Allosteric EGFR inhibitors and methods of use thereof

Abstract

20 26 23 41 02 18 S ep 2 02 6 A B S T R A C T 2 0 2 6 2 3 4 1 0 2 1 8 S e p 2 0 2 6

Description

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under Grant No. R01 CA201049 5 awarded by the National Institute of Health (NIH). The government has certain rights in the invention. RELATED APPLICATIONS This application is a divisional of Australian Patent Application No. 2020383423, the 10 entire content of which is incorporated herein by reference. BACKGROUND The epidermal growth factor receptor (EGFR, Erb-B1) belongs to a family of receptor tyrosine kinases that mediate the proliferation, differentiation, and survival of normal and 15 malignant cells (Arteaga, C. L., J. Clin. Oncol. 19, 2001, 32-40). Deregulation of EGFR has been implicated in many types of human cancer, with overexpression of the receptor present in at least 70% of human cancers (Seymour, L. K., Curr. Drug Targets 2, 2001, 117-133), including non-small lung cell carcinomas, breast cancers, gliomas, squamous cell carcinomas of the head and neck, and prostate cancer (Raymond, E., et al., Drugs 60 20 (Suppl. 1), 2000, 15-23, discussion 41-2; Salomon, D. S., et al., Crit. Rev. Oncol. Hematol. 19, 1995, 183-232; Voldborg B. R., et al., Ann. Oncol. 8, 1997, 1197-1206). EGFR has, therefore, emerged as an attractive target for the design and development of diagnostic and therapeutic agents that can specifically bind and inhibit the receptor’s tyrosine kinase activity and signal transduction pathway in cancer cells. For example, the EGFR tyrosine kinase 25 (EGFR-TK) reversible inhibitor TARCEVA RTM is approved by the FDA for treatment of NSCLC and advanced pancreatic cancer. Other anti-EGFR targeted molecules have also been approved, including LAPATINIB RTM and IRESSA RTM. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective clinical therapies for EGFR mutant advanced non-small cell lung cancer (NSCLC) 30 patients (Mok, T. S., et al., N. Engl. J. Med. 361, 2009, 947-57; Paez, J. G., et al., Science 304, 2004, 1497-500; Lynch, T. J., et al., N. Engl. J. Med. 350, 2004, 2129-39; Rosell, R., et al., Lancet Oncol. 13, 2012, 239-46). Several randomized clinical trials have demonstrated that EGFR TKIs are more effective, as measured by response rate (RR) and progression free survival (PFS), than chemotherapy when used as initial systemic treatment for 35 advanced EGFR mutant NSCLC (Mok, T. S., et al., N. Engl. J. Med. 361, 2009, 947-57; Rosell, R., et al., Lancet Oncol. 13, 2012, 239-46; Sequest, L. V. et al., J. Clin. Oncol. 31, 2026234102   18 Sep 2026 2013, 3327-34; Wu, Y. L, et al., Lancet Oncol. 15, 2014, 213-22; Maemondo, M., et al., N. Engl. J. Med. 362, 2010, 2380-8; Zhou, C., et al., Lancet Oncol. 12, 2011, 735-42; Mitsudomi, T., et al., Lancet Oncol. 11, 2010, 121-8). However, the vast majority of patients will develop disease progression following successful treatment with an EGFR TKI. The 5 most common mechanism of acquired resistance, detected in 60% of patients, is a secondary mutation in EGFR at position T790 (T790M) (Yu, H. A., et al., Clin. Cancer Res. 19, 2013, 2240-7). This mutation leads to an increase in ATP affinity, thus making it more difficult for reversible EGFR TKIs gefitinib and erlotinib to bind the EGFR TKI domain (Yun C. H„ et al., Proc. Natl. Acad. Sci. USA 105, 2008, 2070-5). 10          Covalent EGFR inhibitors have emerged for inhibiting EGFR T790M-containing cancers. However, in lung cancer patients, afatinib is only effective in EGFR TKI naive EGFR mutant cancers and has a RR of less than 10% in patients with NSCLC that have developed resistance to gefitinib or erlotinib (Miller, V. A., et al., Lancet Oncol. 13, 2012, 528-38). Afatinib is a potent inhibitor of both mutant and wild type (WT) EGFR. Inhibition of 15 WT EGFR leads to toxicities, including skin rash and diarrhea, which limits the ability to escalate afatinib doses in patients to those necessary to inhibit EGFR T790M. Irreversible pyrimidine EGFR inhibitors including the tool compound WZ4002 and clinical compounds CO-1686 and AZD9291, overcome many of the limitations of afatinib (Zhou, W., et al., Nature 462, 2009, 1070-4; Walter, A. 0., et al., Cancer Discov. 3, 2013, 1404-15; Cross, D. 20 A. E., et al., Cancer Discov. 4, 2014, 1046-61). They are not only more potent on EGFR T790M, but also selectively inhibit mutant over WT EGFR and hence should lead to increased clinical efficacy and less toxicity compared with afatinib (Zhou, W., et al; Walter A. 0., et al, Cross, D. A. E., et al.). However, all current EGFR TKIs target the ATP site, and while third generation 25 irreversible inhibitors can overcome T790M, they are all rendered impotent by the C797S mutation, which is already arising in treated patients. Cetuximab, an anti-EGFR antibody that blocks receptor dimerization, is not effective in EGFR-mutant NSCLC because mutational activation of the kinase is effectively “downstream” of receptor dimerization. Hence, alternative strategies to inhibit EGFR are needed. At present, suitable compounds with 30 alternative mechanisms of action targeting mutant EGFR are not available. Thus, there is a need for potent small molecule EGFR inhibitors with alternative mechanisms of action targeting mutant EGFR. SUMMARY 35          In an aspect, provided herein is a compound of Formula I: 2026234102   18 Sep 2026 (I) or a pharmaceutically acceptable salt thereof; wherein: 5          A and A’ are each, independently, CH, CR8, or N; W and Z are each, independently, N, CH, C-halo, C-(Ci-Cs alkyl), or C-(Ci-Cs alkoxy); X and Y are each, independently, N, CH, or CR3; provided that at least one of W, X, Y, or Z is CH; 10          R1 is selected from the group consisting of 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, and 3-1Q membered cycloalkyl, all of which are optionally substituted with one, two, or three R8; R2 is selected from the group consisting of 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, and 3-10 membered cycloalkyl, all of which are 15 optionally substituted with one, two, or three R8; R3 is independently, at each occurrence, selected from the group consisting of halogen, OR4, NR4R4, SO2R4, SO2NHR4, NHSO2R4, C(O)OR4, C(O)NHR4, C(O)R4, Ci-C6 alkyl, C2-C6 alkenyl, C2-Cb alkynyl, 3-7 membered cycloalkyl, C4-C7 cycloalkenyl, Cs-Cw aryl, 5-6 membered heteroaryl, and 5-7 membered heterocyclyl, wherein alkyl, alkenyl, or alkynyl 20 are each optionally substituted one, two, or three times with R4, and wherein aryl, heteroaryl, or heterocyclyl are each optionally substituted one, two, or three times with Rs; R4 is independently, at each occurrence, selected from the group consisting of H, (CH2)o-3-(C3-C- cycloalkyl), (CH2)o-3-(C4-C7 cycloalkenyl), (CH2)o-3-(Cb-Cio aryl), (CH2)o-3-(5-6 membered heteroaryl), and (CH2)o-3-(5-7 membered heterocyclyl), wherein the aryl, 25 heteroaryl, or heterocyclyl are each optionally substituted one, two, or three times with Rs; R5 is independently, at each occurrence, selected from the group consisting of O-Ce alkyl, Ci-Ce haloalkyl, Ci-Csalkoxy, Ci-Ce haloalkoxy, C1-C3 alkylamine, 3-10 membered cycloalkyl, halogen, COOH, C(O)O(Ci-Cs alkyl), O(CH2)i.3-OH, NH2, NH(Ci-Cs alkyl), N(Ci-Cs alkyl)2, OH, CN, (CH2)o-3-(C6-Cio aryl), (CH2)o-3-(5-6 membered heteroaryl), and (CH2)o-3-30   (5-7 membered heterocyclyl), wherein the aryl, heteroaryl, or heterocyclyl are each optionally substituted one, two, or three times with R7; R6 is independently, at each occurrence, selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, CrC3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, halogen, OH, NO2, NH2, NH(Ci-Cb alkyl), N(CrC6 alkyl)2, (CH2)i.4OH, S(O)0.2H, S(0)o.2NH2, orCN; 2026234102   18 Sep 2026 alternatively, two Rs, together with the atoms to which they are attached, can form 510 membered heteroaryl, 6-10 membered aryl, 3-10 membered heterocycloalkyl, or 3-10 membered cycloalkyl; R7 is independently, at each occurrence, selected from the group consisting of 5 substituents independently selected from Ci-Cs alkyl, Ci-Cb haioalkyl, CrCe alkoxy, Ci-Cb haioalkoxy, halogen, NH2, NH(CrC6 alkyl), N(Ci-C6 alkyl)2, SO2NH2, SO2NH(C -Ce alkyl), SO2N(Ci-C6 alkyl)2, (CH2)i-2-OH, C(O)(CH2)i.2-OH, C(O)(CrC6 alkyl), and C(O)O(Ci-C6 alkyl); alternatively, two R7, together with the atoms to which they are attached, can form 510   10 membered heteroaryl, 6-10 membered aryl, 3-10 membered heterocycloalkyl, or 3-10 membered cycloalkyl; and R8 is independently, at each occurrence, selected from the group consisting of C1-C3 alkyl, C1-C3 haioalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, 3-6 membered cycloalkyl, halogen, OH, NO2, NH2, NH(CrC6 alkyl), N(Ci-Cs alkyl)2, (CH2)i.4OH, S(O)0.2H, 15   S(O)0.2NH2, orCN. In another aspect, provided herein is a compound of Formula II: W~X (II) or a pharmaceutically acceptable salt thereof; 20 wherein W and Z are each, independently, N, CH, C-halo, C-(Ci-Cs alkyl), or C-(Ci-Cs alkoxy); X and Y are each, independently, N, CH, or CR3; provided that at least one of W, X, Y, or Z is CH; 25          R1 is selected from the group consisting of 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, and 3-10 membered cycioalkyl, all of which are optionally substituted with one, two, or three R8; R2 is selected from the group consisting of 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, and 3-10 membered cycloalkyl, all of which are 30 optionally substituted with one, two, or three Rs; R3 is independently, at each occurrence, selected from the group consisting of halogen, OR4, NR4R4, SO2R4, SO2NHR4, NHSO2R4, C(O)OR4, C(O)NHR4, C(O)R4, Ci-C6 alkyl, C2-Cs alkenyl, C2-Cs alkynyl, 3-7 membered cycloalkyl, C4-C7 cycloalkenyl, C5-C10 aryl, 2026234102   18 Sep 2026 5-6 membered heteroaryl, and 5-7 membered heteracyclyl, wherein alkyl, alkenyl, oralkynyl are each optionally substituted one, two, or three times with R4, and wherein aryl, heteroaryl, or heteracyclyl are each optionally substituted one, two, or three times with R5; R4 is independently, at each occurrence, selected from the group consisting of H, 5    (CH2)o.3-(C3-C7 cycloalkyl), (CH2)0-3-(C4-C7 cycloalkenyl), (CH2)o-3-(C6-Cio aryl), (CH2)0.3-(5-6 membered heteroaryl), and (CH2)o-3-(5-7 membered heteracyclyl), wherein the aryl, heteroaryl, or heteracyclyl are each optionally substituted one, two, or three times with R5; R5 is independently, at each occurrence, selected from the group consisting of Ci-Cb alkyl, Ci-Cs haloalkyl, CrCs alkoxy, Ci-Cb haloalkoxy, C1-C3 alkylamine, 3-10 membered 10 cycloalkyl, halogen, COOH, C(O)O(Ci-C6 alkyl), O(CH2)i.3-OH, NH2, NH(Ci-C8 alkyl), N(Ci-Cs alkyl)2, OH, CN, (CH2)o.3-(C6-Cio aryl), (CH2)o-3-(5-6 membered heteroaryl), and (CH2)o-3~ (5-7 membered heteracyclyl), wherein the aryl, heteroaryl, or heteracyclyl are each optionally substituted one, two, or three times with R7; R13 is independently, at each occurrence, selected from the group consisting of C1-C3 15 alkyl, O-C3 haloalky!, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, halogen, OH, NO2, NH2, NH(Ci-C6 alkyl), N(CrC6 alkyl)2, (CH^mOH, S(O)0.2H, S(O)0-2NH2, orCN; alternatively, two Rs, together with the atoms to which they are attached, can form 510 membered heteroaryl, 6-10 membered aryl, 3-10 membered heterocycloalkyl, or 3-10 membered cycloalkyl; 20          R7 is independently, at each occurrence, selected from the group consisting of substituents independently selected from Ci-C@ alkyl, Ci-Cb haloalkyl, CrCe alkoxy, Ci-Cb haloalkoxy, halogen, NH2, NH(CrC6 alkyl), N(Ci-C8 alkyl)2, SO2NH2, SO2NH(CrC6 alkyl), SO2N(Ci-C6 alkyl)2, (CH2)i.2-OH, C(O)(CH2)i.2-OH, C(O)(Ci-C6 alkyl), and C(O)O(Ci-C6 alkyl); 25          alternatively, two R7, together with the atoms to which they are attached, can form 5 10 membered heteroaryl, 6-10 membered aryl, 3-10 membered heterocycloalkyl, or 3-10 membered cycloalkyl; R8 is independently, at each occurrence, selected from the group consisting of C1-C3 alkyl, C -Cj haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, 3-6 membered 30 cycloalkyl, halogen, OH, NO2, NH2, NH(CrC6 alkyl), N(Ci-C6 alkyl)2, (CH2)i-4OH, S(O)0-2H, S(O)d.2NH2, or CN; and n is 1 or 2. In yet another aspect, provided herein is a compound of Formula III: 2026234102   18 Sep 2026 w=x V R2 (»0 or a pharmaceutically acceptable salt thereof; wherein 5           •••— is an optional double bond; B and D are each, Independently, C or N; W and Z are each, independently, N, CH, C-halo, C-(Ci-C3 alkyl), or C-(Ci-C3 alkoxy); X and Y are each, independently, N, CH, or CR3; 10           provided that at least one of W, X, Y, or Z is CH; R1 is selected from the group consisting of 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, and 3-10 membered cycloalkyl, all of which are optionally substituted with one, two, or three R8; R2 is selected from the group consisting of 6-10 membered aryl, 5-10 membered 15 heteroaryl, 3-10 membered heterocycloalkyl, and 3-10 membered cycloalkyl, all of which are optionally substituted with one, two, or three R6; R3 is independently, at each occurrence, selected from the group consisting of halogen, OR4, NR4R4, SO2R4, SO2NHR4, NHSO2R4, C(O)OR4, C(O)NHR4, C(O)R4, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, C4-C7 cycloalkenyl, Cs-Cw aryl, 20   5-6 membered heteroaryl, and 5-7 membered heterocyclyl, wherein alkyl, alkenyl, or alkynyl are each optionally substituted one, two, or three times with R4, and wherein aryl, heteroaryl, or heterocyclyl are each optionally substituted one, two, or three times with R5; R4 is independently, at each occurrence, selected from the group consisting of H, (CH2)o-3-(C3-C7 cycloalkyl), (CH2)o-3-(C4-C7 cycloalkenyl), (CH2)o-3-(C6-Cio aryl), (CH2)0-3-(5-6 25 membered heteroaryl), and (CH2)o-3~(5-7 membered heterocyclyl), wherein the aryl, heteroaryl, or heterocyclyl are each optionally substituted one, two, or three times with R5; R5 is independently, at each occurrence, selected from the group consisting of Ci-Cb alkyl, Ci-Cb haloalkyl, Ci-Cs alkoxy, CrCe haloalkoxy, C1-C3 alkylamine, 3-10 membered cycloalkyl, halogen, COOH, C(O)O(Ci-Cb alkyl), O(CH2)i-3-OH, NH2, NH(Ci-Cs alkyl), N(Ci-30 Cs alkyl)2, OH, CN, (CH2)o-3-(C6-Cw aryl), (CH2)o-3-(5-6 membered heteroaryl), and (CH2)o-3-(5-7 membered heterocyclyl), wherein the aryl, heteroaryl, cr heterocyclyl are each optionally substituted one, two, or three times with R7; 2026234102   18 Sep 2026 R6 is independently, at each occurrence, selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, halogen, OH, NO2, NH2, NH(C-Ce alkyl), N(Ci-C6 alkyl)2, (CH^mOH, S(0)o-2H, S(O)0.2NH2, orCN; alternatively, two Rs, together with the atoms to which they are attached, can form 55   10 membered heteroaryl, 6-10 membered aryl, 3-10 membered heterocycloalkyl, or 3-10 membered cycloalkyl; R7 is independently, at each occurrence, selected from the group consisting of substituents independently selected from Ci-Cs alkyl, Ci-Cs haloalkyl, O-Cbalkoxy, Ci-Ce haloalkoxy, halogen, NH2, NH(Ci-Cs alkyl), N(Ci-Cs alkyl)2, SO2NH2, SO2NH(Ci-C6 alkyl), 10 SO2N(Ci-Cb alkyl)2, (CH2)i.2-OH, C(O)(CH2)i-2-OH, C(O)(Ci-C6 alkyl), and C(O)O(CrC8 alkyl); alternatively, two R7, together with the atoms to which they are attached, can form 510 membered heteroaryl, 6-10 membered aryl, 3-10 membered heterocycloalkyl, or 3-10 membered cycloalkyl; and 15          R8 is independently, at each occurrence, selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, 3-6 membered cycloalkyl, halogen, OH, NO2, NH2, NH(Ci-Cb alkyl), N(CrCg alkyl)2, (CH2)i-4OH, S(0)o-2H, S(O)0-2NH2, or GN. In an aspect, provided herein is a method of treating cancer or a proliferation 20 disease, comprising administering to a subject in need thereof an effective amount of a compound of disclosed herein or a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable carrier. In one embodiment, the cancer is lung cancer, breast cancer, glioma, squamous cell carcinoma, or prostate cancer. In another embodiment, the method further comprises administering to the subject a second 25 active agent, wherein said second active agent prevents EGFR dimer formation. In another embodiment, the subject is a human. The disclosure also provides a kit comprising a compound capable of inhibiting EGFR activity selected from a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and instructions for use in treating cancer. In one embodiment, the 30 kit further comprises components for performing a test to determine whether a subject has an activating mutation in EGFR or a resistance mutation in EGFR. In another embodiment, the kit further comprises a second active agent, wherein said second active agent prevents EGFR dimer formation. 35 2026234102   18 Sep 2026 DETAILED DESCRIPTION Definitions Listed below are definitions of various terms used to describe the compounds and compositions disclosed herein. These definitions apply to the terms as they are used 5 throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art. Generally, the nomenclature used herein and the laboratory procedures in cell culture, 10 molecular genetics, organic chemistry, and peptide chemistry are those well-known and commonly employed in the art. As used herein, the articles “a" and “an” refer to one or to more than one (i.e,, to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. Furthermore, use of the term “including” as well as 15 other forms, such as “include,” “includes,” and “included,” is not limiting. As used herein, the term “about” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. As used herein when referring to a measurable value such as an amount, a temporal duration, and the like, the term “about" is meant to encompass variations of ±20% or ±10%, including ±5%, ±1%, and 20   +0.1% from the specified value, as such variations are appropriate to perform the disclosed methods. The term “administration” or the like as used herein refers to the providing a therapeutic agent to a subject. Multiple techniques of administering a therapeutic agent exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, 25 pulmonary, and topical administration. The term “treat,” “treated,” “treating,” or “treatment” includes the diminishment or alleviation of at least one symptom associated or caused by the state, disorder or disease being treated. In certain embodiments, the treatment comprises bringing into contact with wild-type or mutant EGFR an effective amount of a compound disclosed herein for 30 conditions related to cancer. As used herein, the term “prevent” or “prevention” means no disorder or disease development if none had occurred, or no further disorder or disease development if there had already been development of the disorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the disorder or disease. 35           As used herein, the term “patient,” “individual," or “subject” refers to a human or a non-human mammal. Non-human mammals include, for example, livestock and pets, such 2026234102   18 Sep 2026 as ovine, bovine, porcine, canine, feline and marine mammals. Preferably, the patient, subject, or individual is human. As used herein, the terms "effective amount,” “pharmaceutically effective amount,” and "therapeutically effective amount” refer to a nontoxic but sufficient amount of an agent to 5 provide the desired biological result. That result may be reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation. As used herein, the term “pharmaceutically acceptable” refers to a material, such as 10 a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained. As used herein, the term “pharmaceutically acceptable salt” refers to derivatives of 15 the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present disclosure include the conventional non-20 toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in 25 an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. The phrase “pharmaceutically acceptable salt” is not limited to a mono, or 1:1, salt. For example, “pharmaceutically acceptable salt” also includes bis-salts, such as a bis-hydrochloride salt. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing 30 Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety. As used herein, the term “prodrug” refers to a precursor compound that will undergo metabolic activation in vivo to produce an active drug. Thus, for example, a prodrug of a compound provided herein will, when administered to a subject, undergo metabolic 35 activation to generate the compound. As used herein, the term “composition” or "pharmaceutical composition” refers to a mixture of at least one compound useful within the disclosure with a pharmaceutically 2026234102   18 Sep 2026 acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration. 5          The term “pharmaceutical combination” as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term “fixed combination” means that the active ingredients, e.g., a compound of the disclosure and a co- agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term 10 “non-fixed combination” means that the active ingredients, e.g. a compound of the disclosure and a co-agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients. 15          As used herein, the term “pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the disclosure within or to the patient such that it may perform its intended function. Typically, 20 such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the disclosure, and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and 25 sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and 30 polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. 35          As used herein, “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the present disclosure, 2026234102   18 Sep 2026 and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. The “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound disclosed herein. Other additional ingredients that may be included in the pharmaceutical compositions are known in 5 the art and described, for example, in Remington’s Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference. As used herein, the term “EGFR” refers to epidermal growth factor receptor (alternately referred to as ErbB-1 or HER1) and may refer to the wild-type receptor or to a receptor containing one or more mutations. 10          As used herein, the term “HER” or Her” refers to members of the ErbB receptor tyrosine kinase family, including EGFR, ERBB2, HER3, and HER4. As used herein, the term “allosteric site” refers to a site on EGFR other than the ATP binding site, such as that characterized in a crystal structure of EGFR. An “allosteric site” can be a site that is close to the ATP binding site, such as that characterized in a crystal 15 structure of EGFR. For example, one allosteric site includes one or more of the following amino acid residues of epidermal growth factor receptor (EGFR): Lys745, Leu788, Ala743, Cys755, Leu777, Phe856, Asp855, Met766, Ile759, Glu762, and / or A!a763. As used herein, the term “agent that prevents EGFR dimer formation,” or iterations thereof, refers to an agent that prevents dimer formation in which the C-lobe of the 20 “activator” subunit impinges on the N-lobe of the “receiver” subunit. Examples of agents that prevent EGFR dimer formation include, but are not limited to, cetuximab, trastuzumab, panitumumab, and Mig6. As used herein, the term “alkyl,” by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of 25 carbon atoms designated (i.e., Ci-Ce alkyl means an alkyl having one to six carbon atoms) and includes straight and branched chains. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert butyl, pentyl, neopentyl, and hexyl. Other examples of Ci-Ce alkyl include ethyl, methyl, isopropyl, isobutyl, n-pentyl, and n-hexyl. As used herein, the term “haloalkyl” refers to an alkyl group, as defined above, 30 substituted with one or more halo substituents, wherein alkyl and halo are as defined herein. Haloalkyl includes, byway of example, chloromethyl, trifluoromethyl, bromoethyl, chlorofluoroethyl, and the like. As used herein, the term “alkoxy” refers to the group -O-alkyl, wherein alkyl is as defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, 35 isopropoxy, n-butoxy, sec-butoxy, t-butoxy and the like. 2026234102   18 Sep 2026 As used herein, the term “alkylamine” refers to the group -NH-alkyl, wherein alkyl is as defined herein. Alkylamine includes, by way of example, methylamine, ethylamine, isopropylamine, n-propylamine, n-butylamine, sec-butylamine, t-butylamine and the like. As used herein, the term “haloalkoxy” refers to the group -O-haloalkyl, wherein 5 haloalkyl is as defined herein. Haioalkoxy includes, by way of example, chloromethoxy, trifluoromethoxy, bromoethoxy, chlorofluoroethoxy, and the like. As used herein, the term “alkenyl" refers to a monovalent group derived from a hydrocarbon moiety containing, in certain embodiments, from two to six, or two to eight carbon atoms having at least one carbon-carbon double bond. The alkenyl group may or 10 may not be the point of attachment to another group. The term “alkenyl" includes, but is not limited to, ethenyi, 1-propenyl, 1-butenyi, heptenyl, octenyl and the like. As used herein, the term “alkynyl" refers to a monovalent group derived from a hydrocarbon moiety containing, in certain embodiments, from two to six, or two to eight carbon atoms having at least one carbon-carbon triple bond. The alkynyl group may or may 15 not be the point of attachment to another group. The term “alkynyl” includes, but is not limited to, ethynyl, 1-propynyl, 1-butynyf heptynyl, octynyl and the like. As used herein, the term “halo” or “halogen” alone or as part of another substituent means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine, more preferably, fluorine or chlorine. 20          As used herein, the term “cycloalkyl” means a non-aromatic carbocyclic system that is fully saturated having 1, 2 or 3 rings wherein such rings may be fused. The term “fused” means that a second ring is present (i.e., attached or formed) by having two adjacent atoms in common (i.e., shared) with the first ring. Cycloalkyl also includes bicyclic structures that may be bridged or spirocyclic in nature with each individual ring within the bicycle varying 25 from 3-8 atoms. The term “cycloalkyl” includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[3.1.0]hexyl, spiro[3.3]heptanyl, and bicyclo[1.1.1]pentyl. As used herein, the term “cycloalkenyl” means a non-aromatic carbocyclic system that is partially saturated having 1, 2 or 3 rings wherein such rings may be fused, and wherein at least one ring contains an sp2 carbon-carbon bond. The term “cycloaikenyl” 30 includes, but is not limited to, cyclopropenyl, cyciobutenyl, cyclopentenyl, cyclohexenyl, bicyclo[3.1.0]hexenyl. spiro[3.3]heptanenyl, and bicyclo[1.1.1]pentenyl. As used herein, the term “heterocyclyl” or “heterocycloalkyl” means a non-aromatic carbocyclic system containing 1, 2, 3 or 4 heteroatoms selected independently from N, O, and S and having 1,2 or 3 rings wherein such rings may be fused, wherein fused is defined 35 above. Heterocyclyl also includes bicyclic structures that may be bridged or spirocyclic in nature with each individual ring within the bicycle varying from 3-8 atoms, and containing 0, 1, or 2 N, O, or S atoms. The term “heterocyclyl” includes cyclic esters (i.e., lactones) and 2026234102   18 Sep 2026 cyclic amides (i.e., lactams) and also specifically includes, but is not limited to, epoxidyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl (i.e., oxanyl), pyranyl, dioxanyl, aziridinyl, azetidinyl, pyrrolidinyl, 2,5-dihydro-1 H-pyrrolyl, oxazolidinyl, thiazolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, 1,3-oxazinanyl, 1,3-thiazinanyl, 2-azabicyclo-5   [2.1.1]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 6-azabicyclo[3.1.1] heptanyl, 2-azabicyclo[2.2.1]- heptanyl, 3-azabicyclo[3.1.1]heptanyl, 2-azabicydo[3.1.1]heptanyl, 3-azabicydo[3.1.0]-hexanyl, 2-azabicydo[3.1.0]hexanyl, 3-azabicyclo[3.2.1]octanyl, 8-azab!cydo[3.2.1]octanyl, 3-oxa-7-azabicyclo[3.3.1]nonanyl, 3-oxa-9-azabicydo[3.3.1]nonanyl, 2-oxa-5-azabicyclo-[2.2.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-6- 10 azaspiro[3.3]heptanyl, 2-oxaspiro[3.3]heptanyl, 2-oxaspiro[3.5]nonanyl, 3-oxaspiro[5.3]nonanyl, and 8-oxabicyclo[3.2.1]octanyl. As used herein, the term “aromatic” refers to a carbocycle or heterocycle with one or more polyunsaturated rings and having aromatic character, i.e., having (4n + 2) delocalized it (pi) electrons, where n is an integer. 