KRAS G12D proteolysis-targeting chimera

Abstract

Provided herein are KRAS G12D proteolytic targeting chimeras (PROTACs), compositions comprising KRAS G12D PROTACs, and methods of making and using KRAS G12D PROTACs, for example, to promote the degradation of KRAS G12D and / or to treat KRAS G12D-associated cancers. KRAS G12D PROTACs have the following structural formula: [KRAS G12Di]-L'-[Degron], or a pharma- ceutically acceptable salt thereof, where KRAS G12Di is a KRAS G12D binding site, L' is a linker, and Degron is a cereblon binding site. Preferably, the compound is of formula (VII). TIFF2025515139000726.tif47165 or a pharma- ceutically acceptable salt thereof, TIFF2025515139000727.tif27165 is TIFF2025515139000728.tif32165)

Description

[Background technology]

[0001] Related Applications 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 which are incorporated herein by reference.

[0002] Kirsten rat sarcoma viral oncogene homologs (KRAS) are a group of genes responsible for making K-Ras proteins, which are important for cell growth and proliferation. Many mutations in KRAS are involved in many different types of cancer. One mutation, in particular, KRAS G12D, is a common oncogenic KRAS mutation and presents a promising target for the treatment of solid tumors associated with the KRAS pathway. Much research has been done to identify binding pockets, such as the switch II pocket, for irreversible inhibition of KRAS harboring the corresponding KRAS G12C 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 the reactive residues adjacent to the switch II pocket present in KRAS G12C.Several studies have attempted to develop a new class 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), but limited cellular activity has been observed. Recently, a small molecule known as MRTX1133 was discovered that binds to the switch II pocket of KRAS G12D. MRTX1133 is a potent, selective, noncovalent inhibitor of KRAS G12D that exhibits picomolar binding affinity, low nanomolar activity in cellular assays, and in vivo efficacy in tumor models harboring KRAS G12D mutations (MAMarx et.al., Identification of MRTX1133, a Noncovalent, Potent, and Selective KRASG12D Inhibitor. J. Med. Chem., 2022, 65(4), 3123-3133).

[0003] Proteolytic targeting chimeras (PROTACs) are bifunctional molecules containing two active domains, colloquially known as "warheads," covalently linked to each other by a linking moiety (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 that targets KRAS G12C is the molecule LC-2. LC-2, based on the KRAS G12C inhibitor MRTX849, can rapidly degrade KRAS G12C in homozygous and heterozygous tumor cells (M. J. Bond et al., Target degradation of oncogenic KRAS G12C by VHL-recruiting PROTACs, 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 remains bound to its target protein, which can affect the catalytic cycle of the PROTAC molecule and thereby limit its efficacy. Thus, there remains a need for PROTACs that are capable of binding to KRAS G12D and inducing its degradation, preferably in a non-covalent manner. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] MA,Marx et.al.,J.Med.Chem.2020,63(13),6679-6693 [Non-patent document 2] VJ,Cee et.al.,J.Med.Chem.2020,63(1),52-65 [Non-patent document 3] X.Lu et.al.,J.Med.Chem.2020,63(23),14404-14424 [Non-patent document 4] G.Fang,et.al.,Proc.Natl.Acad.Sci.USA,2012,109(14),5299-5304 [Non-patent document 5] SW,Fesik,et.al.,Angew.Chem.,Int.Ed.2012,51(25),6140-6143 [Non-patent document 6] MAMarx et.al.,J.Med.Chem.,2022,65(4),3123-3133 [Non-Patent Document 7] Hodges et.al.,Molecules.23(8),1958 [Non-patent document 8] MJBond et.al.,ACS Cent.Sci.,2020,6,1367-1375 [Non-Patent Document 9] J.Halin et.al.,Cancer Discov.10,54-71 Summary of the Invention

[0005] As used herein, a compound of structural formula A: [KRAS G12Di]-L'-[Degron] (A), or a pharmaceutically acceptable salt thereof, wherein the values ​​for the variables (eg, KRAS G12Di, L', Degron) are as described herein.

[0006] Also provided herein are compounds of structural formula VII: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables (e.g., ring A, X 4 , Y, R 2 , R 3 , R 4 , L', Degron) are provided as described herein.

[0007] Also provided herein are compounds of structural formula VI: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables (e.g., X 4 , Y, R 1 , R 2 , R 3 , R 4 , L', Degron) are provided as described herein.

[0008] Also provided herein are compounds of structural formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables (e.g., Y, R 1 , R 2 , R 3 , R 4 , L', Degron) are provided as described herein.

[0009] Also provided herein are pharmaceutical compositions comprising 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) and a pharmaceutically acceptable carrier.

[0010] Also provided herein are pharmaceutical combinations comprising 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) and at least one additional therapeutic agent.

[0011] Also provided herein are methods for reducing the level or activity of KRAS G12D in cells expressing KRAS G12D, comprising contacting the cells 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.

[0012] Also provided herein is a method for reducing the level or activity of KRAS G12D in a subject in need thereof, the method comprising contacting a cell with 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.

[0013] Also provided herein is a method for treating KRAS G12D-associated cancer in a subject in need thereof, the method comprising contacting cells with 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.

[0014] Also provided herein is 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) or a pharmaceutical composition comprising a compound of the present disclosure, for the uses described herein (e.g., reducing the level or activity of KRAS G12D in a subject; treating a KRAS G12D-associated cancer). Also provided herein is the use 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) or a pharmaceutical composition comprising a compound of the present disclosure, for the manufacture of a medicament for the uses described herein (e.g., reducing the level or activity of KRAS G12D in a subject; treating a KRAS G12D-associated cancer). DETAILED DESCRIPTION OF THE INVENTION

[0015] A description of example embodiments follows.

[0016] definition The compounds described herein include those generally described and further described by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th The general principles of organic chemistry are defined according to "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5 th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001 (incorporated herein by reference).

[0017] Unless otherwise specified herein, the nomenclature used herein generally follows the examples and rules set forth in Nomenclature of Organic Chemistry, Sections 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, names of compounds can be generated using a chemical naming program (e.g., CHEMDRAW®, version 17.0.0.206, PerkinElmer Informatics, Inc.).

[0018] When introducing elements disclosed herein, unless indicated otherwise, e.g., explicitly or by context, the articles "a," "an," "the," and "said" are intended to mean that one or more of the elements are present. Furthermore, the one or more elements may be the same or different.

[0019] "Aliphatic" refers to a saturated or unsaturated, branched or straight-chain hydrocarbon radical having the specified number of carbon atoms. Thus, "(C1-C5)aliphatic" refers to a radical having 1 to 5 carbon atoms in a branched or linear arrangement. In some embodiments, aliphatic refers to a (C1-C 15 ) aliphatic, e.g., (C1-C 10 ) aliphatic, (C1-C6) aliphatic, (C1-C5) aliphatic, (C1-C4) aliphatic, or (C1-C3) aliphatic. In some embodiments, the aliphatic is methylene or ethylene. Examples of aliphatic include alkyl, alkenyl, and alkynyl. In some aspects, the aliphatic is alkyl or alkynyl. In some aspects, the aliphatic is alkyl or alkenyl.

[0020] "Alkenyl" refers to a branched or straight-chain hydrocarbon radical having the specified number of carbon atoms and at least one carbon-carbon double bond. Thus, "(C2-C6)alkenyl" refers to a radical having from 2 to 6 carbon atoms in a branched or linear arrangement and at least one carbon-carbon double bond. In some embodiments, alkenyl refers to (C2-C 15 ) alkenyl, for example (C2-C 10 )alkenyl, (C2-C6)alkenyl, (C2-C5)alkenyl, (C2-C4)alkenyl or (C2-C3)alkenyl. Examples of alkenyl include vinyl and the like.

[0021] "Alkoxy" refers to an alkyl attached through an oxygen linking atom, where alkyl is as described herein. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, and the like.

[0022] "Alkyl" refers to a saturated, branched, or straight-chain hydrocarbon radical having the specified number of carbon atoms. Thus, "(C1-C6) alkyl" refers to a radical having from 1 to 6 carbon atoms in a branched or linear arrangement. In some embodiments, alkyl is a (C1-C 15 ) alkyl, for example (C1-C 10 ) alkyl, (C1-C6) alkyl, (C1-C5) alkyl, (C1-C4) alkyl, or (C1-C3) alkyl. Examples of alkyl include methyl, ethyl, propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, isobutyl, sec-butyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl, 2-methylpentyl), hexyl (e.g., n-hexyl), and the like.

[0023] "Alkylene" refers to a divalent alkyl radical, where alkyl is as defined herein. Examples of alkylene include methylene, ethylene, propylene, and the like.

[0024] "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 from 2 to 6 carbon atoms in a branched or linear arrangement and at least one carbon-carbon triple bond. In some embodiments, alkynyl refers to a (C2-C 15 ) alkynyl, for example (C2-C 10 )alkynyl, (C2-C6)alkynyl, (C2-C5)alkynyl, (C2-C4)alkynyl or (C2-C3)alkynyl. Examples of alkynyl include propargyl and the like.

[0025] "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 radical having 6 to 14 ring atoms. In some embodiments, aryl is (C6-C 14 ) aryl, for example (C6-C 12 ) aryl, (C6-C 10 )aryl or (C6)aryl. Examples of aryl 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 to 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 spirocyclic.

[0026] "Arylalkyl" refers to an alkyl in which one hydrogen of the alkyl is replaced by an aryl, wherein the alkyl and aryl are as described herein. Examples of arylalkyl include benzyl, phenethyl, and naphthylmethyl.

[0027] "Cyano" refers to -C≡N.

[0028] "Cyanoalkyl" refers to an alkyl where one hydrogen of the alkyl is replaced with cyano, wherein alkyl and cyano are as described herein. Examples of cyanoalkyl include cyanomethyl, cyanoethyl, cyanopropyl, and the like.

[0029] "Cycloalkyl" refers to a saturated or partially unsaturated, monocyclic or polycyclic (e.g., bicyclic, tricyclic), hydrocarbon ring radical having the specified number of ring atoms. Thus, "(C3-C6)cycloalkyl" refers to a ring radical having from 3 to 6 ring atoms. A cycloalkyl can be monocyclic, fused bicyclic, bridged bicyclic, or polycyclic, but is typically monocyclic. In some embodiments, a cycloalkyl is a (C3-C6) 12 ) cycloalkyl, for example, (C3-C8) cycloalkyl or (C3-C6) cycloalkyl. In some embodiments, cycloalkyl is saturated. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, bicyclo[1.1.1]pentanyl, and the like.

[0030] The suffix "ene" or "enyl" is used herein to indicate that the group modified by the suffix has two or more points of attachment (i.e., divalent, trivalent, or polyvalent) within the described compound. For example, a divalent alkyl group is an alkylene group, a divalent heteroalkyl group is a heteroalkylene, 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 described compound are not referred to using the name "ene." Thus, for example, a trifluoromethyl substituent would not be referred to herein as trifluoromethylene.

[0031] "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.

[0032] "Haloalkyl" refers to an alkyl in which at least one hydrogen of the alkyl is replaced with halo, wherein alkyl and halo are as described herein. Haloalkyl includes mono-, poly-, and perhaloalkyl groups, where each halogen is independently selected. In some embodiments, the haloalkyl is a perhaloalkyl (e.g., perfluoroalkyl). Haloalkyl includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethylethyl, pentafluoroethyl, and the like.

[0033] "Hetero" refers to an atom that is not carbon or hydrogen. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, etc. In some embodiments, hetero is independently selected from nitrogen, oxygen, or sulfur. In some embodiments, hetero is independently selected from nitrogen or oxygen.

[0034] "Heteroaryl" refers to a monocyclic or polycyclic (e.g., bicyclic, tricyclic), aromatic, hydrocarbon ring radical having the specified number of ring atoms, wherein at least one carbon atom in the ring is replaced with a heteroatom (e.g., a heteroatom independently selected from N, O, or S). Thus, "(C5-C6)heteroaryl" refers to an aromatic ring radical having 5 or 6 ring atoms each consisting of carbon and one or more independently selected heteroatoms (e.g., selected from N, O, or S). In some embodiments, a 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, a 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, a heteroaryl is a (C5-C6) 14 ) heteroaryl, for example (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 include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H-indazolyl, indo Indolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl), oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthroline, Anthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl Examples of thiadiazinyl include, but are not limited to, thiazolyl, 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, thiophenyl, 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.

[0035] "Heterocyclyl" or "heterocycloalkyl" refers to a saturated, monocyclic or polycyclic (e.g., bicyclic, tricyclic), hydrocarbon ring radical having the specified number of ring atoms, in which at least one carbon atom in the ring is replaced with a heteroatom. Thus, "(C3-C6)heterocyclyl" refers to a heterocyclic ring system having 3 to 6 ring atoms consisting of carbon and one or more independently selected heteroatoms. A heterocyclyl can be monocyclic, fused bicyclic, bridged bicyclic, or polycyclic, but is typically monocyclic. In some embodiments, a heterocyclyl 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, a heterocyclyl contains 1, 2, 3, or 4 (e.g., 1, 2, or 3; 1 or 2) heteroatoms independently selected from N and O. If one heteroatom is S, it may be optionally mono- or dioxygenated (i.e., -S(O)- or -S(O)2). In some embodiments, heterocyclyl is (C3-C 15 ) heterocyclyl, for example (C3-C 12)heterocyclyl, (C4-C8)heterocyclyl, (C3-C7)heterocyclyl or (C3-C6)heterocyclyl. Examples of monocyclic heterocyclyls include epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydrothiopyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, quinuclidinyl, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, morpholinyl, azepanyl, oxazepanyl, azabicyclohexanyl, azabicycloheptanyl, azabicyclooctanyl, azabicyclononanyl (e.g., octahydroquinolinyl, indolizinyl), azaspiroheptanyl, dihydro-1H,3H,5H-oxazolo[3,4-c]oxazolyl, tetrahydro-1′H,3′H-spiro[cyclopropane-1,2′-pyrrolidine], hexahydro-1H-pyrrolidinyl, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl, octahydroindolizinyl, oxazaspirononanyl, oxazaspirooctanyl, diazaspirononanyl, oxazabiocycloheptanyl, hexahydropyrrolidinyl 4(1H)-oxide, tetrahydro-2H-thiopyranyl 1-oxide, and tetrahydro-2H-thiopyranyl 1,1-dioxide.

[0036] "Hydroxy" refers to --OH.

[0037] "Hydroxyalkyl" refers to an alkyl in which one hydrogen of the alkyl is replaced with hydroxy, where alkyl and hydroxy are as defined herein. Examples of hydroxyalkyl include hydroxymethyl, hydroxyethyl, hydroxypropyl, and the like.

[0038] "Hydroxyalkynyl" refers to alkynyl where one hydrogen of the alkynyl has been replaced with hydroxy, wherein alkynyl and hydroxy are as described herein.

[0039] "Oxo" refers to =O.

[0040] The term "substituted" refers to the replacement of a hydrogen atom with a suitable substituent. Typically, a suitable substituent replaces a hydrogen atom bonded to a carbon atom, but a substituent can also replace a hydrogen atom bonded to a heteroatom, such as a nitrogen atom. When two or more hydrogen atoms are each replaced with independently selected substituents, the substituents can be the same or different. It will be understood that "substituted" or "substituted with" includes the implicit condition that such substitution is in accordance with the allowed valence of the substituted atom. It is also preferred that the substituents and substitutions result in stable compounds that do not spontaneously undergo transformation, for example, by rearrangement, migration, elimination, etc.

[0041] The term "optionally substituted," as used herein, means that substitution is optional, and thus the atom or moiety designated as "optionally substituted" can 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 to 5 (e.g., 1 to 5, 0 to 3, 1-3, 0, 1, 2, 3, 4, 5) substituents. Unless otherwise indicated, groups designated herein are unsubstituted, as for example, by the term "substituted" or "optionally substituted" groups.

[0042] The bond to the substituent may be such that it crosses the bond connecting two atoms in the ring (e.g., R 1 , R 6 and R 8When a substituent is shown crossing a bond to a substituent (a bond to a ring) or a circle representing a ring, then such substituent may be bonded to any substitutable atom in the ring. Further, when the ring in which a bond to a substituent is shown crossing is polycyclic (e.g., bicyclic, e.g., the hexahydropyrrolidinyl ring system in Structural Formula II), then the substituent may be bonded to any substitutable atom in the ring or ring system in which a bond to a substituent is shown crossing.

[0043] When a substituent is listed or shown without indicating the atom to which such substituent is attached to the remainder of a compound of a given formula, then such a substituent may be attached through any atom in such a substituent, as long as such substitution results in a stable compound. Square brackets are used herein to indicate such a substituent without indicating the atom to which such a substituent is attached to the remainder of a compound of a given formula. Thus, for example, a compound of the following structural formula: [ka] wherein the portion of the compound in the square brackets attached to -L'-[Degron] is a compound of the following structural formula: [ka] through the nitrogen atom of the secondary amine of the diazabicyclooctanyl moiety, or to give a compound of the following structural formula: [ka] Similarly, a compound of the following structural formula: [KRAS G12Di]-L'-[Degron], where Degron is [ka] In the above formula, Degron is, for example, [ka] or via the ortho carbon atom of the phthalimide, as in [ka] These examples are given for illustrative purposes only and are not limiting of other attachment sites on the Degron and / or on the moiety in the compound in square brackets that is attached to -L'-[Degron], all of which are contemplated by the present disclosure.

[0044] Suitable substituents for use herein include halogen, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., 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 the substituents may themselves be substituted, if appropriate. Thus, the substituent may further include, for example, acetamide.

[0045] When a divalent substituent is recited without indicating any directionality of such substituent (e.g., variables L′ and / or X), the divalent substituent may be attached in either direction. Thus, for example, a compound of structural formula (I): [ka] (Wherein L' is -X-(CH2) q -) has the following structural formula: [ka] and the following structural formula: [ka] Both compounds are included.

[0046] As used herein, the term "compounds of the present disclosure" refers to compounds of any structural formula set forth herein (e.g., compounds of structural formula I or subformulas thereof, e.g., compounds of structural formula Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, Table 1), as well as isomers, e.g., stereoisomers (including diastereoisomers, enantiomers, and racemates) and tautomers thereof, isotopologues thereof, and inherently formed moieties thereof (e.g., polymorphs and / or solvates, e.g., hydrates). If moieties capable of forming salts are present, then salts, particularly pharmaceutically acceptable salts, are also included.

[0047] The compounds of the present disclosure have asymmetric centers, chiral axes, and chiral planes (as described, for example, in E.L. Eliel and S.H. Wiley, Stereo-chemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119-1190) and can occur 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; all possible isomers and mixtures thereof are included unless otherwise indicated.

[0048] Unless otherwise indicated in terms of use herein, when a disclosed compound or moiety is depicted by a structure without indicating stereochemistry, and the compound or moiety has one or more chiral centers, the structure should be understood to encompass one enantiomer or diastereomer of the compound or moiety separated or substantially separated from the corresponding optical isomer(s), racemic mixtures, and mixtures enriched in one enantiomer or diastereomer relative to its corresponding optical isomer(s).Unless otherwise indicated in terms of use herein, when a disclosed compound or moiety is depicted by a structure using solid and / or broken 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. Unless otherwise indicated in terms of use herein, disclosed compounds or moieties are depicted by structures using solid and / or broken bold lines to indicate stereochemistry, and where a compound or moiety has one or more chiral centers, stereochemistry refers to the relative stereochemistry of the unspecified absolute configuration of substituents around one or more chiral centers. "R" and "S" can 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- can also or alternatively be used to designate stereochemistry. Thus, for example, a single stereoisomer having known relative and absolute configurations of two chiral centers can be designated using the conventional RS system (e.g., (1S,2S)); diastereomers in a racemic mixture can be designated using the two-letter RS ​​system (e.g., (1RS,2RS) for a racemic mixture of (1R,2R) and (1S,2S); (1RS,2SR) for a racemic mixture of (1R,2S) and (1S,2R)).

[0049] "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center.

[0050] "Diastereomers" are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms.

[0051] As used herein, a "racemate" or "racemic mixture" refers to a mixture containing equimolar amounts of two enantiomers of a compound. Such mixtures do not exhibit optical activity (i.e., they do not rotate the plane of polarized light).

[0052] Enantiomeric excess (ee) is defined as the absolute difference between the mole fractions of each enantiomer multiplied by 100% and is calculated using the following equation:

number

[0053] Diastereomeric excess (de) is defined as the absolute difference between each mole fraction of each diastereomer multiplied by 100% and is calculated using the following equation:

number

[0054] Tautomers are isomers of a compound that differ in the location of one or more hydrogen atoms.

[0055] Unless otherwise indicated, all possible isomers and mixtures thereof, including optical isomers, rotamers, tautomers and cis and trans isomers, are included in the present invention.

[0056] The term "isotopologue" refers to a molecule that differs from a reference molecule only in its isotopic composition.

[0057] A given atom naturally exists in various isotopic forms. Natural isotopic abundance refers to the relative abundance of various naturally occurring isotopes of a given atom. Thus, it is understood that a population of molecules represented by a particular chemical structure will typically contain isotopologues of the particular chemical structure. The relative amount of such isotopologues will depend on numerous factors, such as the relative natural isotopic abundance, the isotopic purity of the reagents used to make the compound, and the efficiency of incorporation of isotopic atoms in the various synthetic steps used to prepare the compound. In certain embodiments, the 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% overall.

[0058] The structures depicted herein are meant to represent such natural isotopic abundances, as well as the replacement of one or more atoms in the structure with its isotopically or isotopically enriched counterpart, e.g., at non-natural isotopic abundances, e.g., hydrogen with deuterium or tritium, or 13 C or 14 Compounds produced by replacement of carbon with C are within the scope of the present disclosure. In some embodiments, a hydrogen atom in a compound of the present disclosure is replaced or enriched with D. In some embodiments, a methyl group in a compound of the present disclosure is replaced or enriched with -CD. Isotopologues can be useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the present disclosure.

[0059] The phrase "pharmaceutically acceptable" means that the substance or composition it modifies is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio.

[0060] As used herein, the term "pharmaceutically acceptable salt" refers to those salts that are, within the scope of reasonable medical judgment, suitable for use in contact with mammalian tissues without undue toxicity, irritation, allergic response, etc., and that are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. 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.

[0061] Examples of pharmaceutically acceptable acid addition salts are salts of amino groups formed with 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 using 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, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, glutarate, glycolate, hemisulfate, heptanoate, hexanoate, hydroiodide, hydroxybenzoate, 2-hydroxy-ethanesulfonate, hydrochloride, hydroxybenzoates, 2-hydroxy-ethanesulfonates, hydroxybenzo ... These include the following salts: 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 salts, and the like. Either the mono-, di-, or tri-acid salts can be formed, and such salts can exist in hydrated, solvated, or substantially anhydrous form.

[0062] Pharmaceutically acceptable base addition salts include salts formed with inorganic bases, such as alkali metal, alkaline earth metal, and ammonium bases, and salts formed with aliphatic, alicyclic, or aromatic organic amines, such as methylamine, trimethylamine, and picoline; +((C1-C4) alkyl) salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, barium, and the like. Further pharmaceutically acceptable base addition salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxyls, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0063] The compounds described herein may also exist as "solvates" or "hydrates." A "hydrate" is a compound that exists in a composition with one or more water molecules. A hydrate may contain a stoichiometric amount of water, such as a monohydrate or dihydrate, or may contain a random amount of water. A "solvate" is similar to a hydrate, except that a solvent other than water, such as methanol, ethanol, dimethylformamide, diethyl ether, etc., replaces 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 adventitious to such solvent.

[0064] "Pharmaceutically acceptable carrier" refers to a non-toxic carrier or excipient that does not destroy the pharmacological activity of the drug formulated therewith and is non-toxic when administered in a dose sufficient to deliver a therapeutic amount of the drug. Pharmaceutically acceptable carriers that can be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0065] "Treating," as used herein, refers to using a process to deliver therapy to a subject, e.g., a mammal, in need thereof (e.g., by administering one or more therapeutic agents to the subject). "Treating" includes inhibiting a disease or condition (e.g., by slowing or stopping its progression or by causing regression of the disease or condition), as well as alleviating symptoms caused by the disease or condition.

[0066] "KRAS G12D" refers to a mammalian KRAS protein containing an aspartic acid substitution for glycine at amino acid position 12. The amino acid codon and residue position assignments for human KRAS are based on the amino acid sequence specified by UniProtKB / Swiss-Prot P01116:Variantp.Gly12Asp.

[0067] "KRAS G12D-associated cancer" refers to a cancer that is associated with (e.g., mediated by) or has a KRAS G12D mutation. Those 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, by using a kit or assay approved by a regulatory authority, such as 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-apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR).

