Compounds and methods for targeted degradation of KRAS

Abstract

Described herein are bifunctional compounds that are useful as modulators of Kirsten ras sarcoma protein (KRAS). In particular, the heterobifunctional compounds of the present disclosure contain a moiety that binds to von Hippel-Lindau E3 ubiquitin ligase at one end and a moiety that binds to KRAS at the other end, thereby placing the target protein in close proximity to the ubiquitin ligase, resulting in degradation (and inhibition) of the target protein. The heterobifunctional compounds of the present disclosure exhibit a wide range of pharmacological activities related to the degradation / inhibition of target proteins. Diseases or disorders resulting from aberrant regulation of target proteins are treated or prevented by the compounds and compositions of the present disclosure.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 301,887, filed January 21, 2022, the entire contents of which are incorporated herein by reference in their entirety.

[0002] INCORPORATION BY REFERENCE TO SEQUENCE LISTING This application contains a Sequence Listing that was submitted via EFS-Web in ST.26 XML format and is incorporated herein by reference in its entirety. A copy of said ST.26 XML was created on Jan. 20, 2023, is named "738274_ART-141PC_SeqList_ST26", and is 6KB in size. [Background technology]

[0003] Bifunctional compounds such as those described in US Patent Publication Nos. 2015 / 0291562 and 2014 / 0356322 (herein incorporated by reference) function to recruit endogenous proteins to E3 ubiquitin ligases for ubiquitination and subsequent degradation in the proteasomal degradation pathway. In particular, the above-cited publications describe bifunctional or proteolysis-inducing chimeric (PROTAC®) proteolytic compounds that find utility as modulators that target and subsequently degrade and / or inhibit the ubiquitination of various polypeptides and proteins.

[0004] The Kirsten rat sarcoma (KRAS) gene is an oncogene that encodes the small GTPase signaling protein KRAS. Ras proteins associate with the cell membrane and function as switches that transduce extracellular signals into intracellular responses, thereby controlling, for example, cell division. In normal cells, KRAS functions as a molecular switch, cycling between an inactive GDP-bound "off" state and an active GTP-bound "on" state (Milburn et al.; Ito, Y., et al., Regional polysterism in the GTP-bound form of the human c-Ha-Ras protein. Biochemistry 1997, 36(30), 9109-9119). This switch is tightly controlled by guanine nucleotide exchange factor (GEF) proteins, which convert GDP to GTP, and GTPase-activating proteins (GAPs), which promote the intrinsically slow GTPase activity of KRAS (Bar-Sagi, D., The Sos (Son of sevenless) protein. Trends Endocrinol Metab 1994, 5(4), 165-9; Pierre, S., et al., Understanding SOS (Son of Sevenless). Biochem Pharmacol 2011, 82(9), 1049-56; Harrell Stewart, DR, et al., Pumping the brakes on RAS-negative regulators and death effectors of RAS. J Cell Sci 2020, 133(3)).GEF and GAP effector proteins bind to one or both of two shallow binding pockets in KRAS, termed switch I (residues 30-38) and switch II (residues 59-76), whose conformation changes dramatically between the GDP- and GTP-bound states (Ito et al.; Boriack-Sjodin, PA et al., The structural basis of the activation of Ras by Sos. Nature 1998, 394(6691), 337-43; Scheffzek, K. et al., The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants. Science 1997, 277(5324), 333-8).

[0005] The KRAS gene is one of the most frequently mutated oncogenes in cancer (Prior, IA; Lewis, PD; Mattos, C., A comprehensive survey of Ras mutations in cancer. Cancer Res 2012, 72(10), 2457-67; Land, H.; Parada, LF; Weinberg, RA, Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes. Nature 1983, 304(5927), 596-602; Newbold, RF; Overell, RW, Fibroblast Immortality Is a Prerequisite for Transformation by Ej C-Ha-Ras Oncogene. Nature 1983, 304(5927), 648-651). KRAS encodes a small membrane-bound GTPase that relays signals from receptor tyrosine kinases (RTKs) and promotes cell proliferation, differentiation, or death (Milburn,MV,et al.,Molecular Switch for Signal Transduction-Structural Differences between Active and Inactive Forms of Protooncogenic Ras Proteins.Science 1990,247(4945),939-945;Simanshu,DK,et al.,RAS Proteins and Their Regulators in Human Disease.Cell 2017,170(1),17-33). Somatic mutations in KRAS reduce the enzyme activity of GAP-mediated proteins, resulting in the accumulation of active KRAS bound to GTP, which in turn leads to excessive activation of downstream signaling, resulting in unregulated cell proliferation (Prior et al.;Simanshu et al.).Numerous activating or gain-of-function mutations in the KRAS gene are known, and in fact, KRAS is the most frequently mutated gene in cancer. Gain-of-function KRAS mutations have been found in approximately 30% of all human cancers, including, for example, pancreatic cancer (>80%), colon cancer (approximately 40-50%), lung cancer (approximately 30-50%), non-small cell lung cancer, biliary tract malignancies, endometrial cancer, cervical cancer, bladder cancer, liver cancer, myeloid leukemia, and breast cancer. These activating mutations impair KRAS's ability to switch between active and inactive states. The critical role of mutant KRAS has been established in the development, maintenance, progression, and metastasis of various cancers, and mutations often correlate with poor prognosis and increased resistance to chemotherapy and biological therapy, such as epidermal growth factor receptor-targeted therapies. However, despite its important role and prevalence in cancer, there have been continuing challenges in developing effective therapies that directly target this oncogene. As of January 2022, the only FDA-approved KRAS-targeting drug is sotorasib (sold under the trade names Lumakras® and Lumykras®), which is indicated only for patients with KRAS G12C-mutated cancers, and no other KRAS mutant-targeting drugs have been approved. Furthermore, mutant KRAS remains a challenging therapeutic target due to its prevalence in cancer and the paucity of traditionally druggable pockets on its surface, despite extensive research efforts over the years (Spencer-Smith, R. et al., Direct inhibition of RAS: Quest for the Holy Grail? Semin Cancer Biol 2019, 54, 138-148).

[0006] There is a continuing need in the art for effective treatments for diseases and disorders associated with KRAS, such as pancreatic cancer, colon cancer, colorectal cancer, lung cancer, non-small cell lung cancer, biliary malignancies, endometrial cancer, cervical cancer, bladder cancer, liver cancer, myeloid leukemia, and breast cancer. Summary of the Invention

[0007] The present disclosure describes bifunctional compounds that function to recruit endogenous proteins to E3 ubiquitin ligase for ubiquitination and degradation, as well as methods of use thereof.In particular, the present disclosure provides bifunctional compounds or proteolysis-inducing chimeric compounds (PROTAC® proteolytic agents) that find utility as modulators of targeted ubiquitination of various polypeptides and proteins, which are degraded and / or otherwise inhibited by the bifunctional compounds described herein.In addition, the present disclosure provides methods of using an effective amount of the compounds described herein for the treatment or amelioration of disease conditions, such as cancer, inflammatory diseases / disorders, neurodegenerative diseases, and cardiovascular diseases / disorders.

[0008] In embodiments, disclosed herein are bifunctional compounds having the structure of formula (Ia): [ka] or a pharma- ceutically acceptable salt, solvate, enantiomer, stereoisomer, or isotopic derivative thereof, where PTM is a protein / polypeptide targeting moiety, LNK is a linker, e.g., a bond (absent) or a chemical group that couples the PTM to the ULM, and ULM is an E3 ubiquitin ligase binding moiety. The PTM binds to a target protein or polypeptide to be ubiquitinated by a ubiquitin ligase and is chemically linked to the ULM group, either directly or via the linker moiety LNK.

[0009] In embodiments, disclosed herein are bifunctional compounds having the structure of formula (Ia): [ka] or a pharma- ceutically acceptable salt thereof, where PTM is a protein / polypeptide targeting moiety, LNK is a linker, e.g., a bond (absent) or a chemical group that couples the PTM to ULM, and ULM is an E3 ubiquitin ligase binding moiety. The PTM binds to a target protein or polypeptide to be ubiquitinated by a ubiquitin ligase and is chemically linked to the ULM group, either directly or via the linker moiety LNK.

[0010] In embodiments, disclosed herein are bifunctional compounds having the structure of formula (I): [ka] or a pharma- ceutically acceptable salt, solvate, enantiomer, stereoisomer, or isotopic derivative thereof; During the ceremony, KTM is a KRAS targeting moiety and LNK is a linker (e.g., a bond or chemical linker group) that covalently couples the PTM to a von Hippel-Lindau (VHL) E3 ubiquitin ligase binding moiety or VLM.

[0011] In embodiments, disclosed herein are bifunctional compounds having the structure of formula (I): [ka] or a pharma- ceutically acceptable salt thereof; During the ceremony, KTM is a KRAS targeting moiety and LNK is a linker (e.g., a bond or chemical linker group) that covalently couples the PTM to a von Hippel-Lindau (VHL) E3 ubiquitin ligase binding moiety or VLM.

[0012] In embodiments, disclosed herein are bifunctional compounds having the structure of formula (I): [ka] or a pharma- ceutically acceptable salt, solvate, enantiomer, stereoisomer, or isotopic derivative thereof; During the ceremony, (a) KTM has the structure of formula KTM-I: [ka] wherein X K1 is N or CR K5 and X K2 is N or CR K6 and X K3 is N or CR K7 and X K4 is NR K8 Or C 1 -C 3 alkylene, where the alkylene is one or more R K9 Optionally replaced by R K1 and R K2 are H, OH, Cl, F, Br, I, and C. 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, OC 1 -C 6 Alkyl, and O-(C 1 -C 6 haloalkyl), R K3 and R K4 are H, OH, Cl, F, Br, I, and C. 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocycle, O-(C 1 -C 6 alkyl), and O-(C 1 -C 6 haloalkyl); R K3 and R K4together with the carbon to which they are attached, C 6 -C 10 aryl or 5-6 membered heteroaryl, where the aryl or heteroaryl is selected from 1, 2, 3, 4, or 5 R K11 Optionally replaced by R K5 , R K6 , and R K7 are H, Cl, F, Br, I, and NR K12 R K13 , C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl, [ka] represents the connection point between KTM and LNK, R K8 and R K9 , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl, Each R K11 are H, OH, CN, Cl, F, Br, I, and NR K12 R K13 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, and C 1 -C 6 haloalkyl; R K12 and R K13 , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl, R K14 and R K15 , H, C 1 -C 6 Alkyl, and C 1-C 6 haloalkyl; R K14 and R K15 X K4 and together with the carbon to which they are attached, C 4 -C 7 forming a cycloalkyl or a 4- to 7-membered heterocycle, (b) LNK is a chemical linking moiety that covalently couples the KTM to the VLM and has the structure LI: [ka] wherein Each L is [ka] C 2 -C 6 Alkylene, C 2 -C 6 Alkenylene, C 2 -C 6 Alkynylene, monocyclic C 4 -C 10 Cycloalkylene, fused bicyclic C 4 -C 10 Cycloalkylene, Bridged Bicyclic C 6 -C 10 Cycloalkylene or spiro-fused bicyclic C 5 -C 12 Cycloalkylene, monocyclic 4-10 membered heterocycloalkylene, fused bicyclic 4-10 membered heterocycloalkylene, bridged bicyclic 6-10 membered heterocycloalkylene, spiro-fused 5-12 membered heterocycloalkylene, C 6 -C 10 arylene, and 5- to 6-membered heteroarylene, where each cycloalkylene, heterocycloalkylene, arylene, and heteroarylene is independently selected from 1, 2, 3, 4, or 5 R L5 Optionally replaced by Each A L CR L1 R L2 , N.R. L3 and O are independently selected from Each R L1 and R L2 , H, C 1 -C 6 Alkyl, O-(C 1 -C 6 alkyl), and C 1 -C 6 haloalkyl, where alkyl is Cl, F, OH, NH 2 , CN, or CF 3 Optionally replaced by Each R L3 , H, C 1 -C 6 Alkyl, O-(C 1 -C 6 alkyl), and C 1 -C 6 haloalkyl, where alkyl is Cl, F, OH, NH 2 , CN, or CF 3 Optionally replaced by Each R L4 is C 1 -C 6 Alkyl, O-(C 1 -C 6 Alkyl), C 1 -C 6 Haloalkyl, NH, CN, CF 3 , Cl, F, Br, I, and OH, where alkyl is Cl, F, OH, NH 2 , CN, or CF 3 Optionally replaced by Each R L5 are Cl, F, Br, I, and C. 1 -C 6 Alkyl, O-(C 1 -C 6 Alkyl), C 1 -C 6 Haloalkyl, NH 2 , C.N., C.F. 3 and OH, where alkyl is selected from Cl, F, OH, NH 2 , CN, or CF 3 Optionally replaced by n Lis an integer between 1 and 50, (c) VLM has the structure VLM-I: [ka] wherein Y V1 teeth, [ka] and Y V2 CN or [ka] and [ka] is phenylene or 5- to 6-membered heteroarylene, [ka] is a 5-membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, S, and O; R V1 , R V2 , and R V3 , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl; R V1 and R V2 together with the carbon to which they are attached, C 3 -C 10 Form a cycloalkyl or 5- to 6-membered heterocycle, R V3 , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl; R V4a and R V4b , H, C 1 -C 6 Alkyl, and C 1 -C6 haloalkyl, Each R V5 and R V6 H and C 1 -C 6 independently selected from alkyl, R V7 and R V8 , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl; R V7 and R V8 together with the atoms to which they are attached, C 3 -C 10 Forming a cycloalkyl or 5- to 6-membered heterocycle, [ka] represents the attachment point between the VLM and the LNK, n V is 0, 1, 2, 3, or 4, o V is 0, 1, 2, or 3.

[0013] In another aspect, the present application provides a bifunctional compound having the structure of formula (IA): [ka] or a pharma- ceutically acceptable salt, solvate, enantiomer, stereoisomer, or isotopic derivative thereof, During the ceremony, (a) KTM has the structure of formula KTM-IA: [ka] wherein X K1 is N or CR K5 and X K2 is N or CR K6 and X K3is N or CR K7 and X K4 is NR K8 Or C 1 -C 3 alkylene, where the alkylene is one or more R K9 Optionally replaced by R K1 and R K2 are H, OH, Cl, F, Br, I, and C. 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, OC 1 -C 6 Alkyl, and O-(C 1 -C 6 haloalkyl), R K3 and R K4 are H, OH, Cl, F, Br, I, and C. 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocycle, O-(C 1 -C 6 alkyl), and O-(C 1 -C 6 haloalkyl); R K3 and R K4 together with the carbon to which they are attached, C 6 -C 10 aryl or 5-6 membered heteroaryl, where the aryl or heteroaryl is selected from 1, 2, 3, 4, or 5 R K11 Optionally replaced by R K5 , R K6 , and R K7 are H, Cl, F, Br, I, and NR K12 R K13 , C 1 -C 6 Alkyl, and C 1 -C 6haloalkyl, [ka] represents the connection point between KTM and LNK, R K8 and R K9 , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl, Each R K11 are H, OH, CN, Cl, F, Br, I, and NR K12 R K13 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, and C 1 -C 6 haloalkyl; R K12 and R K13 , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl, R K14 and R K15 , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl; R K14 and R K15 X K4 and together with the carbon to which they are attached, C 4 -C 7 forming a cycloalkyl or a 4- to 7-membered heterocycle, (b) LNK is a chemical linking moiety that covalently couples the KTM to the VLM and has the structure L-IA: [ka] wherein Each L is [ka] C 2 -C 6 Alkylene, C 2 -C 6 Alkenylene, C 2 -C 6 Alkynylene, monocyclic C 4 -C 10 Cycloalkylene, fused bicyclic C 4 -C 10 Cycloalkylene, Bridged Bicyclic C 6 -C 10 Cycloalkylene or spiro-fused bicyclic C 5 -C 12 Cycloalkylene, monocyclic 4-10 membered heterocycloalkylene, fused bicyclic 4-10 membered heterocycloalkylene, bridged bicyclic 6-10 membered heterocycloalkylene, spiro-fused 5-12 membered heterocycloalkylene, C 6 -C 10 arylene, and 5- to 6-membered heteroarylene, where each cycloalkylene, heterocycloalkylene, arylene, and heteroarylene is independently selected from 1, 2, 3, 4, or 5 R L5 Optionally replaced by Each A L CR L1 R L2 , N.R. L3 and O are independently selected from Each R L1 and R L2 , H, C 1 -C 6 Alkyl, O-(C 1 -C 6 alkyl), and C 1 -C 6 haloalkyl, where alkyl is Cl, F, OH, NH 2 , CN, or CF 3 Optionally replaced by Each R L3 , H, C 1 -C 6Alkyl, O-(C 1 -C 6 alkyl), and C 1 -C 6 haloalkyl, where alkyl is Cl, F, OH, NH 2 , CN, or CF 3 Optionally replaced by Each R L4 is C 1 -C 6 Alkyl, O-(C 1 -C 6 Alkyl), C 1 -C 6 Haloalkyl, NH, CN, CF 3 , Cl, F, Br, I, and OH, where alkyl is Cl, F, OH, NH 2 , CN, or CF 3 Optionally replaced by Each R L5 are Cl, F, Br, I, and C. 1 -C 6 Alkyl, O-(C 1 -C 6 Alkyl), C 1 -C 6 Haloalkyl, NH 2 , C.N., C.F. 3 and OH, where alkyl is selected from Cl, F, OH, NH 2 , CN, or CF 3 Optionally replaced by n L is an integer between 1 and 50, (c) VLM has the structure VLM-IA: [ka] wherein Y V1 teeth, [ka] and Y V2 CN or [ka] and [ka] is phenylene or 5- to 6-membered heteroarylene, [ka] is a 5-membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, S, and O; R V1 , R V2 , and R V3 , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl; R V1 and R V2 together with the carbon to which they are attached, C 3 -C 10 Form a cycloalkyl or 5- to 6-membered heterocycle, R V3 , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl; R V4a and R V4b , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl, Each R V5 and R V6 H, halo, and C 1 -C 6 independently selected from alkyl, R V7 and R V8 , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl; R V7and R V8 together with the atoms to which they are attached, C 3 -C 10 Forming a cycloalkyl or 5- to 6-membered heterocycle, [ka] represents the attachment point between the VLM and the LNK, n V is 0, 1, 2, 3, or 4, o V is 0, 1, 2, or 3.

[0014] In an embodiment, the compound of formula IA has the structure according to formula II: [ka] or a pharma- ceutically acceptable salt thereof, where the variables are defined herein.

[0015] In an embodiment, the compound of formula IA has the structure according to formula IIa: [ka] or a pharma- ceutically acceptable salt thereof, where the variables are defined herein.

[0016] In an embodiment, the compound of formula IA has the structure according to formula IIb: [ka] or a pharma- ceutically acceptable salt thereof, where the variables are defined herein.

[0017] In an embodiment, the compound of formula IA has the structure according to formula IIc: [ka] or a pharma- ceutically acceptable salt thereof, where the variables are defined herein.

[0018] In an embodiment of Formula IIa, the compound has a structure according to one of Formulas IIa-i to IIa-v: [ka] [ka] or a pharma- ceutically acceptable salt thereof, where the variables are defined herein.

[0019] In an embodiment of Formula IIb, the compound has a structure according to one of Formulas IIb-i to IIb-vi: [ka] [ka] or a pharma- ceutically acceptable salt thereof, where the variables are defined herein.

[0020] In an embodiment of Formula IIc, the compound has the structure according to Formula IIc-i: [ka] or a pharma- ceutically acceptable salt thereof, where the variables are defined herein.

[0021] In another aspect, the present disclosure provides a pharmaceutical composition comprising a bifunctional compound of the present disclosure, or a pharma- ceutically acceptable salt, solvate, enantiomer, stereoisomer, or isotopic derivative thereof, and one or more pharma- ceutically acceptable excipients.

[0022] In another aspect, the disclosure provides a method of treating a disease or disorder in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound of the disclosure or a pharma- ceutically acceptable salt, solvate, enantiomer, stereoisomer, or isotopic derivative thereof, or a therapeutically effective amount of a pharmaceutical composition of the disclosure. [Brief description of the drawings]

[0023] [Figure 1] A and B. Illustrative general principles of PROTAC function. (A) An exemplary PROTAC includes a protein targeting moiety (PTM; dark shaded rectangle), a ubiquitin ligase binding moiety (ULM; light shaded triangle), and optionally a linker moiety (L; black line) that couples or engages the PTM to the ULM. (B) Illustrates the functional use of PROTACs described herein. Briefly, ULM recognizes and binds a specific E3 ubiquitin ligase, and the PTM binds to the target protein and recruits it into close proximity to the E3 ubiquitin ligase. Typically, the E3 ubiquitin ligase complexes with an E2 ubiquitin-binding protein and catalyzes the attachment of multiple ubiquitins (black circles) via isopeptide bonds to lysines on the target protein, either alone or through the E2 protein. The polyubiquitinated protein (far right) is then targeted for degradation by the cellular proteosome machinery. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] In this specification, the singular form includes the plural form unless the context clearly dictates. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. In case of conflict, the present specification shall prevail. Percentages and ratios used herein are by weight unless otherwise specified.

[0025] Throughout this description, when a composition is described as having, including, or comprising particular components, it is also contemplated that the composition consists essentially of, or consists of, the recited components.

[0026] Specific compounds of the invention are identified herein by chemical name and / or chemical structure. In the event of any discrepancy between the chemical name and the chemical structure, the chemical structure shall control.

[0027] The term "alkyl" as used herein, in certain embodiments, refers to a straight or branched saturated hydrocarbon radical containing 1 to 20, e.g., 1 to 10, or 1 to 6 carbon atoms. Branched refers to one or more lower C alkyl groups, such as methyl, ethyl, or propyl. 1 -C 6 It means that the alkyl group is attached to a linear alkyl chain. Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, and 3-pentyl. 1 -C 6 Examples of alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, neopentyl, and n-hexyl radicals; 1 -C 8 Examples of alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, and octyl radicals. 1 -C 20 Examples of alkyl radicals include, but are not limited to, hexadecamethyl, hexadecaethyl, hexadecopropyl, octadecamethyl, octadecaethyl, octadecapropyl, and the like. An alkyl group may be optionally substituted at any point of attachment with one or more substituents, e.g., 1 to 5 substituents. Exemplary substituents include -H, -halogen, -O-(C 1 -C 6 ) alkyl, (C 1 -C 6) alkyl, -O-(C 2 -C 6 ) alkenyl, -O-(C 2 -C 6 ) alkynyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) Alkynyl, -OH, -OP(O)(OH) 2 , -OC(O)(C 1 -C 6 ) alkyl, -C(O)(C 1 -C 6 ) alkyl, -OC(O)O(C 1 -C 6 ) Alkyl, -NH 2 , NH((C 1 -C 6 ) alkyl), N((C 1 -C 6 )Alkyl) 2 , -S(O) 2 -(C 1 -C 6 ) alkyl, -S(O)NH(C 1 -C 6 ) alkyl, and -S(O)N((C 1 -C 6 )Alkyl) 2 These substituents include, but are not limited to, these may themselves be optionally substituted.

[0028] The addition of the suffix "ene" indicates that the group is a divalent moiety, e.g., alkylene (e.g., methylene (-CH 2 -), ethylene (-CH 2 CH 2-)) is a divalent moiety of an alkyl, alkenylene is a divalent moiety of an alkenyl, alkynylene is a divalent moiety of an alkynyl, heteroalkylene is a divalent moiety of a heteroalkyl, cycloalkylene is a divalent moiety of a cycloalkyl, heterocycloalkylene is a divalent moiety of a heterocycloalkyl, arylene is a divalent moiety of an aryl, and heteroarylene is a divalent moiety of a heteroaryl. Similarly, phenylene, oxazolylene, isoxazolylene, thiazolylene, and isothiazolylene are the divalent moieties of phenyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl, respectively.

[0029] The term "alkenyl," as used herein, in certain embodiments, refers to a monovalent straight or branched group derived from a hydrocarbon moiety containing 2 to 6, 2 to 8, or 2 to 20 carbon atoms having at least one carbon-carbon double bond. The double bond may or may not be the point of attachment to another group. 2 -C 8 Examples of alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl. As defined herein, "alkenyl" groups include both cis and trans isomers. Alkenyl groups may be optionally substituted at any point of attachment with one or more substituents, for example, 1 to 5 substituents. Exemplary substituents include -H, -halogen, -O-(C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkyl, -O-(C 2 -C 6 ) alkenyl, -O-(C 2 -C 6 ) alkynyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) Alkynyl, -OH, -OP(O)(OH) 2 , -OC(O)(C 1 -C 6) alkyl, -C(O)(C 1 -C 6 ) alkyl, -OC(O)O(C 1 -C 6 ) Alkyl, -NH 2 , NH((C 1 -C 6 ) alkyl), N((C 1 -C 6 )Alkyl) 2 , -S(O) 2 -(C 1 -C 6 ) alkyl, -S(O)NH(C 1 -C 6 ) alkyl, and -S(O)N((C 1 -C 6 )Alkyl) 2 These substituents include, but are not limited to, these may themselves be optionally substituted.

[0030] The term "alkynyl," as used herein, in certain embodiments, refers to a monovalent straight or branched chain group derived from a hydrocarbon moiety containing 2 to 6, 2 to 8, or 2 to 20 carbon atoms having at least one carbon-carbon triple bond. The triple bond may or may not be the point of attachment to another group. 2 -C 8 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, and the like. Alkynyl groups may be optionally substituted at any point of attachment with one or more substituents, e.g., 1 to 5 substituents. Exemplary substituents include -H, -halogen, -O-(C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkyl, -O-(C 2 -C 6 ) alkenyl, -O-(C 2 -C 6 ) alkynyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) Alkynyl, -OH, -OP(O)(OH)2 , -OC(O)(C 1 -C 6 ) alkyl, -C(O)(C 1 -C 6 ) alkyl, -OC(O)O(C 1 -C 6 ) Alkyl, -NH 2 , NH((C 1 -C 6 ) alkyl), N((C 1 -C 6 )Alkyl) 2 , -S(O) 2 -(C 1 -C 6 ) alkyl, -S(O)NH(C 1 -C 6 ) alkyl, and -S(O)N((C 1 -C 6 )Alkyl) 2 These substituents include, but are not limited to, these may themselves be optionally substituted.

[0031] The term "aromatic" or "aryl" as used herein refers to a closed ring structure having at least one ring with a conjugated π-electron system, and includes both carbocyclic and heterocyclic aryl groups (or "heteroaryl" or "heteroaromatic groups"). Unless expressly defined otherwise, the term "aryl" refers to a cyclic aromatic hydrocarbon group having one to three aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. When containing two aromatic rings (such as bicyclic), the aromatic rings of the aryl group may be joined at one point (e.g., biphenyl) or fused (e.g., naphthyl). The aryl group may be optionally substituted at any point of attachment with one or more substituents, e.g., 1 to 5 substituents. Exemplary substituents include -H, -halogen, -O-(C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkyl, -O-(C 2 -C 6 ) alkenyl, -O-(C 2 -C 6) alkynyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) Alkynyl, -OH, -OP(O)(OH) 2 , -OC(O)(C 1 -C 6 ) alkyl, -C(O)(C 1 -C 6 ) alkyl, -OC(O)O(C 1 -C 6 ) Alkyl, -NH 2 , NH((C 1 -C 6 ) alkyl), N((C 1 -C 6 )Alkyl) 2 , -S(O) 2 -(C 1 -C 6 ) alkyl, -S(O)NH(C 1 -C 6 ) alkyl, and -S(O)N((C 1 -C 6 )Alkyl) 2 These substituents may themselves be optionally substituted. Furthermore, aryl groups as defined herein, when they contain two fused rings, may have an unsaturated or partially saturated ring fused to a fully saturated ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like.

[0032] "C 6 -C 10 The term "aryl" as used herein refers to a cyclic aromatic hydrocarbon group, phenyl or naphthyl, wherein the C 6 -C 10 Aryl groups may be optionally substituted at any point of attachment with one or more substituents, e.g., 1 to 5 (in the case of phenyl) or 1 to 7 (in the case of naphthyl) substituents. Exemplary substituents include -H, -halogen, -O-(C1 -C 6 ) alkyl, (C 1 -C 6 ) alkyl, -O-(C 2 -C 6 ) alkenyl, -O-(C 2 -C 6 ) alkynyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) Alkynyl, -OH, -OP(O)(OH) 2 , -OC(O)(C 1 -C 6 ) alkyl, -C(O)(C 1 -C 6 ) alkyl, -OC(O)O(C 1 -C 6 ) Alkyl, -NH 2 , NH((C 1 -C 6 ) alkyl), N((C 1 -C 6 )Alkyl) 2 , -S(O) 2 -(C 1 -C 6 ) alkyl, -S(O)NH(C 1 -C 6 ) alkyl, and -S(O)N((C 1 -C 6 )Alkyl) 2 These substituents may themselves be optionally substituted. Additionally, an aryl group as defined herein, when it contains two fused rings, may have a fully saturated ring fused with an unsaturated or partially saturated ring. Exemplary C 6 -C 10 Aryl groups include, but are not limited to, phenyl, naphthyl, and tetrahydronaphthalenyl.

[0033] One or more rings may be designated as "aromatic" by a solid circle within the ring(s). This indicates that the bonds and hydrogen atoms of the atoms within the ring are arranged such that the designated ring(s) is aromatic. For example, naphthalene, a bicyclic aromatic ring, may be represented interchangeably as follows: [ka]

[0034] A ring may also be designated as "non-aromatic," meaning that one of the requirements for aromaticity is not met. For example, a non-aromatic ring may contain one or more saturated carbons or may not be capable of forming a conjugated pi-electron system.

[0035] Binders include, but are not limited to, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), povidone, copovidone (copolymers of vinylpyrrolidone and other vinyl derivatives), methylcellulose, powdered acacia, gelatin, gum arabic, guar gum, carbomers such as Carbopol, and polymethacrylates.

[0036] Carriers include pharma- ceutically acceptable excipients and diluents. The term "carrier" refers to a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting a drug from one organ or body part of a subject to another organ or body part. Examples include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

[0037] The term "cycloalkyl," as used herein, refers to a univalent group derived from a monocyclic or polycyclic saturated carbocyclic ring compound. 3 -C 8Examples of -cycloalkyl (3-8 membered cycloalkyl) include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl and cyclooctyl; 3 -C 12 Examples of -cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, and the like.

[0038] Any variable part (e.g., R K1 , R K2 When R, R(s), etc. occur more than once in any constituent or in formula (I) or other general formulas herein, its definition on each occurrence is not relative to its definition at every other occurrence. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. In selecting compounds of the present invention, those skilled in the art will recognize that various substituents, i.e., R K1 , R K2 It will be recognized that the radicals, etc., should be selected according to well-known principles of connectivity and stability of chemical structures. Unless expressly stated to the contrary, substitution on any atom within a ring (e.g., aryl, heteroaryl, cycloalkyl, heterocycloalkyl, etc.) with a named substituent is permitted if such ring substitution is chemically permissible and results in a stable compound. Similarly, unless expressly stated to the contrary, when ring or chain sizes are expressed as ranges (e.g., C 1 -C 6 Alkyl, C 6- C 10 The alkyl groups, such as aryl, spiro-fused 5-12 membered heterocycloalkyl, chains or rings thereof may be selected from any size within that range, provided such size is chemically permissible and results in a stable compound. A "stable" compound is one which can be prepared and isolated, and which will remain, or can be made to remain, essentially unchanged in structure and properties for a sufficient period of time to permit use of the compound for the purposes described herein (e.g., therapeutic or prophylactic administration to a subject).

[0039] Diluents include, but are not limited to, carbohydrates, e.g., monosaccharides such as glucose, oligosaccharides such as sucrose and lactose (including anhydrous lactose and lactose monohydrate), starches such as corn starch, potato starch, rice starch and wheat starch, pregelatinized starch, calcium hydrogen phosphate, and sugar alcohols such as sorbitol, mannitol, erythritol, and xylitol.

[0040] Disintegrants include, but are not limited to, sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, chitosan, agar, alginic acid, calcium alginate, methylcellulose, microcrystalline cellulose, powdered cellulose, lower alkyl substituted hydroxypropylcellulose, hydroxylpropyl starch, lower substituted hydroxypropylcellulose, polacrilin potassium, starch, pregelatinized starch, sodium alginate, magnesium aluminum silicate, polacrilin potassium, povidone, sodium starch glycolate, mixtures thereof, and the like.

[0041] The term "therapeutically effective amount" as used herein refers to an amount of an agent effective to treat, ameliorate or prevent a particular disease, condition or symptom, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay or other detection method known in the art. As used herein, "therapeutically effective amount" can refer to the amount necessary to produce a clinically observed improvement in a patient. In some embodiments, the composition is formulated to contain an amount that does not produce one or more undesirable side effects. A therapeutically effective amount of an agent can also refer to an amount that produces an objectively identifiable improvement as recognized by a clinician or other qualified observer. The precise therapeutically effective amount for a given subject will depend on the subject's age, sex, weight, size, and health; the nature and extent of the condition; and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation and is within the ability and judgment of the clinician.

[0042] Bulking agents include, but are not limited to, fast dissolving carbohydrates such as mannitol, sucrose, sorbitol, xylitol, microcrystalline cellulose, lactose, silicic acid, silicified microcrystalline cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, starch, pullulan, and Pharmaburst™ fast disintegrating tablets, mixtures thereof, etc. For examples of fast dissolving carbohydrates, see, e.g., U.S. Patent No. 8,617,588, which is incorporated herein by reference.

[0043] Flavoring agents include, but are not limited to, menthol, peppermint oil, peppermint spirits, vanillin, and almond oil.

[0044] Glidants include, but are not limited to, silicon dioxide, colloidal silicon dioxide, calcium silicate, magnesium silicate, magnesium trisilicate, talc, starch, mixtures thereof, and the like.

[0045] The terms "haloalkyl," "haloalkenyl," or "haloalkynyl," as used herein, refer to an alkyl, alkenyl, or alkynyl, including straight or branched chains, substituted with one or more halogen or halo groups. Examples of haloalkyls include CF 3 , C.H. 2 CF 3 , and CCl 3 These include, but are not limited to:

[0046] The terms "hal," "halo," or "halogen," as used herein, refer to an atom selected from fluorine, chlorine, bromine, and iodine.

[0047] The term "heteroaryl" as used herein refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic or higher), fused or unfused radical or ring system having at least one aromatic ring having 5-12 ring atoms, at least one ring atom of which is selected from S, O, P, and N. In other words, a heteroaryl is an aryl containing at least one heteroatom. Examples of heteroaryls include, but are not limited to, pyridinyl, furanyl, thiazolyl, imidazolyl, indolyl, benzofuranyl, and the like. A heteroaryl group may be optionally substituted at any point of attachment with one or more substituents, e.g., 1-5 substituents. Exemplary substituents include -H, -halogen, -O-(C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkyl, -O-(C 2 -C 6 ) alkenyl, -O-(C 2 -C 6 ) alkynyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) Alkynyl, -OH, -OP(O)(OH) 2 , -OC(O)(C 1 -C 6 ) alkyl, -C(O)(C 1-C 6 ) alkyl, -OC(O)O(C 1 -C 6 ) Alkyl, -NH 2 , NH((C 1 -C 6 ) alkyl), N((C 1 -C 6 )Alkyl) 2 , -S(O) 2 -(C 1 -C 6 ) alkyl, -S(O)NH(C 1 -C 6 ) alkyl, and -S(O)N((C 1 -C 6 )Alkyl) 2 These substituents include, but are not limited to, these may themselves be optionally substituted.

[0048] The term "5- or 6-membered heteroaryl" is intended to mean a ring having 5 or 6 ring atoms, at least one of which is selected from S, O, P, and N. Heteroaryl includes pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, quinoxalinyl, and the like.