15          As used herein, the term “aryl” means an aromatic carbocyclic system containing 1, 2 or 3 rings, wherein such rings may be fused, wherein fused is defined above. If the rings are fused, one of the rings must be fully unsaturated and the fused ring(s) may be fully saturated, partially unsaturated or fully unsaturated. The term “aryl” includes, but is not limited to, phenyl, naphthyl, indanyl, and 1,2,3,4-tetrahydronaphthalenyl. In some 20 embodiments, aryl groups have 6 carbon atoms. In some embodiments, aryl groups have from six to ten carbon atoms. In some embodiments, aryl groups have from six to sixteen carbon atoms. As used herein, the term “heteroaryl” means an aromatic carbocyclic system containing 1, 2, 3, or 4 heteroatoms selected independently from N, O, and S and having 1, 25   2, or 3 rings wherein such rings may be fused, wherein fused is defined above. The term “heteroaryl” includes, but is not limited to, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, 5,6,7,8-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroquinolinyl, 6,7-dihydro-5H-cydopenta[b]pyridinyl, 30 6,7-dihydro-5H-cyclopenta[c]pyridinyl, 1,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 2,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazo!y!, 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazolyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, 4,5,6,7-tetrahydro-1H-indazolyl and 4 5,6,7-tetrahydro-2H-indazolyl. 35           It is to be understood that if an aryl, heteroaryl, cycloalkyl, or heterocydyl moiety may be bonded or otherwise attached to a designated moiety through differing ring atoms (i.e., shown or described without denotation of a specific point of attachment), then all possible 2026234102   18 Sep 2026 points are intended, whether through a carbon atom or, for example, a trivaient nitrogen atom. For example, the term “pyridinyl" means 2-, 3- or 4-pyridinyl, the term “thienyl” means 2- or 3-thienyl, and so forth. As used herein, the term “substituted” means that an atom or group of atoms has 5 replaced hydrogen as the substituent attached to another group. As used herein, the term “optionally substituted” means that the referenced group may be substituted or unsubstituted. In one embodiment, the referenced group is optionally substituted with zero substituents, i.e., the referenced group is unsubstituted. In another embodiment, the referenced group is optionally substituted with one or more additional 10 group(s) individually and independently selected from groups described herein. Compounds Provided herein are compounds that are allosteric inhibitors of epidermal growth factor receptor (EGFR) useful in the treatment of kinase-mediated disorders, including 15 cancer and other proliferation diseases. In an aspect provided herein is a compound of Formula I: (I) or a pharmaceutically acceptable salt thereof; 20          wherein: A and A’ are each, independently, CH, CR®, or N; W and Z are each, independently, N, CH, C-halo, C-(Ci-Cs alkyl), or C-(Ci-Cs alkoxy); X and Y are each, independently, N. CH, or CR3; 25          provided that at least one of W, X, Y, or Z is CH; R1 is selected from the group consisting of 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, and 3-10 membered cycloalkyl, all of which are optionally substituted with one, two, or three R8; R2 is selected from the group consisting of 6-10 membered aryl, 5-10 membered 30 heteroaryl, 3-10 membered heterocycloalkyl, and 3-10 membered cycloalkyl, all of which are optionally substituted with one, two, or three Rs; R3 is independently, at each occurrence, selected from the group consisting of halogen, OR4, NR4R4, SO2R4, SO2NHR4, NHSO2R4, C(O)OR4, C(O)NHR4, C(O)R4, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, C4-C7 cycloalkenyl, Cb-Cio aryl, 2026234102   18 Sep 2026 5-6 membered heteroaryl, and 5-7 membered heteracyclyl, wherein alkyl, alkenyl, oralkynyl are each optionally substituted one, two, or three times with R4, and wherein aryl, heteroaryl, or heteracyclyl are each optionally substituted one, two, or three times with R5; R4 is independently, at each occurrence, selected from the group consisting of H, 5    (CH2)o.3-(C3-C7 cycloalkyl), (CH2)0-3-(C4-C7 cycloalkenyl), (CH2)o-3-(C6-Cio aryl), (CH2)0.3-(5-6 membered heteroaryl), and (CH2)o-3-(5-7 membered heteracyclyl), wherein the aryl, heteroaryl, or heteracyclyl are each optionally substituted one, two, or three times with R5; R5 is independently, at each occurrence, selected from the group consisting of Ci-Cb alkyl, Ci-Cs haloaikyl, CrCs alkoxy, Ci-Cb haloalkoxy, C1-C3 alkylamine, 3-10 membered 10 cycloalkyl, halogen, COOH, C(O)O(Ci-C6 alkyl), O(CH2)i.3-OH, NH2, NH(Ci-C8 alkyl), N(Ci-Cs alkyl)2, OH, CN, (CH2)o.3-(Ce-Cio aryl), (CH2)o-3-(5-6 membered heteroaryl), and (CH2)o-3~ (5-7 membered heteracyclyl), wherein the aryl, heteroaryl, or heteracyclyl are each optionally substituted one, two, or three times with R7; R13 is independently, at each occurrence, selected from the group consisting of C1-C3 15 alkyl, O-C3 haloalky!, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, halogen, OH, NO2, NH2, NH(Ci-C6 alkyl), N(CrC6 alkyl)2, (CH^mOH, S(O)0.2H, S(O)0-2NH2, orCN; alternatively, two Rs, together with the atoms to which they are attached, can form 510 membered heteroaryl, 6-10 membered aryl, 3-10 membered heterocycloalkyl, or 3-10 membered cycloalkyl; 20          R7 is independently, at each occurrence, selected from the group consisting of substituents independently selected from Ci-C@ alkyl, Ci-Cb haloaikyl, CrCe alkoxy, Ci-Cb haloalkoxy, halogen, NH2, NH(CrC6 alkyl), N(Ci-C8 alkyl)2, SO2NH2, SO2NH(CrC6 alkyl), SO2N(Ci-C6 alkyl)2, (CH2)i.2-OH, C(O)(CH2)i-2-OH, C(O)(Ci-C6 alkyl), and C(O)O(Ci-C6 alkyl); 25          alternatively, two R7, together with the atoms to which they are attached, can form 5 10 membered heteroaryl, 6-10 membered aryl, 3-10 membered heterocycloalkyl, or 3-10 membered cycloalkyl; and R8 is independently, at each occurrence, selected from the group consisting of C1-C3 alkyl, C -Cj haloaikyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, 3-6 membered 30 cycloalkyl, halogen, OH, NO2, NH2, NH(CrC6 alkyl), N(Ci-C6 alkyl)2, (CH2)i-4OH, S(O)0-2H, S(O)0.2NH2, orCN. In another aspect, provided herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Wand Z are each, independently, N, CH, C-halo, C-(Ci-C3 haloaikyl), C-(Ci-C3 35 alkyl), or C-(Ci-C3 alkoxy); wherein all other variables are defined above. In an embodiment, the compound of Formula I is a compound of Formula la: 2026234102   18 Sep 2026 (la) or a pharmaceutically acceptable salt thereof. In an embodiment of Formula la, R3 is Cb-Cw aryl or 5-6 membered heteroaryl, both 5 of which are optionally substituted one time with R5. In another embodiment of Formula la, R3 is Cb-Cio aryl optionally substituted one time with R5, wherein R5 is 5-7 membered heterocyclyl, Cb-Cw aryl, 3-10 membered cycloalkyl, or 5-6 membered heteroaryl, all of which are optionally substituted one time with R7. In yet another embodiment of Formula la, R3 is phenyl optionally substituted one time with R5, wherein R5 is 5-7 membered 10 heterocyclyl, Cb-Cw aryl, 3-10 membered cycloalkyl, or 5-6 membered heteroaryl, all of which are optionally substituted one time with R7 In still another embodiment of Formula la, R3 is Cb-Cw aryl optionally substituted one time with R5, wherein R5 is 5 membered heterocyclyl optionally substituted one time with R7. In an embodiment of Formula la, R3 is phenyl optionally substituted one time with piperidine, wherein piperidine is substituted one 15 time with R7. In another embodiment, the compound of Formula I is a compound of Formula lb: (lb) or a pharmaceutically acceptable salt thereof. 20          In yet another embodiment, Z is CH. In still another embodiment, Z is N. In an embodiment, Z is CF. In another embodiment, R6 is independently, at each occurrence, hydroxy or halo. In yet another embodiment, R1 is selected from the group consisting of benzimidazole, imidazopyrazine, purine, imidazole, pyrazole, triazole, and imidazopyridine. 25 In still another embodiment, R1 is selected from the group consisting of: 2026234102   18 Sep 2026 aH of which are optionally substituted with one, two, or three R8. In another embodiment, Rs is hydroxy, halo, or two R6, together with the atoms to which they are attached, form 5-10 membered heteroaryl, 6-10 membered aryl, 3-10 5 membered heterocycloalkyl, or 3-10 membered cycloalkyl. In an embodiment, R6 is hydroxy, fluoro, or two R6, together with the atoms to which they are attached, form 5-10 membered heteroaryl, 6-10 membered aryl, 3-10 membered heterocycloalkyl, or 3-10 membered cycloalkyl. In yet another embodiment, R6 is hydroxy. In still another embodiment, R6 is fluoro. In another embodiment, R6 is chloro. In an embodiment, there are two R6 that are 10 hydroxy and fluoro. In another embodiment, there are two R6 that are hydroxy and chloro. In still another embodiment, two R6, together with the atoms to which they are attached, form 510 membered heteroaryl, 6-10 membered aryl, 3-10 membered heterocycloalkyl, or 3-10 membered cycloalkyl. In an embodiment, the compound of Formula I is selected from the group consisting 15 of a compound in Table 1. Table 1. Compound No. Structure 001 / "A.       N ~ hie    II * ho-Aa     AaA^A 11    £ l 002 H ] A II H      11a 2026234102   18 Sep 2026 2026234102   18 Sep 2026 or a pharmaceutically acceptable salt thereof. In another embodiment, the compound of Formula I is selected from the group consisting of a compound in Table 2. 2026234102   18 Sep 2026 Table 2. Compound No. Structure 063 O Qy ? ''S / / z o x 064 ^x^y’yY X, ° 065 066 t AJ         u: ZX / 0 2 /       02 / ,—( V- 2:             ,— / V- z: ti 0==3( y                "n               y W Q     €} 2026234102   18 Sep 2026 2026234102   18 Sep 2026 2026234102   18 Sep 2026 2026234102   18 Sep 2026 2026234102   18 Sep 2026 116 Qz?CCr^ 0 I F 117 \ I    Z - X Q i o |              ?       U- 2=0 il i                       4—7* fry 1 2026234102   18 Sep 2026 provided that at least one of W, X, Y, or Z is CH; R1 is selected from the group consisting of 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, and 3-10 membered cycloalkyl, all of which are optionally substituted with one, two, or three R8; 5          R2 is selected from the group consisting of 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, and 3-10 membered cycloalkyl, all of which are optionally substituted with one, two, or three R8; R3 is independently, at each occurrence, selected from the group consisting of halogen, OR4, NR4R4, SO2R4, SO2NHR4, NHSO2R4, C(O)OR4, C(O)NHR4, C(O)R4, Ci-C6 10 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, C4-C7 cycloaikenyl, Cb-Cio aryl, 5-6 membered heteroaryl, and 5-7 membered heterocyclyl, wherein alkyl, alkenyl, or alkynyl are each optionally substituted one, two, or three times with R4, and wherein aryl, heteroaryl, or heterocyclyl are each optionally substituted one, two, or three times with R5; R4 is independently, at each occurrence, selected from the group consisting of H, 15    (CH2)0.3-(C3-C7 cycloalkyl), (CH2)0.3-(C4-C7 cycloalkenyl), (CH2)o.3-(C6-Cio aryl), (CH2)0.3-(5-6 membered heteroaryl), and (CH2)o-3-(5-7 membered heterocyclyl), wherein the aryl, heteroaryl, or heterocyclyl are each optionally substituted one, two, or three times with R5; R5 is independently, at each occurrence, selected from the group consisting of Ci-Ce alkyl, Ci-Ce haloalkyl, CtCsalkoxy, Ci-Cs haloalkoxy, C1-C3 alkylamine, 3-10 membered 20 cycloalkyl, halogen, COOK, C(O)O(Ci-Ce alkyl), O(CH2)i-3-OH, NH2, NH(Ci-Cg alkyl), N(Ci-C8 alkyl)2, OH, CN, (CH2)0.3-(C6-Ci0 aryl), (CH2)0.3-(5-6 membered heteroaryl), and (CH2)o-3-(5-7 membered heterocyclyl), wherein the aryl, heteroaryl, or heterocyclyl are each optionally substituted one, two, or three times with R7; R6 is independently, at each occurrence, selected from the group consisting of C1-C3 25 alkyl, Ci-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, halogen, OH, NO2, NH2, NH(C -Cr alkyl), N^-Ce alkyl)2, (CH2)i.4OH, S(O)0-2H, S(0)o 2NH2, orCN; alternatively, two R6, together with the atoms to which they are attached, can form 510 membered heteroaryl, 6-10 membered aryl, 3-10 membered heterocycloalkyl, or 3-10 membered cycloalkyl; 30          R7 is independently, at each occurrence, selected from the group consisting of substituents independently selected from Ci-Ce alkyl, Ci-Cb haloalkyl, CrCs alkoxy, Ci-Ce haloalkoxy, halogen, NH2, NH(Ci-Cs alkyl), N(Ci-Ce alkyi)2, SO2NH2, SO.?NH(C -C6 alkyl), SO2N(Ci-Cs alkyl)2, (CH2)i.2-OH, C(O)(CH2)i-2-OH, C(O)(Ci-C6 alkyl), and C(O)O(Ci-Cs alkyl); 35           alternatively, two R7, together with the atoms to which they are attached, can form 5 10 membered heteroaryl, 6-10 membered aryl, 3-10 membered heterocycloalkyl, or 3-10 membered cycloalkyl; 2026234102   18 Sep 2026 R8 is independently, at each occurrence, selected from the group consisting of C1-C3 alkyl, C<-Cs haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, 3-6 membered cycloalkyl, halogen, OH, NO2, NH2, NH(Ci-Ce alkyl), N(Ci-Cs alkyl)2, (CH2)i-4OH, S(0)o-2H, S(O)0.2NH2, or CN; and 5             n is 1 or 2, In an aspect of Formula II, R5 is independently, at each occurrence, selected from the group consisting of Ci-C® alkyl, Ci-Cb haloalkyl, Ci-Csalkoxy, Ci-Cb haloalkoxy, C1-C3 alkylamine, 3-10 membered cycloalkyl, halogen, COOH, C(O)O(Ci-Cs alkyl), O(CH2)i-3-OH, NH2, NH(Ci-Cs alkyl), N(Ci-10 Cs alkylb, OH, CN, (CH2)o.3-(C6-Cio aryl), (CH2)o-3-(5-6 membered heteroaryl), 0(CH2)o-3-(4-7 membered heterocyclyl), and (CH2)o-3-(4-7 membered heterocyclyl), wherein the alkyl, alkoxy, aryl, heteroaryl, or heterocyclyl are each optionally substituted one, two, or three times with R7; wherein all other variables are defined above. 15          In an embodiment, the compound of Formula II is a compound of Formula Ila: (Ila) or a pharmaceutically acceptable salt thereof. In yet another aspect, provided herein is a compound of Formula X: W^X (X) or a pharmaceutically acceptable salt thereof; wherein A is O or S; 25          W and Z are each, independently, N, CH, C-halo, C-(Ci-C3 alkyl), or C-(Ci-C3 alkoxy); X and Y are each, independently, N, CH, or CR3; provided that at least one of W, X, Y, or Z is CH; 2026234102   18 Sep 2026 R1 is selected from the group consisting of 6-10 membered aryl, 5-10 membered heteroaryi, 3-10 membered heterocycloalkyl, and 3-10 membered cycloalkyl, all of which are optionally substituted with one, two, or three R8; R2 is selected from the group consisting of 6-10 membered aryl, 5-10 membered 5 heteroaryi, 3-10 membered heterocycloalkyl, and 3-10 membered cycloalkyl, all of which are optionally substituted with one, two, or three Rs; R3 is independently, at each occurrence, selected from the group consisting of halogen, OR4, NR4R4, SO2R4, SO2NHR4, NHSO2R4, C(O)OR4, C(O)NHR4, C(O)R4, Ci-C6 alkyl, Ca-Cs alkenyl, C2-Cs alkynyl, 3-7 membered cycloalkyl, C4-C7 cycloalkenyl, Cs-Cw aryl, 10   5-6 membered heteroaryi, and 5-7 membered heterocyclyl, wherein alkyl, alkenyl, or alkynyl are each optionally substituted one, two, or three times with R4, and wherein aryl, heteroaryi, or heterocyclyl are each optionally substituted one, two, or three times with R5; R4 is independently, at each occurrence, selected from the group consisting of H, (CH2)0.3-(C3-C7 cycloalkyl), (CH2)o.3-(C4-C7 cycloalkenyl), (CH2)&.3-(C6-Cio aryl), (CH2)0.3-(5-6 15 membered heteroaryi), and (CH2)o.3-(5-7 membered heterocyclyl), wherein the aryl, heteroaryi, or heterocyclyl are each optionally substituted one, two, or three times with R5; R5 is independently, at each occurrence, selected from the group consisting of Ci-Ce alkyl, Ci-Ce haioaikyl, Ci-Ce alkoxy, Ci-Cs haloalkoxy, Ci-C3 alkylamine, 3-10 membered cycloalkyl, halogen, COOK, C(O)O(Ci-Cs alkyl), O(CH2)i.3-OH, NH2, NH(CrC8 alkyl), N(Ci-20 C8 alkyl)2, OH, CN, (CH2)c.3-(C6-Cio aryl), (CH2)0-3-(5-6 membered heteroaryi), 0(CH2)o-3-(4-7 membered heterocyclyl), and (CH2)o-3-(4-7 membered heterocyclyl), wherein the alkyl, alkoxy, aryl, heteroaryi, or heterocyclyl are each optionally substituted one, two, or three times with R7; R6 is independently, at each occurrence, selected from the group consisting of C1-C3 25 alkyl, Ci-C3 haioaikyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, halogen, OH, NO2, NH2, NH{C -Cr alkyl), N(C,-C8 alkyl)2, (CH2)i.4OH, S(O)0-2H, S(0)o 2NH2, orCN; alternatively, two R6, together with the atoms to which they are attached, can form 510 membered heteroaryi, 6-10 membered aryl, 3-10 membered heterocycloalkyl, or 3-10 membered cycloalkyl; 30          R7 is independently, at each occurrence, selected from the group consisting of substituents independently selected from Ci-C8 alkyl, Ci-Cs haioaikyl, CrC8 alkoxy, Ci-Ce haloalkoxy, halogen, NH2, NH(Ci-Cs alkyl), N(Ci-Ce alkyl)2, SO2NH2, SOjNH(C -C6 alkyl), SO2N(Ci-Cs alkyl)2, (CH2)i-2-OH, C(O)(CH2)i.2-OH, C(O)(Ci-C6 alkyl), and C(O)O(Ci-Cs alkyl); 35           alternatively, two R7, together with the atoms to which they are attached, can form 5 10 membered heteroaryi, 6-10 membered aryl, 3-10 membered heterocycloalkyl, or 3-10 membered cycloalkyl; 2026234102   18 Sep 2026 R8 is independently, at each occurrence, selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, 3-6 membered cycloalkyl, halogen, OH, NO2, NH2, NH(Ci-Ce alkyl), N(Ci-Cb alkyl)2, (CH2)i-4OH, S(0)o-2H, S(O)0.2NH2, or CN; and 5             n is 1 or 2, In an embodiment of Formula Ila, R3 is Cb-Cw aryl or 5-6 membered heteroaryl, both of which are optionally substituted one time with R5. In another embodiment of Formula Ila, R3 is Cb-Cw aryl optionally substituted one time with R5, wherein R5 is 5-7 membered heterocyclyl, Cb-Cw aryl, 3-10 membered cycloalkyl, or 5-6 membered heteroaryl, all of 10 which are optionally substituted one time with R7. In yet another embodiment of Formula Ila, R3 is phenyl optionally substituted one time with R5, wherein Rs is 5-7 membered heterocyclyl, Cb-Cw aryl, 3-10 membered cycloalkyl, or 5-6 membered heteroaryl, all of which are optionally substituted one time with R7. In still another embodiment of Formula Ila, R3 is Cb-Cw aryl optionally substituted one time with R5, wherein R5 is 5 membered 15 heterocyclyl optionally substituted one time with R7. In an embodiment of Formula Ila, R3 is phenyl optionally substituted one time with piperidine, wherein piperidine is substituted one time with R7. In another embodiment, the compound of Formula II is a compound of Formula lib: 20                                                      (lib) or a pharmaceutically acceptable salt thereof. In another embodiment, the compound of Formula II is a compound of Formula lie: (lie) 25          or a pharmaceutically acceptable salt thereof. In yet another embodiment, wherein R6 is independently, at each occurrence, hydroxy, halo, or two R6, together with the atoms to which they are attached, form 5-10 2026234102   18 Sep 2026 membered heteroaryl, 6-10 membered aryl, 3-10 membered heterocycloalky!, or 3-10 membered cycloalkyl. In another embodiment, R6 is hydroxy, fluoro, or two R®, together with the atoms to which they are attached, form 5-10 membered heteroaryl, 6-10 membered aryl, 3-10 membered heterocycloalkyl, or 3-10 membered cycloalkyl. In yet another embodiment, 5 R6 is hydroxy. In still another embodiment, R6 is fluoro. In another embodiment, R® is chloro. In an embodiment, there are two Rs that are hydroxy and fluoro. In another embodiment, there are two R8 that are hydroxy and chloro. In still another embodiment, two R6, together with the atoms to which they are attached, form 5-10 membered heteroaryl, 6-10 membered aryl, 3-10 membered heterocycloalkyl, or 3-10 membered cycloalkyl. 10           In an embodiment of Formulae II, Ila, and lib, R1 is selected from the group consisting of benzimidazole, imidazopyrazine, purine, imidazole, pyrazole, triazole, and imidazopyridine. In an embodiment, R1 is selected from the group consisting of: 15           ail of which are optionally substituted with one, two, or three R8. In another embodiment, R3 is phenyl or C2-C3 alkynyl, wherein phenyl is optionally substituted one or two times with R5, and alkynyl is optionally substituted one or two times with R4. In yet another embodiment, R3 is phenyl optionally substituted one or two times with R5. In still another embodiment, R3 is C2-C3 alkynyl optionally substituted one or two times 20 with R4. In an embodiment, R3 is phenyl substituted with one or two R5, and R5 is selected from the group consisting of piperidine, pyridine, and thiomorpholine dioxide, all of which are optionally substituted with one or two R7. In another embodiment, the compound of Formula II is selected from the group consisting of a compound in Table 3. 25 Tabie 3. 2026234102   18 Sep 2026 2026234102   18 Sep 2026 2026234102   18 Sep 2026 2026234102   18 Sep 2026 2026234102   18 Sep 2026 2026234102   18 Sep 2026 2026234102   18 Sep 2026 2026234102   18 Sep 2026 or a pharmaceutically acceptable salt thereof. In yet another embodiment, the compound of Formula II is selected from the group consisting of a compound in Table 4. 2026234102   18 Sep 2026 Table 4. Compound No. Structure 036 HO... ; rOYMY Af 037 and 038 0   p ul. ......... / ____ / t / \______ /      :r / \_______ / ?       /         z      / ' 039 HO > D D / ======%    / ====%    / \ } rAY v / "’"V_ / or a pharmaceutically acceptable salt thereof. In embodiments, the compounds 036-039 provided herein have an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium 5 incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 10   (93.5% deuterium incorporation). 2026234102   18 Sep 2026 In an embodiment of compounds 036-039, each position designated specifically as deuterium has at least 95% incorporation of deuterium. In another embodiment, the compound of Formula X is selected from the group consisting of a compound in Table 5. 5 Table 5. 2026234102   18 Sep 2026 2026234102   18 Sep 2026 2026234102   18 Sep 2026 2026234102   18 Sep 2026 (ill) or a pharmaceutically acceptable salt thereof; wherein -- - is an optional double bond; 5          B and D are each, independently, C or N; W and Z are each, independently, N, CH, C-halo, C-(Ci-Cs alkyl), or C-(Ci-C3 alkoxy); X and Y are each, independently, N. CH, or CR3; provided that at least one of W, X, Y, or Z is CH; 10          R1 is selected from the group consisting of 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, and 3-10 membered cycloalkyl, all of which are optionally substituted with one, two, or three R8; R2 is selected from the group consisting of 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, and 3-10 membered cycloalkyl, all of which are 15 optionally substituted with one, two, or three R8; R3 is independently, at each occurrence, selected from the group consisting of halogen, OR4, NR4R4, SO2R4, SO2NHR4, NHSO2R4, C(O)OR4, C(O)NHR4, C(O)R4, Ci-C6 alkyl, C2-C6 alkenyl, C2-Cs alkynyl, 3-7 membered cycloalkyl, C4-C7 cycloalkenyl, C5-C10 aryl, 5-6 membered heteroaryl, and 5-7 membered heterocydyl, wherein alkyl, alkenyl, or alkynyl 20 are each optionally substituted one, two, or three times with R4, and wherein aryl, heteroaryl, or heterocydyl are each optionally substituted one, two, or three times with R5; R4 is independently, at each occurrence, selected from the group consisting of H, (CH2)o-3-(C3-C7 cycloalkyl), (CH2)o-3-(C4-C7 cycloalkenyl), (CH2)o-3-(C6-Cio aryl), (CH2)0-3-(5-6 membered heteroaryl), and (CH2)0-3-(5-7 membered heterocydyl), wherein the aryl, 25 heteroaryl, or heterocydyl are each optionally substituted one, two, or three times with R5; Rs is independently, at each occurrence, selected from the group consisting of Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Cealkoxy, Ci-Ce haloalkoxy, C1-C3 alkylamine, 3-10 membered cycloalkyl, halogen, COOH, C(O)O(Ci-Cg alkyl), O(CH2)i-3-OH, NH2, NH(Ci-Cg alkyl), N(Ci-Cs alkyl)2, OH, CN, (CH2)0-3-(C6-Ciq aryl), (CH2)o-3-(5-6 membered heteroaryl), and (CH2)o-3- 30   (5-7 membered heterocydyl), wherein the aryl, heteroaryl, or heterocydyl are each optionally substituted one, two, or three times with R7; R6 is independently, at each occurrence, selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, halogen, OH, NO2, NH2, NH(Ci-Ce alkyl), N^-Ce alkyl)2, (CH2)i.4OH, S(O)0.2H, S(0)o 2NH2, orCN; 35           alternatively, two R6, together with the atoms to which they are attached, can form 5 10 membered heteroaryl, 6-10 membered aryl, 3-10 membered heterocycloalkyl, or 3-10 membered cydoalkyl; 2026234102   18 Sep 2026 R7 is independently, at each occurrence, selected from the group consisting of substituents independently selected from Ci-Cs alkyl, CrCs haloalkyl, Ci-Cealkoxy, CrCe haloalkoxy, halogen, NH2, NH(Ci-Cb alkyl), N(Ci-Ce a!kyl)a, SO2NH2, SO2NH(Ci-Cb alkyl), SO2N(Ci-C6 alkyl)2, (CH2)i.2-OH, C(O)(CH2)i.2-OH, C(O)(Ci-C6 alkyl), and C(0)0(O-Ce 5 alkyl); alternatively, two R7, together with the atoms to which they are attached, can form 510 membered heteroaryl, 6-10 membered aryl, 3-10 membered heterocycloalkyl, or 3-10 membered cycloalkyl; and R3 is independently, at each occurrence, selected from the group consisting of C1-C3 10 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, 3-6 membered cycloalkyl, halogen, OH, NO2, NH2, NH(Ci-C6 alkyl), N(Ci-C8 alkyl)2, (CH2)i.4OH, S(0)o-2H, S(O)0.2NH2, orCN. In another aspect, provided herein is a compound of Formula III, or a pharmaceutically acceptable salt thereof, wherein 15          R4 is independently, at each occurrence, selected from the group consisting of H, Cr C3 alkyl, (CH2)o-3-(C3-C7 cycloalkyl), (CH2)o-3-(C4-C7 cycloalkenyl), (CH2)o-3-(C6-Cio aryl), (CH2)o-3-(5-6 membered heteroaryl), and (CH2)o-3-(5-7 membered heterocyclyl), wherein the aryl, heteroaryl, or heterocyclyl are each optionally substituted one, two, or three times with R5; 20          wherein all other variables are defined above. In an embodiment, the compound of Formula III is a compound of Formula Illa: W^X R1 N (R6)0-3-+" j| (Illa) or a pharmaceutically acceptable salt thereof. 25          In an embodiment of Formula Illa, R3 is Ce-Cw aryl or 5-6 membered heteroaryl, both of which are optionally substituted one time with R5. In another embodiment of Formula Illa, R3 is Cb-Cio aryl optionally substituted one time with Rs, wherein Rs is 5-7 membered heterocyclyl, Cb-Cw aryl, 3-10 membered cycloalkyl, or 5-6 membered heteroaryl, all of which are optionally substituted one time with R7. In yet another embodiment of Formula Illa, 30 R3 is phenyl optionally substituted one time with R5, wherein R5 is 5-7 membered heterocyclyl, Ce-Cw aryl, 3-10 membered cycloalkyl, or 5-6 membered heteroaryl, all of which are optionally substituted one time with R7 In still another embodiment of Formula Illa, 2026234102   18 Sep 2026 R3 is Cb-Cw aryl optionally substituted one time with R5, wherein R5 is 5 membered heterocyclyl optionally substituted one time with R7. In an embodiment of Formula ilia, R3 is phenyl optionally substituted one time with piperidine, wherein piperidine is substituted one time with R7. 5          In another embodiment, the compound of Formula III is a compound of Formula lllb: W=X A pi [I —z -y N (R6)o-3”^ j] (lllb) or a pharmaceutically acceptable salt thereof. In yet another embodiment, the compound of Formula III is a compound of Formula 10 Ilic: (Ills) or a pharmaceutically acceptable salt thereof. In still another embodiment, R1 is selected from the group consisting of 15 benzimidazole, imidazopyrazine, purine, imidazole, pyrazole, triazole, and imidazopyridine. In an embodiment, R1 is selected from the group consisting of: all of which are optionally substituted with one, two, or three R8. 20          In another embodiment, Y is CR3, and R3 is 6-10 membered aryl substituted with one or two R5. In yet another embodiment, Z is CF. In still another embodiment, Z is CH. In an embodiment, Z is N. 2026234102   18 Sep 2026 In another embodiment, R6 is hydroxy, halo, or two R6, together with the atoms to which they are attached, form 5-10 membered heteroaryl, 6-10 membered aryl, 3-10 membered heterocycloalkyl, or 3-10 membered cycloalkyl, in an embodiment, R6 is hydroxy, fluoro, or two R6, together with the atoms to which they are attached, form 5-10 membered 5 heteroaryi, 6-10 membered aryl, 3-10 membered heterocycloalkyl, or 3-10 membered cycloalkyl. In yet another embodiment, Rs is hydroxy. In still another embodiment, R® is fluoro. In another embodiment, R'5 is chloro. In an embodiment, there are two R6 that are hydroxy and fluoro. In another embodiment, there are two R6 that are hydroxy and chloro. In still another embodiment, two R6, together with the atoms to which they are attached, form 510   10 membered heteroaryl, 6-10 membered aryl, 3-10 membered heterocycloalkyl, or 3-10 membered cycloalkyl. In another embodiment, the compound of Formula III is selected from the group consisting of a compound from Table 6. Table 6. 2026234102   18 Sep 2026 2026234102   18 Sep 2026 or a pharmaceutically acceptable salt thereof. In an embodiment of Formulas 1,11, and III, R' is C1-C3 alkyl. The compounds disclosed herein may exist as tautomers and optical isomers (e.g., enantiomers, diastereomers, diastereomeric mixtures, racemic mixtures, and the like). 