[0068] " Binding site " is the part of a compound that binds to the indicated target with measurable affinity.In the context of the present disclosure, the target can typically be a protein, for example, KRAS G12D in KRAS G12D binding site; ubiquitin E3 ligase in ubiquitin E3 ligase binding site.In the compound of the present disclosure, the binding of the compound of the present disclosure to the indicated target is typically mediated by the binding site of the target.For example, the binding of the compound of the present disclosure to KRAS G12D in the compound of the present disclosure is typically mediated by KRAS G12D binding site.For example, the binding of the compound of the present disclosure to ubiquitin E3 ligase is typically mediated by ubiquitin E3 ligase binding site.

[0069] Binding (of the binding site and / or compound of the present disclosure) to a target can result, for example, in inhibition and / or agonism (full or partial) of the target, e.g., a target protein. Thus, in some embodiments, the binding site and / or compound of the present disclosure is an inhibitor. In certain embodiments, the binding site and / or compound of the present disclosure has an IC for its indicated target of less than about 50 μM, e.g., 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. 50 and / or have the binding constant with its indicated target, IC 50and methods for determining binding constants are described herein and / or are within the capabilities of one of ordinary skill in the art.

[0070] 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).

[0071] A "therapeutically effective amount" is an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result (e.g., treating, curing, inhibiting, or ameliorating a physiological response or condition, etc.). A full therapeutic effect does not necessarily occur by administration of a single dose, but may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. A therapeutically effective amount may vary depending on 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 a desired response in an individual. The therapeutically effective amount of the agent to be administered can be determined by a clinician of ordinary skill using the guidance provided herein and other methods known in the art.

[0072] As used herein, a "subject" includes humans, domesticated 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, cows, sheep, goats, horses, etc.), and non-domesticated animals. In some embodiments, the subject is a human.

[0073] compound In one embodiment, a KRAS G12D PROTAC of structural formula (A): [KRAS G12Di]-L'-[Degron] (A), or a pharmaceutically acceptable salt thereof, wherein KRAS G12Di is a KRAS G12D binding site, preferably a KRAS G12D inhibitor; L' is a bivalent linker connecting KRAS G12Di to the Degron; Degrons are provided herein, preferably degrons, which are ubiquitin E3 ligase binding sites. Alternative values ​​for each of the variables in Structural Formula A are described in the following sections and throughout this disclosure. The disclosure contemplates all combinations of values ​​and alternative values ​​for the variables presented herein.

[0074] KRAS G12D binding site KRAS G12D binding sites and methods for making same are disclosed in International Publication Nos. WO2021 / 041671; WO2022 / 031678; WO2022 / 066646; and WO2022 / 015375, the entire contents of which are incorporated herein by reference. In some embodiments, the KRAS G12D binding site is a KRAS G12D inhibitor, e.g., a KRAS G12D inhibitor disclosed in WO2021 / 041671; WO2022 / 031678; WO2022 / 066646; or WO2022 / 015375. In some embodiments, the KRAS G12D binding site is a KRAS G12D inhibitor disclosed in WO2021 / 041671 or WO2022 / 015375.

[0075] KRAS G12D binding sites and methods for making 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 embodiments, the KRAS G12D binding site is a KRAS G12D inhibitor disclosed in Mao et al.

[0076] KRAS G12D binding sites and methods for making same are disclosed in International Publication No. WO2022 / 105857, the entire contents of which are incorporated herein by reference. In some embodiments, the KRAS G12D binding site is a KRAS G12D inhibitor disclosed in WO2022 / 105857. KRAS G12D binding sites and methods for making same are also disclosed in International Publication No. WO2022 / 105859, the entire contents of which are incorporated herein by reference. In some embodiments, the KRAS G12D binding site is a KRAS G12D inhibitor disclosed in WO2022 / 105859.

[0077] In a first embodiment, a compound of the following structural formula: [ka] or a pharmaceutically acceptable salt thereof, wherein Y is a bond, O, or NR 5 and; R 1 is hydrogen, hydroxy, halogen, (C1-C3) alkyl, (C1-C3) cyanoalkyl, (C1-C3) hydroxyalkyl, -C(O)H, -COR 5 , -CO2N(R 5 )2 or (C5-C6)heteroaryl; R 2 is hydrogen, -N(R 5 )2, (C3-C 12 )heterocyclyl, (C1-C6) alkyl, -L-(C3-C 12 )heterocyclyl, -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, (C3-C 12 ) Heterocyclyl, -L-NR 5 C(O)-(C6-C 14 ) aryl (C6-C 14 )aryl, -L-(C3-C 12 )heterocyclyl (C3-C 12 )heterocyclyl and -L-(C3-C 12 ) cycloalkyl (C3-C 12 ) Cycloalkyl is a group consisting of one or more R 6 optionally substituted with -L-(C6-C 14 )aryl and -L-(C5-C 14 ) heteroaryl (C5-C 14 ) Heteroaryl is a heteroaryl group consisting of one or more R 7 optionally substituted with; L is hydroxy, (C1-C4) hydroxyalkyl or (C5-C 14 ) (C1-C4) alkylene optionally substituted with heteroaryl; R 3 is (C6-C 14 ) aryl or (C5-C 14 ) heteroaryl, (C6-C 14 ) aryl or (C5-C 14 ) Heteroaryl is a heteroaryl group consisting of one or more R 8 optionally substituted with; R 4 is hydrogen, halogen or (C1-C3) alkyl; Each R 5 are independently hydrogen or (C1-C3) alkyl; Each R 6 are independently selected from deuterio, halogen, hydroxy, (C-C)hydroxyalkyl, (C-C)alkyl, (C-C)haloalkyl, (C-C)alkoxy, cyano, -Q-phenyl, -Q-phenyl-SOF, -N(H)C(O)-phenyl, -N(H)C(O)-phenyl-SOF, (C-C)alkyl-substituted pyrazole, (C-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 ) heterocyclyl, -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 ) heterocyclyl or -CH2-(C3-C 12 ) heterocyclyl, in which the phenyl in —N(H)C(O)phenyl and —OC(O)N(H)(C1-C3)alkyl-O—(C1-C3)alkyl-phenyl is optionally substituted with —C(O)H or —OH, and —CH2—(C3-C 12 )heterocyclyl (C3-C 12 ) heterocyclyl is optionally substituted with oxo; Q is a bond or O; Each R 7 are independently halogen, hydroxy, —C(O)H, (C-C)alkyl, (C-C)alkoxy, (C-C)haloalkyl, (C-C)hydroxyalkyl, or —N(R 5 )2; Each R 8are 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, deuterio(C2-C4)alkynyl, (C1-C3)alkoxy(C1-C3)haloalkyl or (C3-C6)cycloalkyl, wherein (C3-C6)cycloalkyl is optionally substituted with halogen or (C1-C3)alkyl; L' is [ka] is a bivalent linker connecting the Degron to the Degron is a degron) is provided.

[0078] In a first aspect of the first embodiment, Y is O. Values ​​for the remaining variables are as described in the first embodiment.

[0079] In a second aspect of the first embodiment, R 1 is hydrogen. Values ​​for the remaining variables are as described in the first embodiment, or first aspect thereof.

[0080] In a third aspect of the first embodiment, R 2 is -L-(C3-C 12 ) heterocyclyl, -L-(C3-C 12 )heterocyclyl (C3-C 12 ) Heterocyclyl is a heterocyclic group consisting of one or more R 6The values ​​for the remaining variables are as described in the first embodiment, or first or second aspect thereof.

[0081] In a fourth aspect of the first embodiment, L is methylene. Values ​​for the remaining variables are as described in the first embodiment, or its first through third aspects.

[0082] In a fifth aspect of the first embodiment, R 3 is one or more R 8 optionally substituted (C6-C 14 ) aryl. Values ​​for the remaining variables are as described in the first embodiment, or its first through fourth aspects.

[0083] In a sixth aspect of the fourth embodiment, R 1 is halogen. Values ​​for the remaining variables are as described in the first embodiment, or aspects 1 through 5 thereof.

[0084] In a seventh aspect of the fourth embodiment, R 1 is fluoro. Values ​​for the remaining variables are as described in the first embodiment, or aspects 1 through 6 thereof.

[0085] In an eighth aspect of the first embodiment, each R 6 is independently halogen, hydroxy, (C1-C3)hydroxyalkyl, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, or cyano. Values ​​for the remaining variables are as described in the first embodiment, or its first through seventh aspects.

[0086] In a ninth aspect of the first embodiment, each R 8is independently halogen, hydroxy, (C1-C4)alkyl, —S—(C1-C3)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C1-C3)alkoxy, (C1-C3)hydroxyalkyl, or deuterio(C2-C4)alkynyl. Values ​​for the remaining variables are as described in the first embodiment, or its first through eighth aspects.

[0087] In a tenth aspect of the first embodiment, each R 8 is independently halogen, hydroxy, or (C2-C4)alkynyl. Values ​​for the remaining variables are as described in the first embodiment, or its first through ninth aspects.

[0088] In an eleventh aspect of the first embodiment, R 3 teeth, [ka] The values ​​for the remaining variables are as described in the first embodiment, or aspects 1 to 10 thereof.

[0089] In a twelfth aspect of the first embodiment, YR 2 teeth, [ka] ,*-H, [ka] The values ​​for the remaining variables are as described in the first embodiment, or its first to eleventh aspects.

[0090] In a thirteenth aspect of the first embodiment, R 3 teeth, [ka] The values ​​for the remaining variables are as described in the first embodiment, or aspects 1 to 12 thereof.

[0091] In a fourteenth aspect of the first embodiment, each R 6 is independently deuterio, halogen, hydroxy, (C-C)hydroxyalkyl, (C-C)alkyl, (C-C)haloalkyl, (C-C)alkoxy, or cyano. Values ​​for the remaining variables are as described in the first embodiment, or its first through thirteenth aspects.

[0092] In a fifteenth aspect of the first embodiment, each R 6 are independently selected from 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, pyrazole substituted with (C1-C3)alkyl, (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 ) heterocyclyl, -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 ) heterocyclyl or -CH2-(C3-C 12) heterocyclyl, in which the phenyl in —N(H)C(O)phenyl and —OC(O)N(H)(C1-C3)alkyl-O—(C1-C3)alkyl-phenyl is optionally substituted with —C(O)H or —OH, and —CH2—(C3-C 12 )heterocyclyl (C3-C 12 ) heterocyclyl is optionally substituted with oxo. Values ​​for the remaining variables are as described in the first embodiment, or aspects 1 through 14 thereof.

[0093] A second embodiment is a compound of the following structural formula: [ka] or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2 (and in some embodiments, 1 or 2; in further embodiments, 1), and the remaining variables (e.g., R 1 , R 3 , R 4 , R 6 , L', Degron) are as described in the first embodiment, or any aspect thereof).

[0094] In a first aspect of the second embodiment, the compound has the following structural formula: [ka] 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 the second embodiment.

[0095] In a second aspect of the second embodiment, the compound has the following structural formula: [ka] 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 the second embodiment.

[0096] A third embodiment is a compound of the following structural formula: [ka] or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3, 4, or 5 (and in some embodiments, 1, 2, or 3; in further embodiments, 2 or 3; in still further embodiments, 3), and the remaining variables (e.g., R 1 , R 4 , R 6 , R 8 , n, L', Degron) are as described in the first or second embodiment, or any aspect of the foregoing.

[0097] In a first aspect of the third embodiment, the compound has the following structural formula: [ka] 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 of the foregoing.

[0098] In a second aspect of the third embodiment, the compound has the following structural formula: [ka] 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 of the foregoing.

[0099] A fourth embodiment is a compound of the following structural formula: [ka] or a pharmaceutically acceptable salt thereof. 1 , R 4 , R 6 , n, L', Degron) are as described in the first or second embodiment, or any aspect of the foregoing.

[0100] In a first aspect of the fourth embodiment, the compound has the following structural formula: [ka] or a pharmaceutically acceptable salt thereof. 1 , R 4 , R 6 , n, L', Degron) are as described in the first or second embodiment, or any aspect of the foregoing.

[0101] In a second aspect of the fourth embodiment, the compound has the following structural formula: [ka] or a pharmaceutically acceptable salt thereof. 1 , R 4 , R 6 , n, L', Degron) are as described in the first or second embodiment, or any aspect of the foregoing.

[0102] A fifth embodiment is a compound of the following structural formula: [ka] or a pharmaceutically acceptable salt thereof, wherein n′ is 0 or 1 (and in some embodiments, 0), and the remaining variables (e.g., R 1 , R 4 , R 6 , L', Degron) are as described in the first embodiment, or any aspect thereof.

[0103] In a first aspect of the fifth embodiment, the compound has the following structural formula: [ka] 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 the fifth embodiment.

[0104] In a second aspect of the fifth embodiment, the compound has the following structural formula: [ka] 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 the fifth embodiment.

[0105] A sixth embodiment is a compound of the following structural formula: [ka] or a pharmaceutically acceptable salt thereof, wherein X 4 is N or C(R 42 ) and; R 42 is hydrogen, halogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6Haloalkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, oxo, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl), -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -S(haloC 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 1-6alkyl), -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- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, each of which is independently selected from halogen, —C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Haloalkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, oxo, -NH2, -NH(C 1-6 alkyl), -N(C 1-6alkyl), -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -S(haloC 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 1-6 alkyl), -S(=O)2(OC 1-6 alkyl), -OS(=O)2(C1-6 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) optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from 2, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; The remaining variables (e.g., Y, R 1 , R 2 , R 3 , R 4 , L', Degron) are as described in the first to fifth embodiments, or any aspect of the foregoing.

[0106] In a first aspect of the sixth embodiment, X 4 is C(R 42) 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.

[0107] In a second aspect of the sixth embodiment, R 42 is hydrogen, halogen, (C-C)alkyl, (C-C)haloalkyl, (C-C)haloalkoxy, (C-C)alkenyl, (C-C)alkynyl, —CN, (C-C)alkoxy, —S—(C-C)alkyl, or —S—(C-C)haloalkyl. 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.

[0108] In a third aspect of the sixth embodiment, R 42 is hydrogen, fluoro, chloro, methyl, —CF3, —OCF3, —CN, —OCH3, —SCH3, or —SCF3. Values ​​for the remaining variables are as described in the first through fifth embodiments, or any aspect thereof, or the sixth embodiment, or the first or second aspect thereof.

[0109] A seventh embodiment is a compound of the following structural formula: [ka] or a pharmaceutically acceptable salt thereof, wherein [ka] teeth, [ka] and; X 5 is O or CH2; The Two R's o , together with the same carbon atom, C 3-7cycloalkyl or 4- to 7-membered heterocycloalkyl, each (C3-C7)cycloalkyl or 4- to 7-membered heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, oxo, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, hydroxyl, 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 is independently selected from hydroxyl, 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 (and, in some preferred embodiments, 1); q is 0, 1, or 2 (and, in some preferred embodiments, 1); 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.

[0110] In a first aspect of the seventh embodiment, [ka] teeth, [ka] 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.

[0111] In a second aspect of the seventh embodiment, [ka] teeth, [ka] [ka] is. Values ​​for the remaining variables are as described in the first to sixth embodiments, or any aspect thereof, or the seventh embodiment, or its first aspect.

[0112] In a third aspect of the seventh embodiment, [ka] teeth, [ka] The values ​​for the remaining variables are as described in the first through sixth embodiments, or any aspect thereof, or the seventh embodiment, or its first or second aspect.

[0113] An eighth embodiment is a compound of the following structural formula: [ka] or a pharmaceutically acceptable salt thereof, 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 embodiments, 0, 1, 2, 3, 4, 5, or 6; in further embodiments, 0, 1, 2, 3, or 4), and the remaining variables (e.g., ring A, X 4 , R 3 , R 4 , R 6 , L', Degron) are as described in the first to seventh embodiments, or any aspect of the foregoing.

[0114] In a first aspect of the eighth embodiment, R 21 and R 22 and are each D. Values ​​for the remaining variables are as described in the first through seventh embodiments, or any aspect of the foregoing, or the eighth embodiment.

[0115] In a second aspect of the eighth embodiment, R 21 and R 22 are each H. Values ​​for the remaining variables are as described in the first through seventh embodiments, or any aspect of the foregoing, or the eighth embodiment.

[0116] It will be understood that the sites depicted in square brackets in the compounds of structural formulas (I)-(VIII) correspond to the KRAS G12D binding sites in the compounds of structural formulas (I)-(VIII). In some embodiments, the KRAS G12D binding site is a site represented by structural formulas (I)-(VIII) (wherein the variables (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 the moieties shown in square brackets in any one of the first to seventh embodiments, or any aspect thereof, as described in the first to seventh embodiments.

[0117] In some aspects of any of the foregoing embodiments or aspects thereof, the KRAS G12D binding site has structural formulas (I)-(VIII), for example, the following structural formula: [ka] (In the formula, R 23 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, L', Degron) are as described in the first to eighth embodiments, or any aspect of the foregoing. 2 or R 6 is bonded to -L'-[Degron] via an atom of the group corresponding to

[0118] Specific examples of KRAS G12D binding sites include: [ka] In some embodiments, the KRAS G12D binding site includes: [ka] In some embodiments, the KRAS G12D binding site is [ka] In some embodiments, the KRAS G12D binding site is [ka] is.

[0119] Other specific examples of KRAS G12D binding sites include: [ka] In some embodiments, the KRAS G12D binding site includes: [ka] In some embodiments, the KRAS G12D binding site is [ka] In some embodiments, the KRAS G12D binding site is [ka] is.

[0120] Other specific examples of KRAS G12D binding sites include those disclosed in Mao et al. Thus, in some embodiments, the KRAS G12D binding site has the following structural formula: [ka] (In the formula, [ka] teeth, [ka] (which is

[0121] Further specific examples of KRAS G12D binding sites include those described in Wang, et al., "Identification of MRTX1133, a Noncovalent, Potent, and Selective KRAS G12D Inhibitor,” J. Med Chem., https: / / doi.org / 10.1021 / acs.jmedchem.1c01688, the entire contents of which are incorporated herein by reference. In some embodiments, the KRAS G12D binding site is a KRAS G12D inhibitor disclosed in Wang et al. For example, in some embodiments, the KRAS G12D binding site has the following structural formula: [ka] In some embodiments, the KRAS G12D binding site has the following structural formula: [ka] In some embodiments, the KRAS G12D binding site has the following structural formula: [ka] (Wherein R4 is [ka] In some embodiments, the KRAS G12D binding site has the following structural formula: [ka] (Wherein R2 is [ka] ,*-H, [ka] In some embodiments, the KRAS G12D binding site has the following structural formula: [ka] (Wherein R7 is [ka] (which is

[0122] In some embodiments, the KRAS G12D binding site has the following structural formula: [ka] (In the formula, X 1 is a bond or C1-C4 alkylene; Y and Y 1 are each independently a bond, O, or NR 5 and; R 1 is hydroxy, N(R 5 )2, (C3-C 12 ) cycloalkyl, or (C3-C 12 ) heterocyclyl, (C3-C 12 ) cycloalkyl or (C3-C 12 ) Heterocyclyl is a heterocyclic group consisting of one or more R X optionally substituted with; Each RX are independently (C1-C3) alkyl, hydroxy, -N(R 5 )2, -CH2N(R 5 )2, cyanomethyl, or (C3-C 12 ) heterocyclyl; R 2 is hydrogen, -N(R 5 )2, (C3-C 12 )heterocyclyl, (C1-C6) alkyl, -L-(C3-C 12 )heterocyclyl, -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, (C3-C 12 ) Heterocyclyl, -L-NR 5 C(O)-(C6-C 14 ) aryl (C6-C 14 )aryl, -L-(C3-C 12 )heterocyclyl (C3-C 12 )heterocyclyl and -L-(C3-C 12 ) cycloalkyl (C3-C 12 ) Cycloalkyl is a group consisting of one or more R 6 optionally substituted with -L-(C6-C 14 )aryl and -L-(C5-C 14 ) heteroaryl (C5-C 14 ) Heteroaryl is a heteroaryl group consisting of one or more R 7 optionally substituted with; Each L is independently hydroxy, (C1-C4)hydroxyalkyl or (C5-C 14) (C1-C4) alkylene optionally substituted with heteroaryl; R 3 is (C6-C 14 ) aryl or (C5-C 14 ) heteroaryl, (C6-C 14 ) aryl or (C5-C 14 ) Heteroaryl is a heteroaryl group consisting of one or more R 8 optionally substituted with; R 4 is hydrogen, halogen or (C1-C3) alkyl; Each R 5 are independently hydrogen or (C1-C3) alkyl; Each R 6 are independently selected from 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, pyrazole substituted with (C1-C3)alkyl, (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 ) heterocyclyl; each Q is independently a bond or O; Each R 7 are independently halogen, hydroxy, —C(O)H, (C-C)alkyl, (C-C)alkoxy, (C-C)haloalkyl, (C-C)hydroxyalkyl, or —N(R 5 )2; Each R 8are 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. is. Alternative values ​​for the variables are as described in the first, second or third embodiment, or any of the preceding aspects.

[0123] In some embodiments, the KRAS G12D binding site is [ka] [ka] [ka] [ka] is.

[0124] In some embodiments, the KRAS G12D binding site has the following structural formula: [ka] (In the formula, 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; Y is a bond, O, or NR 5 and; Z is -(CH2) 0-20 -CH3 or (C1-C3) alkyl; R 1is hydrogen, hydroxy, halogen, (C1-C3) alkyl, (C1-C3) cyanoalkyl, (C1-C3) hydroxyalkyl, -C(O)H, -COR 5 , -CO2N(R 5 )2 or (C5-C6)heteroaryl; R 2 is hydrogen, -N(R 5 )2, (C3-C 12 )heterocyclyl, (C1-C6) alkyl, -L-(C3-C 12 )heterocyclyl, -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, (C3-C 12 ) Heterocyclyl, -L-NR 5 C(O)-(C6-C 14 ) aryl (C6-C 14 ) aryl, -L-(C3-C 12 )heterocyclyl (C3-C 12 )heterocyclyl and -L-(C3-C 12 ) cycloalkyl (C3-C 12 ) Cycloalkyl is a group consisting of one or more R 6 optionally substituted with -L-(C6-C 14 )aryl and -L-(C5-C 14 ) heteroaryl (C5-C 14 ) Heteroaryl is a heteroaryl group consisting of one or more R 7 optionally substituted with; Each L is independently selected from hydroxy, (C1-C4)hydroxyalkyl (C5-C 14) heteroaryl or (C1-C4) alkylene optionally substituted with 1 to 2 deuterium atoms; R 3 is (C6-C 14 ) aryl or (C5-C 14 ) heteroaryl, (C6-C 14 ) aryl or (C5-C 14 ) Heteroaryl is a heteroaryl group consisting of one or more R 8 optionally substituted with; R 4 is hydrogen, halogen or (C1-C3) alkyl; Each R 5 are independently hydrogen or (C1-C3) alkyl; Each R 6 are independently selected from 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, pyrazole substituted with (C1-C3)alkyl, (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 ) heterocyclyl, -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 )heterocyclyl, -CH2-(C3-C 12 ) heterocyclyl or deuterium, in which the phenyl in —N(H)C(O)phenyl and —OC(O)N(H)(C1-C3)alkyl-O—(C1-C3)alkyl-phenyl is optionally substituted with —C(O)H or —OH, and —CH2—(C3-C 12 )heterocyclyl (C3-C 12 ) heterocyclyl is optionally substituted with oxo; Q is a bond or O; Each R 7 are independently halogen, hydroxy, —C(O)H, (C-C)alkyl, (C-C)alkoxy, (C-C)haloalkyl, (C-C)hydroxyalkyl, or —N(R 5 )2; 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(R 5 )2, deuterio(C2-C4)alkynyl, (C1-C3)alkoxy(C1-C3)haloalkyl, -OC(O)-Z, or (C3-C6)cycloalkyl, wherein (C3-C6)cycloalkyl is optionally substituted with halogen or (C1-C3)alkyl; R 9is hydrogen or (C1-C3) alkyl) is. Alternative values ​​for the variables are as described in the first, second or third embodiment, or any of the preceding aspects.

[0125] In some embodiments, the KRAS G12D binding site is [ka] [ka] is.