[0049] "Heterocyclyl" or "heterocycloalkyl" as used herein refers to a ring system containing carbon and at least one heteroatom selected from N, O, S, and P, which lacks delocalized π-electrons (aromaticity) shared between the ring carbons or heteroatoms, i.e., a non-aromatic cyclic ring system. The heterocycloalkyl ring structure may be substituted by one or more substituents. These substituents may themselves be optionally substituted. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, and homotropanyl. Heterocyclyl groups may be optionally substituted at any point of attachment with one or more substituents, e.g., 1 to 5 substituents. Exemplary substituents include -H, -halogen, -O-(C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkyl, -O-(C 2 -C 6 ) alkenyl, -O-(C 2 -C 6 ) alkynyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) Alkynyl, -OH, -OP(O)(OH) 2 , -OC(O)(C 1 -C 6 ) alkyl, -C(O)(C 1 -C 6 ) alkyl, -OC(O)O(C 1 -C 6 ) Alkyl, -NH 2 , NH((C 1 -C 6 ) alkyl), N((C 1 -C6 )Alkyl) 2 , -S(O) 2 -(C 1 -C 6 ) alkyl, -S(O)NH(C 1 -C 6 ) alkyl, and -S(O)N((C 1 -C 6 )Alkyl) 2 These substituents include, but are not limited to, these may themselves be optionally substituted.

[0050] The term "independently selected" is used herein to indicate that for variables that are present in multiple locations within a genus, the properties of the variables are determined individually in each instance. For example, R x appears as a substituent on two different atoms, two R x may be the same or different moieties. A single atom may have multiple R x The same applies when replaced by R x The property is determined independently of the other property(ies).

[0051] "Isomers" means any compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the spatial arrangement of their atoms are termed "stereoisomers". Stereoisomers that are not mirror images of one another are termed "diastereomers" and stereoisomers that are non-superimposable mirror images of one another are termed "enantiomers" or sometimes "optical isomers". A carbon atom bonded to four non-identical substituents is termed a "chiral center". A compound with one chiral center has two enantiomeric forms with opposite chirality. A mixture of the two enantiomeric forms is termed a "racemic mixture". A compound with multiple chiral centers has 2n-1 enantiomeric pairs, where n is the number of chiral centers. A compound with multiple chiral centers can exist as either individual diastereomers or as a mixture of diastereomers, termed a "diastereomeric mixture". When one chiral center is present, a stereoisomer can be characterized by the absolute configuration of the chiral center. Absolute configuration refers to the spatial arrangement of the substituents attached to the chiral center. Enantiomers are characterized by the absolute configuration of the chiral center and are described by the R-sequencing and S-sequencing rules of Cahn, Ingold and Prelog. Conventions for stereochemical nomenclature, methods for determining stereochemistry and methods for separating stereoisomers are well known in the art (see, for example, "Advanced Organic Chemistry", 4th edition, March, Jerry, John Wiley & Sons, New York, 1992). Compounds of formula (I) may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. Unless otherwise indicated, all stereoisomeric forms of compounds of formula (I) and mixtures thereof, including racemic mixtures, are intended to form part of the present invention. In addition, the present invention encompasses and is within the scope of the present invention all geometric and positional isomers (including cis and trans forms) and mixtures thereof. In general, reference to a compound is intended to encompass all stereoisomers and mixtures of various stereoisomers thereof.

[0052] The present disclosure is intended to include all isotopes of atoms present in the compounds. Isotopes include atoms with the same atomic number but different mass numbers. In particular, one, some, or all hydrogens may be deuterium. Radioisotopes may be used, for example, for structural analysis or to facilitate tracking the fate of a compound or its metabolites after administration. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium, and isotopes of carbon include: 13 C and 14 Contains C.

[0053] The term "isotopic derivative" includes derivatives of a compound in which one or more atoms in the compound are replaced with the corresponding isotope of that atom. For example, a carbon atom (C 12 ) is an isotopic derivative of a compound containing C 13 It has been replaced by an isotope (or isotopes).

[0054] The term "KRAS" refers to a polypeptide sequence (e.g., SEQ ID NO:1 and / or SEQ ID NO:2) that forms a KRAS protein, peptide, or polypeptide. In some embodiments, the term "KRAS" is meant to include not only wild-type KRAS, but also nucleic acid sequences that code for KRAS protein isoforms, mutant KRAS genes, splice variants of the KRAS gene, and KRAS gene polymorphisms. The term "KRAS" is used to refer to a polypeptide gene product of a KRAS gene / transcript, e.g., a KRAS protein, peptide, or polypeptide. The KRAS gene may undergo alternative splicing, resulting in two isoforms: KRAS4A (also known as KRAS2A) and KRAS4B (also known as KRAS2B). As used herein, the term "KRAS" is meant to include both isoforms.

[0055] As used herein, "KRAS G12D" refers to a mutant of a mammalian KRAS protein containing an amino acid substitution of glycine to aspartic acid at amino acid position 12. As used herein, "KRAS G12V" refers to a mutant of a mammalian KRAS protein containing an amino acid substitution of glycine to valine at amino acid position 12.

[0056] Lubricants include, but are not limited to, calcium stearate, glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, hexagonal boron nitride, hydrogenated vegetable oils, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, poloxamer, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate, mixtures thereof, and the like.

[0057] As used herein, "oral dosage form" refers to a pharmaceutical product that contains a specific amount (dose) of a compound of the present disclosure or a pharma- ceutically acceptable salt and / or solvate thereof as an active ingredient and inactive ingredients (excipients) and is formulated into a specific external form suitable for oral administration, such as an oral tablet, liquid, or capsule. In some embodiments, the oral dosage form comprises a tablet. In some embodiments, the oral dosage form comprises a tablet that can be scored. In some embodiments, the oral dosage form comprises a sublingual tablet. In some embodiments, the oral tablet comprises a capsule, which can be taken as is or sprinkled on food (e.g., applesauce or yogurt). In some embodiments, the oral tablet comprises a sachet.

[0058] As used herein, formulations of the present invention providing for "oral administration" refer to enteral, buccal, sublabial, or sublingual medications in the form of tablets, capsules, syrups, powders, granules, lozenges, liquids, tinctures, elixirs, emulsions, hydrogels, teas, films, disintegrating tablets, mouthwashes, and the like.

[0059] Forms suitable for oral administration may contain one or more pharma- ceutically acceptable excipients, such as carriers, fillers, surfactants, diluents, buffers, sweeteners, disintegrants, binders, lubricants, glidants, colorants, flavorings, stabilizers, coatings, or any mixtures thereof.

[0060] A "pharmaceutical composition" is a formulation that contains one or more therapeutic agents (e.g., one or more compounds of the present disclosure) in a form suitable for administration to a subject. In some embodiments, the pharmaceutical composition is in bulk form, for example, for storage. Alternatively, the pharmaceutical composition is in unit dosage form. For ease of administration and uniformity of dosage, it may be advantageous to formulate the composition in unit dosage form. Unit dosage form as used herein refers to a physically discrete unit suitable for unitary administration to a subject to be treated, each unit containing a predetermined amount of active agent calculated to produce a desired therapeutic effect together with the required pharmaceutical carrier. The specifications of the unit dosage form of the present invention are determined by and directly depend on the unique characteristics of the active agent and the particular therapeutic effect to be achieved as well as the limitations in the art of compounding such active agent for the treatment of an individual.

[0061] The compounds of the present disclosure may be administered in the form of a pharmaceutical composition containing one or more pharma- ceutically acceptable excipients.The formulations may be adapted for administration by any of a variety of routes, including parenteral, buccal, rectal, vaginal, oral, intranasal, intraocular, transdermal, subcutaneous, intravenous, or intramuscular.

[0062] The terms "treat," "treated," "treating," or "treatment" include the alleviation or alleviation of at least one symptom associated with or resulting from the condition, disorder, or disease being treated. In certain embodiments, treatment includes alleviating or preventing a symptom of cancer.

[0063] The terms "pharmaceutical" or "pharmaceutical acceptable" when used as an adjective mean substantially non-toxic and not substantially harmful to the recipient. As used herein, the phrase "pharmaceutical acceptable" refers to those compounds, materials, compositions, carriers, and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals, within the scope of sound medical judgment, without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0064] "Pharmaceutically acceptable carrier or excipient" generally means a carrier or excipient that is useful in preparing a pharmaceutical composition that is safe, non-toxic, and not biologically or otherwise undesirable, and includes any excipient that is acceptable for veterinary and / or human pharmaceutical use. As used herein, "pharmaceutically acceptable excipient" includes both one and more than one such excipient.

[0065] As used herein, "pharmaceutically acceptable salts" may refer to derivatives of the disclosed compounds, in which the parent compound is modified to form its acid or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example, formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycolialsanilic acid, hexylresorcylic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, lauric acid, glyceric acid, glyceryl stearate ... These include, but are not limited to, salts derived from inorganic and organic acids selected from: arylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, subacetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid, and commonly occurring amino acids such as glycine, alanine, phenylalanine, arginine, and the like.

[0066] Other examples of pharma- ceutically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The disclosure also encompasses salts formed when acidic protons present in the parent compound are replaced by metal ions, e.g., alkali metal ions, or alkaline earth metal ions, e.g., aluminum ions, or coordinate with organic bases, such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, diethylamine, diethylaminoethanol, ethylenediamine, imidazole, lysine, arginine, morpholine, 2-hydroxyethylmorpholine, dibenzylethylenediamine, trimethylamine, piperidinyl, pyrrolidine, benzylamine, tetramethylammonium hydroxide, and the like.

[0067] It should be understood that all references to pharma- ceutically acceptable salts include the solvent addition forms (solvates) or crystal forms (polymorphs) of the same salt, as defined herein.

[0068] Furthermore, the compounds of the present disclosure, for example, salts of the compounds, can exist in either hydrated or non-hydrated (anhydrous) form, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0069] Some of the compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, such as, for example, hydrated forms.

[0070] "Solvate" refers to a solvent addition form containing either stoichiometric or non-stoichiometric amounts of a solvent. Some compounds have a tendency to form solvates by trapping a fixed molar ratio of solvent molecules in a crystalline solid. When the solvent is water, the solvate formed is a hydrate, and when the solvent is alcohol, the solvate formed is an alcohol compound. A hydrate is a compound in which one or more water molecules are combined with the water to form a H 2 The hydrate is formed by combination with one of the substances that maintains the molecular state as O, and such combination can form one or more hydrates. In a hydrate, the water molecules are bonded through subvalence by intermolecular forces, in particular hydrogen bridges. Solid hydrates contain water as so-called water of crystallization in stoichiometric ratio, in which case the water molecules do not have to be equivalent in terms of their bonding state. Examples of hydrates are sesquihydrates, monohydrates, dihydrates or trihydrates. Hydrates of salts of the compounds of the present disclosure are also suitable.

[0071] "Spirocycloalkyl" or "spirocyclyl" refers to a carbobicyclic ring system in which two rings are linked through a single atom. The rings may be different in size and nature or may be identical in size and nature. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, or spirodecane. One or both of the rings in the spiro ring may be fused to another carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. One or more of the carbon atoms in the spiro ring may be replaced with a heteroatom (e.g., O, N, S, or P). (C 5 -C 12 ) A spirocycloalkyl is a spiro ring containing from 5 to 12 carbon atoms.

[0072] It will be understood that the compounds described herein can be substituted with one, two, three, four, five or more independently selected substituents or functional moieties (up to the total number of possible substituents for a particular compound). In general, the term "substituted," whether preceded by the term "optionally" or not, and the substituents contained in the formulas disclosed herein, refer to the replacement of a hydrogen radical in a given structure with the radical of the specified substituent. When multiple positions in any given structure are substituted with multiple substituents selected from a specified group, the substituents can be the same or different at each position. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In one broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. For purposes of this disclosure, heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituent of organic compounds described herein that satisfies the valence of the heteroatom. The nitrogen and sulfur heteroatoms can be optionally oxidized, and the nitrogen heteroatom can be optionally quaternized. Examples of substituents on the moieties disclosed herein (e.g., alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, cycloalkyl, cycloalkenyl, non-aromatic heterocyclic groups) include, but are not limited to, alkyl, alkenyl, alkynyl, halogen, haloalkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, heteroaryl, aryl, cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, hydroxyl, carbamoyl, oxo, amino, nitro, azido, -SH, and -CN.

[0073] As described herein, the compounds of the present disclosure may be optionally substituted with one or more substituents, such as those generally described above or those exemplified by the particular classes, subclasses, and species of the present disclosure. It is understood that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted". Unless otherwise specified, an optionally substituted group may have a substituent at any position or at each substitutable position of the group, and multiple positions in any given structure may be substituted with two or more substituents independently selected from the designated group, and the substituents may be the same or different at each substitution position.

[0074] Surfactants include, but are not limited to, nonionic, anionic, cationic, amphoteric or zwitterionic surfactants. Examples of suitable nonionic surfactants include ethoxylated triglycerides, fatty alcohol ethoxylates, alkylphenol ethoxylates, fatty acid ethoxylates, fatty amide ethoxylates, fatty amine ethoxylates, sorbitan alkanoates, ethylated sorbitan alkanoates, alkyl ethoxylates, Pluronics™, alkyl polyglucosides, stearol ethoxylates, alkyl polyglycosides. Examples of suitable anionic surfactants include alkyl ether sulfates, alkyl ether carboxylates, alkyl benzene sulfonates, alkyl ether phosphates, dialkyl sulfosuccinates, sarcosinates, alkyl sulfonates, soaps, alkyl sulfates, alkyl carboxylates, alkyl phosphates, paraffin sulfonates, secondary n-alkane sulfonates, alpha-olefin sulfonates, isethionate sulfonates. Examples of suitable cationic surfactants include aliphatic amine salts, aliphatic diamine salts, quaternary ammonium compounds, phosphonium surfactants, sulfonium surfactants, sulfoxonium surfactants. Examples of suitable zwitterionic surfactants include N-alkyl derivatives of amino acids (such as glycine, betaine, aminopropionic acid), imidazoline surfactants, amine oxides, amidobetaines. Non-limiting examples of surfactants that can be used in the solid dispersion include, for example, Tween 20, Tween 80, Span 20, Span 80, sodium docusate (e.g., AOT), sodium lauryl sulfate, and poloxamers (e.g., Poloxamer 407, Kolliphor® EL, Pluronic F68). Poloxamers are also known by the trade names Synperonics®, (Pluronics®, and Kolliphor® / Cremophor®).

[0075] Sweeteners include, but are not limited to, sucrose, high fructose corn syrup, fructose, glucose, aspartame, acesulfame K, sucralose, cyclamate, sodium saccharin, neotame, rebaudioside A, and other stevia-based sweeteners.

[0076] Buffers include, but are not limited to, citrate buffers, phosphate buffers, acetate buffers and bicarbonate buffers.

[0077] Bifunctional compounds of formula (Ia) and formula (I) In embodiments, disclosed herein are bifunctional compounds having the structure of formula (Ia): [ka] or a pharma- ceutically acceptable salt, solvate, enantiomer, stereoisomer, or isotopic derivative thereof, where PTM is a protein / polypeptide targeting moiety, LNK is a linker, e.g., a bond (absent) or a chemical group that couples the PTM to the ULM, and ULM is an E3 ubiquitin ligase binding moiety. The PTM binds to a target protein or polypeptide to be ubiquitinated by a ubiquitin ligase and is chemically linked to the ULM group, either directly or via the linker moiety LNK.

[0078] In embodiments, disclosed herein are bifunctional compounds having the structure of formula (Ia): [ka] or a pharma- ceutically acceptable salt thereof, where PTM is a protein / polypeptide targeting moiety, LNK is a linker, e.g., a bond (absent) or a chemical group that couples the PTM to ULM, and ULM is an E3 ubiquitin ligase binding moiety. The PTM binds to a target protein or polypeptide to be ubiquitinated by a ubiquitin ligase and is chemically linked to the ULM group, either directly or via the linker moiety LNK.

[0079] In embodiments, disclosed herein are bifunctional compounds having the structure of formula (I): [ka] or a pharma- ceutically acceptable salt, solvate, enantiomer, stereoisomer, or isotopic derivative thereof; During the ceremony, KTM is a KRAS targeting moiety and LNK is a linker (e.g., a bond or chemical linker group) that covalently couples the PTM to a von Hippel-Lindau (VHL) E3 ubiquitin ligase binding moiety or VLM.

[0080] In embodiments, disclosed herein are bifunctional compounds having the structure of formula (I): [ka] or a pharma- ceutically acceptable salt thereof; During the ceremony, KTM is a KRAS targeting moiety and LNK is a linker (e.g., a bond or chemical linker group) that covalently couples the PTM to a von Hippel-Lindau (VHL) E3 ubiquitin ligase binding moiety or VLM.

[0081] In some embodiments, the VLM is a derivative of trans-3-hydroxyproline, where both the nitrogen and the carboxylic acid of trans-3-hydroxyproline are functionalized as amides. Other contemplated VLMs are described in U.S. Patent Application Publication No. 2016 / 0272639, U.S. Patent Application Publication No. 2014 / 0356322, each of which is incorporated herein by reference in its entirety.

[0082] In certain embodiments, "LNK" is a bond. In additional embodiments, the linker "LNK" is a connector with a linear number of non-hydrogen atoms ranging from 1 to 20. The connector "LNK" may contain functional groups such as, but not limited to, ether, amide, alkane, alkene, alkyne, ketone, hydroxyl, carboxylic acid, thioether, sulfoxide, and sulfone. The linker may contain aromatic, heteroaromatic, cyclic, bicyclic, and tricyclic moieties. The linker may include substitution with halogens such as Cl, F, Br, and I. In the case of fluorine substitution, it may include one or more fluorines.

[0083] In embodiments, disclosed herein are bifunctional compounds having the structure of formula (I): [ka] .

[0084] In embodiments, disclosed herein are bifunctional compounds having the structure of formula (I): [ka] or a pharma- ceutically acceptable salt, solvate, enantiomer, stereoisomer, or isotopic derivative thereof; During the ceremony, (a) KTM has the structure of formula KTM-I: [ka] wherein X K1 is N or CR K5 and X K2 is N or CR K6 and X K3 is N or CR K7 and X K4 is NR K8 Or C 1 -C 3alkylene, wherein said alkylene is selected from one or more R K9 Optionally replaced by R K1 and R K2 are H, OH, Cl, F, Br, I, and C. 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, OC 1 -C 6 Alkyl, and O-(C 1 -C 6 haloalkyl), R K3 and R K4 are H, OH, Cl, F, Br, I, and C. 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocycle, O-(C 1 -C 6 alkyl), and O-(C 1 -C 6 haloalkyl); R K3 and R K4 together with the carbon to which they are attached, C 6 -C 10 aryl or 5-6 membered heteroaryl, where the aryl or heteroaryl is selected from 1, 2, 3, 4, or 5 R K11 Optionally replaced by R K5 , R K6 , and R K7 are H, Cl, F, Br, I, and NR K12 R K13 , C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl, [ka] represents the connection point between KTM and LNK, R K8 and R K9 , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl, Each R K11 are H, OH, CN, Cl, F, Br, I, and NR K12 R K13 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, and C 1 -C 6 haloalkyl; R K12 and R K13 , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl, R K14 and R K15 , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl; R K14 and R K15 X K4 and together with the carbon to which they are attached, C 4 -C 7 forming a cycloalkyl or a 4- to 7-membered heterocycle, (b) LNK is a chemical linking moiety that covalently couples the KTM to the VLM and has the structure LI: [ka] wherein Each L is [ka] C 2 -C 6 Alkylene, C 2 -C 6 Alkenylene, C 2 -C 6 Alkynylene, monocyclic C 4 -C 10 Cycloalkylene, fused bicyclic C 4 -C 10 Cycloalkylene, Bridged Bicyclic C 6 -C 10 Cycloalkylene or spiro-fused bicyclic C 5 -C 12 Cycloalkylene, monocyclic 4-10 membered heterocycloalkylene, fused bicyclic 4-10 membered heterocycloalkylene, bridged bicyclic 6-10 membered heterocycloalkylene, spiro-fused 5-12 membered heterocycloalkylene, C 6 -C 10 arylene, and 5- to 6-membered heteroarylene, where each cycloalkylene, heterocycloalkylene, arylene, and heteroarylene is independently selected from 1, 2, 3, 4, or 5 R L5 Optionally replaced by Each A L CR L1 R L2 , N.R. L3 and O are independently selected from Each R L1 and R L2 , H, C 1 -C 6 Alkyl, O-(C 1 -C 6 alkyl), and C 1 -C 6 haloalkyl, where said alkyl is selected from Cl, F, OH, NH 2 , CN, or CF 3 Optionally replaced by Each R L3 , H, C 1 -C 6 Alkyl, O-(C 1 -C 6 alkyl), and C 1 -C 6haloalkyl, where said alkyl is selected from Cl, F, OH, NH 2 , CN, or CF 3 Optionally replaced by Each R L4 is C 1 -C 6 Alkyl, O-(C 1 -C 6 Alkyl), C 1 -C 6 Haloalkyl, NH, CN, CF 3 , Cl, F, Br, I, and OH, where alkyl is Cl, F, OH, NH 2 , CN, or CF 3 Optionally replaced by Each R L5 are Cl, F, Br, I, and C. 1 -C 6 Alkyl, O-(C 1 -C 6 Alkyl), C 1 -C 6 Haloalkyl, NH 2 , C.N., C.F. 3 and OH, where alkyl is selected from Cl, F, OH, NH 2 , CN, or CF 3 Optionally replaced by n L is an integer between 1 and 50, (c) VLM has the structure VLM-I: [ka] wherein Y V1 teeth, [ka] and Y V2 CN or [ka] and [ka] is phenylene or 5- to 6-membered heteroarylene, [ka] is a 5-membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, S, and O; R V1 , R V2 , and R V3 , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl; R V1 and R V2 together with the carbon to which they are attached, C 3 -C 10 Form a cycloalkyl or 5- to 6-membered heterocycle, R V3 , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl; R V4a and R V4b , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl, Each R V5 and R V6 H and C 1 -C 6 independently selected from alkyl, R V7 and R V8 , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl; R V7 and R V8 together with the atoms to which they are attached, C 3 -C 10Forming a cycloalkyl or 5- to 6-membered heterocycle, [ka] represents the attachment point between the VLM and the LNK, n V is 0, 1, 2, 3, or 4, o V is 0, 1, 2, or 3.

[0085] In embodiments, disclosed herein are bifunctional compounds having the structure of formula (I): [ka] or a pharma- ceutically acceptable salt, solvate, enantiomer, stereoisomer, or isotopic derivative thereof; During the ceremony, (a) KTM has the structure of formula KTM-I: [ka] wherein X K1 is N or CR K5 and X K2 is N or CR K6 and X K3 is N or CR K7 and X K4 is NR K8 Or C 1 -C 3 alkylene, where the alkylene is one or more R K9 Optionally replaced by R K1 and R K2 are H, OH, Cl, F, Br, I, and C. 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, OC 1 -C 6 Alkyl, and O-(C 1 -C 6haloalkyl), R K3 and R K4 are H, OH, Cl, F, Br, I, and C. 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocycle, O-(C 1 -C 6 alkyl), and O-(C 1 -C 6 haloalkyl); R K3 and R K4 together with the carbon to which they are attached, C 6 -C 10 aryl or 5-6 membered heteroaryl, where the aryl or heteroaryl is selected from 1, 2, 3, 4, or 5 R K11 Optionally replaced by R K5 , R K6 , and R K7 are H, Cl, F, Br, I, and NR K12 R K13 , C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl, [ka] represents the connection point between KTM and LNK, R K8 and R K9 , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl, Each R K11 are H, OH, CN, Cl, F, Br, I, and NR K12 R K13 , C 1 -C 6 Alkyl, C2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, and C 1 -C 6 haloalkyl; R K12 and R K13 , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl, R K14 and R K15 , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl; R K14 and R K15 X K4 and together with the carbon to which they are attached, C 4 -C 7 forming a cycloalkyl or a 4- to 7-membered heterocycle, (b) LNK is a chemical linking moiety that covalently couples the KTM to the VLM and has the structure LI: [ka] wherein Each L is [ka] C 2 -C 6 Alkylene, C 2 -C 6 Alkenylene, C 2 -C 6 Alkynylene, monocyclic C 4 -C 10 Cycloalkylene, fused bicyclic C 4 -C 10 Cycloalkylene, Bridged Bicyclic C 6 -C 10 Cycloalkylene or spiro-fused bicyclic C 5 -C12 Cycloalkylene, monocyclic 4-10 membered heterocycloalkylene, fused bicyclic 4-10 membered heterocycloalkylene, bridged bicyclic 6-10 membered heterocycloalkylene, spiro-fused 5-12 membered heterocycloalkylene, C 6 -C 10 arylene, and 5- to 6-membered heteroarylene, where each cycloalkylene, heterocycloalkylene, arylene, and heteroarylene is independently selected from 1, 2, 3, 4, or 5 R L5 Optionally replaced by Each A L CR L1 R L2 , N.R. L3 and O are independently selected from Each R L1 and R L2 , H, C 1 -C 6 Alkyl, O-(C 1 -C 6 alkyl), and C 1 -C 6 haloalkyl, where alkyl is Cl, F, OH, NH 2 , CN, or CF 3 Optionally replaced by Each R L3 , H, C 1 -C 6 Alkyl, O-(C 1 -C 6 alkyl), and C 1 -C 6 haloalkyl, where alkyl is Cl, F, OH, NH 2 , CN, or CF 3 Optionally replaced by Each R L4 is C 1 -C 6 Alkyl, O-(C 1 -C 6 Alkyl), C 1 -C 6 Haloalkyl, NH, CN, CF 3 , Cl, F, Br, I, and OH, where alkyl is Cl, F, OH, NH2 , CN, or CF 3 Optionally replaced by Each R L5 are Cl, F, Br, I, and C. 1 -C 6 Alkyl, O-(C 1 -C 6 Alkyl), C 1 -C 6 Haloalkyl, NH 2 , C.N., C.F. 3 and OH, where alkyl is selected from Cl, F, OH, NH 2 , CN, or CF 3 Optionally replaced by n L is 2, 3, 4, 5, or 6, (c) VLM has the structure VLM-I: [ka] wherein Y V1 teeth, [ka] and Y V2 CN or [ka] and [ka] is phenylene or 5- to 6-membered heteroarylene, [ka] is a 5-membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, S, and O; R V1 , R V2 , and R V3 , H, C 1 -C 6 Alkyl, and C 1 -C 6haloalkyl; R V1 and R V2 together with the carbon to which they are attached, C 3 -C 10 Form a cycloalkyl or 5- to 6-membered heterocycle, R V3 , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl; R V4a and R V4b , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl, Each R V5 and R V6 H and C 1 -C 6 independently selected from alkyl, R V7 and R V8 , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl; R V7 and R V8 together with the atoms to which they are attached, C 3 -C 10 Forming a cycloalkyl or 5- to 6-membered heterocycle, [ka] represents the attachment point between the VLM and the LNK, n V is 0, 1, 2, 3, or 4, o V is 0, 1, 2, or 3.

[0086] In another aspect, the present application provides a bifunctional compound having the structure of formula (IA): [ka] or a pharma- ceutically acceptable salt, solvate, enantiomer, stereoisomer, or isotopic derivative thereof, During the ceremony, (a) KTM has the structure of formula KTM-IA: [ka] wherein X K1 is N or CR K5 and X K2 is N or CR K6 and X K3 is N or CR K7 and X K4 is NR K8 Or C 1 -C 3 alkylene, where the alkylene is one or more R K9 Optionally replaced by R K1 and R K2 are H, OH, Cl, F, Br, I, and C. 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, OC 1 -C 6 Alkyl, and O-(C 1 -C 6 haloalkyl), R K3 and R K4 are H, OH, Cl, F, Br, I, and C. 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocycle, O-(C 1 -C 6 alkyl), and O-(C 1 -C 6 haloalkyl); RK3 and R K4 together with the carbon to which they are attached, C 6 -C 10 aryl or 5-6 membered heteroaryl, where the aryl or heteroaryl is selected from 1, 2, 3, 4, or 5 R K11 Optionally replaced by R K5 , R K6 , and R K7 are H, Cl, F, Br, I, and NR K12 R K13 , C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl, [ka] represents the connection point between KTM and LNK, R K8 and R K9 , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl, Each R K11 are H, OH, CN, Cl, F, Br, I, and NR K12 R K13 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, and C 1 -C 6 haloalkyl; R K12 and R K13 , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl, R K14 and R K15 , H, C 1 -C6 Alkyl, and C 1 -C 6 haloalkyl; R K14 and R K15 X K4 and together with the carbon to which they are attached, C 4 -C 7 forming a cycloalkyl or a 4- to 7-membered heterocycle, (b) LNK is a chemical linking moiety that covalently couples the KTM to the VLM and has the structure L-IA: [ka] wherein Each L is [ka] C 2 -C 6 Alkylene, C 2 -C 6 Alkenylene, C 2 -C 6 Alkynylene, monocyclic C 4 -C 10 Cycloalkylene, fused bicyclic C 4 -C 10 Cycloalkylene, Bridged Bicyclic C 6 -C 10 Cycloalkylene or spiro-fused bicyclic C 5 -C 12 Cycloalkylene, monocyclic 4-10 membered heterocycloalkylene, fused bicyclic 4-10 membered heterocycloalkylene, bridged bicyclic 6-10 membered heterocycloalkylene, spiro-fused 5-12 membered heterocycloalkylene, C 6 -C 10 arylene, and 5- to 6-membered heteroarylene, where each cycloalkylene, heterocycloalkylene, arylene, and heteroarylene is independently selected from 1, 2, 3, 4, or 5 R L5 Optionally replaced by Each A L CR L1 R L2 , N.R.L3 and O are independently selected from Each R L1 and R L2 , H, C 1 -C 6 Alkyl, O-(C 1 -C 6 alkyl), and C 1 -C 6 haloalkyl, where alkyl is Cl, F, OH, NH 2 , CN, or CF 3 Optionally replaced by Each R L3 , H, C 1 -C 6 Alkyl, O-(C 1 -C 6 alkyl), and C 1 -C 6 haloalkyl, where alkyl is Cl, F, OH, NH 2 , CN, or CF 3 Optionally replaced by Each R L4 is C 1 -C 6 Alkyl, O-(C 1 -C 6 Alkyl), C 1 -C 6 Haloalkyl, NH, CN, CF 3 , Cl, F, Br, I, and OH, where alkyl is Cl, F, OH, NH 2 , CN, or CF 3 Optionally replaced by Each R L5 are Cl, F, Br, I, and C. 1 -C 6 Alkyl, O-(C 1 -C 6 Alkyl), C 1 -C 6 Haloalkyl, NH 2 , C.N., C.F. 3 and OH, where alkyl is selected from Cl, F, OH, NH 2 , CN, or CF 3 Optionally replaced by n L is an integer between 1 and 50, (c) VLM has the structure VLM-IA: [ka] wherein Y V1 teeth, [ka] and Y V2 CN or [ka] and [ka] is phenylene or 5- to 6-membered heteroarylene, [ka] is a 5-membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, S, and O; R V1 , R V2 , and R V3 , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl; R V1 and R V2 together with the carbon to which they are attached, C 3 -C 10 Form a cycloalkyl or 5- to 6-membered heterocycle, R V3 , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl; R V4a and R V4b , H, C 1 -C 6Alkyl, and C 1 -C 6 haloalkyl, Each R V5 and R V6 H, halo, and C 1 -C 6 independently selected from alkyl, R V7 and R V8 , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl; R V7 and R V8 together with the atoms to which they are attached, C 3 -C 10 Forming a cycloalkyl or 5- to 6-membered heterocycle, [ka] represents the attachment point between the VLM and the LNK, n V is 0, 1, 2, 3, or 4, o V is 0, 1, 2, or 3.

[0087] In some embodiments, KTM is a KRAS targeting moiety, hi some embodiments, KTM is a KRAS targeting moiety having the structure of formula KTM-I.

[0088] In some embodiments, the VLM is a von Hippel-Lindau (VHL) E3 ubiquitin ligase binding moiety. In some embodiments, the VLM is a von Hippel-Lindau (VHL) E3 ubiquitin ligase binding moiety having the structure VLM-I.

[0089] In some embodiments, KTM has the structure of formula KTM-I: [ka] wherein X K1 is N or CR K5 and X K2 is N or CR K6 and X K3 is N or CR K7 and X K4 is NR K8 Or C 1 -C 3 alkylene, where the alkylene is one or more R K9 Optionally replaced by R K1 and R K2 are H, OH, Cl, F, Br, I, and C. 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, O-(C 1 -C 6 alkyl), and O-(C 1 -C 6 haloalkyl), R K3 and R K4 are H, OH, Cl, F, Br, I, and C. 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocycle, O-(C 1 -C 6 alkyl), and O-(C 1 -C 6 haloalkyl); R K3 and R K4 together with the carbon to which they are attached, C 6 -C 10 aryl or 5-6 membered heteroaryl, where the aryl or heteroaryl is selected from 1, 2, 3, 4, or 5 R K11 Optionally replaced by R K5 , RK6 , and R K7 are H, Cl, F, Br, I, and NR K12 R K13 , C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl, [ka] represents the connection point between KTM and LNK, R K8 and R K9 , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl, Each R K11 are H, OH, CN, Cl, F, Br, I, and NR K12 R K13 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, and C 1 -C 6 haloalkyl; R K12 and R K13 , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl, R K14 and R K15 , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl; R K14 and R K15 X K4 and together with the carbon to which they are attached, C 4 -C 7It forms a cycloalkyl or a 4- to 7-membered heterocycle.

[0090] In some embodiments, KTM has the formula (KTM-Ia), (KTM-Ib), (KTM-Ic), (KTM-Id), or (KTM-Ie). [ka] where X K1 , X K2 , X K3 , X K4 , R K1 , R K2 , R K3 , R K4 , R K6 , R K11 , R K14 and R K15 is as defined herein.

[0091] In some embodiments, KTM has the structure of formula (KTM-Ia). In some embodiments, KTM has the structure of formula (KTM-Ib). In some embodiments, KTM has the structure of formula (KTM-Ic). In some embodiments, KTM has the structure of formula (KTM-Id). In some embodiments, KTM has the structure of formula (KTM-Ie).

[0092] In some embodiments, X K1 is N. In some embodiments, X K1 CR K5 In some embodiments, X K1 CR K5 and R K5 is Cl. In some embodiments, X K1 CR K5 and R K5 is F. In some embodiments, X K1 CR K5 and R K5 is Br. In some embodiments, X K1 CRK5 and R K5 is I. In some embodiments, X K1 CR K5 and R K5 is NR K12 R K13 In some embodiments, X K1 CR K5 and R K5 is C 1 -C 6 In some embodiments, X is alkyl. K1 CR K5 and R K5 is C 1 -C 6 It is haloalkyl.

[0093] In some embodiments, R K5 is Cl, F, Br, or I. In some embodiments, R K5 is C 1 -C 6 Alkyl or C 1 -C 6 It is haloalkyl.

[0094] In some embodiments, R K5 is C 1 -C 6 In some embodiments, R K5 is methyl. In some embodiments, R K5 is ethyl. In some embodiments, R K5 is propyl. In some embodiments, R K5 is n-propyl. In some embodiments, R K5 is isopropyl. In some embodiments, R K5 is butyl. In some embodiments, R K5 is n-butyl. In some embodiments, R K5 is isobutyl. In some embodiments, R K5 is sec-butyl. In some embodiments, RK5 is tert-butyl. In some embodiments, R K5 is pentyl. In some embodiments, R K5 is hexyl.

[0095] In some embodiments, R K5 is C 1 -C 6 In some embodiments, R K5 is C 1 In some embodiments, R K5 is C 2 In some embodiments, R K5 is C 3 In some embodiments, R K5 is C 4 In some embodiments, R K5 is C 5 In some embodiments, R K5 is C 6 It is haloalkyl.

[0096] In some embodiments, X K2 is N. In some embodiments, X K2 CR K6 In some embodiments, X K2 CR K6 and R K6 is Cl. In some embodiments, X K2 CR K6 and R K6 is F. In some embodiments, X K2 CR K6 and R K6 is Br. In some embodiments, X K2 CR K6 and R K6 is I. In some embodiments, X K2 CR K6 and R K6is NR K12 R K13 In some embodiments, X K2 CR K5 and R K5 is C 1 -C 6 In some embodiments, X is alkyl. K2 CR K5 and R K5 is C 1 -C 6 It is haloalkyl.