5           It is generally well known in the art that any compound that will be converted in viva to provide a compound disclosed herein is a prodrug within the scope of the present disclosure. Compounds provided herein can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic 10 number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more constituent atoms of the compounds of the invention can be replaced or substituted with isotopes of the atoms in natural or non-natural abundance. In some embodiments, the compound includes at least one deuterium atom. For example, one or more hydrogen atoms in a compound of the present disclosure can be replaced or 15 substituted by deuterium. In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 deuterium atoms. Synthetic methods for including isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New 2026234102   18 Sep 2026 York, N.Y., Appleton-Century-Crofts, 1971; The Renaissance of H / D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chern. I nt. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can used in various studies 5 such as NMR spectroscopy, metabolism experiments, and / or assays. In the compounds provided herein, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen,” the position is understood to have hydrogen at its natural abundance isotopic composition. Also, unless 10 otherwise stated, when a position is designated specifically as “D” or “deuterium”, the position is understood to have deuterium at an abundance that is at least 3000 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 45% incorporation of deuterium). In an aspect, provided herein is a pharmaceutical composition comprising any one of 15 the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. In an embodiment, the composition further comprises a second active agent. In another embodiment the second active agent is selected from the group consisting of a MEK inhibitor, a PI3K inhibitor, and an mTor inhibitor. In yet another embodiment, the 20 second active agent prevents EGFR dimer formation in a subject. In still another embodiment, the second active agent is selected from the group consisting of cetuximab, trastuzumab, and panitumumab. In an embodiment, the second active agent is an ATP competitive EGFR inhibitor. In another embodiment, the ATP competitive EGFR inhibitor is osimertinib, gefitinib, or erlotinib. In another embodiment, the ATP competitive EGFR 25 inhibitor is osimertinib. In another aspect, provided herein are pharmaceutical compositions comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In another aspect, the pharmaceutical composition further comprises a second active agent, wherein said second active agent prevents EGFR 30 dimer formation, and a pharmaceutically acceptable carrier. In some embodiments, the second active agent that prevents EGFR dimer formation is an antibody. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab. 35          A compound that binds to an allosteric site in EGFR, such as the compounds of the present disclosure (e.g., the compounds of the formulae disclosed herein), optionally in combination with a second active agent, wherein said second active agent prevents EGFR 2026234102   18 Sep 2026 dimer formation, are capable of modulating EGFR activity. In some embodiments, the compounds of the present disclosure are capable of inhibiting or decreasing EGFR activity without a second active agent (e.g., an antibody such as cetuximab, trastuzumab, or panitumumab). In other embodiments, the compounds of the present disclosure in 5 combination with a second active agent. In an embodiment, the second active agent prevents EGFR dimer formation and / or are capable of inhibiting or decreasing EGFR activity. In some embodiments, the second active agent that prevents EGFR dimer formation is an antibody. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second 10 active agent that prevents EGFR dimer formation is cetuximab. In an embodiment, the second active agent is an ATP competitive EGFR inhibitor. In another embodiment, the ATP competitive EGFR inhibitor is osimertinib, gefitinib or erlotinib. In another embodiment, the ATP competitive EGFR inhibitor is osimertinib. 15 Methods of Treatment In an aspect, provided herein is a method of treating cancer in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound disclosed herein. In an embodiment, the cancer is selected from the group consisting of lung cancer, colon cancer, breast cancer, endometrial cancer, thyroid cancer, 20 glioma, squamous ceil carcinoma, and prostate cancer. In another embodiment, the cancer is non-small ceil lung cancer (NSCLC). In another aspect, provided herein is a method of inhibiting a kinase in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound provided herein. In an embodiment, the kinase is EGFR. 25           In yet another aspect, provided herein is a method of treating or preventing a kinase- mediated disorder in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of the present disclosure. In an embodiment, the kinase-mediated disorder is resistant to an EGFR-targeted therapy. In another embodiment, the EGFR-treated therapy is selected from the group consisting of 30 gefitinib, erlotinib, osimertinib, CO-1686, and WZ4002. In some embodiments, the compounds of the present disclosure are capable of modulating (e.g., inhibiting or decreasing) the activity of EGFR containing one or more mutations. In some embodiments, the mutant EGFR contains one or more mutations selected from T790M, L718Q, L844V, V948R, L858R, 1941R, C797S, and Del. In other 35 embodiments, the mutant EGFR contains a combination of mutations, wherein the combination is selected from Del / L718Q, Del / L844V, Del / T790M, Del / T790M / L718Q, Del / T790M / L844V, L858R / L718Q, L858R / L844V, L858R7T790M, L858R / T790M / I941R, 2026234102   18 Sep 2026 Del / T790M, Del / T790M / C797S, L858R / T790M / C797S, and L858R / T790M / L718Q. In other embodiments, the mutant EGFR contains a combination of mutations, wherein the combination is selected from Del / L844V, L858R / L844V, L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M, De! / T790M / C797S, 5 and L858R / T790M. In other embodiments, the mutant EGFR contains a combination of mutations, wherein the combination is selected from L858R / T790M, L858R / T790IWI941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M. In some embodiments, the compounds of the present disclosure in combination with a second active agent, wherein said second active agent prevents EGFR dimer formation, 10 are capable of modulating (e.g., inhibiting or decreasing) the activity of EGFR containing one or more mutations. In some embodiments, the mutant EGFR contains one or more mutations selected from T790M, L718Q, L844V, V948R, L858R, 1941R, C797S, and Del. In other embodiments, the mutant EGFR contains a combination of mutations, wherein the combination is selected from Del / L718Q, Del / L844V, Del / T790M, Del / T790M / L718Q, 15   Del / T790M / L844V, L858R / L718Q, L858R / L844V, L858R / T790M, L858R / T790M / I941R, Del / T790M, Del / T790M / C797S, L858R7T790M / C797S, and L858R / T790M / L718Q. In other embodiments, the mutant EGFR contains a combination of mutations, wherein the combination is selected from Del / L844V, L858R / L844V, L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and 20   L858R / T790M. In other embodiments, the mutant EGFR contains a combination of mutations, wherein the combination is selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M. In some embodiments, the second active agent that prevents EGFR dimer formation is an antibody. In further embodiments, the second active agent that prevents EGFR dimer formation is 25 cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab, in an embodiment, the second active agent is an ATP competitive EGFR inhibitor. In another embodiment, the ATP competitive EGFR inhibitor is osimertinib, gefitinib or erlotinib. In some embodiments, the compounds of the present disclosure are capable of 30 modulating (e.g., inhibiting or decreasing) the activity of EGFR containing one or more mutations, but do not affect the activity of a wild-type EGFR. In other embodiments, the compounds of the present disclosure in combination with a second active agent, wherein said second active agent prevents EGFR dimer formation, are capable of modulating (e.g., inhibiting or decreasing) the activity of EGFR containing one 35 or more mutations, but do not affect the activity of a wild-type EGFR. In some embodiments, the second active agent that prevents EGFR dimer formation is an antibody. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab, 2026234102   18 Sep 2026 trastuzumab, or panitumumab. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab, in an embodiment, the second active agent is an ATP competitive EGFR inhibitor. In another embodiment, the ATP competitive EGFR inhibitor is osimertinib, gefitinib or erlotinib. In another embodiment, the ATP competitive 5 EGFR inhibitor is osimertinib. Modulation of EGFR containing one or more mutations, such as those described herein, but not a wild-type EGFR, provides an approach to the treatment, prevention, or amelioration of diseases including, but not limited to, cancer and metastasis, inflammation, arthritis, systemic lupus erythematosus, skin-related disorders, pulmonary disorders, 10 cardiovascular disease, ischemia, neurodegenerative disorders, liver disease, gastrointestinal disorders, viral and bacterial infections, central nervous system disorders, Alzheimer's disease, Parkinson’s disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, and peripheral neuropathy. In some embodiments, the compounds of the disclosure exhibit greater inhibition of 15 EGFR containing one or more mutations as described herein relative to a wild-type EGFR. In certain embodiments, the compounds of the disclosure exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or 100-fold greater inhibition of EGFR containing one or more mutations as described herein relative to a wild-type EGFR. In various embodiments, the compounds of the disclosure exhibit up to 1000-fold greater inhibition of EGFR containing 20 one or more mutations as described herein relative to a wild-type EGFR. In various embodiments, the compounds of the disclosure exhibit up to 10000-fold greater inhibition of EGFR having a combination of mutations described herein (e.g., L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M) relative to a wild-type EGFR. 25 In other embodiments, the compounds of the disclosure in combination with a second active agent, wherein said second active agent prevents EGFR dimer formation, exhibit greater inhibition of EGFR containing one or more mutations as described herein relative to a wildtype EGFR. In certain embodiments, the compounds of the disclosure in combination with a second active agent, wherein said second active agent prevents EGFR dimer formation, 30 exhibit at least 2-fold, 3-fold, 5-fold, 10-foid, 25-fold, 50-fold or 100-fold greater inhibition of EGFR containing one or more mutations as described herein relative to a wild-type EGFR. In various embodiments, the compounds of the disclosure in combination with a second active agent, wherein said second active agent prevents EGFR dimer formation, exhibit up to 1000fold greater inhibition of EGFR containing one or more mutations as described herein 35 relative to a wild-type EGFR. In various embodiments, the compounds of the disclosure in combination with a second active agent, wherein said second active agent prevents EGFR dimer formation, exhibit up to 10000-fold greater inhibition of EGFR having a combination of 2026234102   18 Sep 2026 mutations described herein (e.g., L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M) relative to a wildtype EGFR. In some embodiments, the second active agent that prevents EGFR dimer formation is an antibody. In further embodiments, the second active agent that prevents 5 EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab. In an embodiment, the second active agent is an ATP competitive EGFR inhibitor. In another embodiment, the ATP competitive EGFR inhibitor is osimertinib, gefitinib or erlotinib. In another embodiment, the ATP competitive EGFR inhibitor is osimertinib. 10          In some embodiments, the compounds of the disclosure exhibit from about 2-fold to about 10-fold greater inhibition of EGFR containing one or more mutations as described herein relative to a wild-type EGFR. In various embodiments, the compounds of the disclosure exhibit from about 10-fold to about 100-fold greater inhibition of EGFR containing one or more mutations as described herein relative to a wild-type EGFR. In various 15 embodiments, the compounds of the disclosure exhibit from about 100-fold to about 1000fold greater inhibition of EGFR containing one or more mutations as described herein relative to a wild-type EGFR. In various embodiments, the compounds of the disclosure exhibit from about 1000-fold to about 10000-fold greater inhibition of EGFR containing one or more mutations as described herein relative to a wild-type EGFR. 20 In other embodiments, the compounds of the disclosure in combination with a second active agent, wherein said second active agent prevents EGFR dimer formation, exhibit from about 2-fold to about 10-fold greater inhibition of EGFR containing one or more mutations as described herein relative to a wild-type EGFR. In other embodiments, the compounds of the disclosure in combination with a second active agent, wherein said second active agent 25 prevents EGFR dimer formation, exhibit from about 10-fold to about 100-fold greater inhibition of EGFR containing one or more mutations as described herein relative to a wildtype EGFR. In other embodiments, the compounds of the disclosure in combination with a second active agent wherein said second active agent prevents EGFR dimer formation exhibit from about 100-fold to about 1000-fold greater inhibition of EGFR containing one or 30 more mutations as described herein relative to a wild-type EGFR. In other embodiments, the compounds of the disclosure in combination with a second active agent, wherein said second active agent prevents EGFR dimer formation, exhibit from about 1000-fold to about 10000-fold greater inhibition of EGFR containing one or more mutations as described herein relative to a wild-type EGFR. In other embodiments, the second active agent that prevents 35 EGFR dimer formation is an antibody. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab. In 2026234102   18 Sep 2026 an embodiment, the second active agent is an ATP competitive EGFR inhibitor, in another embodiment, the ATP competitive EGFR inhibitor is osimertinib, gefitinib or erlotinib. In another embodiment, the ATP competitive EGFR inhibitor is osimertinib. In certain embodiments, the compounds of the disclosure exhibit at least 2-fold 5 greater inhibition of EGFR having a combination of mutations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M relative to a wild-type EGFR. In certain embodiments, the compounds of the disclosure exhibit at least 3-fold greater inhibition of EGFR having a combination of mutations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, 10 Del / T790M, Del / T790M / C797S, and L858R / T790M relative to a wild-type EGFR. In certain embodiments, the compounds of the disclosure exhibit at least 5-fold greater inhibition of EGFR having a combination of mutations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M relative to a wild-type EGFR. In certain embodiments, the compounds of the 15 disclosure exhibit at least 10-fold greater inhibition of EGFR having a combination of mutations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M relative to a wild-type EGFR. In certain embodiments, the compounds of the disclosure exhibit at least 25-fold greater inhibition of EGFR having a combination of mutations selected from L858R / T790M, 20   L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M relative to a wild-type EGFR. In certain embodiments, the compounds of the disclosure exhibit at least 50-fold greater inhibition of EGFR having a combination of mutations selected from L L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M relative to a wild-type EGFR. In certain 25 embodiments, the compounds of the disclosure exhibit at least 100-fold greater inhibition of EGFR having a combination of mutations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M relative to a wild-type EGFR. In certain embodiments, the compounds of the disclosure in combination with a 30 second active agent, wherein said second active agent prevents EGFR dimer formation, exhibit at least 2-fold greater inhibition of EGFR having a combination of mutations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M relative to a wild-type EGFR. In certain embodiments, the compounds of the disclosure in combination with a second active agent, wherein said 35 second active agent prevents EGFR dimer formation, exhibit at least 3-fold greater inhibition of EGFR having a combination of mutations selected from L858R / T790M, L85BR / T790M / I941R, L858R / T790M / C797S, Del / T790M, DelH790M / C797S, and 2026234102   18 Sep 2026 L858R / T790M relative to a wild-type EGFR. In certain embodiments, the compounds of the disclosure in combination with a second active agent, wherein said second active agent prevents EGFR dimer formation, exhibit at least 5-foid greater inhibition of EGFR having a combination of mutations selected from L858R / T790M, L858R / T790M / I941R, 5   L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M relative to a wild type EGFR. In certain embodiments, the compounds of the disclosure in combination with a second active agent, wherein said second active agent prevents EGFR dimer formation, exhibit at least 10-fold greater inhibition of EGFR having a combination of mutations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, 10   Del / T790M / C797S, and L858R / T790M relative to a wild-type EGFR. In certain embodiments, the compounds of the disclosure in combination with a second active agent, wherein said second active agent prevents EGFR dimer formation, exhibit at least 25-fold greater inhibition of EGFR having a combination of mutations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and 15   L858R / T790M relative to a wild-type EGFR. In certain embodiments, the compounds of the disclosure in combination with a second active agent, wherein said second active agent prevents EGFR dimer formation, exhibit at least 50-fold greater inhibition of EGFR having a combination of mutations selected from L L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T79QM, Del / T790M / C797S, and L858R / T790M relative to a wild- 20 type EGFR. In certain embodiments, the compounds of the disclosure in combination with a second active agent, wherein said second active agent prevents EGFR dimer formation, exhibit at least 100-fold greater inhibition of EGFR having a combination of mutations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M relative to a wild-type EGFR. In some embodiments, 25 the second active agent that prevents EGFR dimer formation is an antibody. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab. In an embodiment, the second active agent is an ATP competitive EGFR inhibitor. In another embodiment, the ATP competitive EGFR 30 inhibitor is osimertinib. In some embodiments, the inhibition of EGFR activity is measured by IC50. In some embodiments, the inhibition of EGFR activity is measured by ECso. In some embodiments, the inhibition of EGFR by a compound of the disclosure can be measured via a biochemical assay. By illustrative and non-limiting example, a 35 homogenous time-resolved fluorescence (HTRF) assay may be used to determine inhibition of EGFR activity using conditions and experimental parameters disclosed herein. The HTRF assay may, for example, employ concentrations of substrate (e.g., biotin-Lck-peptide 2026234102   18 Sep 2026 substrate) of about 1 pM; concentrations of EGFR (mutant or WT) from about 0.2 nM to about 40 nM; and concentrations of inhibitor from about 0.000282 pM to about 50 pM. A compound of the disclosure screened under these conditions may, for example, exhibit an ICso value from about 1 nM to >1 pM; from about 1 nM to about 400 nM; from about 1 nM to 5 about 150 nM; from about 1 nM to about 75 nM; from about 1 nM to about 40 nM; from about 1 nM to about 25 nM; from about 1 nM to about 15 nM; or from about 1 nM to about 10 nM. In certain embodiments, a compound of the disclosure screened under the above conditions for inhibition of EGFR having a mutation or combination of mutations selected from L858R / T790M, L858R, and T790M may, for example, exhibit an ICso value from about 1 nM 10 to >1 pM; from about 1 nM to about 400 nM; from about 1 nM to about 150 nM; from about 1 nM to about 75 nM; from about 1 nM to about 40 nM; from about 1 nM to about 25 nM; from about 1 nM to about 15 nM; or from about 1 nM to about 10 nM. In some embodiments, the compounds of the disclosure bind to an allosteric site in EGFR. In some embodiments, the compounds of the disclosure interact with at least one 15 amino acid residue of epidermal growth factor receptor (EGFR) selected from Lys745, Leu788, and Ala 743. In other embodiments, the compounds of the disclosure interact with at least one amino acid residue of epidermal growth factor receptor (EGFR) selected from Cys755, Leu777, Phe856, and Asp855. In other embodiments, the compounds of the disclosure interact with at least one amino acid residue of epidermal growth factor receptor 20 (EGFR) selected from Met766, Ile759, Glu762, and Ala763. in other embodiments, the compounds of the disclosure interact with at least one amino acid residue of epidermal growth factor receptor (EGFR) selected from Lys745, Leu788, and Ala 743; at least one amino acid residue of epidermal growth factor receptor (EGFR) selected from Cys755, Leu777, Phe856, and Asp855; and at least one amino acid residue of epidermal growth 25 factor receptor (EGFR) selected from Met766, Ile759, Glu762, and Ala763. in other embodiments, the compounds of the disclosure do not interact with any of the amino acid residues of epidermal growth factor receptor (EGFR) selected from Met793, Gly796, and Cys797. In some embodiments, the disclosure provides a compound comprising an allosteric 30 kinase inhibitor, wherein the compound is a more potent inhibitor of a drug-resistant EGFR mutant relative to a wild type EGFR. For example, the compound can be at least about 2-foid, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or about 100-fold more potent at inhibiting the kinase activity of the drug-resistant EGFR mutant relative to a wild-type EGFR. In some embodiments, the drug -resistant EGFR mutant is resistant to one or more known EGFR 35 inhibitors, including but not limited to gefitinib, erlotinib, iapatinib, WZ4002, HKI-272, CL-387785, and osimertinib. 2026234102   18 Sep 2026 In some embodiments, the drug-resistant EGFR mutant comprises a sensitizing mutation, such as Del and L858R. In some embodiments, the disclosure provides a compound comprising an allosteric kinase inhibitor in combination with a second active agent, wherein said second active agent 5 prevents EGFR dimer formation, wherein the compound is a more potent inhibitor of a drugresistant EGFR mutant relative to a wild type EGFR. For example, the compound in combination with a second active agent, wherein said second active agent prevents EGFR dimer formation, can be at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or about 100-fold more potent at inhibiting the kinase activity of the drug-resistant EGFR mutant 10 relative to a wild-type EGFR. In some embodiments, the drug-resistant EGFR mutant is resistant to one or more known EGFR inhibitors, including but not limited to gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib. In some embodiments, the drug-resistant EGFR mutant comprises a sensitizing mutation, such as Del and L858R. In some embodiments, the second active agent that prevents EGFR dimer formation is an 15 antibody. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab, in an embodiment, the second active agent is an ATP competitive EGFR inhibitor. In another embodiment, the ATP competitive EGFR inhibitor is osimertinib. 20          In some embodiments, the disclosure provides a compound comprising an allosteric kinase inhibitor, wherein the compound inhibits kinase activity of a drug-resistant EGFR mutant harboring a sensitizing mutation (e.g., Del and L858R) and a drug-resistance mutation (e.g., T790M, L718Q, C797S, and L844V) with less than a 10-fold difference in potency (e.g., as measured by IC50) relative to an EGFR mutant harboring the sensitizing 25 mutation but not the drug-resistance mutation. In some embodiments, the difference in potency is less than about 9-fold, 8-fold, 7-fold, 6-fold, 5-fold, 4-fold, 3-fold, or 2-fold. In other embodiments, the disclosure provides a compound comprising an allosteric kinase inhibitor in combination with a second active agent, wherein said second active agent prevents EGFR dimer formation, wherein the compound in combination with the second 30 active agent inhibits kinase activity of a drug-resistant EGFR mutant harboring a sensitizing mutation (e.g., Del and L858R) and a drug-resistance mutation (e.g., T790M, L718Q, C797S, and L844V) with less than a 10-fold difference in potency (e.g., as measured by IC50) relative to an EGFR mutant harboring the sensitizing mutation but not the drugresistance mutation. In some embodiments, the difference in potency is less than about 9 35 fold, 8-fold, 7-fold, 6-fold, 5-fold, 4-fold, 3-fold, or 2-fold. In some embodiments, the second active agent that prevents EGFR dimer formation is an antibody. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab, trastuzumab, or 2026234102   18 Sep 2026 panitumumab. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab, in an embodiment, the second active agent is an ATP competitive EGFR inhibitor. In another embodiment, the ATP competitive EGFR inhibitor is osimertinib, gefitinib or erlotinib. In another embodiment, the ATP competitive EGFR inhibitor is 5 osimertinib. In some embodiments, the disclosure provides a compound comprising an allosteric kinase inhibitor, wherein the compound is more potent than one or more known EGFR inhibitors, including but not limited to gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib, at inhibiting the activity of EGFR containing one or more mutations 10 as described herein, such as T790M, L718Q, L844V, L858R, C797S, and Del. For example, the compound can be at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or about 100-foid more potent (e.g., as measured by IC50) than gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib at inhibiting the activity of the EGFR containing one or more mutations as described herein. 15          In other embodiments, the disclosure provides a compound comprising an allosteric kinase inhibitor in combination with a second active agent, wherein said second active agent prevents EGFR dimer formation, wherein the compound in combination with the second active agent is more potent than one or more known EGFR inhibitors, including but not limited to gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib, at 20 inhibiting the activity of EGFR containing one or more mutations as described herein, such as T790M, L718Q, L844V, L858R, C797S, and Del. For example, the compound in combination with a second active agent, wherein said second active agent prevents EGFR dimer formation, can be at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or about 100-fold more potent (e.g., as measured by IC50) than gefitinib, erlotinib, lapatinib, WZ4002, 25   HKI-272, CL-387785, and osimertinib at inhibiting the activity of the EGFR containing one or more mutations as described herein. In some embodiments, the second active agent that prevents EGFR dimer formation is an antibody. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that prevents EGFR dimer formation is 30 cetuximab. In an embodiment, the second active agent is an ATP competitive EGFR inhibitor. In another embodiment, the ATP competitive EGFR inhibitor is osimertinib, gefitinib or erlotinib. In another embodiment, the ATP competitive EGFR inhibitor is osimertinib. In some embodiments, the disclosure provides a compound comprising an allosteric kinase inhibitor, wherein the compound is less potent than one or more known EGFR 35 inhibitors, including but not limited to gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib, at inhibiting the activity of a wild-type EGFR. For example, the compound can be at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or about 100- 2026234102   18 Sep 2026 fold less potent (e.g., as measured by ICso) than gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib, at inhibiting the activity of a wild-type EGFR. In other embodiments, the disclosure provides a compound comprising an allosteric kinase inhibitor in combination with a second active agent, wherein said second active agent 5 prevents EGFR dimer formation, wherein the compound in combination with the second active agent is less potent than one or more known EGFR inhibitors, including but not limited to gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib, at inhibiting the activity of a wild-type EGFR. For example, the compound in combination with a second active agent, wherein said second active agent prevents EGFR dimer formation can be at 10 least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or about 100-fold less potent (e.g., as measured by ICso) than gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib, at inhibiting the activity of a wild-type EGFR. In some embodiments, the second active agent that prevents EGFR dimer formation is an antibody, in further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab, trastuzumab, or 15 panitumumab. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab. In an embodiment, the second active agent is an ATP competitive EGFR inhibitor. In another embodiment, the ATP competitive EGFR inhibitor is osimertinib, gefitinib or erlotinib. In another embodiment, the ATP competitive EGFR inhibitor is osimertinib. 20          Potency of the inhibitor can be determined by ECso value. A compound with a lower ECso value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher ECso value. In some embodiments, the substantially similar conditions comprise determining an EGFR-dependent phosphorylation level, in vitro or in vivo (e.g., in 3T3 cells expressing a wild type EGFR, a mutant EGFR, or a fragment of 25 any thereof). Potency of the inhibitor can also be determined by ICso value. A compound with a lower ICso value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher ICso value, in some embodiments, the substantially similar conditions comprise determining an EGFR-dependent phosphorylation 30 level, in vitro or in vivo (e.g., in 3T3 cells expressing a wild type EGFR, a mutant EGFR, or a fragment of any thereof). An EGFR sensitizing mutation comprises without limitation L858R, G719S, G719C, G719A, L861Q, a deletion in exon 19 and / or an insertion in exon 20. A drug-resistant EGFR mutant can have without limitation a drug resistance mutation comprising T790M, T854A, 35   L718Q, C797S, or D761Y. The selectivity between wild-type EGFR and EGFR containing one or more mutations as described herein can also be measured using cellular proliferation assays 2026234102   18 Sep 2026 where ceil proliferation is dependent on kinase activity. For example, murine Ba / F3 cells transfected with a suitable version of wild-type EGFR (such as VIII; containing a WT EGFR kinase domain), or Ba / F3 cells transfected with L858R / T790M, Del / T790M / L718Q, L858R / T790M / L718Q, L858R / T790M / C797S, Del / T790M / C797S, L858R / T790M / I941R, or 5 Exon 19 deletion / T790M can be used. Proliferation assays are performed at a range of inhibitor concentrations (10 pM, 3 pM, 1.1 pM, 330 nM, 110 nM, 33 nM, 11 nM, 3 nM, I nW) and an ECso is calculated. An alternative method to measure effects on EGFR activity is to assay EGFR phosphorylation. Wild type or mutant (L858R / T790M, Del / T790M, DelfT790M / L718Q, 10   L858R / T790M / C797S, Del / T790M / C797S, L858R / T790M / I941R, or L858R / T790M / L718Q) EGFR can be transfected into NIH-3T3 cells (which do not normally express endogenous EGFR) and the ability of the inhibitor (using concentrations as above) to inhibit EGFR phosphorylation can be assayed. Ceils are exposed to increasing concentrations of inhibitor for 6 hours and stimulated with EGF for 10 minutes. The effects on EGFR phosphorylation 15 are assayed by Western Blotting using phospho-specific (Y1068) EGFR antibodies. In another aspect, the present disclosure relates to a compound that binds to an allosteric site in EGFR, wherein the compound exhibits greater than 2-fold, 3-fold, 5-fold, 10fold, 25-fold, 50-fold, 100-fold, or 1000-fold inhibition of EGFR containing one or more mutations as described herein (e.g., L858R / T790M, Del / T790M, Del / T790M / L718Q, 20   L858R / T790M / C797S. Del / T790M / C797S, L858R / T790M / I941R, or L858R / T790M / L718Q) relative to a wild-type EGFR. In other embodiments, the disclosure provides a compound that binds to an allosteric site in EGFR in combination with a second active agent, wherein said second active agent prevents EGFR dimer formation, wherein the compound in combination with the second 25 active agent greater than 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, 100-fold, or 1000fold inhibition of EGFR containing one or more mutations as described herein (e.g., L858R / T790M, Del / T790M, Del / T790M / L718Q, Del / T790M / C797S,L858R / T790M / C797S, L858R / T790M / I941R, or L858R / T790M / L718Q) relative to a wild-type EGFR. In some embodiments, the second active agent that prevents EGFR dimer formation is an antibody. 30 In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab. In an embodiment, the second active agent is an ATP competitive EGFR inhibitor. In another embodiment, the ATP competitive EGFR inhibitor is osimertinib, gefitinib or erlotinib. In another embodiment, the ATP 35 competitive EGFR inhibitor is osimertinib. In still another aspect, the disclosure provides a method of inhibiting epidermal growth factor receptor (EGFR), the method comprising administering to a subject in need 2026234102   18 Sep 2026 thereof an effective amount of a compound of disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises administering a second active agent, wherein said second active agent prevents EGFR dimer formation, in some embodiments, the second active agent that prevents EGFR dimer formation is an 5 antibody. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab. In an embodiment, the second active agent is an ATP competitive EGFR inhibitor. In another embodiment, the ATP competitive EGFR inhibitor is osimertinib, gefitinib or erlotinib. In another embodiment, the 10 ATP competitive EGFR inhibitor is osimertinib. In another aspect, provided herein is a method of treating or preventing a disease, the method comprising administering to a subject in need thereof an effective amount of a compound of disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the disease is mediated by a kinase. In further embodiments, the kinase 15 comprises a mutated cysteine residue. In further embodiments, the mutated cysteine residue is located in or near the position equivalent to Cys 797 in EGFR, including such positions in Jak3, Blk, Bmx, Btk, HER2 (ErbB2), HER4 (ErbB4), Itk, Tec, and Txk. In some embodiments, the method further comprises administering a second active agent, wherein said second active agent prevents dimer formation of the kinase. In some embodiments, the 20 second active agent that prevents kinase dimer formation is an antibody. In further embodiments, the second active agent prevents EGFR dimer formation. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab. In an embodiment, the second active agent is 25 an ATP competitive EGFR inhibitor. In another embodiment, the ATP competitive EGFR inhibitor is osimertinib, gefitinib or erlotinib. In another embodiment, the ATP competitive EGFR inhibitor is osimertinib. In some embodiments, the disease is mediated by EGFR (e.g., EGFR plays a role in the initiation or development of the disease). In some embodiments, the disease is mediated 30 by a Her-kinase. In further embodiments, the Her-kinase is HER1, HER2, or HER4. In certain embodiments, the disease is resistant to a known EGFR inhibitor, including but not limited to, gefitinib, erlotinib, osimertinib, CO-1686, or WZ4002. In certain embodiments, a diagnostic test is performed to determine if the disease is associated with an activating mutation in EGFR. In certain embodiments, a diagnostic test is performed to 35 determine if the disease is associated with an EGFR harboring an activating mutation and / or a drug resistance mutation. Activating mutations comprise without limitation L858R, G719S, G719C, G719A, L718Q, L861Q, a deletion in exon 19 and / or an insertion in exon 20. Drug 2026234102   18 Sep 2026 resistant EGFR mutants can have without limitation a drug resistance mutation comprising T790M, T854A, L718Q, C797S, or D761Y. The diagnostic test can comprise sequencing, pyrosequencing, PCR, RT-PCR, or similar analysis techniques known to those of skill in the art that can detect nucleotide sequences. 5           In certain embodiments, the disease is cancer or a proliferation disease. In further embodiments, the disease is lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreas cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal carcinoma, head and neck 10 squamous cell carcinoma, leukemias, lymphomas, myelomas, or solid tumors. In further embodiments, the disease is lung cancer, breast cancer, glioma, squamous cell carcinoma, or prostate cancer, in still further embodiments, the disease is non-small cell lung cancer. In certain embodiments, the disease is resistant to a known EGFR inhibitor, including but not limited to, gefitinib, erlotinib, osimertinib, CO-1686, or WZ4002. In certain 15 embodiments, a diagnostic test is performed to determine if the disease is associated with an activating mutation in EGFR. In certain embodiments, a diagnostic test is performed to determine if the disease is associated with an EGFR harboring an activating mutation and / or a drug resistance mutation. Activating mutations comprise without limitation L858R, G719S, G719C, G719A, L718Q, L861Q, a deletion in exon 19 and / or an insertion in exon 20. Drug 20 resistant EGFR mutants can have without limitation a drug resistance mutation comprising T790M, T854A, L718Q, C797S, or D761Y. The diagnostic test can comprise sequencing, pyrosequencing, PCR, RT-PCR, or similar analysis techniques known to those of skill in the art that can detect nucleotide sequences. In yet another aspect, provided herein is a method of treating a kinase-mediated 25 disorder comprising administering to a subject in need thereof an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is an inhibitor of HER1, HER2, or HER4. In other embodiments, the subject is administered an additional therapeutic agent. In other embodiments, the compound and the additional therapeutic agent are administered 30 simultaneously or sequentially. In another aspect, the disclosure provides a method of treating a kinase mediated disorder, the method comprising administering to a subject in need thereof an effective amount of a compound of disclosed herein, or a pharmaceutically acceptable salt thereof, and a second active agent, wherein said second active agent prevents EGFR dimer 35 formation. In some embodiments, the compound is an inhibitor of HER1, HER2, or HER4. In other embodiments, the subject is administered an additional therapeutic agent. In other embodiments, the compound, the second active agent that prevents EGFR dimer formation, 2026234102   18 Sep 2026 and the additional therapeutic agent are administered simultaneously or sequentially. In some embodiments, the second active agent that prevents EGFR dimer formation is an antibody. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second 5 active agent that prevents EGFR dimer formation is cetuximab. In an embodiment, the second active agent is an ATP competitive EGFR inhibitor. In another embodiment, the ATP competitive EGFR inhibitor is osimertinib, gefitinib or erlotinib, in another embodiment, the ATP competitive EGFR inhibitor is osimertinib. In other embodiments, the disease is cancer, in further embodiments, the cancer is 10 lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreas cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal carcinoma, head and neck squamous cell carcinoma, leukemias, lymphomas, myelomas, or solid tumors. In further embodiments, the disease is lung cancer, 15 breast cancer, glioma, squamous ceil carcinoma, or prostate cancer. In still further embodiments, the disease is non-small ceil lung cancer. In another aspect, provided herein is a method of treating cancer, wherein the cancer cell comprises activated EGFR, comprising administering to a subject in need thereof an effective amount of a compound of disclosed herein, or a pharmaceutically acceptable salt 20 thereof. In another aspect, provided herein is a method of treating cancer, wherein the cancer cell comprises activated EGFR, comprising administering to a subject in need thereof an effective amount of a compound of disclosed herein, or a pharmaceutically acceptable salt thereof and a second active agent, wherein said second active agent prevents EGFR dimer 25 formation. In some embodiments, the second active agent that prevents EGFR dimer formation is an antibody. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab. In an embodiment, the second active agent is an ATP competitive EGFR inhibitor. In another 30 embodiment, the ATP competitive EGFR inhibitor is osimertinib, gefitinib or erlotinib. In another embodiment, the ATP competitive EGFR inhibitor is osimertinib. In certain embodiments, the EGFR activation is selected from mutation of EGFR, amplification of EGFR, expression of EGFR, and ligand mediated activation of EGFR. In further embodiments, the mutation of EGFR is selected from G719S, G719C, 35   G719A, L858R, L861Q, an exon 19 deletion mutation, and an exon 20 insertion mutation. In still another aspect, provided herein is a method of treating cancer in a subject, wherein the subject is identified as being in need of EGFR inhibition for the treatment of 2026234102   18 Sep 2026 cancer, comprising administering to the subject an effective amount of a compound disciosed herein, or a pharmaceutically acceptable salt thereof. In certain embodiments, the subject identified as being in need of EGFR inhibition is resistant to a known EGFR inhibitor, including but not limited to, gefitinib, erlotinib, 5 osimertinib, CO-1686, or WZ4002. In certain embodiments, a diagnostic test is performed to determine if the subject has an activating mutation in EGFR. In certain embodiments, a diagnostic test is performed to determine if the subject has an EGFR harboring an activating mutation and / or a drug resistance mutation. Activating mutations comprise without limitation L858R, G719S, G719C, G719A, L718Q, L861Q, a deletion in exon 19 and / or an insertion in 10 exon 20. Drug resistant EGFR mutants can have without limitation a drug resistance mutation comprising T790M, T854A, L718Q, C797S, or D761Y. The diagnostic test can comprise sequencing, pyrosequencing, PCR, RT-PCR, or similar analysis techniques known to those of skill in the art that can detect nucleotide sequences. In an aspect, provided herein is a method of preventing resistance to a known EGFR 15 inhibitor (including but not limited to gefitinib, erlotinib, osimertinib, CO-1686, or WZ4002) in a subject, comprising administering to a subject in need thereof an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof. In another aspect, provided herein is a method of preventing resistance to a known EGFR inhibitor (including but not limited to gefitinib, erlotinib, osimertinib, CO-1686, or 20   WZ4002) in a disease, comprising administering to a subject in need thereof an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a second active agent, wherein said second active agent prevents EGFR dimer formation. In some embodiments, the second active agent that prevents EGFR dimer formation is an antibody. In further embodiments, the second active agent that prevents EGFR dimer 25 formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab. In an embodiment of the methods disclosed herein, the subject is a human. In another aspect, the disclosure provides a compound disclosed herein, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for 30 treating or preventing a disease in which EGFR plays a role. In an aspect, provided herein is a method of treating or preventing a condition selected from the group consisting of autoimmune diseases, inflammatory diseases, proliferative and hyperproliterative diseases, immunologically-mediated diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cardiovascular 35 diseases, hormone related diseases, allergies, asthma, and Alzheimer's disease, in other embodiments, said condition is selected from a proliferative disorder and a neurodegenerative disorder. 2026234102   18 Sep 2026 One aspect of this disclosure provides compounds that are useful for the treatment of diseases, disorders, and conditions characterized by excessive or abnormal cell proliferation. Such diseases include, but are not limited to, a proliferative or hyperproliferative disease, and a neurodegenerative disease. Examples of proliferative and hyperproliferative 5 diseases include, without limitation, cancer. The term “cancer” includes, but is not limited to, the following cancers: breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone, colon, colorectal, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, 10 undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, myeloid disorders, lymphoid disorders, Hodgkin's, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colon, rectum, large intestine, rectum, brain and central nervous system, chronic myeloid leukemia (CML), and leukemia. The term “cancer” 15 includes, but is not limited to, the following cancers: myeloma, lymphoma, or a cancer selected from gastric, renal, head and neck, oropharangeal, non-small cell lung cancer (NSCLC), endometrial, hepatocarcinoma, non-Hodgkin’s lymphoma, and pulmonary. The term “cancer” refers to any cancer caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, lymphomas 20 and the like. For example, cancers include, but are not limited to, mesothelioma, leukemias and lymphomas such as cutaneous T-cell lymphomas (CTCL), noncutaneous peripheral T-cell lymphomas, lymphomas associated with human T-cell lymphotrophic virus (HTLV) such as adult T-cell leukemia / lymphoma (ATLL), B-cell lymphoma, acute nonlymphocytic leukemias, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute 25 myelogenous leukemia, lymphomas, and multiple myeloma, non-Hodgkin lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), Hodgkin's lymphoma, Burkitt lymphoma, adult T-cell leukemia lymphoma, acute-myeloid leukemia (AML), chronic myeloid leukemia (CML), or hepatocellular carcinoma. Further examples include myelodysplastic syndrome, childhood solid tumors such as brain tumors, neuroblastoma, retinoblastoma, 30 Wilms' tumor, bone tumors, and soft-tissue sarcomas, common solid tumors of adults such as head and neck cancers (e.g., oral, laryngeal, nasopharyngeal and esophageal), genitourinary cancers (e.g., prostate, bladder, renal, uterine, ovarian, testicular), lung cancer (e.g., small-cell and non-small cell), breast cancer, pancreatic cancer, melanoma and other skin cancers, stomach cancer, brain tumors, tumors related to Gorlin syndrome (e.g., 35 medulloblastoma, meningioma, etc.), and liver cancer. Additional exemplary forms of cancer which may be treated by the subject compounds include, but are not limited to, cancer of skeletal or smooth muscle, stomach cancer, cancer of the small intestine, rectum carcinoma, 2026234102   18 Sep 2026 cancer of the salivary gland, endometrial cancer, adrenal cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer. Additional cancers that the compounds described herein may be useful in preventing, treating and studying are, for example, colon carcinoma, familial adenomatous polyposis 5 carcinoma and hereditary non-polyposis colorectal cancer, or melanoma. Further, cancers include, but are not limited to, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tongue carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, thyroid cancer (medullary and papillary thyroid carcinoma), renal carcinoma, kidney parenchyma carcinoma, cervix carcinoma, uterine corpus carcinoma, endometrium carcinoma, chorion 10 carcinoma, testis carcinoma, urinary carcinoma, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, gall bladder carcinoma, bronchial carcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma, choroidea melanoma, seminoma, rhabdomyosarcoma, craniopharyngeoma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, 15 fibrosarcoma, Ewing sarcoma, and plasmocytoma. In one aspect of the disclosure, the present disclosure provides for the use of one or more compounds of the disclosure in the manufacture of a medicament for the treatment of cancer, including without limitation the various types of cancer disclosed herein. In some embodiments, the compounds of this disclosure are useful for treating 20 cancer, such as colorectal, thyroid, breast, and lung cancer; and myeloproliferative disorders, such as polycythemia vera, thrombocythemia, myeloid metaplasia with myelofibrosis, chronic myelogenous leukemia, chronic myelomonocytic leukemia, hypereosinophilic syndrome, juvenile myelomonocytic leukemia, and systemic mast cell disease. In some embodiments, the compounds of this disclosure are useful for treating 25 hematopoietic disorders, in particular, acute-myelogenous leukemia (AML), chronic-myelogenous leukemia (CML), acute-promyelocytic leukemia, and acute lymphocytic leukemia (ALL). The term “cancerous cell” as provided herein, includes a cell afflicted by any one of the above-identified conditions. 30          The disclosure further provides a method for the treatment or prevention of cell proliferative disorders such as hyperplasias, dysplasias and pre-cancerous lesions. Dysplasia is the earliest form of pre-cancerous lesion recognizable in a biopsy by a pathologist. The subject compounds may be administered for the purpose of preventing said hyperplasias, dysplasias, or pre-cancerous lesions from continuing to expand or from 35 becoming cancerous. Examples of pre-cancerous lesions may occur in skin, esophageal tissue, breast and cervical intra-epithelial tissue. 2026234102   18 Sep 2026 Examples at neurodegenerative diseases include, without limitation, adrenoleukodystrophy (ALD), Alexander's disease, Alper’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis (Lou Gehrig's Disease), ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), bovine spongiform 5 encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, familial fatal insomnia, frontotemporal lobar degeneration, Huntington's disease, HIV-associated dementia, Kennedy's disease, Krabbe's disease, Lewy body dementia, neuroborreliosis, Machado-Joseph disease (spinocerebellar ataxia type 3), multiple system atrophy, multiple sclerosis, narcolepsy, Niemann Pick disease, Parkinson's 10 disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prion diseases, progressive supranuclear palsy, Refsum's disease, Sandhoff disease, Schilder’s disease, subacute combined degeneration of spinal cord secondary to pernicious anaemia, Spielmeyer-Vogt-Sjogren-Batten disease (also known as Batten disease), spinocerebellar ataxia (multiple types with varying characteristics), spinal muscular atrophy, Steele- 15 Richardson-Olszewski disease, tabes dorsalis, and toxic encephalopathy. Another aspect of this disclosure provides a method for the treatment or lessening the severity of a disease selected from a proliferative or hyperproliferative disease, or a neurodegenerative disease, comprising administering an effective amount of a compound, or a pharmaceutically acceptable composition comprising a compound, to a subject in need 20 thereof. In other embodiments, the method further comprises administering a second active agent, wherein said second active agent prevents EGFR dimer formation. In some embodiments, the second active agent that prevents EGFR dimer formation is an antibody. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent 25 that prevents EGFR dimer formation is cetuximab. In an embodiment, the second active agent is an ATP competitive EGFR inhibitor. In another embodiment, the ATP competitive EGFR inhibitor is osimertinib. gefitinib or erlotinib. In another embodiment, the ATP competitive EGFR inhibitor is osimertinib. The activity of the compounds and compositions of the present disclosure as EGFR 30 kinase inhibitors may be assayed in vitro, in vivo, or in a cell line. In vitro assays include assays that determine inhibition of either the kinase activity or ATPase activity of the activated kinase. Alternate in vitro assays quantitate the ability of the inhibitor to bind to the protein kinase and may be measured either by radio labelling the inhibitor prior to binding, isolating the inhibitor / kinase complex and determining the amount of radio label bound, or by 35 running a competition experiment where new inhibitors are incubated with the kinase bound to known radioligands. Detailed conditions for assaying a compound utilized in this disclosure as an inhibitor of various kinases are set forth in the Examples below. 2026234102   18 Sep 2026 In accordance with the foregoing, the present disclosure further provides a method for preventing or treating any of the diseases or disorders described above in a subject in need of such treatment, which method comprises administering to said subject a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically 5 acceptable salt thereof, and optionally a second active agent, wherein said second active agent prevents EGFR dimer formation. For any of the above uses, the required dosage will vary depending on the mode of administration, the particular condition to be treated and the effect desired. In other embodiments, the compound and the second active agent that prevents 10 EGFR dimer formation are administered simultaneously or sequentially. Administration / Dosages / Formulations Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the 15 active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, 20 tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Injectable preparations (for example, sterile injectable aqueous or oleaginous 25 suspensions) may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P., and 30 isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. In order to prolong the effect of a drug, it is often desirable to slow the absorption of 35 the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, 2026234102   18 Sep 2026 may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Compositions for rectal or vaginal administration are preferably suppositories which 5 can be prepared by mixing the compounds of this disclosure with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. Solid compositions of a similar type may also be employed as fillers in soft and hard 10 filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release 15 controlling coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of 20 capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Dosage forms for topical or transdermal administration of a compound of this disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be 25 required. Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this disclosure. The ointments, pastes, creams and gels may contain, in addition to an active compound of this disclosure, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, 30 bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Powders and sprays can contain, in addition to the compounds of this disclosure, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons. 35          Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the 2026234102   18 Sep 2026 flux at the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel. According to the methods of treatment of the present disclosure, disorders are treated or prevented in a subject, such as a human or other animal, by administering to the 5 subject a therapeutically effective amount of a compound of the disclosure, in such amounts and for such time as is necessary to achieve the desired result. The term “therapeutically effective amount” of a compound of the disclosure, as used herein, means a sufficient amount of the compound so as to decrease the symptoms of a disorder in a subject. As is well understood in the medical arts a therapeutically effective amount of a compound of this 10 disclosure will be at a reasonable benefit / risk ratio applicable to any medical treatment. In general, compounds of the disclosure will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with one or more therapeutic agents. A therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the 15 subject, the potency of the compound used and other factors. In general, satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.03 to 2.5 mg / kg per body weight. An indicated daily dosage in the larger mammal, e.g., humans, is in the range from about 0.5 mg to about 100 mg, conveniently administered, e.g., in divided doses up to four times a day or in retard form. Suitable unit dosage forms for oral administration 20 comprise from ca. 1 to 50 mg active ingredient. In certain embodiments, a therapeutic amount or dose of the compounds of the present disclosure may range from about 0.1 mg / Kg to about 500 mg / Kg, alternatively from about 1 to about 50 mg / Kg. In general, treatment regimens according to the present disclosure comprise administration to a patient in need of such treatment from about 10 mg 25 to about 1000 mg of the compound(s) of this disclosure per day in single or multiple doses. Therapeutic amounts or doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents. Upon improvement of a subject's condition, a maintenance dose of a compound, composition or combination of this disclosure may be administered, if necessary. 