are replaced by X; Each X is independently -O-, -N(R)-, -S-, -OC(O)-, -C(O)-, -C(H)(F)-, -C(F)2-, -Cy-, -S(O)-, -S(O)2-, -N(R)S(O)2-, -N(R)C(O)-, -OC(O)N(R)-, -N(R)C(O)N(R-, each -Cy- is independently an optionally substituted bivalent ring selected from: a 4-7 membered saturated or partially unsaturated carbocyclopropylene, a 4-11 membered saturated or partially unsaturated spirocarbocyclopropylene, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclopropylene, a 4-7 membered saturated or partially unsaturated heterocyclopropylene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 4-11 membered saturated or partially unsaturated spiroheterocyclopropylene having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an 8-10 membered bicyclic saturated or partially unsaturated heterocyclopropylene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R is independently hydrogen or (C1-C3)alkyl; and Degron is the combined part of Celerbron. Provided that the compound is not: or a salt thereof.

6. The compound of claim 5, which has the formula: or a pharmaceutically acceptable salt thereof.

7. The compound of claim 6, wherein X 4 is C(R 42 ).

8. The compound of claim 6 or 7, wherein R 42 It is hydrogen, fluoro, chloro, methyl, -CF3, -OCF3, -CN, -OCH3, -SCH3 or -SCF3.

9. The compound of claim 6, having the formula: or a pharmaceutically acceptable salt thereof.

10. The compound of any one of claims 5-9, wherein Y is O.

11. A compound as described in any one of claims 5 to 10, wherein R 1 It's hydrogen.

12. A compound as described in any one of claims 5 to 11, wherein R 2 Yes-L-(C3-C 12 ) heterocyclic group, wherein -L-(C3-C 12 )heterocyclic group (C3-C 12 ) The heterocyclic group is optionally substituted with one or more R 6 replace.

13. The compound of any one of claims 5-12, wherein L is methylene.

14. A compound as described in any one of claims 5 to 13, wherein R 3 is optionally replaced by one or more R 8 Substituted (C6-C 14 )aryl.

15. The compound of claim 14, wherein R 3 yes 16. The compound of claim 15, wherein R 3 yes 17. A compound as described in any one of claims 5 to 16, wherein R 4 It's a halogen.

18. The compound of claim 17, wherein R 4 It is fluorinated.

19. A compound as described in any one of claims 5-18, wherein each R 6 are independently halogen, hydroxy, (C1-C3)hydroxyalkyl, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy or cyano.

20. The compound of any one of claims 5-14 and 17-19, wherein each R 8 are independently halogen, hydroxy, (C1-C4)alkyl, -S-(C1-C3)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C1-C3)alkoxy, (C1-C3)hydroxyalkyl or deuterated (C2-C4)alkynyl.

21. A compound as described in any one of claims 9-20, which has the following formula: or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 or 2.

22. The compound of claim 21, having the following structural formula: or a pharmaceutically acceptable salt thereof.

23. The compound of claim 21, having the following structural formula: or a pharmaceutically acceptable salt thereof.

24. The compound of any one of claims 21-23, wherein n is 1 or 2.

25. The compound of claim 24, wherein n is 1.

26. The compound of any one of claims 1 to 25, wherein L' is a divalent saturated or unsaturated straight or branched C1-C 15 A hydrocarbon chain, wherein 0-5 methylene groups of L' are independently replaced by X.

27. The compound of any one of claims 1 to 25, wherein L' is a divalent saturated or unsaturated straight or branched C1-C 15 A hydrocarbon chain wherein 1 or 2 methylene groups of L' are replaced by Cy, and 1 to 3 methylene groups of L' are replaced by X, wherein: Each X is independently -O-, -C(O)-, -N(R)-, or -N(R)C(O)-.

28. A compound as described in any one of claims 1-27, wherein each -Cy- is independently a 4-7-membered saturated or partially unsaturated heterocyclohetero ...

29. compounds as claimed in claim 28, wherein each -Cy- is a saturated or partially unsaturated heterocyclic ring propinyl with 1 nitrogen-atoms and optionally one other heteroatomic 4-7 yuan selected from nitrogen, oxygen and sulphur, a saturated or partially unsaturated spiro heterocyclic ring propinyl with 1 nitrogen-atoms and optionally 1-2 other heteroatomic 4-11 yuan selected independently from nitrogen, oxygen and sulphur, or a saturated or partially unsaturated heterocyclic ring propinyl with 1 nitrogen-atoms and optionally one other heteroatomic 8-10 yuan bicyclic with 1 nitrogen-atoms and independently selected from nitrogen, oxygen and sulphur, and is connected via a nitrogen-atoms.