[0097] In some embodiments, R K6 is Cl, F, Br, or I. In some embodiments, R K6 is C 1 -C 6 Alkyl or C 1 -C 6 It is haloalkyl.

[0098] In some embodiments, R K6 is C 1 -C 6 In some embodiments, R K6 is methyl. In some embodiments, R K6 is ethyl. In some embodiments, R K6 is propyl. In some embodiments, R K6 is n-propyl. In some embodiments, R K6 is isopropyl. In some embodiments, R K6 is butyl. In some embodiments, R K6 is n-butyl. In some embodiments, R K6 is isobutyl. In some embodiments, R K6 is sec-butyl. In some embodiments, R K6 is tert-butyl. In some embodiments, R K6 is pentyl. In some embodiments, R K6 is hexyl.

[0099] In some embodiments, R K6 is C 1 -C 6 In some embodiments, R K6 is C 1 In some embodiments, R K6 is C 2 In some embodiments, R K6 is C 3 In some embodiments, R K6 is C 4 In some embodiments, R K6 is C 5 In some embodiments, R K6 is C 6 It is haloalkyl.

[0100] In some embodiments, X K3 is N. In some embodiments, X K3 CR K7 In some embodiments, X K3 CR K7 and R K7 is Cl. In some embodiments, X K3 CR K7 and R K7 is F. In some embodiments, X K3 CR K7 and R K7 is Br. In some embodiments, X K3 CR K7 and R K7 is I. In some embodiments, X K3 CR K7 and R K7 is NR K12 R K13 In some embodiments, X K3 CR K7 and R K7 is C1 -C 6 In some embodiments, X is alkyl. K3 CR K7 and R K7 is C 1 -C 6 It is haloalkyl.

[0101] In some embodiments, R K7 is Cl, F, Br, or I. In some embodiments, R K7 is C 1 -C 6 Alkyl or C 1 -C 6 It is haloalkyl.

[0102] In some embodiments, R K7 is C 1 -C 6 In some embodiments, R K7 is methyl. In some embodiments, R K7 is ethyl. In some embodiments, R K7 is propyl. In some embodiments, R K7 is n-propyl. In some embodiments, R K7 is isopropyl. In some embodiments, R K7 is butyl. In some embodiments, R K7 is n-butyl. In some embodiments, R K7 is isobutyl. In some embodiments, R K7 is sec-butyl. In some embodiments, R K7 is tert-butyl. In some embodiments, R K7 is pentyl. In some embodiments, R K7 is hexyl.

[0103] In some embodiments, R K7 is C 1 -C 6In some embodiments, R K7 is C 1 In some embodiments, R K7 is C 2 In some embodiments, R K7 is C 3 In some embodiments, R K7 is C 4 In some embodiments, R K7 is C 5 In some embodiments, R K7 is C 6 It is haloalkyl.

[0104] In some embodiments, X K4 is NR K8 In some embodiments, X K4 is NH. In some embodiments, X K4 is C 1 -C 3 It is alkylene.

[0105] In some embodiments, X K4 is the unsubstituted C 1 -C 3 In some embodiments, X is an alkylene. K4 is one R K9 C replaced with 1 -C 3 In some embodiments, X is an alkylene. K4 There are two R K9 C replaced with 1 -C 3 In some embodiments, X is an alkylene. K4 The three R's K9 C replaced with 1 -C 3 It is alkylene.

[0106] In some embodiments, X K4 is the unsubstituted C 1Alkylene (i.e., CH 2 In some embodiments, X K4 is the unsubstituted C 2 Alkylene (i.e., CH 2 CH 2 In some embodiments, X K4 is the unsubstituted C 3 Alkylene (i.e., CH 2 CH 2 CH 2 ).

[0107] In some embodiments, R K1 is H, OH, Cl, F, Br, or I. In some embodiments, R K1 is Cl, F, Br, or I. In some embodiments, R K1 is C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, O-(C 1 -C 6 alkyl), or O-(C 1 -C 6 haloalkyl). In some embodiments, R K1 is C 1 -C 6 Alkyl or C 1 -C 6 In some embodiments, R K1 is O-(C 1 -C 6 alkyl), or O-(C 1 -C 6 haloalkyl).

[0108] In some embodiments, R K1 is H. In some embodiments, R K1 is OH. In some embodiments, R K1 is F. In some embodiments, R K1 is Cl. In some embodiments, R K1 is Br. In some embodiments, RK1 is I. In some embodiments, R K1 is C 1 -C 6 In some embodiments, R K1 is C 1 -C 6 In some embodiments, R K1 is O-(C 1 -C 6 In some embodiments, R K1 is O-(C 1 -C 6 haloalkyl).

[0109] In some embodiments, R K1 is methyl. In some embodiments, R K1 is ethyl. In some embodiments, R K1 is propyl. In some embodiments, R K1 is n-propyl. In some embodiments, R K1 is isopropyl. In some embodiments, R K1 is butyl. In some embodiments, R K1 is n-butyl. In some embodiments, R K1 is isobutyl. In some embodiments, R K1 is sec-butyl. In some embodiments, R K1 is tert-butyl. In some embodiments, R K1 is pentyl. In some embodiments, R K1 is hexyl.

[0110] In some embodiments, R K1 is C 1 In some embodiments, R K1 is C 2 In some embodiments, R K1 is C 3In some embodiments, R K1 is C 4 In some embodiments, R K1 is C 5 In some embodiments, R K1 is C 6 It is haloalkyl.

[0111] In some embodiments, R K1 is O-methyl. In some embodiments, R K1 is O-ethyl. In some embodiments, R K1 is O-propyl. In some embodiments, R K1 is On-propyl. In some embodiments, R K1 is O-isopropyl. In some embodiments, R K1 is O-butyl. In some embodiments, R K1 is On-butyl. In some embodiments, R K1 is O-isobutyl. In some embodiments, R K1 is O-sec-butyl. In some embodiments, R K1 is O-tert-butyl. In some embodiments, R K1 is O-pentyl. In some embodiments, R K1 is O-hexyl.

[0112] In some embodiments, R K1 is O.C. 1 In some embodiments, R K1 is O.C. 2 In some embodiments, R K1 is O.C. 3 In some embodiments, R K1 is O.C. 4 In some embodiments, R K1 is O.C.5 In some embodiments, R K1 is O.C. 6 It is haloalkyl.

[0113] In some embodiments, R K2 is H, OH, Cl, F, Br, or I. In some embodiments, R K2 is Cl, F, Br, or I. In some embodiments, R K2 is C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, O-(C 1 -C 6 alkyl), or O-(C 1 -C 6 haloalkyl). In some embodiments, R K2 is C 1 -C 6 Alkyl or C 1 -C 6 In some embodiments, R K2 is O-(C 1 -C 6 alkyl), or O-(C 1 -C 6 haloalkyl).

[0114] In some embodiments, R K2 is H. In some embodiments, R K2 is OH. In some embodiments, R K2 is F. In some embodiments, R K2 is Cl. In some embodiments, R K2 is Br. In some embodiments, R K2 is I. In some embodiments, R K2 is C 1 -C 6 In some embodiments, R K2 is C 1 -C 6In some embodiments, R K2 is O-(C 1 -C 6 In some embodiments, R K2 is O-(C 1 -C 6 haloalkyl).

[0115] In some embodiments, R K2 is methyl. In some embodiments, R K2 is ethyl. In some embodiments, R K2 is propyl. In some embodiments, R K2 is n-propyl. In some embodiments, R K2 is isopropyl. In some embodiments, R K2 is butyl. In some embodiments, R K2 is n-butyl. In some embodiments, R K2 is isobutyl. In some embodiments, R K2 is sec-butyl. In some embodiments, R K2 is tert-butyl. In some embodiments, R K2 is pentyl. In some embodiments, R K2 is hexyl.

[0116] In some embodiments, R K2 is C 1 In some embodiments, R K2 is C 2 In some embodiments, R K2 is C 3 In some embodiments, R K2 is C 4 In some embodiments, R K2 is C 5 In some embodiments, R K2 is C6 It is haloalkyl.

[0117] In some embodiments, R K2 is O-methyl. In some embodiments, R K2 is O-ethyl. In some embodiments, R K2 is O-propyl. In some embodiments, R K2 is On-propyl. In some embodiments, R K2 is O-isopropyl. In some embodiments, R K2 is O-butyl. In some embodiments, R K2 is On-butyl. In some embodiments, R K2 is O-isobutyl. In some embodiments, R K2 is O-sec-butyl. In some embodiments, R K2 is O-tert-butyl. In some embodiments, R K2 is O-pentyl. In some embodiments, R K2 is O-hexyl.

[0118] In some embodiments, R K2 is O.C. 1 In some embodiments, R K2 is O.C. 2 In some embodiments, R K2 is O.C. 3 In some embodiments, R K2 is O.C. 4 In some embodiments, R K2 is O.C. 5 In some embodiments, R K2 is O.C. 6 It is haloalkyl.

[0119] In some embodiments, R K3are H, OH, Cl, F, Br, I, and C. 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocycle, O-(C 1 -C 6 alkyl), or O-(C 1 -C 6 haloalkyl). In some embodiments, R K3 is H, OH, Cl, F, Br, or I. In some embodiments, R K3 is Cl, F, Br, or I. In some embodiments, R K3 is C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, O-(C 1 -C 6 alkyl), or O-(C 1 -C 6 haloalkyl). In some embodiments, R K3 is C 1 -C 6 Alkyl or C 1 -C 6 In some embodiments, R K3 is C 1 -C 6 Haloalkyl or O-(C 1 -C 6 haloalkyl). In some embodiments, R K3 CF 3 Or O-CF 3 In some embodiments, R K3 is O-(C 1 -C 6 alkyl) or O-(C 1 -C 6 haloalkyl). In some embodiments, R K3 is C 3 -C 10 It is a cycloalkyl or a 3- to 10-membered heterocycle.

[0120] In some embodiments, R K3 is H. In some embodiments, R K3 is OH. In some embodiments, R K3 is F. In some embodiments, R K3 is Cl. In some embodiments, R K3 is Br. In some embodiments, R K3 is I. In some embodiments, R K3 is C 1 -C 6 In some embodiments, R K3 is C 1 -C 6 In some embodiments, R K3 is C 3 -C 10 In some embodiments, R K3 is C 3 -C 10 In some embodiments, R K3 is O-(C 1 -C 6 In some embodiments, R K3 is O-(C 1 -C 6 haloalkyl).

[0121] In some embodiments, R K3 is methyl. In some embodiments, R K3 is ethyl. In some embodiments, R K3 is propyl. In some embodiments, R K3 is n-propyl. In some embodiments, R K3 is isopropyl. In some embodiments, R K3 is butyl. In some embodiments, R K3 is n-butyl. In some embodiments, R K3is isobutyl. In some embodiments, R K3 is sec-butyl. In some embodiments, R K3 is tert-butyl. In some embodiments, R K3 is pentyl. In some embodiments, R K3 is hexyl.

[0122] In some embodiments, R K3 is C 1 In some embodiments, R K3 is C 2 In some embodiments, R K3 is C 3 In some embodiments, R K3 is C 4 In some embodiments, R K3 is C 5 In some embodiments, R K3 is C 6 In some embodiments, R K3 CF 3 It is.

[0123] In some embodiments, R K3 is cyclopropyl. In some embodiments, R K3 is cyclobutyl. In some embodiments, R K3 is cyclopentyl. In some embodiments, R K3 is cyclohexyl. In some embodiments, R K3 is cycloheptyl. In some embodiments, R K3 is cyclooctyl. In some embodiments, R K3 is cyclononyl. In some embodiments, R K3 is cyclodecyl.

[0124] In some embodiments, RK3 is a 3- to 10-membered heterocycle. In some embodiments, R K3 is a 3-8 membered heterocycle. In some embodiments, R K3 is a 5- to 9-membered heterocycle.

[0125] In some embodiments, R K3 is a monocyclic heterocycle. In some embodiments, R K3 is a polycyclic heterocycle.

[0126] In some embodiments, R K3 is a 3-membered heterocycle. In some embodiments, R K3 is a 4-membered heterocycle. In some embodiments, R K3 is a 5-membered heterocycle. In some embodiments, R K3 is a 6-membered heterocycle. In some embodiments, R K3 is a 7-membered heterocycle. In some embodiments, R K3 is an 8-membered heterocycle. In some embodiments, R K3 is a 9-membered heterocycle. In some embodiments, R K3 is a 10-membered heterocycle.

[0127] In some embodiments, R K3 is O-methyl. In some embodiments, R K3 is O-ethyl. In some embodiments, R K3 is O-propyl. In some embodiments, R K3 is On-propyl. In some embodiments, R K3 is O-isopropyl. In some embodiments, R K3 is O-butyl. In some embodiments, R K3 is On-butyl. In some embodiments, R K3 is O-isobutyl. In some embodiments, R K3 is O-sec-butyl. In some embodiments, RK3 is O-tert-butyl. In some embodiments, R K3 is O-pentyl. In some embodiments, R K3 is O-hexyl.

[0128] In some embodiments, R K3 is O.C. 1 In some embodiments, R K3 is O.C. 2 In some embodiments, R K3 is O.C. 3 In some embodiments, R K3 is O.C. 4 In some embodiments, R K3 is O.C. 5 In some embodiments, R K3 is O.C. 6 It is haloalkyl.

[0129] In some embodiments, R K4 are H, OH, Cl, F, Br, I, and C. 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocycle, O-(C 1 -C 6 alkyl), or O-(C 1 -C 6 haloalkyl). In some embodiments, R K4 is H, OH, Cl, F, Br, or I. In some embodiments, R K4 is Cl, F, Br, or I. In some embodiments, R K4 is C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, O-(C 1 -C 6alkyl), or O-(C 1 -C 6 haloalkyl). In some embodiments, R K4 is C 1 -C 6 Alkyl or C 1 -C 6 In some embodiments, R K4 is C 1 -C 6 Haloalkyl or O-(C 1 -C 6 haloalkyl). In some embodiments, R K4 CF 3 Or O-CF 3 In some embodiments, R K4 is O-(C 1 -C 6 alkyl) or O-(C 1 -C 6 haloalkyl). In some embodiments, R K4 is C 3 -C 10 It is a cycloalkyl or a 3- to 10-membered heterocycle.

[0130] In some embodiments, R K4 is H. In some embodiments, R K4 is OH. In some embodiments, R K4 is F. In some embodiments, R K4 is Cl. In some embodiments, R K4 is Br. In some embodiments, R K4 is I. In some embodiments, R K4 is C 1 -C 6 In some embodiments, R K4 is C 1 -C 6 In some embodiments, R K4 is C 3 -C 10 In some embodiments, RK4 is C 3 -C 10 In some embodiments, R K4 is O-(C 1 -C 6 In some embodiments, R K4 is O-(C 1 -C 6 haloalkyl).

[0131] In some embodiments, R K4 is methyl. In some embodiments, R K4 is ethyl. In some embodiments, R K4 is propyl. In some embodiments, R K4 is n-propyl. In some embodiments, R K4 is isopropyl. In some embodiments, R K4 is butyl. In some embodiments, R K4 is n-butyl. In some embodiments, R K4 is isobutyl. In some embodiments, R K4 is sec-butyl. In some embodiments, R K4 is tert-butyl. In some embodiments, R K4 is pentyl. In some embodiments, R K4 is hexyl.

[0132] In some embodiments, R K4 is C 1 In some embodiments, R K4 is C 2 In some embodiments, R K4 is C 3 In some embodiments, R K4 is C 4 In some embodiments, R K4 is C 5In some embodiments, R K4 is C 6 In some embodiments, R K4 CF 3 It is.

[0133] In some embodiments, R K4 is cyclopropyl. In some embodiments, R K4 is cyclobutyl. In some embodiments, R K4 is cyclopentyl. In some embodiments, R K4 is cyclohexyl. In some embodiments, R K4 is cycloheptyl. In some embodiments, R K4 is cyclooctyl. In some embodiments, R K4 is cyclononyl. In some embodiments, R K4 is cyclodecyl.

[0134] In some embodiments, R K4 is a 3- to 10-membered heterocycle. In some embodiments, R K4 is a 3-8 membered heterocycle. In some embodiments, R K4 is a 5- to 9-membered heterocycle.

[0135] In some embodiments, R K4 is a monocyclic heterocycle. In some embodiments, R K4 is a polycyclic heterocycle.

[0136] In some embodiments, R K4 is a 3-membered heterocycle. In some embodiments, R K4 is a 4-membered heterocycle. In some embodiments, R K4 is a 5-membered heterocycle. In some embodiments, R K4 is a 6-membered heterocycle. In some embodiments, R K4is a 7-membered heterocycle. In some embodiments, R K4 is an 8-membered heterocycle. In some embodiments, R K4 is a 9-membered heterocycle. In some embodiments, R K4 is a 10-membered heterocycle.

[0137] In some embodiments, R K4 is O-methyl. In some embodiments, R K4 is O-ethyl. In some embodiments, R K4 is O-propyl. In some embodiments, R K4 is On-propyl. In some embodiments, R K4 is O-isopropyl. In some embodiments, R K4 is O-butyl. In some embodiments, R K4 is On-butyl. In some embodiments, R K4 is O-isobutyl. In some embodiments, R K4 is O-sec-butyl. In some embodiments, R K4 is O-tert-butyl. In some embodiments, R K4 is O-pentyl. In some embodiments, R K4 is O-hexyl.

[0138] In some embodiments, R K4 is O.C. 1 In some embodiments, R K4 is O.C. 2 In some embodiments, R K4 is O.C. 3 In some embodiments, R K4 is O.C. 4 In some embodiments, R K4 is O.C. 5 In some embodiments, RK4 is O.C. 6 It is haloalkyl.

[0139] In some embodiments, R K3 and R K4 are unsubstituted together with the carbon to which they are attached. 6 -C 10 It forms an aryl or a 5- to 6-membered heteroaryl.

[0140] In some embodiments, R K3 and R K4 together with the carbon to which they are attached form one R K11 C replaced with 6 -C 10 aryl or 5-6 membered heteroaryl, where R K11 are OH, CN, Cl, F, Br, I, and NR K12 R K13 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, and C 1 -C 6 In some embodiments, R K3 and R K4 together with the carbon to which they are attached form one R K11 C replaced with 6 -C 10 aryl or 5-6 membered heteroaryl, where R K11 are CN, Cl, F, Br, I, and C 1 -C 6 In some embodiments, R K3 and R K4 together with the carbon to which they are attached form one R K11 C replaced with 6 -C 10 aryl or 5-6 membered heteroaryl, where R K11 CN, Cl, F, and C 1-C 6 In some embodiments, R K3 and R K4 together with the carbon to which they are attached form one R K11 C replaced with 6 -C 10 aryl or 5-6 membered heteroaryl, where R K11 is CN. In some embodiments, R K3 and R K4 together with the carbon to which they are attached form one R K11 C replaced with 6 -C 10 aryl or 5-6 membered heteroaryl, where R K11 is Cl. In some embodiments, R K3 and R K4 together with the carbon to which they are attached form one R K11 C replaced with 6 -C 10 aryl or 5-6 membered heteroaryl, where R K11 is F. In some embodiments, R K3 and R K4 together with the carbon to which they are attached form one R K11 C replaced with 6 -C 10 aryl or 5-6 membered heteroaryl, where R K11 is Br. In some embodiments, R K3 and R K4 together with the carbon to which they are attached form one R K11 C replaced with 6 -C 10 aryl or 5-6 membered heteroaryl, where R K11 is I. In some embodiments, R K3 and R K4 together with the carbon to which they are attached form one R K11 C replaced with 6 -C 10aryl or 5-6 membered heteroaryl, where R K11 is C 1 -C 6 In some embodiments, R K3 and R K4 together with the carbon to which they are attached form one R K11 C replaced with 6 -C 10 aryl or 5-6 membered heteroaryl, where R K11 is C 1 -C 3 In some embodiments, R K3 and R K4 together with the carbon to which they are attached form one R K11 C replaced with 6 -C 10 aryl or 5-6 membered heteroaryl, where R K11 is C 1 In some embodiments, R K3 and R K4 together with the carbon to which they are attached form one R K11 C replaced with 6 -C 10 aryl or 5-6 membered heteroaryl, where R K11 is C 2 In some embodiments, R K3 and R K4 together with the carbon to which they are attached form one R K11 C replaced with 6 -C 10 aryl or 5-6 membered heteroaryl, where R K11 is C 3 In some embodiments, R K3 and R K4 together with the carbon to which they are attached form one R K11 C replaced with 6 -C 10 aryl or 5-6 membered heteroaryl, where R K11 is C4 In some embodiments, R K3 and R K4 together with the carbon to which they are attached form one R K11 C replaced with 6 -C 10 aryl or 5-6 membered heteroaryl, where R K11 is C 5 In some embodiments, R K3 and R K4 together with the carbon to which they are attached form one R K11 C replaced with 6 -C 10 aryl or 5-6 membered heteroaryl, where R K11 is C 6 It is an alkyl.

[0141] In some embodiments, R K3 and R K4 together with the carbon to which they are attached form one R K11 C replaced with 6 -C 10 aryl, where R K11 are CN, Cl, F, Br, I, and C 1 -C 6 In some embodiments, R K3 and R K4 together with the carbon to which they are attached form one R K11 C replaced with 6 -C 10 aryl, where R K11 CN, Cl, F, and C 1 -C 6 is selected from alkyl.

[0142] In some embodiments, R K3 and R K4 together with the carbon to which they are attached form one R K11 Form a 5-6 membered heteroaryl substituted with, where R K11are CN, Cl, F, Br, I, and C 1 -C 6 In some embodiments, R K3 and R K4 together with the carbon to which they are attached form one R K11 Form a 5-6 membered heteroaryl substituted with, where R K11 CN, Cl, F, and C 1 -C 6 is selected from alkyl.

[0143] In some embodiments, R K3 and R K4 together with the carbon to which they are attached form two R K11 C replaced with 6 -C 10 aryl or 5-6 membered heteroaryl, where one R K11 are OH, CN, Cl, F, Br, I, and NR K12 R K13 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, and C 1 -C 6 haloalkyl, and the other R K11 are CN, Cl, F, Br, I, and C 1 -C 6 In some embodiments, R K3 and R K4 together with the carbon to which they are attached form two R K11 C replaced with 6 -C 10 aryl or 5-6 membered heteroaryl, where one R K11 are OH, CN, Cl, F, Br, I, and NR K12 R K13 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2-C 6 Alkynyl, and C 1 -C 6 haloalkyl, and the other R K11 CN, Cl, F, and C 1 -C 6 is selected from alkyl.

[0144] In some embodiments, R K3 and R K4 together with the carbon to which they are attached form two R K11 C replaced with 6 -C 10 aryl or 5-6 membered heteroaryl, where both R K11 are CN, Cl, F, Br, I, and C 1 -C 6 In some embodiments, R K3 and R K4 together with the carbon to which they are attached form two R K11 C replaced with 6 -C 10 aryl or 5-6 membered heteroaryl, where both R K11 CN, Cl, F, and C 1 -C 6 is selected from alkyl.

[0145] In some embodiments, R K3 and R K4 together with the carbons to which they are attached form three R K11 C replaced with 6 -C 10 aryl or 5-6 membered heteroaryl, where each R K11 are OH, CN, Cl, F, Br, I, and NR K12 R K13 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, and C 1 -C 6In some embodiments, R K3 and R K4 together with the carbons to which they are attached form three R K11 C replaced with 6 -C 10 aryl or 5-6 membered heteroaryl, where each R K11 are CN, Cl, F, Br, I, and C 1 -C 6 In some embodiments, R K3 and R K4 together with the carbons to which they are attached form three R K11 C replaced with 6 -C 10 aryl or 5-6 membered heteroaryl, where each R K11 CN, Cl, F, and C 1 -C 6 alkyl.

[0146] In some embodiments, R K3 and R K4 Together with the carbons to which they are attached, they form four R K11 C replaced with 6 -C 10 aryl or 5-6 membered heteroaryl, where each R K11 are OH, CN, Cl, F, Br, I, and NR K12 R K13 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, and C 1 -C 6 In some embodiments, R K3 and R K4 Together with the carbons to which they are attached, they form four R K11 C replaced with 6 -C 10aryl or 5-6 membered heteroaryl, where each R K11 are CN, Cl, F, Br, I, and C 1 -C 6 In some embodiments, R K3 and R K4 Together with the carbons to which they are attached, they form four R K11 C replaced with 6 -C 10 aryl or 5-6 membered heteroaryl, where each R K11 CN, Cl, F, and C 1 -C 6 alkyl.

[0147] In some embodiments, R K3 and R K4 Together with the carbons to which they are attached, they form five R K11 C replaced with 6 -C 10 aryl or 5-6 membered heteroaryl, where each R K11 are OH, CN, Cl, F, Br, I, and NR K12 R K13 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, and C 1 -C 6 In some embodiments, R K3 and R K4 Together with the carbons to which they are attached, they form five R K11 C replaced with 6 -C 10 aryl or 5-6 membered heteroaryl, where each R K11 are CN, Cl, F, Br, I, and C 1 -C 6 In some embodiments, R K3 and R K4Together with the carbons to which they are attached, they form five R K11 C replaced with 6 -C 10 aryl or 5-6 membered heteroaryl, where each R K11 CN, Cl, F, and C 1 -C 6 alkyl.

[0148] In some embodiments, R K3 and R K4 together with the carbon to which they are attached, C 6 -C 10 Forming an aryl.

[0149] In some embodiments, R K3 and R K4 together with the carbon to which they are attached, C 6 In some embodiments, R K3 and R K4 together with the carbon to which they are attached, C 7 In some embodiments, R K3 and R K4 together with the carbon to which they are attached, C 8 In some embodiments, R K3 and R K4 together with the carbon to which they are attached, C 9 In some embodiments, R K3 and R K4 together with the carbon to which they are attached, C 10 Forming an aryl.

[0150] In some embodiments, R K3 and R K4 are unsubstituted together with the carbon to which they are attached. 6 -C 10 In some embodiments, R K3 and R K4together with the carbon to which they are attached form one R K11 C replaced with 6 -C 10 In some embodiments, R K3 and R K4 together with the carbon to which they are attached form two R K11 C replaced with 6 -C 10 In some embodiments, R K3 and R K4 together with the carbons to which they are attached form three R K11 C replaced with 6 -C 10 In some embodiments, R K3 and R K4 Together with the carbons to which they are attached, they form four R K11 C replaced with 6 -C 10 In some embodiments, R K3 and R K4 Together with the carbons to which they are attached, they form five R K11 C replaced with 6 -C 10 Forming an aryl.

[0151] In some embodiments, R K3 and R K4 together with the carbons to which they are attached form a 5- or 6-membered heteroaryl.

[0152] In some embodiments, R K3 and R K4 taken together with the carbons to which they are attached form a 5-membered heteroaryl. K3 and R K4 taken together with the carbons to which they are attached form a 6-membered heteroaryl.

[0153] In some embodiments, R K3 and RK4 taken together with the carbons to which they are attached form an unsubstituted 5- or 6-membered heteroaryl. In some embodiments, R K3 and R K4 together with the carbon to which they are attached form one R K11 In some embodiments, R K3 and R K4 together with the carbon to which they are attached form two R K11 In some embodiments, R K3 and R K4 together with the carbons to which they are attached form three R K11 In some embodiments, R K3 and R K4 Together with the carbons to which they are attached, they form four R K11 In some embodiments, R K3 and R K4 Together with the carbons to which they are attached, they form five R K11 forming a 5- or 6-membered heteroaryl substituted with

[0154] In some embodiments, R K8 , H, C 1 -C 6 Alkyl or C 1 -C 6 In some embodiments, R K8 is C 1 -C 6 Alkyl or C 1 -C 6 In some embodiments, R K8 is H. In some embodiments, R K8 is C 1 -C 6 In some embodiments, R K8 is C1 -C 6 It is haloalkyl.

[0155] In some embodiments, R K8 is methyl. In some embodiments, R K8 is ethyl. In some embodiments, R K8 is propyl. In some embodiments, R K8 is n-propyl. In some embodiments, R K8 is isopropyl. In some embodiments, R K8 is butyl. In some embodiments, R K8 is n-butyl. In some embodiments, R K8 is isobutyl. In some embodiments, R K8 is sec-butyl. In some embodiments, R K8 is tert-butyl. In some embodiments, R K8 is pentyl. In some embodiments, R K8 is hexyl.

[0156] In some embodiments, R K8 is C 1 In some embodiments, R K8 is C 2 In some embodiments, R K8 is C 3 In some embodiments, R K8 is C 4 In some embodiments, R K8 is C 5 In some embodiments, R K8 is C 6 It is haloalkyl.

[0157] In some embodiments, R K9 , H, C 1 -C6 Alkyl or C 1 -C 6 In some embodiments, R K9 is C 1 -C 6 Alkyl or C 1 -C 6 In some embodiments, R K9 is H. In some embodiments, R K9 is C 1 -C 6 In some embodiments, R K9 is C 1 -C 6 It is haloalkyl.

[0158] In some embodiments, R K9 is methyl. In some embodiments, R K9 is ethyl. In some embodiments, R K9 is propyl. In some embodiments, R K9 is n-propyl. In some embodiments, R K9 is isopropyl. In some embodiments, R K9 is butyl. In some embodiments, R K9 is n-butyl. In some embodiments, R K9 is isobutyl. In some embodiments, R K9 is sec-butyl. In some embodiments, R K9 is tert-butyl. In some embodiments, R K9 is pentyl. In some embodiments, R K9 is hexyl.

[0159] In some embodiments, R K9 is C 1 In some embodiments, R K9 is C 2 In some embodiments, RK9 is C 3 In some embodiments, R K9 is C 4 In some embodiments, R K9 is C 5 In some embodiments, R K9 is C 6 It is haloalkyl.

[0160] In some embodiments, R K12 , H, C 1 -C 6 Alkyl, and C 1 -C 6 In some embodiments, R K12 is H. In some embodiments, R K12 is C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl.

[0161] In some embodiments, R K12 is C 1 -C 6 It is an alkyl.

[0162] In some embodiments, R K12 is methyl. In some embodiments, R K12 is ethyl. In some embodiments, R K12 is propyl. In some embodiments, R K12 is n-propyl. In some embodiments, R K12 is isopropyl. In some embodiments, R K12 is butyl. In some embodiments, R K12 is n-butyl. In some embodiments, R K12 is isobutyl. In some embodiments, R K12 is sec-butyl. In some embodiments, RK12 is tert-butyl. In some embodiments, R K12 is pentyl. In some embodiments, R K12 is hexyl.

[0163] In some embodiments, R K12 is C 1 -C 6 It is haloalkyl.

[0164] In some embodiments, R K12 is C 1 In some embodiments, R K12 is C 2 In some embodiments, R K12 is C 3 In some embodiments, R K12 is C 4 In some embodiments, R K12 is C 5 In some embodiments, R K12 is C 6 It is haloalkyl.

[0165] In some embodiments, R K13 , H, C 1 -C 6 Alkyl, and C 1 -C 6 In some embodiments, R K13 is selected from H. In some embodiments, R K13 is C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl.

[0166] In some embodiments, R K13 is C 1 -C 6 It is an alkyl.

[0167] In some embodiments, R K13 is methyl. In some embodiments, R K13 is ethyl. In some embodiments, R K13 is propyl. In some embodiments, R K13 is n-propyl. In some embodiments, R K13 is isopropyl. In some embodiments, R K13 is butyl. In some embodiments, R K13 is n-butyl. In some embodiments, R K13 is isobutyl. In some embodiments, R K13 is sec-butyl. In some embodiments, R K13 is tert-butyl. In some embodiments, R K13 is pentyl. In some embodiments, R K13 is hexyl.

[0168] In some embodiments, R K13 is C 1 -C 6 It is haloalkyl.

[0169] In some embodiments, R K13 is C 1 In some embodiments, R K13 is C 2 In some embodiments, R K13 is C 3 In some embodiments, R K13 is C 4 In some embodiments, R K13 is C 5 In some embodiments, R K13 is C 6 It is haloalkyl.

[0170] In some embodiments, R K12 is H and R K13 is C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl.

[0171] In some embodiments, R K12 is H and R K13 is C 1 -C 6 It is an alkyl.

[0172] In some embodiments, R K12 is H and R K13 is methyl. In some embodiments, R K12 is H and R K13 is ethyl. In some embodiments, R K12 is H and R K13 is propyl. In some embodiments, R K12 is H and R K13 is n-propyl. In some embodiments, R K12 is H and R K13 is isopropyl. In some embodiments, R K12 is H and R K13 is butyl. In some embodiments, R K12 is H and R K13 is n-butyl. In some embodiments, R K12 is H and R K13 is isobutyl. In some embodiments, R K12 is H and R K13 is sec-butyl. In some embodiments, R K12 is H and R K13 is tert-butyl. In some embodiments, R K12 is H and R K13 is pentyl. In some embodiments, R K12 is H and RK13 is hexyl.

[0173] In some embodiments, R K12 is H and R K13 is C 1 -C 6 It is haloalkyl.

[0174] In some embodiments, R K12 is H and R K13 is C 1 In some embodiments, R K12 is H and R K13 is C 2 In some embodiments, R K12 is H and R K13 is C 3 In some embodiments, R K12 is H and R K13 is C 4 In some embodiments, R K12 is H and R K13 is C 5 In some embodiments, R K12 is H and R K13 is C 6 It is haloalkyl.

[0175] In some embodiments, R K12 is H and R K13 is C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl.

[0176] In some embodiments, R K12 is H and R K13 is C 1 -C 6 It is an alkyl.

[0177] In some embodiments, R K12is H and R K13 is methyl. In some embodiments, R K12 is H and R K13 is ethyl. In some embodiments, R K12 is H and R K13 is propyl. In some embodiments, R K12 is H and R K13 is n-propyl. In some embodiments, R K12 is H and R K13 is isopropyl. In some embodiments, R K12 is H and R K13 is butyl. In some embodiments, R K12 is H and R K13 is n-butyl. In some embodiments, R K12 is H and R K13 is isobutyl. In some embodiments, R K12 is H and R K13 is sec-butyl. In some embodiments, R K12 is H and R K13 is tert-butyl. In some embodiments, R K12 is H and R K13 is pentyl. In some embodiments, R K12 is H and R K13 is hexyl.

[0178] In some embodiments, R K12 is H and R K13 is C 1 -C 6 It is haloalkyl.

[0179] In some embodiments, R K12 is H and R K13 is C 1 In some embodiments, R K12 is H and R K13 is C 2In some embodiments, R K12 is H and R K13 is C 3 In some embodiments, R K12 is H and R K13 is C 4 In some embodiments, R K12 is H and R K13 is C 5 In some embodiments, R K12 is H and R K13 is C 6 It is haloalkyl.

[0180] In some embodiments, R K14 , H, C 1 -C 6 Alkyl, and C 1 -C 6 In some embodiments, R K14 is selected from H. In some embodiments, R K14 is C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl.

[0181] In some embodiments, R K14 is C 1 -C 6 It is an alkyl.

[0182] In some embodiments, R K14 is methyl. In some embodiments, R K14 is ethyl. In some embodiments, R K14 is propyl. In some embodiments, R K14 is n-propyl. In some embodiments, R K14 is isopropyl. In some embodiments, R K14 is butyl. In some embodiments, RK14 is n-butyl. In some embodiments, R K14 is isobutyl. In some embodiments, R K14 is sec-butyl. In some embodiments, R K14 is tert-butyl. In some embodiments, R K14 is pentyl. In some embodiments, R K14 is hexyl.

[0183] In some embodiments, R K14 is C 1 -C 6 It is haloalkyl.

[0184] In some embodiments, R K14 is C 1 In some embodiments, R K14 is C 2 In some embodiments, R K14 is C 3 In some embodiments, R K14 is C 4 In some embodiments, R K14 is C 5 In some embodiments, R K14 is C 6 It is haloalkyl.

[0185] In some embodiments, R K15 , H, C 1 -C 6 Alkyl, and C 1 -C 6 In some embodiments, R K15 is selected from H. In some embodiments, R K15 is C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl.