30 Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained; when the symptoms have been alleviated to the desired level, treatment should cease. The subject may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms. 35          It will be understood, however, that the total daily usage of the compounds and compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific inhibitory dose for any particular patient will 2026234102   18 Sep 2026 depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the 5 duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. The disclosure also provides for a pharmaceutical combination, e.g., a kit, comprising a) a first agent which is a compound of the disclosure as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent. The kit can comprise 10 instructions for its administration. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents. For example, an agent that prevents EGFR dimer formation, chemotherapeutic agents or other antiproliferative agents may be combined with the compounds of this disclosure to treat proliferative diseases and cancer. 15          Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate; disodium hydrogen 20 phosphate; potassium hydrogen phosphate; sodium chloride; zinc salts; colloidal silica; magnesium trisilicate; polyvinyl pyrrolidone; polyacrylates; waxes; polyethylenepolyoxypropylene-block polymers; wool fat; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered 25 tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such a propylene glycol or polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; 30 and phosphate buffer solutions. Further, non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. The protein kinase inhibitors or pharmaceutical salts thereof may be formulated into pharmaceutical 35 compositions for administration to animals or humans. These pharmaceutical compositions, which comprise an amount of the protein inhibitor effective to treat or prevent a protein 2026234102   18 Sep 2026 kinase-mediated condition and a pharmaceutically acceptable carrier, are other embodiments of the present disclosure. Kits 5          In an aspect, provided herein is a kit comprising a compound capable of inhibiting kinase activity selected from one or more compounds of disclosed herein, or pharmaceutically acceptable salts thereof, and instructions for use in treating cancer. In certain embodiments, the kit further comprises components for performing a test to determine whether a subject has activating and / or drug resistance mutations in EGFR. 10          In another aspect, the disclosure provides a kit comprising a compound capable of inhibiting EGFR activity selected from a compound disclosed herein, or a pharmaceutically acceptable salt thereof. In another aspect, the disclosure provides a kit comprising a compound capable of inhibiting kinase activity selected from one or more compounds of disclosed herein, or 15 pharmaceutically acceptable salts thereof; a second active agent, wherein said second active agent prevents EGFR dimer formation; and instructions for use in treating cancer. In certain embodiments, the kit further comprises components for performing a test to determine whether a subject has activating and / or drug resistance mutations in EGFR. in some embodiments, the second active agent that prevents EGFR dimer formation is an 20 antibody. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab. In another aspect, the disclosure provides a kit comprising a compound capable of inhibiting EGFR activity selected from a compound of disclosed herein, or a 25 pharmaceutically acceptable salt thereof and a second active agent, wherein said second active agent prevents EGFR dimer formation. In some embodiments, the second active agent that prevents EGFR dimer formation is an antibody. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that prevents EGFR dimer 30 formation is cetuximab. In an embodiment, the second active agent is an ATP competitive EGFR inhibitor. In another embodiment, the ATP competitive EGFR inhibitor is osimertinib, gefitinib or erlotinib. In another embodiment, the ATP competitive EGFR inhibitor is osimertinib. The disclosure is further illustrated by the following examples and synthesis 35 schemes, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is 2026234102   18 Sep 2026 intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and / or scope of the appended claims. 5 EXAMPLES The application is further illustrated by the following examples, which should not be construed as further limiting. The practice of the present disclosure will employ, unless otherwise indicated, conventional techniques of organic synthesis, 10 cell biology, cell culture, and molecular biology, which are within the skill of the art. Abbreviations ACN dba acetonitrile dibenzylideneacetone 15 DCM dichloromethane DI PEA diisopropylethylamine DMF dimethylformamide DMSO dimethylsulfoxide dppf 1,1 '-bis(dipheny!phosphino)ferrocene 20 EtOAc ethyl acetate EtOH ethanol HATU 1-[dis(dimethylamino)methy!ene]-1 H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate LDA lithium diisopropylamide 25 MeOH methanol SPhos 2-dicyclohexylphosphino-2',6-dimethoxybiphenyl TBTU 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate TEA triethylamine TEA trifluoroacetic acid 30 THF tetrahydrofuran XPhos 2-dicyclohexylphosphino-2',4',6'-tnisopropylbipheny! 2026234102   18 Sep 2026 Example 1: Preparation of 2-[ 1H-Benzimidazol-2-yl-(34fuorophenvl)methyll-644-(1-methyl-4- pipendvl)phenyljisoindolin-1-one (Compound 026) Scheme 1. 5 Step 1. Methyl 2-(6-bromo-1-oxo-isoindolin-2-yl)-2-(3-fluoropheriYl)acetate To a solution of methyl 2-amino-2-(3-fluorophenyl)acetate (4.00 g, 21.8 mmol) in DMF (109 mL) was added DIPEA (10.6 mL, 61.0 mmol). The reaction mixture was stirred at room temperature for 5 min before methyl 5”bromo"2"(bromomethyl)benzoate (6.71 g, 21.8 10 mmol) was added. The reaction mixture was heated at 80 °C overnight. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate three times. The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 0-20% ethyl acetate in hexane 15 to give the title compound (4.75 g, 58%). MS m / z: 379.1 [M+1 ]+. Step 2. Methyl 2-(3-fluorophenYl)-2-[6-[4-(1-methyl-4-piperidyl)phenyll-1-oxo-isoindolin-2- yllacetate 20           A mixture of methyl 2-(6-bromo-1-oxo-isoindolin-2-yl)-2-(3-fluorophenyl)acetate (4.13 g, 10.9 mmol), 1-methyl-4-[4-(4l4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine (4.91 g, 16.3 mmol), 1.0 M sodium carbonate solution (21.8 mL, 21.8 mmol) and dioxane 2026234102   18 Sep 2026 (109 mL) was degassed with nitrogen twice. [1,1' bis(diphenylphosphino)ferrocene]dichloropal!adium(ll), complex with dichloromethane (0.534 g, 0.654 mmol) and XPhos (0.519 g, 1.09 mmol) were added and then the reaction was degassed with nitrogen once more. The reaction mixture was heated at 100 °C for 2 h. After 5 cooling to room temperature, the reaction mixture was poured into water and extracted with dichloromethane twice. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by C18 column chromatography eluting with 0-80% ACN / water containing 10 mM ammonium acetate to give the title compound (4.17 g, 81%). MS m / z: 473.2 [M+1]*. 0 Step 3. 2-(3-Fluorophenyl)-2-[6-[4-(1-methyl-4-piperidyl)phenyl]-1-oxo-isoindolin-2-yllacetic acid A mixture of methyl 2-(6-bromo-1-oxo-isoindolin-2-yl)-2-(3-fluorophenyl)acetate (4.13 15 g, 10.9 mmol), 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperid!ne (4.91 g, 16.3 mmol), 1.0 M sodium carbonate solution (21.8 mL, 21.8 mmol) and dioxane (109 mL) was degassed with nitrogen twice. [1,1' bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane (0.534 g, 0.654 mmol) and XPhos (0.519 g, 1.09 mmol) were added and then the reaction was 20 degassed with nitrogen once more. The reaction mixture was heated at 100 °C for 2 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with dichloromethane twice. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by C18 column chromatography eluting with 0-80% ACN / water containing 10 mM 25 ammonium acetate to give the title compound (4.17 g, 81%). MS m / z: 473.2 [M+1]*. Step 4: 2-[1H-Benzimidazol-2-yl-(3-fluorophenvl)methvll-6-[4-(1-methyl-4-piperidyl)phenyllisoindolin-1-one (026) 2026234102   18 Sep 2026 To a solution of 2-(3-fiuorophenyl)-2-[6-[4-(1-methyl-4-piperidyl)phenyl]-1-oxo-isoindolin-2-yl]acetic acid (0.100 g, 0.218 mmol), 1,2-diaminobenzene (0.053 g, 0.491 mmol) and HATU (0.166 g, 0.436 mmol) in DMF (4.4 mL) was added DI PEA (0.150 mL, 0.872 mmol). After stirring at room temperature overnight, the reaction mixture was added sat. 5 sodium chloride solution. The resulting solid was collected by filtration and washed with water to give the amide intermediate which was used in the next reaction without further purification. MS m / z: 549.3 [M+1]+. To the above amide intermediate was added acetic acid (5 mL). After stirring at 80 °C overnight, the solvent was removed under reduced pressure. The crude product was purified 10 by C18 column chromatography eluting with 0-100% ACN / water containing 10 mM ammonium acetate to give the title compound (18 mg, 17%). 1H NMR (400 MHz, DMSO-d6) 5: 8.22-8.26 (m, 1H), 7.89-7.97 (m, 2H), 7.63-7.71 (m, 3H), 7.52-7.63 (m, 2H), 7.44-7.51 (m, 1H), 7.36 (d, 2H), 7.16-7.26 (m, 5H), 6.96 (s, 1H), 4.92 (d, 1H), 4.31 (d, 1H), 2.89-2.98 (m, 2H), 2.53-2.66 (m, 1H), 2.24 (s, 3H), 2.01-2.10 (m, 2H), 1.66-1.81 (m, 4H); MS m / z: 531.3 15 [M+ir. Compound 025 was prepared by a similar method to Example 1 from 2-(3-fluorophenyl)-2-[6-[4-(1-methyl-4-piperidyl)phenyl]-1-oxo-isoindolin-2-yl]acetic acid and pyridine-2,3-diamine: No. Structure / Name m / z [M+1? JH NMR (DMSO-ds) 5 025 A1 ^^F 2-[(3-Fluorophenyl)-(3H-imidazo-[4,5-b]pyridin-2-yl)methyl]-6-[4-(1-methyl-4-piperidyl)ph6nyl]-!soindolin-1-one 532.3 8.23-8.32 (m, 1H), 7.77-7.98 (m, 3H), 7.54-7.68 (m, 3H), 7.34-7.47 (m, 1H), 7.25-7.33 (m, 2H) 7.097.25 (m, 4H), 6.88 (s, 1H), 4.85 (d, 1H), 4.23 (d, 1H), 2.80-3.24 (m, 2H), 2.52-2.70 (m, 1H), 1.91-2.38 (m, 5H), 1.58-1.89 (m, 4H) 2026234102   18 Sep 2026 Example 2: Preparation of2-[(5-Fluom-2-hvdroxv-phenyl)-(1H-imidazo[4,5-clpvridin-2-vl)methvn-6-[4~(1-meihvl-4-pipendvl)phenvlJisoindolin-1-one;hydrochlonde (Compound 015) Scheme 2. To a solution of 2-bromo-4-fluoro-phenol (100 g, 523 mmol) in THF (1 L) was added sodium hydride (23.0 g, 575 mmol, 60% in mineral oil) at 0 °C for 4 h, followed by addition of methoxymethyl chloride (44.9 mL, 601 mmol). After stirring at room temperature for 10 h, the 10 reaction mixture was quenched by water and extracted with ethyl acetate three times. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 1-10% ethyl acetate in petroleum ether to give the title compound (80 g, 65%). 1H NMR (400 MHz, CDCI3) 0: 7.30 (dd, 1H), 7.12 (dd, 1H), 6.97 (m, 15   1H), 5.07-5.24 (m, 2H), 3.46-3.62 (m, 3H). 2026234102   18 Sep 2026 Step 2. Ethyl 2-F5-fluoro-2-(methoxymethoxv)phenyl1-2-oxo-acetate To a solution of 2-bromo-4-fluoro-1-(methoxymethoxy)benzene (80.0 g, 340 mmol) in THF (1 L) at -78 °C was added dropwise n-butyllithium (2.5 M in hexane, 142 mL, 357 5 mmol). After stirring at -78 °C for 1 h, the reaction mixture was cannulated to a pre-cooled (78 °C) solution of diethyl oxalate (74.4 g, 510 mmol) in THF (500 mL). Upon completion of addition, the reaction mixture was allowed to warm to room temperature. The reaction mixture was quenched by water and extracted with ethyl acetate three times. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and 10 concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 10% ethyl acetate in petroleum ether to give the title compound (70 g. 80%). 1H NMR (400 MHz, CDCh) 5: 7.57 (dd, 1H), 7.26-7.31 (m, 1H), 7.18-7.23 (m, 1H), 5.15 (s, 2H), 4.37-4.43 (m, 2H), 3.46-3.50 (m, 3H), 1.35-1.41 (m, 3H). 15 Step 3. Ethyl-2-[5-fluoro-2-(methoxymethoxy)phenyn-2-hydroxyimino-acetate Eto'^y-' To a solution of hydroxylamine hydrochloride (37.9 g, 546 mmol) in ethanol (500 mL) was added ethyl 2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-oxo-acetate (70.0 g 273 mmol) and sodium acetate (44.7 g, 132 mmol). After stirring at 80 °C for 2.5 h, the solvent was 20 removed under reduced pressure and the resulting residue was partitioned between water and dichloromethane. The aqueous phase was extracted with additional dichloromethane. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (68 g, 92%). 1H NMR (400 MHz, CDCb) 6: 9.76 (br s, 1H), 7.17-7.23 (m, 1H), 7.07-7.14 (m, 2H), 5.10 (s, 2H), 25   4.31-4.39 (m, 2H), 3.44-3.48 (m, 3H), 1.35-1.40 (m, 3H). Step 4. Ethyl 2-amino-2-f5-fluoro-2-(methoxymethoxy)phenyi1acetate 2026234102   18 Sep 2026 To a solution of Raney Ni (1.46 g, 25.0 mmol) in EtOH / THF (650 mL, 4 / 1) was added ethyl-2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-hydroxy!m!no-acetate (34.0 g, 125 mmol). The flask was evacuated and backfilled with hydrogen and the reaction mixture was allowed to stir at 70 °C under an atmosphere of hydrogen (50 psi) for 24 h. The reaction mixture was 5 filtered through a pad of Celite which was washed several times with ethanol. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography eluting with 33% ethyl acetate in petroleum ether to give the title compound (30.6 g, 48%). 1H NMR (400 MHz, DMSO-d6) 5: 7.23 (dd, 1H), 7.04-7.08 (m, 2H), 5.14-5.18 (m, 2H), 4.66 (s, 1H), 3.92-4.12 (m, 2H), 3.37 (s, 3H), 1.06-1.22 (m, 3H). 0 Step 5. Ethyl 2-(6-bromo-1-oxo-isoindolin-2-yl)-2-[5-fluoro-2-(methoxymethoxy)phenyllacetate To a solution of ethyl 2-am!no-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetate (30.6 g, 15   118 mmol) in DMF (300 mL) was added DIPEA (58.4 mL, 354 mmol). The reaction mixture was stirred at room temperature for 5 min before methyl 5-bromo-2-(bromomethyl)benzoate (32.6 g, 106 mmol) was added. The reaction mixture was heated at 100 °C for 10 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate three times. The combined organic extracts were washed with water, brine, 20 dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 33% ethyl acetate in petroleum ether to give the title compound (35 g, 66%). 1H NMR (400 MHz, CDCL) 6: 8.00 (d, 1H), 7.63 (dd, 1H), 7.22-7.36 (m, 1H), 7.10-7.19 (m, 1H), 6.94-7.08 (m, 2H), 6.36-6.54 (m, 1H), 5.06-5.21 (m, 2H), 4.72 (d, 1H), 4.13-4.34 (m, 2H), 3.94 (d, 1H) 3.31-3.45 (m, 3H), 25   1.24-1.28 (m, 3H); MS m / z: 453.8 [M+1]T Step 6. Ethyl 2-[5-fluoro-2-(methoxymethoxy)phenyll-2-[6-[4-(1-methyl-4-piperidyl)phenyll-1-oxo-isoindolin-2-yllacetate 2026234102   18 Sep 2026 A mixture of ethyl 2-(6-bromo-1-oxo-isoindolin-2-yl)-2-[5-f!uoro-2-(methoxymethoxy)-phenyljacetate (5.34 g, 11.8 mmol), 1-methyl-4-[4-(4,4,5,5-tetramethy!-1,3,2-dioxaboro!an-2-yl)phenyl]piperidine (4.60 g, 15.3 mmol), sodium carbonate (3.12 g, 29.5 mmol) and dioxane / water (125 mL, 4 / 1) was degassed under nitrogen twice. [1,1' 5 bis(diphenylphosphino)-ferrocene]dichloropalladium(ll), complex with dichloromethane (1.44 g, 1.77 mmol) was added and then the reaction was degassed under nitrogen once more. The reaction mixture was heated at 100 °C for 2 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate three times. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and 10 concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 0-15% methanol in dichloromethane to give the title compound (4.91 g, 76%). MS m / z: 547.3 [M+1]+. Stepj^JJTHuoroTMmethg)^^ 15 isoindolin-2-vllacetic acid To a solution of ethyl 2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-[6-[4-(1-methyl-4-piperidyl)phenyl]-1-oxo-isoindolin-2-yl[acetate (4.91 g, 8.98 mmol) in THF / MeOH / water (90 mL, 1 / 1 / 1) was added lithium hydroxide monohydrate (1.50 g, 35.9 mmol). After stirring at 20 room temperature for 2 h, the solvent was removed under reduced pressure and the resulting residue was neutralized with cone. HCI. The crude product was purified by C18 column chromatography eluting with 0-45% ACN / water containing 0.1% formic acid to give the title compound (4.01 g, 86%). MS m / z: 519.3 [M+1]+. 25 Step 8. 2-R5-Fluoro-2-(methoxvmethoxv)phenyll-(1H-imidazo[4,5-clpvridin-2-vl)methvll-6-[4-(1-methvl-4-piperidvl)phenyllisoindolin-1-one To a solution of 2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-[6-[4-(1-methyl-4-piperidyl)-phenyl]-1-oxo-isoindolin-2-yl]acetic acid (0.2Q0 g, 0.385 mmol), 3,4-diaminopyridine (0.084 30 g, 0.770 mmol) and HATU (0.219 g, 0.577 mmol) in DMF (4 mL) was added DI PEA (0.265 2026234102   18 Sep 2026 mL, 1.53 mmol). After stirring at room temperature for 2 h, the reaction mixture was diluted with ethyl acetate and washed twice with sat. sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by C18 column chromatography eluting with 0 5   50% ACN / water containing 0.1% formic acid to give the amide intermediate (172 mg, 73%) as a white solid. MS m / z: 610.3 [M+1]+. To the above amide intermediate (0.172 g, 0.282 mmol) was added acetic acid (3.66 mL). After stirring 30 min at 80 °C, the solvent was removed under reduced pressure. The crude product was purified by C18 column chromatography eluting with 0-40% ACN / water 10 containing 0.1% formic acid. The product fractions were pooled and concentrated under reduced pressure to remove the organic solvent. The remaining aqueous solution was basified with sat. sodium bicarbonate solution and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (143 mg, 86%). MS m / z: 15   592.3 [M+1]+ Step 9. 2-f(5-Fluoro-2-hvdroxv-phenvl)-(1H-imidazof4.5-c]pyridin-2-vl)methyll-6-[4-(1-methvl- 4-piperidyl)phenyHisoindolin-1-one;hydrochloride (Compound 015) 20           To a solution of 2-[[5-fluoro-2-(methoxymethoxy)phenyl]-(1 H-imidazo[4,5-c]pyridin-2- yl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one (0.143 g, 0.241 mmol) in dichloromethane (5.2 mL) was added HCI in dioxane (4 M, 0.6 mL, 2.40 mmol). After stirring 1 h at room temperature, the solvent was removed under reduced pressure. Diethyl ether was added to the residue and the resulting solid was isolated via filtration to give the title 25 compound (131 mg, 93%). 1H NMR (400 MHz, DMSO-d6) 6: 10.52 (brs, 1H), 10.09 (s, 1H), 9.31 (brs, 1H), 8.50 (d, 1H), 8.00 (d, 1H), 7.84-7.89 (m, 2H), 7.62-7.68 (m, 3H), 7.30 (d, 2H), 7.01-7.09 (m, 2H), 6.91-6.96 (m, 1H), 6.85 (m, 1H), 4.74 (d, 1H), 4.16 (d, 1H), 3.38-3.50 (m, 2H), 2.92-3.08 (m, 2H), 2.74-2.85 (m, 1H), 2.66-2.73 (m, 3H), 1.84-2.08 (m, 4H); MS m / z: 548.3 [M+1]+. 30 The following compounds were prepared by a similar method to Example 2 from ethyl 2-amino-2-[5-f!uoro-2-(methoxymethoxy)phenyi]acetate and either methyl 5-bromo-2- oo co oe h5 n H d m bO © © © © © © oo WO 2021 / 096948                                                 PCT / US2020 / 060001 2026234102   18 Sep 2026 010 HO 1 0 XX 548.3 9.08 (d, 1H), 8.33 (d, 1H), 7.71-7.81 (m, 2H), 7.49-7.60 (m, 2H), 7.36-7.45 (m, 2H), 7.15-7.23 (m, 2H), 7.04-7.11 (m, 2H), 6.80-6.95 (m, 2H), 0 6-[1H-Benzimidazoi-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-3-[4-(1-methyl-4-piperidyl)pheny!]-7H-pyrrolo[3,4-b]pyridin-5-one 4.85 (d, 1H), 4.21 (d, 1H), 3.11-3.19 (m, 1H), 2.85-2.92 (m, 2H), 2.21 (s, 3H), 1.962.05 (m, 2H), 1.64-1.79 (m, 4H) o' -o XT- and X^nh2 The following compounds were prepared by a similar method to Example 2 from ethyl 2-amino-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate and either methyl 5-bromo-2-(bromo-methyi)-benzoate or methyl 6-(bromomethyl)-3-chloro-2-fluorobenzoate: and the corresponding boronate and diamino aryl starting materials: No. Structure / Name m / z [M+1f ’H NMR (DMSO-ds) 5 Starting materials 079 Gy HO-y'k. °       2HC! XAF 2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[4-(3-methyi-3-azabicyclo[4.1 .OJheptan-6-yl) phenyl] isoindolin-1 -one;dihydrochloride 559.4 10.63 (brs, 1H), 10.37 (brs, 1H), 7.92-8.05 (m, 2H), 7.677.75 (m, 5H) 7.44-7.64 (m, 4H), 7.10-7.25 (m, 3H), 6.987.07 (m, 1H), 4.78 (d, 1H), 4.27 (d, 1H), 3.22-3.31 (m, 1H), 2.97-3.07 (m, 1H), 2.81-2.94 (m, 1H), 2.77-2.90 (m, 1H), 2.68 (d, 3H). 2.552.61 (m, 1H), 2.26-2.35 (m, 1H) 1.43-1.59 (m, 1H), 1.071.27 (m, 2H) p and 080 F \A fl / —\_ HO-yX &     2HCI 2-[1H-benzimidazol-2-yl-(5-fluora- 2-hydroxy-phenyl)methyl]-7-fluoro-6-[3-fluoro-4-(1 -methyl-4- piperidyl)phenyl]isoindolin-1-one;dihydrochloride 583.5 *H NMR (methanol-A) 6: 7.73-7.88 (m, 3H), 7.60-7.67 (m, 2H), 7.37-7.55 (m, 4H), 7.26-7.31 (m, 1H), 7.18-7.25 (m, 1H), 7.13-7.17 (m, 1H), 7.00-7.06 (m, 1H), 4.81-4.87 (m, 2H), 4.46 (d, 1H). 3.613.72 (m, 2H), 3.20-3.29 (m, 2H), 2.96 (S, 3H), 2.12-2.24 (m, 4H) A I O' '0 and 081 F XrY-ix XX 2Ha 7-fluoro-2-[(4-fiuoro-1 H-benzimidazol-2-yl)-(5-fluoro-2- 601.1 10.64 (brs, 1H), 10.29 (brs, 1H), 7.73-7.84 (m, 1H), 7.52 (d, 1H), 7.36-7.47 (m, 4H), 7.24-7.32 (m, 1H), 7.09-7.19 (m, 2H), 6.97-7.04 (m, 2H), 6.89-6.96 (m, 1H), 4.80 (d, 1H), 4.20 (d, 1H), 3.40-3.51 (m, 2H), 3.09-3.19 (m, 3H), a vo and 2026234102   18 Sep 2026 h yd roxy- phe n y I) m ethy H-5- [3-f I u o ro- 4-(1-methyl-4- piperidyl)phenyl]isoindoiin-1- onejdihydrochloride 2.76 (d, 3H), 2.03-2.20 (m, 2H), 1.89-2.02 (m, 2H) Example 3: Preparation Qf2-[(R)-1H-Benzimidazol42-yl-(541uoro42-hydroxY-phenyl)methy!l-6-(4-( 1~methyl-4-piperidyl)phenvl]isoindolin~1~one and 2-((8)- 1H-benzimidazoE2-yl-(5-^uoro-2~hYdroxv~phenyl)methvl]-6-[4~(1~methyl~4~pipendyl)phenyllisoindolin-1-one 5 (Compounds 022 and 023) 2-[1H-Benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[4-(1-methyl-4-piperidyl)-phenyi]isoindolin-1-one;hydrochloride (0.600 g, 1.02 mmol) was partitioned between sat. sodium bicarbonate solution and ethyl acetate. The aqueous phase was 10 extracted with additional ethyl acetate three times. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by prep SFC with Chiralpak IA column eluting with 45% (0.3% TEA in MeOH) / 55% CO2 at 10 MPa to separate enantiomers. Absolute configuration of the chiral center for each isolated enantiomer is unknown. First eluting peak 15   (022) (120 mg, 22% yield, 94:6 er); [a]2%-34.2° (c = 0.12, MeOH); 1H NMR (400 MHz, methanoi-d4) 6: 8.02 (s, 1H), 7.84-7.90 (m, 1H), 7.52-7.63 (m, 5H), 7.36 (d, 2H), 7.20-7.27 (m, 2H), 7.14 (s, 1H), 6.97-7.05 (m, 1H), 6.86-6.91 (m, 1H), 6.73-6.79 (m, 1H), 4.76 (d, 1H), 4.26 (d, 1H), 2.99-3.08 (m, 2H), 2.56-2.66 (m, 1H), 2.35 (s, 3H), 2.21 (m, 2H), 1.77-1.94 (m, 4H); MS m / z: 547.2 [M+1]+. Second eluting peak (023) (154 mg, 28% yield, 89:11 er); [a]2% 20   +28.0° (c— 0.1, MeOH); 'H NMR (400 MHz, methanol-^) 5: 8.02 (s, 1H), 7.84-7.89 (m, 1H), 7.52-7.64 (m, 5H), 7.36 (d, 2H), 7.20-7.27 (m, 2H), 7.14 (s, 1H). 6.96-7.06 (m, 1H), 6.86-6.92 (m, 1H), 6.74-6.79 (m, 1H), 4.76 (d, 1H), 4.27 (d, 1H), 3.00-3.09 (m, 2H), 2.56-2.68 (m, 1H), 2.36 (s, 3H), 2.23 (m, 2H), 1.78-1.94 (m, 4H); MS m / z: 547.3 [M+1]+. 2026234102   18 Sep 2026 Example 4: Preparation of 6-f2~(6-amino-3-pyridvi)ethvnvll-2-l'1H-benz!m!dazoi-2-vl~(5-fiuom- 2-hvdroxv-phenvl)methylJisoindolin-1 -one (Compound 012) Scheme 3. Step 1.2-(6-Bromo-1-oxo-isoindoi!n-2-yi)-2-f5-f!uoro-2-(methoxymethoxy)phenynacet!C acid To a solution of ethyl 2-(6-bromo-1-oxo-isoindolin-2-yl)-2-[5-fluoro-2-(methoxymethoxy)-phenyl]acetate (22.0 g, 48.6 mmol) in THF / MeOH / water (300 mL, 1 / 1 / 1) 10 was added lithium hydroxide monohydrate (6.10 g, 145 mmol). After stirring at room temperature for 3 h, the solvent was removed under reduced pressure and the resulting residue was adjusted to pH 3 by HCI (1 M). The solid was collected by filtration and washed with water to give the title compound (18.2 g, 88%). NMR (400 MHz, CDCh) 6: 8.20 (br s, 1H), 7.90 (d, 1H), 7.56 (dd, 1H), 7.19 (s, 1H), 6.94-7.15 (m, 3H), 6.35 (s, 1H), 5.03-5.10 (m, 15   2H), 4.63 (d, 1H), 3.89 (d, 1H): 3.27-3.36 (m, 3H). Step 2. 2-[1H-Benzimidazoi-2-vl-[5-fluoro-2-(methoxvmethoxy)phenyilmethyll-6-bromo- isoindolin-1-one 2026234102   18 Sep 2026 To a solution of 2-(6-bromo-1-oxo-isoindolin-2-yl)-2-[5-fluoro-2-(methoxymethoxy)-phenyljacetic acid (18.2 g, 42.9 mmol), 1,2-diaminobenzene (9.27 g, 85.8 mmol) and HATU (32.6 g, 85.8 mmol) in DMF (200 mL) was added DIPEA (30.3 mL, 42.4 mmol). After stirring at room temperature for 10 h, the reaction mixture was diluted with ethyl acetate and washed 5 twice with sat. sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with NH4OH / MeOH / DCM (1 / 5 / 100) to give the amide intermediate (15.5 g, 70%) as a yellow solid. NMR (400 MHz, DMSO-de) 6: 9.72 (s, 1 H), 7.88 (d, 1H), 7.75-7.85 (m, 1H), 7.51-7.69 (m, 1H), 7.08-7.23 (m, 4H), 6.8910   6.96 (m, 1H),6.74(dd, 1H), 6.53-6.60 (m, 1H), 6.31 (s, 1H), 5.11-5.27 (m, 2H), 4.85 (br s, 2H), 4.62 (d, 1H), 3.94-4.08 (m, 1H), 3.25 (s, 3H). To the above amide intermediate (15.5 g, 30.1 mmol) was added acetic acid (150 mL). After stirring 30 min at 80 °C, the solvent was removed under reduced pressure. The reaction mixture was neutralized with sat. sodium bicarbonate solution and extracted with 15 ethyl acetate three times. The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was re-crystallized from ethyl acetate to give the title compound (12.5 g, 84%). MS m / z: 497.3 [M+1p. Step 3. 6-[2-(6-Amino-3-pyridvl)ethvnvn-2-[1 H-benzimidazol-2-yl~[5-fluoro~2~ 20 (methoxymethoxy)-phenyllmethvnisoindolin-l-one A mixture of 2-[1 H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-bromo-isoindolin-1-one (0.150 g, 0.302 mmol), 5-ethynylpyridin-2-amine (0.071 g, 0.604 mmol), bis(triphenylphosphine)palladium(!l) dichloride (0.012 g, 0.017 mmol), copper(l) 25 iodide (0.006 g, 0.030 mmol), and TEA / DMF (3 mL, 1 / 1) was degassed under nitrogen twice. The reaction mixture was heated at 100 °C overnight. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate twice. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by C18 column 30 chromatography eluting with 5-100% ACN / water containing 0.1% formic acid to give the title compound (66 g, 41%). MS m / z: 534.2 [M+1]+. 2026234102   18 Sep 2026 Step 4. 6-r2-(6-Amino-3-pyridyl)ethynyl]-2-ri H-benzimidazol-2-yl-(5-fluoro-2-hydroxv-phenyl)methyllisoindolin-1-one (Compound 012) To a solution of 6-[2-(6-amino-3-pyndyi)ethynyij-2-[1H-benzimidazol-2-yi-[5-fluoro-2- 5 (methoxymethoxy)phenyl]methyl]isoindolin-1-one (0.066 g, 0.123 mmol) in dichloromethane (2.6 mL) was added HCI in dioxane (4 M, 0.305 mL, 1.22 mmol). After stirring 2 h at room temperature, the solvent was removed under reduced pressure. The crude product was purified by reverse phase HPLC eluting with 0-100% ACN / water containing 10 mM ammonium acetate to give the title compound (6 mg, 10%). 1H NMR (400 MHz, DMSO-de) 6: 10   8.16 (s, 1H), 7.68-7.78 (m, 2H). 7.59-7.64 (m, 1H). 7.44-7.56 (m, 3H), 7.11-7.19 (m, 2H), 7.00-7.09 (m, 1H), 6.77-6.97 (m, 3H), 6.43-6.48 (m, 3H) 4.70-4.86 (m, 1H), 4.20-4.36 (m, 1H); MS m / z: 490.2 [M+1]+. The following compounds were prepared by a similar method to Example 4 from 2 15 [1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-bromo-isoindolin-1-one and the corresponding acetylene starting materials: Structure / Name 2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-pheny!)methy!]-6-[3-(1,1-dioxo-1,4-thiazinan-4-yl)prop-1 -ynyl]isoindolin-1-one;hydrochloride m / z [M+1? 545.2 1H NMR (DMSO-ds) 6 10.39 (brs. 1H). 7.83-7.89 (m, 1H), 7.67-7.82 (m, 4H), 7.50-7.58 (m, 2H), 7.17-7.26 (m, 2H), 7.13 (s, 1H), 6.997.08 (m, 1H), 4.78 (d. 1H), 4.29 (d, 1H), 4.09 (S, 2H), 3.30-3.53 (m, 8H) 2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[2-(1-methyl-4-piperidyl)-ethynyi]isoindoiin-1-one;hydrochioride 495.2 7.49-7.64 (m, 5H), 7.14-7.19 (m, 2H). 7.02-7.08 (m, 1H), 6.97 (s, 1H), 6.87-6.92 (m, 1H). 6.75-6.81 (m, 1H), 4.78 (d, 1H), 4.20 (d, 1H), 2.582.66 (m, 3H), 2.16 (s, 3H), 2.02-2.13 (m, 2H), 1.83-1.90 (m, 2H). 1.59-1.69 (m, 2H) 2026234102   18 Sep 2026 Example 5: Preparation of 2-[ 1H-benzimidazol-2-yl-(5dluoro-2-hvdroxy-phenyl)methvn-7-fluoro-6-[4-(1-methyl-4-pipendyl)phenylJisoindolin-1-one;.hydrochloride (Compound 032) Scheme 4. Step 1: 3-Chloro-2-fluoro-6-methyl-berizoic acid To a solution of 1-chloro-2-fluoro-4-methyl-benzene (10.0 g, 69.1 mmol) in THF (100 mL) at -70 °C was added dropwise LDA (2 M in THF, 36.2 mL, 72.5 mmol). .After stirring at - 10   70 °C for 0.5 h, CO2 (9.10 g) was added to the reaction mixture and stirred at the same temperature for 1 h. After warming to room temperature, the solvent was removed under reduced pressure. Water was added to the residue and the mixture was washed with ethyl acetate twice. The aqueous phase was adjusted to pH 1 by HC! (1 M) and extracted with ethyl acetate three times. The combined organic extracts were washed with brine, dried over 15 sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (3.5 g, 27%). 