[0126] In some embodiments, the KRAS G12D binding site has the following structural formula: [ka] (In the formula, X 3 is N or CR 5 and; Y is a bond, O, or NR 5 and; Z is -(CH2) 0-20 -CH3 or (C1-C3) alkyl; 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; R 2 is hydrogen, -N(R 5 )2, (C3-C 12 )heterocyclyl, (C1-C6) alkyl, -L-(C3-C 12 )heterocyclyl, -L-(C6-C 14 ) aryl, -L-(C5-C14 ) 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, (C3-C 12 ) Heterocyclyl, -L-NR 5 C(O)-(C6-C 14 ) aryl (C6-C 14 ) aryl, -L-(C3-C 12 )heterocyclyl (C3-C 12 )heterocyclyl and -L-(C3-C 12 ) cycloalkyl (C3-C 12 ) Cycloalkyl is a group consisting of one or more R 6 optionally substituted with -L-(C6-C 14 )aryl and -L-(C5-C 14 ) heteroaryl (C5-C 14 ) Heteroaryl is a heteroaryl group consisting of one or more R 7 optionally substituted with; Each L is independently hydroxy, (C1-C4)hydroxyalkyl or (C5-C 14 ) (C1-C4) alkylene optionally substituted with heteroaryl; R 3 is -L-(C6-C 14 ) aryl, (C6-C 14 ) aryl, -L-(C5-C 14 ) heteroaryl or (C5-C 14 ) heteroaryl, (C6-C 14 ) aryl or (C5-C 14 ) Heteroaryl is a heteroaryl group consisting of one or more R 8 optionally substituted with; Each R 5are independently hydrogen, (C-C) alkyl, or (C-C) hydroxyalkyl, or two R 5 are connected together with the atoms that are bonded to them (C3-C 12 ) form a heterocyclyl, and two R 5 It is formed by (C3-C 12 ) heterocyclyl is optionally substituted with one or more substituents independently selected from (C1-C3) alkyl, hydroxy, or (C1-C3) alkoxy; Each R 6 are independently selected from 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, pyrazole substituted with (C1-C3)alkyl, (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 and; Q is a bond or O; Each R 7 are independently halogen, hydroxy, —C(O)H, (C-C)alkyl, (C-C)alkoxy, (C-C)haloalkyl, (C-C)hydroxyalkyl, or —N(R 5 )2; Each R 8are independently selected from 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; R 9 is hydrogen or oxo) It has. Alternative values ​​for the variables are as described in the first, second or third embodiment, or any of the preceding aspects.

[0127] In some embodiments, the KRAS G12D binding site is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] is.

[0128] In some embodiments, the KRAS G12D binding site has the following structural formula: [ka] (In the formula, Y is a bond, O, or NR 55 , S, S=O, or S(=O)2; R 1 and R 2 form, together with the nitrogen atom to which they are all bonded, a 5- to 20-membered spirocyclic heterocyclic ring, a 5- to 20-membered fused heterocyclic ring, a 5- to 20-membered bridged heterocyclic ring, a 4-membered monocyclic heterocyclic ring, a 7-membered monocyclic heterocyclic ring, or an 8- to 20-membered monocyclic heterocyclic ring, and the 5- to 20-membered spirocyclic heterocyclic ring, the 5- to 20-membered fused heterocyclic ring, the 5- to 20-membered bridged heterocyclic ring, the 4-membered monocyclic heterocyclic ring, the 7-membered monocyclic heterocyclic ring, or the 8- to 20-membered monocyclic heterocyclic ring is not selected from the group consisting of -O-, -S-, -S(=O)-, -S(=O)2-, -C optionally further containing a ring member selected from (=O)-, -NH-, -CH2-, -CHF-, -CF2-, -C(=O)NH-, -NHC(=O)-, -S(=O)NH-, -NHS(=O)-, -S(=O)2NH- or -NHS(=O)2-, wherein said 5-20 membered spirocyclic 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; R8, at each occurrence, is a halogen -C 1-6 Alkyl, -C1-6 Haloalkyl, -C 1-6 Haloalkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, oxo, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl), -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -S(haloC 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(C1-6 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- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein said —C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Haloalkoxy, -C 2-6 Alkenyl, -C 2-6Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl are independently selected from the group consisting of -F, -Cl, -Br, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Haloalkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, oxo, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl), -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -S(haloC 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)(OC1-6 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) optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from 2, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; R3 is selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, or 10-membered heteroaryl; each of which is independently selected from one or more R 31 optionally substituted with; R 31 is, in each occurrence, a halogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Haloalkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, oxo, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl), -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -S(haloC 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 1-6alkyl)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- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, each of which is independently selected from halogen, —C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Haloalkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, oxo, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl), -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -S(haloC 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 1-6alkyl)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) optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from 2, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; R 41 , R 42 or R 43 is, in each occurrence, hydrogen, halogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Haloalkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, oxo, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl), -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -S(haloC 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)(OC1-6 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- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, each of which is independently selected from halogen, —C 1-6 Alkyl, -C1-6 Haloalkyl, -C 1-6 Haloalkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, oxo, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl), -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -S(haloC 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(C1-6 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) optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from 2, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; R 51 , R 52 , R 53 , R 54 or R 55 is, in each occurrence, hydrogen, halogen, -C1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Haloalkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, oxo, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl), -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -S(haloC 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 1-6alkyl), -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- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, each of which is independently selected from halogen, —C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Haloalkoxy, -C 2-6 Alkenyl, -C 2-6Alkynyl, -CN, oxo, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl), -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -S(haloC 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) optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from 2, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; R 6 is, in each occurrence, a halogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Haloalkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, oxo, -NH2, -NH(C 1-6 alkyl), -N(C1-6 alkyl), -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -S(haloC 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 1-6 alkyl), -S(=O)2(OC 1-6alkyl), -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- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, each of which is independently selected from halogen, —C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Haloalkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, oxo, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl), -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -S(haloC 1-6alkyl), -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 1-6alkyl)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) optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from 2, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; R 7 is, in each occurrence, a halogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Haloalkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, oxo, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl), -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -S(haloC 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(C1-6 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- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, each of which is independently selected from halogen, —C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Haloalkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, oxo, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl), -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -S(haloC 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)(C1-6 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 1-6 alkyl), -NHS(=O)2O(C 1-6alkyl), -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) optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from 2, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; m, n, p, and q are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; The heterocyclyl, heterocyclic, or heteroaryl, in each occurrence, contains 1, 2, 3, 4, or 5 ring members selected from N, O, S, S(=O) or S(=O)2. It has.

[0129] In some embodiments, the KRAS G12D binding site is [ka] [ka] [ka] [ka] [ka] [ka] is.

[0130] In some embodiments, the KRAS G12D binding site has the following structural formula: [ka] (In the formula, n1 is selected from 0, 1, 2, 3, 4, 5, or 6; n2 is selected from 0, 1, 2, 3, 4, 5, or 6; n3 is selected from 0, 1, 2, 3, 4, 5, or 6; n4 is selected from 0, 1, 2, 3, 4, 5, or 6; n5 is selected from 0, 1, 2, 3, 4, 5, or 6; R S1 Each of, in each occurrence, is a halogen, -C 1-10 Alkyl, HaloC 1-10 Alkyl, HaloC 1-10 Alkoxy, -C 2-10 Alkenyl, HaloC 2-10 Alkenyl, -C 2-10 Alkynyl, HaloC 2-10 Alkynyl, -CN, oxo, -N(R 61 )2, -OR 61 , -SR 61 , -S(=O)R 62 , -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(R61 )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) independently selected from 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; 1-10 Alkyl, HaloC 1-10 Alkyl, HaloC 1-10 Alkoxy, -C 2-10 Alkenyl, HaloC 2-10 Alkenyl, -C 2-10 Alkynyl, HaloC 2-10 Alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl are optionally independently selected from halogen, —C 1-6 Alkyl, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, -C 2-6 Alkenyl, HaloC 2-6 Alkenyl, -C 2-6 Alkynyl, HaloC 2-6 Alkynyl, -CN, -N(R 63 )2, -OR 63 , -SR 63 , -S(=O)R 64 , -S(=O)2R 64 , -C(=O)R64 , -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 ) substituted with one or more substituents selected from 2, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; Optionally, two R S1 form a 3- to 10-membered carbocyclic ring or a 3- to 10-membered heterocyclic ring together with the carbon atom to which they are both attached; said 3- to 10-membered carbocyclic ring or 3- to 10-membered heterocyclic ring is 6b optionally substituted with; Arbitrarily, two adjacent R S1 are each bonded together to form a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aryl ring, or a 5- to 10-membered heteroaryl ring, each of which independently contains one or more R6c optionally substituted with; each q1 is independently selected from 0, 1, 2, 3, 4, 5, or 6; L1 is a bond, O, S, S(=O), S(=O)2, or NR 6a and; R1 is [ka] Selected from; L2 is a bond or one or more R 6d C optionally substituted with 1-10 alkylene; L3 is a bond or one or more R 6e C optionally substituted with 1-10 alkylene; L4 is a bond or one or more R 6f C optionally substituted with 1-10 alkylene; Ring A or ring B is independently selected from a 3- to 10-membered heterocyclic ring optionally further containing 1, 2, or 3 heteroatoms selected from N, O, or S; Ring C is selected from a 3- to 10-membered carbocyclic ring or a 3- to 10-membered heterocyclic ring; the -L3- and -L4X1 moieties are bonded to the same atom or different atoms of Ring C; X1 is -N(R 65 )2, -OR 65 , -SR 65 , 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl is optionally independently selected from one or more R S3 is replaced by; (R S2 and R S3 ) each, in each occurrence, is a halogen, —C 1-6 Alkyl, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, -C 2-6 Alkenyl, HaloC 2-6 Alkenyl, -C 2-6 Alkynyl, HaloC 2-6Alkynyl, -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) independently selected from 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 3- to 8-membered cycloalkynyl, 4- to 8-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; 1-6 Alkyl, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, -C 2-6 Alkenyl, HaloC 2-6 Alkenyl, -C 2-6Alkynyl, HaloC 2-6 Alkynyl, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 3- to 8-membered cycloalkynyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl are optionally independently selected from halogen, —C 1-6 Alkyl, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, -C 2-6 Alkenyl, HaloC 2-6 Alkenyl, -C 2-6 Alkynyl, HaloC 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 ) substituted with one or more substituents selected from 2, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 3- to 6-membered cycloalkynyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; Optionally, two R S2 together with the carbon atom to which they are attached, or two R S3 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or a 3- to 10-membered heterocyclic ring; said 3- to 10-membered carbocyclic ring or a 3- to 10-membered heterocyclic ring is 6h optionally substituted with; Arbitrarily, two adjacent R S2 are the carbon atoms to which they are respectively bonded or two adjacent R S3 together with the carbon atoms to which they are each attached form a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aryl ring, or a 5- to 10-membered heteroaryl ring, each of which independently contains one or more R 6i optionally substituted with; Optionally, two non-adjacent R S2 or two non-adjacent R S3 are connected together to form a bridge containing 0, 1, 2, 3, 4, 5, or 6 carbon atoms, each of the carbon atoms in the bridge is optionally replaced by 1 or 2 heteroatoms selected from N, O, S, S=O, or S(=O)2; and the hydrogen on each of the carbon atoms or N atoms is optionally independently replaced by R 6j is replaced by; q2 is selected from 0, 1, 2, 3, 4, 5 or 6; R S4 Each of, in each occurrence, is a halogen, -C 1-6 Alkyl, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, -C 2-6 Alkenyl, HaloC 2-6 Alkenyl, -C 2-6 Alkynyl, HaloC 2-6 Alkynyl, -CN, oxo, -N(R71 )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, -NR 71 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, independently selected from 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 3- to 6-membered cycloalkynyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; 1-6 Alkyl, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, -C 2-6 Alkenyl, HaloC 2-6 Alkenyl, -C 2-6 Alkynyl, HaloC 2-6Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 3- to 6-membered cycloalkynyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl are optionally independently selected from halogen, —C 1-6 Alkyl, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, -C 2-6 Alkenyl, HaloC 2-6 Alkenyl, -C 2-6 Alkynyl, HaloC 2-6 Alkynyl, -CN, -N(R 73 )2, -OR 73 , -SR 73 , -S(=O)R 74 , -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) substituted with one or more substituents selected from 2, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 3- to 6-membered cycloalkynyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; q4 is selected from 0, 1, 2, 3, 4, 5 or 6; R3 is selected from a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl, wherein the 6- to 10-membered aryl or the 5- to 10-membered heteroaryl is optionally independently selected from one or more R 31 is replaced by; R 31 is, in each occurrence, a halogen, -C 1-10 Alkyl, HaloC 1-10 Alkyl, HaloC 1-10 Alkoxy, -C 2-10 Alkenyl, HaloC 2-10 Alkenyl, -C 2-10 Alkynyl, HaloC 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)2R76 , -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- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; 1-10 Alkyl, HaloC 1-10 Alkyl, HaloC 1-10 Alkoxy, -C 2-10 Alkenyl, HaloC 2-10 Alkenyl, -C 2-10 Alkynyl, HaloC 2-10 Alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl are optionally independently selected from halogen, —C 1-6 Alkyl, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, -C 2-6 Alkenyl, HaloC 2-6 Alkenyl, -C 2-6 Alkynyl, HaloC 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 77C(=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 ) substituted with one or more substituents selected from 2, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 3- to 6-membered cycloalkynyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; Each of R2, R4 and R5 is hydrogen, halogen, -C 1-10 Alkyl, HaloC 1-10 Alkyl, HaloC 1-10 Alkoxy, -C 2-10 Alkenyl, HaloC 2-10 Alkenyl, -C 2-10 Alkynyl, HaloC 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(R81 )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) independently selected from 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; 1-10 Alkyl, HaloC 1-10 Alkyl, HaloC 1-10 Alkoxy, -C 2-10 Alkenyl, HaloC 2-10 Alkenyl, -C 2-10 Alkynyl, HaloC 2-10 Alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl are optionally independently selected from halogen, —C 1-6 Alkyl, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, -C 2-6 Alkenyl, HaloC 2-6 Alkenyl, -C 2-6 Alkynyl, HaloC 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(R 83 )2, -P(R 83 )2, -P(=O)(R 84 ) substituted with one or more substituents selected from 2, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 3- to 6-membered cycloalkynyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; 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 the following may be selected in each occurrence from hydrogen, halogen, -C 1-10 Alkyl, HaloC1-10 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) independently selected from 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; 1-10 Alkyl, HaloC 1-10 Alkyl, -C 2-10 Alkenyl, -C 2-10 Alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl are optionally independently selected from halogen, —C 1-6 Alkyl, HaloC 1-6 Alkyl, HaloC 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 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(Rc )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 ) substituted with one or more substituents selected from 2, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 3- to 6-membered cycloalkynyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; 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 ) independently form, together with the nitrogen atom to which they are all attached, a 3- to 20-membered heterocyclic ring or a 5- to 10-membered heteroaryl ring, and said 3- to 20-membered heterocyclic ring or 5- to 10-membered heteroaryl ring optionally and independently contain one or more R 6k is replaced by; R 62 , R 64 , R 67 , R 69 , R 72 , R 74 , R 76 , R 78 , R 82 and R84 Each of the following is selected from the group consisting of hydrogen, -C, 1-10 Alkyl, HaloC 1-10 Alkyl, HaloC 1-10 Alkoxy, -C 2-10 Alkenyl, HaloC 2-10 Alkenyl, -C 2-10 Alkynyl, HaloC 2-10 Alkynyl, -N(R b )2, -OR b , -SR b , 3 to 10-membered cycloalkyl, 3 to 10-membered cycloalkenyl, 3 to 10-membered cycloalkynyl, 3 to 10-membered heterocyclyl, 6 to 10-membered aryl, or 5 to 10-membered heteroaryl; 1-10 Alkyl, HaloC 1-10 Alkyl, HaloC 1-10 Alkoxy, -C 2-10 Alkenyl, -C 2-10 Alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl are optionally independently selected from halogen, —C 1-6 Alkyl, HaloC 1-6 Alkyl, HaloC 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 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- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 3- to 6-membered cycloalkynyl, 3- to 10-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, substituted with one or more substituents selected from; R a , R b , R c and R d Each of the following is selected from the group consisting of hydrogen, -C, 1-6 Alkyl, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, -C 2-6 Alkenyl, -C 2-6 alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 3- to 6-membered cycloalkynyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; 1-6 Alkyl, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, -C 2-6 Alkenyl, -C 2-6 The alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 3- to 6-membered cycloalkynyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl may optionally independently be one or more R 6l is replaced by; Optionally, two R a , two Rb and two R c each independently form, together with the atom to which they are both attached, a 3- to 6-membered heterocyclic ring, said 3- to 6-membered heterocyclic ring independently containing one or more R 6m optionally substituted with; 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, in each occurrence, is a halogen, -C 1-6 Alkyl, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, oxo, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl), -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(C1-6 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, independently selected from 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 3- to 6-membered cycloalkynyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; 1-6 Alkyl, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 3- to 6-membered cycloalkynyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl is selected from the group consisting of halogen, -C 1-3 Alkyl, HaloC 1-3 Alkyl, HaloC 1-3 Alkoxy, -C 2-3 Alkenyl, -C 2-3 Alkynyl, -CN, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl), -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)(OC1-3 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 1-3 alkyl)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 1-3alkyl)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) optionally substituted with one or more substituents selected from 2, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 3- to 6-membered cycloalkynyl, 3- to 6-membered heterocyclyl, 6-membered aryl, or 5- to 6-membered heteroaryl; Each of heterocyclyl and heteroaryl, at each occurrence, contains 1, 2, 3, or 4 heteroatoms independently selected from N, O, S, S(=O) or S(=O)2. It has.

[0131] In some embodiments, the KRAS G12D binding site is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

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[0132] Further specific examples of KRAS G12D binding sites are disclosed in International Publication No. WO2021 / 249519 (the entire contents of which are incorporated herein by reference). In some embodiments, the KRAS G12D binding site is a KRAS G12D inhibitor binding site (e.g., inhibitor) disclosed in WO2021 / 249519. For example, in some embodiments, the KRAS G12D binding site has the following structural formula: [ka] (In the formula, Ring A is aryl or heteroaryl; R 1 is hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyloxy, heterocyclyloxy, alkenyl, alkynyl, hydroxyl, cyano, amino, -NR 5 R 6 , nitro, cycloalkyl, heterocyclic, aryloxy, heteroaryloxy, aryl, or heteroaryl, wherein alkyl, alkoxy, cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryloxy, heteroaryloxy, aryl, and heteroaryl are each optionally and independently selected from halogen, alkyl, alkoxy, haloalkoxy, hydroxyl, amino, oxo, —C(O)(CH) q OR 7 , -NHC(O)R 8 , -C(O)R 8 , -NR 9 R 10 , -C(O)(CH2) p NR 9 R 10 substituted by one or more substituents independently selected from nitro, cyano, cycloalkyl, heterocyclic, aryl, or heteroaryl; R 2is selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, amino, or cycloalkyl; R 3 are the same or different and each represents hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, hydroxyl, cyano, amino, -(CH2) r NR 5 R 6 , cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally and independently selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, amino, —(CH) s NR 9 R 10 substituted with one or more substituents independently selected from , cyano, cycloalkyl, or heterocyclyl; R 4 is selected from hydrogen, alkyl, or cycloalkyl; 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; R 5 and R 6 are the same or different and each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, hydroxyl, amino, cycloalkyl, or heterocyclyl; R 7 is selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, or heterocyclyl; R 8are the same or different and each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, hydroxyl, amino, cycloalkyl, or heterocyclyl; alkyl, haloalkyl, cycloalkyl, and heterocyclyl 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; R 9 and R 10 are the same or different and each is independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, hydroxyl, amino, cycloalkyl, or heterocyclyl; n is 1, 2, 3 or 4; p is 0, 1, 2 or 3; q is 0, 1, 2 or 3; r is 0, 1, 2 or 3; s is 0, 1, 2, or 3) It has.

[0133] In some embodiments, the KRAS G12D binding site is [ka] [ka] is.

[0134] Further specific examples of KRAS G12D binding sites are disclosed in International Publication No. WO2022 / 221739 (the entire contents of which are incorporated herein by reference). In some embodiments, the KRAS G12D binding site is a KRAS G12D inhibitor binding site (e.g., inhibitor) disclosed in WO2022 / 221739. For example, in some embodiments, the KRAS G12D binding site has the following structural formula: [ka] (In the formula, Ring A is a saturated or partially unsaturated 8-10 membered N-containing bridged ring containing at least one additional heteroatom selected from the group consisting of N, S, and O; Ring A is unsubstituted or contains 1 to 3 R independently selected from the group consisting of C-C alkyl, C-C alkenyl, C-C alkoxy, C-C alkoxy(C-C)alkyl, halo, C-C fluoroalkyl, hydroxy, C-C hydroxyalkyl, CF—C(H)(OH)—, C(H)(F)—C(H)(OH)—, cyano, and C-C cyanoalkyl. A is substituted by a substituent; Ring B is a 5- or 6-membered partially unsaturated or aromatic ring having 0, 1, or 2 heteroatoms selected from the group consisting of N, S, and O, and Ring B is fused to the pyrimidine ring shown; Ring B is unsubstituted or contains 1 to 2 R independently selected from the group consisting of halo, hydroxy, oxo, cyano, C-C alkyl, C-C fluoroalkyl, and C-C alkoxy. B is substituted by a substituent; Ring Y is a 6-membered monocyclic, 9-10-membered bicyclic, or 13-14-membered tricyclic ring system, said ring system being partially unsaturated or aromatic, and ring Y containing 0-3 heteroatoms selected from the group consisting of N, S, and O; Ring Y is unsubstituted or selected from the group consisting of 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 1 to 4 R independently selected from the group consisting of cycloalkyl, tri(C1-C3 alkyl)silyl, and cyano; Y is substituted by a substituent; Ring Z is (i) 3- to 10-membered mono- or bicyclic cycloalkyl; (ii) a 3- to 10-membered mono- or bicyclic heterocycloalkyl, wherein the heterocycloalkyl is saturated and contains 1-2 heteroatoms selected from the group consisting of N, S, and O; or (iii) a 3- to 8-membered spiroheterocycloalkyl, wherein the spiroheterocycloalkyl is saturated and contains 1-2 heteroatoms selected from the group consisting of N, S, and O; Ring Z is unsubstituted or contains 1 to 4 R independently selected from the group consisting of halo, hydroxy, C-C alkyl, C-C alkoxy, C-C hydroxyalkyl, C-C fluoroalkyl, carboxy, carbamoyl, methoxy(C-C)alkyl, amino(C-C)alkyl, C-C alkylamino(C-C)alkyl, C-C dialkylamino, and C-C dialkylamino(C-C)alkyl. Z is substituted by a substituent; Ring Z is a single -MR ZC and optionally replaced by M is -CH2- or absent; R ZC is a 5- to 6-membered monocyclic or 9- to 10-membered bicyclic saturated heterocycloalkyl containing 1 to 3 heteroatoms selected from the group consisting of N, S, and O; R ZC is unsubstituted or substituted with substituents 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; L is O or absent; m is 0, 1, or 2) It has.

[0135] In some embodiments, the KRAS G12D binding site is [ka] [ka] [ka] is.

[0136] Further specific examples of KRAS G12D binding sites are disclosed in International Publication No. WO2023 / 018810 (the entire contents of which are incorporated herein by reference). In some embodiments, the KRAS G12D binding site is a KRAS G12D binding site (e.g., inhibitor) disclosed in WO2023 / 018810. For example, in some embodiments, the KRAS G12D site has the following structural formula: [ka] (In the formula, [ka] is a single or double bond; W is C, CH or N, and when W is CH or N, [ka] is a single bond; X is O, S, S(O), S(O)(NR z ), S(O)2, CH2 or CH=CH; n is 0, 1 or 2; m is 0, 1 or 2; p is 2, 3 or 4; The Two R's x is combined with the same carbon atom as C 3-7 Form a cycloalkyl or 4- to 7-membered heterocycloalkyl, and each C 3-7 Cycloalkyl or 4- to 7-membered heterocycloalkyl is R y and when p is 3 or 4, each remaining R x is hydroxyl, halogen, oxo, cyano, -N(R z )2, C 1-4 Alkyl, C1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 3-6 cycloalkyl, 5-7 membered heteroaryl; L is C 1-6 Alkylene, -OC 1-6 Alkylene, -SC 1-6 Alkylene, NR z , O or S, and each C 1-6 Alkylene, -OC 1-6 Alkylene and -SC 1-6 The alkylene chain is R 2 is substituted with 0-2 occurrences of; R 1 is hydroxyl, aryl, heteroaryl, C 3-8 Cycloalkyl or heterocycloalkyl (R 5 substituted with 0-3 occurrences of ); R 2 is halogen, hydroxyl, C 1-4 alkyl, or two R on the same or adjacent carbon atoms 2 Let's get together and C 3-7 can form a cycloalkyl; R 3 is R 6 is an aryl or heteroaryl substituted with 0-3 occurrences of; R 4 is hydrogen, hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-7 is cycloalkyl or cyano; Each R 5 is halogen, oxo, hydroxyl, cyano, amino or C 1-4 is alkyl; Each R 6 is halogen, hydroxyl, cyano, -N(R z )2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4Haloalkyl, C 1-4 Haloalkoxy, C 2-4 Alkynyl or C 3-6 is cycloalkyl; 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-; R y is halogen, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, hydroxyl, cyano, -S(O)2-C 1-4 Alkyl, =NR z or -N(R z )2; R z is hydrogen or C 1-4 alkyl) It has.