[0186] In some embodiments, R K15 is C 1 -C 6 It is an alkyl.

[0187] In some embodiments, R K15 is methyl. In some embodiments, R K15 is ethyl. In some embodiments, R K15 is propyl. In some embodiments, R K15 is n-propyl. In some embodiments, R K15 is isopropyl. In some embodiments, R K15 is butyl. In some embodiments, R K15 is n-butyl. In some embodiments, R K15 is isobutyl. In some embodiments, R K15 is sec-butyl. In some embodiments, R K15 is tert-butyl. In some embodiments, R K15 is pentyl. In some embodiments, R K15 is hexyl.

[0188] In some embodiments, R K15 is C 1 -C 6 It is haloalkyl.

[0189] In some embodiments, R K15 is C 1 In some embodiments, R K15 is C 2 In some embodiments, R K15 is C 3 In some embodiments, R K15 is C 4 In some embodiments, R K15 is C5 In some embodiments, R K15 is C 6 It is haloalkyl.

[0190] In some embodiments, R K14 is H and R K15 is C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl.

[0191] In some embodiments, R K14 is H and R K15 is C 1 -C 6 It is an alkyl.

[0192] In some embodiments, R K14 is H and R K15 is methyl. In some embodiments, R K14 is H and R K15 is ethyl. In some embodiments, R K14 is H and R K15 is propyl. In some embodiments, R K14 is H and R K15 is n-propyl. In some embodiments, R K14 is H and R K15 is isopropyl. In some embodiments, R K14 is H and R K15 is butyl. In some embodiments, R K14 is H and R K15 is n-butyl. In some embodiments, R K14 is H and R K15 is isobutyl. In some embodiments, R K14 is H and R K15 is sec-butyl. In some embodiments, R K14 is H and R K15is tert-butyl. In some embodiments, R K14 is H and R K15 is pentyl. In some embodiments, R K14 is H and R K15 is hexyl.

[0193] In some embodiments, R K14 is H and R K15 is C 1 -C 6 It is haloalkyl.

[0194] In some embodiments, R K14 is H and R K15 is C 1 In some embodiments, R K14 is H and R K15 is C 2 In some embodiments, R K14 is H and R K15 is C 3 In some embodiments, R K14 is H and R K15 is C 4 In some embodiments, R K14 is H and R K15 is C 5 In some embodiments, R K14 is H and R K15 is C 6 It is haloalkyl.

[0195] In some embodiments, R K14 is H and R K15 is C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl.

[0196] In some embodiments, R K14 is H and RK15 is C 1 -C 6 It is an alkyl.

[0197] In some embodiments, R K14 is H and R K15 is methyl. In some embodiments, R K14 is H and R K15 is ethyl. In some embodiments, R K14 is H and R K15 is propyl. In some embodiments, R K14 is H and R K15 is n-propyl. In some embodiments, R K14 is H and R K15 is isopropyl. In some embodiments, R K14 is H and R K15 is butyl. In some embodiments, R K14 is H and R K15 is n-butyl. In some embodiments, R K14 is H and R K15 is isobutyl. In some embodiments, R K14 is H and R K15 is sec-butyl. In some embodiments, R K14 is H and R K15 is tert-butyl. In some embodiments, R K14 is H and R K15 is pentyl. In some embodiments, R K14 is H and R K15 is hexyl.

[0198] In some embodiments, R K14 is H and R K15 is C 1 -C 6 It is haloalkyl.

[0199] In some embodiments, R K14is H and R K15 is C 1 In some embodiments, R K14 is H and R K15 is C 2 In some embodiments, R K14 is H and R K15 is C 3 In some embodiments, R K14 is H and R K15 is C 4 In some embodiments, R K14 is H and R K15 is C 5 In some embodiments, R K14 is H and R K15 is C 6 It is haloalkyl.

[0200] In some embodiments, R K14 and R K15 X K4 and together with the carbon to which they are attached, C 4 -C 7 It forms a cycloalkyl or a 4- to 7-membered heterocycle.

[0201] In some embodiments, X K4 is C 1 -C 3 alkylene, R K14 and R K15 X K4 and together with the carbon to which they are attached, C 4 -C 7 Forms a cycloalkyl.

[0202] In some embodiments, X K4 is C 1 -C 3 alkylene, R K14 and R K15 X K4 and together with the carbon to which they are attached, C 4In some embodiments, X K4 is C 1 -C 3 alkylene, R K14 and R K15 X K4 and together with the carbon to which they are attached, C 5 In some embodiments, X K4 is C 1 -C 3 alkylene, R K14 and R K15 X K4 and together with the carbon to which they are attached, C 6 In some embodiments, X K4 is C 1 -C 3 alkylene, R K14 and R K15 X K4 and together with the carbon to which they are attached, C 7 Forms a cycloalkyl.

[0203] In some embodiments, R K14 and R K15 X K4 and together with the carbon to which they are attached form a 4- to 7-membered heterocycle. K14 and R K15 X K4 and together with the carbon to which they are attached form a 5- or 6-membered heterocycle.

[0204] In some embodiments, R K14 and R K15 X K4 and together with the carbon to which they are attached form a four-membered heterocycle. K14 and R K15 X K4 and together with the carbon to which they are attached form a 5-membered heterocycle. K14 and R K15X K4 and together with the carbons to which they are attached form a 6-membered heterocycle. K14 and R K15 X K4 and together with the carbons to which they are attached form a seven-membered heterocyclic ring.

[0205] In some embodiments, KTM is selected from the group consisting of (KTM-1), (KTM-2), (KTM-3), (KTM-4), (KTM-5), (KTM-6), (KTM-7), (KTM-8), (KTM-9), (KTM-10), (KTM-11), (KTM-12), (KTM-13), and (KTM-14): [ka] [ka] The structure is selected from:

[0206] In some embodiments, LNK is a chemical linking moiety that covalently couples KTM to VLM and has the structure LI: [ka] wherein L and n L is as described herein.

[0207] In some embodiments, n L is any integer from 1 to 50. In some embodiments, n L is any integer from 1 to 40. In some embodiments, n L is any integer from 1 to 30. In some embodiments, n L is any integer from 1 to 20. In some embodiments, n L is any integer from 1 to 10. In some embodiments, n L is any integer from 1 to 60. In some embodiments, n Lis 2, 3, 4, 5, or 6. In some embodiments, n L is 2, 3, 4, or 5. In some embodiments, n L is 2 or 3. In some embodiments, n L In some embodiments, n L is 3. In some embodiments, n L In some embodiments, n L In some embodiments, n L is 6.

[0208] In some embodiments, LNK has the structure (L-Ia), (L-Ib), (L-Ic), (L-Id), (L-Ie), or (L-If): [ka] where L is as described herein.

[0209] In some embodiments, LNK has structure (L-Ia) or (L-Ib). In some embodiments, LNK has structure (L-Ia), (L-Ib), or (L-Id). In some embodiments, LNK has structure (L-Ia), (L-Ib), or (L-Id). In some embodiments, LNK has structure (L-Ia), (L-Ib), (L-Id), or (L-Ie). In some embodiments, LNK has structure (L-Ia) or (L-Id). In some embodiments, LNK has structure (L-Ib) or (L-Ie). In some embodiments, LNK has structure (L-Ic) or (L-Id). In some embodiments, LNK has structure (L-Ic), (L-Id), or (I-If). In some embodiments, LNK has structure (L-Id) or (L-If). In some embodiments, LNK has structure (L-Ia). In some embodiments, LNK has structure (L-Ib). In some embodiments, LNK has structure (L-Ic). In some embodiments, LNK has structure (L-Id). In some embodiments, LNK has structure (L-Ie). In some embodiments, LNK has structure (L-If).

[0210] In some embodiments, LNK has the structure (L-Ia'), (L-Ib'), (L-Ic'), (L-Id'), (L-Ie'), or (L-If'): [ka] Each L a , L b , L c , L d , L e , L f , L g , L h , L i , L j , L k , and L l is, independently, absent, or [ka] C 2 -C 6 Alkylene, C 2 -C 6 Alkenylene, C 2 -C 6 Alkynylene, monocyclic C 4 -C 10 Cycloalkylene, fused bicyclic C 4 -C 10 Cycloalkylene, Bridged Bicyclic C 6 -C 10 Cycloalkylene or spiro-fused bicyclic C 5 -C 12 Cycloalkylene, monocyclic 4-10 membered heterocycloalkylene, fused bicyclic 4-10 membered heterocycloalkylene, bridged bicyclic 6-10 membered heterocycloalkylene, spiro-fused 5-12 membered heterocycloalkylene, C 6 -C 10 cycloalkylene, heterocycloalkylene, arylene, and heteroarylene, each of which is selected from 1, 2, 3, 4, or 5 R L5 Optionally replaced by A L , R L1 , R L2 , R L3 , R L4 , R L5 , and n L is as described herein.

[0211] In some embodiments, each L a , L b , L c , L d , L e , L f , L g , L h , L i , L j , L k , and L l teeth, [ka] C 2 -C6 Alkylene, C 2 -C 6 Alkenylene, C 2 -C 6 Alkynylene, monocyclic C 4 -C 10 Cycloalkylene, fused bicyclic C 4 -C 10 Cycloalkylene, Bridged Bicyclic C 6 -C 10 Cycloalkylene or spiro-fused bicyclic C 5 -C 12 Cycloalkylene, monocyclic 4-10 membered heterocycloalkylene, fused bicyclic 4-10 membered heterocycloalkylene, bridged bicyclic 6-10 membered heterocycloalkylene, spiro-fused 5-12 membered heterocycloalkylene, C 6 -C 10 arylene, and 5- to 6-membered heteroarylene, where each cycloalkylene, heterocycloalkylene, arylene, and heteroarylene is independently selected from 1, 2, 3, 4, or 5 R L5 Optionally replaced by A L , R L1 , R L2 , R L3 , R L4 , R L5 , and n L is as described herein.

[0212] In some embodiments, LNK has structure (L-Ia') or (L-Ib'). In some embodiments, LNK has structure (L-Ia'), (L-Ib'), or (L-Id'). In some embodiments, LNK has structure (L-Ia'), (L-Ib'), or (L-Id'). In some embodiments, LNK has structure (L-Ia'), (L-Ib'), (L-Id'), or (L-Ie'). In some embodiments, LNK has structure (L-Ia') or (L-Id'). In some embodiments, LNK has structure (L-Ib') or (L-Ie'). In some embodiments, LNK has structure (L-Ic') or (L-Id'). In some embodiments, LNK has structure (L-Ic'), (L-Id'), or (I-If'). In some embodiments, LNK has structure (L-Id') or (L-If'). In some embodiments, LNK has structure (L-Ia'). In some embodiments, LNK has structure (L-Ib'). In some embodiments, LNK has structure (L-Ic'). In some embodiments, LNK has structure (L-Id'). In some embodiments, LNK has structure (L-Ie'). In some embodiments, LNK has structure (L-If').

[0213] In some embodiments, L a -A L -, [ka] In some embodiments, L a -A L -, [ka] In some embodiments, L a teeth, [ka] In some embodiments, L a teeth, [ka] In some embodiments, L a teeth, [ka] In some embodiments, L a teeth, [ka] In some embodiments, L a teeth, [ka] In some embodiments, L a teeth, [ka] It is.

[0214] In some embodiments, L b -A L -, [ka] In some embodiments, L b -A L -, [ka] In some embodiments, L b teeth, [ka] In some embodiments, L b teeth, [ka] In some embodiments, L b teeth, [ka] In some embodiments, L b teeth, [ka] In some embodiments, L b teeth, [ka] In some embodiments, L b teeth, [ka] It is.

[0215] In some embodiments, L c -A L -, [ka] In some embodiments, L c -A L -, [ka] In some embodiments, L c teeth, [ka] In some embodiments, L c teeth, [ka] In some embodiments, L c teeth, [ka] In some embodiments, L c teeth, [ka] In some embodiments, L c teeth, [ka] In some embodiments, L c teeth, [ka] It is.

[0216] In some embodiments, L d -A L -, C 2 -C 6 Alkylene, C 2 -C 6 Alkenylene, C 2 -C 6 In some embodiments, L is selected from alkynylene. d -A L In some embodiments, L d is C 2 -C 6 In some embodiments, L is selected from alkylene. d is C 2 -C 6 In some embodiments, L is selected from the group consisting of alkenylene. d is C 2 -C 6 In some embodiments, L is selected from alkynylene. d is -CH 2 In some embodiments, L d is -CH 2 CH 2 In some embodiments, L d is -CH 2 CH 2 CH 2In some embodiments, L d -CH 2 CH 2 CH 2 CH 2 In some embodiments, L d -CH 2 CH 2 CH 2 CH 2 CH 2 In some embodiments, L d -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -It is.

[0217] In some embodiments, L e teeth, [ka] In some embodiments, L e teeth, [ka] In some embodiments, L e teeth, [ka] In some embodiments, L e teeth, [ka] In some embodiments, L e teeth, [ka] In some embodiments, L e teeth, [ka] In some embodiments, L e teeth, [ka] In some embodiments, L e teeth, [ka] In some embodiments, L e teeth, [ka] It is.

[0218] In some embodiments, L f -A L -, [ka] In some embodiments, L f -A L -, [ka] In some embodiments, L f teeth, [ka] In some embodiments, L f teeth, [ka] In some embodiments, L f teeth, [ka] In some embodiments, L f teeth, [ka] In some embodiments, L f teeth, [ka] In some embodiments, L f teeth, [ka] It is.

[0219] In some embodiments, L g -A L -, [ka] In some embodiments, L g -A L -, [ka] In some embodiments, L g teeth, [ka] In some embodiments, L g teeth, [ka] In some embodiments, L g teeth, [ka] In some embodiments, L g teeth, [ka] In some embodiments, L g teeth, [ka] In some embodiments, L g teeth, [ka] It is.

[0220] In some embodiments, L h is a monocyclic C 4 -C 10 Cycloalkylene, fused bicyclic C 4 -C 10 Cycloalkylene, Bridged Bicyclic C 6 -C 10 Cycloalkylene or spiro-fused bicyclic C 4 -C 12 Cycloalkylene, monocyclic 4-10 membered heterocycloalkylene, fused bicyclic 4-10 membered heterocycloalkylene, bridged bicyclic 6-10 membered heterocycloalkylene, spiro-fused 4-12 membered heterocycloalkylene, C 6 -C 10 arylene, and 5- to 6-membered heteroarylene, where L h is 1, 2, 3, 4, or 5 R L5 In some embodiments, L h is a monocyclic C 4 -C 10 Cycloalkylene, fused bicyclic C 4 -C 10 Cycloalkylene, Bridged Bicyclic C 6 -C 10 Cycloalkylene or spiro-fused bicyclic C 4 -C 12 Cycloalkylene, monocyclic 4-10 membered heterocycloalkylene, fused bicyclic 4-10 membered heterocycloalkylene, bridged bicyclic 6-10 membered heterocycloalkylene, spiro-fused 4-12 membered heterocycloalkylene, C 6 -C 10 arylene, and 5- to 6-membered heteroarylene, where L h is non-substituted.

[0221] In some embodiments, L h is a monocyclic C 4 -C 10 Cycloalkylene, fused bicyclic C 4 -C 10 Cycloalkylene, Bridged Bicyclic C 6 -C 10 Cycloalkylene or spiro-fused bicyclic C 4 -C 12 In some embodiments, L is selected from the group consisting of cycloalkylene. h is selected from monocyclic 4-10 membered heterocycloalkylene, fused bicyclic 4-10 membered heterocycloalkylene, bridged bicyclic 6-10 membered heterocycloalkylene, and spiro-fused 4-12 membered heterocycloalkylene. h is C 6 -C 10 It is selected from arylene and 5- to 6-membered heteroarylene.

[0222] In some embodiments, L h is selected from monocyclic 4-10 membered heterocycloalkylene. h is selected from fused bicyclic 4-10 membered heterocycloalkylene. h is selected from bridged bicyclic 6-10 membered heterocycloalkylene. h is selected from spiro-fused bicyclic 4- to 12-membered heterocycloalkylenes.

[0223] In some embodiments, L h is a monocyclic 4-10 membered heterocycloalkylene. h is a monocyclic 4- to 7-membered heterocycloalkylene. h is a monocyclic 5- or 6-membered heterocycloalkylene.

[0224] In some embodiments, L h is a monocyclic 4-membered heterocycloalkylene. In some embodiments, Lh is a monocyclic 5-membered heterocycloalkylene. In some embodiments, L h is a monocyclic 6-membered heterocycloalkylene. In some embodiments, L h is a monocyclic 7-membered heterocycloalkylene. In some embodiments, L h is a monocyclic 8-membered heterocycloalkylene. In some embodiments, L h is a monocyclic 9-membered heterocycloalkylene. In some embodiments, L h is a monocyclic 10-membered heterocycloalkylene.

[0225] In some embodiments, L h is a fused bicyclic 6-10 membered heterocycloalkylene. In some embodiments, L h is a fused bicyclic 8-10 membered heterocycloalkylene. h is a fused bicyclic 5- or 6-membered heterocycloalkylene.

[0226] In some embodiments, L h is a fused bicyclic 4-membered heterocycloalkylene. In some embodiments, L h is a fused bicyclic 5-membered heterocycloalkylene. In some embodiments, L h is a fused bicyclic 6-membered heterocycloalkylene. In some embodiments, L h is a fused bicyclic seven-membered heterocycloalkylene. In some embodiments, L h is a fused bicyclic 8-membered heterocycloalkylene. In some embodiments, L h is a fused bicyclic 9-membered heterocycloalkylene. In some embodiments, L h is a fused bicyclic 10-membered heterocycloalkylene.

[0227] In some embodiments, L his a bridged bicyclic 6-10 membered heterocycloalkylene. In some embodiments, L h is a bridged bicyclic 6- or 7-membered heterocycloalkylene.

[0228] In some embodiments, L h is a bridged bicyclic 6-membered heterocycloalkylene. In some embodiments, L h is a bridged bicyclic seven-membered heterocycloalkylene. In some embodiments, L h is a bridged bicyclic 8-membered heterocycloalkylene. In some embodiments, L h is a bridged bicyclic 9-membered heterocycloalkylene. In some embodiments, L h is a bridged bicyclic 10-membered heterocycloalkylene.

[0229] In some embodiments, L h is a spiro-fused bicyclic 4-12 membered heterocycloalkylene. h is a spiro-fused bicyclic 7-11 membered heterocycloalkylene. h is a spiro-fused bicyclic 7- or 8-membered heterocycloalkylene.

[0230] In some embodiments, L h is a spiro-fused bicyclic 4-membered heterocycloalkylene. In some embodiments, L h is a spiro-fused bicyclic 5-membered heterocycloalkylene. In some embodiments, L h is a spiro-fused bicyclic 6-membered heterocycloalkylene. h is a spiro-fused bicyclic seven-membered heterocycloalkylene. h is a spiro-fused bicyclic 8-membered heterocycloalkylene. In some embodiments, L h is a spiro-fused bicyclic 9-membered heterocycloalkylene. In some embodiments, L his a spiro-fused bicyclic 10-membered heterocycloalkylene. h is a spiro-fused bicyclic 11-membered heterocycloalkylene. h is a spiro-fused bicyclic 12-membered heterocycloalkylene.

[0231] In some embodiments, L h teeth, [ka] In some embodiments, L h teeth, [ka] In some embodiments, L h teeth, [ka] In some embodiments, L h teeth, [ka] In some embodiments, L h teeth, [ka] is selected from.

[0232] In some embodiments, L h teeth, [ka] In some embodiments, L h teeth, [ka] In some embodiments, L h teeth, [ka] In some embodiments, L h teeth, [ka] In some embodiments, L h teeth, [ka] In some embodiments, L h teeth, [ka] In some embodiments, L h teeth, [ka] In some embodiments, L h teeth, [ka] In some embodiments, L h In some embodiments, L h teeth, [ka] In some embodiments, L h teeth, [ka] In some embodiments, L h teeth, [ka] It is.

[0233] In some embodiments, L i is a monocyclic C 4 -C10 Cycloalkylene, fused bicyclic C 4 -C 10 Cycloalkylene, Bridged Bicyclic C 6 -C 10 Cycloalkylene or spiro-fused bicyclic C 4 -C 12 Cycloalkylene, monocyclic 4-10 membered heterocycloalkylene, fused bicyclic 4-10 membered heterocycloalkylene, bridged bicyclic 6-10 membered heterocycloalkylene, spiro-fused 4-12 membered heterocycloalkylene, C 6 -C 10 arylene, and 5- to 6-membered heteroarylene, where L i is 1, 2, 3, 4, or 5 R L5 In some embodiments, L i is a monocyclic C 4 -C 10 Cycloalkylene, fused bicyclic C 4 -C 10 Cycloalkylene, Bridged Bicyclic C 6 -C 10 Cycloalkylene or spiro-fused bicyclic C 4 -C 12 Cycloalkylene, monocyclic 4-10 membered heterocycloalkylene, fused bicyclic 4-10 membered heterocycloalkylene, bridged bicyclic 6-10 membered heterocycloalkylene, spiro-fused 4-12 membered heterocycloalkylene, C 6 -C 10 arylene, and 5- to 6-membered heteroarylene, where L i is non-substituted.

[0234] In some embodiments, L i is a monocyclic C 4 -C 10 Cycloalkylene, fused bicyclic C 4 -C 10 Cycloalkylene, Bridged Bicyclic C 6 -C 10 Cycloalkylene or spiro-fused bicyclic C 4 -C 12 In some embodiments, L is selected from the group consisting of cycloalkylene.i is selected from monocyclic 4-10 membered heterocycloalkylene, fused bicyclic 4-10 membered heterocycloalkylene, bridged bicyclic 6-10 membered heterocycloalkylene, and spiro-fused 4-12 membered heterocycloalkylene. i is C 6 -C 10 It is selected from arylene and 5- to 6-membered heteroarylene.

[0235] In some embodiments, L i is selected from monocyclic 4-10 membered heterocycloalkylene. i is selected from fused bicyclic 4-10 membered heterocycloalkylene. i is selected from bridged bicyclic 6-10 membered heterocycloalkylene. i is selected from spiro-fused bicyclic 4- to 12-membered heterocycloalkylenes.

[0236] In some embodiments, L i is a monocyclic 4-10 membered heterocycloalkylene. i is a monocyclic 4- to 7-membered heterocycloalkylene. i is a monocyclic 5- or 6-membered heterocycloalkylene.

[0237] In some embodiments, L i is a monocyclic 4-membered heterocycloalkylene. In some embodiments, L i is a monocyclic 5-membered heterocycloalkylene. In some embodiments, L i is a monocyclic 6-membered heterocycloalkylene. In some embodiments, L i is a monocyclic 7-membered heterocycloalkylene. In some embodiments, L i is a monocyclic 8-membered heterocycloalkylene. In some embodiments, L iis a monocyclic 9-membered heterocycloalkylene. In some embodiments, L i is a monocyclic 10-membered heterocycloalkylene.

[0238] In some embodiments, L i is a fused bicyclic 6-10 membered heterocycloalkylene. In some embodiments, L i is a fused bicyclic 8-10 membered heterocycloalkylene. i is a fused bicyclic 5- or 6-membered heterocycloalkylene.

[0239] In some embodiments, L i is a fused bicyclic 4-membered heterocycloalkylene. In some embodiments, L i is a fused bicyclic 5-membered heterocycloalkylene. In some embodiments, L i is a fused bicyclic 6-membered heterocycloalkylene. In some embodiments, L i is a fused bicyclic seven-membered heterocycloalkylene. In some embodiments, L i is a fused bicyclic 8-membered heterocycloalkylene. In some embodiments, L i is a fused bicyclic 9-membered heterocycloalkylene. In some embodiments, L i is a fused bicyclic 10-membered heterocycloalkylene.

[0240] In some embodiments, L i is a bridged bicyclic 6-10 membered heterocycloalkylene. In some embodiments, L i is a bridged bicyclic 6- or 7-membered heterocycloalkylene.

[0241] In some embodiments, L i is a bridged bicyclic 6-membered heterocycloalkylene. In some embodiments, L i is a bridged bicyclic seven-membered heterocycloalkylene. In some embodiments, L iis a bridged bicyclic 8-membered heterocycloalkylene. In some embodiments, L i is a bridged bicyclic 9-membered heterocycloalkylene. In some embodiments, L i is a bridged bicyclic 10-membered heterocycloalkylene.

[0242] In some embodiments, L i is a spiro-fused bicyclic 4-12 membered heterocycloalkylene. i is a spiro-fused bicyclic 7-11 membered heterocycloalkylene. i is a spiro-fused bicyclic 7- or 8-membered heterocycloalkylene.

[0243] In some embodiments, L i is a spiro-fused bicyclic 4-membered heterocycloalkylene. In some embodiments, L i is a spiro-fused bicyclic 5-membered heterocycloalkylene. In some embodiments, L i is a spiro-fused bicyclic 6-membered heterocycloalkylene. i is a spiro-fused bicyclic seven-membered heterocycloalkylene. i is a spiro-fused bicyclic 8-membered heterocycloalkylene. In some embodiments, L i is a spiro-fused bicyclic 9-membered heterocycloalkylene. In some embodiments, L i is a spiro-fused bicyclic 10-membered heterocycloalkylene. i is a spiro-fused bicyclic 11-membered heterocycloalkylene. i is a spiro-fused bicyclic 12-membered heterocycloalkylene.

[0244] In some embodiments, L i teeth, [ka] In some embodiments, L i teeth, [ka] In some embodiments, L i teeth, [ka] In some embodiments, L i teeth, [ka] In some embodiments, L i teeth, [ka] In some embodiments, L i teeth, [ka] In some embodiments, L i teeth, [ka] In some embodiments, L i teeth, [ka] is selected from.

[0245] In some embodiments, L i teeth, [ka] In some embodiments, L i teeth, [ka] In some embodiments, L i teeth, [ka] In some embodiments, L i teeth, [ka] In some embodiments, L i teeth, [ka] In some embodiments, L i teeth, [ka] In some embodiments, L i teeth, [ka] In some embodiments, L i teeth, [ka] In some embodiments, L i In some embodiments, L i teeth, [ka] In some embodiments, L i teeth, [ka] In some embodiments, L i teeth, [ka] In some embodiments, L i teeth, [ka] In some embodiments, L i teeth, [ka] In some embodiments, L i teeth, [ka] In some embodiments, L i teeth, [ka] In some embodiments, L i teeth, [ka] In some embodiments, L i teeth, [ka] It is.

[0246] In some embodiments, L j is a monocyclic C 4 -C 10 Cycloalkylene, fused bicyclic C 4 -C 10 Cycloalkylene, Bridged Bicyclic C 6 -C 10 Cycloalkylene or spiro-fused bicyclic C 4 -C 12 Cycloalkylene, monocyclic 4-10 membered heterocycloalkylene, fused bicyclic 4-10 membered heterocycloalkylene, bridged bicyclic 6-10 membered heterocycloalkylene, spiro-fused 4-12 membered heterocycloalkylene, C 6 -C 10 arylene, and 5- to 6-membered heteroarylene, where L j 1, 2, 3, 4, or 5 RL5 In some embodiments, L j is a monocyclic C 4 -C 10 Cycloalkylene, fused bicyclic C 4 -C 10 Cycloalkylene, Bridged Bicyclic C 6 -C 10 Cycloalkylene or spiro-fused bicyclic C 4 -C 12 Cycloalkylene, monocyclic 4-10 membered heterocycloalkylene, fused bicyclic 4-10 membered heterocycloalkylene, bridged bicyclic 6-10 membered heterocycloalkylene, spiro-fused 4-12 membered heterocycloalkylene, C 6 -C 10 arylene, and 5- to 6-membered heteroarylene, where L j is non-substituted.

[0247] In some embodiments, L j is a monocyclic C 4 -C 10 Cycloalkylene, fused bicyclic C 4 -C 10 Cycloalkylene, Bridged Bicyclic C 6 -C 10 Cycloalkylene or spiro-fused bicyclic C 4 -C 12 In some embodiments, L is selected from the group consisting of cycloalkylene. j is selected from monocyclic 4-10 membered heterocycloalkylene, fused bicyclic 4-10 membered heterocycloalkylene, bridged bicyclic 6-10 membered heterocycloalkylene, and spiro-fused 4-12 membered heterocycloalkylene. j is C 6 -C 10 It is selected from arylene and 5- to 6-membered heteroarylene.

[0248] In some embodiments, L j is selected from monocyclic 4-10 membered heterocycloalkylene. jis selected from fused bicyclic 4-10 membered heterocycloalkylene. j is selected from bridged bicyclic 6-10 membered heterocycloalkylene. j is selected from spiro-fused bicyclic 4- to 12-membered heterocycloalkylenes.

[0249] In some embodiments, L j is a monocyclic 4-10 membered heterocycloalkylene. j is a monocyclic 4- to 7-membered heterocycloalkylene. j is a monocyclic 5- or 6-membered heterocycloalkylene.

[0250] In some embodiments, L j is a monocyclic 4-membered heterocycloalkylene. In some embodiments, L j is a monocyclic 5-membered heterocycloalkylene. In some embodiments, L j is a monocyclic 6-membered heterocycloalkylene. In some embodiments, L j is a monocyclic 7-membered heterocycloalkylene. In some embodiments, L j is a monocyclic 8-membered heterocycloalkylene. In some embodiments, L j is a monocyclic 9-membered heterocycloalkylene. In some embodiments, L j is a monocyclic 10-membered heterocycloalkylene.

[0251] In some embodiments, L j is a fused bicyclic 6-10 membered heterocycloalkylene. In some embodiments, L j is a fused bicyclic 8-10 membered heterocycloalkylene. j is a fused bicyclic 5- or 6-membered heterocycloalkylene.

[0252] In some embodiments, Lj is a fused bicyclic 4-membered heterocycloalkylene. In some embodiments, L j is a fused bicyclic 5-membered heterocycloalkylene. In some embodiments, L j is a fused bicyclic 6-membered heterocycloalkylene. In some embodiments, L j is a fused bicyclic seven-membered heterocycloalkylene. In some embodiments, L j is a fused bicyclic 8-membered heterocycloalkylene. In some embodiments, L j is a fused bicyclic 9-membered heterocycloalkylene. In some embodiments, L j is a fused bicyclic 10-membered heterocycloalkylene.

[0253] In some embodiments, L j is a bridged bicyclic 6-10 membered heterocycloalkylene. In some embodiments, L j is a bridged bicyclic 6- or 7-membered heterocycloalkylene.

[0254] In some embodiments, L j is a bridged bicyclic 6-membered heterocycloalkylene. In some embodiments, L j is a bridged bicyclic seven-membered heterocycloalkylene. In some embodiments, L j is a bridged bicyclic 8-membered heterocycloalkylene. In some embodiments, L j is a bridged bicyclic 9-membered heterocycloalkylene. In some embodiments, L j is a bridged bicyclic 10-membered heterocycloalkylene.

[0255] In some embodiments, L j is a spiro-fused bicyclic 4-12 membered heterocycloalkylene. j is a spiro-fused bicyclic 7-11 membered heterocycloalkylene. jis a spiro-fused bicyclic 7- or 8-membered heterocycloalkylene.

[0256] In some embodiments, L j is a spiro-fused bicyclic 4-membered heterocycloalkylene. In some embodiments, L j is a spiro-fused bicyclic 5-membered heterocycloalkylene. In some embodiments, L j is a spiro-fused bicyclic 6-membered heterocycloalkylene. j is a spiro-fused bicyclic seven-membered heterocycloalkylene. j is a spiro-fused bicyclic 8-membered heterocycloalkylene. In some embodiments, L j is a spiro-fused bicyclic 9-membered heterocycloalkylene. In some embodiments, L j is a spiro-fused bicyclic 10-membered heterocycloalkylene. j is a spiro-fused bicyclic 11-membered heterocycloalkylene. j is a spiro-fused bicyclic 12-membered heterocycloalkylene.

[0257] In some embodiments, L j teeth, [ka] In some embodiments, L j teeth, [ka] In some embodiments, L j teeth, [ka] In some embodiments, L j teeth, [ka] In some embodiments, L j teeth, [ka] is selected from.

[0258] In some embodiments, L j teeth, [ka] In some embodiments, L j teeth, [ka] In some embodiments, L j teeth, [ka] In some embodiments, L j teeth, [ka] In some embodiments, L j teeth, [ka] In some embodiments, L j teeth, [ka] In some embodiments, L j teeth, [ka] In some embodiments, L j teeth, [ka] In some embodiments, L j In some embodiments, L j teeth, [ka] In some embodiments, L j teeth, [ka] In some embodiments, L j teeth, [ka] It is.

[0259] In some embodiments, L k is a monocyclic C 4 -C 10 Cycloalkylene, fused bicyclic C 4 -C 10 Cycloalkylene, Bridged Bicyclic C 6 -C 10 Cycloalkylene or spiro-fused bicyclic C 4 -C 12 Cycloalkylene, monocyclic 4-10 membered heterocycloalkylene, fused bicyclic 4-10 membered heterocycloalkylene, bridged bicyclic 6-10 membered heterocycloalkylene, spiro-fused 4-12 membered heterocycloalkylene, C 6 -C 10 arylene, and 5- to 6-membered heteroarylene, where L k 1, 2, 3, 4, or 5 R L5 In some embodiments, L k is a monocyclic C 4 -C 10 Cycloalkylene, fused bicyclic C 4 -C 10 Cycloalkylene, Bridged Bicyclic C 6 -C 10 Cycloalkylene or spiro-fused bicyclic C 4 -C 12Cycloalkylene, monocyclic 4-10 membered heterocycloalkylene, fused bicyclic 4-10 membered heterocycloalkylene, bridged bicyclic 6-10 membered heterocycloalkylene, spiro-fused 4-12 membered heterocycloalkylene, C 6 -C 10 arylene, and 5- to 6-membered heteroarylene, where L k is non-substituted.

[0260] In some embodiments, L k is a monocyclic C 4 -C 10 Cycloalkylene, fused bicyclic C 4 -C 10 Cycloalkylene, Bridged Bicyclic C 6 -C 10 Cycloalkylene or spiro-fused bicyclic C 4 -C 12 In some embodiments, L is selected from the group consisting of cycloalkylene. k is selected from monocyclic 4-10 membered heterocycloalkylene, fused bicyclic 4-10 membered heterocycloalkylene, bridged bicyclic 6-10 membered heterocycloalkylene, and spiro-fused 4-12 membered heterocycloalkylene. k is C 6 -C 10 It is selected from arylene and 5- to 6-membered heteroarylene.

[0261] In some embodiments, L k is selected from monocyclic 4-10 membered heterocycloalkylene. k is selected from fused bicyclic 4-10 membered heterocycloalkylene. k is selected from bridged bicyclic 6-10 membered heterocycloalkylene. k is selected from spiro-fused bicyclic 4- to 12-membered heterocycloalkylenes.

[0262] In some embodiments, L kis a monocyclic 4-10 membered heterocycloalkylene. k is a monocyclic 4- to 7-membered heterocycloalkylene. k is a monocyclic 5- or 6-membered heterocycloalkylene.

[0263] In some embodiments, L k is a monocyclic 4-membered heterocycloalkylene. In some embodiments, L k is a monocyclic 5-membered heterocycloalkylene. In some embodiments, L k is a monocyclic 6-membered heterocycloalkylene. In some embodiments, L k is a monocyclic 7-membered heterocycloalkylene. In some embodiments, L k is a monocyclic 8-membered heterocycloalkylene. In some embodiments, L k is a monocyclic 9-membered heterocycloalkylene. In some embodiments, L k is a monocyclic 10-membered heterocycloalkylene.

[0264] In some embodiments, L k is a fused bicyclic 6-10 membered heterocycloalkylene. In some embodiments, L k is a fused bicyclic 8-10 membered heterocycloalkylene. k is a fused bicyclic 5- or 6-membered heterocycloalkylene.