30. A compound as described in any of claims 1-27, wherein each -Cy- is independently selected from cyclohexylene, piperidinylene, azetidinylene, pyrrolidinylene, piperazinylene, morpholinylene, 1-oxa-4,9-diazaspiro[5.5]undecylene, 3-azaspiro[5.5]undecylene, 2-azaspiro[3.3]heptylene, 7-azaspiro[3.5]nonylene, 3-azabicyclo[3.2.1]octanylene, 2,7-diazaspiro[3.5]nonanylene, 3,9-diazaspiro[5.5]undecylene or triazinylene.

31. A compound as described in any one of claims 1-30, wherein L' comprises -Cy 1 -(CH2) 0-1 -X-(CH2) 0-1 -Cy 2 -, where Cy 1 and Cy 2 Each is independently -Cy-.

32. The compound of claim 31, wherein Cy 1 is a 4-7 membered saturated or partially unsaturated heterocycloalkylene having 1 nitrogen atom and optionally one additional heteroatom selected from nitrogen, oxygen and sulfur, a 4-11 membered saturated or partially unsaturated spiroheterocycloalkylene having 1 nitrogen atom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, or an 8-10 membered bicyclic saturated or partially unsaturated heterocycloalkylene having 1 nitrogen atom and optionally 1 additional heteroatom independently selected from nitrogen, oxygen and sulfur, and is attached via the nitrogen atom.

33. The compound of claim 32, wherein Cy 1 is piperidinylene, azetidinylene, pyrrolidinylene, piperazinylene, morpholinylene, 1-oxa-4,9-diazaspiro[5.5]undecylene, 3-azaspiro[5.5]undecylene, 2-azaspiro[3.3]heptylene, 7-azaspiro[3.5]nonanylene, 3-azabicyclo[3.2.1]octanylene, 2,7-diazaspiro[3.5]nonanylene or 3,9-diazaspiro[5.5]undecylene.

34. A compound as described in any one of claims 31-33, wherein Cy 2 is cyclohexylene, piperidinylene, azetidinylene, pyrrolidinylene, piperazinylene, morpholinylene, 1-oxa-4,9-diazaspiro[5.5]undecylene, 3-azaspiro[5.5]undecylene, 2-azaspiro[3.3]heptylene, 7-azaspiro[3.5]nonanylene, 3-azabicyclo[3.2.1]octanylene, 2,7-diazaspiro[3.5]nonanylene, 3,9-diazaspiro[5.5]undecylene or triazinylene.

35. The compound of any one of claims 1-34, wherein X is O or N(R).

36. The compound of any one of claims 1-35, wherein R is H.

37. A compound as described in any one of claims 1-36, wherein Degron is One or more hydrogen atoms on the benzene ring of the Degron are optionally replaced by fluorine atoms.

38. The compound of claim 37, wherein Degron is One or more hydrogen atoms on the benzene ring of the Degron are optionally replaced by fluorine atoms.

39. The compound of claim 38, wherein Degron is One or more hydrogen atoms on the benzene ring of the Degron are optionally replaced by fluorine atoms.

40. The compound of claim 39, wherein Degron is One or more hydrogen atoms on the benzene ring of the Degron are optionally replaced by fluorine atoms.

41. A compound of Table 1, or a pharmaceutically acceptable salt thereof.

42. A pharmaceutical composition comprising a compound according to any one of claims 1 to 41 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

43. A pharmaceutical combination comprising a compound according to any one of claims 1 to 41 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 42 and at least one additional therapeutic agent.

44. A method of reducing the level or activity of KRAS G12D in a cell expressing KRAS G12D, comprising contacting the cell with a compound of any one of claims 1 to 41 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 42, or a pharmaceutical combination of claim 43.

45. A method of reducing the level or activity of KRAS G12D in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of claims 1-41 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 42, or a pharmaceutical combination of claim 43.

46. ​​A method of treating a KRAS G12D-related cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-41 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 42, or a pharmaceutical combination of claim 43.

47. The method of claim 46, wherein the cancer is a solid tumor cancer.

48. The method of claim 46, wherein the cancer is a hematological cancer.

49. The method of claim 46, wherein the cancer is cardiac cancer, gastrointestinal cancer, genitourinary tract cancer, liver cancer, biliary tract cancer, bone cancer, nervous system cancer, gynecological cancer, hematological cancer, skin cancer, or adrenal cancer.

50. The method of claim 46, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, or pancreatic cancer.

51. The method of any one of claims 46-50, further comprising determining that the subject has a KRASG12D-related cancer.

52. The method of any one of claims 46-50, further comprising administering to the subject at least one additional therapeutic agent.

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