[0137] In some embodiments, the KRAS G12D binding site is 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 6-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one; 6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one; 3-chloro-4-cyclopropyl-5-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)phenol; 6-(7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol; 6-(7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol; 7-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one; 6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-methyl-6-azaspiro[3.5]nonan-2-ol; 6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,6-diazaspiro[3.5]nonan-1-one; 6-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol; 9-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-oxa-1,9-diazaspiro[3.6]decan-2-one; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 7-(7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,7-diazaspiro[4.5]decan-2-one; 7-(7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decan-3-one; 7-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decan-3-one; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-7-azaspiro[4.5]decane 2,2-dioxide; 6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-methyl-1,6-diazaspiro[3.5]nonan-2-one; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-imino-2l6-thia-7-azaspiro[4.5]decane 2-oxide; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-oxa-1,7-diazaspiro[4.5]decan-2-one; 8-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol; or 5-ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol is.

[0138] Further specific examples of KRAS G12D binding sites are disclosed in International Publication No. WO2022 / 194191 (the entire contents of which are incorporated herein by reference). In some embodiments, the KRAS G12D binding site is the KRAS G12D binding site (e.g., inhibitor) disclosed in WO2022 / 194191. For example, in some embodiments, the KRAS G12D site has the following structural formula: [ka] provided that the compound has the following structural formula: [ka] wherein [ka] teeth, [ka] and; [ka] is a single or double bond; X and X 1 is a bond, O, S, S(O)2, CH2, CHF, CF2 or NR x are independently selected from, with the proviso that X and X 1 At least one of the x and; X 2 is CH2 or absent; W is C, CH, C(C 1-6 alkyl) or N; [ka] The following parts: [ka] [ka] [ka] Selected from one of; R x is H, C 1-3 alkyl, cyclopropyl; R 1 , H, NR a R b , C 1-3 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-3 Alkoxy, NH-C 1-3 Alkyl, N(C 1-3 Alkyl)2, CO2R 8 ,CONR a Rb or 5-6 membered heteroaryl; R 2 Ha, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, 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-COR a , or -Y-NR c C(O)NR a R b , -YS(O)2 aryl, -YS(O)2C 1-6 Alkyl, S(O)NR a R b and R 2 A part of R is 10 may be optionally substituted with 0 to 3 occurrences of; 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, [ka] Z is a bond, O, S, or NR c and; R 3 is aryl or heteroaryl, and the aryl or heteroaryl is R 10optionally substituted with 0 to 4 occurrences of; R 4 , R 5 , R 6 and R 7 is H, halogen, -CN, C1-C3 alkyl, C 3-6 Cycloalkyl, C 3-6 independently selected from halocycloalkyl or C1-C3 haloalkyl; R 8 and R 9 is H, C1-C3 alkyl, C 3-6 independently selected from cycloalkyl; 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 to 10 membered heteroaryl or 5 to 10 membered heterocyclyl (preferably hydrogen or C 1-6 Alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered heterocyclyl); or R a and R b together with the atom(s) to which they are attached represent an optionally substituted 5- to 10-membered carbocyclyl, or R 10 0 to 5 occurrences of R to form an optionally substituted heterocyclyl; b , R c and R e are independently 10 is substituted with 0 to 5 occurrences of; R 10 is 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 Ra , C 0-6 Alkylene-NR a C(O)R b , C 0-6 Alkylene-S(O)R b , C 0-6 Alkylene-S(O)NR a R b , C 0-6 Alkylene-NR c S(O)2R b , C 0-6 Alkylene-NR c S(O)NR 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 heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl (preferably 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)R b , C 0-6 Alkylene-S(O)NR a R b , C 0-6 Alkylene-NR a S(O)2R b , C 0-6 Alkylene-NR c S(O)NR a Rb , 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 heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl; two adjacent R 10 For example, two Rs attached to two adjacent atoms (two atoms connected to each other only through bonds) 10 , or two R attached to the same atom 10 taken together with the atom to which they are attached form an optionally substituted 5- to 10-membered cyclyl or 5- to 10-membered heterocyclyl (containing 0-3 heteroatoms); R 11 and R 12 is H, F, C1-C3 alkyl, C 3-6 independently selected from cycloalkyl, C1-C3 haloalkyl, or cyclopropyl; Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl may be substituted with one or more substituents.

[0139] In some embodiments, the KRAS G12D binding site is [ka] is.

[0140] Further specific examples of KRAS G12D binding sites are disclosed in International Publication No. WO2022 / 194066 (the entire contents of which are incorporated herein by reference).In some embodiments, the KRAS G12D binding site is the KRAS G12D binding site (e.g., inhibitor) disclosed in WO2022 / 194066.For example, in some embodiments, the KRAS G12D binding site has the following structural formula: [ka] (In the formula, Ring A is C 3-6 selected from cycloalkyl or 3- to 6-membered heterocyclyl; L1 is -O-(CH2) 0-3 , -S-(CH2) 0-3 , -NH-(CH2) 0-3 or C 1-3 alkylene; L2 is a bond or C 1-3 alkylene groups; R1 is independently selected from H, halogen, alkyl, alkoxy, haloalkyl, hydroxy, and hydroxyalkyl; R2 is C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl and 5- to 14-membered heteroaryl; 3-14 Cycloalkyl, 3-14 membered heteroaryl, C 6-14 Aryl and 5- to 14-membered heteroaryl are substituted with 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, optionally further substituted with 1 to 4 substituents selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl; R a is H or C 1-6 independently selected from alkyl; R3 is H, halogen, C 1-6 Alkyl or -OR 2a Selected from R 2a is C 1-6 Alkyl, C 3-8 selected from cycloalkyl or haloalkyl; R4 is one or more R 3a cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally further substituted with; each R 3ais 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)R 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-C 3-14 Cycloalkyl, substituted or unsubstituted -C 0-3 Alkylene-(3- to 14-membered heterocycloalkyl), substituted or unsubstituted -C 0-3 Alkylene-C 6-14 Aryl or substituted or unsubstituted -C 0-3 alkylene-(5- to 14-membered heteroaryl), and each R b are independently H, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 is haloalkyl; R5 is H, amino, substituted amino, C 1-6 Alkyl, substituted C 1-6 Alkyl, halogen, C 2-6 Alkenyl, substituted C 2-6 Alkenyl, C3-6 Cycloalkyl or substituted C 3-6 cycloalkyl; R6 is H, halogen or C 1-6 alkyl; m is selected from 0, 1, 2, 3 or 4 It has.

[0141] In some embodiments, the KRAS G12D binding site is [ka] is.

[0142] Other specific examples of KRAS G12D binding sites are disclosed in International Publication No. WO2022 / 148421 (the entire contents of which are incorporated herein by reference). In some embodiments, the KRAS G12D binding site is a KRAS G12D binding site (e.g., inhibitor) disclosed in WO2022 / 148421. For example, in some embodiments, the KRAS G12D binding site has the following structural formula: [ka] (In the formula, Ring A is an aryl group, a 5- to 7-membered monocyclic heteroaryl group, or an 8- to 12-membered bicyclic heteroaryl group; [ka] are each independently a single bond or a double bond; Y1 is -NH- or -C(R Y1a )(NHR Y1b )-and; [ka] is a single bond, Y2 is N or CR Y2 is; or [ka] is a double bond, Y2 is C, and R 1b is non-existence; 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; p is 0, 1, 2, 3, 4, 5 or 6; q is 0, 1, 2, 3, 4, 5, 6, or 7, provided that valence theory is satisfied; 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 are, if present, each independently hydrogen, halogen, -C 1-8 Alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Aryl, 5-12 membered heteroaryl, -CN, -OR 1e , -NR 1e R 1f and ;-C 1-8 Alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each aryl or 5- to 12-membered heteroaryl may contain at least one substituent R 1g optionally substituted with; (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 At least one pair of -CH2- groups forms a bridge containing, in addition to the two bridgeheads, one, two, three, or four -CH2- moieties, one of which is optionally replaced by -O-, -S-, or -NH-, and the bridge is 1g optionally substituted with; 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 3-12 membered ring, said ring containing 0-3 heteroatoms selected from nitrogen, sulfur and oxygen, said bridge containing at least one substituent R 1g optionally substituted with; R 1e and R 1f is hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 1-8 Alkoxy-C 1-8Alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 are independently selected from aryl or 5- to 12-membered heteroaryl; R 1g is, in each occurrence, independently a halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 Aryl, or 5- to 12-membered heteroaryl, -C 1-8 Haloalkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -CN, -OH, -NH2, -C 1-8 Alkoxyl, -COOH, - or CO-C 1-8 is alkyl; R6 is hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Aryl, 5-12 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 and -C 1-8 Alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 aryl or 5- to 12-membered heteroaryl; each of which is selected from the group consisting of at least one substituent R 6c optionally substituted with; R 6a and R6b is hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 1-8 Alkoxy-C 1-8 Alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 aryl or 5- to 12-membered heteroaryl; 1-8 Alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each aryl or 5- to 12-membered heteroaryl may contain at least one substituent R 6d optionally substituted with; R 6c is, in each occurrence, independently a halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -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, said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring contains at least one substituent R 6d optionally substituted with; R 6d is hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Aryl, 5-12 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 COR6f , -NR 6e CO2R 6f , or -NR 6e SO2R 6f and;C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each aryl or 5- to 12-membered heteroaryl may contain at least one substituent R 6g is optionally replaced by R 6e and R 6f is hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 1-8 Alkoxy-C 1-8 Alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 are independently selected from aryl or 5- to 12-membered heteroaryl; R 6g is, in each occurrence, independently a halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 aryl, or 5- to 12-membered heteroaryl; R4 is hydrogen, halogen, -C 1-8 Alkyl, C3-C8 cycloalkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, 3-8 membered heterocyclyl, C6-C 12 Aryl, 5-12 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 , -NR4a COR 4b , -NR 4a CO2R 4b , or -NR 4a SO2R 4b and ;-C 1-8 Alkyl, C3-C8 cycloalkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, 3-8 membered heterocyclyl, C6-C 12 Each aryl or 5- to 12-membered heteroaryl may contain at least one substituent R 4c or two R4 are joined together to form a spirocyclic or bicyclic ring; R 4a and R 4b is hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 1-8 Alkoxy-C 1-8 Alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 aryl or 5- to 12-membered heteroaryl; 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 1-8 Alkoxy-C 1-8 Alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each aryl or 5- to 12-membered heteroaryl may contain at least one substituent R 4d optionally substituted with; R 4c and R 4d is, in each occurrence, independently a halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 aryl, or 5- to 12-membered heteroaryl; L1 is a single bond, -O-, or -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 is selected from [ka] 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 -C1-8 Alkylene-C(O)-** L1 , * L1 -NR L1a -C 1-8 Alkylene-** L1 , * L1 -C 1-8 Alkylene-NR L1a -** L1 , [ka] Each of the L1b optionally substituted with; ** L1 teeth, [ka] * indicates the position where the molecule is bound to the site L1 refers to the position attached to the other side; R L1a is hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 aryl or 5- to 12-membered heteroaryl, 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each aryl or 5- to 12-membered heteroaryl may contain at least one substituent R L1c optionally substituted with; R L1b and R L1c each independently represents a halogen, a hydroxy, a -C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 aryl or 5- to 12-membered heteroaryl; or The Two R's L1bor two R's L1c together with the atoms to which they are attached form a 3- to 6-membered unsaturated or saturated ring, said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring containing at least one substituent halogen, hydroxy, -C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 optionally substituted with aryl or 5-12 membered heteroaryl; Each of X5 and X6 is selected from CH or N; n4 and n5 are each independently 0, 1, or 2; R5 is hydrogen, halogen, -C 1-8 Alkyl, C3-C8 cycloalkyl, 3-12 membered heterocyclyl, C6-C 12 Aryl, 5-12 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 and ;-C 1-8 Alkyl, C3-C8 cycloalkyl, 3-12 membered heterocyclyl, C6-C 12 Each aryl or 5- to 12-membered heteroaryl may contain at least one substituent R 5c optionally substituted with; R 5a and R 5b is hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 1-8 Alkoxy-C 1-8 Alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12aryl, 5- to 12-membered heteroaryl, or oxo; 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 1-8 Alkoxy-C 1-8 Alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups has at least one substituent R 5d optionally substituted with; or R 5a and R 5b together with the carbon atoms to which they are attached form a 3-8 membered unsaturated or saturated ring, said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring containing at least one substituent R 5c optionally substituted with; R 5c is, in each occurrence, independently a halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 Aryl, 5-12 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 and -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 Each aryl or 5- to 12-membered heteroaryl may contain at least one substituent R 5d optionally substituted with; or The Two R's 5ctogether with the carbon atoms to which they are attached form a 3-8 membered unsaturated or saturated ring, said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring containing at least one substituent R 5d optionally substituted with R 5d is hydrogen, halogen, -C 1-8 Alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Aryl, 5-12 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 and ;-C 1-8 Alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each aryl or 5- to 12-membered heteroaryl may contain at least one substituent R 5i optionally substituted with R 5e , R 5f , R 5g , R 5h and R 5i is hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 1-8 Alkoxy-C 1-8 Alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 aryl or 5- to 12-membered heteroaryl) It has.

[0143] In some embodiments, the KRAS G12D binding site is [ka] [ka] [ka] is.

[0144] Other specific examples of KRAS G12D binding sites are disclosed in International Publication No. WO2023 / 284537 (the entire contents of which are incorporated herein by reference). In some embodiments, the KRAS G12D binding site is a KRAS G12D binding site (e.g., inhibitor) disclosed in WO2023 / 284537. For example, in some embodiments, the KRAS G12D binding site has the following structural formula: [ka] (In the formula, Ring A is heterocyclyl or heteroaryl; [ka] represents an N-linked ring A, [ka] represents a C-linked ring A; Each R 1 is oxo, hydroxyl, halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, -C(O)OR a , -C(O)N(R a )2, -N(R a )2 or heteroaryl, wherein alkyl, alkenyl, alkynyl and heteroaryl are independently selected from cyano, hydroxyl, halogen, -OR b , or -N(R b ) optionally substituted with one or more groups independently selected from Each R a and R b are independently hydrogen, alkyl, alkenyl, or alkynyl; Ring B may be one or more R c is a cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with; Each R c is independently selected from the group consisting of oxo, hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, and heteroaryl, and alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, and heteroaryl are independently selected from the group consisting of hydroxyl, halogen, cyano, -OR a , -N(R a )2, and optionally substituted with one or more groups consisting of heteroaryl; Ring W is cycloalkyl, heterocyclyl, aryl, or heteroaryl; R' is hydrogen, hydroxyl, halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, -C(O)OR a , -C(O)N(R a )2, -N(R a )2 or heteroaryl, wherein alkyl, alkenyl, alkynyl and heteroaryl are selected from cyano, hydroxyl, halogen, -OR b , or -N(R b ) optionally substituted with one or more groups independently selected from Each R 2 is independently selected from the group consisting of hydrogen, oxo, hydroxyl, halogen, 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 hydroxyl, halogen, cyano, amino, nitro, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; X is O or S; M is O or S; Y is an aryl or heteroaryl, and the aryl or heteroaryl is selected from one or more R c optionally substituted with; L is a bond, -O-, -S-, -N(R a )-, alkenyl, cycloalkyl or alkynyl; L' is a bond, -S-, -N(R a )-, alkenyl, cycloalkyl or alkynyl, provided that ring B is [ka] When B is, L' is alkenyl, cycloalkyl or alkynyl; [ka] If not, L' is a bond, -S-, -N(R a )-, alkenyl or cycloalkyl; [ka] is optionally substituted with hydroxyl, halogen, cyano, or amino; 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 hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl, or heteroaryl; Z is 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 cycloalkyl, heterocyclyl, aryl, and heteroaryl are selected from the group consisting of one or more R d and optionally substituted with -N(R a )C(O)-aryl and the aryl moiety in -(CH2) p The heterocyclyl moiety in -heterocyclyl may be one or more R e optionally substituted with; Each R d is hydroxyl, halogen, -C(O)H, alkyl, alkoxy, haloalkyl, hydroxyalkyl, or -N(R a ) independently selected from 2; Each R e is oxo, hydroxyl, halogen, alkyl, heteroalkyl, hydroxyalkyl, haloalkyl, alkoxy, -T-phenyl, -T-phenylSOF, -N(R a )2, —SO2F, —C(O)(alkyl), or —C(O)(haloalkyl), wherein alkyl, heteroalkyl, hydroxyalkyl, haloalkyl, and alkoxy are optionally substituted with one or more groups independently selected from aryl, heteroaryl, or tert-butyldimethylsilyloxy; T is a bond, —O—, or —NHC(O)—; m is 0 or 1; n is 0 or 1; s is an integer from 0 to 5; t is an integer from 0 to 4; p is an integer from 0 to 4. It has one of the following.

[0145] In some embodiments, the KRAS G12D binding site is [ka] [ka] [ka] is.

[0146] Other specific examples of KRAS G12D binding sites are disclosed in International Publication No. WO2023 / 001141 (the entire contents of which are incorporated herein by reference). In some embodiments, the KRAS G12D binding site is a KRAS G12D binding site (e.g., inhibitor) disclosed in WO2023 / 001141. For example, in some embodiments, the KRAS G12D binding site has the following structural formula: [ka] (In the formula, Y is O or S; Ring A is heterocyclyl or heteroaryl; Each R 1 is oxo, hydroxyl, 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 and wherein alkyl, alkenyl, alkynyl, and heteroaryl are independently selected from the group consisting of cyano, hydroxyl, halogen, -OR b , or -N(R b ) optionally substituted with one or more groups independently selected from Each R a and R b are independently hydrogen, alkyl, alkenyl, or alkynyl; R * is selected from hydrogen, alkyl, alkylaryl, or aryl; R ** is selected from hydrogen, alkyl, alkenyl, or alkynyl; or R * and R **together with the oxygen atom to which they are attached form a heterocyclyl optionally substituted with an aryl or haloaryl; Z 1 -OC(O)-#, -OP(=O)(OR *** )O-#, or -OP(=O)(OR * )N(R a )-#, and the # end is Z 2 is connected to; Z 2 is hydrogen or aryl or -C(O)OR a is alkyl optionally substituted with; R *** are independently selected from hydrogen, alkyl, alkenyl, or alkynyl; or R *** and Z 2 together with the oxygen atom to which they are attached form a heterocyclyl optionally substituted with an aryl or haloaryl; Ring B is selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R'; Each R' is independently selected from the group consisting of oxo, hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, and heteroaryl are independently selected from hydroxyl, halogen, cyano, -OR a , -N(R a )2, and optionally substituted with one or more groups consisting of heteroaryl; Ring Q is selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl; Each R 2 is hydrogen, oxo, hydroxyl, 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 hydroxyl, halogen, cyano, amino, nitro, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; Ring W is selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl; Each R 3 are independently selected from the group consisting of hydrogen, oxo, hydroxyl, halogen, 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 hydroxyl, halogen, cyano, amino, nitro, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; G 1 is a bond, -O-, -S(O) p -, -SS-, -N(R c )-, or -C(R d )=C(R d )-and; G 2 is a bond, -[C(R d )2] u -, -C(O)- or -C(O)C(R d )2- and; R c is selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, and heterocyclyl; Each R dis independently selected from the group consisting of hydrogen, hydroxyl, 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 independently with one or more groups consisting of hydroxyl, halogen, cyano, amino, nitro, alkyl, alkoxy, haloalkyl, and hydroxyalkyl; or The Two R's d together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl, the cycloalkyl and heterocyclyl being optionally substituted with cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, hydroxyalkyl, and alkyl; Z is C(R e ) or N; R e is absent or hydrogen; L 1 is a bond, -O-, -S-, -N(R a )-, -C(O)N(R a )-, alkenyl, alkynyl or cycloalkyl [ka] is optionally substituted with hydroxyl, halogen, cyano, or amino; 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 hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl, or heteroaryl; E is hydrogen, hydroxyl, 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 cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R″; and —N(R a )C(O)-aryl and the aryl moiety in -(CH2) u the heterocyclyl moiety in -heterocyclyl and -CH2OC(O)-heterocyclyl is optionally substituted with one or more R'"; Each R'' is hydroxyl, halogen, -C(O)H, alkyl, alkoxy, haloalkyl, hydroxyalkyl, or -N(R a ) independently selected from 2; Each R''' is oxo, hydroxyl, halogen, alkyl, heteroalkyl, hydroxyalkyl, haloalkyl, alkoxy, -T-phenyl, -T-phenylSOF, -N(R a )2, —SO2F, —C(O)(alkyl), or —C(O)(haloalkyl), wherein alkyl, heteroalkyl, hydroxyalkyl, haloalkyl, and alkoxy are optionally substituted with one or more groups independently selected from aryl, heteroaryl, or tert-butyldimethylsilyloxy; T is a bond, —O—, or —NHC(O)—; m is an integer from 0 to 6; n is an integer from 0 to 5; r is an integer from 0 to 4; s is an integer from 0 to 5; p is an integer from 0 to 2; u is an integer from 0 to 4. It has one of the following.

[0147] In some embodiments, the KRAS G12D binding site is [ka] is.

[0148] Further specific examples of KRAS G12D binding sites are disclosed in International Publication No. WO2022 / 262838 (the entire contents of which are incorporated herein by reference). In some embodiments, the KRAS G12D binding site is a KRAS G12D binding site (e.g., inhibitor) disclosed in WO2022 / 262838. For example, in some embodiments, the KRAS G12D binding site has the following structural formula: [ka] X 0 H, deuterium, halo, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, or C 1-6 and alkoxyl, each of which independently may be optionally unsubstituted or substituted by a 3- to 7-membered heterocycle having one or more heteroatoms independently selected from N, O, or S, at least one of which is selected from C. 1-6 Alkyl or C 1-6 N directly connected to one of the C atoms of the hydroxyalkyl; the 3- to 7-membered heterocycle is optionally further substituted by -CH3 or -N(CH3)2; R 1 and R 2 Each of these is H, deuterium, halogen, -NH2, -CN, -OH, -C 1-6 Alkyl, or -C 1-6 alkoxy, each of which is independently optionally unsubstituted or selected from deuterium, halogen, —NH, —CN, —OH, —C 1-6 Alkyl, or -C 1-6substituted by alkoxy; R 3 and R 4 Each of these is H, deuterium, halogen, -NH2, -CN, -OH, -C 1-4 Alkyl, or -C 1-4 alkoxy, each of which is independently optionally unsubstituted, or is selected from the group consisting of deuterium, halogen, —NH, —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, [ka] -C 1-6 Alkyl, or -C 1-6 substituted by alkoxy; R 5 and R 6 Each of these is H, deuterium, halogen, -NH2, -CN, -OH, -C 1-6 Alkyl, or -C 1-6 alkoxy, each of which is independently optionally unsubstituted or selected from deuterium, halogen, —NH, —CN, —OH, —C 1-6 Alkyl, or -C 1-6 substituted by alkoxy; R 1 , R 2 , R 3 , R 4 , R 5 and R 6 at least one of is deuterium; R is independently [ka] (In the formula, n is 0, 1, 2, or 3; q is 0, 1, 2, or 3; X 1 H, -CHCN, C 1-6 Alkyl, or C 1-6is alkoxy; X 2 is a 6- to 10-membered aryl, or a 5- to 10-membered heteroaryl; each of the 6- to 10-membered aryl, or the 5- to 10-membered heteroaryl, independently, is optionally unsubstituted or is optionally substituted by one or more R 2x has been replaced by; R 2x Each of these is a halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, 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 1-6 and independently selected from alkoxy, 3- to 7-membered cycloalkyl, or 3- to 7-membered heterocycloalkyl, each of which is independently optionally unsubstituted or selected from one or more of -NH, halogen, deuterium, -CN, -OH, -C 1-6 Alkyl, or -C 1-6 substituted by alkoxy; X 3 H, halogen, C 1-6 Alkyl, or C 1-6 independently selected from alkoxy; [ka] is a single or double bond; 5 X is N or CR 7 and: 5 X is N, or 5 X is CR 7 If [ka] is a double bond; 5 X is C(R 7 )2, or 5 X is NR 7 If [ka] is a single bond; R 7 each independently represents H, a halogen, -C 1-6 Alkyl, or -C substituted by one or more halogens, deuterium, -OH, or NH2 1-6 is alkyl; or The Two R's 7 are two R 7 forms an oxo (=O) with the C atom bonded to both, and the oxo is X 2 forms a lactam together with the N atom to which it is attached; or R 7 and R 7 form together with the C atom to which they are respectively attached a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycle; or W is O or NR w and R w is H, deuterium, or C 1-6 alkyl) It has.