1H NMR (400 MHz, DMSO-d6) 6: 13.38 (brs, 1H), 7.51-7.58 (m, 1H), 7.16 (d, 1H), 2.33 (s, 3H). Step 2: Methyl 3-chioro-2-fluoro-6-methyl-benzoate 20 2026234102   18 Sep 2026 To a solution of 3-chloro-2-fluoro-6-methyl-benzoic add (3.50 g, 18.5 mmol) in dichloromethane (50 mL) was added oxalyl chloride (4.69 g, 37.0 mmol) at 0 °C. After stirring at the same temperature for 0.5 h, the solvent was removed under reduced pressure. The residue was dissolved in methanol (20 mL) and was added triethylamine (7.47 g, 74.0 5 mmol). After stirring at room temperature for 1 h, the solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography eluting with 3% ethyl acetate in petroleum ether to give the title compound (1.9 g: 51%). 1H NMR (400 MHz, DMSO-d6) 6: 7.60-7.66 (m, 1H), 7.20 (d, 1H), 3.90 (s, 3H), 2.32 (s, 3H). 10 Step 3: Methyl 6-(bromomethyl)-3-chloro-2"fluoro-benzoate To a solution of methyl 3-chloro-2-fluoro-6-methyl-benzoate (1.90 g, 9.37 mmol) in carbon tetrachloride (20 mL) was added N-bromosuccinimide (1.66 g, 9.37 mmol) and benzoyl peroxide (0.452 g, 1.87 mmol). After stirring at 80 °C for 12 h, the solvent was 15 removed under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 1% ethyl acetate in petroleum ether to give the title compound (0.9 g, 34%). 1H NMR (400 MHz, CDCh) 5: 7.45-7.52 (m, 1H), 7.19 (d, 1H), 4.62 (s, 2H), 4.02 (s, 3H). 20 Step 4: Ethyl 2-(6-chloro-7-fluoro-1-oxo-isoindolin-2-yl)-2-[5-fluoro-2-(methoxymethoxy)-phenyHacetate To a solution of ethyl 2-amino-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetate (1.06 g, 4.14 mmol) in DMF (15 mL) was added DIPEA (1.23 g, 9.57 mmol). The reaction mixture 25 was stirred at room temperature for 5 min before methyl 6-(bromomethyl)-3-chloro-2-fluoro-benzoate (0.900 g, 3.19 mmol) was added. The reaction mixture was heated at 100 °C for 1 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate three times. The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. 30 The crude product was purified by silica gel column chromatography eluting with 33% ethyl acetate in petroleum ether to give the title compound (800 mg, 59%). MS m / z: 426.1 [M+1]+. 2026234102   18 Sep 2026 Step 5: 2-(6-Chloro-7-fluoro-1-oxo-isoindolin-2-yl)-2-[5-fluoro-2- (methoxymethoxy)phenynacetic acid 5           To a solution of ethyl 2-(6-chloro-7-fluoro-1-oxo-isoindolin-2-yl)-2-[5-fluoro-2- (methoxy-methoxy)phenyljacetate (0.800 g, 1.87 mmol) in THF / MeOH / water (15 mL. 1 / 1 / 1) was added lithium hydroxide monohydrate (0.314 g, 7.48 mmol). After stirring at room temperature for 1 h, the solvent was removed under reduced pressure and the resulting residue was adjusted to pH 3 by HCI (1 M). The resulting solid was collected by filtration and 10 washed with water to give the title compound (750 mg, quant.). MS m / z: 398.0 [M+1]+. Step 6: 2-MH-Benzimidazol-2-vl-[5-fluoro-2-(methoxvmethoxy)phenyl]methyll-6-chlorc>-7-fluoro-isoindolin-1-one 15           To a solution of 2-(6-chloro-7-fluoro-1-oxo4soindo!in-2-yl)-2-[5-fluoro-2-(methoxy- methoxy)phenyl]acetic acid (0.750 g, 1.88 mmol), 1,2-diaminobenzene ¢0.213 g, 1.37 mmol) and HATU (1.07 g, 2.82 mmol) in DMF (10 mL) was added DI PEA (0.728 g, 5.64 mmol). After stirring at room temperature overnight, the reaction mixture was partitioned between water and ethyl acetate. The aqueous phase was extracted with additional ethyl acetate 20 three times. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the amide intermediate (800 mg, 87%) which was used in the next reaction without further purification. MS m / z: 488.3 [M+1]+. To the above amide intermediate was added acetic acid (15 mL). After stirring at 80 25 °C for 0.5 h, the solvent was removed under reduced pressure. The reaction mixture was neutralized with sat. sodium bicarbonate solution and extracted with ethyl acetate three times. The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was re-crystallized from ethyl acetate to give the title compound (550 mg, 72%). MS m / z: 470.Q [M+1]T 2026234102   18 Sep 2026 Step 7: 2-MH-Benz!m!dazol-2-vl-f5-fluoro-2-(methoxvmethoxv)phenyl'|methvn-7-fluoro-6-[,4- (1~methyl-4-piperidvl)phenyHiso!ndolin-1-one 5          A mixture of 2-[1 H-benzim!dazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6- chloro-7-fluoro-isoindolin-1-one (0.550 g, 1.17 mmol), 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3.2-dioxaboro!an-2-y!)phenyl]piperidine (0.385 g, 1.28 mmol), sodium carbonate (0.487 g, 3.51 mmol), SPhos (0.192 g, 0.468 mmol), Pd2(dba)3 (0.321 g, 0.351 mmol) and dioxane (10 mL) was degassed with nitrogen twice. The reaction mixture was heated at 105 °C for 4 10 h. After cooling to room temperature, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 10% methanol in dichloromethane to give the title compound (120 mg, 17%). MS m / z: 609.3 [M+1]+. Step 8: 2-[1H-Benzimidazol-2-vl-(5-fluoro-2-hvdroxv-phenyl)methyl1-7-fluoro-6-[4-(1-methyl- 15 4-piperidyl)phenyllisoindolin-1-one;hydrochloride (Compound 032) To a solution of 2-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methy!]-7-fluoro-6-[4-(1-methyl-4-piperidyl)phenyl]iso!ndolin-1-one (0.120 g, 0.197 mmol) in dichloromethane (5 mL) was added HCI in dioxane (4 M, 0.985 mL, 3.94 mmol). After stirring 20   1 h at roam temperature, the solvent was removed under reduced pressure. Diethyl ether was added to the residue and the resulting solid was isolated via filtration to give the title compound (112 mg, 94%). 1H NMR (400 MHz, DMSO-d6) 6: 10.51 (br s, 1H), 10.29 (br s, 1H), 7.74-7.82 (m, 1H), 7.65-7.73 (m, 2H), 7.49-7.59 (m, 3H), 7.35-7.49 (m, 4H), 6.97-7.22 (m, 4H), 4.80 (d, 1H). 4.25 (d, 1H), 3.48-3.51 (m, 2H), 3.03-3.13 (m, 2H), 2.85-2.93 (m, 1H), 25   2.73-2.81 (m, 3H), 1.91-2.15 (m, 4H); MS m / z: 565.3 [M+1]+. 2026234102   18 Sep 2026 Example 6: Preparation of 2-( 1H-benzimidazol-2-v!-(5-fluoro-2-methoxy-phenyl)methyll-7-fluoro-6-[4-( 1-methyl-4-piperidyl)phenyr!indazole (035) and 2-( 1 H-benzimidazol-2-y!-(7-fluoro-6-(4-(1-methyl-4-piperidyl)phenyl]indazol-2-yl]methyl]-4-fluoro~phenol; hydrochloride (034) Scheme 5. Step 1. Methyl 2-(5-fluoro-2-methoxv-phenyl)acetate o Mecr\ MeO 1 To a solution of 2-(5-fluoro-2-methoxy-phenyl)acetic acid (0.900 g, 4.88 mmol) in 10 methanol (20 mL) was added sulfuric acid (0.983 ml, 18.5 mmol). After stirring at 70 °C for 2 h, the solvent was removed under reduced pressure and the resulting residue was diluted with ethyl acetate and washed with sat. sodium bicarbonate three times, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (900 mg, 93%). NMR (400 MHz, CDCh) 5: 7.01-6.90 (m, 2H), 6.85-6.77 (m, 1H), 3.81 (s, 3H), 15   3.72 (s, 3H), 3.66-3.61 (m, 2H). 2026234102   18 Sep 2026 MeO MeO To a solution of methyl 2-(5-fluoro-2-methoxy-phenyl)acetate (0.900 g, 5.44 mmol) in carbon tetrachloride (20 mL) was added N-bromosuccinimide (0.968 g, 5.44 mmol) and 5 benzoyl peroxide (0.109 g, 0.454 mmol). After stirring at 80 °C for 16 h, the solvent was removed under reduced pressure. The crude compound was purified by silica gel column chromatography eluting with 12% ethyl acetate in petroleum ether to give the title compound (1.2 g, 96%). 1H NMR (400 MHz, CDCh) 6: 7.42 (dd, 1H), 6.98-7.07 (m, 1H), 6.83 (dd, 1H), 5.90-5.80 (m, 1H), 3.87 (s, 3H), 3.82 (s, 3H). 0 Step 3. 2-(6-Bromo-7-fiuoro-indazo!-2-vl)-2-(5-f!uoro-2-methoxv-phenyl)acetic acid To a solution of methyl 2-bromo-2"(5”fluoro-2-methoxy-phenyl)acetate (0.579 g, 2.09 mmol) and 6-bromo-7-fluoro-1H-indazole (0.450 g, 2.09 mmol) in acetonitrile (15 mL) was 15 added cesium carbonate (0.814 g, 2.50 mmol). After stirring at 0 °C for 30 min and then room temperature for 1 h, the reaction mixture was partitioned between water and ethyl acetate. The aqueous phase was extracted with additional ethyl acetate three times. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the ester intermediate. MS m / z: 412.9 [M+1]+. 20          To a solution of the above intermediate in THF / MeOH / water (15 mL, 1 / 1 / 1) was added lithium hydroxide monohydrate (0.336 g, 8.01 mmol). After stirring at room temperature for 1 h, the solvent was removed under reduced pressure and the resulting residue was partitioned between water and ethyl acetate. The aqueous phase was adjusted to pH 3 with 5% citric acid and extracted with ethyl acetate three times. The combined 25 organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 35% ethyl acetate in petroleum ether to give the title compound (280 mg, 26%). 1H NMR (400 MHz, DMSO-d6) & 8.57 (d, 1H), 7.53 (d, 1H), 7.38-7.11 (m, 4H), 6.82 (s, 1H), 3.82 (s, 3H). MS m / z: 398.8 [M+1]+. 30 2026234102   18 Sep 2026 indazole To a solution of 2-(6-bromo-7-f!uoro-indazol-2-yl)-2-(5-fluoro-2-methoxy-phenyl)acetic 5 acid (0.280 g, 0.704 mmol), 1,2-diaminobenzene (0.091 g, 0.844 mmol) and TBTU (0.270 g, 0.844 mmol) in DMF (10 mL) was added DIPEA (0.091 g, 0.704 mmol). After stirring at room temperature for 16 h, the reaction mixture was partitioned between sat. sodium chloride and ethyl acetate. The aqueous phase was extracted with ethyl acetate three times, and the combined organic extracts were dried over sodium sulfate, filtered and concentrated under 10 reduced pressure. The crude product was purified by silica gel column chromatography eluting with 35% ethyl acetate in petroleum ether to give the amide intermediate. MS m / z: 488.8 [M+1]+. To the above amide intermediate was added acetic acid (15 mL). After stirring at 80 °C for 30 min, the solvent was removed under reduced pressure. The reaction mixture was 15 diluted with ethyl acetate and washed three times with sat. sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (330 mg, 67%). 1H NMR (400 MHz, CDCI3) 5: 10.75 (br s, 1H), 8.20 (d, 1H), 7.67 (s, 1H), 7.56 (s, 1H), 7.46-7.36 (m, 1H), 7.29-7.20 (m, 2H), 7.07 (dd, 1H), 7.00 (dd, 1H), 6.90-6.99 (m, 1H), 6.75 (dd, 1H), 6.64 (s, 1H), 3.69 (s, 3H); MS m / z: 470.8 [M+1]+. 20 Step 5. 2-[1H-Benzimidazoi-2-vl-(5-fiuoro-2-methoxy-phenyi)methyll-r-fluoro-6-[4-(1-methyl- 4-piperidyl)phenyllindazole (Compound 035) A mixture of 2-[1 H-benzimidazol-2~yi-(5~fluoro-2-methoxy-phenyl)methyl]~6-bromo-7- 25 fluoro-indazole (0.200 g, 0.426 mmol), 1-methyl-4-[4-(4,4,5,5-tetramethy!-1,3,2-dioxaboro!an-2-yl)phenyl]piperidine (0.140 g, 0.468 mmol), sodium carbonate (0.146 g, 1.06 mmol), [1,1' bis-(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane (0.047 g, 0.064 mmol) and dioxane / water (8 mL, 4 / 1) was degassed with nitrogen twice. The reaction mixture was heated at 100 °C for 20 h. After cooling to room temperature, the 2026234102   18 Sep 2026 reaction mixture was poured into water and extracted with ethyl acetate three times. The combined organic extracts were washed with brine, dried over sodium suifate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 6% methanol in dichloromethane to give the title compound 5   (150 mg, 62%). 1H NMR (400 MHz, DMSO-d6) 6: 12.67 (s, 1H), 8.58 (d, 1H), 7.60-7.65 (m, 3H), 7.49-7.57 (m, 3H), 7.37 (d, 2H), 7.14-7.33 (m, 5H), 6.98 (m, 1H), 3.80 (s, 3H), 2.99-3.14 (m, 2H), 2.56-2.65 (m, 1H), 2.19-2.42 (m, 5H), 1.68-1.91 (m, 4H); MS m / z: 564.3 [M+1]+. Step 6. 2-[1H-Benzimidazol-2-vl-|7-fluoro-6-f4-(1-methvl-4-piper!dyl)phenyllindazol-2- 10 yl1methyll-4-fiuoro-phenoi;hydrochloride (Compound 034) To a solution of 2-[1H-benzimidazol-2-yl-(5-fluoro-2-methoxy-phenyl)methyl]-7-fluoro-6-[4-(1-methyl-4-piperidyl)phenyl]indazole (0.150 g, 0.266 mmol) in dichloromethane (8 mL) at 15   0 °C was added boron tribromide (0.666 g, 2.66 mmol). After stirring at the room temperature for 2 h, the reaction mixture was diluted with dichloromethane and poured into ice-water. The aqueous phase was extracted with dichloromethane three times. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase 20 HPLC eluting with 0-100% ACN / water (0.05% HCI modifier) to give the title compound (25 mg, 30%). NMR (400 MHz, DMSO-cf6) 5: 10.10-10.47 (m, 2H), 8.65 (d, 1H), 7.51-7.72 (m, 6H), 7.29-7.42 (m, 4H), 7.11-7.23 (m, 2H), 6.99 (m, 1H), 6.90 (m, 1H), 3.48-3.57 (m, 2H), 3.00-3.14 (m, 2H), 2.76-2.93 (m, 4H), 1.92-2.10 (m, 4H); MS m / z: 550.3 [M+lf. 25 The following examples were prepared by a similar method to Example 6 from methyl 2- bromo-2-(5-fluoro-2-methoxyphenyl)acetate or methyl 2-bromo-2-phenylacetate and the corresponding bicyclic starting materials: No. Structure / Name m / z [M+1]+ !H NMR (DMSO-ds) 6 Starting materials 063 Qt on kA 2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-7-[4-(1- 559.5 12.79 (brs, 1H), 10.02 (brs, 1H), 8.44 (d, 1H), 8.01-8.09 (m, 1H), 7.75 (d, 1H), 7.657.71 (m, 3H), 7.41-7.62 (m, 2H), 7.37 (d, 2H), 7.12-7.30 (m, 3H), 7.03-7.11 (m, 1H), 6.82-6.93 (m, 1H), 6.63-6.71 HN     .A 2026234102   18 Sep 2026 methyl-4- piperidyl)phenyl]isoquinolin-1-one (m, 2H), 2.91 (d, 2H), 2.532.58 (m, 1H), 2.23 (s, 3H), 1.98-2.12 (m, 2H), 1.65-1.81 (m, 4H) 082 rXXHZyXD'1” HO X (      2HCI 241H-benzimidazo!-2-yi-(5-fiuoro-2-hydroxy-phenyi)methyi]-7-methy!-6-[4-(1 -methyl-4- piperidyOphenylJisoindolin-1-onejdihydrochloride 561.2 10.68 (br s, 1H), 10.35 (brs, 1H), 7.67-7.78 (m, 2H), 7.427.56 (m, 4H), 7.28-7.40 (m, 4H), 7.07-7.26 (m, 3H), 6.967.04 (m, 1H), 4.70 (d, 1H), 4.17 (d, 1H), 3.50 (d, 2H), 3.00-3.17 (m, 2H). 2.84-2.92 (m, 1H), 2.77 (d, 3H), 2.57 (s, 3H), 1.91-2.16 (m, 4H) 'Br 064 Ayt O «=' 2-(1 H-benzimidazol-2- yl(pheny!)methy!]-8-fluoro-6-[4-(1- methyk4-piperidyl)pheny0- isoquinoiin-1-one;dihydrochloride 543.1 10.81 (brs, 1H), 7.80-7.87 (m, 3H), 7.60-7.72 (m, 4H), 7.45-7.52 (m, 6H), 7.33-7.44 (m, 4H), 6.78 (d, 1H), 3.48 (d, 2H), 3.01-3.13 (m, 2H), 2.82-2.90 (m, 1H), 2.76 (d, 3H), 1.95-2.14 (m, 4H) X7 069 yyy XX “ 2-n H-benzimidazo!-2-yl-(5-f!uoro-2-hydroxy-phenyl)methyl]-644-(1-methyl-4-piperidyl)pheny!J- isoquinoiin-1-one;dihydrochloride 559.6 :0.54 (brs, 1H), 10.33 (brs, 1H), 8.28 (d, 1H), 8.01 (d, 1H), 7.82-7.89 (m, 1H), 7.80 (d, 2H), 7.59-7.70 (m, 3H), 7.35-7.48 (m, 4H), 7.33 (d, 1H), 7.12-7.23 (m, 1H), 6.897.05 (m, 2H), 6.79 (d, 1H), 2.98-3.22 (m, 4H), 2.72-2.94 (m, 4H), 1.97-2.11 (m, 4H) hOO ^Br 070 Vr^H xvx XX ■ 2-(1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-8-ffuoro-6-(4-(1-methyl-4-piperidyl)phenyi]-isoquinoiin-1-one;hydroch!oride 577.1 10.58 (brs, 1H), 10.35 (brs, 1H), 7.81-7.91 (m, 3H), 7.607.71 (m, 3H), 7.55 (s, 1H), 7.28-7.44 (m, 5H), 7.12-7.23 (m, 1H), 6.88-7.04 (m, 2H), 6.77 (Ci, 1H), 3.17-3.29 (m, 2H), 2.98-3.14 (m, 2H), 2.832.91 (m, 1H), 2.77 (d, 3H), 1.90-2.09 (m, 4H) 1 J IT 071 Qr nr 0 f kX 2-((1 H-benzo[d]imidazo!-2- yl)(phenyi)methyi)-8-fiuoro-7-(4-(1- 9.44 (brs, 1H), 7.83 (m, 1H), 7.64 (s, 1H) 7.59-7.55 (m, 5H), 7.47-7.42 (m, 4H), 7.38 (d, 2H), 7.34 (d, 2H), 7.25 (m, 2H), 6.71 (m, 1H), 3.60 (m, 2H), 3.10 (m,2H), 2.88 O F '"'Br 2026234102   18 Sep 2026 methyl piperidin-4- yl)phenyl) isoquinolin-1 (2H)-one (m, 1H), 2.83 (d, 3H), 2.07 (m, 2H) 1.87 (m, 2H) 072 HO \2Lr- hci Ln 2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-8-fluoro-7-(4-(1-methyl-4-piperidyl)phenyi]-isoquinolin-1-one;hydrochloride 577.5 9.98-10.27 (m, 2H), 7.787.87 (m, 1H), 7.52-7.62 (m, 6H), 7.37 (d, 2H). 7.22-7.32 (m, 3H), 7.10-7.20 (m, 1H), 7.07-7.19 (m, 1H), 6.67-6.83 (m, 2H), 3.15-3.22 (m, 2H), 3.03-3.10 (m, 2H), 2.75-2.90 (m, 4H), 1.92-2.08 (m, 4H) HfC jlXl rrBr 073 / =, #~NH HO i O XX 2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyi)methyi]-7-fIuoro-6-(4-(1 -methyl-4-piperidyl)phenyl]-isoquinolin-1-one 577.2 12.79 (brs, 1H), 10.08 (brs, 1H). 8.21 (s, 1H), 7.97 (d, 1H). 7.88 (d, 1H), 7.55-7.68 (m, 4H), 7.41 (d, 2H), 7.27 (d, 1H), 7.16-7.23 (m, 2H), 7.07-7.15 (m, 1H), 6.88-6.94 (m, 1H), 6.71 (d, 1H), 6.626.68 (m, 1H), 2.94 (d, 2H), 2.54-2.59 (m, 1H), 2.26 (s, 3H), 2.04-2.12 (m, 2H), 1.671.85 (m, 4H) .JC h i 0 092 Qr .CXXXO-h"xX       2hc> 2-[1H-benzimidazol-2-yl-[7-chloro- 6-(4-(1 -methyl-4-piperidyl)phenyl]-indazol-2-yl]methyl]-4-fluoro- phenol;dihydrochloride 566.4 ’H NMR (methanol-^) 6: 8.62 (s, 1H), 7.90 (s, 1H), 7.72-7.80 (m, 3H), 7.56-7.62 (m, 2H), 7.50 (d, 2H), 7.39 (d, 2H), 7.12-7.19 (m, 2H), 6.94-7.01 (m, 1H), 6.80-6.88 (m, 1H), 3.58-3.69 (m, 2H), 3.14-3.25 (m, 2H), 2.95-3.04 (m, 1H), 2.93 (s, 3H), 2.132.24 (m, 2H), 1.97-2.11 (m, 2H) 074 CXH H^rco . Xaf 2hci XX 3-(1H-benzimidazoi-2-yi-(5-fiuoro-2-hydroxy-phenyl)methyl]-5-ethyl-6-(4-(1 -methyl-4-piperidyl)phenyl]-quinazolin-4-one;dihydrochloride 588.4 ’H NMR (methanol-c / 4) 6: 8.53-8.66 (m, 1H), 7.76-7.83 (m, 2H). 7.62-7.74 (m, 4H), 7.58 (s, 1H), 7.42 (d, 2H), 7.22-7.37 (m, 4H), 7.01-7.09 (m, 1H), 3.60-3.72 (m, 2H), 3.13-3.27 (m, 4H). 2.89-3.06 (m, 4H), 2.00-2.28 (m, 4H), 1.00 (t, 3H) HfT 1 JX Tu! Compounds 067 and 068: Preparation of 2-RR)-1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy- benzimidazoi-2-yl-(5-fluoro-2-hydroxy-phenyl)methyll-6-[4-(1-methyl-4- 5 piperidyi)pheny!]isoquinoiin-1-one 2026234102   18 Sep 2026 2-[(rac)-1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[4-(1-methyl-4-piperidyl)-phenyl]isoquinolin-1-one;dihydrochloride (069, 0.050 g, 0.079 mmol) was purified by prep SFC with a Chiral Technologies Chiraipak IG (5micron 250x10mm) column @ 40 °C eluting 5 with 55% (0.3% TEA in MeOH) / 45% CO2 at 10 MPa BPR to separate enantiomers. Absolute configuration of the chiral center for each isolated enantiomer is unknown. First eluting peak (067) (17.0 mg, 38% yield, 98.5:1.5 er); [a]2%-12.9 (c = 0.31, MeOH); 1H NMR (DMSO-cfe) 6: 12.6-12.9 (m, 1H), 9.9-10.2 (m, 1H), 8.28 (d, 1H), 7.94 (s, 1H), 7.82 (dd. 1H), 7.74 (d, 2H), 7.65 (s, 1H), 7.54 (br s, 2H), 7.39 (d, 2H), 7.29 (d, 1H), 7.19 (br dd, 2H), 7.1 (m, 10    1H), 6.89 (dd, 1H), 6.6-6.7 (m, 2H), 2.88 (d, 2H), 2.5-2.6 (m, 1H), 2.20 (s, 3H), 1.9-2.1 (m, 2H), 1.6-1.8 (m, 4H); MS m / z: 559.3 [M+1]+. Second eluting peak (068) (14.1 mg, 31% yield, 1.5:98.5 er); [a]2%+14.1 (c = 0.64, MeOH); 1H NMR (DMSO-ds) 6: 12.6-12.9 (m, 1H), 9.910.2 (m, 1H), 8.28 (d, 1H), 7.94 (s, 1H), 7.82 (dd, 1H), 7.74 (d, 2H), 7.65 (s, 1H), 7.54 (br s, 2H), 7.39 (d, 2H), 7.29 (d, 1H), 7.19 (br dd, 2H), 7.1 (m, 1H), 6.89 (dd, 1H), 6.6-6.7 (m, 2H), 15   2.88 (d, 2H), 2.5-2.6 (m, 1H), 2.20 (s, 3H), 1.9-2.1 (m, 2H), 1.6-1.8 (m, 4H); MS m / z: 559.3 [M+1K. Compounds 065 and 066: Preparation of 2-[(R)-1H-benzimidazol-2-vl-(5-fluoro-2-hydroxv-phenvl)methvll-8-fiuoro-6-[4-(1-methvl-4-piperidvS)phenvllisoquinolin-1-one and 2-[(S)-1H-20 benz!m!dazol-2-vl-(5-fluoro-2-hvdroxy-phenvl)methyn-8-fluoro-6-[4-(1-methyl-4-piperidyl)phenyllisoquinolin-1-one 2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-8-fluoro-6-[4-(1-rnethyl-4-piperidyl)phenyl]isoquinolin-1 -one;hydrochloride (070, 0.012 g, 0.020 mmol) was purified by 25 prep SFC with Phenomenex Lux Cellulose-4 column eluting with 55% (0.3% TEA in MeOH) / 45% CO2 at 10 MPa to separate enantiomers. Absolute configuration of the chiral center for each isolated enantiomer is unknown. First eluting peak (065) (3 mg, 27% yield, 100:0 er); [a]2%-13.3 (c — 0.37, MeOH); jH NMR (DMSO-d6) 5: 12.69 (br s, 1H), 9.95 (br s, 1H), 7.68- 2026234102   18 Sep 2026 7.73 (m, 3H), 7.37-7.58 (m, 4H), 7.32 (d, 2H), 7.22 (d, 1H) 7.08-7.16 (m, 2H), 6.99-7.07 (m, 1H), 6.80-6.86 (m, 1H), 6.56-6.63 (m, 2H), 2.81 (d, 2H), 2.45-2.50 (m, 1H), 2.13 (s, 3H), 1.85-1.96 (m, 2H), 1.57-1.73 (m, 4H); MS m / z: 577.3 [M+1]+. Second eluting peak (066) (4 mg, 36% yield, 100:0 er); [a]2CD+14.8 (c = 0.27, MeOH); 1H NMR (DMSO-ds) 3: 12.69 (brs, 5    1H), 9.98 (brs, 1H), 7.68-7.73 (m, 3H), 7.38-7.58 (m, 4H), 7.32 (d, 2H), 7.22 (d, 1H), 7.08 7.18 (m, 2H), 6.99-7.06 (m, 1H), 6.80-6.86 (m, 1H), 6.56-6.63 (m, 2H), 2.81 (d, 2H), 2.45 2.52 (m, 1H), 2.13(5, 3H), 1.83-1.96 (m, 2H), 1.57-1.73 (m, 4H); MS m / z: 577.3 [M+1]+. Exampie r. Preparation of 3-: 1H-benzim!dazol-2-yl~(5-fluoro-2-hydroxy-phenvl)methyll-6-l'4- 10   (1-methyl-4-piperidyl)phenyllquinazolin-4-one; hydrochloride (Compound 006) Scheme 6. 006 Step 1. Ethyl 2-[(2-amino-5-bromo-benzoyl)aminol-2-[5-fluoro-2-(methoxymethoxy)phenyll- acetate To a solution of ethyl 2-amino-2-[5-fluoro-2-(methoxymethoxy)phenyi]acetate (10.0 g, 38.8 mmol) and 6-bromo-2,4-dihydro-1H-3,1-benzoxazine-2,4-dione (10.3 g, 42.6 mmol) in THF (80 mL) was added triethylamine (7.85 g, 77.6 mmol). After stirring at 40 °C for 3 h, the solvent was removed under reduced pressure. The crude product was purified by silica gel 2026234102   18 Sep 2026 column chromatography eluting with 25% ethyl acetate in petroleum ether to give the title compound (5 g, 28%). 1H NMR (400 MHz, DMSO-ofe) 6: 8.95 (d, 1H), 7.77 (d, 1H), 7.29 (dd, 1H), 7.15-7.22 (m, 3H), 6.69 (d, 1H), 6.57 (s, 2H), 5.99 (d, 1H), 5.19-5.27 (m, 2H), 4.09-4.18 (m, 2H), 3.38 (s, 3H), 1.14-1.18 (m, 3H). Step 2. Ethyl 2-(6-bromo-4-oxo-quinazolin-3-yl)-2-[5-fluoro-2-(methoxymethoxy)phenyllacetate A solution of ethyl 2-[(2-amino-5-bromo-benzoy!)amino]-2-[5-fluoro-2- 10 (methoxymethoxy)-phenyl]acetate (5.25 g, 11.5 mmol) in triethoxy methane (20 mL) was stirred at 110 °C for 22 h. After cooling to room temperature, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 10-33% ethyl acetate in petroleum ether to give the title compound (2.2 g, 41%). 1H NMR (400 MHz, DMSO-d6) 5: 8.25-8.29 (m, 2H), 8.02 (dd, 1H), 7.66 (d, 1H), 7.26-7.37 15   (m, 2H), 7.14-7.21 (m, 1H), 6.68 (s, 1H), 5.17-5.25 (m, 2H), 4.22-4.30 (m, 2H), 3.26 (s, 3H) 1.15-1.25 (m, 3H). Step 3. Ethyl 2-[5-fluoro-2-(methoxvmethoxy)phenvll-2-[6-[4-(1-methvl-4-piperidyl)phenvn-4- oxo-quinazolin-3-yllacetate A mixture of ethyl 2-(6-bromo-4-oxo-quinazolin-3-yl)-2-[5-fluoro-2-(methoxymethoxy)-phenyljacetate (2.2 g, 4.72 mmol), 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine (1.98 g, 6.60 mmol), potassium carbonate (1.96 g, 14.1 mmol) and dioxane / water (20 mL, 4 / 1) was degassed with nitrogen gas. [1,1'-Bis(diphenylphosphino)- 25 ferrocene]dichioropalladium(il) complex with dichloromethane (0.690 g, 0.944 mmol) was added and then the reaction was degassed under nitrogen once more. The reaction mixture was heated at 105 °C for 3 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate three times. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under 30 reduced pressure. The crude product was purified by silica gel column chromatography 2026234102   18 Sep 2026 eluting with 0-15% methanol in dichloromethane to give the title compound (1.8 g, 68%). MS m / z: 560.4 [M+1]+. Step 4. 2-[5-Fluoro-2-(methoxymethoxy)phenyll-2-f6-[4-(1-methyi-4-p!peridyl)phenyi1-4-oxo- 5 quinazolin-3-ynacetic acid To a solution of ethyl 2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-[6-[4-(1-methy!-4-piperidyl)-phenyl]-4-oxo-quinazolin-3-yl]acetate (1.80 g, 3.21 mmol) in THF / MeOH / water (30 mL, 1 / 1 / 1) was added lithium hydroxide monohydrate (0.404 g, 9.62 mmol). After stirring at 10 the room temperature for 3 h, the solvent was removed under reduced pressure and the resulting residue was adjusted to pH 3 by HCI (1 M). The resulting solid was collected by filtration and washed with water to give the title compound (1.5 g 88%). MS m / z: 532.1 w. 15 Step 5. 3-[1H-Benzimidazol-2-yl-[5-fiuoro-2-(methoxvmethoxy)phenynmethyll-6-[4-(1-methyi-4-piperidyl)phenyHqu!nazolin-4-one To a solution of 2-[5-fluoro-2-(methoxymethoxy)pheny!]-2-[6-[4-(1-methyl-4-piperidyl)-phenyl]-4-oxo-quinazolin-3-yl]acetic acid (0.900 g, 1.69 mmol), 1,2-diaminobenzene (0.218 20 g, 2.02 mmol) and HATU (0.962 g, 2.53 mmol) in DMF (10 mL) was added DIPEA (0.545 g, 4.22 mmol). After stirring at room temperature for 10 h, sat. sodium chloride was added to the reaction mixture. The resulting solid was collected by filtration and washed with water. The crude product was purified by silica gel column chromatography eluting with 0-10% methanol in dichloromethane to give the amide intermediate. MS m / z: 622.3 [M+1]+. 25          To the above amide intermediate was added acetic acid (8 mL). After stirring at 80 °C for 3 h, the solvent was removed under reduced pressure. The reaction mixture was neutralized with sat. sodium bicarbonate and extracted with ethyl acetate three times. The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was re-crystallized from ethyl acetate to give the title 30 compound (170 mg, 50%). MS m / z: 604.3 [M-Hf. 2026234102   18 Sep 2026 5          To a solution of 3-[1 H-benzimidazol-2-yH5-fluoro-2- (methoxymethoxy)phenyl]methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]quinazolin-4-one (0.120 g, 0.198 mmol) in dichloromethane (10 mL) was added HCI in dioxane (4 M, 0.495 mL, 1.98 mmol). After stirring 1 h at room temperature, the solvent was removed under reduced pressure. To the residue was added diethyl ether and the resulting solid was isolated via 10 filtration to give the title compound (160 mg, 91%). A NMR (400 MHz, DMSO-de) 5: 10.2810.48 (m, 2H), 8.38 (s, 1H), 8.29 (s, 1H), 8.22 (d, 1H), 7.75-7.86 (m, 3H), 7.68 (m, 2H), 7.59 (s, 1H), 7.34-7.45 (m, 4H), 7.20 (m, 1H), 6.96-7.06 (m, 2H), 3.47-3.54 (m, 2H), 3.00-3.15 (m, 2H), 2.75-2.92 (m, 4H), 1.92-2.13 (m, 4H); MS m / z. 560.3 [M+1]+. 15         The following compounds were prepared by a similar method to Example 7 from ethyl 2-(6-bromo-4-oxo-quinazolin-3-yl)-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetate and the corresponding boronate, or from ethyl 2-amino-2-phenylacetate: No. Structure / Name m / z [M+1F NMR (DMSO-ds) G 001 ft A ,-A      F AY, $ L Ji n-a I & 3-[1H-Benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[3-fiuoro-4-(1-methyl-4-piperidyl)phenyf]quinazolin-4-one; hydrochloride 578.3 10.32 (brs, 1H), 8.35-8.46 (m, 1H), 8.14-8.32 (m, 2H), 7.83 (d, 1H), 7.60-7.69 (m, 4H), 7.57 (s, 1H), 7.38-7.45 (m, 1H), 7.24-7.36 (m, 2H), 7.13-7.23 (m, 1H), 6.94-7.04 (m, 1H), 6.78-6.93 (m, 1H), 3.523.56 (m, 3H), 3.08-3.19 (m, 2H), 2.74-2.95 (m, 3H), 1.94-2.14 (m, 4H) 002 / ~\    n A.............%. 3-[1H-Benzimidazoi-2-yl(phenyl)methyl]-6-[4-(1-methyl-4-piperidyi)phenyl]quinazolin-4-one 526.3 9.44 (brs, 1H), 8.39-8.44 (m, 1H), 8.35 (s, 1H), 8.19 (d, 1H), 7.757.83 (m, 3H), 7.56-7.63 (m, 3H), 7.37-7.51 (m, 7H), 7.22-7.27 (m, 2H), 3.55 (d, 2H), 3.10 (d, 2H), 2.81-2.95 (m, 4H), 2.07 (d, 2H), 1.81-1.94 (m, 2H) 2026234102   18 Sep 2026 Example 8: Preparation of2-[1H-benzimidazol-2-vl(1,4.5,6-tetrahvdrocYClopenta[clpyrazol-3- vl)methvl]-6-[4-(1-methyl-4-pipendvl)plienvlJisoindolin- 1-one (Compound 033) Scheme 7. Step 1.2-(6-Bromo-1-oxo4soindoiin-2-yl)-2-41-(2-trimethylsilylethoxymethyl)-5,6-dihydro-4H- cyciopentaMpyrazoi-S-yllacetonitriie To a solution of 1-(2-trimethylsilylethoxymethy!)-5,6-dihydro-4H- 10 cyciopenta[c]pyrazoie-3-carbaldehyde (3.25 g, 11.5 mmol) in acetonitrile (30 mL) was added methyl 2-(aminomethyl)-5-bromobenzoate hydrochloride (3.25 g, 11.5 mmol), DIPEA (4.73 mL, 28.7 mmol) and trimethylsilyl cyanide (1.35 g, 13.7 mmol). The reaction mixture was heated at 75 °C for 16 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate three times. The combined organic extracts were 15 washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 1-20% ethyl acetate in petroleum ether to give the title compound (1.77 g, 32%). MS m / z: 488.2 [M+1]+. 20 2026234102   18 Sep 2026 cyc!openta[clpvrazok3-vl1acetic acid To a solution of 2-(6-bromo-1-oxo-isoindolin-2-yl)-2-[1-(2-trimethylsilylethoxymethyl)- 5 5,6-dihydro-4H-cyclopenta[c]pyrazQl-3-yl]acetonitrile (0.950 g, 1.94 mmol) in ethanol (10 mL) in an ice bath was added dropwise potassium hydroxide aqueous solution (2 M, 4.85 mL, 9.70 mmol). After stirring at 100 °C for 2 h, the reaction mixture was diluted with water and adjusted to pH 5 by acetic acid. The aqueous phase was extracted with ethyl acetate three times. The combined organic extracts were dried over sodium sulfate, filtered and 10 concentrated under reduced pressure. The crude product was purified by C18 column chromatography eluting with 0-70% ACN / water containing 10 mM ammonium acetate to give the title compound (420 mg, 43%). MS m / z\ 507.1 [M+1]+. Step 3: 2-[1H-Benzimidazol-2-yl-[1-(2-trimethylsilylethoxymethyl)-5,6-dihydro-4H- 15 cyclopenta|'clpyrazol-3-yllmethyn-6-bromo-isoindolin-1-one To a solution of 2-(6-bromo-1-oxo-isoindolin-2-yl)-2-[1-(2-trimethylsilylethoxymethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-3-yl]acetic acid (0.250 g, 0.494 mmol), 1,2-diaminobenzene (0.120 g, 1.11 mmol) and HATU (0.377 g, 0.987 mmol) in DMF (10 mL) 20 was added DIPEA (0.342 mL, 1.97 mmol). After stirring at room temperature for 5 h, sat. sodium chloride was added to the reaction mixture. The resulting solid was collected by filtration and washed with water to give the amide intermediate which was used in the next reaction without further purification. MS m / z: 597.2 [M+1p. To the above amide intermediate was added acetic acid (8 mL). After stirring at 80 °C 25 for 1 h, the solvent was removed under reduced pressure. The crude product was purified by C18 column chromatography eluting with 0-100% ACN / water containing 0.1% formic acid to give the title compound (220 mg, 58%). MS m / z: 579.2 [M+1 2026234102   18 Sep 2026 cyclopentafclpyrazol-3-vllmethyn-6-[4-(1-methvl-4-piperidyl)phenyllisoindolin-1-one A mixture of 2-[1H-benzimidazol-2-yl-[1-(2-trimethylsilylethoxymethyl)-5,6-dihydro- 5 4H-cyclopenta[c]pyrazol-3-yl]methyl]-6-bromo-isoindolin-1-one (0.100 g, 0.173 mmol), 1-methy!