[0265] In some embodiments, L k is a fused bicyclic 4-membered heterocycloalkylene. In some embodiments, L k is a fused bicyclic 5-membered heterocycloalkylene. In some embodiments, L k is a fused bicyclic 6-membered heterocycloalkylene. In some embodiments, L k is a fused bicyclic seven-membered heterocycloalkylene. In some embodiments, L kis a fused bicyclic 8-membered heterocycloalkylene. In some embodiments, L k is a fused bicyclic 9-membered heterocycloalkylene. In some embodiments, L k is a fused bicyclic 10-membered heterocycloalkylene.

[0266] In some embodiments, L k is a bridged bicyclic 6-10 membered heterocycloalkylene. In some embodiments, L k is a bridged bicyclic 6- or 7-membered heterocycloalkylene.

[0267] In some embodiments, L k is a bridged bicyclic 6-membered heterocycloalkylene. In some embodiments, L k is a bridged bicyclic seven-membered heterocycloalkylene. In some embodiments, L k is a bridged bicyclic 8-membered heterocycloalkylene. In some embodiments, L k is a bridged bicyclic 9-membered heterocycloalkylene. In some embodiments, L k is a bridged bicyclic 10-membered heterocycloalkylene.

[0268] In some embodiments, L k is a spiro-fused bicyclic 4-12 membered heterocycloalkylene. k is a spiro-fused bicyclic 7-11 membered heterocycloalkylene. k is a spiro-fused bicyclic 7-8 membered heterocycloalkylene.

[0269] In some embodiments, L k is a spiro-fused bicyclic 4-membered heterocycloalkylene. In some embodiments, L k is a spiro-fused bicyclic 5-membered heterocycloalkylene. In some embodiments, L kis a spiro-fused bicyclic 6-membered heterocycloalkylene. k is a spiro-fused bicyclic seven-membered heterocycloalkylene. k is a spiro-fused bicyclic 8-membered heterocycloalkylene. In some embodiments, L k is a spiro-fused bicyclic 9-membered heterocycloalkylene. In some embodiments, L k is a spiro-fused bicyclic 10-membered heterocycloalkylene. k is a spiro-fused bicyclic 11-membered heterocycloalkylene. k is a spiro-fused bicyclic 12-membered heterocycloalkylene.

[0270] In some embodiments, L k teeth, [ka] In some embodiments, L k teeth, [ka] In some embodiments, L k teeth, [ka] In some embodiments, L k teeth, [ka] In some embodiments, L k teeth, [ka] In some embodiments, L k teeth, [ka] In some embodiments, L k teeth, [ka] In some embodiments, L k teeth, [ka] is selected from.

[0271] In some embodiments, L k teeth, [ka] In some embodiments, L k teeth, [ka] In some embodiments, L k teeth, [ka] In some embodiments, L k teeth, [ka] In some embodiments, L k teeth, [ka] In some embodiments, L k teeth, [ka] In some embodiments, L k teeth, [ka] In some embodiments, L k teeth, [ka] In some embodiments, L k In some embodiments, L k teeth, [ka] In some embodiments, L k teeth, [ka] In some embodiments, L k teeth, [ka] In some embodiments, L k teeth, [ka] In some embodiments, L k teeth, [ka] In some embodiments, L k teeth, [ka] In some embodiments, L k teeth, [ka] In some embodiments, L k teeth, [ka] In some embodiments, L k teeth, [ka] It is.

[0272] In some embodiments, (L-If′) is L l In some embodiments, (L-If') does not contain one L l In some embodiments, (L-If') contains two L l Contains:

[0273] In some embodiments, (L-If') is -A L -, [ka] One L to be selected l In some embodiments, (L-If') contains -A L -, [ka] One L to be selected l In some embodiments, (L-If') contains [ka] One L to be selected l In some embodiments, (L-If') contains [ka] One L to be selected l In some embodiments, (L-If') contains one L l [ka] In some embodiments, (L-If') contains one L l [ka] In some embodiments, (L-If') contains one L l [ka] In some embodiments, (L-If') contains one L l [ka] Contains:

[0274] In some embodiments, (L-If') is a group consisting of two L l where both L l -A L -, [ka] In some embodiments, (L-If') is selected from two L l Wherein one L l -A L -, [ka] and the other L l -A L -, [ka] In some embodiments, (L-If') is selected from two L l Wherein one L l -A L -, [ka] and the other L l teeth, [ka] In some embodiments, two L lWherein one L l -A L -, [ka] and the other L l teeth, [ka] In some embodiments, two L l Wherein one L l -A L -, [ka] and the other L l teeth, [ka] In some embodiments, two L l Wherein one L l -A L -, [ka] and the other L l teeth, [ka] In some embodiments, two L l Wherein one L l -A L -, [ka] and the other L l teeth, [ka] In some embodiments, two L l Wherein one L l-A L -, [ka] and the other L l teeth, [ka] It is.

[0275] In some embodiments, (L-If') is a group consisting of two L l Wherein one L l is O, and the other L l -A L -, [ka] In some embodiments, (L-If') is selected from two L l Wherein one L l is O, and the other L l teeth, [ka] In some embodiments, two L l Wherein one L l -A L -, [ka] and the other L l teeth, [ka] In some embodiments, two L l Wherein one L l is O, and the other L l teeth, [ka] In some embodiments, two Ll Wherein one L l is O, and the other L l teeth, [ka] In some embodiments, two L l Wherein one L l is O, and the other L l teeth, [ka] In some embodiments, two L l Wherein one L l is O, and the other L l teeth, [ka] It is.

[0276] In some embodiments, LNK is selected from the group consisting of (LNK-1), (LNK-2), (LNK-3), (LNK-4), (LNK-5), (LNK-6), (LNK-7), (LNK-8), (LNK-9), and (LNK-10): [ka] In some embodiments, LNK has a structure selected from the group consisting of (LNK-1), (LNK-2), (LNK-3), (LNK-4), or (LNK-5). In some embodiments, LNK has a structure of (LNK-6), (LNK-7), (LNK-8), (LNK-9), (LNK-10), (LNK-11), (LNK-12), or (LNK-13). In some embodiments, LNK has a structure of (LNK-9), (LNK-11), or (LNK-12). In some embodiments, LNK has a structure of (LNK-1). In some embodiments, LNK has a structure of (LNK-2). In some embodiments, LNK has a structure of (LNK-3). In some embodiments, LNK has a structure of (LNK-4). In some embodiments, LNK has a structure of (LNK-5). In some embodiments, LNK has the structure of (LNK-6). In some embodiments, LNK has the structure of (LNK-7). In some embodiments, LNK has the structure of (LNK-8). In some embodiments, LNK has the structure of (LNK-9). In some embodiments, LNK has the structure of (LNK-10). In some embodiments, LNK has the structure of (LNK-11). In some embodiments, LNK has the structure of (LNK-12). In some embodiments, LNK has the structure of (LNK-13).

[0277] In some embodiments, the VLM is a von Hippel-Lindau (VHL) E3 ubiquitin ligase binding moiety having the structure VLM-I: [ka] where: Y V1 teeth, [ka] and Y V2 CN or [ka] and [ka] is phenylene or 5- to 6-membered heteroarylene, [ka] is a 5-membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, S, and O; R V1 , R V2 , and R V3 , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl; R V1 and R V2 together with the carbon to which they are attached, C 3 -C 10 Form a cycloalkyl or 5- to 6-membered heterocycle, R V3 , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl; R V4a and R V4b , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl, Each R V5 and R V6 H and C 1 -C 6 independently selected from alkyl, R V7 and R V8 , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl; R V7 and R V8 together with the atoms to which they are attached, C 3 -C 10 Forming a cycloalkyl or 5- to 6-membered heterocycle, [ka] represents the attachment point between the VLM and the LNK, n V is 0, 1, 2, 3, or 4, o V is 0, 1, 2, or 3.

[0278] In some embodiments, the VLM is a von Hippel-Lindau (VHL) E3 ubiquitin ligase binding moiety having the structure VLM-I': [ka] It is.

[0279] In some embodiments, the VLM is a von Hippel-Lindau (VHL) E3 ubiquitin ligase binding moiety having the structure VLM-I″: [ka] It is.

[0280] In some embodiments, the VLM has the structure of formula (VLM-Ia), (VLM-Ib), (VLM-Ic), or (VLM-Id): [ka] where [ka] Y V1 , Y V2 , Z V1 , Z V2 , R V1 , R V2 , R V3 , RV4a , R V4b R V5 , R V6 , R V7 , R V8 , n V , and o V is as disclosed herein.

[0281] In some embodiments, Y V1 teeth, [ka] In some embodiments, Y V1 teeth, [ka] It is.

[0282] In some embodiments, Y V1 teeth, [ka] In some embodiments, Y V1 teeth, [ka] In some embodiments, Y V1 teeth, [ka] In some embodiments, Y V1 teeth, [ka] It is.

[0283] In some embodiments, Y V1 teeth, [ka] In some embodiments, Y V1 teeth, [ka] In some embodiments, Y V1 teeth, [ka] In some embodiments, Y V1 teeth, [ka] It is.

[0284] In some embodiments, Y V1 teeth, [ka] In some embodiments, Z V1 is phenylene. In some embodiments, Z V1 is 5-6 membered heteroarylene. V1 is a 5-membered heteroarylene. V1 is a 6-membered heteroarylene. V1 is selected from oxazolylene, isoxazolylene, thiazolylene, and isothiazolylene. V1 is selected from oxazolylene and isoxazolylene. V1 is selected from thiazolylene and isothiazolylene. V1 is oxazolylene. In some embodiments, Z V1 is isoxazolylene. In some embodiments, Z V1 is thiazolylene. In some embodiments, Z V1 is an isothiazolylene.

[0285] In some embodiments, ZV1 teeth, [ka] In some embodiments, Z V1 teeth, [ka] In some embodiments, Z V1 teeth, [ka] In some embodiments, Z V1 teeth, [ka] In some embodiments, Z V1 teeth, [ka] In some embodiments, Z V1 teeth, [ka] In some embodiments, Z V1 teeth, [ka] It is.

[0286] In some embodiments, Y V2 CN or [ka] In some embodiments, Y V2 is CN. In some embodiments, Y V2 teeth, [ka] It is.

[0287] In some embodiments, Z V2 is a 5-membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, S, and O. In some embodiments, Z V2 is a 5-membered heteroaryl containing one heteroatom selected from N, S, and O. In some embodiments, Z V2 is a 5-membered heteroaryl containing two heteroatoms independently selected from N, S, and O. In some embodiments, Z V2 is a 5-membered heteroaryl containing two heteroatoms independently selected from N and O. In some embodiments, Z V2 is a 5-membered heteroaryl containing two heteroatoms independently selected from N and S. In some embodiments, Z V2 is selected from pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. V2 is selected from pyrazolyl and imidazolyl. V2 is selected from oxazolyl and isoxazolyl. V2 is selected from thiazolyl and isothiazolyl. V2 is pyrazolyl. In some embodiments, Z V2 is imidazolyl. In some embodiments, Z V2 is oxazolyl. In some embodiments, Z V2 is isoxazolyl. In some embodiments, Z V2 is thiazolyl. In some embodiments, Z V2 is isothiazolyl.

[0288] In some embodiments, Y V2 teeth, [ka] In some embodiments, Y V2 teeth, [ka] In some embodiments, Y V2 teeth, [ka] It is.

[0289] In some embodiments, V is 0, 1, 2, or 3. In some embodiments, o V is 1, 2, or 3. In some embodiments, o V is 0 or 1. In some embodiments, o V is 0. In some embodiments, o V is 1. In some embodiments, o V is 2. In some embodiments, o V is 3.

[0290] In some embodiments, each R V6 H and C 1 -C 6 In some embodiments, each R V6 is independently 1 -C 6 It is an alkyl.

[0291] In some embodiments, V is 1, and R V6 is C 1 -C 6 In some embodiments, o is alkyl. V is 1, and R V6 is methyl. In some embodiments, o V is 1, and R V6 is ethyl. In some embodiments, o V is 1, and R V6is propyl. In some embodiments, o V is 1, and R V6 is n-propyl. In some embodiments, o V is 1, and R V6 In some embodiments, o is isopropyl. V is 1, and R V6 is butyl. In some embodiments, o V is 1, and R V6 is n-butyl. In some embodiments, o V is 1, and R V6 In some embodiments, o is isobutyl. V is 1, and R V6 is sec-butyl. In some embodiments, o V is 1, and R V6 is tert-butyl. In some embodiments, o V is 1, and R V6 is pentyl. In some embodiments, o V is 1, and R V6 is hexyl.

[0292] In some embodiments, R V1 , R V2 , and R V3 , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl.

[0293] In some embodiments, R V1 , H, C 1 -C 6 Alkyl, and C 1 -C 6 In some embodiments, R V1 is C 1 -C 6 Alkyl and C 1 -C 6In some embodiments, R V1 H and C 1 -C 6 In some embodiments, R V1 is H.

[0294] In some embodiments, R V1 is C 1 -C 6 It is an alkyl.

[0295] In some embodiments, R V1 is methyl. In some embodiments, R V1 is ethyl. In some embodiments, R V1 is propyl. In some embodiments, R V1 is n-propyl. In some embodiments, R V1 is isopropyl. In some embodiments, R V1 is butyl. In some embodiments, R V1 is n-butyl. In some embodiments, R V1 is isobutyl. In some embodiments, R V1 is sec-butyl. In some embodiments, R V1 is tert-butyl. In some embodiments, R V1 is pentyl. In some embodiments, R V1 is hexyl.

[0296] In some embodiments, R V1 is C 1 -C 6 It is haloalkyl.

[0297] In some embodiments, R V1 is C 1 In some embodiments, R V1 is C 2In some embodiments, R V1 is C 3 In some embodiments, R V1 is C 4 In some embodiments, R V1 is C 5 In some embodiments, R V1 is C 6 It is haloalkyl.

[0298] In some embodiments, R V2 , H, C 1 -C 6 Alkyl, and C 1 -C 6 In some embodiments, R V2 is C 1 -C 6 Alkyl and C 1 -C 6 In some embodiments, R V2 H and C 1 -C 6 In some embodiments, R V2 is H.

[0299] In some embodiments, R V2 is C 1 -C 6 It is an alkyl.

[0300] In some embodiments, R V2 is methyl. In some embodiments, R V2 is ethyl. In some embodiments, R V2 is propyl. In some embodiments, R V2 is n-propyl. In some embodiments, R V2 is isopropyl. In some embodiments, R V2 is butyl. In some embodiments, R V2is n-butyl. In some embodiments, R V2 is isobutyl. In some embodiments, R V2 is sec-butyl. In some embodiments, R V2 is tert-butyl. In some embodiments, R V2 is pentyl. In some embodiments, R V2 is hexyl.

[0301] In some embodiments, R V2 is C 1 -C 6 It is haloalkyl.

[0302] In some embodiments, R V2 is C 1 In some embodiments, R V2 is C 2 In some embodiments, R V2 is C 3 In some embodiments, R V2 is C 4 In some embodiments, R V2 is C 5 In some embodiments, R V2 is C 6 It is haloalkyl.

[0303] In some embodiments, R V3 , H, C 1 -C 6 Alkyl, and C 1 -C 6 In some embodiments, R V3 is C 1 -C 6 Alkyl and C 1 -C 6 In some embodiments, R V3 H and C 1 -C 6In some embodiments, R V3 is H.

[0304] In some embodiments, R V3 is C 1 -C 6 It is an alkyl.

[0305] In some embodiments, R V3 is methyl. In some embodiments, R V3 is ethyl. In some embodiments, R V3 is propyl. In some embodiments, R V3 is n-propyl. In some embodiments, R V3 is isopropyl. In some embodiments, R V3 is butyl. In some embodiments, R V3 is n-butyl. In some embodiments, R V3 is isobutyl. In some embodiments, R V3 is sec-butyl. In some embodiments, R V3 is tert-butyl. In some embodiments, R V3 is pentyl. In some embodiments, R V3 is hexyl.

[0306] In some embodiments, R V3 is C 1 -C 6 It is haloalkyl.

[0307] In some embodiments, R V3 is C 1 In some embodiments, R V3 is C 2 In some embodiments, R V3 is C 3 In some embodiments, R V3 is C4 In some embodiments, R V3 is C 5 In some embodiments, R V3 is C 6 It is haloalkyl.

[0308] In some embodiments, R V1 and R V2 together with the carbon to which they are attached, C 3 -C 10 Form a cycloalkyl or 5- to 6-membered heterocycle, R V3 , H, C 1 -C 6 Alkyl, and C 1 -C 6 In some embodiments, R V1 and R V2 together with the carbon to which they are attached, C 3 -C 10 Form a cycloalkyl or 5- to 6-membered heterocycle, R V3 is C 1 -C 6 Alkyl and C 1 -C 6 In some embodiments, R V1 and R V2 together with the carbon to which they are attached, C 3 -C 10 Form a cycloalkyl or 5- to 6-membered heterocycle, R V3 H and C 1 -C 6 In some embodiments, R V1 and R V2 together with the carbon to which they are attached, C 3 -C 10 Form a cycloalkyl or 5- to 6-membered heterocycle, R V3 is H.

[0309] In some embodiments, R V1 and R V2together with the carbon to which they are attached, C 3 -C 10 It forms a cycloalkyl or a 5- to 6-membered heterocycle.

[0310] In some embodiments, R V1 and R V2 together with the carbon to which they are attached, C 3 -C 10 In some embodiments, R V1 and R V2 together with the carbon to which they are attached form a cyclopropyl. V1 and R V2 together with the carbon to which they are attached form a cyclobutyl. V1 and R V2 together with the carbon to which they are attached form a cyclopentyl. V1 and R V2 together with the carbon to which they are attached form a cyclohexyl. V1 and R V2 together with the carbon to which they are attached form a cycloheptyl. V1 and R V2 together with the carbons to which they are attached form cyclooctyl. V1 and R V2 together with the carbon to which they are attached form cyclononyl. In some embodiments, R V1 and R V2 together with the carbon to which they are attached to form cyclodecyl.

[0311] In some embodiments, R V1 and R V2 together with the carbons to which they are attached form a 5-6 membered heterocycle. V1 and RV2 taken together with the carbons to which they are attached form a 5-membered heterocycle. V1 and R V2 together with the carbons to which they are attached form a six-membered heterocyclic ring.

[0312] In some embodiments, R V4a and R V4b , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl.

[0313] In some embodiments, R V4a , H, C 1 -C 6 Alkyl, and C 1 -C 6 In some embodiments, R V4a is C 1 -C 6 Alkyl and C 1 -C 6 In some embodiments, R V4a H and C 1 -C 6 In some embodiments, R V4a is H.

[0314] In some embodiments, R V4a is C 1 -C 6 It is an alkyl.

[0315] In some embodiments, R V4a is methyl. In some embodiments, R V4a is ethyl. In some embodiments, R V4a is propyl. In some embodiments, R V4a is n-propyl. In some embodiments, R V4ais isopropyl. In some embodiments, R V4a is butyl. In some embodiments, R V4a is n-butyl. In some embodiments, R V4a is isobutyl. In some embodiments, R V4a is sec-butyl. In some embodiments, R V4a is tert-butyl. In some embodiments, R V4a is pentyl. In some embodiments, R V4a is hexyl.

[0316] In some embodiments, R V4a is C 1 -C 6 It is haloalkyl.

[0317] In some embodiments, R V4a is C 1 In some embodiments, R V4a is C 2 In some embodiments, R V4a is C 3 In some embodiments, R V4a is C 4 In some embodiments, R V4a is C 5 In some embodiments, R V4a is C 6 It is haloalkyl.

[0318] In some embodiments, R V4b , H, C 1 -C 6 Alkyl, and C 1 -C 6 In some embodiments, R V4b is C 1 -C 6 Alkyl and C 1 -C 6In some embodiments, R V4b H and C 1 -C 6 In some embodiments, R V4b is H.

[0319] In some embodiments, R V4b is C 1 -C 6 It is an alkyl.

[0320] In some embodiments, R V4b is methyl. In some embodiments, R V4b is ethyl. In some embodiments, R V4b is propyl. In some embodiments, R V4b is n-propyl. In some embodiments, R V4b is isopropyl. In some embodiments, R V4b is butyl. In some embodiments, R V4b is n-butyl. In some embodiments, R V4b is isobutyl. In some embodiments, R V4b is sec-butyl. In some embodiments, R V4b is tert-butyl. In some embodiments, R V4b is pentyl. In some embodiments, R V4b is hexyl. In some embodiments, R V4b is C 1 -C 6 It is haloalkyl.

[0321] In some embodiments, R V4b is C 1 In some embodiments, R V4b is C 2 In some embodiments, R V4b is C 3In some embodiments, R V4b is C 4 In some embodiments, R V4b is C 5 In some embodiments, R V4b is C 6 It is haloalkyl.

[0322] In some embodiments, R V4b is H and R V4a , H, C 1 -C 6 Alkyl, and C 1 -C 6 In some embodiments, R V4b is H and R V4a is C 1 -C 6 Alkyl and C 1 -C 6 In some embodiments, R V4b is H and R V4a H and C 1 -C 6 In some embodiments, R V4b is H and R V4a is H.

[0323] In some embodiments, R V4b is H and R V4a is C 1 -C 6 It is an alkyl.

[0324] In some embodiments, R V4b is H and R V4a is methyl. In some embodiments, R V4b is H and R V4a is ethyl. In some embodiments, R V4b is H and R V4a is propyl. In some embodiments, R V4b is H and RV4a is n-propyl. In some embodiments, R V4b is H and R V4a is isopropyl. In some embodiments, R V4b is H and R V4a is butyl. In some embodiments, R V4b is H and R V4a is n-butyl. In some embodiments, R V4b is H and R V4a is isobutyl. In some embodiments, R V4b is H and R V4a is sec-butyl. In some embodiments, R V4b is H and R V4a is tert-butyl. In some embodiments, R V4b is H and R V4a is pentyl. In some embodiments, R V4b is H and R V4a is hexyl.

[0325] In some embodiments, R V4b is H and R V4a is C 1 -C 6 It is haloalkyl.

[0326] In some embodiments, R V4b is H and R V4a is C 1 In some embodiments, R V4b is H and R V4a is C 2 In some embodiments, R V4b is H and R V4a is C 3 In some embodiments, R V4b is H and R V4a is C 4 In some embodiments, R V4bis H and R V4a is C 5 In some embodiments, R V4b is H and R V4a is C 6 It is haloalkyl.

[0327] In some embodiments, R V4a is H and R V4b , H, C 1 -C 6 Alkyl, and C 1 -C 6 In some embodiments, R V4a is H and R V4b is C 1 -C 6 Alkyl and C 1 -C 6 In some embodiments, R V4a is H and R V4b H and C 1 -C 6 In some embodiments, R V4a is H and R V4b is H.

[0328] In some embodiments, R V4a is H and R V4b is C 1 -C 6 It is an alkyl.

[0329] In some embodiments, R V4a is H and R V4b is methyl. In some embodiments, R V4a is H and R V4b is ethyl. In some embodiments, R V4a is H and R V4b is propyl. In some embodiments, R V4a is H and R V4b is n-propyl. In some embodiments, R V4ais H and R V4b is isopropyl. In some embodiments, R V4a is H and R V4b is butyl. In some embodiments, R V4a is H and R V4b is n-butyl. In some embodiments, R V4a is H and R V4b is isobutyl. In some embodiments, R V4a is H and R V4b is sec-butyl. In some embodiments, R V4a is H and R V4b is tert-butyl. In some embodiments, R V4a is H and R V4b is pentyl. In some embodiments, R V4a is H and R V4b is hexyl.

[0330] In some embodiments, R V4a is H and R V4b is C 1 -C 6 It is haloalkyl.

[0331] In some embodiments, R V4a is H and R V4b is C 1 In some embodiments, R V4a is H and R V4b is C 2 In some embodiments, R V4a is H and R V4b is C 3 In some embodiments, R V4a is H and R V4b is C 4 In some embodiments, R V4a is H and R V4b is C 5In some embodiments, R V4a is H and R V4b is C 6 It is haloalkyl.

[0332] In some embodiments, R V7 , H, C 1 -C 6 Alkyl, and C 1 -C 6 In some embodiments, R V7 is C 1 -C 6 Alkyl and C 1 -C 6 In some embodiments, R V7 H and C 1 -C 6 In some embodiments, R V7 is H.

[0333] In some embodiments, R V7 is C 1 -C 6 It is an alkyl.

[0334] In some embodiments, R V7 is methyl. In some embodiments, R V7 is ethyl. In some embodiments, R V7 is propyl. In some embodiments, R V7 is n-propyl. In some embodiments, R V7 is isopropyl. In some embodiments, R V7 is butyl. In some embodiments, R V7 is n-butyl. In some embodiments, R V7 is isobutyl. In some embodiments, R V7 is sec-butyl. In some embodiments, R V7is tert-butyl. In some embodiments, R V7 is pentyl. In some embodiments, R V7 is hexyl.

[0335] In some embodiments, R V7 is C 1 -C 6 It is haloalkyl.

[0336] In some embodiments, R V7 is C 1 In some embodiments, R V7 is C 2 In some embodiments, R V7 is C 3 In some embodiments, R V7 is C 4 In some embodiments, R V7 is C 5 In some embodiments, R V7 is C 6 It is haloalkyl.

[0337] In some embodiments, R V8 , H, C 1 -C 6 Alkyl, and C 1 -C 6 In some embodiments, R V8 is C 1 -C 6 Alkyl and C 1 -C 6 In some embodiments, R V8 H and C 1 -C 6 In some embodiments, R V8 is H.

[0338] In some embodiments, R V8 is C1 -C 6 It is an alkyl.

[0339] In some embodiments, R V8 is methyl. In some embodiments, R V8 is ethyl. In some embodiments, R V8 is propyl. In some embodiments, R V8 is n-propyl. In some embodiments, R V8 is isopropyl. In some embodiments, R V8 is butyl. In some embodiments, R V8 is n-butyl. In some embodiments, R V8 is isobutyl. In some embodiments, R V8 is sec-butyl. In some embodiments, R V8 is tert-butyl. In some embodiments, R V8 is pentyl. In some embodiments, R V8 is hexyl.

[0340] In some embodiments, R V8 is C 1 -C 6 It is haloalkyl.

[0341] In some embodiments, R V8 is C 1 In some embodiments, R V8 is C 2 In some embodiments, R V8 is C 3 In some embodiments, R V8 is C 4 In some embodiments, R V8 is C 5 In some embodiments, R V8 is C 6It is haloalkyl.

[0342] In some embodiments, R V7 and R V8 together with the carbon to which they are attached, C 3 -C 10 It forms a cycloalkyl or a 5- to 6-membered heterocycle.

[0343] In some embodiments, R V7 and R V8 together with the carbon to which they are attached, C 3 -C 10 In some embodiments, R V7 and R V8 together with the carbon to which they are attached form a cyclopropyl. V7 and R V8 together with the carbon to which they are attached form a cyclobutyl. V7 and R V8 together with the carbon to which they are attached form a cyclopentyl. V7 and R V8 together with the carbon to which they are attached form a cyclohexyl. V7 and R V8 together with the carbon to which they are attached form a cycloheptyl. V7 and R V8 together with the carbons to which they are attached form cyclooctyl. V7 and R V8 together with the carbon to which they are attached form cyclononyl. In some embodiments, R V7 and R V8 together with the carbon to which they are attached to form cyclodecyl.

[0344] In some embodiments, RV7 and R V8 together with the carbons to which they are attached form a 5-6 membered heterocycle. V7 and R V8 taken together with the carbons to which they are attached form a 5-membered heterocycle. V7 and R V8 together with the carbons to which they are attached form a six-membered heterocyclic ring.

[0345] In some embodiments, n V is 0, 1, 2, 3 or. In some embodiments, n V is 1, 2, 3, or 4. In some embodiments, n V is 0 or 1. In some embodiments, n V is 0. In some embodiments, n V is 1. In some embodiments, n V In some embodiments, n V is 3. In some embodiments, n V is 4.

[0346] In some embodiments, each R V5 H and C 1 -C 6 In some embodiments, each R V5 is independently 1 -C 6 It is an alkyl.

[0347] In some embodiments, n V is 1, and R V5 is C 1 -C 6 In some embodiments, n V is 1, and R V5 In some embodiments, n is methyl. V is 1, and R V5In some embodiments, n is ethyl. V is 1, and R V5 is propyl. In some embodiments, n V is 1, and R V5 is n-propyl. In some embodiments, n V is 1, and R V5 In some embodiments, n is isopropyl. V is 1, and R V5 is butyl. In some embodiments, n V is 1, and R V5 is n-butyl. In some embodiments, n V is 1, and R V5 In some embodiments, n V is 1, and R V5 is sec-butyl. In some embodiments, n V is 1, and R V5 is tert-butyl. In some embodiments, n V is 1, and R V5 is pentyl. In some embodiments, n V is 1, and R V5 is hexyl.

[0348] In some embodiments, the VLM is selected from the group consisting of (VLM-1), (VLM-2), (VLM-3), (VLM-4), (VLM-5), (VLM-6), (VLM-7), (VLM-8), (VLM-9), and (VLM-10): [ka] [ka] The structure is selected from:

[0349] In some embodiments, the VLM has the structure of (VLM-1). In some embodiments, the VLM has the structure of (VLM-2). In some embodiments, the VLM has the structure of (VLM-3). In some embodiments, the VLM has the structure of (VLM-4). In some embodiments, the VLM has the structure of (VLM-5). In some embodiments, the VLM has the structure of (VLM-6). In some embodiments, the VLM has the structure of (VLM-7). In some embodiments, the VLM has the structure of (VLM-8). In some embodiments, the VLM has the structure of (VLM-9). In some embodiments, the VLM has the structure of (VLM-10).

[0350] In an embodiment, the compound of formula I has the structure according to formula II: [ka] or a pharma- ceutically acceptable salt thereof; During the ceremony, Q 1 CR 1 or N, R K1 , R K2 , R K3 , and R K4 are H, OH, Cl, F, Br, I, and C. 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, OC 1 -C 6 Alkyl, OC 1 -C 6 Haloalkyl, C 3 -C 10 cycloalkyl, and 3- to 10-membered heterocycle; Or, R K3 and R K4 together with the carbon to which they are attached, C 6 aryl or 5-6 membered heteroaryl, where the aryl and heteroaryl are each independently one or two RK11 Optionally replaced by Each R K11 are OH, CN, Cl, F, Br, I, and C. 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, and C 1 -C 6 haloalkyl; R 1 are H, OH, CN, Cl, F, Br, I, and C 1 -C 6 alkyl, R 2 , H, C 1 -C 6 Alkyl, 4-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, and C 6 -C 10 aryl, wherein C 1 -C 6 Alkyl, 4-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, and C 6 -C 10 Aryl is OH, C(O)OH, C(O)H, or C(O)OC 1-6 optionally substituted with alkyl; R 3 are H, OH, CN, Cl, F, Br, I, and C. 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl; R 4 are H, OH, CN, Cl, F, Br, I, and C 1 -C 6 alkyl, R V4a , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl; R V5 H, halo, and C 1 -C 6alkyl, Y V2 is CN or a 5-10 membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, S, and O, where the 5-10 membered heteroaryl is C 1 -C 6 Alkyl or C 1 -C 6 optionally substituted with haloalkyl; Each L is CH 2 , NH, N(C 1 -C 6 alkyl), O, C(O), 5-10 membered heteroarylene, C 2 -C 6 Alkylene, monocyclic C 4 -C 10 and independently selected from cycloalkylene, monocyclic 4-10 membered heterocycloalkylene, fused bicyclic 4-10 membered heterocycloalkylene, and spiro-fused 5-12 membered heterocycloalkylene, where each heterocycloalkylene is selected from one or two halo, C 1 -C 6 Alkyl, OC 1 -C 6 Alkyl, and C 1 -C 6 optionally substituted with haloalkyl; A is selected from C(O), NH, C(O)N(H), N(H)C(O), 6- to 10-membered arylene, and 5- to 10-membered heteroarylene; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[0351] In an embodiment of Formula II, Q 1 CR 1 or N, R K1 , R K2 , R K3 , and R K4 are H, OH, Cl, F, Br, I, and C. 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, OC 1-C 6 Alkyl, OC 1 -C 6 Haloalkyl and C 3 -C 10 cycloalkyl; Or, R K3 and R K4 together with the carbon to which they are attached, C 6 Form an aryl or a 5-6 membered heteroaryl, where the aryl or heteroaryl is one or two R K11 Optionally replaced by Each R K11 are H, OH, CN, Cl, F, Br, I, and C. 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, and C 1 -C 6 haloalkyl; R 1 is selected from H, OH, CN, Cl, F, Br, and I; R 2 , H, C 1 -C 6 alkyl, and 4-10 membered heterocycloalkyl, where 4-10 membered heterocycloalkyl is OH, C(O)OH, C(O)H, or C(O)OC 1-6 optionally substituted with alkyl; R 3 , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl; R 4 is selected from H, OH, CN, Cl, F, Br, and I; R V4a , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl; R V5 H, halo, and C1 -C 6 alkyl, Y V2 is CN or a 5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, S, and O, wherein the 5-7 membered heteroaryl is C 1 -C 6 Alkyl or C 1 -C 6 optionally substituted with haloalkyl; Each L is CH 2 , NH, N(C 1 -C 6 alkyl), O, C(O), 5-10 membered heteroarylene, C 2 -C 6 Alkylene, monocyclic C 4 -C 10 and independently selected from cycloalkylene, monocyclic 4-10 membered heterocycloalkylene, fused bicyclic 4-10 membered heterocycloalkylene, and spiro-fused 5-12 membered heterocycloalkylene, where each heterocycloalkylene is selected from one or two halo, C 1 -C 6 Alkyl, OC 1 -C 6 Alkyl, and C 1 -C 6 optionally substituted with haloalkyl; A is selected from C(O)N(H), N(H)C(O), and 5- to 7-membered heteroarylene; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0352] In an embodiment of Formula II, Q 1 CR 1 or N, R K1 , R K2 , R K3 , and R K4 are H, OH, Cl, F, Br, I, and C. 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, OC 1 -C6 Alkyl, OC 1 -C 6 Haloalkyl and C 3 -C 6 cycloalkyl; Or, R K3 and R K4 together with the carbon to which they are attached, C 6 Form an aryl or a 5-6 membered heteroaryl, where the aryl or heteroaryl is one or two R K11 Optionally replaced by Each R K11 are H, OH, CN, Cl, F, Br, I, and C. 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, and C 1 -C 6 haloalkyl; R 1 is selected from H, OH, CN, Cl, F, Br, and I; R 2 , H, C 1 -C 6 alkyl, and 7- to 8-membered heterocycloalkyl, where 7- to 8-membered heterocycloalkyl is OH, C(O)OH, C(O)H, or C(O)OC 1-6 optionally substituted with alkyl; R 3 , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl; R 4 is selected from H, OH, CN, Cl, F, Br, and I; R V4a , H, C 1 -C 6 Alkyl, and C 1 -C 6 haloalkyl; R V5 H, halo, and C1 -C 6 alkyl, Y V2 is CN or a 5-membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, S, and O, where the 5-membered heteroaryl is C 1 -C 6 Alkyl or C 1 -C 6 optionally substituted with haloalkyl; Each L is CH 2 , NH, N(C 1 -C 6 alkyl), O, C(O), 5-7 membered heteroarylene, C 2 -C 6 Alkylene, monocyclic C 4 -C 10 and independently selected from cycloalkylene, monocyclic 4-10 membered heterocycloalkylene, fused bicyclic 4-10 membered heterocycloalkylene, and spiro-fused 5-12 membered heterocycloalkylene, where each heterocycloalkylene is selected from one or two halo, C 1 -C 6 Alkyl, OC 1 -C 6 Alkyl, and C 1 -C 6 optionally substituted with haloalkyl; A is selected from C(O)N(H), N(H)C(O), and 5-membered heteroarylene; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0353] In an embodiment, the compound of formula I has the structure according to formula IIa: [ka] or a pharma- ceutically acceptable salt thereof.

[0354] In an embodiment, the compound of formula I has the structure according to formula IIb: [ka] or a pharma- ceutically acceptable salt thereof.

[0355] In an embodiment, the compound of formula I has the structure according to formula IIc: [ka] or a pharma- ceutically acceptable salt thereof.