[0149] In some embodiments, the KRAS G12D binding site is [ka] [ka] [ka] [ka] is.

[0150] Linker (L') The linker is a bivalent moiety that connects KRAS G12Di to the degron. Linkers are disclosed, for example, in International Publication No. WO2021 / 127278 (the entire contents of which are incorporated herein by reference), and are referred to therein by the variable L. See, in particular, paragraphs

[0491] to

[0501] and Table B thereof. In some aspects (e.g., of any of the foregoing embodiments, aspects, or combinations of aspects), L' is a linker disclosed in WO2021 / 127278. Linkers are also disclosed, for example, in U.S. Patent No. US11,352,350 (the entire contents of which are incorporated herein by reference), and are referred to therein by the variable L. See, in particular, columns 408-409 and 2573-2574 thereof. In some aspects (eg, of any of the foregoing embodiments, aspects, or combinations of aspects), L' is a linker disclosed in US Pat. No. 11,352,350.

[0151] 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] to

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

[0152] In some aspects (e.g., of any of the foregoing embodiments, aspects, or combinations of aspects), L' is a covalent bond or a divalent, saturated or unsaturated, linear or branched C 1-50 a hydrocarbon chain, wherein 0 to 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)-, [ka] and; Each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 1-3 (and in some embodiments, 1-2) heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted bivalent ring selected from a 4-11-membered saturated or partially unsaturated spiroheterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6-membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10-membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen, deuterium, or C 1-6 an optionally substituted group selected from aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R on the same nitrogen, taken together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the 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.

[0153] In some aspects (e.g., of any of the foregoing embodiments, aspects, or combinations of aspects), L' is a covalent bond or a divalent, saturated or unsaturated, straight or branched C-C 25 a hydrocarbon chain, wherein 0 to 10 methylenes 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)-, [ka] (and in some further embodiments, -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)-); Each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 1-3 (and in some embodiments, 1-2) heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted bivalent ring selected from a 4-11-membered saturated or partially unsaturated spiroheterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6-membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10-membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen or (C1-C3) alkyl. In a further embodiment, L' is a divalent, saturated or unsaturated, linear or branched C-C 25 is a hydrocarbon chain, wherein 0 to 10 methylenes of L' are replaced by X. In still further embodiments, L' is a divalent, saturated or unsaturated, straight or branched C-C 15 It is a hydrocarbon chain, and 0 to 10 methylenes of L' are replaced by X.

[0154] In some aspects (e.g., of any of the foregoing embodiments, aspects, or combinations of aspects), L' is a covalent bond or a divalent, saturated or unsaturated, straight or branched C-C 25 a hydrocarbon chain, wherein 0 to 10 methylenes of L' are replaced by X; Each -Cy- is independently a 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, a 4- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4- to 11-membered saturated or partially unsaturated spiroheterocyclylenyl having 1-3 (and in some embodiments, 1-2) heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. partially unsaturated heterocyclylenyl (and in some further embodiments, each -Cy- is independently an optionally substituted (e.g., unsubstituted) bivalent ring selected from a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-11 membered saturated or partially unsaturated spiroheterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur); 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)-; Each R is independently hydrogen or (C1-C3) alkyl. In a further embodiment, L' is a divalent, saturated or unsaturated, linear or branched C-C 25 is a hydrocarbon chain, wherein 0 to 10 methylenes of L' are replaced by X. In still further embodiments, L' is a divalent, saturated or unsaturated, straight or branched C-C 15 It is a hydrocarbon chain, and 0 to 10 methylenes of L' are replaced by X.

[0155] In some aspects (e.g., of any of the foregoing embodiments, aspects, or combinations of aspects), L' is a divalent, saturated or unsaturated, linear or branched C-C 15 and R is a hydrocarbon chain, wherein 1, 2, or 3 (e.g., 1 or 2; 1; 2) methylenes of L' are replaced by Cy, and 0-5 (e.g., 0-3, 1-3, 1 or 2) methylenes of L' are replaced by X, and Cy, X, and R are as described in any of the embodiments herein. In some further embodiments, 1 or 2 methylenes of L' are replaced by Cy. In some still further embodiments, 1 methylene of L' is replaced by Cy. In some still further embodiments, 2 methylenes of L' are replaced by Cy.

[0156] In some embodiments, L' is saturated. In some embodiments, L' is straight-chained. In some embodiments, L' is both saturated and straight-chained.

[0157] In some embodiments, 0 to 8 methylenes of L' are replaced by X, eg, 0 to 7, 1 to 8, 2 to 8, or 1 to 5 methylenes of L' are replaced by X.

[0158] In some embodiments, each -Cy- is independently an optionally substituted bivalent ring selected from a 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, a 4- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4- to 11-membered saturated or partially unsaturated spiroheterocyclylenyl having 1-3 (and in some embodiments, 1-2) heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each -Cy- is independently an optionally substituted (e.g., unsubstituted) bivalent ring selected from a 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 4- to 11-membered saturated or partially unsaturated spiroheterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In further embodiments, each -Cy- is independently an optionally substituted (e.g., unsubstituted) divalent 4- to 7-membered saturated or partially unsaturated (e.g., saturated) heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4- to 11-membered saturated or partially unsaturated (e.g., saturated) spiroheterocyclylenyl having 1 to 3 (and in some embodiments, 1 to 2) heteroatoms independently selected from nitrogen, oxygen, and sulfur. In still further embodiments, each -Cy- is independently an optionally substituted (e.g., unsubstituted) divalent 4- to 7-membered saturated or partially unsaturated (e.g., saturated) heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.In some embodiments, each -Cy- is independently selected from cyclohexylene, piperidinylene, azetidinylene, pyrrolidinylene, piperazinylene, morpholinylene, 1-oxa-4,9-diazaspiro[5.5]undecanylene, 3-azaspiro[5.5]undecanylene, 2-azaspiro[3.3]heptanylene, 7-azaspiro[3.5]nonanylene, 3-azabicyclo[3.2.1]octanylene, 2,7-diazaspiro[3.5]nonanylene, 3,9-diazaspiro[5.5]undecanylene, or triazinylene.

[0159] In some embodiments, each -Cy- is independently optionally substituted with halo, alkyl, or haloalkyl.

[0160] In some aspects (e.g., of any of the preceding embodiments, aspects, or combinations 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-X—(C1-C5)aliphatic-, —X XXX-(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- (wherein X is as defined herein). For example, in some embodiments, 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-(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 and * indicates the point of attachment of L' to the Degron).

[0161] In some aspects (e.g., of any of the foregoing embodiments, aspects, or combinations of aspects), 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-(C1-C5)aliphatic-*, -X-Cy-(C1-C5)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-* (where * indicates the point of attachment of L' to the Degron); each X is independently -O-, -C(O)-, -N(R)-, or -N(R)C(O)-; Each -Cy- is independently selected from any of the values ​​for -Cy- described herein, e.g., cyclohexylene, piperidinylene, azetidinylene, pyrrolidinylene, piperazinylene, morpholinylene, 1-oxa-4,9-diazaspiro[5.5]undecanylene, 3-azaspiro[5.5]undecanylene, 2-azaspiro[3.3]heptanylene, 7-azaspiro[3.5]nonanylene, 3-azabicyclo[3.2.1]octanylene, 2,7-diazaspiro[3.5]nonanylene, 3,9-diazaspiro[5.5]undecanylene, or triazinylene. In some further embodiments, 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-X-(C1-C5)aliphatic-Cy-(C1-C5)aliphatic-*, -X-Cy-(C1-C5)aliphatic 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-*または-X-Cy-*である。 -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-(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-*または-X-Cy-*である。

[0162] In some embodiments of L', L' is linked to KRAS G12Di via -X-Cy-. In some embodiments, when -X-Cy- links L' to KRAS G12Di, -X-Cy- is -C(O)-Cy-, where Cy is a 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having one nitrogen atom and optionally one additional heteroatom selected from nitrogen, oxygen, and sulfur, a 4- to 11-membered saturated or partially unsaturated spiroheterocyclylenyl having one nitrogen atom and optionally one to two (and in some embodiments, one) additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered saturated or partially unsaturated spiroheterocyclylenyl having one nitrogen atom and optionally one additional heteroatom independently selected from nitrogen, oxygen, and sulfur. and -Cy- is a membered bicyclic saturated or partially unsaturated heterocyclyl linked to -C(O)- via a nitrogen atom, e.g., -Cy- is piperidinylene, azetidinylene, pyrrolidinylene, piperazinylene, morpholinylene, 1-oxa-4,9-diazaspiro[5.5]undecanylene, 3-azaspiro[5.5]undecanylene, 2-azaspiro[3.3]heptanylene, 7-azaspiro[3.5]nonanylene, 3-azabicyclo[3.2.1]octanylene, 2,7-diazaspiro[3.5]nonanylene, or 3,9-diazaspiro[5.5]undecanylene. In some further embodiments, -X-Cy- is when -X-Cy- links L' to KRAS G12Di: [ka] In some still further embodiments, -X-Cy-, when -X-Cy- links L' to KRAS G12Di, is: [ka] is.

[0163] In some embodiments of L', L' can include -Cy 1 -(CH2) 0-1 -X-(CH2) 0-1 -Cy 2 - Contains Cy 1 and Cy 2is independently selected from any of the values ​​for Cy described herein; and X is absent or selected from any of the values ​​for X described herein. For example, in some embodiments, Cy 1 is a 4-7 membered saturated or partially unsaturated heterocyclyl having one nitrogen atom and optionally one additional heteroatom selected from nitrogen, oxygen, and sulfur, a 4-11 membered saturated or partially unsaturated spiroheterocyclylenyl having one nitrogen atom and optionally one to two (and in some embodiments one) additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having one nitrogen atom and optionally one additional heteroatom independently selected from nitrogen, oxygen, and sulfur, which is linked via the nitrogen atom (e.g., to the remainder of L' (if present), KRAS G12Di or Degron), e.g., to Cy 1 is piperidinylene, azetidinylene, pyrrolidinylene, piperazinylene, morpholinylene, 1-oxa-4,9-diazaspiro[5.5]undecanylene, 3-azaspiro[5.5]undecanylene, 2-azaspiro[3.3]heptanylene, 7-azaspiro[3.5]nonanylene, 3-azabicyclo[3.2.1]octanylene, 2,7-diazaspiro[3.5]nonanylene, or 3,9-diazaspiro[5.5]undecanylene. In some further embodiments, Cy 1 teeth, [ka] In some still further embodiments, Cy 1 teeth, [ka] In some preferred embodiments, Cy 1 is closer to KRAS G12Di in the compounds of the present disclosure. 1 -(CH2) 0-1 -X-(CH2) 0-1 -Cy 2In some further or alternative embodiments, Cy 2 is cyclohexylene, piperidinylene, azetidinylene, pyrrolidinylene, piperazinylene, morpholinylene, 1-oxa-4,9-diazaspiro[5.5]undecanylene, 3-azaspiro[5.5]undecanylene, 2-azaspiro[3.3]heptanylene, 7-azaspiro[3.5]nonanylene, 3-azabicyclo[3.2.1]octanylene, 2,7-diazaspiro[3.5]nonanylene, 3,9-diazaspiro[5.5]undecanylene, or triazinylene. In some preferred embodiments, Cy 2 is closer to the Degron in the compounds of the present disclosure. 1 -(CH2) 0-1 -X-(CH2) 0-1 -Cy 2 In some embodiments, X is C(O), O, or N(R), where R is as described herein. In some further embodiments, X is O or N(R). In some embodiments, Cy 1 is linked to KRAS G12Di via X, where X is as described herein, e.g., -C(O)- or -C(O)O-. 1 In some embodiments, wherein Cy is linked to KRAS G12Di via —C(O)— or —C(O)O—, 1 Cy 1 is linked to the carbonyl carbon of -C(O)- or -C(O)O- through the nitrogen atom of

[0164] In some aspects (e.g., of any of the foregoing embodiments, aspects, or combinations of aspects), L′ is —X—(C—C 15 ) Aliphatic -X-, -X-(C0-C 15 ) Aliphatic-, -XX-(C0-C 15 ) Aliphatic-X-, -XXX-(C1-C 15 ) Aliphatic - or -XX-(C1-C 15 ) aliphatic-. For example, in some embodiments, L' is -X-(C0-C 15)aliphatic-X-*, -X-(C0-C 15 )aliphatic-*, -XX-(C0-C 15 ) Aliphatic-X-*, -XXX-(C1-C 15 ) Aliphatic -* or -XX-(C1-C 15 ) aliphatic -* (where * indicates the point of attachment of L' to the Degron). In some embodiments, 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 embodiments, L' is -X-(C-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 -* (where * indicates the point of attachment of L' to the Degron). In some embodiments, L' is -C(O)-Cy-O-(C-C 10 ) aliphatic or -C(O)-Cy-(C1-C 10 ) aliphatic, for example, -C(O)-Cy-O-(C1-C 10 ) aliphatic* or -C(O)-Cy-(C1-C 10 ) aliphatic* (where * indicates the point of attachment of L' to Degron).

[0165] In some aspects (e.g., of any of the preceding embodiments, aspects, or combinations of aspects), L' is -X-(CH) p -X-, -X-(CH2) q - or -X-(CH2CH2O) r CH2CH2-X-, where 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 embodiments, L' is -X-(CH2) p -X-*, -X-(CH2) q-* or -X-(CH2CH2O) r In some embodiments, L' is -C(O)N(H)-(CH) p -N(H)-, -C(O)N(H)-(CH2) p - or -C(O)N(H)-(CH2CH2O) r In a further embodiment, L' is -C(O)N(H)-(CH) p -N(H)-*, -C(O)N(H)-(CH2) p -* or -C(O)N(H)-(CH2CH2O) r CH2CH2-N(H)-* (where * indicates the point of attachment of L' to Degron).

[0166] In some embodiments, p is an integer between 2 and 10, eg, between 3 and 10; between 6 and 10; or 9 or 10.

[0167] In some embodiments, q is an integer from 2 to 11, e.g., 3 to 11; 5 to 11; or 9, 10, or 11. In some embodiments, q is an integer from 6 to 15, e.g., 8 to 12.

[0168] In some embodiments, r is 1, 2, 3, 4, or 5. In some embodiments, r is 1, 2, or 3, e.g., 2 or 3;

[0169] In some embodiments, 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)-, [ka] In some embodiments, 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 embodiments, 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 embodiments, each X is independently -O-, -N(R)-, -S-, -OC(O), -N(R)C(O)-, or -OC(O)N(R)-. In some embodiments, each X is independently -O-, -C(O)-, -N(R)-, -Cy-, or -N(R)C(O)-. In some embodiments, each X is independently -O-, -C(O)-, -N(R)-, or -N(R)C(O)-. In some embodiments, each X is independently -O-, -N(R)-, or -N(R)C(O)-.

[0170] In some embodiments, each R is independently hydrogen or methyl. In further embodiments, each R is hydrogen.

[0171] 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 Other specific examples of L' include: CH2CH2-N(H)-*, where * indicates the point of attachment of L' to the Degron. [ka] (In the formula, [ka] indicates the attachment point to KRAS G12Di, and * indicates the attachment point of L' to Degron).

[0172] Other specific examples of L' include the linkers shown in Table A. In some embodiments, L' is a linker in Table A. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8] [Table 4-9] [Table 4-10] [Table 4-11] [Table 4-12] [Table 4-13] [Table 4-14] [Table 4-15] [Table 4-16] [Table 4-17] [Table 4-18] [Table 4-19] [Table 4-20] [Table 4-21] [Table 4-22] [Table 4-23] [Table 4-24] [Table 4-25]

[0173] From the foregoing, for example, unless specified by "*", values ​​for L' are 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 the case of -CHCH-N(H)-), it will be understood that the value can be oriented in either direction between KRASG12Di and Degron. Thus, for example, unless specified, -C(O)N(H)- can be oriented to produce a compound of either of the following structural formulas: [KRASG12Di]-C(O)N(H)-[Degron] or [KRASG12Di]-N(H)C(O)-[Degron]. On the other hand, the description -C(O)N(H)-* (where * indicates the point of attachment of L' to Degron) can be used to describe a compound of the following structural formula: [KRASG12Di]-C(O)N(H)-[Degron].

[0174] Degron Degrons bring a ligase enzyme into proximity with the target protein, allowing the protein to be labeled with a ubiquitin tag and targeted for degradation by the ubiquitin-proteasome system.

[0175] "Degron," as used herein, refers to a moiety that, under suitable conditions (e.g., in vitro, in vivo), is capable of promoting degradation of a target protein, such as KRAS G12D, via the ubiquitin proteasome pathway (UPP). Typically, in a PROTAC, e.g., a compound of the present disclosure, the degron is capable of binding a ubiquitin E3 ligase, thereby recruiting the ubiquitin E3 ligase to the vicinity of the PROTAC and, by extension, the target protein that is bound to KRAS G12D in the compound of the present disclosure, under suitable conditions. Formation of the ternary ligase-PROTAC-target protein complex results in ubiquitination and degradation of the target protein, e.g., by the 26S proteasome, a component of the UPP. Thus, examples of degrons include a ubiquitin E3 ligase binding site that binds to a ubiquitin E3 ligase. Examples of E3 ligases include cereblon (CRBN), von Hippel-Lindau (VHL), inhibitor of apoptosis proteins (IAPs), mouse double minute 2 homolog (MDM2), DDB1 and CUL4-associated factor 16 (DCAF16), and ring finger protein 114 (RNF114). Other examples of degrons include hydrogen atom and lysine mimetics, both of which are disclosed in International Publication No. WO 2021 / 127278, the entire contents of which are incorporated herein.

[0176] In some aspects (e.g., of any of the foregoing embodiments, aspects, or combinations of aspects), the Degron is a ubiquitin E3 ligase binding site (e.g., a cereblon binding site). In further aspects, the ubiquitin E3 ligase is CRBN, VHL, IAP, MDM2, DCAF16, or RNF114. In still further aspects, the ubiquitin E3 ligase is CRBN, such that the ubiquitin E3 ligase binding site is a cereblon binding site. Thus, in some aspects, the Degron is a cereblon binding site.

[0177] Ubiquitin E3 ligase binding sites, including cereblon binding sites, are disclosed in International Publication No. WO2021 / 127278. See, e.g., Table A therein. In some aspects (e.g., of any of the foregoing embodiments, aspects, or combinations of aspects), the Degron is a ubiquitin E3 ligase binding site (e.g., a cereblon binding site) disclosed in WO2021 / 127278.

[0178] Cereblon-binding sites are also disclosed in U.S. Patent No. 10,849,982; and U.S. Patent Application Publication Nos. US2020 / 0140456 and US2020 / 0377469. In some aspects (e.g., of any of the foregoing embodiments, aspects, or combinations of aspects), the Degron is a cereblon-binding site disclosed in U.S. Patent No. 10,849,982, or U.S. Patent Application Publication Nos. US2020 / 0140456 or US2020 / 0377469.

[0179] In some aspects (e.g., of any of the foregoing embodiments, aspects, or combinations of aspects), the Degron comprises: [ka] (for example, [ka] ), [ka] (for example, [ka] ), [ka] (for example, [ka] ),or [ka] (for example, [ka] )

[0180] In some aspects (e.g., of any of the foregoing embodiments, aspects, or combinations of aspects), the Degron comprises: [ka] In a further aspect, the Degron is [ka] is.

[0181] In some aspects (e.g., of any of the foregoing embodiments, aspects, or combinations of aspects), the Degron comprises: [ka] In a further aspect, the Degron is [ka] In yet a further aspect, the Degron is [ka] In another embodiment, the Degron is [ka] In a further aspect, the Degron is [ka] is.

[0182] In some aspects (e.g., of any of the foregoing embodiments, aspects, or combinations of aspects), the Degron comprises: [ka] In a further aspect, the Degron is [ka] In yet a further aspect, the Degron is [ka] In another embodiment, the Degron is [ka] In a further aspect, the Degron is [ka] is.

[0183] In any of the Degron structures containing a benzene ring (e.g., any of the aforementioned Degron structures), one or more hydrogen atoms of the benzene ring may be bonded to a ring having, for example, the following structural formula: [ka] It will be understood that Degron may be substituted as follows. Where indicated, such substitutions are encompassed by the present disclosure. Thus, in some embodiments, one or more hydrogen atoms (e.g., 1-4; 1-3; 1 or 2) on the benzene ring of Degron are optionally replaced with a fluorine atom. In some embodiments, one hydrogen atom on the benzene ring of Degron is replaced with a fluorine atom. In some embodiments, two hydrogen atoms on the benzene ring of Degron are replaced with fluorine atoms. In some embodiments, three fluorine atoms on the benzene ring of Degron are replaced with fluorine atoms. In some embodiments, the benzene ring of Degron is fully fluorinated. In some embodiments, the benzene ring of Degron is unsubstituted.

[0184] Other specific examples of ubiquitin E3 ligase binding sites include those shown in Table B. In some embodiments, the Degron is a ubiquitin E3 ligase binding site in Table B. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5]

[0185] In some aspects (e.g., of any of the foregoing embodiments, aspects, or combinations of aspects), the Degron comprises: [ka] In some aspects (e.g., of any of the foregoing embodiments, aspects, or combinations of aspects), Degron is [ka] isn't it.

[0186] 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.

[0187] In some aspects (e.g., of any of the foregoing embodiments, aspects, or combinations of aspects), the compound is [ka] [ka] [ka] [ka] or a salt thereof. In some embodiments, the compound is [ka] [ka] or a salt thereof. In some embodiments, the compound is [ka] Or its salts. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10]

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

[0188] Methods for making the compounds of the present disclosure are described in the Examples herein.

[0189] Compositions, combinations, and kits Typically, for administration to a subject, the compounds of the present disclosure are formulated with one or more pharmaceutically acceptable carriers. The present disclosure provides such compositions, including pharmaceutical compositions. Thus, 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 in accordance with the uses and / or methods described herein, for example, to provide a compound of the present disclosure for administration to a subject.

[0190] The compositions described herein, and thus the compounds of the present disclosure, can be administered orally, parenterally (including subcutaneously, intramuscularly, intravenously, and intradermally), by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. The terms "parenteral" and "parenterally," as used herein, include subcutaneous, intradermal, intravenous, intramuscular, intraocular, intravitreal, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional, intrahepatic, intraperitoneal, intralesional, and intracranial injection or infusion techniques. In some embodiments, the compositions described herein can be administered intravenously and / or intraperitoneally. In some embodiments, the compositions described herein can be administered orally. Preferably, the compositions described herein are administered orally, subcutaneously, intraperitoneally, or intravenously.

[0191] 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.For tablets for oral use, 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 are required for oral use, the active ingredient can be suspended or dissolved in an oily phase and combined with emulsifying and / or suspending agents.If desired, certain sweeteners, flavors, or coloring agents can also be added.

[0192] In some embodiments, the oral formulations are formulated for immediate release or sustained / delayed release.

[0193] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is present in 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, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; (c) humectants, such as glycerol; and (d) disintegrants, such as agar, calcium carbonate, and the like. The formulation may be mixed with (e) dissolution retarders such as paraffin, (f) absorption accelerators such as quaternary ammonium salts, (g) wetting agents such as acetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0194] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.In addition to the compounds of the present disclosure, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol (ethanol), isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed, peanut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, or mixtures thereof.In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweeteners, flavors, coloring agents, fragrances, and preservatives.

[0195] 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.

[0196] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like. The 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 pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) 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.

[0197] The compound of the present disclosure can also be in microencapsulated form with one or more excipients as described above.In such solid dosage form, compound can be mixed with at least one inert diluent, such as sucrose, lactose or starch.Such dosage form can also contain, as usual practice, other additional materials than inert diluent, such as tableting lubricant and other tableting aids, such as magnesium stearate and microcrystalline cellulose.

[0198] Compositions for oral administration may be designed to protect the active ingredient against degradation as it passes through the gastrointestinal tract, for example by an outer coating of the formulation on a tablet or capsule.

[0199] In another embodiment, the compounds of the present disclosure can be provided in an extended (or "delayed" or "sustained") release composition. The delayed release composition comprises a compound of the present disclosure and a delayed release component. Such a composition allows for targeted release of the compound, for example, into the lower gastrointestinal tract, e.g., the small intestine, large intestine, colon, and / or rectum. In certain embodiments, 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, methacrylates (Eudragits)). Alternatively, the delayed release composition may provide controlled release in the small intestine and / or colon by providing a pH-sensitive methacrylate coating, pH-sensitive polymeric microspheres, or a polymer that undergoes hydrolytic degradation. The delayed release composition can be formulated using hydrophobic or gelling excipients or coatings. Colonic delivery can further be provided by coatings 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 linked to azoaromatic bond coatings.