-4-[4-(4,4,5,5-tetramethyl-1l3.2-dioxaborolan-2-yl)phenyl]piperidine (0.060 g, 0.199 mmol), sodium carbonate (0.024 g, 0.222 mmol) in dioxane / water (4.5 mL, 7 / 2) was degassed with nitrogen twice. [1,T-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) complex with dichloro-methane (0.028 g, 0.035 mmol) was added and then the reaction was 10 degassed with nitrogen once more. The reaction mixture was heated at 105 °C for 1.5 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate three times. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by C18 column chromatography eluting with 0-100% ACN / water containing 15   0.1% formic acid to give the title compound (88 mg, 76%). MS m / z: 673.4 [M+1 ]+. methyl-4-piperidvi)phenynisoindolin-1-one (Compound 033) 20           To a solution of 2-(1 H-benzimidazol-2-yl-[1-(2-trimethylsilylethoxymethyl)-5,6-dihydro- 4H-cyclopenta[c]pyrazol-3-yl]methyl]-6-[4-(1-methyl-4-plperidyl)phenyl]isoindolin-1-one (0.087 g, 0.129 mmol) in water (0.464 mL) was added trifluoroacetic acid (2 mL). After stirring overnight at room temperature, the solvent was removed under reduced pressure. The crude product was purified by C18 column chromatography eluting with 0-100% 25 ACN / water containing 0.1% formic acid to give the title compound (44 mg, 63%). 1H NMR (400 MHz, DMSO-cfe) 6: 12.56 (br s, 1H), 8.20 (s, 1H), 7.87-7.98 (m, 2H), 7.64-7.75 (m, 3H), 7.47-7.62 (m, 2H), 7.37 (d, 2H), 7.12-7.24 (m, 2H), 6.85 (s, 1H), 4.92 (d, 1H), 4.35 (d, 1H), 2.98-3.05 (m, 2H), 2.54-2.66 (m, 3H), 2.27-2.38 (m, 5H), 2.14-2.27 (m, 3H), 1.89-2.01 (m, 1H), 1.69-1.86 (m, 4H); MS m / z: 543.4 [M+1F. 2026234102   18 Sep 2026 Compound 031 was prepared by a similar method to Exampie 8 from 2-(6-bromo-1-oxo-isoindoiin-2-yl)-2-[1-(2-trimethyisilylethoxymethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol- 3-yl]acetic acid and pyridine-2,3-diamine: No. Structure / Name m / z [M+1]+ NMR (DMSO-ds) 6 031 Qr hD.....OO..... cCx' 2-(1 Hdmidazo[4,5-b]pyridin-2-yl(1,4,5,6- tetrahydrocyclopenta[c]pyrazol-3-yl)methyl]-6-[4-(1 -methyl-4-p!peridyl)phenyl]!Soindo!in-1 -one 544.4 8.30-8.38 (m, 1H), 8.24 (s, 1H), 7.86-7.98 (m, 3H), 7.63-7.74 (m, 3H), 7.36 (d, 2H), 7.18-7.25 (m, 1H), 6.84 (S, 1H), 4.95 (d, 1H), 4.33 (d, 1H), 2.87-2.96 (m, 2H), 2.55-2.67 (m, 2H), 2.17-2.38 (m, 6H), 1.932.08 (m, 3H), 1.64-1.85 (m, 5H) Exampie 9: Preparation of 3-((1H-benzo[dl!midazol-2-vl)(5-fluoro-2-hvdroxyphenvl)methvl)-6- (4-(1-methylpiperidin~4~vl)phenyl)pvrido[3,2~d]pyrimidin-4(3H)~one 2,2.2-trifluoroacetate (Compound 009) 10 Scheme 8, 009 Step 1. Methyl 3-am!no-6-bromopicolinate 2026234102   18 Sep 2026 A mixture of methyl 3-aminopicolinate (650 mg, 4.27 mmol) in a solution of H2SO4 (207 mL, 4 mmol) and water (13 mL) was treated dropwise over one minute with a solution of bromine (200 mL, 4.27 mmol) in acetic acid (800 mL). The reaction mixture was stirred at room temperature for 15 minutes and basified with 10N NaOH to pH 6. The mixture was 5 extracted with EtOAc three times. The combined organic extracts were washed with saturated brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-60% EtOAc in hexane to give the title compound (600 mg, 61%). 1 H NMR (500 MHz, DMSO-cfe) d ppm 7.45 (d, 1H) 7.22 (d, 1H) 6.89 (s, 2 H) 3.82 (s, 3 H); MS m / z: 232.9 [M+1p. 0 Step 2. 3-Amino-6-bromopicoiinic acid A mixture of methyl 3-amino-6-bromopicolinate (600 mg, 2.6 mmol), lithium hydroxide monohydrate (600 mg 14.3 mmol) in THF (6 mL), MeOH (1.5 mL) and water (1.5 mL) was 15 stirred at room temperature for 45 minutes. The solvent was removed under reduced pressure. The residue was dissolved in water (20 mL) and treated with 2N HCI to pH 6. The white solid was collected by filtration, washed with cold water, and dried to give the title compound (400 mg, 71%). NMR (500 MHz, DMSO-d3) d ppm 7.19 (d, 1H) 7.43 (d, 1H); MS m / z: 218.9 [M+1]+. 20 Step 3. Ethyl 2-(3-amino-6-bromopicolinamido)-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate A mixture of 3-amino-6-bromopicolinic acid (167 mg, 0.77 mmol), ethyl 2-amino-2-(5-25 fluoro-2-(methoxymethoxy)phenyl)acetate (237 mg, 0.92 mmol), HATU (585 mg, 1.54 mmol), and DIPEA (401 mL, 2.31 mmol) in degassed DMF (2 mL) was stirred at 60 °C for 1 h. After cooling, the reaction mixture was poured into saturated brine (20 mL) and extracted three times with EtOAc. The combined organic extracts were dried over NazSO*, filtered and concentrated under reduced pressure. The residue was purified by silica gel 30 chromatography eluting with 0-55% EtOAc in hexane to give the title compound (315 mg, 90%). MS m / z:. 458.0 [M+1]L 2026234102   18 Sep 2026 (methoxvmethoxv)-phenyl)acetate 5          A mixture of ethyl 2-(3-am!no-6-bromop!coi!namido)-2-(5-f!uoro-2-(methoxymethoxy)- phenyl)acetate (315 mg, 0.68 mmol) in triethylorthoformate (4 mL) in a sealed vial was heated in a microwave for 2 h at 210 °C. After cooling, excess triethylorthoformate was removed under reduced pressure, and the residue was purified by silica gel chromatography, eluting with 0-65% EtOAc in hexane to give the title compound (310 mg, 10   98%). 1H NMR (500 MHz, DMSO-cfe) d ppm 8.37 (s, 1H) 8.06-8.09 (m, 2H) 7.36 (dd, 1H) 7.25-7.32 (m, 1H) 7.17-7.23 (m, 1H) 6.71 (s, 1 H) 5.19-5.25 (m, 2H) 4.27 (q, 2H) 3.29 (s, 3H) 1.19-1.23 (m, 3H); MS m / z: 468.0 [M+1]+. Step 5. 2-(5-Fluoro-2-(methoxvmethoxv)phenvl)-2-(6-(4-(1-methvlpiperidin-4-vi)phenvl)-4- 15 oxopvridof3,2-dlpyrimidin-3(4H)-vl)acetic acid A mixture of ethyl 2-(6-bromo-4-oxopyrido[3!2-d]pyrimidin-3(4H)-yl)-2-(5-f!uoro-2-(methoxymethoxy)phenyl)acetate (310 mg, 0.73 mmol), 1-methyi-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (265 mg, 0.88 mmol), Pd(dppf)Cl2. DCM (119 mg, 20   0.146 mmol) and sodium carbonate (232 mg, 2.19 mmol) in dioxane:water (4:1, 7.5 mL) was heated at 100 CC for 24 h under nitrogen. After cooling, the reaction mixture was filtered, and the filtrate was concentrated and purified by reverse phase HPLC, eluting with 0-80% ACN / water (0.035% TFA modifier) to give the title compound (151 mg, 39%). 1H NMR (500 MHz, DMSO-d6) d ppm 9.36 (br s, 1H) 8.43 (d, 1H) 8.33 (d, 1H) 8.20 (m, 3H) 7.44 (d, 2H) 25    7.41 (dd, 1H) 7.24-7.33 (m, 1H) 7.19 (dd, 1H) 6.67 (s, 1H) 5.25 (d, 1H) 5.22 (d, 1H) 3.56 (d, 2H) 3.28 (s, 3H) 3.11 (m, 2H) 2.91 (m, 1H) 2.84 (d, 3H) 2.03-2.13 (m, 2H) 1.81-1.96 (m, 2H). MS m / z: 533 [M+ip. 2026234102   18 Sep 2026 Step 6. 3-((1 H-Benzofd1imidazol-2-Yl)(5-fluoro-2-(methoxvmethoxy)phenyl)methyl)-6-(4-(1- methylpiperidin-4-yi)phenyi)pyndof3,2-dlpyrimidin-4(3H)-one A mixture of 2-(5-fluoro-2-(methoxymethoxy)phenyl)-2-(6-(4-(1-methylpiperidin-4- 5 yl)phenyl)-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)acetic acid (75 mg, 0.14 mmol), ortho phenylenediamine (31 mg, 0.28 mmol), HATU (106 mg, 0.28 mmol), and DIPEA (156 mL, 0.90 mmol) in degassed DMF (3 mL) was stirred at 60°C for 1.5 h. The reaction mixture was purified by reverse phase HPLC, eluting with 0-80% ACN / water (0.035 %TFA modifier) to give the amide intermediate. MS m / z: 623.7 [M+1]+. 10          The above amide intermediate was dissolved in acetic acid (5 mL) and heated at 110 °C for 1h. Excess acetic acid was removed under reduced pressure to give the title compound, used without further purification. MS m / z: 605.4 [M+1]+ Step 7. 3-((1H-Benzo[d1imidazol-2-yl)(5-fluoro-2-hydroxyphenyi)methyl)-6-(4-(1- 15 methySpiperidin-4-yl)phenyi)pyrido|'3.2-d1pyrimidin-4(3H)-one 2,2,2-trifiuoroacetate (Compound 009) The above material of 3-((1 H-benzo[d]imidazol-2-yl)(5-fluoro-2-(methoxymethoxy)-phenyl)methyl)-6-(4-(1-methylpiperidin-4-yl)phenyl)pyrido[3,2-d]pyrimidin-4(3H)-one was 20 treated with 5 mL of 1:1 DCM / TFA for 6 h. Solvents were removed under reduced pressure, and the residue was purified by reverse phase HPLC, eluting with 0-80% ACN / water (0.035 %TFA modifier) to give the title compound (14 mg, 15%). 1H NMR (500 MHz, DMSO-ds) d ppm 10.20 (s, 1H) 9.30 (br s 1H) 8.46 (d, 1H) 8.31 (s, 1H) 8.23 (d, 1H) 8.21 (d, 2H) 7.58 (m, 3H) 7.43 (d, 2H) 7.24 (m, 2H) 7.17 (m, 1H) 6.94 (dd, 1H) 6.80 (m, 1H) 3.55 (d, 2H) 3.10 (m, 25   2H) 2.90 (m„ 1H) 2.85 (d, 3H) 2.08 (m, 2H) 1.87 (m, 2H); MS m / z: 561.3 [M+1]+. 2026234102   18 Sep 2026 The following compounds were prepared by a similar method to Example 9 from the corresponding amine and acid starting materials: No. Structure / Name m / z [M+1]+ 1H NMR (DMSO-ds) 6 Starting materials 008 Qx f XX tfa 3-((1 H-Benzo[d]imidazol-2-yl)(3-fluorophenyl)methyl)-6-(4-(1 -methyl pi peridin-4-yl)phenyl)-pyrido[3,2-d]pyrimidin-4(3H)-one 2,2,2-trifiuoroacetate 545.3 9.29 (brs, 1H) 8.45-8.47 (m, 2H) 8.21-8.24 (m, 3H) 7.60 (m, 2H) 7.58 (s, 1H) 7.50-7.53 (m, 1H) 7.43 (d, 2H) 7.39 (d, 1H) 7.27-7.31 (m, 2H) 7.25 (m, 2H) 3.55 (d, 2H) 3.07-3.14 (m, 2H) 2.89-2.95 (m, 1H) 2.84 (d, 3H) 2.08 (d, 2H) 1.821.91 (m, 2H) Me&X^NHz Qx and HO X X 004 3-((1 H-Benzo[d]imidazo i-2-yi)(5-fluoro-2-hydroxyphenyl)methyl)-5-fluoro-6-(4-(1-methylpiperidin-4- yl)phenyl)quinazolin-4(3H)-one 2,2,2-trifiuoroacetate 578.2 10.19 (s, 1H) 9.29 (br. s, 1H) 8.22 (s, 1H) 7.97 (m, 1H) 7.62 (d, 1H) 7.58 (m, 4H) 7.50 (S, 1H) 7.39 (d, 2H) 7.24 (dd, 2H) 7.16 (m, 1H)6.94(dd, 1H)6.75(dd, 1H) 3.54 (d, 2H) 3.09 (m, 2H) 2.87 (m, 1H)2.82(d, 3H) 2.07 (m, 2H) 1.85 (m, 2H) .NH? E:t0‘ MeO O 1 xx and h2n.^~ ho^ XsX.. XT 005 Qi / 'XX -Yaa. 3-((1 H-Benzo[d]imidazol-2-yl)(3- fluorophenyl)methyl)-5-fluoro-6-(4-(1-methylpiperidin-4-yl)phenyl)-quinazolln-4(3H)-one 2,2,2-trifiuoroacetate 562.3 9.43 (brs, 1H) 8.31 (s, 1H) 7.90 (m, 1H) 7.51-7.56 (m, 5H) 7.42-7.47 (m, 2H) 7.32 (d, 2H) 7.28 (d, 1H) 7.23 (m, 1H) 7.18 (m, 3H) 3.48 (d, 2H) 2.99-3.06 (m, 2H) 2.78-2.83 (m, 1H)2.77(d, 3H) 2.00 (d, 2H) 1.76-1.85 (m, 2H) ex and HO Ar- X r The following compounds were prepared by a similar method to Example 9 from 5 ethyl 2-amino-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate and the corresponding acid starting materials: No. Structure / Name m / z 'H NMR (DMSO-X) 6 Starting materials 075 Q-t Xyy ho J. 6 Cl YX XXF 2™ XX 3-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-5-chloro- 594.3 11.00 (brs, 1H), 10.77 (brs, 1H), 8.35 (s, 1H), 7.74-7.85 (m, 4H), 7.50-7.57 (m, 3H), 7.32-7.47 (m, 4H), 7.17-7.28 (m, 2H), 7.09-7.15 (m, 1H), 3.48 (d, 2H), 2.97-3.21 (m, 2H), 2.84-2.91 (m, 1H), 2.75 (d, 3H), 1.96-2.19 (m, 4H) HC) X. Il J       Br 2026234102   18 Sep 2026 6-(4-(1-methyl-4-piperidyl)phenyl]-quinazolin-4-one;dihydroch ioride 076 Qx / Yx HC>X °   - X:Y z^x L. £-.    2HCI     I ,% 3-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]-5-(trifluoromethyl)quinazolin-4-one;dihydrochloride 628.1 10.72 (brs, 1H), 10.59 (brs, 1H), 8.42 (s, 1H), 8.01 (d, 1H), 7.86 (d, 1H), 7.66-7.78 (m, 2H), 7.56 (s, 1H), 7.427.50 (m, 2H), 7.35-7.41 (m, 4H), 7.16-7.28 (m, 1H), 6.997.13 (m, 2H), 3.51 (d, 2H), 3.02-3.16 (m, 2H), 2.84-2.96 (m, 1H), 2.78 (d, 3H), 1.872.18 (m, 4H) H2N HCC jxjkr. XT Compound 077: 3-nH-benzimidazQl-2-yl-(5-fluoro-2-h¥droxy-phenyl)methyl]-5-methoxv-6-[4- (1-methyi-4-piperidyi)phenynquinazolin-4-one; di hydrochloride Scheme 9 Step 1.6-amino-N-f1H-benzimidazoi-2-yl-r5-fluoro-2-(methoxymethoxv)phenyi1methyll-3-bromo-2-methoxy-benzamide To a solution of 6-bromo-5-methoxy-2l4-dihydro-1H-3,1-benzoxazine-2,4-dione 10   (0.350 g, 1.28 mmol) in THF (30 mL) was added ethyl 2-amino-2-(5-fluoro-2- (methoxymethoxy)phenyl)-acetate (0.385 g, 1.28 mmol). After stirring at 70 °C for 12 h, the reaction mixture was concentrated under reduced pressure, and purified by reverse phase HPLC eluting with 0-100% ACN / water (0.035% TFA modifier) to give the title compound (0.21 g, 31%). 1H NMR (DMSO-ds) 6: 12.28-12.38 (m, 1H), 9.34-9.45 (m, 1H), 7.52-7.60 (m, 15    1H), 7.39-7.48 (m, 1H), 7.26-7.32 (m, 2H), 7.13-7.20 (m, 4H), 6.83 (d, 1H), 6.46 (d, 1H), 6.11 (s, 2H), 5.24 (d, 1H), 5.17 (d, 1H), 3.62 (s, 3H), 3.26 (s, 3H); MS m / z'. 529.1 [M+1]% 2026234102   18 Sep 2026 methoxy-quinazolin-4-one A mixture of 6-amino-N-[1 H-benzim!dazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]-5 methyl]-3-bromo-2-methoxy-benzamide (0.200 g, 0.377 mmol) in triethylorthoformate (20 mL) was heated at 210 °C for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and purified by reverse phase HPLC eluting with 0-100% ACN / water (0.035% TFA modifier) to give the title compound (0.14 g, 69%). ''H NMR (DMSO-ds) 6: 12.88 (br s, 1H), 8.18-8.32 (m, 1H), 7.94-8.14 (m, 1H), 7.59-7.75 (m, 10   2H), 7.47-7.56 (m, 1H), 7.38-7.47 (m, 1H), 7.23 (d, 4H), 6.76-6.96 (m, 1H), 5.10-5.26 (m, 2H), 3.82 (s, 3H), 3.13 (s, 3H); MS m / z: 539.1 [M+1]+. Step 3. 3-[1H-benzimidazol-2-¥S-[5-fluoro-2-(methox¥methoxv)phenvllmethyl1-5-methoxv-6- A mixture of 3-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-bromo-5-methoxy-quinazolin-4-one (0.100 g, 0.185 mmol), 1-methy!-4-(4-(4.4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pheny!)piperidine (0.056 g, 0.185 mmol), Pd(dppf)Ch (0.014 g, 0.019 mmol) and potassium carbonate (0.050 g, 0.370 mmol) in 20 dioxane: DM F:water (1:1:1, 10 mL) was heated at 100 °C for 12 h under nitrogen. After cooling, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure, and purified by reverse phase HPLC eluting with 0-100% ACN / water (0.035% TFA modifier) to give the title compound (0.085 g, 73%). ’H NMR (400 MHz, methanol-^) 6: 8.27-8.37 (m, 2H), 8.11-8.19 (m, 1H), 7.81-7.90 (m, 1H), 7.70-7.74 (m, 1H), 7.59-7.64 (m, 25   4H), 7.35-7.43 (m, 2H), 7.28-7.31 (m, 2H), 7.19-7.25 (m, 1H), 6.82-6.88 (m, 1H), 5.17-5.25 (m, 2H), 3.60-3.68 (m, 2H), 3.53 (s, 3H), 3.11-3.25 (m, 5H), 2.93-2.97 (m, 4H), 1.98-2.24 (m, 4H); MS m / z: 634.5 [M+1]+. 2026234102   18 Sep 2026 methy!-4-piperidvl)pheny!lquinazo!in-4-one;dihydrochloride To a solution of 3-[1H-benzimidazol-2-yl-[5-fluoro-2- 5 (methoxymethoxy)phenyl]methyl]-5-methoxy-6-[4-(1-methyl-4-piperidyl)phenyl]quinazol!n-4-one (0.075 g, 0.118 mmol) in dichloromethane (10 mb) was added HCI in methanol (4 M, 0.590 mL, 2.36 mmol). After stirring 12 h at room temperature, the solvent was removed under reduced pressure. The crude product was purified by reverse phase HPLC eluting with 0-100% ACN / water (0.05% HCI modifier) to give the title compound (0.026 g, 37%). !H 10 NMR (400 MHz, methanol-d4) 6: 8.41 (s, 1H), 7.92 (d, 1H), 7.73-7.82 (m, 2H), 7.52-7.69 (m, 6H), 7.37-7.45 (m, 2H), 7.21-7.35 (m, 2H), 6.99-7.07 (m, 1H), 3.60-3.68 (m, 2H), 3.53 (s, 3H), 3.15-3.26 (m, 2H), 2.89-3.05 (m, 4H), 1.98-2.20 (m, 4H); MS m / z: 590.7 [M+1]+. Compound 078: 2-[1H-benzimidazol-2-vl-(5-fluoro-2-hvdroxy-phenyl)methvl1-6-[4-(1-methyl- 15 4-p!peridyl)phenyHisoindol!ne-1-thione;d!hydrochloride To a solution of 2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one (1.00 g, 1.82 mmol) in toluene (20 mL) was added Lawesson reagent (3.68 g, 9.10 mmol). After stirring at 120 °C for 72 h, the solvent was 25 removed under reduced pressure. The crude product was purified by reverse phase HPLC eluting with 0-100% ACN / water (0.05% HCI modifier) to give the title compound (0.026 g, 3%). 1H NMR (DMSO-de) 5: 10.33-10.99 (m, 2H), 7.96-8.21 (m, 2H), 7.63-7.90 (m, 6H), 2026234102   18 Sep 2026 7.36-7.54 (m, 4H), 7.14-7.24 (m, 1H), 6.92-7.16 (m, 2H), 5.08-5.26 (m, 1H), 4.40-4.57 (m, 1H), 3.00-3.14 (m, 3H), 2.86-2.98 (m, 2H), 2.80 (s, 3H), 1.96-2.19 (m, 4H); MS m / z: 563.1 [M+1]7 5 Compounds 083 and 084: Preparation of2-[(R)-1H-benzimidazol-2-vl-(5-fluoro-2-hydroxy-phenyl)methyl1-6-[4-(1-methyl-4-piperidyl)phenyllisoindoline-1-thione and 2-[(S)-1H-benzimidazol-2-vi-(5-f!uoro-2-hvdroxy-phenyQmethv!l-6-[4-(1-methyi-4- piperidypphenyllisoindoline-l-thione 10           2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[4-(1-methyl-4- piperidyl)phenyl]isoindoline-1-thione;dihydrochloride (0.013 g, 0.020 mmo!) was purified by prep SFC with Phenomenex Lux Cellulose-4 column eluting with 45% (0.3% TEA in MeOH) / 55% CO2 at 10 MPa to separate enantiomers. Absolute configuration of the chiral center for each isolated enantiomer is unknown. First eluting peak (083) (4 mg, 31% yield, 100:0 er); 15   [af%-88.9 (c = 0.18, MeOH); NMR (DMSO-ds) 6: 12.74 (br s, 1H), 10.06 (brs, 1H), 8.06 (s, 1H), 7.93 (d, 1H), 7.73 (d, 1H), 7.45-7.69 (m, 5H), 7.39 (d, 2H), 7.08-7.26 (m, 3H), 6.886.98 (m, 1H), 6.62-6.71 (m, 1H), 5.08-5.20 (m, 1H), 4.38-4.49 (m, 1H), 2.85-2.94 (m, 2H), 2.53-2.57 (m, 1H), 2.21 (s, 3H), 1.94-2.06 (m, 2H), 1.66-1.83 (m, 4H); MS m / z: 563.3 [M+1]\ Second eluting peak (084) (4 mg, 31% yield, 99:1 er); [a]2%+56.0 (c ~ 0.25, MeOH); 1H 20 NMR (DMSO-d3) 0: 12.74 (brs, 1H), 10.08 (brs, 1H), 8.06 (s, 1H), 7.93 (d, 1H), 7.73 (d, 1H), 7.44-7.69 (m, 5H), 7.39 (d, 2H), 7.08-7.24 (m, 3H), 6.89-7.00 (m, 1H), 6.60-6.71 (m, 1H), 5.07-5.20 (m, 1H), 4.37-4.51 (m, 1H), 2.84-2.95 (m, 2H), 2.53-2.58 (m, 1H), 2.21 (s, 3H), 1.93-2.06 (m, 2H), 1.64-1.84 (m, 4H)); MS m / z: 563.2 [M+1]\ 2026234102   18 Sep 2026 Compo yj2!108fL:2JI5^^ methv!-4-piperidyi)pheny!lisoindo!in-1-one Scheme 11 To a solution of 4-methy!-1 H-imidazoie-2-carboxaldehyde (5.00 g, 45.4 mmol) and 2-methylpropane-2-sulfinamide (8.25 g, 68.1 mmol) in THF (80 mL) was added tetraethyl 10 orthotitanate (15.5 g, 68.1 mmol). After stirring at 75 °C for 16 h, the reaction mixture was quenched by water and extracted with ethyl acetate three times. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 0-100% ethyl acetate in petroleum ether to give the title compound (3 g, 31%). 15 1H NMR (400 MHz, CDCh) 6: 10.13-10.62 (m, 1H), 8.41 (s, 1H), 6.76-7.04 (m, 1H), 2.192.45 (m, 3H), 1.09-1.25 (m, 9H); MS m / z: 214.2 (M+1). Step 2. N-f(5-fluoro-2-methoxy-phenyl)-(4-methyl-1 H-!midazol-2-yl)methyll-2-methyl- propane-2-sulfinamide 2026234102   18 Sep 2026 To a solution of 2-methyl-N-[(4-methyl-1H-imidazol-2-yl)methylene]propane-2-sulfinamide (2.30 g, 10.7 mmol) in THF (50 mL) was added dropwise a solution of 5-fluoro-2-methoxyphenylmagnesium bromide in THF (0.5 M, 64.0 mL, 32.0 mmol) at-78 °C. After stirring at room temperature for 16 h, the reaction mixture was poured into sat. ammonium 5 chloride solution and extracted with ethyl acetate three times. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 0-10% methanol in ethyl acetate to give the title compound (0.5 g, 14%). MS m / z\ 340.1 [M+1p. 0 Step 3. (5-fluoro-2-methoxy-phenyl)-(4-methyl-1 H-imidazol-2-yl)methanamine ,o. To a solution of N-[(5-fluoro-2-methoxy-phenyl)-(4-methyl-1H-!midazol-2-yl)methyl]-2-methyl-propane-2-sulfinamide (0.560 g, 1.64 mmol) in methanol (10 mL) was added HCI in 15 dioxane (4 M, 1.23 mL, 4.92 mmol) at 0 °C. After stirring at room temperature for 16 h, the solvent was removed under reduced pressure to give the title compound (0.385 g, quant.) which was used in the next reaction without further purification. MS m / z: 236.0 [M+1]+. Step 4. 6-bromo-2-[(5-fluoro-2-methoxy-phenyl)-(4-methyl-1 H-imidazol-2- 20 yl)methvHisoindolin-1-one To a solution of (5-fluoro-2-methoxy-phenyl)-(4-methyl-1H-imidazol-2-yl)methanamine (0.380 g, 1.61 mmol) in DMF (5 mL) was added DIPEA (1.31 mL, 8.04 mmol). The reaction mixture was stirred at room temperature for 5 min before methyl 5 25 bromo-2-(bromomethyl)-benzoate (0.495 g, 1.61 mmol) was added. The reaction mixture was heated at 90 °C for 16 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate three times. The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column 30 chromatography eluting with 0-100% ethyl acetate in petroleum ether to give the title compound (0.28 g, 40%). 1H NMR (DMSO-d6) 5: 11.76-12.10 (m, 1H), 7.75-7.84 (m, 2H), 2026234102   18 Sep 2026 7.50- / .60 (m, 1H), / .1 / - / .26 (m, 1H), / .02- / .13 (m, 1H), 6.88-6.96 (m, 1H), 6. / 4-6.83 (m, 1H), 6.56 (s, 1H), 4.64-4.75 (m, 1H), 3.96-4.08 (m, 1H), 3.72 (d, 3H), 2.10 (d, 3H). Step 5. 2-[(5-fluoro-2-methoxy-phenyl)-(4-methyl-1 H-imidazol-2-yl)methyll-6-[4-(1-methyl-4- 5 piperidvDphenyllisoindolin-1-one A mixture of 6-bromo-2-[(5-fluoro-2-methoxy-phenyl)-(4-methyl-1 H-imidazol-2-yl)methyi]isoindolin-1-one (0.280 g, 0.650 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (0.293 g, 0.975 mmol), Pd(dppf)CL (0.024 g, 0.033 10 mmol) and potassium carbonate (0.271 g, 1.95 mmol) in dioxane:water (9:1, 5 mL) was heated at 100 °C for 16 h under nitrogen. After cooling, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure, and purified by reverse phase HPLC eluting with 0-100% ACN / water ACN / water (0.05% HCI modifier) to give the title compound (0.2 g, 59%). MS m / z: 525.3 [M+1]+. 15 Step 6. 2-[(5-fluoro-2-hydroxy-phenylM4-methyl-1H-imidazol-2-yl)methyll-6-r4-(1-methyl-4-piperidyl)phenyl1isoindolin-1-one To a solution of 2-[(5-fluoro-2-methoxy-phenyl)-(4-methy!-1H-imidazol-2-yl)methyl]-6-20 [4-(1-methyl-4-piperidyl)phenyl]isoindo!in-1-one (0.150 g, 0.285 mmol) in dichloromethane (15 mL) at 0 °C was added boron tribromide (0.713 g, 2.85 mmol). After stirring at room temperature for 2 h, the reaction mixture was diluted with dichloromethane and poured into ice-water. The aqueous phase was extracted with dichloromethane three times. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and 25 concentrated under reduced pressure. The crude product was purified by reverse phase HPLC eluting with 0-100% ACN / water containing 10 mH ammonium acetate to give the title compound (0.068 g, 47%). !H NMR (400 MHz, DMSO-d6) 6: 11.81-12.07 (m, 1H), 10.05 (br s, 1H), 7.80-7.95 (m, 2H), 7.59-7.6 (m, 3H), 7.35 (d, 2H), 6.96-7.08 (m, 1H), 6.53-6.90 (m, 4H), 4.72 (d, 1H), 4.10 (d, 1H), 2.89 (d, 2H), 2.53-2.57 (m, 1H), 2.21 (s, 3H), 1.90-2.12 (m, 30   5H), 1.62-1.80 (m, 4H); MS m / z: 511.4 [M+1JT 2026234102   18 Sep 2026 The following compounds were prepared by a similar method to Compound 085 from (5-f!uoro-2-methoxy-phenyl)-(4-methyl-1H-imidazol-2-yl)methanamine and methyl 6-(bromomethyl)-3-chloro-2-fluorobenzoate: No. Structure / Name m / z [M+ir ’H NMR (DMSO-cfe) 5 093 rO-O-'O" ix 7-Fluoro-2-[(5-fluoro-2-hydroxy-phenyl)-(5-methyl-1H-imldazol-2-yl)methyl]-6-[4-(1 -methyi-4-piperidy!)phenyl]isoindolin-1 -one 529.5 11.87-12.06 (m, 1H), 10.04 (brs, 1H), 7.657.73 (m, 1H), 7.42-7.53 (m, 3H), 7.32-7.39 (m, 2H), 6.97-7.06 (m, 1H), 6.74-6.88 (m, 3H), 6.72 (s. 1H), 4.73 (d, 1H), 4.08 (d, 1H). 3.293.32 (m, 1H), 2.83-2.93 (m, 2H), 2.20 (s, 3H), 2.05-2.16 (m, 3H), 1.92-2.02 (m, 2H), 1.611.82 (m, 4H). Compound 086: 2-r(3-fluorophenvl)-(4-methyl-1H-imidazol-2-vl)methvll-6-[4-(1-methvl-4-piperidyl)phenyl]isoindolin-1-one 10 The title compound was prepared in a similar manner to Compound 085 from 2-methyl-N-[(4-methyl-1H-im!dazol-2-yl)methylene]propane-2-sulf!namide and 3-fluorophenylmagnesium bromide. 1H NMR (DMSO-de) 6: 11.80-12.26 (m, 1H), 8.19 (s, 1H), 7.86-7.96 (m, 2H), 7.637.71 (m, 3H), 7.41-7.49 (m, 1H), 7.37 (d, 2H), 7.15-7.23 (m, 1H), 7.02-7.12 (m, 2H), 6.72 (s, 1H), 4.82 (d, 1H), 4.28 (d, 1H), 2.93-3.01 (m, 2H), 2.56-2.62 (m, 1H), 2.29 (s, 3H), 2.09-2.19 15   (m, 5H), 1.67-1.84 (m, 4H); MS m / z. 495.3 [M+1f Compound 087: 2"[(4l5-dimethyl-1H-imidazol-2-yl)-(5-fluoro-2"hydroxy-phenyl)methyll-6-g'4" (1-methyl-4-piperidyl)phenvllisoindolin-1-one 20          The title compound was prepared in a similar manner to Compound 085 from 4,5- dimethyi-1H-imidazole-2-carbaidehyde and 2-methylpropane-2-sulfinamide. 1H NMR (DMSO-cfe) 5: 11.75 (br s, 1H), 10.19 (br s, 1H), 7.84-7.89 (m, 2H), 7.59-7.70 (m, 3H), 7.36 2026234102   18 Sep 2026 (d, 2H), 6.98-7.08 (m, 1H), 6.80-6.91 (m, 2H), 6.72 (s, 1H), 4.69 (d, 1H), 4.13 (d, 1H). 2.89 (d, 2H), 2.45-2.49 (m, 1H), 2.21 (s, 3H), 1.94-2.12 (m, 8H), 1.63-1.84 (m, 4H); MS m / z: 525.3 [M+1]1' 5 meihyMTgigeridy^pht^ The title compound was prepared in a similar manner to Compound 085 from 2-methyl-1H-imidazole-5-carbaldehyde and 2-methyipropane-2-sulfinamide. 1H NMR (DMSO- 10   ds)6: 10.54 (br s, 1H), 10.11 (br s, 1H), 7.86-7.99 (m, 2H), 7.62-7.75 (m, 3H), 7.33-7.44 (m, 3H), 7.05-7.15 (m, 1H), 6.87-7.01 (m, 2H), 6.75 (s, 1H): 4.54 (d, 1H), 4.22 (d, 1H), 3.49-3.52 (m, 2H), 2.99-3.12 (m, 2H), 2.70-2.91 (m, 4H), 2.54 (s, 3H), 1.94-2.10 (m, 4H); MS m / z: 511.2 [M+1]+ 15 Compound 089 2-K5-fluoro-2-hydroxy-phenyl)-(5-methyl-4H-1,2;4-triazok3-ynmethyl]-6-[4- (1-methyl-4-piperidyl)phenynisoindoHn-1-one;hydrochloride Step 1.2-(6-bromo-1-oxo-isoindolin-2-vi)-2-[5-fluoro-2-(methoxvmethoxv)phenYl1- 20 acetohydrazide 2026234102   18 Sep 2026 To a solution of ethyl 2-(6-bromo-1 -oxo-isoindolin-2-yi)-2-[5-fluoro-2-(methoxymethoxy)-phenyl]acetate (0.900 g, 1.98 mmol) in ethanol (30 mL) was added hydrazine (0.618 mL, 19.7 mmol). After stirring at 80 °C for 16 h. the reaction mixture was concentrated under reduced pressure to give the title compound (0.75 g, 86%). NMR 5 (DMSO-cfe) 6: 9.62 (s, 1H), 8.92 (br s, 2H), 7.73-7.89 (m, 2H), 7.52 (d, 1H), 7.04-7.25 (m, 3H), 6.11 (s, 1H), 5.02-5.20 (m, 2H), 4.63 (d, 1H), 3.88 (d, 1H), 3.19 (s, 3H); MS m / z: 438.1 [M+1P. Step 2. 6-bromO"2-[[5-fluoro-2-(methoxYmethoxv)phenvl1-(5-methyl-4H-1,2,4-triazol-3-10 yl)methvllisoiridolin-1-one To a suspension of 2-(6-bromo-1-oxo-isoindolin-2-yl)-2-[5-fluoro-2-(methoxymethoxy)-phenyl]acetohydrazide (0.400 g, 0.912 mmol) and ethanimidamide hydrochloride (0.258 g, 2.73 mmol) in butanol (80 mL) was added potassium tert-butoxide in 15 THF (1 M, 2.73 mL, 2.73 mmol). The reaction mixture was heated at 120 °C for 16 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate three times. The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 0-10% methanol in 20 dichloromethane to give the title compound (0.185 g, 44%). NMR (DMSO-de) 6: 13.63 (br s, 1H), 7.72-7.86 (m, 2H), 7.54 (d, 1H), 7.09-7.25 (m, 2H), 6.81-6.98 (m, 2H), 5.14 (d, 2H), 4.65 (d, 1H), 3.95-4.08 (m, 1H), 3.21 (s, 3H), 2.34 (s, 3H); MS m / z: 461.0 [M+1]+. Step 3. 2-[[5-fluoro-2-(methoxymethoxy)phenyl]-(5-methyl-4H-1,2,4-tr!azol-3-yl)methvn-6-[4-25 (1-methvl-4-piperidyl)phenyllisQindolin-1-one A mixture of 6-bromo-2-[[5-fluoro-2-(methoxymethoxy)phenyl]-(5-methyl-4H-1,2,4-triazol-3-yl)methyl]isoindolin-1-one (0.100 g, 0.216 mmol), [4-(1~methylpiperidin-4-yl)phenyl]boronic acid (0.057 g, 0.259 mmol), Pd(dppf)Cl2 (0.016 g, 0.022 mmol) and sodium 2026234102   18 Sep 2026 carbonate (0.071 g, 0.648 mmol) In dioxane:water (4:1, 5 mL) was heated at 100 °C for 16 h under nitrogen. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate three times. The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude 5 product was purified by silica gel column chromatography eluting with 15% methanol in dichioromethane to give the title compound (0.07 g, 58%). MS m / z: 556.3 [M+1 ]+. 4-piperidv0phenyllisoindol!n-1-one:hydrochloride The title compound was prepared in a similar manner to Example 076, step 4 from 2-[[5-fluoro-2-(methoxymethoxy)phenyl]-(5-methyl-4H-1,2.4-triazol-3-yi)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one. ''H NMR (400 MHz, methanol-A) 8: 8.02 (d, 1H), 7.857.93 (m, 1H), 7.60-7.69 (m, 3H), 7.41 (d, 2H), 7.03-7.10 (m, 2H), 6.87-6.99 (m, 2H), 4.76 (d, 15   1H), 4.24 (d, 1H), 3.64 (d, 2H), 3.14-3.25 (m, 2H), 2.86-3.01 (m, 4H), 2.62 (s, 3H), 2.00-2.21 (m, 4H); MS m / z: 512.4 [M+1]T Example 10: Preparation of 3-((1 H-Benzo[d1imidazo!-2-vl)(phenvl)methyl)-5-fluoro-6-(4-(1-methylpipendin-4-yl)phenyl)Quinazolin-4(3H)-one 2,2,2-trifluoroacetate (Compound 003) 20 Scheme 13. 2026234102   18 Sep 2026 Step 1.6-Amino-3-bromo-2-fluorobenzoic acid nh2 ho2c^1^ Br A mixture of 6-amino-3-bromo-2-fluorobenzonitrile (2.56 mg, 11.8 mmol), lithium hydroxide monohydrate (4.99g, 118 mmol) and water (70 mL) was heated at reflux for 1 h. 5 After cooling, the solution was treated with 6N HCI to pH 4. The resulting precipitate was filtered, washed with water and dried to give the title compound (2.51g, 92%). 1H NMR (500 MHz, DMSO-de) d ppm 7.39 (dd, 1H) 6.57 (dd, 1H); MS m / z: 234.0 [M+1]+. Step 2. 6-Bromo-5-fluoroquinazolin-4(3H)-one A mixture of 6-amino-3-bromo-2-fluorobenzoic acid (950 mg, 4.0 mmol) and formamide (20 mL) was heated at 160°C for 8 h. After cooling, the reaction mixture was poured into water (100 mL) and extracted three times with EtOAc. The combine organic extracts were washed saturated brine, dried over MgSCu, filtered and concentrated under 15 reduced pressure. The residue was purified by silica gel flash chromatograph eluting with 035% EtOAc in hexane to give the title compound (490 mg, 50%). NMR (500 MHz, DMSO-ck) d ppm 8.13 (d, 1H) 8.05 (dd, 1H) 7.45 (dd, 1H); MS m / z: 241.9 [M+1]+. Step 3. Methyl 2-(6-bromo-5-fluoro-4-oxoquinazolin-3(4H)-yl)-2-phenylacetate Methyl 2-bromo-2-phenylacetate (349 mL, 2.2 mmol) was added to 6-bromo-5-fluoroquinazolin-4(3H)-one (440 mg, 1.9 mmol) and Cs2COs(1.20 g, 3.7 mmol) in DMF (3 mL), and the mixture was heated to 30°C for 1 h. After cooling, the reaction mixture was poured into water (250 mL) and extracted with EtOAc three times. The combined organic 25 extracts were washed with saturated brine, dried over MgSCh, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluting with 0-30% EtOAc in hexane to give the title compound (290 mg, 39%). !H NMR (500 2026234102   18 Sep 2026 MHz, CDCh-d) d ppm 7.82-7.91 (m, 2H) 7.45-7.52 (m, 3H) 7.33-7.43 (m, 3H) 6.72 (s, 1 Hl 3.88 (s, 3H); MS m / z: 390.0 [M+1]+. Step4.2-(5-Hyara~6~(4~M~methvipipericHn-4-ynphanH^^ 5 phenylacetic acid The title compound was prepared in a similar manner to Example 9, step 5, from methyl 2-(6-bromo-5-fluoro-4-oxoqu!nazolin-3(4H)-yl)-2-phenylacetate and 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3!2-dioxaboro!an-2-yl)phenyl)piperidine. !H NMR (500 MHz, DMSO- 10 ds) d ppm 9.35 (brs, 1H) 8.11 (s, 1H) 7.94-7.99 (m, 1H) 7.60 (m, 3H) 7.52-7.56 (m, 2H) 7.43-7.51 (m, 3H) 7.40 (m, 2H) 6.49 (s, 1H) 3.56 (d, 2H) 3.06-3.16 (m, 2H) 2.84 (d, 4H) 2.052.13 (m, 2H) 1.80-1.93 (m, 2H); MS m / z: 472.2 [M+1]+. Step 5. 