[0356] In an embodiment of Formula IIa, the compound has a structure according to one of Formulas IIa-i to IIa-v: [ka] [ka] or a pharma- ceutically acceptable salt thereof; During the ceremony, Each R L H, halo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or OC 1 -C 6 independently selected from alkyl, Or, both R L together with the carbon to which they are attached, C 3 -C 6 Forming a cycloalkyl, Q is CR L or N, m, n, and q are each independently 0, 1, or 2.

[0357] In an embodiment of Formula IIb, the compound has a structure according to one of Formulas IIb-i to IIb-vi: [ka] [ka] or a pharma- ceutically acceptable salt thereof; During the ceremony, B is, [ka] is selected from Each Q is independently L or N, R L H, OH, halo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or OC 1 -C 6 is alkyl, p is 0 or 1; each q is independently 0, 1, or 2; Each s is independently 1 or 2.

[0358] In an embodiment of Formula IIc, the compound has the structure according to Formula IIc-i: [ka] or a pharma- ceutically acceptable salt thereof; During the ceremony, B is, [ka] is selected from R L H, OH, halo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or OC 1 -C 6 is alkyl, p is 0 or 1.

[0359] In embodiments, R 2 teeth, [ka] is selected from.

[0360] In embodiments, R K1 , R K2 , R K3 , and R K4 are H, OH, Cl, F, Br, I, and C. 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, OC 1 -C 6 Haloalkyl and C 3 -C 5 cycloalkyl.

[0361] In embodiments, R K3 and R K4 together with the carbon to which they are attached, C 6 Aryl, wherein the aryl is one or two of Cl, F, Br, I, C 1 -C 6 Alkyl, C 2 -C 6 Alkynyl, and C 1 -C 6 Optionally substituted with haloalkyl.

[0362] In embodiments, R K3 and R K4 taken together with the carbons to which they are attached form a 5-membered heteroaryl.

[0363] In embodiments, R 1 is selected from Cl, F, Br, and I. In embodiments, R 2 is 7-8 membered heterocycloalkyl. In embodiments, R 3 is C 1 -C 6 In an embodiment, R 4 is OH.

[0364] In embodiments, R V4a is H or C 1 -C 6In an embodiment, Y is an alkyl group. V2 is CN or a 5-membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, S, and O, where the 5-membered heteroaryl is C 1 -C 6 Alkyl or C 1 -C 6 In an embodiment, Y is optionally substituted with haloalkyl. V2 is CN. In an embodiment, Y V2 is C 1 -C 6 Thiazolyl optionally substituted with alkyl.

[0365] In an embodiment, Y V2 is C 1 -C 6 and pyrazolyl optionally substituted with alkyl.

[0366] Various embodiments of Formula II, Formula IIa, and Formula IIb. In one embodiment, n is 6 and each L is selected from the following LNK:(O)-(C 1 -C 6 alkyl)-(fused bicyclic 4- to 10-membered heterocycloalkylene)-(C 1 -C 6 Alkyl)-(O)-(C 1 -C 6 alkyl).

[0367] In one embodiment, n is 6 and each L is selected from the following LNK:(O)-(C 1 -C 6 alkyl)-(fused bicyclic 8-membered heterocycloalkylene)-(C 1 -C 6 Alkyl)-(O)-(C 1 -C 6 alkyl).

[0368] In one embodiment, n is 7 and each L is selected from the following LNK:(O)-(C 1 -C 6alkyl)-(fused bicyclic 4- to 10-membered heterocycloalkylene)-(C 1 -C 6 alkyl)-(O)-C(O)-(monocyclic 4-10 membered heterocycloalkylene), where the heterocycloalkylene is one or two C 1-6 Optionally substituted with alkyl.

[0369] In one embodiment, n is 7 and each L is selected from the following LNK:(O)-(C 1 -C 6 alkyl)-(fused bicyclic 8-membered heterocycloalkylene)-(C 1 -C 6 alkyl)-(O)-C(O)-(monocyclic 6-membered heterocycloalkylene), where the heterocycloalkylene is selected from 1 or 2 C 1-6 Optionally substituted with alkyl.

[0370] In one embodiment, n is 3 and each L is selected from the following LNK:(O)-(C 1 -C 6 alkyl)-(spiro-fused 5- to 12-membered heterocycloalkylene).

[0371] In one embodiment, n is 3 and each L is selected from the following LNK:(O)-(C 1 -C 6 alkyl)-(spiro-fused 9-membered heterocycloalkylene).

[0372] In one embodiment, n is 3 and each L is selected from the following LNK:(O)-(C 1 -C 6 alkyl)-(fused bicyclic 4- to 10-membered heterocycloalkylene).

[0373] In one embodiment, n is 3 and each L is selected from the following LNK:(O)-(C 1 -C 6 alkyl)-(fused bicyclic 8-membered heterocycloalkylene).

[0374] In one embodiment, n is 3 and each L is selected from the following LNK:(O)-(C 1 -C 6 alkyl)-(fused bicyclic 9-membered heterocycloalkylene).

[0375] In one embodiment, n is 5 and each L is selected from the following LNK:(O)-(C 1 -C 6 alkyl)-(fused bicyclic 4-10 membered heterocycloalkylene)-(C 1 -C 6 alkyl)-(spiro-fused 5- to 12-membered heterocycloalkylene).

[0376] In one embodiment, n is 5 and each L is selected from the following LNK:(O)-(C 1 -C 6 alkyl)-(fused bicyclic 8-membered heterocycloalkylene)-(C 1 -C 6 alkyl)-(spiro-fused 9-membered heterocycloalkylene).

[0377] In one embodiment, n is 8 and each L is selected from the following LNK:(O)-(C 1 -C 6 alkyl)-(fused bicyclic 4-10 membered heterocycloalkylene)-(C 1 -C 6 Alkyl)-(O)-C(O)-N(C 1 -C 6 Alkyl)-(C 1-6 alkyl).

[0378] In one embodiment, n is 8 and each L is selected from the following LNK:(O)-(C 1 -C 6 alkyl)-(fused bicyclic 8-membered heterocycloalkylene)-(C 1 -C 6 Alkyl)-(O)-C(O)-N(C 1 -C 6 Alkyl)-(C 1 -C 6 alkyl).

[0379] In one embodiment, n is 5 and each L is selected from the following LNK:(O)-(C 1 -C 6 alkyl)-(fused bicyclic 4-10 membered heterocycloalkylene)-(C 1 -C 6 alkyl)-(monocyclic 4- to 10-membered heterocycloalkylene).

[0380] In one embodiment, n is 5 and each L is selected from the following LNK:(O)-(C 1 -C 6 alkyl)-(fused bicyclic 8-membered heterocycloalkylene)-(C 1 -C 6 alkyl)-(monocyclic 6-membered heterocycloalkylene).

[0381] In one embodiment, n is 7 and each L is selected from the following LNK:(O)-(C 1 -C 6 alkyl)-(fused bicyclic 4-10 membered heterocycloalkylene)-(C 1 -C 6 alkyl)-(monocyclic 4-10 membered heterocycloalkylene)-(C 1 -C 6 Forms alkyl)-(O).

[0382] In one embodiment, n is 7 and each L is selected from the following LNK:(O)-(C 1 -C 6 alkyl)-(fused bicyclic 8-membered heterocycloalkylene)-(C 1 -C 6 alkyl)-(monocyclic 6-membered heterocycloalkylene)-(C 1 -C 6 Forms alkyl)-(O).

[0383] In one embodiment, n is 7 and each L is selected from the following LNK:(O)-(C 1 -C 6 alkyl)-(fused bicyclic 4-10 membered heterocycloalkylene)-(C 1 -C 6alkyl)-(O)-C(O)-(spiro-fused 5- to 12-membered heterocycloalkylene).

[0384] In one embodiment, n is 7 and each L is selected from the following LNK:(O)-(C 1 -C 6 alkyl)-(fused bicyclic 8-membered heterocycloalkylene)-(C 1 -C 6 alkyl)-(O)-C(O)-(spiro-fused 7-membered heterocycloalkylene).

[0385] In one embodiment, n is 9 and each L is selected from the following LNK:(O)-(C 1 -C 6 alkyl)-(fused bicyclic 4- to 10-membered heterocycloalkylene)-(C 1 -C 6 alkyl)-(O)-C(O)-(monocyclic 4-10 membered heterocycloalkylene)-(C 1 -C 6 alkyl)-(O).

[0386] In one embodiment, n is 9 and each L is selected from the following LNK:(O)-(C 1 -C 6 alkyl)-(fused bicyclic 8-membered heterocycloalkylene)-(C 1 -C 6 alkyl)-(O)-C(O)-(monocyclic 4-membered heterocycloalkylene)-(C 1 -C 6 alkyl)-(O).

[0387] In one embodiment, n is 8 and each L is selected from the following LNK:(O)-(C 1 -C 6 alkyl)-(fused bicyclic 4- to 10-membered heterocycloalkylene)-(C 1 -C 6 alkyl)-(O)-C(O)-(monocyclic 4-10 membered heterocycloalkylene)-(O).

[0388] In one embodiment, n is 8 and each L is selected from the following LNK:(O)-(C 1 -C 6 alkyl)-(fused bicyclic 8-membered heterocycloalkylene)-(C 1 -C 6 alkyl)-(O)-C(O)-(monocyclic 6-membered heterocycloalkylene)-(O).

[0389] In one embodiment, n is 4 and each L is selected from the following LNK:(O)-(C 1 -C 6 Alkyl)-(monocyclic 4-10 membered heterocycloalkylene)-N(C 1 -C 6 alkyl).

[0390] In one embodiment, n is 4 and each L is selected from the following LNK:(O)-(C 1 -C 6 Alkyl)-(monocyclic 6-membered heterocycloalkylene)-N(C 1 -C 6 alkyl).

[0391] In one embodiment, n is 5 and each L is selected from the following LNK:(O)-(C 1 -C 6 alkyl)-(monocyclic 4-10 membered heterocycloalkylene)-(C 1 -C 6 alkyl)-(O), where heterocycloalkylene is C 1 -C 6 Alkyl, O-(C 1 -C 6 alkyl), and C 1 -C 6 Optionally substituted with haloalkyl.

[0392] In one embodiment, n is 5 and each L is selected from the following LNK:(O)-(C 1 -C 6 alkyl)-(monocyclic 6-membered heterocycloalkylene)-(C 1 -C 6alkyl)-(O), where heterocycloalkylene is C 1 -C 6 Optionally substituted with alkyl.

[0393] In one embodiment, n is 7 and each L is selected from the following LNK:(O)-(C 1 -C 6 alkyl)-(monocyclic 4-10 membered heterocycloalkylene)-(C 1 -C 6 alkyl)-(O)-C(O)-(monocyclic 4-10 membered heterocycloalkylene), where the heterocycloalkylene is C 1 -C 6 Alkyl, O-(C 1 -C 6 alkyl), and C 1 -C 6 Optionally substituted with haloalkyl.

[0394] In one embodiment, n is 7 and each L is selected from the following LNK:(O)-(C 1 -C 6 alkyl)-(monocyclic 5-membered heterocycloalkylene)-(C 1-6 alkyl)-(O)-C(O)-(monocyclic 6-membered heterocycloalkylene), where the heterocycloalkylene is C 1 -C 6 Optionally substituted with alkyl.

[0395] In one embodiment, n is 5 and each L is selected from the following LNK:(O)-(C 1 -C 6 alkyl)-(monocyclic 4-10 membered heterocycloalkylene)-(C 1 -C 6 alkyl)-(monocyclic 4-10 membered heterocycloalkylene), where the heterocycloalkylene is C 1 -C 6 Alkyl, O-(C 1 -C 6 alkyl), and C 1 -C 6 Optionally substituted with haloalkyl.

[0396] In one embodiment, n is 5 and each L is selected from the following LNK:(O)-(C 1 -C 6 alkyl)-(monocyclic 6-membered heterocycloalkylene)-(C 1 -C 6 alkyl)-(monocyclic 4-membered heterocycloalkylene).

[0397] In one embodiment, n is 4 and each L is selected from the following LNK:(O)-(C 1 -C 6 alkyl)-(monocyclic 4- to 10-membered heterocycloalkylene)-(O).

[0398] In one embodiment, n is 4 and each L is selected from the following LNK:(O)-(C 1 -C 6 alkyl)-(monocyclic 6-membered heterocycloalkylene)-(O).

[0399] In one embodiment, each L forms the following LNK: [ka] [ka]

[0400] In another aspect, the present application relates to a compound, wherein the compound is: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

Table 1-6

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[0401] The compounds of the present disclosure can be synthesized using standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations, including the use of protecting groups, which can be obtained in light of the present disclosure from the relevant scientific literature or from standard reference texts in the field. Reference texts recognized for organic synthesis include, but are not limited to, Smith, MB; March, J. March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Edition, 1999; Smith, MB; March, J. March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Edition, 1999; th ed.; John Wiley & Sons: New York, 2001; and Greene, TW; Wuts, PGMProtective Groups in Organic Synthesis, 3 rd ; John Wiley & Sons: New York, 1999. The synthetic methods described in International Publication No. WO / 2021 / 207172 are incorporated herein by reference in their entirety.

[0402] How to ubiquitinate and degrade target proteins in cells The present disclosure provides a method for ubiquitinating / degrading a target protein in a cell. The method preferably comprises administering a bifunctional composition comprising an E3 ubiquitin ligase binding moiety and a protein targeting moiety linked via a linker moiety as described elsewhere herein, wherein the E3 ubiquitin ligase binding moiety is coupled to the protein targeting moiety, the E3 ubiquitin ligase binding moiety recognizes a ubiquitin pathway protein (e.g., a ubiquitin ligase, preferably an E3 ubiquitin ligase), and the protein targeting moiety recognizes a target protein such that when the target protein is placed in close proximity to the ubiquitin ligase, the target protein is ubiquitinated, resulting in degradation / inhibition of the action of the target protein and control of protein levels. The control of protein levels provided by the present disclosure provides treatment of a disease state or condition regulated via the target protein by lowering the target protein in the patient's cells.

[0403] In some embodiments, the bifunctional compounds described herein bind to KRAS. In some embodiments, the bifunctional compounds described herein bind reversibly to KRAS. In some embodiments, the KTM of the bifunctional compounds binds to KRAS. In some embodiments, the KTM of the bifunctional compounds binds reversibly to KRAS.

[0404] In some embodiments, the bifunctional compounds described herein bind to KRAS, resulting in degradation of KRAS. In some embodiments, the bifunctional compounds described herein reversibly bind to KRAS, resulting in degradation of KRAS.

[0405] In an aspect, disclosed herein are compounds of formula (I), or pharma- ceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs, isotopic derivatives, or prodrugs thereof, that degrade KRAS.

[0406] In some embodiments, KRAS exists in two isoforms: KRAS4A (also known as KRAS2A) and KRAS4B (also known as KRAS2B). In some embodiments, these isoforms differ in HVR residues 167 to 189. In some embodiments, KRAS residues 151, 153, 165, and 166 are dissimilar between the KRAS4A and KRAS4B isoforms.

[0407] KRAS contains a membrane-anchored flexible C-terminal structural element called the hypervariable region (HVR). Because KRAS signaling occurs at the membrane, the HVR undergoes post-translational modifications including farnesylation at C185, proteolytic cleavage of the three terminal residues, and methylation of the terminal carboxyl group of C185. A polybasic region of the HVR consisting of multiple lysine residues is also involved in membrane association. KRAS4A does not contain this polybasic region and is therefore further palmitoylated at an additional cysteine ​​residue, C180.

[0408] In some embodiments, the KRAS is the isoform KRAS4B. In some embodiments, the KRAS4B isoform comprises the amino acid sequence of SEQ ID NO:1.

[0409] SEQ ID NO:1 MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHHYREQIKRVKDSEDVPMVLVGNKCDLPSRTVDTKQAQDLARSYGIPFIETSAKTRQGVDDAFYTLVREIRKHKEKMSKDGKKKKKKSKTKCVIM

[0410] In some embodiments, the KRAS is the isoform KRAS4A. In some embodiments, the KRAS4A isoform comprises the amino acid sequence of SEQ ID NO:3.

[0411] SEQ ID NO:3 MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHHYREQIKRVKDSEDVPMVLVGNKCDLPSRTVDTKQAQDLARSYGIPFIETSAKTRQRVEDAFYTLVREIRQYRLKKISKEEKTPGCVKIKKCIIM

[0412] In some embodiments, the KRAS is a mutant KRAS. In some embodiments, the mutant KRAS is selected from one or more of KRAS G12D, KRAS G12C, KRAS G12V, KRAS G12S, KRAS G12R, KRAS G12A, and KRAS G13C. In some embodiments, the mutant KRAS is selected from one or more of KRAS G12D, KRAS G12C, and KRAS G12V. In some embodiments, the mutant KRAS is a G12D mutant. In some embodiments, the mutant KRAS is a G12C mutant. In some embodiments, the mutant KRAS is a G12V mutant. In some embodiments, the mutant KRAS G12D comprises the amino acid sequence of SEQ ID NO:2. In some embodiments, the mutant KRAS G12D comprises the amino acid sequence of SEQ ID NO:4.

[0413] In some embodiments, the KRAS is a mammalian KRAS. In some embodiments, the KRAS is a human KRAS. In some embodiments, the KRAS is a non-human primate KRAS. In some embodiments, the bifunctional compounds described herein bind to a KRAS comprising the amino acid sequence of SEQ ID NO:1. In some embodiments, the bifunctional compounds described herein bind to a KRAS comprising the amino acid sequence of SEQ ID NO:2. In some embodiments, the bifunctional compounds described herein bind to a KRAS comprising the amino acid sequence of SEQ ID NO:3. In some embodiments, the bifunctional compounds described herein bind to a KRAS comprising the amino acid sequence of SEQ ID NO:4. In some embodiments, the bifunctional compounds described herein bind to a KRAS comprising the amino acid sequence of SEQ ID NO:1, resulting in its degradation. In some embodiments, the bifunctional compounds described herein bind to a KRAS comprising the amino acid sequence of SEQ ID NO:2, resulting in its degradation. In some embodiments, the bifunctional compounds described herein bind to a KRAS comprising the amino acid sequence of SEQ ID NO:3, resulting in its degradation. In some embodiments, the bifunctional compounds described herein bind to a KRAS comprising the amino acid sequence of SEQ ID NO:4, resulting in its degradation.

[0414] In some embodiments, the bifunctional compounds described herein bind to a KRAS mutant comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 1. In some embodiments, the bifunctional compounds described herein bind to and result in the degradation of a KRAS mutant comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 1.

[0415] In some embodiments, the bifunctional compounds described herein bind to a KRAS G12D mutant comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 2. In some embodiments, the bifunctional compounds described herein bind to and result in the degradation of a KRAS G12D mutant comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 2.

[0416] In some embodiments, the bifunctional compounds described herein bind to a KRAS mutant comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 3. In some embodiments, the bifunctional compounds described herein bind to and result in the degradation of a KRAS mutant comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 3.

[0417] In some embodiments, the bifunctional compounds described herein bind to a KRAS G12D mutant comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 4. In some embodiments, the bifunctional compounds described herein bind to and result in the degradation of a KRAS G12D mutant comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 4.

[0418] SEQ ID NO:2 MTEYKLVVVGADGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHHYREQIKRVKDSEDVPMVLVGNKCDLPSRTVDTKQAQDLARSYGIPFIETSAKTRQGVDDAFYTLVREIRKHKEKMSKDGKKKKKKSKTKCVIM

[0419] SEQ ID NO:4 MTEYKLVVVGADGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHHYREQIKRVKDSEDVPMVLVGNKCDLPSRTVDTKQAQDLARSYGIPFIETSAKTRQRVEDAFYTLVREIRQYRLKKISKEEKTPGCVKIKKCIIM

[0420] In some embodiments, the bifunctional compounds described herein bind to all KRAS mutants and isoforms. In some embodiments, the bifunctional compounds described herein bind to all KRAS mutants and isoforms, resulting in their degradation.

[0421] In some embodiments, the present disclosure is directed to a method of treating a patient in need of treatment for a disease state or condition regulated through a protein, where degradation of the protein provides a therapeutic benefit to the patient, the method comprising administering to a patient in need thereof an effective amount of a compound of the present disclosure of formula (I), optionally in combination with another anti-cancer agent. The disease state or condition may be a disease caused by a microbial agent or other foreign agent, such as a virus, bacteria, fungus, protozoa, or other microorganism, or may be a disease state caused by overexpression of a protein that results in the disease state and / or condition.

[0422] Treatment method In an aspect, disclosed herein is a method of treating and / or preventing a disease or disorder in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound of the present disclosure, or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, or isotopic derivative thereof.

[0423] In some embodiments, the disease or disorder is causally related to KRAS, hi some embodiments, the disease or disorder is associated with activity, overactivity, constitutive activity, expression, overexpression, or accumulation of KRAS.

[0424] In some embodiments, the disease or disorder is cancer, hi some embodiments, the cancer is pancreatic cancer, colon cancer, colorectal cancer, lung cancer, non-small cell lung cancer, endometrial cancer, cervical cancer, bladder cancer, liver cancer, myeloid leukemia, ovarian cancer, or breast cancer.

[0425] In an aspect, disclosed herein is a method for treating and / or preventing cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure, or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, in combination with one or more additional anti-cancer agents. In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is pancreatic cancer, colon cancer, colorectal cancer, lung cancer, non-small cell lung cancer, endometrial cancer, cervical cancer, bladder cancer, liver cancer, myeloid leukemia, ovarian cancer, or breast cancer.

[0426] The methods of treating cancer described herein may result in a reduction in tumor size. Alternatively or additionally, the cancer is a metastatic cancer and the method of treatment involves inhibiting invasion of metastatic cancer cells.

[0427] In one embodiment, the treatment of cancer reduces the size of the tumor. The reduction in tumor size is also referred to as "tumor regression". Preferably, the tumor size after treatment is reduced by 5% or more compared to the tumor size before treatment, more preferably, the tumor size is reduced by 10% or more, more preferably, by 20% or more, more preferably, by 30% or more, more preferably, by 40% or more, even more preferably, by 50% or more, and most preferably, by 75% or more. The size of the tumor can be measured by any reproducible measurement means. In a preferred embodiment, the size of the tumor can be measured as the tumor diameter.

[0428] In another embodiment, the tumor volume is reduced by treating the cancer. Preferably, the tumor volume after treatment is reduced by 5% or more compared to the tumor volume before treatment, more preferably, the tumor volume is reduced by 10% or more, more preferably, by 20% or more, more preferably, by 30% or more, more preferably, by 40% or more, even more preferably, by 50% or more, and most preferably, by 75% or more. The tumor volume can be measured by any reproducible measurement means.

[0429] In another embodiment, the number of tumors is reduced by treating cancer. Preferably, the number of tumors after treatment is reduced by 5% or more compared to the number of tumors before treatment, more preferably, the number of tumors is reduced by 10% or more, more preferably, by 20% or more, more preferably, by 30% or more, more preferably, by 40% or more, even more preferably, by 50% or more, and most preferably, by more than 75%. The number of tumors can be measured by any reproducible measuring means. In a preferred embodiment, the number of tumors can be measured by counting tumors visible to the naked eye or at a specific magnification. In a preferred embodiment, the specific magnification is 2x, 3x, 4x, 5x, 10x, or 50x.

[0430] In another embodiment, the treatment of cancer reduces the number of metastatic lesions in other tissues or organs distant from the primary tumor site. Preferably, the number of metastatic lesions after treatment is reduced by 5% or more compared to the number before treatment, more preferably, the number of metastatic lesions is reduced by 10% or more, more preferably, by 20% or more, more preferably, by 30% or more, more preferably, by 40% or more, even more preferably, by 50% or more, and most preferably, by more than 75%. The number of metastatic lesions can be measured by any reproducible measuring means. In a preferred embodiment, the number of metastatic lesions can be measured by counting metastatic lesions visible to the naked eye or at a specific magnification. In a preferred embodiment, the specific magnification is 2x, 3x, 4x, 5x, 10x, or 50x.

[0431] In another embodiment, the treatment of cancer increases the average survival time of a population of treated subjects compared to a population administered with carrier alone. Preferably, the average survival time increases by more than 30 days, more preferably more than 60 days, more preferably more than 90 days, and most preferably more than 120 days. The increase in the average survival time of a population can be measured by any reproducible means. In a preferred embodiment, the increase in the average survival time of a population can be measured, for example, by calculating the average survival time of a population after the start of treatment with an active agent or compound of the present disclosure. In another preferred embodiment, the increase in the average survival time of a population can also be measured, for example, by calculating the average survival time of a population after the completion of a first round of treatment with an active agent or compound of the present disclosure.

[0432] In another embodiment, the treatment of cancer increases the average survival time of a population of treated subjects compared to a population of untreated subjects. Preferably, the average survival time increases by more than 30 days, more preferably more than 60 days, more preferably more than 90 days, and most preferably more than 120 days. The increase in the average survival time of a population can be measured by any reproducible means. In a preferred embodiment, the increase in the average survival time of a population can be measured by calculating the average survival time of the population after the start of treatment with an active agent or compound of the present disclosure. In another preferred embodiment, the increase in the average survival time of a population can be measured by calculating the average survival time of the population after the completion of the first round of treatment with a compound of the present disclosure.

[0433] In another embodiment, the treatment of cancer reduces the tumor growth rate. Preferably, the tumor growth rate after treatment is reduced by at least 5% compared to the growth rate before treatment, more preferably, the tumor growth rate is reduced by at least 10%, more preferably, by at least 20%, more preferably, by at least 30%, more preferably, by at least 40%, more preferably, by at least 50%, even more preferably, by at least 50%, and most preferably, by at least 75%. The tumor growth rate can be measured by any reproducible measurement means. In a preferred embodiment, the tumor growth rate is measured by the change in tumor diameter per unit time.

[0434] In another embodiment, the treatment of cancer reduces tumor regrowth. Preferably, tumor regrowth after treatment is less than 5%, more preferably, tumor regrowth is less than 10%, more preferably, less than 20%, more preferably, less than 30%, more preferably, less than 40%, more preferably, less than 50%, even more preferably, less than 50%, and most preferably, less than 75%. Tumor regrowth can be measured by any reproducible measurement means. In a preferred embodiment, tumor regrowth is measured by measuring the increase in tumor diameter from a previous tumor shrinkage after treatment. In another preferred embodiment, the reduction in tumor regrowth is indicated by the absence of tumor recurrence after the end of treatment.

[0435] Dosages of the compounds of the disclosure for any of the methods and uses described herein will vary according to the agent, the age, weight, and clinical condition of the recipient subject, as well as the experience and judgment of the treating clinician or physician, among other factors which will affect the selected dosage.

[0436] In one non-limiting embodiment, a therapeutically effective amount of the compound of the present disclosure can be administered one or more times a day for up to 30 days or more, followed by one or more days without administration of the compound.This type of treatment regimen, i.e., administering the compound of the present disclosure on consecutive days, followed by not administering the compound on consecutive days, can be called a treatment cycle.The treatment cycle can be repeated as many times as necessary to achieve the intended effect.

[0437] In some embodiments, a therapeutically effective amount of a compound of the present disclosure is 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 , 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 11 1, 92, 93, 94, 95, 96, 97, 98, 99, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220 , 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 5 35, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, 600, 605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 69 0, 695, 700, 705, 710, 715, 720, 725, 730, 735, 740, 745, 750, 755, 760, 765, 770, 775, 780, 785, 790, 795, 800, 805, 810, 815, 820, 825, 830, 835, 840, 845,850, 855, 860, 865, 870, 875, 880, 885, 890, 895, 900, 905, 910, 915, 920, 925, 930, 935, 940, 945, 950, 955, 960, 965, 970, 975, 980, 985, 990, 995, or 1,000 mg taken once, twice, three times, or four times a day. or more for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30 consecutive days, or once, twice, three, four or more times daily, in single or divided doses, for 2, 3, 4, 5, 6, or more months.

[0438] In some embodiments, a therapeutically effective amount of a compound of the present disclosure is about 10 to about 40 mg, about 20 to about 50 mg, about 30 to about 60 mg, about 40 to about 70 mg, about 50 to about 80 mg, about 60 to about 90 mg, about 70 to about 100 mg, about 80 to about 110 mg, about 90 to about 120 mg, about 100 to about 130 mg, about 110 to about 140 mg, about 120 to about 150 mg, about 130 to about 160 mg, about 140 to about 170 mg, about 150 to about 180 mg, about 160 to about 190 mg, about 170 to about 200 mg, about 180 to about 210 mg, about 190 to about 220 mg, about 200 to about 230 mg, about 210 to about 240 mg, about 220 to about 250 mg, about 230 to about 260 mg, about 240 to about 270 mg, about 250 to about 280 mg, about 260 to about 290 mg, about 270 to about 300 mg, about 280 to about 310 mg, about 290 to about 320 mg, about 300 to about 330 mg , about 310 to about 340 mg, about 320 to about 350 mg, about 330 to about 360 mg, about 340 to about 370 mg, about 350 to about 380 mg, about 360 to about 390 mg, about 370 to about 400 mg, about 380 to about 410 mg, about 390 to about 420 mg, about 400 to about 430 mg, about 410 ~ about 440mg, about 420 to about 450mg, about 430 to about 460mg, about 440 to about 470mg, about 450 to about 480mg, about 460 to about 490mg, about 470 to about 500mg, about 480 to about 510mg, about 490 to about 520mg, about 500 to about 530mg, about 510 to about 540mg, about 520 to about 550mg, about 530 to about 560mg, about 540 to about 570mg, about 550 to about 580mg, about 560 to about 590mg, about 570 to about 600mg, about 580 to about 610mg, about 590 to about 620mg, about 600 to about 630mg, about 610 to about 640mg, about 20 to 650 mg, 630 to 660 mg, 640 to 670 mg, 650 to 680 mg, 660 to 690 mg, 670 to 700 mg, 680 to 710 mg, 690 to 720 mg, 700 to 730 mg, 710 to 740 mg, 720 to 7 50 mg, about 730 to about 760 mg, about 740 to about 770 mg, about 750 to about 780 mg, about 760 to about 790 mg, about 770 to about 800 mg, about 780 to about 810 mg, about 790 to about 820 mg, about 800 to about 830 mg, about 810 to about 840 mg, about 820 to about 850 mg,The dose is about 830 to about 860 mg, about 840 to about 870 mg, about 850 to about 880 mg, about 860 to about 890 mg, about 870 to about 900 mg, about 880 to about 910 mg, about 890 to about 920 mg, about 900 to about 930 mg, about 910 to about 940 mg, about 920 to about 950 mg, about 930 to about 960 mg, about 940 to about 970 mg, about 950 to about 980 mg, about 960 to about 990 mg, or about 970 to about 1,000 mg, and may be administered once, twice, three times, four or more times a day in a single dose or in divided doses (the dose depends on the patient's body weight (kg), body surface area (m, 2 ), and / or may be adjusted for age.

[0439] In some embodiments, a therapeutically effective amount of a compound of the present disclosure is from about 70 mg to about 1000 mg, administered once, twice, three times, four or more times daily in a single or divided dose (dosage is based on the patient's body weight (kg), body surface area (m 2 ), and / or may be adjusted for age.

[0440] In some embodiments, a therapeutically effective amount of a compound of the disclosure is about 70 mg, 105 mg, 140 mg, 175 mg, 210 mg, 245 mg, 280 mg, 315 mg, 350 mg, 385 mg, 420 mg, 455 mg, 490 mg, 525 mg, 560 mg, 595 mg, 630 mg, 665 mg, or 700 mg administered once, twice, three times, four or more times daily in a single or divided dose (dosage is based on the patient's body weight (kg), body surface area (m 2 ), and / or may be adjusted for age.

[0441] The therapeutically effective amount of the compound of the present disclosure may also range from about 0.01 mg / kg per day to about 100 mg / kg per day. In one embodiment, the therapeutically effective amount of the compound of the present disclosure may range from about 0.05 mg / kg per day to about 10 mg / kg per day. In one embodiment, the therapeutically effective amount of the compound of the present disclosure may range from about 0.075 mg / kg per day to about 5 mg / kg per day. In one embodiment, the therapeutically effective amount of the compound of the present disclosure may range from about 0.10 mg / kg per day to about 1 mg / kg per day. In one embodiment, the therapeutically effective amount of the compound of the present disclosure may range from about 0.20 mg / kg per day to about 0.70 mg / kg per day.

[0442] In some embodiments, the therapeutically effective amount of a compound of the present disclosure is about 0.10 mg / kg per day, about 0.15 mg / kg per day, about 0.20 mg / kg per day, about 0.25 mg / kg per day, about 0.30 mg / kg per day, about 0.35 mg / kg per day, about 0.40 mg / kg per day, about 0.45 mg / kg per day, about 0.50 mg / kg per day, about 0.55 mg / kg per day, about 0.60 mg / kg per day, about 0.65 mg / kg per day, about 0.70 mg / kg per day, about 0.75 mg / kg per day, about 0.80 mg / kg per day, about 0.85 mg / kg per day, about 0.90 mg / kg per day, about 0.95 mg / kg per day, or about 1.00 mg / kg per day.

[0443] In some embodiments, a therapeutically effective amount of a compound of the present disclosure is about 1.05 mg / kg per day, about 1.10 mg / kg per day, about 1.15 mg / kg per day, about 1.20 mg / kg per day, about 1.25 mg / kg per day, about 1.30 mg / kg per day, about 1.35 mg / kg per day, about 1.40 mg / kg per day, about 1.45 mg / kg per day, about 1.50 mg / kg per day, about 1.55 mg / kg per day, about 1.60 mg / kg per day, about 1.70 mg / kg per day, about 1.75 mg / kg per day, about 1.80 mg / kg per day, about 1.85 mg / kg per day, about 1.90 mg / kg per day, about 1.9 ... about 1.50 mg / kg per day, about 1.55 mg / kg per day, about 1.60 mg / kg per day, about 1.65 mg / kg per day, about 1.70 mg / kg per day, about 1.75 mg / kg per day, about 1.80 mg / kg per day, about 1.85 mg / kg per day, about 1.90 mg / kg per day, about 1.95 mg / kg per day, or about 2.00 mg / kg per day.

[0444] In some embodiments, the therapeutically effective amount of a compound of the present disclosure is about 2 mg / kg per day, about 2.5 mg / kg per day, about 3 mg / kg per day, about 3.5 mg / kg per day, about 4 mg / kg per day, about 4.5 mg / kg per day, about 5 mg / kg per day, about 5.5 mg / kg per day, about 6 mg / kg per day, about 6.5 mg / kg per day, about 7 mg / kg per day, about 7.5 mg / kg per day, about 8.0 mg / kg per day, about 8.5 mg / kg per day, about 9.0 mg / kg per day, about 9.5 mg / kg per day, or about 10 mg / kg per day.

[0445] In some embodiments, a therapeutically effective amount of a compound of the present disclosure is administered to a subject once a day. In some embodiments, the daily dose of a compound of the present disclosure may be administered to a subject all at once. In some embodiments, the daily dose of a compound of the present disclosure may be administered to a subject in two separate doses (i.e., split doses). In some embodiments, the daily dose of a compound of the present disclosure may be administered to a subject in three separate doses. In some embodiments, the daily dose of a compound of the present disclosure may be administered to a subject in four separate doses. In some embodiments, the daily dose of a compound of the present disclosure may be administered to a subject in five or more separate doses. In some embodiments, these partial or split doses are administered to a subject at regular intervals throughout the day, such as, for example, every 12 hours, every 8 hours, every 6 hours, every 5 hours, every 4 hours, etc.

[0446] Therapeutically effective amounts of compounds of the disclosure can be estimated initially either in cell culture assays or animal models (usually rats, mice, rabbits, dogs, or pigs). Animal models can also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic / prophylactic efficacy and toxicity can be determined using standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED 50 (the dose therapeutically effective in 50% of the population) and LD 50 (the dose that is lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 / ED 50 The therapeutic index can be expressed as a ratio of 0.01 to 0.05. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage can vary within this range depending on the dosage form employed, sensitivity of the patient, and the route of administration.