[0200] The compositions described herein can also be administered subcutaneously, intraperitoneally, or intravenously, for example, in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to techniques known in the art using suitable dispersing or wetting agents (e.g., Tween® 80, etc.) and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include mannitol, dextrose, water, Ringer's solution, lactated Ringer's solution, and isotonic sodium chloride solution. Sterile, fixed oils are also conventionally used as solvents or suspending media. For this purpose, any sterile, fixed oil, including synthetic mono- or diglycerides, can be used. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethylated versions. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, or carboxymethylcellulose or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms, such as emulsions and / or suspensions. Other commonly used surfactants, such as Tweens® or Spans®, and / or other similar emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, may also be used for formulation purposes.

[0201] 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 a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0202] The compositions described herein may also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0203] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topical-transdermal patches may also be used.

[0204] For other topical applications, the composition can be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers.Carriers for topical administration of the compounds described herein include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water, and penetration enhancers.Alternatively, the composition can be formulated in 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 using a suitable lotion or cream containing the active compound suspended or dissolved in a carrier with a suitable emulsifier.Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. Suitable carriers also include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water and penetration enhancers.

[0205] For ophthalmic use, the composition may 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 benzylalkonium chloride. Alternatively, for ophthalmic use, the composition may be formulated in an ointment, such as petrolatum.

[0206] Compositions can also be administered by nasal aerosol or inhalation.Such compositions can be prepared according to the techniques well known in the art of pharmaceutical formulations, and can be prepared as a solution in saline, using benzyl alcohol or other suitable preservatives, absorption enhancers to improve bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.Without being bound by any particular theory, it is believed that the local delivery of the compositions described herein, as can be achieved by nasal aerosol or inhalation, can reduce the risk of systemic consequences of the composition, for example, consequences on red blood cells.

[0207] Other pharmaceutically acceptable carriers that may 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-tocopherol 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 salts, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat. Cyclodextrins, such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives, such as hydroxyalkyl cyclodextrins (including 2- and 3-hydroxypropyl-β-cyclodextrin), or other solubilizing derivatives, may also be advantageously used to enhance delivery of the agents described herein.

[0208] In some embodiments, the compositions described herein further include one or more additional therapeutic agents, eg, for use in combination with the compounds of the present disclosure.

[0209] Some embodiments provide combinations (e.g., pharmaceutical combinations) comprising a compound of the present disclosure (e.g., a composition described herein comprising a compound of the present disclosure) 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 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.

[0210] Some embodiments provide kits comprising a compound of the present disclosure (e.g., a composition described herein comprising a compound of the present disclosure) and additional therapeutic agent(s) (e.g., a composition comprising additional therapeutic agent(s)). In one embodiment, the kit comprises a therapeutically effective amount of a compound of the present disclosure for treating a disease, disorder, or condition described herein, and a therapeutically effective amount of one or more additional therapeutic agents for treating the disease, disorder, or condition. In some aspects, the kit further comprises instructions for administering a compound of the present disclosure and / or the additional agent(s) to a subject to treat a disease, disorder, or condition described herein.

[0211] Additional therapeutic agents for use in the compositions, combinations and / or kits provided herein include any of those discussed herein with respect to combination therapy.

[0212] The compositions described herein are provided in unit dosage forms in some aspects. Thus, some embodiments provide unit dosage forms comprising a compound of the present disclosure, for example, and a pharmaceutically acceptable carrier. The amount of a compound of the present disclosure or other therapeutic agent that can be combined with a carrier material(s) to produce a unit dosage form of the composition will vary depending, for example, on the subject being treated, the particular mode of administration, and the activity of the agent used. Preferably, the composition and / or unit dosage form can be formulated so that the compound of the present disclosure or other therapeutic agent can be administered to a subject ingesting the composition and / or unit dosage form at a dose and / or frequency consistent with those described herein. Typically, the unit dosage form contains from about 1 mg to about 5,000 mg, from about 10 mg to about 2,500 mg, from about 100 mg to about 1,000 mg, from about 1 mg to about 1,000 mg, from about 1 mg to about 500 mg, from about 1 mg to about 250 mg, from about 1 mg to about 150 mg, from about 0.5 mg to about 100 mg, or from about 1 mg to about 50 mg of the active ingredient(s).

[0213] In some embodiments, the concentration of a 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 a therapeutic agent (e.g., a compound of the present disclosure) in the composition ranges from 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 a therapeutic agent (e.g., a compound of the present disclosure) in the composition ranges from 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.

[0214] use It has been found that various compounds of the present disclosure exhibit effects consistent with the degradation of KRAS G12D.Therefore, in one embodiment, provided herein is a method for reducing the level or activity of KRAS G12D in cells (e.g., cells that express KRAS G12D), comprising contacting the cells 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 carried out in vitro.In some aspects, the method is carried out ex vivo.In some aspects, the method is carried out in vivo.In some aspects, the cell is in a subject, for example, a subject with KRAS G12D-related cancer.

[0215] Thus, in another embodiment, the present specification provides a method for reducing the level or activity of KRAS G12D in a subject in need thereof, the method comprising administering to the subject an effective amount (e.g., a therapeutically effective amount) of a compound of the present disclosure or a composition comprising a compound of the present disclosure.

[0216] KRAS G12D level or activity can be reduced by promoting the degradation of KRAS G12D, for example, and / or inhibiting the activity of KRASG12D, for example, via UPP, according to the methods described herein. In some embodiments, the method for reducing KRAS G12D level or activity is a method for promoting (e.g., inducing) the degradation of KRAS G12D. Additionally or alternatively, in some embodiments, the method for reducing KRAS G12D level or activity is a method for inhibiting the activity of KRAS G12D.

[0217] Also provided herein, in one embodiment, is a method for treating cancer (e.g., KRAS G12D-associated cancer) in a subject in need thereof, the method 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 blood cancer (e.g., leukemia, lymphoma, or myeloma). In some aspects, the cancer is a solid tumor cancer. In some aspects, the cancer is a blood cancer.

[0218] Cancers (e.g., KRAS G12D cancers) that can be treated according to the methods described herein include, but are not limited to, astrocytic, breast, cervical, skin, colon, endometrial, esophageal, stomach, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, testicular, and prostate cancers, thyroid cancers, and sarcomas. For example, the following cancers (e.g., KRAS G12D cancers): cardiac cancers, such as sarcomas (e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung cancers, such as bronchial carcinomas (e.g., squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchial) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroitin hamartoma, mesothelioma; digestive cancers, such as esophageal cancers (e.g., squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (e.g., carcinoma, lymphoma, leiomyosarcoma), pancreas (e.g., ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (e.g., adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (e.g., adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract cancers, e.g., of the kidney Cancer (e.g., adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (e.g., squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (e.g., adenocarcinoma, sarcoma), testis (e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver cancer, e.g., liver cancer (e.g., hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, Hemangioma; biliary tract cancer, such as gallbladder cancer, ampullary cancer, bile duct cancer; bone cancer, such as osteogenic sarcoma (e.g., osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (e.g., reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (e.g., osteochondroma), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor;Nervous system cancers, for example, cancer of the skull (e.g., osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (e.g., meningioma, meningeal sarcoma, gliomatosis), brain (e.g., astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (e.g., pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord (e.g., neurofibroma, meningioma, glioma, sarcoma); gynecological cancers, for example, cancer of the uterus (e.g., endometrial cancer), cervix (e.g., cervical carcinoma, pre-cervical dysplasia), ovary (e.g., ovarian cancer (e.g., serous cystadenocarcinoma, mucinous eysiadenocarcinoma, unclassified carcinoma), granulosa cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (e.g., squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (e.g., clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (e.g., embryonal rhabdomyosarcoma), fallopian tube (e.g., carcinoma); hematological cancers, e.g., cancers of the blood (e.g., myeloid leukemia (e.g., acute, chronic), Acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma (e.g., malignant lymphoma); skin cancers, e.g., malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, lentiloid dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland cancers, e.g., neuroblastoma, can be treated according to the methods described herein.

[0219] 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 central nervous system atypical teratoid / rhabdoid tumor; 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 tumor / carcinoma; breast cancer; Burkitt's lymphoma; carcinoid tumor (gastrointestinal); childhood carcinoma Tinoid tumor; childhood cardiac (heart) tumor; childhood embryonal tumor; childhood germ cell tumor; primary CNS lymphoma; cervical cancer; childhood cervical cancer; bile duct cancer; childhood chordoma; chronic lymphocytic leukemia (CLL); chronic myeloid leukemia (CML); chronic myeloproliferative neoplasm; colorectal cancer; childhood colorectal cancer; childhood craniopharyngioma; cutaneous T-cell lymphoma (e.g., mycosis fungoides and Sézary syndrome); ductal carcinoma in situ (DCIS); childhood embryonal tumor of the central nervous system; endometrial cancer (uterine cancer); childhood ependymoma; esophageal cancer; childhood esophageal cancer; nasal neuroblastoma; Ewing's sarcoma; childhood extracranial germ cell tumor; extragonadal Germ cell tumors; eye cancer; childhood intraocular melanoma; intraocular melanoma; retinoblastoma; fallopian tube cancer; malignant fibrous histiocytoma of bone 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., childhood 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) carcinoma; Langerhans lymphoma Hans cell histiocytosis; Hodgkin's lymphoma; Hypopharyngeal carcinoma; Intraocular melanoma; Childhood intraocular melanoma; Pancreatic islet cell tumor, pancreatic neuroendocrine tumor; Kaposi's sarcoma; Renal (renal cell) cancer; Langerhans cell histiocytosis; Laryngeal cancer; Leukemia; Lip and oral cavity 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 of unknown primary; Midline carcinoma with NUT gene alterations; Oral cancer;Multiple endocrine neoplasia syndrome; multiple myeloma / plasma cell neoplasm; mycosis fungoides; myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm; chronic myeloid leukemia (CML); acute myeloid leukemia (AML); chronic myeloproliferative neoplasm; nasal cavity and paranasal sinus cancer; nasopharyngeal carcinoma; neuroblastoma; non-Hodgkin's lymphoma; non-small cell lung cancer; 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 (childhood larynx);Parangioma;Childhood paraganglioma;Sinus and nasal cancer;Parathyroid cancer;Penile cancer;Pharyngeal cancer;Pheochromocytoma;Childhood pheochromocytoma;Pituitary tumors;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;Retinal Blastocytoma; childhood rhabdomyosarcoma; salivary gland carcinoma; sarcoma (e.g., childhood rhabdomyosarcoma, childhood vascular tumor, Ewing's sarcoma, Kaposi's sarcoma, osteosarcoma (bone cancer), soft tissue sarcoma, uterine sarcoma); Sezary syndrome; skin cancer; childhood skin cancer; small cell lung cancer; small intestine cancer; soft tissue sarcoma; squamous cell carcinoma of the skin; metastatic squamous cell carcinoma of the neck of unknown primary; gastric (stomach) cancer; childhood gastric (stomach) These include: astric cancer; T-cell lymphoma, skin (e.g., mycosis fungoides and Sézary syndrome); testicular cancer; childhood testicular cancer; throat cancer (e.g., nasopharyngeal, oropharyngeal, and hypopharyngeal cancer); thymoma and thymic carcinoma; thyroid cancer; transitional cell carcinoma of the renal pelvis and ureter; ureter and renal pelvis, transitional cell carcinoma; urethral cancer; uterine cancer, endometrium; uterine sarcoma; vaginal cancer; childhood vaginal cancer; vascular tumors; vulvar cancer; and Wilms' tumor and other childhood kidney tumors.

[0220] Metastases of the aforementioned cancers may also be treated according to the methods described herein. In some aspects, the cancer is a metastatic cancer.

[0221] In some embodiments, the cancer is cardiac cancer, gastrointestinal cancer, genitourinary tract cancer, liver cancer, biliary tract cancer, bone cancer, nervous system cancer, gynecological cancer, blood cancer, skin cancer, or adrenal cancer. In some embodiments, the cancer is non-small cell lung cancer, small cell lung cancer, colon cancer, rectal cancer, or pancreatic cancer.

[0222] In some embodiments, the method further includes determining whether the cell and / or the subject has a KRAS G12D mutation. In some embodiments, the method includes determining whether a subject (e.g., a subject in need thereof, e.g., a subject with cancer) has a KRAS G12D-associated cancer, and administering to the subject with a KRAS G12D-associated cancer a therapeutically effective amount of a compound of the present disclosure or a composition comprising a compound of the present disclosure. Common KRAS G12D-associated cancers are known in the art. Methods for determining whether a subject has a KRAS G12D mutation, and thereby whether a subject has a KRAS G12D-associated cancer, are known in the art and described herein.

[0223] The compounds of the present disclosure may also be administered in combination with one or more other therapies (e.g., radiation therapy, chemotherapy, e.g., chemotherapeutic agents; immunotherapy, e.g., immunotherapeutic agents) for treating the diseases, disorders, or conditions described herein (e.g., cancer, autoimmune diseases). When administered "in combination," the compounds of the present disclosure may be administered before, after, or simultaneously with the other therapy(ies) (e.g., radiation therapy, additional therapeutic agent(s)). When co-administered simultaneously (e.g., simultaneously), the compounds of the present disclosure and the other therapeutic agent may be in separate formulations or the same formulation. Alternatively, the compounds of the present disclosure and the other therapeutic agent may be administered sequentially, either at approximately the same time or at different times, as separate compositions. When the compounds of the present disclosure and the other therapy (e.g., therapeutic agents) are administered as separate formulations or compositions, the compounds of the present disclosure and the other therapy may be administered by the same or different routes of administration. A skilled clinician will be able to determine the appropriate timing for administration of each therapy used in combination (e.g., timing sufficient to allow for overlap of the pharmaceutical effects of the therapies).

[0224] In some aspects, the methods described herein further comprise administering to the subject (e.g., a therapeutically effective amount of) additional therapy(ies) (e.g., radiation therapy; additional therapeutic agent(s), e.g., a chemotherapeutic agent, an immunotherapeutic agent, an antibody, e.g., a monoclonal antibody; a vaccine), e.g., in combination with a compound of the present disclosure. In some aspects, the compound of the present disclosure is administered before the additional therapy(ies). In some aspects, the compound of the present disclosure is administered after the additional therapy(ies). In some aspects, the compound of the present disclosure is administered simultaneously with the additional therapy(ies).

[0225] In some embodiments, the method further comprises administering radiation therapy (eg, a therapeutically effective amount of radiation therapy), eg, proton beam therapy, to the subject.

[0226] In some embodiments, the method further comprises administering to the subject a hormone therapy (e.g., a therapeutically effective amount of hormone therapy), e.g., an anti-estrogen therapy, an 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.

[0227] In some embodiments, the method further includes administering to the subject an epidermal growth factor receptor (EGFR) inhibitor (e.g., a therapeutically effective amount of an EGFR inhibitor), e.g., cetuximab. Other examples of EGFR inhibitors include the pan-EGFR inhibitors dacomitinib and mefatinib.

[0228] In some embodiments, the method further includes administering to the subject (e.g., a therapeutically effective amount of) a cyclin-dependent kinase (CDK) inhibitor (e.g., a CDK4 / 6 inhibitor). Examples of CDK inhibitors include abemaciclib, alvocidib, palbociclib, and ribociclib.

[0229] In some embodiments, the method further includes administering to the subject (e.g., a therapeutically effective amount) an inhibitor of Sons of Sevenless (SOS), e.g., SOS1. SOS1 inhibitors are disclosed, for example, in International Publication No. WO2021 / 173524.

[0230] In some embodiments, the method further includes administering to the subject (e.g., a therapeutically effective amount) of a small heterodimer partner (SHP), e.g., SHP2, inhibitor. Examples of SHP2 inhibitors include SHP-099, RMC-4550, RMC4360, and TNO155.

[0231] In some embodiments, the method further includes administering to the subject an immunotherapy (e.g., a therapeutically effective amount of an immunotherapy). Immunotherapeutic agents include antibodies that inhibit proteins expressed by cancer cells, vaccines, and immune cell (e.g., T cell) infusions. Antibody agents useful for promoting anti-tumor responses include anti-CTLA-4 antibodies (e.g., ipilimumab, tremelimumab), anti-PD-1 antibodies (e.g., pembrolizumab, nivolumab, cemiplimab), anti-PD-L1 antibodies (e.g., atezolizumab, avelumab, durvalumab), anti-PD-L2 antibodies, anti-TIM-3 antibodies, anti-LAG-3 antibodies (e.g., leratolimab), anti-OX40 antibodies, and anti-GITR antibodies. In some embodiments, the immunotherapy is an immune checkpoint inhibitor (e.g., a therapeutically effective amount of an immune checkpoint inhibitor), e.g., for treating solid tumor cancer. Examples of immune checkpoint inhibitors include inhibitors of CTLA-4 (e.g., ipilimumab, tremelimumab), inhibitors of PD-1 (e.g., nivolumab, pembrolizumab), inhibitors of PD-L1 (e.g., avelumab), inhibitors of PD-L2, inhibitors of TIM-3, inhibitors of LAG-3 (e.g., leratolimab), inhibitors of OX40, and inhibitors of GITR. In some embodiments, the immune checkpoint inhibitor (e.g., for treating solid tumor cancers) is an inhibitor of CTLA-4, PD-1, PD-L1, or LAG-3. In some embodiments, the immune checkpoint inhibitor (e.g., for treating solid tumor cancers) is an inhibitor of PD-1 or PD-L1. In some embodiments, the immune checkpoint inhibitor (e.g., for treating solid tumor cancers) is an inhibitor of PD-1, e.g., pembrolizumab.

[0232] In some embodiments, the method further includes administering to the subject chemotherapy (e.g., a therapeutically effective amount of chemotherapy), e.g., including 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, abraxane, taxotere); epothilones; histone deacetylase inhibitors (e.g., vorinostat, romidepsin); topoisomerase inhibitors (e.g., irinotecan, topotecan, etoposide, teniposide, tafluposide); kinase inhibitors (e.g., Examples include bortezomib, erlotinib, gefitinib, imatinib, vemurafenib, vismodegib; 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™); alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, metuledopa, and uredopa; ethyleneimines and methylamelamines such as altretamine, triethylenemelamine, triethylenephosphoramide, triethyleneethiophosphaolamide, and trimethylolomelamine; acetogenins such as bullatacin and butalacinone; camptothecin; bryostatin (including the synthetic analog topotecan); kallistatin;CC-1065 (including its adozelesin, carzelesin, and bizelesin analogs); cryptophycins, e.g., cryptophycin 1 and cryptophycin 8; dolastatins; duocarmycins (including synthetic analogs, KW-2189 and CBI-TMI); eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards, e.g., chlorambucil, chromafadine, chlorophosphamide, estramustine , ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembitine, phenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics, such as enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gamma 1 and calicheamicin theta I, e.g., Angew See Chem. Intl. Ed. Engl. 33:183-186 (1994); dynemicins, e.g., dynemicin A; esperamicin; and neocarzinostatin chromophores and related enediyne antibiotic chromophores), aclacinomycin, actinomycin, autramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (morpholino-doxorubicin, cyano ... doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, nitomycin, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfilomycin, puromycin, queramycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, and trimethotrexate;Purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, and 5-FU; androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; antiadrenal agents such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as folinic acid acid); Aceglatone; Aldophosphamide glycosides; Aminolevulinic acid; Amsacrine; Bestravcil; Bisantrene; Edatraxate; Defofamine; Demecolcine; Diazicon; Elfomitine; Elliptinium acetate; Epothilone; Etoglucide; Gallium nitrate; Hydroxyurea; Lentinan; Lonidamine; Maytansinoids, such as maytansine and ansamitocin; Mitoguazone; Mitoxantrone; Mopidamol; Nitracrine; Pentostatin; Fenameth; Pirarubicin; Podophyllic acid; 2-Ethylhydrazide; Procaine Rubadine; PSK®; razoxane; rhizoxin; schizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; trichothecenes, such as T-2 toxin, veracrine A, roridin A, and anguidine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, such as paclitaxel (e.g., TAXOL®, Bristol-Myers Squibb Squibb Oncology, Princeton, NJ; nab-paclitaxel (e.g., the nanoparticulate albumin-bound form of paclitaxel sold as ABRAXANE®) and doxetaxel (TAXOTERE®, Rhone-Poulenc Rorer, Antony, France); chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; folinic acid; platinum analogs, e.g., cisplatin, oxaliplatin, and carboplatin;Examples of anti-inflammatory drugs include vinblastine, platinum, etoposide (VP-16), ifosfamide, mitomycin C, mitoxantrone, vincristine, vinorelbine, navelbine, novantrone, teniposide, daunomycin, aminopterin, xeloda, ibandronate, CPT-11, topoisomerase inhibitors such as irinotecan and RFS 2000, difluoromethylomitin (DFMO), retinoic acid, and capecitabine, as well as pharmaceutically acceptable salts thereof.

[0233] Specific examples of chemotherapeutic agents include aclarubicin, actinomycin, alitretinone, altretamine, aminopterin, aminolevulinic acid, amrubicin, amsacrine, anagrelide, arsenic trioxide, asparaginase, atrasentan, belotecan, bexarotene, bendamustine, bleomycin, bortezomib, busulfan, camptothecin, capecitabine, carboplatin, carboquone, carmofur, carmustine, celecoxib, chlorambucil, chlormethine, cisplatin, cladribine, clofarabine, crisantaspase, Cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, decitabine, demecolcine, docetaxel, doxorubicin, efaproxiral, elesclomol, elsamitrucin, enocitabine, epirubicin, estramustine, etoglucide, etoposide, floxuridine, fludarabine, fluorouracil (5FU), fotemustine, gemcitabine, gliadel implant, hydroxycarbamide, hydroxyurea, idarubicin, ifosfamide, irinotecan, irofulven, ixabepilone, larotazapine oxal, leucovorin, liposomal doxorubicin, liposomal daunorubicin, lonidamine, lomustine, lucanthone, mannosulfan, masoprocol, melphalan, mercaptopurine, mesna, methotrexate, methylaminolevulinate, mitobronitol, mitoguazone, mitotane, mitomycin, mitoxantrone, nedaplatin, nimustine, oblimersen, omacetaxel, ortataxel, oxaliplatin, paclitaxel, pegaspargase, pemetrexed, pentostatin, pirarubicin, pixantrone, prilosporin Kamycin, porfimer sodium, prednimustine, procarbazine, raltitrexed, ranimustine, rubitecan, sapacitabine, semustine, citimagenseladenovec, strataplatin, streptozocin, talaporfin, tegafur-uracil, temoporfin, temozolomide, teniposide, tesetaxel, testolactone, tetranitrate, thiotepa, tiazofurin, thioguanine, tipifarnib, topotecan, trabectedin, triaziquone, triethylenemelamine, triplatin, tretinoin, treosulfan,Trofosfamide, uramustine, valrubicin, verteporfin, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vorinostat, and zorubicin, or pharmaceutically acceptable salts of the foregoing.

[0234] Numerous other therapies may also be administered during treatment (e.g., cancer treatment, treatment of autoimmune diseases) to reduce the effects of the disease and / or side effects of the treatment, including therapies to manage pain (e.g., anesthetics, acupuncture), therapies to manage stomach discomfort (e.g., antacids), therapies to manage dizziness (e.g., antivertigo medications), therapies to manage nausea (e.g., antinausea medications), therapies to manage infections (e.g., medications to increase red / white blood cell counts), etc. (all of which would be readily understood by one of ordinary skill in the art).

[0235] Compounds of the present disclosure or other therapeutic agents described herein can be administered via a variety of routes of administration, depending on the compound and the particular disease being treated, including, for example, oral, dietary, topical, transdermal, rectal, parenteral (e.g., intra-arterial, intravenous, intramuscular, subcutaneous injection, intradermal injection), intravenous infusion, and inhalation (e.g., intrabronchial, intranasal, or oral inhalation, intranasal drops) routes of administration. Administration can be local or systemic, as indicated. In some embodiments, administration (e.g., of a compound of the present disclosure) is oral. In some embodiments, administration (e.g., of a compound of the present disclosure) is intravenous. In some embodiments, administration (e.g., of a compound of the present disclosure) is by injection or infusion. The preferred mode of administration can vary depending on the particular compound or agent.

[0236] Typically, a compound of the disclosure or other therapeutic agent will be administered about 1 to about 6 (e.g., 1, 2, 3, 4, 5, or 6) times per day, or alternatively, as an infusion (e.g., continuous infusion). In some embodiments, a compound of the disclosure or other therapeutic agent is administered once daily (QD) or twice daily (BID). In some embodiments, a compound of the disclosure or other therapeutic agent is administered BID.

[0237] The compounds of the present disclosure or other therapeutic agents may be administered at dosages ranging from about 0.001 mg / kg to about 100 mg / kg body weight, or alternatively, at dosages ranging from about 1 mg / dose to about 5,000 mg / dose, every 4 to 120 hours, or according to the requirements of the particular agent. For example, suitable dosages may be about 0.001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 10 mg / kg, or about 0.01 mg / kg to about 1 mg / kg body weight per treatment. Suitable dosages may be about 1 mg / dose to about 5,000 mg / dose, about 10 mg / dose to about 2,500 mg / dose, or about 100 mg / dose to about 1,000 mg / dose.

[0238] Lower or higher doses than those described above may be required. The specific dosage and treatment regimen for any particular patient will depend on a variety of factors, such as the activity of the specific agent used, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, severity and course of the disease, condition or symptom, the subject's propensity to the disease, condition or symptom, and the judgment of the treating physician. Determining the dosage for a particular agent, subject, and disease, disorder, or condition is within the ability of one skilled in the art. [Example]

[0239] The compounds of the present disclosure can be prepared in a number of ways known to those skilled in the art in light of the methods, reaction schemes, and examples provided herein. The compounds of the present disclosure can be synthesized using the methods described below, along with synthetic methods known in the art of synthetic organic chemistry or variations thereof, as will be understood by those skilled in the art. Preferred methods include, but are not limited to, those described below. Reactions are carried out in a solvent or solvent mixture appropriate to the reagents and materials used and suitable for the transformations being achieved. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the proposed transformations. This will sometimes require judgment to modify the order of synthetic steps or to select one particular process scheme over another to obtain the desired compound.

[0240] The starting materials are generally available from commercial sources, e.g., Sigma Aldrich or other commercial vendors, or are prepared as described herein, or are readily prepared using methods well known to those skilled in the art (e.g., Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, New York (1967-1999 ed.), Larock, R.C., Comprehensive Organic Transformations, 2 nd ed., Wiley-VCH Weinheim, Germany (1999), or Beilstein's Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database).

[0241] For illustrative purposes, the reaction schemes shown below provide potential routes for synthesizing the compounds and intermediates of the present disclosure. Those of skill in the art will appreciate that other synthetic routes can be used to synthesize the compounds of the present disclosure. While specific starting materials and reagents are shown in the schemes and discussed below, other starting materials and reagents can be readily substituted to provide a variety of derivatives and / or reaction conditions. Additionally, many of the compounds prepared by the methods described below can be further modified in light of the present disclosure using conventional chemistry well known to those skilled in the art.

[0242] In preparing the compounds of the present disclosure, protection of distal functionalities of intermediates may be necessary. The need for such protection will vary depending on the nature of the distal functionality and the conditions of the preparation method. The need for such protection is readily determined by one of ordinary skill in the art. For a general description of protecting groups and their use, see Greene, T.W. et al., Protecting Groups in Organic Synthesis, 4th Ed., Wiley (2007). Protecting groups incorporated in preparing the compounds of the present disclosure, such as trityl protecting groups, may be depicted as one regioisomer, but may also exist as a mixture of regioisomers.

[0243] As used hereinafter, the following abbreviations have the corresponding meanings: ACN acetonitrile; Boc tert-butyloxycarbonyl; C Celsius; d doublet; dd doublet of doublets; DCM dichloromethane; DMAP 4-dimethylaminopyridine; DIEA N,N-Diisopropylethylamine; DMSO dimethyl sulfoxide; Dtbbpy 4,4'-di-tert-butyl-2,2'-dipyridyl; DME dimethoxyethane; EtOAc / EA ethyl acetate; EtOH ethanol; FA formic acid; g gram(s); h / hr time(s); HPLC high pressure liquid chromatography; HCl Hydrochloric acid L liters; LC liquid chromatography; LCMS liquid chromatography and mass spectrometry; LiAlH4 lithium aluminum hydride; LiHMDS lithium bis(trimethylsilyl)amine; MeOH methanol; MS mass spectrometry; M molarity; m multiplet; Me methyl; min / min. minute(s); mL milliliter(s); μM micromolar; m / z mass-to-charge ratio; nM nanomolar concentration; NMP N-methylpyrrolidone; NMR nuclear magnetic resonance; NaH sodium hydride; NaHCO3 sodium bicarbonate; Pd / C Palladium supported on carbon; PG protecting group; PE petroleum ether; POCl3phosphoryl chloride; rt room temperature s singlet; sat. saturation; SFC supercritical fluid chromatography; t triplet; t-Bu tert-butyl; TEA triethylamine; TBAF tetra-n-butylammonium fluoride; TTMSS tris(trimethylsilyl)silane; TFA trifluoroacetic acid; THF tetrahydrofuran; TLC thin layer chromatography;

[0244] Example 1. Synthesis of Int.B a) Synthesis of O1-benzyl O2-methyl 2-but-3-enylpyrrolidine-1,2-dicarboxylate [ka] A solution of O1-benzyl O2-methyl (2S)-pyrrolidine-1,2-dicarboxylate (120 g, 455 mmol, CAS#182210-00-0) in THF (200 mL) was added dropwise to a solution of LiHMDS (1 M, 546 mL) at -78 °C for 1 h. 4-Bromobut-1-ene (123 g, 911 mmol, CAS#5162-44-7) was added to the mixture and stirred at 25 °C for 16 h under a N2 atmosphere. Upon completion, the reaction mixture was concentrated in vacuo to provide a residue. The residue was purified via column chromatography (SiO2, PE:EA = 0:1 to 5:1) to provide the title compound (120 g, 66% yield) as a white oil. LC-MS (ESI + ) m / z 318.0(M+H) + .

[0245] b) Synthesis of O1-benzyl O2-methyl 2-[2-(oxiran-2-yl)ethyl]pyrrolidine-1,2-dicarboxylate [ka] A solution of O1-benzyl O2-methyl 2-but-3-enylpyrrolidine-1,2-dicarboxylate (146 g, 460 mmol) and m-CPBA (233 g, 1.15 mol, 85% purity) in DCM (1500 mL) was stirred at 20 °C for 16 h. After completion, the reaction mixture was extracted with EA (3 × 400 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified via column chromatography (SiO2, PE:EA = 0:1 to 3:1) to provide the title compound (110 g, 45% yield) as a white oil. 1 H NMR (400 MHz, CDCl3) δ 7.40 - 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) + .

[0246] c) Synthesis of methyl 3-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolidine-8-carboxylate [ka] To a solution of O1-benzyl O2-methyl 2-[2-(oxiran-2-yl)ethyl]pyrrolidine-1,2-dicarboxylate (110 g, 329 mmol) in MeOH (1000 mL) was added Pd / C (10.0 g, 330 mmol, 10% purity) under a N2 atmosphere. The suspension was degassed and purged with hydrogen gas three times. The reaction mixture was stirred under hydrogen (50 psi) at 20 °C for 16 h. After completion, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to provide the title compound (62.0 g, 94% yield) as a yellow oil. LC-MS (ESI + ) m / z 200.0 (M+H) + .

[0247] d) Synthesis of methyl 3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidine-8-carboxylate [ka] A solution of methyl 3-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolidine-8-carboxylate (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 h. After completion, the mixture was filtered, and the filtrate was concentrated in vacuo to provide a residue. The residue was purified by column chromatography (SiO, PE:EA = 0:1 to 3:1) to provide the title compound (trans racemate) (61.0 g, 41% yield) as a yellow oil. LC-MS (ESI) + ) m / z 438.7(M+H) + .

[0248] e) Synthesis of [3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methanol [ka] To a solution of methyl 3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidine-8-carboxylate (10.4 g, 23.0 mmol) in THF (100 mL) was added LiAlH (1.80 g, 47.0 mmol). The mixture was stirred at -20 °C for 2 h. After completion, HO (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 condition) to provide the title compound (trans racemate) (7.10 g, 73% yield) as a white solid. LC-MS (ESI + ) m / z 410.3 (M+H)+ .

[0249] [(3S,8S)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-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-HO EtOH]; B%: 50%-50%, B 2.95; 300 min) to give Int.A (15.0 g, 37% yield) (retention time: 2.088 min) as a yellow oil and Int.B (15.0 g, 37% yield) (retention time: 1.823 min) as a yellow oil.

[0250] Int.A: 1 H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 7.58 - 7.53 (m, 4H), 7.41 - 7.30 (m, 6H), 3.93 - 3.88 (m, 1H), 3.81 (d, J = 13.2 Hz, 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) + .

[0251] Int.B: 1H NMR (400 MHz, CDCl3) δ 7.70 - 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) + .

[0252] Initially, absolute structures were randomly assigned to Int.A and Int.B, with Int.A assigned as [(3R,8R)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methanol and Int.B assigned as [(3S,8S)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methanol.

[0253] Subsequent X-ray crystallographic analysis revealed that Int. A corresponded to [(3S,8S)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methanol, and Int. B corresponded to [(3R,8R)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methanol. Briefly, 10 mg of Int. A and 25 μL of HCl (1 mol / L) were dissolved in 600 μL of heptane and kept in a sealed 4 mL vial. In another sealed 4 mL vial, 10 mg of Int. B and 25 μL of HCl (1 mol / L) were dissolved in 600 μL of heptane and kept in a sealed 4 mL vial. The solution was allowed to slowly evaporate at room temperature. The resulting crystals were analyzed using a Rigaku Oxford Diffraction XtaLAB Synergy-S 4-circle diffractometer equipped with a HyPix-6000HE area detector and the following equipment: Cryogenic system: Oxford Cryostream 800 Cu: λ = 1.54184 Å, 50 W, microfocus source with multilayer mirror (μ-CMF). Distance from crystal to CCD detector: d = 35 mm Tube voltage: 50kV Tube current: 1mA The resulting Int. A HCl crystals had the following dimensions: 0.30 × 0.30 × 0.20 mm 3 The symmetry of the crystal structure was assigned to the monoclinic space group P21 with the following parameters: a = 10.9303(10) Å, b = 7.80050(10) Å, c = 15.03770(10) Å, α = 90°, β = 103.4170(10)°, γ = 90°, V = 1247.15(2) Å 3 , Z=2, Dc=1.188g / cm3, F(000)=480.0, (Cu Kα)=1.966mm -1 , and T = 293(2) K. The resulting Int. B HCl crystals had the following dimensions: 0.30 × 0.30 × 0.20 mm 3The symmetry of the crystal structure was assigned to the monoclinic space group P21 with the following parameters: a = 10.9653(3) Å, b = 7.7994(2) Å, c = 15.0838(3) Å, α = 90°, β = 103.489(2)°, γ = 90°, V = 1254.42(5) Å 3 , Z=2, Dc=1.181g / cm3, F(000)=480.0, μ(Cu Kα)=1.955mm -1 , and T=293(2)K.

[0254] Based on these and other data collected, the initial randomly assigned absolute configurations of Int.A and Int.B were analyzed in conjunction with x-ray crystallographic analysis of Int.A and Int.B.

[0255] Example 2. Synthesis of Int.C a) Synthesis of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine [ka] 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 POCl (10.6 g, 69.5 mmol) at 0 °C. The mixture was stirred at 110 °C for 2 h. After completion, the mixture was concentrated in vacuo to provide a residue. The residue was then diluted with EA (200 mL) and added dropwise to HO (300 mL). The pH was then adjusted to 7-8 with saturated NaHCO solution, and the mixture was extracted with EA (3 × 200 mL). The organic layer was dried over anhydrous NaSO, filtered, and the filtrate was concentrated in vacuo to provide a residue. The residue was purified by column chromatography (SiO2, PE:EA=50:1 to 5:1) to give the title compound (8.00 g, 68% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H).

[0256] 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. [ka] 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. Then, a solution of tert-butyl (1S,5R)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.24 g, 5.82 mmol, CAS#149771-44-8) in DCM (120 mL) was 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 HO (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 NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, PE:EA=20:1 to 4:1) to give the title compound (4.40 g, 62% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 8.85 (s, 1H), 4.70 - 4.27 (m, 4H), 3.90 - 3.54 (m, 2H), 2.04 - 1.94 (m, 2H), 1.68 (d, J = 7.2 Hz, 2H), 1.53 (s, 9H);LC-MS(ESI + ) m / z 428.0(M+H) + .

[0257] c) Synthesis of tert-butyl 3-[2-[[(3S,8S)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7-chloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. [ka] To a solution of Int. 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 h. Then tert-butyl 3-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.61 g, 3.76 mmol) was added to the mixture. The mixture was stirred at 25 °C for 12 h. After completion, the residue was quenched with HO (30 mL) and extracted with EA (2 × 100 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Welch Ultimate XB-SiOH 250*50*10 μm; mobile phase: [hexane-EtOH]; B%: 0% to 26%, 25 min) to give the title compound (1.50 g, 55% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 8.72 (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, 10.4 Hz, 1H), 3.81 (dd, J = 7.2, 10.0 Hz, 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 - 1.89 (m, 4H), 1.88 - 1.73 (m, 4H), 1.69 (d, J = 7.6 Hz, 2H), 1.52 (s, 9H), 1.06 (s, 9H);LC-MS(ESI + ) m / z 801.4(M+H) + .

[0258] d) Synthesis of tert-butyl 3-[2-[[(3S,8S)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-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. [ka] tert-Butyl 3-[2-[[(3S,8S)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7-chloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (569 mg, 709 μmol), 2-[2-fluoro A solution of -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), ditert-butyl(cyclopentyl)phosphane; dichloropalladium; iron (92.5 mg, 141 μmol), and CsCO (693 mg, 2.13 mmol) was degassed and purged with N atmosphere three times. The mixture was stirred at 100 °C for 0.5 h under N atmosphere. Upon completion, the reaction mixture was concentrated in vacuo to provide a residue. The residue was purified by column chromatography (SiO, PE:EA = 1:0 to 0:1) to provide the title compound (562 mg, 69% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.08 - 9.03 (m, 1H), 7.79 (dd, J = 5.6, 9.2 Hz, 1H), 7.70 - 7.67 (m, 3H), 7.64 (d, J = 4.0 Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.41 (d, J = 7.2 Hz, 6H), 7.30 (d, J = 10.4 Hz, 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, 10.0 Hz, 1H), 3.82 (s, 2H), 3.51 (s, 3H), 3.46 - 3.17 (m, 2H), 2.93 - 2.73 (m, 2H), 2.32 - 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) + .

[0259] 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-hexahydropyrrolidin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. [ka] To a solution of tert-butyl 3-[2-[[(3S,8S)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-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) was added TBAF (1 M, 1.46 mL) at 0 °C. The mixture was stirred at 25 °C for 16 h under a N atmosphere. Upon completion, the mixture was concentrated in vacuo to give a residue. The residue was diluted with HO (15 mL) and then extracted with EA (3 × 15 mL). The combined organic layer was washed with brine (2 x 15 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to provide a residue. The residue was purified by column chromatography (SiO, PE:EA = 50:1 to 1:1) to provide the title compound (220 mg, 59% yield) as a yellow solid. LC-MS (ESI + ) m / z 757.4(M+H) + .

[0260] 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-hexahydropyrrolidin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int. C) [ka] 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-hexahydropyrrolidin-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 μg, 2.64 μmol) and TEA (8.02 mg, 79.2 μmol) at 25° C. Then (4-nitrophenyl)carbonochloridate (15.9 mg, 79.2 μmol) was added to the mixture. The mixture was stirred at 25° C. for 2 hours. Upon completion, the reaction mixture was concentrated in vacuo to provide a residue. The residue was diluted with HO (5 mL) and extracted with DCM (2 x 10 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo to provide the title compound (24 mg, 98% yield) as a yellow oil. LC-MS (ESI + ) m / z 922.3(M+H) + .

[0261] Example 3. Synthesis of Compound 028 a) Synthesis of tert-butyl N-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]carbamate. [ka] 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-piperidyl)-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 h. 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 NaSO, filtered, and the filtrate was concentrated in vacuo to provide a residue. The crude product was purified by reverse phase (0.1% FA condition) to provide the title compound (1.5 g, 39% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 7.62 - 7.54 (m, 1H), 7.15 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 7.2 Hz, 1H), 6.78 - 6.69 (m, 1H), 6.61 - 6.58 (m, 1H), 5.05 (dd, J = 5.2, 12.8 Hz, 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 = 9.2 Hz, 1H), 2.06 - 1.99 (m, 1H), 1.36 (s, 9H);LC-MS(ESI + ) m / z 549.1(M+H) + .

[0262] b) Synthesis of -4-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione. [ka] To a solution of tert-butyl N-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-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 provide the title compound (130 mg, 95% yield, HCl salt) as a green solid. LC-MS (ESI + ) m / z 449.0(M+H) + .

[0263] c) Synthesis of tert-butyl 3-[2-[[(3S,8S)-3-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-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. [ka] To a solution of 4-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (18.9 mg, 39.0 μmol, HCl salt) and Int. 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 h. After completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (FA)-ACN]; B%: 28%-58%, 15 min) to provide the title compound (20 mg, 62% yield) as a yellow solid. LC-MS (ESI +) m / z 1231.2 (M+H) + .

[0264] 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-hexahydropyrrolidin-3-yl]methyl N-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]carbamate (028). [ka] To a solution of tert-butyl 3-[2-[[(3S,8S)-3-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-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 prep-HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (FA)-ACN]; B%: 9%~38%, 15 min) to give the title compound (6.80 mg, 38% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.20 - 10.99 (m, 1H), 9.03 (s, 1H), 8.23 ​​(s, 1H), 7.97 (dd, J = 6.0, 9.2 Hz, 1H), 7.61 - 7.53 (m, 1H), 7.46 (t, J = 9.2 Hz, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 2.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H), 6.60 - 6.57 (m, 1H), 5.05 (dd, J = 5.2, 12.8 Hz, 1H), 4.47 (d, J = 11.2 Hz, 1H), 4.30 (d, J = 11.2 Hz, 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) + .

[0265] Example 4. Synthesis of Int.D a) Synthesis of tert-butyl 3-[2-[[(3R,8R)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7-chloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. [ka] To a solution of Int. 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 h, and then tert-butyl 3-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (345 mg, 805 μmol) was added to the mixture at 25 °C. The mixture was stirred at 25 °C for 15.5 h under a N atmosphere. Upon completion, the reaction was quenched with HO (10 mL) and dissolved in DCM (30 mL). The aqueous layer was separated and extracted with DCM (2 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, DCM:MeOH = 10:1). The residue was purified by pre-NPLC (column: Welch Ultimate XB-CN 250*50*10 μm; mobile phase: [hexane-EtOH]; B%: 5% to 35%, 30 min) to provide the title compound (320 mg, 51% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 7.73 - 7.60 (m, 4H), 7.49 - 7.35 (m, 6H), 4.56 - 4.32 (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, 3H), 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 = 7.6 Hz, 2H), 1.52 (s, 8H), 1.11 - 1.01 (m, 9H);LC-MS(ESI + ) m / z 801.3(M+H) + .

[0266] b) Synthesis of tert-butyl 3-[2-[[(3R,8R)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-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 [ka] tert-Butyl 3-[2-[[(3R,8R)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7-chloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 249 μmol), 2-[2-fluoro-6-(methoxymethoxy) A solution of -8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl]ethynyl-triisopropyl-silane (255 mg, 499 μmol, CAS#2621932-37-2), di-tert-butyl(cyclopentyl)phosphane; dichloropalladium; iron (32.5 mg, 49.9 μmol), and CsCO (243 mg, 748 μmol) was degassed and purged with N three times, then the mixture was stirred at 100 °C for 0.5 h under a N atmosphere. Upon completion, the reaction was concentrated in vacuo to provide a residue. The residue was purified by prep-TLC (SiO, DCM:MeOH=10:1) to provide the title compound (270 mg, 88% yield) as a brown solid. 1H NMR (400 MHz, CDCl3) δ 9.12 - 8.99 (m, 1H), 7.78 (dd, J = 5.6, 9.2 Hz, 1H), 7.69 (t, J = 6.4 Hz, 2H), 7.62 (s, 2H), 7.51 (d, J = 2.4 Hz, 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, 10.8 Hz, 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) + .

[0267] 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-hexahydropyrrolidin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. [ka] To a solution of tert-butyl 3-[2-[[(3R,8R)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-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 μL) at 0 °C. The mixture was stirred at 25 °C for 2 h under a N atmosphere. After completion, the reaction mixture was diluted with HO (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 give a residue, which 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 (400 MHz, CDCl3) δ 9.01 (s, 1H), 7.80 - 7.84 (m, 1H), 7.57 - 7.51 (m, 1H), 7.38 (dd, J = 2.4, 8.0 Hz, 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) + .

[0268] 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-hexahydropyrrolidin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int. D) [ka] 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-hexahydropyrrolidin-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 μg, 1.32 μmol) in DCM (2 mL) was added (4-nitrophenyl)carbonochloridate (7.99 mg, 39.6 μmol, CAS#7693-46-1). The mixture was stirred at 25 °C for 12 h under a N atmosphere. After completion, the mixture was diluted with DCM (10 mL) and extracted with HO (3 x 10 mL). The organic layer was washed with brine (2 x 10 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated in vacuo to provide the title compound (12.0 mg, 57% yield) as a brown solid. LC-MS (ESI + ) m / z 922.3(M+H) + .

[0269] Example 5. Synthesis of Compound 027 [ka] To a solution of Int.D (12.0 mg, 13.0 μmol) and 4-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)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 prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (FA)-ACN]; B%: 31%-61%, 10 min) to provide the title compound (7.00 mg, 43% yield) as a yellow solid. LC-MS (ESI + ) m / z 1232.0(M+H) + .

[0270] 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-hexahydropyrrolidin-3-yl]methyl N-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]carbamate (027). [ka] To a solution of tert-butyl 3-[2-[[(3R,8R)-3-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-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 (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 hours. After completion, the mixture was concentrated in vacuo to provide a residue, which was purified by prep-HPLC (column: Welch Xtimate C18 150*25 mm*5 μm; mobile phase: [water (HCl)-ACN]; B%: 11%-41%, 8 min) to provide the title compound (720 μg, 11% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.09 (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, 9.2 Hz, 1H), 7.60 - 7.55 (m, 1H), 7.47 (t, J = 9.2 Hz, 1H), 7.41 (d, J = 2.4 Hz, 1H), 7.26 - 7.17 (m, 2H), 7.13 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 6.8 Hz, 1H), 6.62 - 6.55 (m, 1H), 5.05 (dd, J = 5.2, 12.8 Hz, 1H), 4.68 (d, J = 13.2 Hz, 1H), 4.64 - 4.52 (m, 3H), 4.32 (d, J = 5.6 Hz, 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) + .

[0271] Example 6. Synthesis of Compound 025 a) Synthesis of tert-butyl N-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]amino]ethoxy]ethoxy]ethyl]carbamate. [ka] 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-piperidyl)-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 h. Upon completion, HO (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 NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by reverse-phase HPLC (0.1% FA condition) to provide the title compound (1.00 g, 24% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.15 (t, J = 5.2 Hz, 1H), 7.00 (d, J = 2.0 Hz, 1H), 6.90 (dd, J = 2.0, 8.4 Hz, 1H), 6.74 (t, J = 5.6 z, 1H), 5.03 (J = 5.2, 12.8 Hz, 1H), 3.59 (t, J = 5.6 Hz, 2H), 3.55 - 3.53 (m, 2H), 3.53 - 3.50 (m, 2H), 3.38 - 3.34 (m, 4H), 3.05 (q, J = 6.0 Hz, 2H), 2.55 (s, 4H), 1.36 (s, 10H);LC-MS(ESI + ) m / z 504.9(M+H) + .

[0272] b) Synthesis of 4-[2-[2-(2-aminoethoxy)ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione. [ka] To a solution of tert-butyl N-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-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 provide the title compound (174 mg, 99% yield, HCl salt) as a yellow solid. LC-MS (ESI + ) m / z 405.0(M+H) + .

[0273] c) Synthesis of tert-butyl 3-[2-[[(3R,8R)-3-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]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. [ka] To a solution of Int. D (120 mg, 130 μmol) and 4-[2-[2-(2-aminoethoxy)ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)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 provide the title compound (154 mg, 64% yield) as a yellow oil. LC-MS (ESI + ) m / z 1187.3(M+H) + .

[0274] d) Synthesis of tert-butyl 3-[2-[[(3R,8R)-3-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]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 (025). [ka] To a solution of tert-butyl 3-[2-[[(3R,8R)-3-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]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 (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 obtain a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (FA)-ACN]; B%: 17%~47%, 15min) to provide the title compound (4.71mg, 5.3% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 11.15 - 11.07 (m, 1H), 9.03 (s, 1H), 8.21 (s, 1H), 7.97 (dd, J = 6.0, 9.6 Hz, 1H), 7.57 (t, J = 8 Hz, 1H), 7.46 (t, J = 9.2 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 7.13 (br d, J = 8.0 Hz, 1H), 7.02 (d, J = 7.2 Hz, 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 LC-MS(ESI) + ) m / z 1043.7 (M+H) + .