[0447] Dosage and administration are adjusted to provide sufficient concentration of the disclosed compound or to maintain the desired effect.Factors that may be considered include the severity of the condition, the subject's general health, the subject's age, weight and sex, diet, time and frequency of administration, drug combination(s), reaction sensitivity, and tolerance / response to therapy.Long-acting pharmaceutical compositions may be administered once every 3-4 days, every week, or every two weeks, depending on the half-life and clearance rate of the particular formulation.

[0448] Pharmaceutical Compositions In an aspect, the present application relates to a pharmaceutical composition comprising a bifunctional compound disclosed herein and one or more pharma- ceutically acceptable excipients.

[0449] In some embodiments, the compounds of the present disclosure are formulated for parenteral administration. In some embodiments, the parenteral formulation is prepared as an injectable formulation, for example, for intravenous administration. For example, in some embodiments, when the compounds of the present disclosure are formulated for parenteral administration by injection (for example, continuous infusion or bolus injection), the formulation may be in the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, and such formulation may further include pharma- ceutical necessary additives, such as one or more stabilizers, suspending agents, dispersing agents, and the like. When the compounds of the present disclosure are injected parenterally, it may be, for example, in the form of an isotonic sterile solution. The compounds of the present disclosure may be in the form of a powder that is reconstituted as an injectable formulation.

[0450] In some embodiments, the compounds of the present disclosure are formulated for oral administration.For example, in some embodiments, the compounds of the present disclosure are formulated as a tablet that includes zero, one, two or more of each of the following: emulsifiers; surfactants, binders; disintegrants, glidants; and lubricants.

[0451] The pharmaceutical composition containing the compound of the present disclosure can be manufactured by a generally known method, for example, by conventional mixing, dissolving, granulating, sugar-coating, levigating, emulsifying, encapsulating, encapsulating or lyophilizing process.The pharmaceutical composition can be formulated in a conventional manner using one or more pharma-ceutically acceptable carriers, including excipients and / or auxiliaries that facilitate the processing of the compound of the present disclosure into a preparation that can be used pharma-ceutically.Of course, the appropriate formulation depends on the selected route of administration.

[0452] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and must be fluid to the extent that easy syringability exists. The composition must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it is preferable to include isotonic agents, for example, sugars, polyalcohols, for example, mannitol, sorbitol, sodium chloride, etc. in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0453] Sterile solution for injection can be prepared by incorporating the compound of the present disclosure in the required amount in a suitable solvent with one or combination of the above-mentioned components as required, followed by sterilization by filtration.Generally, dispersion is prepared by incorporating active agent or compound in a sterile vehicle, which contains basic dispersion medium and other components required from above.In the case of sterile powder for preparing sterile solution for injection, the preparation method is vacuum drying and freeze-drying, which makes the powder of active ingredient and any desired additional ingredient from the solution that has been previously sterilized and filtered.

[0454] Oral compositions generally include an inert diluent or a pharma- ceutically acceptable edible carrier. Oral compositions can be enclosed in gelatin capsules or compressed into tablets. For oral therapeutic administration, the compounds of the present disclosure can be incorporated with excipients and used in the form of tablets, lozenges, or capsules. Oral compositions can also be prepared using a liquid carrier used as a mouthwash, where the agent or compound in the liquid carrier is orally applied, swished in the mouth, and expectorated or swallowed. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0455] For administration by inhalation, the agents or compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

[0456] Systemic administration may be by transmucosal or transdermal means. For transmucosal or transdermal administration, a penetrant suitable for the barrier to be permeated is used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be carried out by using nasal sprays or suppositories. For transdermal administration, the active agent or compound is formulated into ointments, salves, gels, or creams generally known in the art.

[0457] In an embodiment, the compounds of the present disclosure are prepared with pharma- ceutically acceptable carriers that prevent the agent or compound from being rapidly excreted from the body, such as controlled release formulations, including implants and microencapsulated delivery systems. Biodegradable biocompatible polymers, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid, can be used. Methods for preparing such formulations are clear to those skilled in the art. Materials can also be commercially obtained from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions, including liposomes targeted to infected cells that contain monoclonal antibodies against viral antigens, can also be used as pharma-ceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, the methods described in U.S. Pat. No. 4,522,811.

[0458] Oral or parenteral compositions are particularly advantageously formulated in unit dosage form for ease of administration and uniformity of dosage.Unit dosage form as used herein refers to a physically separate unit suitable for unitary administration to the subject to be treated, each unit containing a predetermined amount of active agent or compound calculated to produce a desired therapeutic effect together with the required pharmaceutical carrier.The specification of unit dosage form of the present application is determined and directly depends on the inherent characteristics of the compound of the present disclosure and the specific therapeutic effect to be achieved.

[0459] The pharmaceutical compositions can be included in a container, box, or dispenser together with instructions for administration.

[0460] Exemplary modes of administration of the compounds of the present disclosure include systemic or local administration, such as parenteral, oral, nasal, transdermal, subcutaneous, vaginal, buccal, rectal, or topical modes of administration. In some embodiments, the compounds of the present disclosure are administered orally. In some embodiments, the compounds of the present disclosure are administered as tablets, capsules, caplets, liquids, suspensions, syrups, granules, beads, powders, or pellets.

[0461] Exemplary pharmaceutical compositions include a salt of a compound of the present disclosure and a pharma- ceutically acceptable carrier, such as: a) a diluent, such as purified water, triglyceride oil, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oil, such as EPA or DHA, or esters thereof, or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose, and / or glycine; b) a lubricant, such as silica, talc, stearic acid, magnesium or calcium salts thereof, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium oleate, sodium stearate, magnesium stearate, sodium acetate, sodium oleate, sodium stearate, sodium acetate ... for tablets, further additives include, for example, c) binders, e.g. magnesium aluminium silicate, starch paste, gelatine, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars, e.g. glucose or beta-lactose, corn sweeteners, natural and synthetic gums, e.g. gum arabic, tragacanth or sodium alginate, waxes and / or polyvinylpyrrolidone (optionally); d) disintegrants, e.g. starch, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures; e) hygroscopic agents, colouring agents, flavouring agents and sweeteners; f) emulsifiers or dispersing agents, e.g. Tween 80, Labrasol, HPMC, DOSS, Caproyl 909, Labrafac, Labrafil, Peceol, Transcutol, Capmul MCM, Capmul PG-12, Captex 355, Gelucire, Vitamin E TGPS or other acceptable emulsifier; and / or g) an agent that enhances salt absorption, such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG 400, and / or PEG 200.

[0462] Pharmaceutically acceptable inert carriers for preparing pharmaceutical compositions from the compounds of the present disclosure, or salts or hydrates thereof, can be either solid or liquid. Solid preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories. Powders and tablets can be composed of about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, for example, magnesium carbonate, magnesium stearate, talc, sugar, or lactose. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharma-ceutically acceptable carriers and methods for preparing various compositions can be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pa.

[0463] Liquid preparations include solutions, suspensions, and emulsions, such as water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions, and emulsions. Liquid preparations may also include solutions for intranasal administration.

[0464] Liquid compositions, particularly injectable compositions, can be prepared, for example, by dissolving, dispersing, etc., for example, by dissolving or mixing a salt of the present disclosure in a pharma- ceutically acceptable solvent, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, etc., to form an injectable isotonic solution or suspension. Proteins, such as albumin, chylomicron particles, or serum proteins, can be used to solubilize the disclosed compounds.

[0465] Parenteral injection administration is usually used for subcutaneous, intramuscular or intravenous injection and infusion. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, or solid forms suitable for dissolving in liquid prior to injection.

[0466] Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharma- ceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.

[0467] Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions, and emulsions.

[0468] Depending on the intended mode of administration, the compositions of the present disclosure may be in solid, semi-solid, or liquid dosage forms, optionally in unit dosage amounts, consistent with conventional pharmaceutical practice, such as injectables, tablets, suppositories, pills, sustained release capsules, elixirs, tinctures, emulsions, syrups, powders, solutions, suspensions, etc. Similarly, the compositions may also be administered in intravenous (both bolus and infusion), intraperitoneal, intrathecal, subcutaneous, or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0469] The pharmaceutical compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and may contain about 0.1% to about 99%, about 5% to about 90%, or about 1% to about 20% of the free base or salt of the present disclosure by weight or volume.

[0470] Pharmaceutical compositions containing the compounds of the present disclosure may further comprise one or more additional anti-cancer agents, including any of those disclosed herein.

[0471] All amounts of any component of an oral dosage form, e.g., a tablet, described herein given on a % w / w basis refer to the total weight of the oral dosage form, unless otherwise specified. EXAMPLES

[0472] The present disclosure is further illustrated by the following examples, which are not to be construed as limiting the scope or spirit of the present disclosure to the specific procedures described herein. It should be understood that the examples are provided to illustrate certain embodiments, and are not intended to limit the scope of the present disclosure. It should also be understood that various other embodiments, modifications thereof, and equivalents thereof that may be suggested to those skilled in the art can be relied upon without departing from the spirit of the present disclosure and / or the scope of the appended claims.

[0473] Abbreviation: Ac 2 O Acetic anhydride Boc tert-butoxycarbonyl Boc 2 O Di-tert-butyl dicarbonate BSA Bovine Serum Albumin CbzCl Benzyl chloroformate DABCO 1,4-diazabicyclo[2.2.2]octane DCE 1,2-dichloroethane DIEA N,N-Diisopropylethylamine DMAP 4-Dimethylaminopyridine DMEM Dulbecco's Modified Eagle's Medium DMF Dimethylformamide DMSO Dimethyl sulfoxide dppf 1,1'-bis(diphenylphosphino)ferrocene EtOAc Ethyl acetate EtOH Ethanol FBS Fetal Bovine Serum HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate i-PrOH or IPA Isopropanol KOAc Potassium Acetate LiHMDS Lithium bis(trimethylsilyl)amide m-CPBA meta-chloroperoxybenzoic acid MOMCl Methoxymethyl chloride MOPS 3-(N-morpholino)propanesulfonic acid NIS N-iodosuccinimide OAc Acetic acid group PBS Phosphate Buffered Saline Pd(dppf)Cl 2 1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) PG protecting group p-TsOH p-Toluenesulfonic acid SFC Supercritical Fluid Chromatography TBAF Tetra-n-butylammonium fluoride TBDPSCl tert-Butyldiphenylchlorosilane TBME tert-Butyl methyl ether TBS Tris-buffered saline TBS-T A mixture of Tris-buffered saline and polysorbate 20 (also known as Tween 20) Tf 2 O Trifluoromethanesulfonic anhydride TFA Trifluoroacetic acid THF Tetrahydrofuran THP Tetrahydropyran TLC Thin Layer Chromatography

[0474] Example 1: General synthetic scheme. Compounds of the present disclosure can be prepared, for example, according to the routes depicted in Schemes 1-4: [ka] [ka] [ka] [ka]

[0475] Exemplary Synthesis of (2S,4R)-1-[(2S)-2-[[2-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methoxy]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 23) Step 1: Preparation of 2-chloro-3-fluoro-5-iodo-pyridin-4-amine [ka] CH 3 To a solution of 2-chloro-3-fluoro-pyridin-4-amine (2.00 g, 13.7 mmol, 1 equiv) and NIS (3.68 g, 16.4 mmol, 1.2 equiv) in CN (15 mL) was added p-TsOH (118 mg, 0.682 mmol, 0.05 equiv) and the reaction mixture was stirred at 70° C. for 16 h. The reaction mixture was diluted with EtOAc (40 mL) and the resulting mixture was washed with saturated Na 2 CO 3 Aqueous solution (2 x 30 mL), saturated Na 2 SO 3 Wash with aqueous solution (40 mL), brine (30 mL), and anhydrous Na 2 SO 4 Drying at 40° C., filtration and concentration under reduced pressure gave 2-chloro-3-fluoro-5-iodo-pyridin-4-amine (3.63 g, 13.3 mmol, 98% yield) as a yellow solid. LC / MS (ESI) m / z: 272.8 [M+H] + . 1 H-NMR (400 MHz, DMSO-d 6 ) δ 8.09 (s, 1H), 6.67 (br s, 2H).

[0476] Step 2: Preparation of ethyl 4-amino-6-chloro-5-fluoro-pyridine-3-carboxylate [ka] To a solution of 2-chloro-3-fluoro-5-iodo-pyridin-4-amine (3.63 g, 13.3 mmol, 1 equiv.) in EtOH (70 mL) was added triethylamine (4.85 g, 48.0 mmol, 6.68 mL, 3.6 equiv.) and Pd(PPh 3 ) 2 Cl 2 (935 mg, 1.33 mmol, 0.1 equiv) was added and the reaction mixture was stirred at 80° C. under CO (15 psi) (degassed under vacuum and purged with CO several times) for 16 h. The reaction mixture was concentrated under reduced pressure to remove approximately 70% of the EtOH and then filtered. The filter cake was washed with TBME (2×30 mL) and then dried under reduced pressure to give ethyl 4-amino-6-chloro-5-fluoro-pyridine-3-carboxylate (3.40 g, crude) as a yellow solid. LC / MS (ESI) m / z: 219.0 [M+H] + .

[0477] Step 3: Preparation of ethyl 6-chloro-5-fluoro-4-[(2,2,2-trichloroacetyl)carbamoylamino]pyridine-3-carboxylate [ka] To a solution of ethyl 4-amino-6-chloro-5-fluoro-pyridine-3-carboxylate (3.40 g, 15.6 mmol, 1 equiv) in THF (10 mL) was added 2,2,2-trichloroacetyl isocyanate (3.22 g, 17.1 mmol, 2.03 mL, 1.1 equiv) and the reaction mixture was cooled to 37° C. for 1 h and cooled to 37° C. 2 The mixture was stirred at 20° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give ethyl 6-chloro-5-fluoro-4-[(2,2,2-trichloroacetyl)carbamoylamino]pyridine-3-carboxylate (6.10 g, crude) as a brown solid. LC / MS (ESI) m / z: 408.1 [M+H] + .

[0478] Step 4: Preparation of 7-chloro-8-fluoro-pyrido[4,3-d]pyrimidine-2,4-diol [ka] CH 3 To a solution of ethyl 6-chloro-5-fluoro-4-[(2,2,2-trichloroacetyl)carbamoylamino]pyridine-3-carboxylate (6.10 g, 15.0 mmol, 1 equiv.) in OH (55 mL) was added ammonia (7 M, 10.7 mL, 5 equiv.) and the reaction mixture was stirred at 20° C. for 1 h. The reaction mixture was filtered and the filter cake was washed with TBME (3×20 mL) and then dried under reduced pressure to give 7-chloro-8-fluoro-pyrido[4,3-d]pyrimidine-2,4-diol (3.03 g, 14.06 mmol, 94% yield) as a white solid. LC / MS (ESI) m / z: 216.1 [M+H] + .

[0479] Step 5: Preparation 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 (2.50 g, 11.6 mmol, 1 equiv.) in toluene (30 mL), DIEA (4.50 g, 34.8 mmol, 6.06 mL, 3 equiv.) and POCl 3 (8.89 g, 58.0 mmol, 5.39 mL, 5 equiv.) was added and the reaction mixture was cooled to 4° C. 2 The mixture was stirred at 100° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (2.9 g, crude) as a yellow oil. LC / MS (ESI) m / z: 253.7 [M+H] + .

[0480] Step 6: Preparation 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] CH 2 Cl 2 To a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (2.90 g, 11.5 mmol, 1 equiv.) in 100 mL of DIEA (7.42 g, 57.4 mmol, 5 equiv.) and tert-butyl (1S,5R)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.44 g, 11.5 mmol, 1 equiv.) were added at −40° C. and the reaction mixture was cooled to 37° C. with N 2 The mixture was stirred at −40° C. for 0.5 h. The reaction mixture was poured into water (50 mL) and 2 Cl 2 (3×50 mL). The combined organic layers were washed with brine (2×60 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (elution: 0-25% EtOAc / petroleum ether) to give tert-butyl 3-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.47 g, 5.77 mmol, 50% yield) as a yellow solid, characterized. LC / MS (ESI) m / z: 428.2 [M+H] + . 1 H-NMR (400 MHz, DMSO-d 6 ) δ 9.06 (s, 1H), 4.60-4.40 (Sm, 2H), 4.31-4.22 (m, 2H), 3.80-3.59 (m, 2H), 1.85-1.74 (m, 2H), 1.66-1.57 (m, 2H), 1.46 (s, 9H).

[0481] Step 7: Preparation of tert-butyl 3-[7-chloro-2-(2,2-dimethoxyethoxy)-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] CH 3 To a solution 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 (500 mg, 1.17 mmol, 1 equiv.) and 2,2-dimethoxyethanol (186 mg, 1.75 mmol, 1.5 equiv.) in CN (10 mL) was added Cs 2 CO 3 (456 mg, 1.40 mmol, 1.2 equiv.) and DABCO (13 mg, 0.17 mmol, 0.1 equiv.) were added and the reaction mixture was treated with N 2 The mixture was stirred at 20° C. for 16 h under reduced pressure. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (elution: 0-15% THF / petroleum ether) to give tert-butyl 3-[7-chloro-2-(2,2-dimethoxyethoxy)-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (685 mg, 1.38 mmol, 98% yield) as a yellow solid. LC / MS (ESI) m / z: 498.3 [M+H] + . 1 H-NMR (400 MHz, CDCl 3 ) δ 8.74(s,1H),4.81(t, J =5.6 Hz,1H),4.54-4.45(m,4H)S,4.43-4.27(m,2H),3.74-3.55(m,2H),3.48(s,6H),2.02-1.90(m,2H),1.75-1.65(m,2H),1.52(s,9H).

[0482] Step 8: Preparation of tert-butyl 3-[2-(2,2-dimethoxyethoxy)-8-fluoro-7-(3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of tert-butyl 3-[7-chloro-2-(2,2-dimethoxyethoxy)-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (685 mg, 1.38 mmol, 1 equiv.) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (557 mg, 2.06 mmol, 1.5 equiv.) in dioxane (8 mL) / water (2 mL), Cs 2 CO 3 (896 mg, 2.75 mmol, 2 equiv.) and Pd(PPh 3 ) 4 (207 mg, 0.179 mmol, 0.13 equiv.) was added and the reaction mixture was cooled to 4°C with N 2 (Degassed under vacuum with N 2 The reaction mixture was stirred at 100° C. for 16 h. The reaction mixture was diluted with EtOAc (20 mL) and then diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (elution: 0-40% THF / petroleum ether) to give tert-butyl 3-[2-(2,2-dimethoxyethoxy)-8-fluoro-7-(3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (688 mg, 1.14 mmol, 83% yield) as a yellow solid. LC / MS (ESI) m / z: 606.5 [M+H] + .

[0483] Step 9: Preparation of tert-butyl 3-[8-fluoro-7-(3-hydroxy-1-naphthyl)-2-(2-oxoethoxy)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] A mixture of tert-butyl 3-[2-(2,2-dimethoxyethoxy)-8-fluoro-7-(3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.495 mmol, 1 equiv.) in acetone (0.62 mL) / HCl (12 M, 0.619 mL, 15 equiv.) was stirred at 20° C. for 20 min. Then, NaHCO in water (2 mL) was added. 3 (1.25g, 14.9mmol, 30eq) solution of Boc 2 O (324 mg, 1.49 mmol, 3 equiv.) and THF (2 mL) were added and the resulting mixture was stirred at 20° C. for 0.5 h. The reaction mixture was extracted with EtOAc (3×5 mL) and the combined organic layers were washed with brine (2×5 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (elution: 0-50% THF / petroleum ether) to give tert-butyl 3-[8-fluoro-7-(3-hydroxy-1-naphthyl)-2-(2-oxoethoxy)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (222 mg, 0.397 mmol, 80% yield) as a white solid. LC / MS (ESI) m / z: 560.4 [M+H] + .

[0484] Step 10: Preparation of tert-butyl 4-[(2-ethoxy-2-oxo-ethoxy)methyl]piperidine-1-carboxylate [ka] CH 2 Cl 2 To a solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (2.00 g, 9.29 mmol, 1.00 equiv) in SiO (50 mL) was added diacetoxyrhodium (1.20 g, 4.64 mmol, 0.50 equiv) and ethyl 2-diazoacetate (12.00 g, 92.90 mmol, 10 mL, 10.00 equiv) at 0° C. and the reaction mixture was stirred at 25° C. for 12 h. The solution was concentrated under reduced pressure and dried under vacuum. SiO 2 Purification by column chromatography (0-20% EtOAc / petroleum ether) afforded tert-butyl 4-[(2-ethoxy-2-oxo-ethoxy)methyl]piperidine-1-carboxylate (1.50 g, 4.98 mmol, 54% yield) as a yellow oil. LC / MS (ESI) m / z: 202.2 [M-Boc+1] + .

[0485] Step 11: Preparation of 2-[(1-tert-butoxycarbonyl-4-piperidyl)methoxy]acetic acid [ka] THF (10 mL), CH 3 OH (5 mL) and H 2 To a solution of tert-butyl 4-[(2-ethoxy-2-oxo-ethoxy)methyl]piperidine-1-carboxylate (1.50 g, 4.98 mmol, 1.00 equiv) in O (5 mL) was added LiOH hydrate (700 mg, 14.93 mmol, 3.00 equiv) and the reaction mixture was stirred for 12 h at 25° C. The reaction was acidified with dilute hydrochloric acid (pH=5) and the resulting mixture was concentrated under reduced pressure to give 2-[(1-tert-butoxycarbonyl-4-piperidyl)methoxy]acetic acid (1.00 g, 3.66 mmol, 74% yield) as a yellow oil.

[0486] Step 12: Preparation of tert-butyl 4-[[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]methyl]piperidine-1-carboxylate [ka] CH 2 Cl 2 A mixture of 2-[(1-tert-butoxycarbonyl-4-piperidyl)methoxy]acetic acid (115 mg, 0.42 mmol, 1.00 equiv.) and (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (200 mg, 0. To a solution of 42 mmol, 1.00 equiv, hydrochloride (42 mmol, 1.00 equiv), hydroxybenzotriazole (85 mg, 0.62 mmol, 1.50 equiv), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (120 mg, 0.62 mmol, 1.50 equiv), and diisopropylethylamine (270 mg, 2.08 mmol, 5.00 equiv) were added and the reaction mixture was stirred at 25° C. for 12 h. The solution was concentrated under reduced pressure and dried under vacuum. Thin layer chromatography (EtOAc / CH 3 Purification by HPLC (HPLC-MS / HPLC) (OH=20 / 1) afforded tert-butyl 4-[[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]methyl]piperidine-1-carboxylate (210 mg, 0.30 mmol, 72% yield) as a yellow oil. LC / MS (ESI) m / z: 700.4 [M+H] + .

[0487] Step 13: Preparation of (2S,4R)-1-[(2S)-3,3-dimethyl-2-[[2-(4-piperidylmethoxy)acetyl]amino]butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide [ka] CH 2 Cl 2 To a solution of tert-butyl 4-[[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]methyl]piperidine-1-carboxylate (100 mg, 0.14 mmol, 1.00 equiv) in (2 mL) was added HCl (4 M in dioxane, 2 mL) and the reaction mixture was stirred at 25 °C for 0.5 h. The solution was concentrated under reduced pressure and dried under vacuum to give (2S,4R)-1-[(2S)-3,3-dimethyl-2-[[2-(4-piperidylmethoxy)acetyl]amino]butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (90 mg, 0.14 mmol, 99% yield, hydrochloride salt) as a yellow solid.

[0488] Step 14: Preparation of tert-butyl 3-[8-fluoro-2-[2-[4-[[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]methyl]-1-piperidyl]ethoxy]-7-(3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] CH2 Cl 2 tert-Butyl 3-[8-fluoro-7-(3-hydroxy-1-naphthyl)-2-(2-oxoethoxy)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (110 mg, 0.197 mmol, 1 equiv.) and (2S,4R)-1-[(2S)-3,3-dimethyl-2-[[2-(4-piperidyl) To a solution of [(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (118 mg, 0.197 mmol, 1 equiv.), acetic acid (35 mg, 0.59 mmol, 3 equiv.) and 2-methylpyridine borane (105 mg, 0.983 mmol, 5 equiv.) were added, and the reaction mixture was stirred at 20° C. for 0.5 h. The reaction mixture was filtered, and the filtrate was purified by flash silica gel chromatography (elution: 0-10% CH 3 OH / CH 2 Cl 2 ) to give tert-butyl 3-[8-fluoro-2-[2-[4-[[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]methyl]-1-piperidyl]ethoxy]-7-(3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (131 mg, 0.115 mmol, 58% yield) as a white solid. LC / MS (ESI) m / z: 1144.7 [M+H] + .

[0489] Step 15: Preparation of (2S,4R)-1-[(2S)-2-[[2-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methoxy]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide [ka] CH 2 Cl 2 To a solution of tert-butyl 3-[8-fluoro-2-[2-[4-[[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]methyl]-1-piperidyl]ethoxy]-7-(3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (131 mg, 0.115 mmol, 1 equiv.) in (2 mL) was added TFA (2 mL) and the reaction mixture was stirred at 20° C. for 1 h. The reaction mixture was concentrated under reduced pressure to provide a residue. The residue was diluted with water (1 mL) and the resulting mixture was diluted with saturated NaHCO 3 The pH was adjusted to 8 with aqueous solution of 100% NaCl. The resulting suspension was filtered and the cake was diluted with EtOAc / THF (3×20 mL, 1 / 1). The organic layer was washed with anhydrous Na 2 SO 4 The crude product was purified by preparative HPLC (gradient: 0-40% CH 3Purification by CN / water (0.225% formic acid)). Pure fractions were combined and dried by lyophilization to give (2S,4R)-1-[(2S)-2-[[2-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methoxy]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (61.6 mg, 0.055 mmol, 48% yield, formate salt) as a white solid. LC / MS (ESI) m / z: 1043.4 [M+H] + . 1 H-NMR (400 MHz, CD 3 OD) δ 9.15 (s, 1H), 8.89-8.84 (m, 1H), 8.47 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.46-7.35 (m, 5H), 7.29 (d, J = 2.4 Hz, 1H), 7.27-7.S20 (m, 2H), 5.01-4.95 (m, 1H), 4.80-4.70 (m, 4H), 4.69 (s, 1H), 4.60-4.50 (m, 3H), 4.09-3.70 (m, 8H), 3.59-3.36 (m, 5H), 2.89-2.68 (m, 2H), 2.46 (s, 3H), 2.26-2.17 (m, 1H), 2.05-1.88 (m, 8H), 1.63-1.42 (m, 5H), 1.05-0.99 (m, 9H).

[0490] Exemplary Synthesis of (2S,4R)-1-[(2R)-2-[3-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methoxy]isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 22) Step 1: Preparation of tert-butyl 4-[[5-(1-methoxycarbonyl-2-methyl-propyl)isoxazol-3-yl]oxymethyl]piperidine-1-carboxylate [ka] To a solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (1.30 g, 6.02 mmol, 1.2 equiv.) and methyl 2-(3-hydroxyisoxazol-5-yl)-3-methyl-butanoate (1 g, 5.02 mmol, 1 equiv.) in THP (10 mL) was added Ph 3 P (1.58 g, 6.02 mmol, 1.2 equiv) and diisopropyl azodicarboxylate (1.22 g, 6.02 mmol, 1.17 mL, 1.2 equiv) were added and the reaction mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by flash silica gel chromatography (0-60% EtOAc / petroleum ether) to give tert-butyl 4-[[5-(1-methoxycarbonyl-2-methyl-propyl)isoxazol-3-yl]oxymethyl]piperidine-1-carboxylate (1.8 g, 4.54 mmol, 90% yield) as a white solid. LC / MS (ESI) m / z: 297.2 [M+H] + ; 1 H-NMR (400 MHz, CDCl 3) δ 5.88 (s, 1H), 4.21 - 4.10 (m, 2H), 4.07 (d, J = 6.4 Hz, 2H), 3.73 (s, 3H), 3.49 (d, J = 8.7 Hz, 1H), 2.82 - 2.62 (m, 2H), 2.35 (qd, J = 7.1, 14.2 Hz, 1H), 1.96 (br d, J = 3.4 Hz, 1H), 1.77 (br d, J = 12.8 Hz, 2H), 1.46 (s, 9H), 1.29 - 1.22 (m, 2H), 1.00 (d, J = 6.7 Hz, 3H), 0.93 (d, J = 6.7 Hz, 3H).

[0491] Step 2: Preparation of 2-[3-[(1-tert-butoxycarbonyl-4-piperidyl)methoxy]isoxazol-5-yl]-3-methyl-butanoic acid [ka] THF (8 mL), CH 3 OH (5 mL), and H 2 To a solution of tert-butyl 4-[[5-(1-methoxycarbonyl-2-methyl-propyl)isoxazol-3-yl]oxymethyl]piperidine-1-carboxylate (1.8 g, 4.54 mmol, 1 equiv.) in O (3 mL) was added LiOH monohydrate (544 mg, 22.70 mmol, 5 equiv.) and the reaction mixture was stirred for 1 h at 25° C. The reaction mixture was acidified (pH=3) by addition of 1 M hydrochloric acid and the resulting precipitate was filtered to give crude 2-[3-[(1-tert-butoxycarbonyl-4-piperidyl)methoxy]isoxazol-5-yl]-3-methyl-butanoic acid (1.9 g) as a white solid.

[0492] Step 3: Preparation of tert-butyl 4-[[5-[1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl-propyl]isoxazol-3-yl]oxymethyl]piperidine-1-carboxylate [ka] CH 2 Cl 2 To a solution of 2-[3-[(1-tert-butoxycarbonyl-4-piperidyl)methoxy]isoxazol-5-yl]-3-methyl-butanoic acid (1.0 g, 2.61 mmol, 1.0 equiv) in (30 mL) was added DIEA (2.3 mL, 13.07 mmol, 5.0 equiv) and HATU (1.3 g, 3.40 mmol, 1.3 equiv) and the reaction mixture was cooled to 37° C. with N 2 The mixture was stirred at 25° C. for 10 min under reduced pressure. Then, (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (962 mg, 2.61 mmol, 1.0 equiv., HCl) was added and the reaction mixture was diluted with N 2 The mixture was stirred at 25° C. for 2 hours. The reaction mixture was poured onto water (30 mL) and the organic layer was separated. The aqueous layer was diluted with CH 2 Cl 2 (3×30 mL). The combined organic layers were washed with brine (50 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give the crude product which was purified by flash chromatography on silica gel (gradient: (0-58% THF / petroleum ether) to give tert-butyl 4-[[5-[1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl-propyl]isoxazol-3-yl]oxymethyl]piperidine-1-carboxylate (1.3 g, 1.55 mmol, 59% yield) as a yellow solid. LC / MS (ESI) m / z: 696.4 [M+H]+ This material was purified by SFC (column: DAICEL CHIRALPAK AD (250mm*50mm, 10um); mobile phase: 35% isopropanol / water (0.1% NH 3 ) to give tert-butyl 4-[[5-[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl-propyl]isoxazol-3-yl]oxymethyl]piperidine-1-carboxylate and tert-butyl 4-[[5-[(1R)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl-propyl]isoxazol-3-yl]oxymethyl]piperidine-1-carboxylate.

[0493] tert-Butyl 4-[[5-[(1R)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl-propyl]isoxazol-3-yl]oxymethyl]piperidine-1-carboxylate 1 H-NMR (400 MHz, CDCl 3) δ 8.68 (s, 1H), 7.48 (br d, J = 7.5 Hz, 1H), 7.39 (q, J = 8.3 Hz, 4H), 5.88 (s, 1H), 5.07 (t, J = 7.2 Hz, 1H), 4.67 - 4.60 (m, 2H), 4.19 - 4.02 (m, 4H), 3.80 (dd, J = 5.1, 10.5 Hz, 1H), 3.60 (dd, J = 3.7, 10.4 Hz, 1H), 3.53 - 3.48 (m, 1H), 2.78 - 2.66 (m, 2H), 2.58 - 2.47 (m, 4H), 2.46 - 2.35 (m, 1H), 1.96 (ddd, J = 5.0, 8.0, 12.8 Hz, 2H), 1.75 (br d, J = 12.1 Hz, 3H), 1.50 (d, J = 7.0 Hz, 3H), 1.46 (s, 9H), 1.28 - 1.19 (m, 2H), 1.05 (d, J = 6.6 Hz, 3H), 0.93 (d, J = 6.7 Hz, 3H).

[0494] tert-Butyl 4-[[5-[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl-propyl]isoxazol-3-yl]oxymethyl]piperidine-1-carboxylate 1 H-NMR (400 MHz, CDCl 3) δ 8.70 - 8.68 (m, 1H), 7.42 - 7.39 (m, 2H), 7.36 - 7.32 (m, 3H), 5.86 (s, 1H), 5.02 - 4.94 (m, 1H), 4.78 (dd, J = 4.3, 8.3 Hz, 1H), 4.66 (quin, J = 5.4 Hz, 1H), 4.16 - 4.09 (m, 1H), 4.08 - 4.01 (m, 2H), 3.74 - 3.68 (m, 1H), 3.60 - 3.48 (m, 2H), 2.78 - 2.62 (m, 3H), 2.52 - 2.41 (m, 1H), 2.02 - 1.93 (m, 2H), 1.75 (br d, J = 9.9 Hz, 6H), 1.46 (s, 9H), 1.38 (d, J = 7.0 Hz, 3H), 1.30 - 1.18 (m, 3H), 1.06 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.7 Hz, 3H).

[0495] Step 4: Preparation of (2S,4R)-4-hydroxy-1-[(2R)-3-methyl-2-[3-(4-piperidylmethoxy)isoxazol-5-yl]butanoyl]-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide [ka] CH 2 Cl 2 To a solution of tert-butyl 4-(((5-((R)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)oxy)methyl)piperidine-1-carboxylate (720 mg, 1.03 mmol, 1 equiv) in (5 mL) was added HCl (4N in dioxane, 3.6 mL, 14 equiv) and the reaction mixture was stirred at 25° C. for 1 h. The mixture was concentrated and then diluted with H 2HO (5 mL) was added and the pH of the resulting aqueous mixture was adjusted to 0.05 with saturated NaHCO 3 The pH was adjusted to about 8 by the addition of aqueous solution of CH 2 Cl 2 / CH 3 OH (3×20 mL, V / V:10 / 1) and the combined organic extracts were washed with Na 2 SO 4 Drying at 40° C., filtration and concentration under reduced pressure afforded (2S,4R)-4-hydroxy-1-[(2R)-3-methyl-2-[3-(4-piperidylmethoxy)isoxazol-5-yl]butanoyl]-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (610 mg, crude) as a white solid. LC / MS (ESI) m / z: 596.3 [M+H] + .

[0496] Step 5: Preparation of tert-butyl 3-[8-fluoro-2-[2-[4-[[5-[(1R)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl-propyl]isoxazol-3-yl]oxymethyl]-1-piperidyl]ethoxy]-7-(3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] CH 2 Cl 2tert-Butyl 3-[8-fluoro-7-(3-hydroxy-1-naphthyl)-2-(2-oxoethoxy)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (110 mg, 197 mmol, 1 equiv.) and (2S,4R)-4-hydroxy-1-[(2R)-3-methyl-2-[3-(4-piperidine)-2-yl]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5 mL) / i-PrOH (0.5 mL) To a solution of [(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (117 mg, 0.197 mmol, 1 equiv.), acetic acid (35 mg, 0.59 mmol, 3 equiv.) and 2-methylpyridine borane (105 mg, 0.983 mmol, 5 equiv.) were added, and the reaction mixture was stirred at 20° C. for 0.5 h. The reaction mixture was filtered, and the filtrate was purified by flash silica gel chromatography (elution: 0-10% CH 3 OH / CH 2 Cl 2 ) to give tert-butyl 3-[8-fluoro-2-[2-[4-[[5-[(1R)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl-propyl]isoxazol-3-yl]oxymethyl]-1-piperidyl]ethoxy]-7-(3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (127 mg, 0.111 mmol, 57% yield) as a yellow solid. LC / MS (ESI) m / z: 1139.5 [M+H] + .