[0275] Example 7. Synthesis of Compound 020 a) Synthesis of N-[3-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]propyl]carbamate. [ka] To a solution of 2-(2,6-dioxo-3-piperidyl)-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 h. After completion, the reaction mixture was filtered and concentrated in vacuo to provide a residue. The residue was diluted with HO (50 mL) and extracted with EA (2 x 100 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo to provide a residue. The residue was purified by prep-HPLC (column: UniSil 10-120 C18 50x250mm; mobile phase: [water (FA)-ACN]; B%: 30%-60%, 22 min) to afford the title compound (760 mg, 61% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.57 (dd, J = 7.2, 8.4 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H), 6.93 - 6.90 (m, 1H), 6.67 - 6.64 (m, 1H), 5.05 (dd, J = 5.2, 12.8 Hz, 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) + .

[0276] a) Synthesis of 4-(3-aminopropylamino)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione. [ka] To a solution of tert-butyl N-[3-[[2-(2,6-dioxo-3-piperidyl)-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 h. After completion, the reaction mixture was concentrated in vacuo to provide the title compound (85 mg, 99% yield, HCl salt) as a yellow solid. LC-MS (ESI + ) m / z 330.8(M+H) + .

[0277] a) Synthesis of tert-butyl 3-[2-[[(3S,8S)-3-[3-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]propylcarbamoyloxymethyl]-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. [ka] To a solution of Int.C (60.0 mg, 65.0 μmol) and 4-(3-aminopropylamino)-2-(2,6-dioxo-3-piperidyl)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 h. After completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters xbridge 150*25 mm 10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 30%-60%, 8 min) to provide the title compound (55.0 mg, 75% yield) as a yellow solid. LC-MS (ESI + ) m / z 1113.4 (M+H) + .

[0278] 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-hexahydropyrrolidin-3-yl]methyl N-[3-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]propyl]carbamate (020). [ka] To a solution of tert-butyl 3-[2-[[(3S,8S)-3-[3-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]propylcarbamoyloxymethyl]-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 (55.0 mg, 49.4 μmol) in DCM (1 mL) was added HCl / dioxane (4 M, 550 μL). The mixture was stirred at 25 °C for 0.5 hours. After completion, the reaction mixture was concentrated in vacuo to provide a residue. The residue was purified by prep-HPLC (column: Waters xbridge 150*25mm 10μm; mobile phase: [water (TFA)-ACN]; B%: 10%~40%, 8 min) to give the title compound (12.5 mg, 22% yield, TFA salt) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.09 (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, 9.2 Hz, 1H), 7.59 - 7.55 (m, 1H), 7.50 - 7.45 (m, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.33 (d, J = 6.0 Hz, 1H), 7.18 (d, J = 2.0 Hz, 1H), 7.10 - 7.07 (m, 1H), 7.03 (d, J = 7.2 Hz, 1H), 6.65 (t, J = 5.2 Hz, 1H), 5.04 (dd, J = 5.2, 12.8 Hz, 1H), 4.70 (d, J = 15.6 Hz, 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 = 6.0 Hz, 2H), 3.10 - 3.08 (m, 2H), 2.95 - 2.81 (m, 2H), 2.61 (d, J = 2.4 Hz, 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 / z 969.4(M+H) + .

[0279] Example 8. Synthesis of Compound 019 a) Synthesis of tert-butyl N-[4-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]butyl]carbamate. [ka] To a solution of 2-(2,6-dioxo-3-piperidyl)-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 h. Upon completion, the reaction mixture was filtered and concentrated in vacuo to provide a residue. The residue was diluted with HO (50 mL) and extracted with EA (2 x 100 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo to provide a residue. The residue was purified by prep-HPLC (column: UniSil 10-120 C18 50x250mm; mobile phase: [water (FA)-ACN]; B%: 32%~62%, 25 min) to provide the title compound (812 mg, 68% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.57 (dd, J = 7.2, 8.4 Hz, 1H), 7.10 (d, J = 8.8 Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H), 6.84 - 6.81 (m, 1H), 6.56 - 6.53 (m, 1H), 5.05 (dd, J = 5.6, 12.8 Hz, 1H), 3.31 - 3.25 (m, 2H), 2.96 - 2.92 (m, 2H), 2.90 - 2.82 (m, 1H), 2.60 (d, J = 2.8 Hz, 1H), 2.55 (d, J=10.0 Hz, 1H), 2.07 - 1.97 (m, 1H), 1.59 - 1.50 (m, 2H), 1.49 - 1.41 (m, 2H), 1.36 (s, 9H) + ) m / z 345.1 (M+H-100) + .

[0280] b) Synthesis of 4-(4-aminobutylamino)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione. [ka] To a solution of tert-butyl N-[4-[[2-(2,6-dioxo-3-piperidyl)-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 h. After completion, the reaction mixture was concentrated in vacuo to provide the title compound (85.0 mg, 99% yield, HCl salt) as a yellow solid. LC-MS (ESI + ) m / z 344.8(M+H) + .

[0281] c) Synthesis of tert-butyl 3-[2-[[(3S,8S)-3-[4-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]butylcarbamoyloxymethyl]-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. [ka] To a solution of Int.C (60.0 mg, 65.0 μmol) and 4-(4-aminobutylamino)-2-(2,6-dioxo-3-piperidyl)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 provide a residue. The residue was purified by prep-HPLC (column: Waters xbridge 150*25 mm 10 μm; mobile phase: [water (FA)-ACN]; B%: 30%-60%, 8 min) to provide the title compound (52.0 mg, 70% yield) as a yellow solid. LC-MS (ESI + ) m / z 1127.5(M+H) + .

[0282] 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-hexahydropyrrolidin-3-yl]methyl-N-[4-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]butyl]carbamate (019). [ka] To a solution of tert-butyl 3-[2-[[(3S,8S)-3-[4-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]butylcarbamoyloxymethyl]-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 (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. After completion, the reaction mixture was concentrated in vacuo to provide a residue. The residue was purified by prep-HPLC (column: Waters xbridge 150*25mm 10μm; mobile phase: [water (TFA)-ACN]; B%: 12%~42%, 10 min) to give the title compound (14.8 mg, 29% yield, TFA salt) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.13 - 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, 9.2 Hz, 1H), 7.61 - 7.53 (m, 1H), 7.50 - 7.45 (m, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.26 (d, J = 1.6 Hz, 1H), 7.18 (s, 1H), 7.12 - 7.05 (m, 1H), 7.02 (d, J = 7.2 Hz, 1H), 6.60 - 6.47 (m, 1H), 5.04 (dd, J = 5.6, 12.8 Hz, 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 = 6.0 Hz, 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) + .

[0283] Example 9. Synthesis of Compound 024 a) Synthesis of N-[6-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]hexyl]carbamate. [ka] To a solution of tert-butyl N-(6-aminohexyl)carbamate (2.00 g, 9.25 mmol, CAS#51857-17-1) and 2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (2.30 g, 8.32 mmol, CAS#835616-60-9) in NMP (30 mL) was added DIEA (2.39 g, 18.4 mmol). The mixture was stirred at 135 °C for 4 h. 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 NaSO, filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse-phase HPLC (0.1% FA condition) to provide the title compound (1.50 g, 34% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H), 6.76 (t, J = 5.2 Hz, 1H), 6.53 (t, J = 5.6 Hz, 1H), 5.05 (J = 5.2, 12.8 Hz, 1H), 3.28 (d, J = 6.4 Hz, 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) + .

[0284] b) Synthesis of 4-(6-aminohexylamino)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione. [ka] To a solution of tert-butyl N-[6-[[2-(2,6-dioxo-3-piperidyl)-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 provide the title compound (150 mg, 86% yield, HCl salt) as a yellow solid. LC-MS (ESI + ) m / z 373.1 (M+H) + .

[0285] c) Synthesis of tert-butyl 3-[2-[[(3RS,8RS)-3-[6-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]hexylcarbamoyloxymethyl]-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. [ka] To a solution of 4-(6-aminohexylamino)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (43.9 mg, 85.9 μmol, HCl salt) and Int.E (trans racemate) (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 for 2 h under a N atmosphere. Upon completion, the mixture was concentrated in vacuo to provide the title compound (trans racemate) (100 mg, 74% yield) as a yellow oil. LC-MS (ESI + ) m / z 1155.8(M+H) + .

[0286] 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-hexahydropyrrolidin-3-yl]methyl N-[6-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]hexyl]carbamate (024). [ka] To a solution of tert-butyl 3-[2-[[3-[6-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]hexylcarbamoyloxymethyl]-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 (trans racemic) (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. After completion, the mixture was concentrated in vacuo to provide a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (FA)-ACN]; B%: 14%~44%, 10 min) to provide the title compound (trans racemate) (22.05 mg, 50% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.08 (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 = 8.8 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.20 - 7.14 (m, 2H), 7.07 (d, J = 8.6 Hz, 1H), 7.00 (d, J = 7.2 Hz, 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, 10H), 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) + .

[0287] Example 10. Synthesis of Compound 022 a) Synthesis of tert-butyl 3-[2-[[(3R,8R)-3-[6-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]hexylcarbamoyloxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]me...

Claims

1. A compound of the formula: [KRAS G12Di]-L'-[Degron] (A), or a pharma- ceutically acceptable salt thereof, KRAS G12Di is the KRAS G12D binding site; L′ is a covalent bond or a divalent, saturated or unsaturated, linear or branched C １－５０ is a hydrocarbon chain, wherein 0 to 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)(NR ２ ), -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)-, 【Chemistry 539】 and Each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4- to 11-membered saturated or partially unsaturated heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted bivalent ring selected from 1-membered saturated or partially unsaturated spiroheterocyclylenyl, 8-10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-6-membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8-10-membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen, deuterium, or C １－６ an optionally substituted group selected from aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R on the same nitrogen together with their intervening atoms form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having, in addition to said 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; Degron is the cereblon binding site; 【Chemistry 540】 However, the compound is 【Chemistry 541-1】 【Chemistry 541-2】 【Chemistry 541-3】 【Chemistry 541-4】 or its salts).

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

3. The KRAS G12Di is 【Chemical 542】 2. The compound of claim 1,

4. L' is a covalent bond or a divalent, saturated or unsaturated, linear or branched C １ -C ２５ is a hydrocarbon chain, and 0 to 10 methylenes of L' are replaced by X; Each X is independently -O-, -N(R)-, -S-, -OC(O)-, -C(O)-, -C(H)(F)-, or -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)-, 【Chemistry 543】 and each -Cy- is independently an optionally substituted bivalent ring selected from a 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, a 4- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4- to 11-membered saturated or partially unsaturated spiroheterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen or (C １ -C ３ ) alkyl; 4. A compound according to claim 1, 2 or 3.

5. A compound of the formula: 【Chemical 544】 or a pharma- ceutically acceptable salt thereof, 【Chemistry 545】 teeth, 【Chemical 546】 and X ５ is O or CH ２ and Two R's ｏ With the same carbon atom, C ３－７ cycloalkyl or 4- to 7-membered heterocycloalkyl, ３ -C ７ ) Cycloalkyl or 4- to 7-membered heterocycloalkyl is selected from halogen, oxo, (C １ -C ４ ) alkyl, (C １ -C ４ ) alkoxy, (C １ -C ４ ) haloalkyl, hydroxyl, cyano, -S(O) ２ (C １ -C ４ ) alkyl, =NH, =N(C １ -C ４ ) alkyl, -NH ２ , -N(H)(C １ -C ４ ) alkyl or -N((C １ -C ４ ) alkyl) ２ and when p is 3 or 4, each remaining R ｏ is hydroxyl, halogen, oxo, cyano, -N((C １ -C ４ ) alkyl) ２ , (C １ -C ４ ) alkyl, (C １ -C ４ ) alkoxy, (C １ -C ４ ) haloalkyl or (C １ -C ４ ) 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 ) and R ４２ is hydrogen, halogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) haloalkyl, (C １ -C ６ ) haloalkoxy, (C ２ -C ６ ) alkenyl, (C ２ -C ６ ) alkynyl, -CN, (C １ -C ６ ) alkoxy, —S—(C １ -C ６ ) alkyl or -S-(C １ -C ６ ) haloalkyl; Y is a bond, O or NR ５ and R １ is hydrogen, hydroxy, halogen, (C １ -C ３ ) alkyl, (C １ -C ３ ) cyanoalkyl, (C １ -C ３ ) Hydroxyalkyl, —C(O)H, —CO ２ R ５ , -CO ２ N (R ５ ) ２ Or (C ５ -C ６ ) heteroaryl; R ２ is hydrogen, -N(R ５ ) ２ , (C ３ -C １２ ) heterocyclyl, (C １ -C ６ ) alkyl, -L-(C ３ -C １２ ) heterocyclyl, -L-(C ６ -C １４ ) aryl, -L-(C ５ -C １４ ) heteroaryl, -L-(C ３ -C １２ ) cycloalkyl, -L-N(R ５ ) ２ , -L-N(H)C(NH)NH ２ , -LC(O)N(R ５ ) ２ , -L-(C １ -C ６ ) haloalkyl, -L-OR ５ , -L-NR ５ C(O)-(C ６ -C １４ )aryl, -L-COOH or -L-C(O)O(C １ -C ６ ) alkyl, and the (C ３ -C １２ ) heterocyclyl, the aforementioned -L-NR ５ C(O)-(C ６ -C １４ ) aryl (C ６ -C １４ ) aryl, the -L-(C ３ -C １２ ) Heterocyclyl (C ３ -C １２ )heterocyclyl and the above-L-(C ３ -C １２ ) cycloalkyl (C ３ -C １２ ) Cycloalkyl is one or more R ６ is optionally substituted with -L-(C ６ -C １４ ) aryl of aryl and -L-(C ５ -C １４ ) Heteroaryl (C ５ -C １４ ) Heteroaryl is one or more R ７ optionally substituted with; L is hydroxy, (C １ -C ４ ) hydroxyalkyl or (C ５ -C １４ ) optionally substituted with heteroaryl (C １ -C ４ ) alkylene; R ３ (C ６ -C １４ ) aryl or (C ５ -C １４ ) heteroaryl, ６ -C １４ ) aryl or (C ５ -C １４ ) Heteroaryl is one or more R ８ optionally substituted with; R ４ is hydrogen, halogen or (C １ -C ３ ) alkyl; Each R ５ are independently hydrogen or (C １ -C ３ ) alkyl; Each R ６ are independently halogen, hydroxy, (C １ -C ３ ) hydroxyalkyl, (C １ -C ３ ) alkyl, (C １ -C ３ ) haloalkyl, (C １ -C ３ ) Alkoxy, cyano, -Q-phenyl, -Q-phenyl-SO ２ F, -N(H)C(O)-phenyl, -N(H)C(O)-phenyl-SO ２ F, (C １ -C ３ ) alkyl-substituted pyrazole; ６ -C １４ ) Aryl (C １ -C ３ ) alkyl, tert-butyldimethylsilyloxy-CH ２ -, -N(R ５ ) ２ , (C １ -C ３ ) Alkoxy (C １ -C ３ ) alkyl, (C １ -C ３ ) alkyl-C(O)-, oxo, (C １ -C ３ ) Haloalkyl-C(O)-, -SO ２ F, (C １ -C ３ ) Alkoxy (C １ -C ３ ) alkoxy, —CH ２ O.C. (O) N (R ５ ) ２ , -CH ２ N(H)C(O)O-(C １ -C ６ ) alkyl, —CH ２ N(H)C(O)N(R ５ ) ２ , -CH ２ N(H)C(O)(C １ -C ６ ) alkyl, —CH ２ (pyrazolyl), -CH ２ N(H)S(O) ２ (C １ -C ６ ) alkyl, —CH ２ O.C. (O) (C ３ -C １２ ) heterocyclyl, —OC(O)N(R ５ ) ２ , -OC(O)N(H)(C １ -C ３ ) alkyl-O-(C １ -C ３ ) alkyl, —OC(O)N(H)(C １ -C ３ ) alkyl-O-(C １ -C ３ ) alkyl-phenyl-(C １ -C ３ ) alkyl-N(CH ３ ) ２ , -OC(O)N(H)(C １ -C ３ ) alkyl-O-(C １ -C ３ ) alkyl-phenyl, —OC(O)(C ３ -C １２ ) heterocyclyl or -CH ２ - (C ３ -C １２ )heterocyclyl, including —N(H)C(O)phenyl and —OC(O)N(H)(C １ -C ３ ) alkyl-O-(C １ -C ３ ) The phenyl of the alkyl-phenyl is optionally substituted with —C(O)H or —OH, and is not —CH ２ - (C ３ -C １２ ) Heterocyclyl (C ３ -C １２ ) heterocyclyl is optionally substituted with oxo; Q is a bond or O; Each R ７ are independently halogen, hydroxy, —C(O)H, (C １ -C ４ ) alkyl, (C １ -C ４ ) alkoxy, (C １ -C ４ ) haloalkyl, (C １ -C ４ ) hydroxyalkyl or -N(R ５ ) ２ and Each R ８ are independently halogen, cyano, hydroxy, (C １ -C ４ ) alkyl, —S—(C １ -C ３ ) alkyl, (C ２ -C ４ ) alkenyl, (C ２ -C ４ ) alkynyl, (C ２ -C ４ ) hydroxyalkynyl, (C １ -C ３ ) cyanoalkyl, triazolyl, (C １ -C ３ ) haloalkyl, —O—(C １ -C ３ ) haloalkyl, -S-(C １ -C ３ ) haloalkyl, (C １ -C ３ ) alkoxy, (C １ -C ３ ) Hydroxyalkyl, —CH ２ C(O)N(R ５ ) ２ , (C ３ -C ４ ) alkynyl-N(R ５ ) ２ , N(R ５ ) ２ , Juuterio (C ２ -C ４ ) alkynyl, (C １ -C ３ ) Alkoxy (C １ -C ３ ) haloalkyl or (C ３ -C ６ ) cycloalkyl, ３ -C ６ ) Cycloalkyl is halogen or (C １ -C ３ ) optionally substituted with alkyl; L' is a covalent bond or a divalent, saturated or unsaturated, linear or branched C １ -C ２５ is a hydrocarbon chain, wherein 0 to 10 methylenes of L' are replaced by X; Each X is independently -O-, -N(R)-, -S-, -OC(O)-, -C(O)-, -C(H)(F)-, or -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)-, 【Chemical 547】 and each -Cy- is independently an optionally substituted bivalent ring selected from a 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, a 4- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4- to 11-membered saturated or partially unsaturated spiroheterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen or (C １ -C ３ ) alkyl; Degron is the cereblon binding site; However, the compound is 【Chemistry 548-1】 【Chemistry 548-2】 or its salts).

6. The compound according to claim 5 of the formula: 【Chemical 549】 or a pharma- ceutically acceptable salt thereof.

7. X ４ is C(R ４２ 7. The compound according to claim 6, wherein

8. R ４２ is hydrogen, fluoro, chloro, methyl, -CF ３ , -OCF ３ , -CN, -OCH ３ , -SCH ３ or - SCF ３ 8. The compound according to claim 6 or 7,

9. The compound according to claim 6 of the formula: 【Chemistry 550】 or a pharma- ceutically acceptable salt thereof.

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

11. R １ The compound according to any one of claims 5 to 10, wherein is hydrogen.

12. R ２ is -L-(C ３ -C １２ ) heterocyclyl, and said -L-(C ３ -C １２ ) Heterocyclyl (C ３ -C １２ ) Heterocyclyl is one or more R ６ The compound according to any one of claims 5 to 11, optionally substituted with

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

14. R ３ is one or more R ８ (C ６ -C １４ 14. The compound according to any one of claims 5 to 13, wherein:

15. R ３ teeth, 【Chemistry 551】 15. The compound of claim 14, wherein

16. R ３ teeth, 【Chemistry 552】 16. The compound of claim 15,

17. R ４ The compound according to any one of claims 5 to 16, wherein is a halogen.

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

19. Each R ６ are independently halogen, hydroxy, (C １ -C ３ ) hydroxyalkyl, (C １ -C ３ ) alkyl, (C １ -C ３ ) haloalkyl, (C １ -C ３ 20. The compound according to any one of claims 5 to 18, wherein said aryl group is alkoxy or cyano.

20. Each R ８ are independently halogen, hydroxy, (C １ -C ４ ) alkyl, —S—(C １ -C ３ ) alkyl, (C ２ -C ４ ) alkenyl, (C ２ -C ４ ) alkynyl, (C １ -C ３ ) alkoxy, (C １ -C ３ ) hydroxyalkyl or deuterio (C ２ -C ４ 20. The compound according to any one of claims 5 to 14 and 17 to 19, wherein:

21. The compound according to any one of claims 9 to 20, having the following formula: 【Chemistry 553】 or a pharma- ceutically acceptable salt thereof, wherein n is 0, 1 or 2.

22. The compound of claim 21 having the following structural formula: 【Chemical 554】 or a pharma- ceutically acceptable salt thereof.

23. The compound of claim 21 having the following structural formula: 【Chemistry 555】 or a pharma- ceutically acceptable salt thereof.

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

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

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

27. L' is a divalent, saturated or unsaturated, linear or branched C １ -C １５ a hydrocarbon chain, in which 1 or 2 methylenes of L' are replaced by Cy and 1 to 3 methylenes of L' are replaced by X; 26. The compound of any one of claims 1 to 25, wherein each X is independently -O-, -C(O)-, -N(R)-, or -N(R)C(O)-.

28. 28. The compound of any one of claims 1 to 27, wherein each -Cy- is independently a 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4- to 11-membered saturated or partially unsaturated spiroheterocyclylenyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

29. 29. The compound according to 28, wherein each -Cy- is a 4-7 membered saturated or partially unsaturated heterocyclylenyl having one nitrogen atom and optionally one additional heteroatom selected from nitrogen, oxygen, and sulfur, a 4-11 membered saturated or partially unsaturated spiroheterocyclylenyl having one nitrogen atom and optionally one to two additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having one nitrogen atom and optionally one additional heteroatom independently selected from nitrogen, oxygen, and sulfur, and is linked via the nitrogen atom.

30. 28. The compound of any one of claims 1 to 27, wherein each -Cy- is independently selected from cyclohexylene, piperidinylene, azetidinylene, pyrrolidinylene, piperazinylene, morpholinylene, 1-oxa-4,9-diazaspiro[5.5]undecanylene, 3-azaspiro[5.5]undecanylene, 2-azaspiro[3.3]heptanylene, 7-azaspiro[3.5]nonanylene, 3-azabicyclo[3.2.1]octanylene, 2,7-diazaspiro[3.5]nonanylene, 3,9-diazaspiro[5.5]undecanylene, or triazinylene.

31. L' is -Cy １ - (CH ２ ) ０－１ -X-(CH ２ ) ０－１ -Cy ２ -, Cy １ and Cy ２ The compound according to any one of claims 1 to 30, wherein each is independently -Cy-.

32. Cy １ is a 4-7 membered saturated or partially unsaturated heterocyclylenyl having one nitrogen atom and optionally one additional heteroatom independently selected from nitrogen, oxygen, and sulfur, a 4-11 membered saturated or partially unsaturated spiroheterocyclylenyl having one nitrogen atom and optionally one additional heteroatom independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having one nitrogen atom and optionally one additional heteroatom independently selected from nitrogen, oxygen, and sulfur, linked via the nitrogen atom.

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

34. Cy ２ is cyclohexylene, piperidinylene, azetidinylene, pyrrolidinylene, piperazinylene, morpholinylene, 1-oxa-4,9-diazaspiro[5.5]undecanylene, 3-azaspiro[5.5]undecanylene, 2-azaspiro[3.3]heptanylene, 7-azaspiro[3.5]nonanylene, 3-azabicyclo[3.2.1]octanylene, 2,7-diazaspiro[3.5]nonanylene, 3,9-diazaspiro[5.5]undecanylene, or triazinylene. The compound according to any one of claims 31 to 33.

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

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

37. Degron is 【Chemistry 556】 and one or more of the hydrogen atoms on the benzene ring of the Degron are optionally replaced by a fluorine atom.

38. Degron is 【Chemistry 557】 38. The compound of claim 37, wherein one or more of the hydrogen atoms on the benzene ring of the Degron are optionally replaced by a fluorine atom.

39. Degron is 【Chemistry 558】 39. The compound of claim 38, wherein one or more of the hydrogen atoms on the benzene ring of the Degron are optionally replaced by a fluorine atom.

40. Degron is 【Chemical Formula 559】 40. The compound of claim 39, wherein one or more of the hydrogen atoms on the benzene ring of the Degron are optionally replaced by a fluorine atom.

41. A compound of Table 1, or a pharma- ceutically acceptable salt thereof.

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

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

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

45. 43. 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 according to any one of claims 1 to 41, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 42, or a pharmaceutical combination according to claim 43.

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

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

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

49. 47. 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, blood cancer, skin cancer or adrenal gland cancer.

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

51. The method of any one of claims 46 to 50, further comprising determining that the subject has a KRAS G12D-associated cancer.

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

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