[0497] Step 5: Preparation of (2S,4R)-1-[(2R)-2-[3-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methoxy]isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide [ka] CH 2 Cl 2 To a solution of tert-butyl 3-[8-fluoro-2-[2-[4-[[5-[(1R)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl-propyl]isoxazol-3-yl]oxymethyl]-1-piperidyl]ethoxy]-7-(3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (127 mg, 0.111 mmol, 1 equiv.) in (2 mL) was added TFA (2 mL) and the reaction mixture was stirred at 20° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (1 mL) and the resulting mixture was diluted with saturated NaHCO 3 The pH was adjusted to 8 with aqueous solution of 100% NaCl. The resulting suspension was filtered and the cake was diluted with EtOAc / THF (3×20 mL, 1 / 1). The organic layer was washed with anhydrous Na 2 SO 4 The crude product was purified by preparative HPLC (gradient: 0-40% CH 3Purification by CN / water (0.225% formic acid)). Pure fractions were combined and dried by lyophilization to give (2S,4R)-1-[(2R)-2-[3-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(3-hydroxy-1-naphthyl)pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methoxy]isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (81.8 mg, 0.072 mmol, 65% yield, formate salt) as a white solid. LC / MS (ESI) m / z: 1039.4 [M+H] + . 1 H-NMR (400 MHz, CD 3 OD) δ 9.15 (s, 1H), 8.88-8.85 (m, 1H), 8.48 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.47-7.36 (m, 5H), 7.31-7.28 (m, 1H), 7.26-7.20 (m, 2H), 6.00-5.92 (m, 1H), 5.03 (q, J = 7.2 Hz, 1H), 4.78-4.71 (m, 5H), 4.51 (t, J = 8.4 Hz, 1H), 4.08 (d, J = 6.0 Hz, 2H), 3.97-3.90 (m, 2H), 3.87-3.72 (m, 3H), 3.67 (d, J = 10.0 Hz, 1H), 3.60 (d, J = 10.8 Hz, 1H), 3.49-3.41 (m, 2H), 3.28-3.21 (m, 2H), 2.75-2.62 (m, 2H), 2.50-2.45 (m, 3H), 2.42-2.32 (m, 1H), 2.22-2.12 (m, 1H), 2.03-1.89 (m, 8H), 1.63-1.47 (m, 5H), 1.05 (d, J = 6.5 Hz, 3H), 0.92-0.85 (m, 3H).

[0498] Exemplary Synthesis of (2S,4R)-1-[(2S)-2-[[2-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methoxy]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 21) Step 1: Preparation of 8-(2-triisopropylsilylethynyl)naphthalene-1,3-diol [ka] To a solution of naphthalene-1,3-diol (9.17 g, 57.25 mmol, 1.0 equiv.) and 2-bromoethynyl(triisopropyl)silane (17.95 g, 68.70 mmol, 1.2 equiv.) in anhydrous 1,4-dioxane (120 mL), KOAc (11.24 g, 114.50 mmol, 2.0 equiv.) and (1-isopropyl-4-methyl-benzene)ruthenium dichloride dimer (3.51 g, 5.73 mmol, 0.10 equiv.) were added and the reaction mixture was stirred at 110° C. for 16 h. The mixture was filtered through a Celite pad and the resulting filtrate was concentrated and then diluted with EtOAc (400 mL). The organic phase was washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by flash chromatography on silica gel (gradient: 0-5% EtOAc / petroleum ether) to give 8-(2-triisopropylsilylethynyl)naphthalene-1,3-diol (12.12 g, 30.25 mmol, 53% yield) as a yellow solid.

[0499] Step 2: Preparation of 3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)naphthalen-1-ol [ka] Anhydrous CH 2 Cl2 To a solution of 8-(2-triisopropylsilylethynyl)naphthalene-1,3-diol (12.12 g, 30.25 mmol, 1.0 equiv) in 120 mL of DIEA (13.80 g, 106.77 mmol, 3.53 equiv) and MOMCl (4.30 g, 53.39 mmol, 1.76 equiv) were added dropwise and the reaction mixture was stirred at 0° C. for 40 min. The reaction mixture was quenched with water (100 mL) at 0° C. and then diluted with CH 2 Cl 2 (3×100 mL). The combined organic extracts were washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by flash chromatography on silica gel (gradient: 0-2% EtOAc / petroleum ether) to give 3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)naphthalen-1-ol (8.50 g, 22.10 mmol, 62% yield) as a yellow oil. 1 H-NMR (400 MHz, CDCl 3 ) δ 9.25 (s, 1H), 7.69 (dd, J = 8.4, 0.8, Hz, 1H), 7.50 (dd, J = 7.2, 1.2, Hz, 1H), 7.31 (dd, J = 8.0, 7.2, Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.78 (d, J = 2.4 Hz, 1H), 5.27 (s, 2H), 3.51 (s, 3H), 1.22-1.16 (m, 21H).

[0500] Step 3: Preparation of [3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl] acetate [ka] Anhydrous CH 2 Cl 2To a solution of 3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)naphthalen-1-ol (4.5 g, 11.70 mmol, 1.0 equiv) in 10 mL of hexane (45 mL) was added DIEA (3.78 g, 29.25 mmol, 2.5 equiv) and acetyl chloride (1.38 g, 17.55 mmol, 1.5 equiv) and the reaction mixture was stirred at 0° C. for 1 h. 2 Quench with 20O (30 mL) at 0 °C, then add CH 2 Cl 2 (3×40 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by flash chromatography on silica gel (gradient: 0-3% EtOAc / petroleum ether) to give crude [3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl] acetate (5.27 g) as a yellow oil. LC / MS (ESI) m / z: 427.4 [M+H] + .

[0501] Step 4: Preparation of [8-ethynyl-3-(methoxymethoxy)-1-naphthyl] acetate [ka] To a solution of [3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl] acetate (4.99 g, 11.70 mmol, 1.0 equiv.) in DMF (50 mL) was added CsF (12.44 g, 81.88 mmol, 7.0 equiv.) and the reaction mixture was stirred at 20° C. for 2 h. The reaction mixture was diluted with methyl tert-butyl ether (500 mL) and the organic phase was washed with water (8×50 mL) followed by brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by flash chromatography on silica gel (gradient: 0-5% EtOAc / petroleum ether) to give [8-ethynyl-3-(methoxymethoxy)-1-naphthyl] acetate (1.69 g, 6.13 mmol, 52% yield) as a black-brown solid. 1H-NMR (400 MHz, CDCl 3 ) δ 7.76 (d, J = 7.6 Hz, 1H), 7.65 (dd, J = 7.2, 1.2 Hz, 1H), 7.38 (dd, J = 8.0, 7.2 Hz, 1H), 7.34 (d, J = 2.4 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 5.29 (s, 2H), 3.53 (s, 3H), 3.39 (s, 1H), 2.42 (s, 3H).

[0502] Step 5: Preparation of [8-ethyl-3-(methoxymethoxy)-1-naphthyl] acetate [ka] CH 3 To a solution of [8-ethynyl-3-(methoxymethoxy)-1-naphthyl] acetate (1.69 g, 6.13 mmol) in OH (30 mL) and THF (10 mL), 10% Pd / C (100 mg) was added under argon and the reaction mixture was cooled to 10° C. 2 The mixture was stirred at 25° C. under (15 psi) for 4 h. The mixture was filtered through a pad of Celite and rinsed with EtOAc (3×40 mL). The filtrate was concentrated to dryness to give [8-ethyl-3-(methoxymethoxy)-1-naphthyl] acetate (1.63 g, 5.94 mmol, 95% yield) as a yellow oil. LC / MS (ESI) m / z: 275.0 [M+H] + .

[0503] Step 6: Preparation of 8-ethyl-3-(methoxymethoxy)naphthalen-1-ol [ka] THF (15 mL) and H 2To a solution of [8-ethyl-3-(methoxymethoxy)-1-naphthyl] acetate (1.63 g, 5.94 mmol, 1.0 equiv) in 2H2O (5 mL) was added LiOH monohydrate (1.25 g, 29.71 mmol, 5.0 equiv) and the reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was concentrated to remove the organic solvent and the pH of the remaining aqueous portion was adjusted to 5 by addition of 3N hydrochloric acid at 0 °C. The resulting aqueous mixture was extracted with EtOAc (3 × 50 mL) and the combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by flash chromatography on silica gel (gradient: 0-5% EtOAc / petroleum ether) to give 8-ethyl-3-(methoxymethoxy)naphthalen-1-ol (925 mg, 3.98 mmol, 67% yield) as a yellow solid. LC / MS (ESI) m / z: 233.1 [M+H] + .

[0504] Step 7: Preparation of [8-ethyl-3-(methoxymethoxy)-1-naphthyl] trifluoromethanesulfonate [ka] Anhydrous CH 2 Cl 2 To a solution of 8-ethyl-3-(methoxymethoxy)naphthalen-1-ol (920 mg, 3.96 mmol, 1.0 equiv) in 12 mL of N2O was added DIEA (2.56 g, 19.80 mmol, 5.0 equiv) and trifluoromethanesulfonic anhydride (1.68 g, 5.94 mmol, 1.5 equiv) dropwise and the reaction mixture was diluted with N2O. 2 The reaction mixture was stirred at −40° C. for 30 min. The reaction mixture was quenched with water (10 mL) at −40° C., warmed to room temperature, and then diluted with CH 2 Cl 2(3×30 mL). The combined organic extracts were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by flash chromatography on silica gel (gradient: 0-1% EtOAc / petroleum ether) to give [8-ethyl-3-(methoxymethoxy)-1-naphthyl] trifluoromethanesulfonate (1.23 g, 3.27 mmol, 83% yield) as a yellow oil.

[0505] Step 8: Preparation of 2-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] [8-Ethyl-3-(methoxymethoxy)-1-naphthyl] trifluoromethanesulfonate (1.23 g, 3.38 mmol, 1.0 equiv.), bis(pinacolato)diboron (1.89 g, 7.43 mmol, 2.2 equiv.), Pd(dppf)Cl in anhydrous 1,4-dioxane (12 mL). 2 A mixture of (494 mg, 0.675 mmol, 0.20 equiv.) and KOAc (1.16 g, 11.82 mmol, 3.5 equiv.) was degassed and diluted with N 2 (3X) and then N 2 The mixture was stirred at 110° C. under atmospheric pressure for 16 hours. The reaction mixture was filtered and the filter cake was washed with methyl tert-butyl ether (3×40 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by flash chromatography on silica gel (gradient: 0-2% EtOAc / petroleum ether) to give 2-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (670 mg, 1.86 mmol, 55% yield) as a yellow oil. LC / MS (ESI) m / z: 343.2 [M+H] + .

[0506] Step 9: Preparation of tert-butyl 3-[2-(2,2-dimethoxyethoxy)-7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] Dioxane (15 mL) and H 2 To a solution of tert-butyl 3-[7-chloro-2-(2,2-dimethoxyethoxy)-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.6 g, 3.21 mmol, 1 equiv.) and 2-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.28 g, 3.73 mmol, 1.16 equiv.) in 20O (3 mL) was added Cs 2 CO 3 (2.62 g, 8.03 mmol, 2.5 equiv.) and [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (418.8 mg, 0.643 mmol, 0.2 equiv.) were added and the reaction mixture was treated with N 2 The mixture was stirred at 110° C. for 16 h under reduced pressure. The mixture was diluted with EtOAc (150 mL) and the combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (gradient: 10-30% EtOAc / petroleum ether) to give tert-butyl 3-[2-(2,2-dimethoxyethoxy)-7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.922 g, 1.28 mmol, 40% yield) as a brown solid. LC / MS (ESI) m / z: 678.4 [M+H] + .

[0507] Step 10: Preparation of tert-butyl 3-[7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-2-(2-oxoethoxy)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-(2,2-dimethoxyethoxy)-7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.148 mmol, 1 equiv.) in acetone (0.37 mL), concentrated HCl (12 M, 0.37 mL, 30 equiv.) was added dropwise and the reaction mixture was stirred at 20° C. for 5 min (a total of 9 batches were performed). Then, saturated NaHCO 3 Aqueous solution was added until pH=8, and the resulting mixture was filtered and washed with water (10 mL) and petroleum ether (10 mL) to give 2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyacetaldehyde (crude 640 mg) as a yellow solid. 2 O (343.8 mg, 1.58 mmol, 1.2 equiv.) and H 2 NaHCO in O (2.5 mL) 3A solution of (330.8 mg, 3.94 mmol, 3 equiv) was added and the reaction mixture was stirred at 20 °C for 2 h. The mixture was diluted with EtOAc (120 mL) and the organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by flash chromatography on silica gel (gradient: 10-50% EtOAc / petroleum ether) to give tert-butyl 3-[7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-2-(2-oxoethoxy)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (430 mg, 46% yield) as a yellow solid. LC / MS (ESI) m / z: 588.4 [M+H] + .

[0508] Step 11: Preparation of tert-butyl 3-[7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-2-[2-[4-[[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]methyl]-1-piperidyl]ethoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] CH 2 Cl 2(2 mL) and tert-butyl 3-[7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-2-(2-oxoethoxy)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (130 mg, 0.221 mmol, 1 equiv.) and (2S,4R)-1-[(2S)-3,3-dimethyl-2-[[2-(4-piperidyl) To a solution of N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (132.7 mg, 0.221 mmol, 1 equiv.) was added acetic acid (66.4 mg, 1.11 mmol, 5 equiv.) and 2-methylpyridine borane (118.3 mg, 1.11 mmol, 5 equiv.) and the reaction mixture was stirred at 25° C. for 3 h. Triethylamine was then added and the resulting mixture (pH approx. 8) was purified by flash chromatography on silica gel (gradient: 0 to 5% CH 3 OH / CH 2 Cl 2 ) to give tert-butyl 3-[7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-2-[2-[4-[[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]methyl]-1-piperidyl]ethoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (160 mg, 38% yield) as a yellow solid. LC / MS (ESI) m / z: 586.7 [M / 2+H] + .

[0509] Step 12: Preparation of (2S,4R)-1-[(2S)-2-[[2-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methoxy]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide [ka] tert-Butyl = 3-[7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-2-[2-[4-[[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]a in DCE (2 mL) To a solution of [amino]-2-oxo-ethoxy]methyl-1-piperidyl]ethoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (160 mg, 0.137 mmol, 1 equiv.) was added TFA (778.7 mg, 6.83 mmol, 0.51 mL, 50 equiv.) and the reaction mixture was stirred at 25° C. for 1 h. 2 Remove most of the solvent by bubbling with saturated NaHCO 3 Basify to pH=8 with aqueous solution of CH 3 OH / CH 2 Cl 2 (3×30 mL, 1 / 10). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by preparative HPLC (gradient 0-40% CH 3Purification by CN / water (0.225% formic acid). Pure fractions were combined and lyophilized to give (2S,4R)-1-[(2S)-2-[[2-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methoxy]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (48.0 mg, 30% yield, formate salt) as a white solid. LC / MS (ESI) m / z: 1071.9 [M+H] + . 1 H-NMR (400 MHz, CD 3 OD) δ 9.10 (s, 1H), 8.89 - 8.84 (m, 1H), 8.49 (m, 1H, HCOOH), 7.65 - 7.60 (m, 1H), 7.45 - 7.33 (m, 5H), 7.29 (d, J = 2.4 Hz, 1H), 7.16 (d, J = 7.2 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 5.03 - 4.95 (m, 1H), 4.82 - 4.66 (m, 7H), 4.60 - 4.51 (m, 1H), 4.45 - 4.36 (m, 1H), 4.08 - 3.72 (m, 7H), 3.65 - 3.55 (m, 2H), 3.50 - 3.38 (m, 4H), 3.01 - 2.84 (m, 2H), 2.47 (s, 3H), 2.40 - 2.18 (m, 3H), 2.10 - 1.87 (m, 8H), 1.66 - 1.54 (m, 2H), 1.47 (dd, J = 7.2, 2.4 Hz, 2H), 1.08 - 0.96 (s, 9H), 0.89 (t, J = 7.4 Hz, 3H).

[0510] Exemplary Synthesis of (2S,4R)-1-[(2S)-2-[3-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methoxy]isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 8) Step 1: Preparation of (2S,4R)-4-hydroxy-1-[(2S)-3-methyl-2-[3-(4-piperidylmethoxy)isoxazol-5-yl]butanoyl]-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide [ka] CH 2 Cl 2 To a solution of tert-butyl 4-[[5-[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl-propyl]isoxazol-3-yl]oxymethyl]piperidine-1-carboxylate (200 mg, 0.287 mmol, 1.0 equiv) in (1 mL) was added HCl in dioxane (4 M, 1.0 mL, 14 equiv) and the reaction mixture was stirred at 25° C. for 1 h. The pH was adjusted to 100 with saturated NaCl. 2 CO 3 The pH was adjusted to approximately 8 by slowly adding aqueous solution of 100. The resulting mixture was diluted with water (2 mL) and added to CH 2 Cl 2 / CH 3 The combined organic layers were washed with brine (10 mL) and extracted with NaOH (3×20 mL, 10:1). 2 SO 4Drying at 40° C., filtering and concentrating afforded (2S,4R)-4-hydroxy-1-[(2S)-3-methyl-2-[3-(4-piperidylmethoxy)isoxazol-5-yl]butanoyl]-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (166 mg, 0.261 mmol, 91% yield) as a yellow gum. LC / MS (ESI) m / z: 596.4 [M+H] + .

[0511] Step 2: Preparation of tert-butyl 3-[7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-2-[2-[4-[[5-[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl-propyl]isoxazol-3-yl]oxymethyl]-1-piperidyl]ethoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] IPA (1.0 mL) and CH 2 Cl 2tert-Butyl 3-[7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-2-(2-oxoethoxy)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.170 mmol, 1.0 equiv.) and (2S,4R)-4-hydroxy-1-[(2S)-3-methyl-2-[3-(4-piperidyl) To a solution of N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (101 mg, 0.170 mmol, 1.0 equiv.) was added acetic acid (681 mmol, 0.039 mL, 4 equiv.) and 2-methylpyridine borane (91 mg, 0.851 mmol, 5.0 equiv.) and the reaction mixture was stirred at 25° C. for 30 min. The pH was adjusted to approximately 8 by the addition of triethylamine. The crude product was purified by flash chromatography on silica gel (gradient: 0 to 8% CH 3 OH / CH 2 Cl 2 ) to give tert-butyl 3-[7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-2-[2-[4-[[5-[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl-propyl]isoxazol-3-yl]oxymethyl]-1-piperidyl]ethoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (133 mg, 0.102 mmol, 60% yield) as a yellow solid. LC / MS (ESI) m / z: 1167.5 [M+H] + .

[0512] Step 3: Preparation of (2S,4R)-1-[(2S)-2-[3-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methoxy]isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide [ka] CH 2 Cl 2 To a solution of tert-butyl 3-[7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-2-[2-[4-[[5-[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl-propyl]isoxazol-3-yl]oxymethyl]-1-piperidyl]ethoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (130 mg, 0.111 mmol, 1.0 equiv) in (3.0 mL) was added TFA (13.51 mmol, 1.0 mL, 121.28 equiv) and the reaction mixture was stirred at 25° C. for 1 h. pH, saturated NaHCO 3 The pH was adjusted to approximately 8 by the addition of aqueous solution. Water (2.0 mL) was added and the resulting mixture was diluted with CH 2 Cl 2 / CH 3 The combined organic layers were washed with brine (10 mL) and extracted with NaOH (3×15 mL, 10:1). 2 SO 4 The crude product was purified by preparative HPLC (gradient: 5-45% CH 3Purification by CN / water (0.225% formic acid)) was performed. Pure fractions were combined, concentrated under reduced pressure, and then lyophilized to give (2S,4R)-1-[(2S)-2-[3-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methoxy]isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (52.5 mg, 0.048 mmol, 43% yield) as a white solid. LC / MS (ESI) m / z: 1067.4 [M+H] + . 1 H-NMR (400 MHz, CD 3OD) δ 9.08 (s, 1H), 8.90 - 8.85 (m, 1H), 8.49 (s, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.48 - 7.33 (m, 5H), 7.29 (d, J = 1.6 Hz, 1H), 7.16 (d, J = 7.2 Hz, 1H), 7.00 (t, J = 2.4 Hz, 1H), 6.04 - 5.95 (m, 1H), 5.01 - 4.95 (m, 1H), 4.78 - 4.72 (m, 3H), 4.70 - 4.66 (m, 1H), 4.57 (t, J = 8.2 Hz, 1H), 4.42 (br s, 1H), 4.10 - 4.01 (m, 2H), 3.94 - 3.88 (m, 2H), 3.86 - 3.74 (m, 3H), 3.74 - 3.68 (m, 1H), 3.67 - 3.62 (m, 1H), 3.42 (br d, J = 10.6 Hz, 2H), 3.21 (br d, J = 4.8 Hz, 2H), 2.63 (br t, J = 11.4 Hz, 2H), 2.49 - 2.45 (m, 3H), 2.39 - 2.19 (m, 4H), 2.02 - 1.87 (m, 8H), 1.60 - 1.51 (m, 2H), 1.48 (d, J = 7.0 Hz, 3H), 1.08 - 0.93 (m, 3H), 0.93 - 0.82 (m, 6H).

[0513] Exemplary Synthesis of (2S,4R)-1-[(2R)-2-[3-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methoxy]isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 20) Step 1: Preparation of tert-butyl 3-[7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-2-[2-[4-[[5-[(1R)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl-propyl]isoxazol-3-yl]oxymethyl]-1-piperidyl]ethoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] CH 2 Cl 2 (2 mL) and tert-butyl 3-[7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-2-(2-oxoethoxy)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (130 mg, 0.221 mmol, 1 equiv.) and (2S,4R)-4-hydroxy-1-[(2R)-3-methyl-2-[3-(4-piperidine)-2-yl]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2 mL) and tert-butyl 3-[7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-2-(2-oxoethoxy) ... To a solution of [(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (131.8 mg, 0.221 mmol, 1 equiv.), acetic acid (66.4 mg, 1.11 mmol, 5 equiv.) and 2-methylpyridine borane (118.3 mg, 1.11 mmol, 5 equiv.) were added and the reaction mixture was stirred at 25° C. for 2 h. The pH was adjusted to 8 by the addition of triethylamine and the resulting mixture was subjected to flash chromatography on silica gel (gradient: 0 to 5% CH 3 OH / CH 2 Cl 2) to give tert-butyl 3-[7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-2-[2-[4-[[5-[(1R)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl-propyl]isoxazol-3-yl]oxymethyl]-1-piperidyl]ethoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (210 mg, 54%) as a yellow solid. LC / MS (ESI) m / z: 584.6 [M / 2+H] + .

[0514] Step 2: Preparation of (2S,4R)-1-[(2R)-2-[3-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methoxy]isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide [ka] To a solution of tert-butyl 3-[7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-2-[2-[4-[[5-[(1R)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl-propyl]isoxazol-3-yl]oxymethyl]-1-piperidyl]ethoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (210 mg, 0.180 mmol, 1 equiv.) in DCE (2.7 mL) was added TFA (1.03 g, 8.99 mmol, 50 equiv.) and the reaction mixture was stirred at 25° C. for 1 h. The mixture was cooled to 5° C. with 5% CO.sub.2O.sub.3.2 Remove most of the solvent by bubbling with saturated NaHCO 3 The resulting material was purified by preparative HPLC (30-80% CH 3 CN / Water(NH 4 The pure fractions were combined and lyophilized to give (2S,4R)-1-[(2R)-2-[3-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methoxy]isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (42.6 mg, 22% yield) as a white solid. LC / MS (ESI) m / z: 1067.8 [M+H] + . 1 H-NMR (400 MHz, CD 3 OD) δ 9.05 (s, 1H), 8.87 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.47 - 7.33 (m, 5H), 7.29 (d, J = 2.4 Hz, 1H), 7.16 (d, J = 6.8 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 5.97 (s, 1H), 5.08 - 4.97 (m, 2H), 4.70 - 4.61 (m, 4H), 4.53 - 4.48 (m, 1H), 4.46 - 4.41 (m, 1H), 4.08 - 4.00 (m, 2H), 3.86 - 3.59 (m, 7H), 3.20 - 3.11 (m, 2H), 2.97 - 2.88 (m, 2H), 2.48 (s, 3H), 2.41 - 2.13 (m, 6H), 2.00 - 1.77 (m, 8H), 1.61 - 1.49 (m, 2H), 1.48 - 1.35 (m, 2H), 1.05 (d, J = 6.4 Hz, 3H), 0.94 - 0.85 (m, 6H).

[0515] Exemplary Synthesis of (2S,4R)-1-[(2S)-2-[[2-[[1-[2-[4-(3-azabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methoxy]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 19) Step 1: Preparation of 3-oxabicyclo[3.2.1]octane-2,4-dione [ka] Ac 2 A mixture of cyclopentane-1,3-dicarboxylic acid (5.90 g, 37.3 mmol, 1 equiv) in O (30 mL) was stirred at 140° C. for 24 h. The reaction mixture was concentrated under reduced pressure and the resultant was washed with EtOAc / petroleum ether (3×30 mL, 1 / 30) to give 3-oxabicyclo[3.2.1]octane-2,4-dione (4.70 g, 33.5 mmol, 90% yield) as a grey solid. 1 H-NMR (400 MHz, DMSO-d 6 ) δ 3.23-3.11 (m, 2H), 2.35 (d, J = 12.4 Hz, 1H), 2.15-2.05 (m, 2H), 1.94-1.84 (m, 2H), 1.71-1.64 (td, J = 12.8, 4.0 Hz, 1H).

[0516] Step 2: Preparation of 3-azabicyclo[3.2.1]octane-2,4-dione [ka] NH 3A mixture of 3-oxabicyclo[3.2.1]octane-2,4-dione (2.70 g, 19.3 mmol, 1 equiv) in 1H / MeOH (7 M, 27.5 mL, 10 equiv) was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was heated at 180 °C for 15 min. After cooling to 25 °C, the residue was purified by CH 2 Cl 2 (50 mL) and the mixture was filtered through silica gel. The filtrate was concentrated under reduced pressure to give 3-azabicyclo[3.2.1]octane-2,4-dione (755 mg, 5.43 mmol, 28% yield) as a white solid. LC / MS (ESI) m / z: 140.1 [M+H] + . 1 H-NMR (400 MHz, DMSO-d 6 ) δ 10.43 (brs, 1H), 2.88-2.82 (m, 2H), 2.10 (d, J = 12.0 Hz, 1H), 2.06-1.98 (m, 2H), 1.77-1.69 (m, 2H), 1.59 (dt, J = 12.0, 4.0 Hz, 1H).

[0517] Step 3: Preparation of 3-azabicyclo[3.2.1]octane [ka] To a solution of 3-azabicyclo[3.2.1]octane-2,4-dione (755 mg, 5.43 mmol, 1 equiv) in THF (20 mL) at 0 °C was added LiAlH 4 (412 mg, 10.9 mmol, 2 equiv.) was added and the reaction mixture was treated with N ...

Claims

1. A bifunctional compound having the structure of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof (In the formula, (a) KTM has the structure of formula KTM-I: 【Chemistry 2】 wherein X Ｋ１ is N or CR Ｋ５ and X Ｋ２ is N or CR Ｋ６ and X Ｋ３ is N or CR Ｋ７ and X Ｋ４ is NR Ｋ８ or C １ -C ３ alkylene, wherein said alkylene is selected from one or more R Ｋ９ optionally replaced by R Ｋ１ and R Ｋ２ are H, OH, Cl, F, Br, I, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, O—(C １ -C ６ alkyl), and O—(C １ -C ６ haloalkyl); R Ｋ３ and R Ｋ４ are H, OH, Cl, F, Br, I, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C １０ Cycloalkyl, 3- to 10-membered heterocycle, O—(C １ -C ６ alkyl), and O—(C １ -C ６ haloalkyl); R Ｋ３ and R Ｋ４ together with the carbon to which they are attached form C ６ -C １０ forming an aryl or a 5- to 6-membered heteroaryl, wherein the aryl or heteroaryl is selected from 1, 2, 3, 4, or 5 R Ｋ１１ optionally replaced by R Ｋ５ , R Ｋ６ , and R Ｋ７ is H, Cl, F, Br, I, NR Ｋ１２ R Ｋ１３ , C １ -C ６ Alkyl, and C １ -C ６ haloalkyl; R Ｋ８ and R Ｋ９ is H, C １ -C ６ Alkyl, and C １ -C ６ haloalkyl; Each R Ｋ１１ are H, OH, CN, Cl, F, Br, I, NR Ｋ１２ R Ｋ１３ , C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, and C １ -C ６ haloalkyl; R Ｋ１２ and R Ｋ１３ is H, C １ -C ６ Alkyl, and C １ -C ６ haloalkyl; R Ｋ１４ and R Ｋ１５ is H, C １ -C ６ Alkyl, and C １ -C ６ haloalkyl; R Ｋ１４ and R Ｋ１５ is X Ｋ４ and together with the carbon to which they are attached, C ４ -C ７ forming a cycloalkyl or 4- to 7-membered heterocycle, 【Transformation 3】 represents the connection point between KTM and LNK, (b) LNK is a chemical linking moiety that covalently couples the KTM to the VLM, and has the structure LI: 【Chemistry 4】 wherein Each L is 【Transformation 5】 C ２ -C ６ Alkylene, C ２ -C ６ Alkenylene, C ２ -C ６ Alkynylene, monocyclic C ４ -C １０ Cycloalkylene, fused bicyclic C ４ -C １２ Cycloalkylene, bridged bicyclic C ６ -C １０ Cycloalkylene or spiro-fused bicyclic C ５ -C １２ Cycloalkylene, monocyclic 4- to 10-membered heterocycloalkylene, fused bicyclic 4- to 10-membered heterocycloalkylene, bridged bicyclic 6- to 10-membered heterocycloalkylene, spiro-fused 5- to 12-membered heterocycloalkylene, C ６ -C １０ cycloalkylene, heterocycloalkylene, arylene, and heteroarylene are independently selected from 1, 2, 3, 4, or 5 R Ｌ５ optionally replaced by Each A Ｌ is CR Ｌ１ R Ｌ２ , N.R. Ｌ３ , and O are independently selected from Each R Ｌ１ and R Ｌ２ is H, C １ -C ６ Alkyl, O—(C １ -C ６ alkyl), and C １ -C ６ haloalkyl, wherein said alkyl is selected from Cl, F, OH, NH ２ , CN, or CF ３ optionally replaced by Each R Ｌ３ is H, C １ -C ６ Alkyl, O—(C １ -C ６ alkyl), and C １ -C ６ haloalkyl, wherein said alkyl is selected from Cl, F, OH, NH ２ , CN, or CF ３ optionally replaced by Each R Ｌ４ is C １ -C ６ Alkyl, O—(C １ -C ６ alkyl), C １ -C ６ Haloalkyl, NH, CN, CF ３ , Cl, F, Br, I, and OH, wherein said alkyl is selected from Cl, F, OH, NH ２ , CN, or CF ３ optionally replaced by Each R Ｌ５ are Cl, F, Br, I, C １ -C ６ Alkyl, O—(C １ -C ６ alkyl), C １ -C ６ Haloalkyl, NH ２ , C.N., C.F. ３ and OH, wherein said alkyl is selected from Cl, F, OH, NH ２ , CN, or CF ３ optionally replaced by n Ｌ is 2, 3, 4, 5, or 6, (c) VLM has the structure VLM-I: 【Transformation 6】 wherein Y Ｖ１ teeth, 【Transformation 7】 and Y Ｖ２ is CN or 【Transformation 8】 and 【Chemistry 9】 is phenyl or 5- to 6-membered heteroarylene; 【Chemistry 10】 is a 5-membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, S, and O; R Ｖ１ , R Ｖ２ , and R Ｖ３ is H, C １ -C ６ Alkyl, and C １ -C ６ haloalkyl; R Ｖ１ and R Ｖ２ together with the carbon to which they are attached, C ３ -C １０ forms a cycloalkyl or a 5- to 6-membered heterocyclic ring, R Ｖ３ is H, C １ -C ６ Alkyl, and C １ -C ６ haloalkyl; R Ｖ４ａ and R Ｖ４ｂ is H, C １ -C ６ Alkyl, and C １ -C ６ haloalkyl; Each R Ｖ５ and R Ｖ６ is H and C １ -C ６ independently selected from alkyl, R Ｖ７ and R Ｖ８ is H, C １ -C ６ Alkyl, and C １ -C ６ haloalkyl; R Ｖ７ and R Ｖ８ together with the atoms to which they are attached to the carbon, ３ -C １０ forming a cycloalkyl or 5- to 6-membered heterocycle, n Ｖ is 0, 1, 2, 3, or 4, o Ｖ is 0, 1, 2, or 3, 【Chemistry 11】 represents the junction between the VLM and the LNK).

2. The KTM is represented by formula (KTM-Ia), (KTM-Ib), (KTM-Ic), (KTM-Id), or (KTM-Ie), 【Chemistry 12】 2. The bifunctional compound of claim 1 having the structure:

3. X Ｋ２ But, CR Ｋ６ and R Ｋ６ The bifunctional compound of claim 1 , wherein is F.

4. X Ｋ４ The bifunctional compound of claim 1 , wherein is NH.

5. X Ｋ４ But CH ２ 2. The bifunctional compound of claim 1, wherein:

6. X Ｋ４ But CH ２ CH ２ 2. The bifunctional compound of claim 1, wherein:

7. R Ｋ３ and R Ｋ４ One of them is CF ３ and O-CF ３ and R Ｋ３ and R Ｋ４ The bifunctional compound according to claim 1 , wherein the other of the above is H.

8. KTM is (KTM-1), (KTM-2), (KTM-3), (KTM-4), (KTM-5), (KTM-6), and (KTM-7): 【Chemistry 13】 2. The bifunctional compound of claim 1, having a structure selected from:

9. LNK has the structure (L-Ia), (L-Ib), (L-Ic), (L-Id), (L-Ie), or (L-If): 【Chemistry 14】 The bifunctional compound according to any one of claims 1 to 8, having the formula:

10. 9. The bifunctional compound of claim 1, wherein the LNK has the structure (L-Ia), (L-Ib), or (L-Ic).

11. LNK is (LNK-1), (LNK-2), (LNK-3), (LNK-4), (LNK-5), (LNK-6), (LNK-7), (LNK-8), (LNK-9), and (LNK-10): 【Chemistry 15】 The bifunctional compound according to any one of claims 1 to 8, having a structure selected from:

12. The VLM has the structure (VLM-Ia), (VLM-Ib), (VLM-Ic), or (VLM-Id): 【Chemistry 16】 The bifunctional compound of claim 11 having the formula:

13. Y Ｖ２ but, 【Chemistry 17】 13. The bifunctional compound of claim 12, wherein:

14. VLM is (VLM-1), (VLM-2), (VLM-3), (VLM-4), (VLM-5), (VLM-6), (VLM-7), (VLM-8), (VLM-9), and (VLM-10): 【Chemistry 18-1】 【Chemistry 18-2】 13. The bifunctional compound of claim 12, having a structure selected from:

15. 2. The bifunctional compound of claim 1, wherein the compound is selected from compounds 1-245 and 247-343, or a pharmaceutically acceptable salt thereof.

16. The bifunctional compound of any one of claims 1 to 8, wherein the KTM reversibly binds to KRAS.

17. 17. The bifunctional compound of claim 16, wherein KRAS contains a mutation compared to wild-type, said mutation being G12C, G12D or G12V.

18. A bifunctional compound selected from compounds 246 to 247, or a pharmaceutically acceptable salt thereof.

19. 13. A pharmaceutical composition comprising the bifunctional compound of claim 12 and one or more pharmaceutically acceptable excipients.

20. A pharmaceutical composition for treating cancer in a subject, comprising a therapeutically effective amount of a bifunctional compound according to any one of claims 1 to 8 or 15, and one or more pharmaceutically acceptable excipients.

21. 21. The pharmaceutical composition of claim 20, wherein the cancer is pancreatic cancer, colon cancer, colorectal cancer, lung cancer, non-small cell lung cancer, endometrial cancer, cervical cancer, bladder cancer, liver cancer, myeloid leukemia, ovarian cancer, or breast cancer.

22. A pharmaceutical composition comprising the bifunctional compound of any one of claims 1 to 8 or 15 and one or more pharmaceutically acceptable excipients.

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