3-((1 H-Benzo[dlimidazol-2-vl)(phenvr)methyl)-5-fluoro-6-(4-(1-methylpiperidin-4- 15 yl)phenyl)quinazolin-4(3H)-one 2,2,2-trifluoroacetate (Compound 003) The title compound was prepared in a similar manner to Example 9, step 6, from 2- (5-fluoro-6-(4-(1-methy!piperid!n-4-yl)phenyl)-4-oxoqu!nazo!!n-3(4H)-yl)-2-phenylacetic acid. 1H NMR (500 MHz, DMSO-de) d ppm 9.23 (br s, 1H) 8.32 (s, 1H) 7.94-8.03 (m, 1H) 7.56 20   7.64 (m, 5H) 7.54 (s, 1H) 7.44-7.49 (m, 3H) 7.35-7.42 (m, 4H) 7.17-7.29 (m, 2H) 3.50-3.59 (m, 2H) 3.04-3.16 (m, 2H) 2.84 (m, 4H) 2.04-2.13 (m, 2H) 1.79-1.93 (m, 2H); MS m / z: 544.3 [M+1j+ 2026234102   18 Sep 2026 Example 11: Preparation of Intermediates Scheme 14. 5 Step 1, 4-(4-Bromo-2-f!uoro-phenv!)-1-methyi-p!perid!n-4-oi To a solution of 4-bromo-2-fluoro-1-iodo-benzene (24.0 g, 79.7 mmol) in THF (400 mL) at -70 °C was added dropwise n-butyllithium (2.5 M in hexane, 31.9 mL, 79.7 mmol). After stirring at -70 °C for 30 min, a solution of 1-methylpiperidin-4-one (9.01 g, 79.7 mmol) 10 in THF (20 mL) was added dropwise. After stirring at -70 °C for 1 h, the reaction mixture was poured into sat. ammonium chloride solution and extracted with ethyl acetate three times. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 5-66% ethyl acetate in petroleum ether to give the title 15 compound (13.0 g, 57%). MS m / z: 289.8 [M+1]+. Step 2. 4-(4-Bromo-2-fluoro-phenyl)-1-methyl-3,6-dihydro-2H-pyridine F A mixture of 4-(4-bromo-2-fluoro-phenyl)-1-methyl-piperidin-4-ol (13.0 g. 45.1 mmol) 20 and 6 M HCI (70 mL) was heated at 85 °C overnight. After cooling to room temperature, the reaction mixture was poured into water, adjusted to pH 8 by sat. sodium bicarbonate and extracted with ethyl acetate three times. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 5-66% ethyl 25 acetate in petroleum ether to give the title compound (4.0 g, 31%). MS m / z: 271.7 [M+1]+. 2026234102   18 Sep 2026 Step 3. 4-[2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyll-1-methyl-3,6-dihydro-2H-pyridine 5          A mixture of 4-(4-bromo-2-f!uoro-phenyi)-1-methy!-3,6-dihydro-2H-pyr!dine (3.00 g, 11.1 mmol), 4,4,5,5-tetramethyi-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.81 g, 11.1 mmol), [1,r-bis(dipheny!phosphino)ferrocene]dichloropalladium(ll) (0.812 g, 1.11 mmol), potassium acetate (3.26 g, 33.3 mmol) and dioxane (30 mL) was degassed under nitrogen twice. The 10 reaction mixture was heated at 90 °C for 16 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate three times. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 5-50% ethyl acetate in petroleum ether to give the title 15 compound (3.0 g, 85%). 'H NMR (400 MHz, methanol-A) 6: 7.49 (dd, 1H), 7.27-7.40 (m, 2H), 6.01-6.03 (m, 1H), 3.18-3.21 (m, 2H), 2.72-2.80 (m, 2H) 2.57-2.65 (m, 2H), 2.43 (s, 3H) 1.30-1.39 (m, 12H). 20 piperidine To a solution of palladium (10% on carbon, 1.10g, 0.945 mmol) in methanol (200 mL) was added 4-[2-fluoro-4-(4,4,5!5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-3l6-dihydro-2H-pyridine (3.00 g, 9.45 mmol). The flask was evacuated and backfilled with 25 hydrogen and the reaction mixture was allowed to stir at 30 °C under an atmosphere of hydrogen (30 psi) for 16 h. The reaction mixture was filtered through a pad of Celite which was washed several times with methanol. The filtrate was concentrated under reduced pressure to give the title compound (2.7 g, 85%). 1H NMR (400 MHz, methanol-^) 6: 7.49 (d, 1H), 7.26-7.36 (m, 2H), 3.00-3.10 (m, 2H), 2.83-2.98 (m, 1H), 2.37 (s, 3H), 2.18-2.31 (m, 30   2H), 1.79-1.89 (m, 4H), 1.27-1.39 (m, 12H). 2026234102   18 Sep 2026 Scheme SM-1 To a solution of diethylzinc (1 M in hexanes, 10.0 mL, 10.0 mmol) in dichloromethane (5 mL) at 0 GC was added diiodomethane (2.67 g, 10.0 mmol). After stirring at the same temperature for 0.5 h, a solution of 4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenylboronic 10 acid pinacol ester (0.500 g, 1.67 mmol) in dichloromethane (5 mL) was added dropwise to the reaction mixture. After stirring at room temperature for 18 h, the reaction mixture was poured into sat. ammonium chloride solution and extracted with ethyl acetate three times. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel 15 column chromatography eluting with 5-50% ethyl acetate in petroleum ether to give the title compound (0.310 g, 59%). MS m / z: 314.2 [M+1]+. Scheme SM-2 To a solution of 6-amino-2-ethyl-3-iodobenzoic acid (3.50 g, 12.0 mmol) in ethanol (70 mL) was added formamidine acetate (5.94 g, 57.1 mmol) and the reaction mixture was heated at 95 °C for 6 h. After cooling to room temperature, the resulting solid was collected 2026234102   18 Sep 2026 by filtration and washed with ethanol to give the title compound (2.10 g, 58%). 1H NMR (DMSO-dg) 6: 8.19 (d, 1H), 8.06 (s, 1H), 7.26 (d, 1H), 3.41-3.59 (m, 2H), 1.04-1.16 (m, 3H). Example 12: Preparation of 2-(( 1H-benzo(d]imidazol~2-yl)(5-fluoro-2-hydroxyphenyl)methyl- 5 d)-6-(4-(1-methylp!pendin-4-yl)phenvDisoindolin-1-one (Compound 036) Scheme 15. 2-((1 H-Benzo[d]imidazol-2-y!)(5-f!uoro-2-hydroxyphenyl)methy!)-6-(4-(1 -methylpiperidin-4-yl)phenyl) isoindolin-1-one (101 mg, 0.185 mmol) was stirred in CD3OD 10   (10 g) and D2O (1 mL) to give a heterogeneous mixture. Formic acid (40 uL, 1.07 mmol) was then added and the resulting solution was stirred overnight. After 16 hours, NMR (methanol-cW of the reaction solution indicated -50% incorporation of deuterium on the methine carbon based on the integration area of methine peak @ 7.16 ppm. The reaction was heated to 50 °C and stirred for an additional 8 hours, with NMR (methanol-cfe) 15 indicating >90% incorporation of deuterium. Additional formic acid 4Q uL formic acid (1.07 mmol) was added and the reaction stirred at 50 °C with stirring under a nitrogen atmosphere for another 6 hours. !H NMR (methanol-di) indicated 100% incorporation of deuterium on the methine carbon. A solution of DO (100 uL, 35 weight % in D2O) was added to the reaction solution. After 10 minutes, the reaction solution was concentrated, and the residue was 20 dried under vacuum overnight to give 96 mg of a white solid. The crude product was purified by silica chromatography, eluting with 100% ethyl acetate to 60% ethyl acetate / 40% [10% (28% ammonia in water) / 90% MeOH] to give the title compound as a white powder. 1H NMR (400 MHz, methanol- d4) 5: 8.02 (s, 1H), 7.84-7.90 (m, 1H), 7.52-7.63 (m, 5H), 7.33-7.39 (m, 2H), 7.20-7.27 (m, 2H), 6.97-7.05 (m, 1H), 6.86 25   6.91 (m, 1H), 6.73-6.79 (m, 1H), 4.76 (d, 1H), 4.26 (d, 1H), 2.99-3.08 (m, 2H), 2.56-2.66 (m, 1H), 2.35 (s, 3H), 2.21 (m, 2H), 1.77-1.94 (m, 4H); MS m / z: 548.3 [M+1]+. Compounds 037 and 038 were prepared following the procedure of Example 12. The crude product was then purified to separate enantiomers using a Chiralpak IA (10x250 mm 5 30 micron) column eluting with 45% (0.3% TEA in MeOH) / 55% CO2 at Back Pressure Regulator (BPR) value of 10 MPa and flow rate of 10 mL / min on a Jasco semi-prep SFC. Absolute configuration of the chiral center for each isolated enantiomer is unknown. First eluting peak (27.4 mg, 27%); 1H NMR (400 MHz, methanol-^) 0: 8.02 (s, 1H), 7.84-7.90 (m, 2026234102   18 Sep 2026 1H), 7.52-7.63 (m, 5H), 7.33-7.39 (m, 2H), 7.20-7.27 (m, 2H), 6.97-7.05 (m, 1H). 6.86-6.91 (m, 1H) 6.73-6.79 (m, 1H), 4.76 (d, 1H), 4.26 (d, 1H), 2.99-3.08 (m, 2H), 2.56-2.66 (m, 1H), 2.35 (s, 3H), 2.21 (m, 2H), 1.77-1.94 (m, 4H); MS m / z: 548.3 FM+1]’ Second eluting peak (31 mg, 28%); 1H NMR (400 MHz, methanol-d4) 5: 8.02 (s, 1H), 7.84-7.89 (m, 1H), 7.52-7.64 5   (m, 5H), 7.36 (d, 2H), 7.20-7.27 (m, 2H), 6.96-7.06 (m, 1H), 6.86-6.92 (m, 1H), 6.74-6.79 (m, 1H), 4.76 (d, 1H), 4.27 (d, 1H), 3.00-3.09 (m, 2H), 2.56-2.68 (m, 1H), 2.36 (s, 3H), 2.23 (m, 2H), 1.78-1.94 (m, 4H); MS m / z: 548.3 [M+1f. Example 13: Preparation of 2-((1H-Benzo[dlimidazol-2-vl)(5-fluoro-2-hvdroxyphenyl)methvl-10 d)-6-(4-(1-methylpiperidin-4-yl)phenyl)isoindolin-1-one-3,3-cfe (Compound 039) Scheme 16. c 033 ■          ।                                                                                                                                  r 2-((1 H-Benzo[d]imidazol-2-y!)(5-fluoro-2-hydroxyphenyl)methy!)-6-(4-(1- methylpiperidin-4-y!)phenyl) isoindolin-1-one (24.5 mg, 0.047 mmol) was stirred in CD3OD (1 15   g). D2O (0.5 mL) and sodium carbonate (9.84 mg, 0.093 mmol) were added and the mixture was stirred in a sealed vial at 50 °C for 18 hours. 'H NMR of the reaction mixture (methanol-d / ) indicated >95% incorporation of deuterium on the methine carbon, based on integration area of the methine peak @7.16 ppm as well as -60% incorporation of deuterium on the lactam methylene carbon. The reaction was stirred at 60 °C for an additional 48 hours. 1H 20 NMR of the reaction mixture (methanol-A) indicated complete deuteration of both the methine carbon and the lactam methylene carbon. The reaction was cooled to room temperature then a solution of 35 weight % DCI in D2O (50 uL, 0.48 mmol) was added. After stirring a few minutes, the reaction was concentrated and the residue purified by silica chromatography, eluting with 100% DCM to 100% (10% 7N NH3 in MeOH / DCM) to give the 25 title compound (18 mg, 70%) as a white powder. NMR (400 MHz, DMSO-d®) 5 ppm 12.08 -13.11 (m, 1 H) 9.72-10.71 (m. 1 H) 7.86 - 7.92 (m, 2 H) 7.60 - 7.69 (m, 3 H) 7.52 (br s, 2 H) 7,35 (d, 7=8.19 Hz, 2 H) 7.17 (br dd, 7=5.81, 3.00 Hz, 2 H) 7.01-7.11 (m, 1 H)) 6.91 (dd, 7=8.80, 4.77 Hz, 1 H) 6.80 (dd, 7=9.41, 3.06 Hz, 1 H) 3.05 - 3.21 (m, 1 H) 2.87 (br d, 7=11.25 Hz, 2 H) 1.87-2.06 (m, 2 H) 2.19 (s, 3 H) 1.62- 1.81 (m, 4 H); MS m / z: 550.3 30   [M+1]+. 2026234102   18 Sep 2026 Example 14: 2-nH~benzimidazol~2-vl-(5-fluoro-2-hydroxv-pherM)methvh-6~(4-(2-(dimethvl- amino)ethoxylphenyl]isoindolin-1-one; hydrochloride (Compound 040) Scheme 17 Step 1. N-(1H-benzimidazol-2-ylmethylene)-2-methyi-propane-2-sulf!namide \ / r--- aN N—d "° To a solution of 1H-1,3-benzodiazo!e-2-carbaldehyde (75.0 g, 513 mmol) and 2-methyl-2-propanesulfinamide (93.2 g, 769 mmol) in THF (1 L) was added titanium (IV) 10 ethoxide (175 g, 769 mmol). After stirring at 75 °C for 16 h, water was added and the reaction mixture was extracted with ethyl acetate three times. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. A solution of ethyl acetate and petroleum ether (1 / 1) was added to the residue and the resulting solid was isolated via filtration to give the title compound (65 g, 51%). 1H NMR 15   (400 MHz, CDCh) 5: 10.92 (s, 1H), 8.70-8.91 (m, 1H), 7.89 (d, 1H), 7.53 (d, 1H), 7.37 (dd, 2H), 1.19-1.32 (m, 9H). 2026234102   18 Sep 2026 propane-2-sulfinamide To a solution of 2-bromo-4-fluoro-1-(methoxymethoxy)benzene (84.6 g, 360 mmol) in 5 THF (600 mL) at -65 °C was added dropwise n-butyllithium (2.5 M in hexane, 158 mL, 396 mmol). After stirring at -65 °C for 20 minutes, the reaction mixture was cannulated to a precooled (-65 °C) solution of N-(1H-benzimidazol-2-ylmethylene)-2-methyl-propane-2-sulfinamide (45.0 g, 180 mmol) in THF (1100 mL). After stirring at -65 °C for 40 minutes, the reaction mixture was allowed to warm to 15 °C. The reaction mixture was quenched by 10 saturated ammonium chloride solution and extracted with ethyl acetate three times. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 33-100% ethyl acetate in petroleum ether to give the title compound (40 g, 38%). 1H NMR (400 MHz, CDCI3) 6: 11.26 (s, 1H), 7.32-7.77 (m, 2H), 7.14 15   7.23 (m, 3H), 7.10 (dd, 1H), 6.87-7.02 (m, 1H), 5.96 (d, 1H), 5.13 (d, 1H), 4.93-5.05 (m, 2H), 3.29 (s, 3H), 1.27-1.41 (m, 9H). Step 3. 1 H-benzimidazol-2-yl-F5-fluoro-2-(methoxymethoxy)phenyllmethanamine 20           To a solution of N-[1 H-benzimidazol-2-yl-[5-fluoro-2- (methoxymethoxy)phenyl]methyl]-2-methyl-propane-2-sulfinamide (30.0 g, 73.9 mmol) in methanol (600 mL) was added HCI in dioxane (4 M. 55.2 mL, 221 mmol) at 0 °C. After stirring 15 h at room temperature, the reaction mixture was diluted with water and adjusted to pH 8 by saturated sodium bicarbonate solution. The aqueous phase was extracted with 25 ethyl acetate three times. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (30.0 g, quant). 1H NMR (400 MHz, CDCh) 6: 7.56 (s, 2H), 7.19-7.26 (m, 2H), 7.06-7.12 (m, 2H), 6.89-6.97 (m, 1H), 5.64 (s, 1H), 5.12 (d, 2H), 3.32-3.41 (m, 3H). MS m / z: 302.3 [M+1]+. 2026234102   18 Sep 2026 isoindolin-1-one Ox,^' To a solution of 1H-benzimidazol-2-yl-[5-fluoro-2- 5 (methoxymethoxy)phenyl]methanam!ne (23,0 g, 76.3 mmol) in DMF (250 mL) was added DIPEA (37.5 mL, 228 mmol). The reaction mixture was stirred at room temperature for 5 min and then methyl 5-bromo-2-(bromomethyl)-benzoate (28.1 g, 91.5 mmol) was added. The reaction mixture was heated at 90 °C for 16 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate three times. The 10 combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (29.5 g, 78%). !H NMR (400 MHz, DMSO-de) 5: 12.69 (s, 1H), 7.87 (d, 1H), 7.80 (dd, 1H), 7.54-7.64 (m, 2H), 7.47 (d, 1H), 7.13-7.25 (m, 4H), 7.09 (s, 1H), 6.92 (dd, 1H), 5.10-5.22 (m, 2H), 4.74 (d, 1H), 4.17 (d, 1H), 3.14-3.23 (m, 3H); MS m / z: 496.1 [M+1JT 15 Step 5. 2-( 1 H-benzimidazol-2-vH5-fluoro-2-(methoxvmethoxy)phenvllmethyH-6-[4-f2-(dimethylamino)ethoxy]phenyllisoindolin-1-one A mixture of 2-(1 H-benzimidazoi-2-yi-[5-fluoro-2-(methoxymethoxy)phenyi]methyl]-6- 20 bromo-isoindolin-1-one (160 mg, 0.322 mmol), N-[2-(dimethylamino)ethyl]-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboralan-2-yi)aniline (132 mg, 0.436 mmol), sodium carbonate (89.0 mg, 0.840 mmol) and dioxane / water (5 mL, 4 / 1) was degassed under nitrogen twice. (1,r-bis(diphenylphosphino)ferrocene]dichloropalladium(n), complex with dichloromethane (41.1 mg, 0.050 mmol) was added and then the reaction mixture was degassed under 25 nitrogen once more. The reaction mixture was heated at 100 °C for 2 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate three times. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC eluting with 0-55% ACN / water containing 0.1% formic acid 30 to give the title compound (101 mg, 53%). 1H NMR (400 MHz, methanol-ds) ¢): 8.00 (s, 1H), 2026234102   18 Sep 2026 7.84 (dd, 1H), 7.51-7.64 (m, 5H), 7.19-7.27 (m, 4H), 7.09-7.17 (m, 1H), 7.05 (d, 2H), 6.86 (dd, 1H), 5.06-5.19 (m, 2H), 4.70 (d, 1H), 4.28 (d, 1H), 4.16 (m, 2H), 3.20 (s, 3H), 2.80 (m, 2H), 2.36 (s, 6H); MS m / z: 581.3 [M+1f. 5 Stey3jBJ2J4JH4)enzimjdazol^^ ethoxy]phenyHisoindolin-1-one;hydrochloride (Compound 040) To a solution of 2-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-[4-[2-(dimethyiam!no)ethoxy]phenyl]isoindolin-1-one 10   (0.108 g, 0.185 mmol) in dichloromethane (3.97 mL) was added HCI in dioxane (4 M, 0.462 mL, 1.85 mmol). After stirring 1 h at room temperature the solvent was removed under reduced pressure. Diethyl ether was added to the residue and the resulting solid was isolated via filtration to give the title compound (91 mg, 86%). 1H NMR (400 MHz, DMSO-ds) 5: 10.37 (br s, 1H), 10.22 (br s, 1H), 7.83-7.89 (m, 2H), 7.60-7.69 (m, 5H), 7.34-7.45 (m, 2H), 15   7.01-7.13 (m, 5H), 6.94 (dd, 1H), 4.71 (d, 1H), 4.35 (t, 2H), 4.19 (d, 1H), 3.42-3.49 (m, 2H), 2.79 (d, 6H); MS m / z: 537.3 [M+1]+. Example 15: 2-[1H-benz!midazoi-2~vl-(5-fluoro-2-hvdroxv-phenvl)methvH-6-[4~(1~ methvlazetidin-3-vl)phenvl1isoindolin~ 1-one (Compound 049} 20 Scheme 18 2026234102   18 Sep 2026 3-oxo-isoindoiin-5-yllphenyllazetidine-1-carboxylate J. ° A mixture of 2-(1 H-benzimidazol-2-yl-(5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6- 5 bromo-isoindolin-1-one (191 mg, 0.384 mmol), tert-butyl 3-[4-(4,4,5,5-tetramethyl-1,3)2-dioxaborolan-2-yl)phenyl]- 1-azetidinecarboxylate (158 mg, 0.441 mmol), sodium carbonate (105 mg, 0.990 mmol) and dioxane / water (9 mL, 4 / 1) was degassed under nitrogen twice. (1,T-bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane (62.7 mg, 0.077 mmol) was added and then the reaction mixture was degassed under 10 nitrogen once more. The reaction mixture was heated at 100 °C for 1 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate three times. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 0-75% ethyl acetate in hexanes to 15 give the title compound (164 mg, 66%). NMR (400 MHz, methanol-^) 6: 8.08 (s, 1H), 7.89-7.96 (m, 1H), 7.68-7.75 (m, 2H), 7.45-7.67 (m, 5H), 7.21-7.31 (m, 4H), 7.12-7.19 (m, 1H), 6.86-6.93 (m, 1H), 5.12-5.19 (m, 2H), 4.75 (d, 1H), 4.36-4.45 (m, 2H), 4.33 (d, 1H), 3.96-4.04 (m, 2H), 3.90 (d, 1H), 3.23 (s, 3H), 1.50 (s, 9H); MS m / z: 649.3 [M+1]+. 20 Step 2. 6-[4-(azetidin-3-yl)phenyll-2-[1 H-benzimidazol-2-yl-[5-fiuoro-2-(methoxymethoxy)-phenynmethyHisoindolin-1-one To a solution of tert-butyl 3-(4-(2-(1 H-benzimidazo!-2-yl-[5-fluoro-2-(methoxymethoxy)-phenyl]methyl]-3-oxo-isoindolin-5-yl]phenyl]azetidine-1-carboxylate (164 25 mg, 0.252 mmol) in dichloromethane (5 mL) was added ethanol (73.5 pL, 1.26 mmol) and zinc bromide (283 mg, 1.26 mmol). After stirring overnight at room temperature, the reaction mixture was added to a mixture of 1N NaOH solution and methanol and the resulting solid was isolated via filtration to give the title compound (44 mg, 32%). MS m / z: 549.3 [M+1 ]+. 2026234102   18 Sep 2026 azetidin-3-yl)phenyl]isoindolin-1-one To a solution of 6-[4-(azetidin-3-yl)phenyl]-2-[1H-benz!m!dazol-2-yl-[5-fluoro-2- 5 (methoxymethoxy)phenyl]methyl]isoindol!n-1-one (45 mg, 0.082 mmol) in methanol (0.983 mL) was added formaldehyde (37% in water, 60.9 pL, 0.164 mmol) The reaction mixture was stirred at room temperature for 5 min and then sodium cyanoborohydride (10,3 mg, 91,5 mmol) was added. The reaction mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with saturated sodium bicarbonate solution and extracted 10 with ethyl acetate three times. The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC eluting with 10-100% ACN / water containing 0.1% formic acid to give the title compound (14 mg, 30%). 1H NMR (400 MHz, methanol-ck) 5: 8.57 (s, 1H), 8.07 (d, 1H), 7.89-7.96 (m, 1H), 7.53-7.74 (m, 5H), 7.44-7.49 15   (m, 2H), 7.22-7.29 (m, 4H), 7.10-7.18 (m, 1H), 6.85-6.91 (m, 1H), 5.13-5.18 (m, 2H), 4.75 (d, 1H), 4.33 (d, 1H), 4.04-4.14 (m, 2H), 3.91-4.03 (m, 1H), 3.59-3.73 (m, 2H), 3.23 (s, 3H), 2.65 (s, 3H); MSm / z: 563.3 [M+lf. Step 4. 2-[1H-benz!midazol-2-vl-(5-fluoro-2-hvdroxv-phenvl)methvll-6-[4-(1-methvlazetidin-3- 20 yl)phenyllisoindolin-1-one (Compound 049) To a solution of 2-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-[4-(1-methylazetidin-3-yl)phenyl]isoindolin-1-one (14.0 mg, 0.0248 mmol) in dichloromethane (1 mL) was added HCI in dioxane (4 M, 62.0 pL, 25   0.248 mmol). After stirring overnight at room temperature, the solvent was removed under reduced pressure. The crude product was purified by reverse phase HPLC eluting with 10100% ACN / water containing 0.1% formic acid to give the title compound (3 mg, 23%). 1H NMR (400 MHz, methanol-cW 5: 8.06 (s, 1H), 7.88-7.94 (m, 1H), 7.68-7.74 (m, 2H), 7.637.67 (m, 1H), 7.52-7.61 (m, 2H), 7.44-7.51 (m, 2H), 7.23-7.29 (m, 2H), 7.16 (s, 1H), 7.00- 2026234102   18 Sep 2026 7.07 (m, 1H), 6.89-6.95 (m, 1H), 6.75-6.81 (m, 1H), 4.74-4.82 (m, 1H), 4.29 (d, 1H). 4.09 4.19 (m, 2H), 3.94-4.06 (m, 1H), 3.70-3.80 (m, 2H). 2.70 (s, 3H); MS m / z: 519.2 [M+1]T 5 rnethylazetidimTPyQpxypheny^^ Scheme 19 Step 1.2-[1H-benzimidazol-2-vi-[5-f!uoro-2-(methoxymethoxy)phenyl]methySl-6-(4,4,5,5- 10 tetramethyl-1.3,2-dioxaborolan-2-yl)isoindolin-1-one A mixture of 2-[1 H-benzimidazo!-2-yl-[5-f!uoro-2-(methoxymethoxy)pheny!]methyi]-6-bromo-isoindolin-1-one (6.30 g, 12.6 mmol), bis(pinacolato)diboron (3.19 g, 12.6 mmol), potassium acetate (3.70 g, 37.8 mmol) and dioxane (160 mL) was degassed under nitrogen 15 twice. [1,T-bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane (0.921 mg, 1.26 mmol) was added and then the reaction mixture was degassed under nitrogen once more. The reaction mixture was heated at 100 °C for 12 h. After cooling to room temperature, the reaction mixture was filtered through a pad of Ceiite. The filtrate was concentrated and triturated with a mixture of ethyl acetate and petroleum 20 ether (1 / 1) to give the title compound (5.10 g, 75%). 1H NMR (400 MHz, CDCh) 6: 11.78 (br s, 1H), 8.17 (s, 1H), 7.89 (d, 1H), 7.75 (s, 1H), 7.35-7.47 (m, 2H), 7.16-7.26 (m, 4H), 6.94 (dd, 2H), 4.75-4.83 (m, 2H), 4.69 (d, 1H), 4.45 (d, 1H), 2.98 (s, 3H), 1.33 (d, 12H); MS m / z: 544.1 [M+1]+ 2026234102   18 Sep 2026 methylazet!din-3-vl)oxyphenyllisoindolin-1-one A mixture of 2-[1 H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6- 5 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (0.309 g, 0.569 mmol), 3-(4-iodophenoxy)-1-methylazetidine (0.150 g, 0.518 mmol), potassium carbonate (0.215 g, 1.55 mmol) and dioxane / water (6 mL, 10 / 1) was degassed under nitrogen twice. (1,1'-bis(diphenyl-phosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane (75.3 mg, 0.259 mmol) was added and then the reaction mixture was degassed under 10 nitrogen once more. The reaction mixture was heated at 105 °C for 4 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate three times. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 11% methanol in dichloromethane 15 to give the title compound (150 mg, 50%). MS m / z: 579.1 (M+1]+. Step 3. 2-[1H-benz!midazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyll-6-[4-(1-methylazetidin-3-yl)oxyphenynisoindolin-1-one;dihydrochloride (Compound 056) 20           To a solution of 2-(1 H-benzimidazol-2-yl-[5-fluoro-2- (methoxymethoxy)phenyl]methyl]-6-[4-(1-methylazetidin-3-yl)oxyphenyl]isoindolin-1-one (0.150 g, 0.259 mmol) in dioxane (5 mL) was added HCI in dioxane (4 M, 3.0 mL, 12.0 mmol). After stirring 3 h at room temperature, the solvent was removed under reduced pressure. The crude product was purified by reverse phase HPLC eluting with 0-100% 25 ACN / water (0.05% HCI modifier) to give the title compound (22 mg, 15%). 1H NMR (400 MHz, DMSO-d6) 5: 10.59-10.96 (m, 1H), 10.28 (brs, 1H), 7.91-7.96 (m, 2H), 7.67-7.77 (m, 5H), 7.46 (s, 2H), 7.07-7.22 (m, 3H), 6.96-7.05 (m, 3H), 5.02-5.30 (m, 1H), 4.70-4.84 (m, 2H), 4.39-4.47 (m, 1H), 4.22-4.33 (m, 2H), 4.04-4.12 (m, 1H), 2.92 (m, 3H); MS m / z: 535.2 [M+1]L 2026234102   18 Sep 2026 The following examples were prepared by a similar method to Example 14 from 2-(1 H-benzimidazoi-2-yl-(5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-bromo-isoindolin-1-one and the corresponding boronate starting materials: No. Structure! Name m / z [M+1J* Y NMR (DMSO-ds) 0 Starting materials 057 2-[1H-benzimidazol-2-yl-(5-fluoro- 2-hydroxy-phenyl)-methyl]-6-[4- (1H-pyrazol-4-yl)-phenyl]isoindolin-1-one 516.2 8.05-8.20 (m, 2H), 7.92-7.97 (m, 2H), 7.67-7.75 (m, 5H), 7.47-7.57 (m, 2H), 7.11-7.24 (m, 2H), 6.98-7.08 (m, 2H), 6.87-6.97 (m, 1H), 6.79 (m, 1H), 4.81 (d, 1H), 4.21 (d, 1H) N-NH o cr "o 058 Qx ho I & Y X        2hci 2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)-methyl]-6-[4-(1-methylpyrazol-4-yl)phenyl]isoindolin-1 -one; dihydrochloride 530.2 10.25 (brs, 1H), 8.14 (s, 1H), 7.90-7.98 (m, 2H), 7.85 (s, 1H), 7.55-7.73 (m, 7H), 7.38-7.50 (m, 2H), 7.05-7.17 (m, 3H), 6.89-6.99 (m, 1H), 4.70 (d, 1H), 4.21 (d, 1H), 3.81 (s, 3H) n-i / V & O' "O 059 HO 1 O HCi Xyx 2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)-methyl]-6-(4-morpholinophenyl)-isoindolin-1-one; hydrochloride 535.2 7.90-7.95 (m, 2H), 7.72-7.79 (m, 2H), 7.63-7.71 (m, 3H), 7.51-7.57 (m, 2H), 7.17-7.25 (m, 2H), 7.03-7.17 (m, 4H), 4.76 (d, 1H), 4.27 (d, 1H), 3.75-3.82 (m, 4H), 3.14-3.26 (m, 4H) 0 060 / =\ / =\ MI O-Av hS 1I     kA Y^4!          HCI 2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)-methyl]-6-[1 -(1-methyl-4-piperidyl)pyrazol-4-yl]isoindolin-1-one;hydrochloride 537.2 10.99 (brs, 1H), 10.45 (brs, 1H), 8.45 (s, 1H), 8.08-8.13 (m, 1H), 7.99-8.05 (m, 1H), 7.90-7.96 (m, 1H), 7.73-7.80 (m, 2H), 7.61-7.68 (m, 1H), 7.52-7.59 (m, 2H), 7.13-7.24 (m, 3H), 7.03-7.11 (m, 1H), 4.71-4.80 (m, 1H), 4.43-4.50 (m, 1H), 4.24 (d, 1H), 3.493.60 (m, 2H), 3.18 (d, 2H), 2.73-2.81 (m, 3H), 2.29-2.40 (m, 4H) / -N / o cr A । । 2026234102   18 Sep 2026 061 —N. Z—   - - HO JI HCI 6-[4-(6-amino-3-pyridyl)phenyl]-2- [1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)-methyl]isoindo!in-1-one; hydrochloride 542 2 10.31 (brs, 1H), 8.36-8.42 (m, 2H), 8.15-8.31 (m, 2H), 8.00-8.08 (m, 2H), 7.87-7.93 (m, 2H), 7.66-7.85 (m, 5H), 7.38-7.51 (m, 2H), 6.99-7.25 (m, 5H), 4.83 (d, 1H), 4.29 (d, 1H) nh2 5 062 Qj fP-O-O" HO I & Y Y       HCI 2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)-methyl]-6-[4-(4-piperidyl)-phenyl]isoindolin-1-one; hydrochloride 533.3 10.31 (brs, 1H), 8.82-9.05 (m, 2H), 7.94-8.00 (m, 2H), 7.68-7.77 (m, 5H). 7.43-7.55 (m, 2H), 7.37 (d, 2H), 7.097.22 (m, 3H), 6.96-7.09 (m, 1H), 4.79 (d, 1H), 4.27 (d, 1H), 3.35-3.42 (m, 2H), 2.873.07 (m, 3H), 1.86-2.01 (m, 4H) ri Z Q d £ 041 Qj f 4 J--O-Z >-Ar St HO 1 b Yj       HCI 2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)-methyl]-6-[4-[2-(dimethylamino)-ethyl-methyl-amino]phenyl]-isoindolin-1 -one; hydrochloride 550.3 10.74 (brs, 1H), 10.30 (brs, 1H), 7.80-7.86 (m, 2H), 7.527.69 (m, 5H), 7.41-7.49 (m, 2H), 7.03-7.16 (m, 3H), 6.98 (d, 1H), 6.87 (d, 2H), 4.68 (d, 1H), 4.19 (d, 1H), 3.73 (m, 2H), 3.11-3.20 (m, 2H), 2.91 (s, 3H), 2.73 (d, 6H) \ / \=J b Y 029 / \ w„ / \ / \ Z x *              hcooh 2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyi)-methyl]-6-[2-flu oro-4-(1 -methyl-4-piperidyl)phenyl]isoindolin-1-onejformic acid 565.3 12.61 (brs, 1H), 9.99 (brs, 1H), 8.24 (s, 1H), 7.76-7.85 (m, 2H), 7.65-7.73 (m, 1H), 7.41-7.63 (m, 3H), 7.15-7.26 (m, 4H), 7.06-7.14 (m, 1H), 7.03 (s, 1H), 6.88-6.96 (m, 1H), 6.77-6.84 (m, 1H), 4.83 (d, 1H), 4.19 (d, 1H), 2.872.93 (m, 2H), 2.55-2.62 (m, 1H), 2.22 (s, 3H), 1.96-2.05 (m, 2H), 1.66-1.84 (m, 4H) ......      ...J o / The following examples were prepared by a similar method to Example 14 from the corresponding halogen-substituted phenol and boronate starting materials. The corresponding phenol was protected as methoxymethyl derivative prior to react with the 5 sulfinamide: 2026234102   18 Sep 2026 No. Structure / Name m / z [M+1]+ 1H NMR (DMSO-cfs) 6 Starting materials 042 HO      0 ||     1                 2HCi 2-[1H-benzimidazol-2-yl-(3-fluoro-2-hydroxy-phenyl)-methyl]-6-[4-(1-methyl-4- piperidyl)phenyl]isoindolin-1 -one;dihydrochloride 547.3 10.64 (brs, 1H), 10.45 (brs, 1H), 7.94-8.00 (m, 2H), 7.687.76 (m, 5H), 7.43-7.52 (m, 2H), 7.29-7.42 (m, 3H), 7.22 (s, 1H), 7.02-7.10 (m, 1H), 6.89-6.98 (m, 1H), 4.78 (d. 1H), 4.24 (d, 1H), 3.45-3.54 (m, 2H), 3.07 (d, 2H), 2.832.92 (m, 1H), 2.77 (d, 3H), 1.92-2.15 (m, 4H) Br HC\ 1 Xl and 0 £ -YX- 043 cxy ho x $ J| I               2HCi Ci 2-[1H-benzimidazol-2-yi-(3-chloro- 2-hydroxy-phenyl)-methyl]-6-[4-(1- methyl-4- piperidyl)phenyl]isoindolin-1- one;dihydrochloride 564.3 10.82 (brs, 1H), 10.18 (brs, 1H), 7.95-8.01 (m, 2H), 7.707.78 (m, 5H), 7.47-7.57 (m, 3H), 7.38 (d, 2H). 7.21-7.28 (m, 2H), 7.00 (m, 11-1),4.78 (d, 1H), 4.27 (d, 1H), 3.463.53 (m, 2H), 3.02-3.14 (m, 2H), 2.74-2.92 (m, 4H), 1.942.16 (m, 4H) X cr and fit y £ O' Y) XX 044 ‘X...?X:::X\...X HO X^ "Jl X           HCI 2-[1H-benzimidazol-2-yl-(5-chloro- 2-hydroxy-phenyl)-methyl]-6-[4-(1- methyl-4- piperidyl)phenyl]isoindolin-1-one;hydroch!oride 564.3 10.66 (brs, 2H), 7.95-8.01 (m, 2H), 7.68-7.79 (m, 5H), 7.45-7.53 (m, 2H), 7.29-7.44 (m, 4H), 7.14 (s, 1H), 7.06 (d, 1H), 4.80 (d, 1H), 4.28 (d, 1H), 3.46-3.55 (m, 2H), 2.973.14 (m, 2H), 2.84-2.92 (m, 1H), 2.78 (d, 3H), 1.93-2.16 (m, 4H) HO XAci and y 0 o- Y) The following example was prepared by a similar method to Example 14 from She corresponding aldehyde and boronate starting materials: No. Structure / Name m / z [M+1]+ 'H NMR (DMSO-cfs) 6 Starting materials 045 HcyX $ 2-[(5-fluoro-2-hydroxy-phenyl)-(1H-pyrazol-3-yl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]-isoindolin-1-one 497.2 12.84 (brs, 1H), 9.78 (brs, 1H), 7.84-7.96 (m, 2H), 7.607.80 (m, 4H), 7.31-7.49 (m, 2H), 7.00-7.12 (m, 1H), 6.796.98 (m, 3H), 6.22 (s, 1H), 4.61 (d, 1H), 4.19 (d, 1H), 3.17-3.23 (m, 1H), 2.86-3.00 (m, 2H), 2.26 (s, 3H), 1.98- hn_n Y and 2026234102   18 Sep 2026 2.12 (m, 2H), 1.66-1.90 (m, 4H) N u O' -O The following examples were prepared by a similar method to Example 2 from ethyl 2-amino-2-[5-fiuoro-2-(methoxymethoxy)phenyl]acetate and either methyl 5-bromo-2-(bromo-methyl)-benzoate or methyl 6-bromo-3-(bromomethyl)picolinate; and the corresponding diamino aryl starting materials: No. Structure / Name m / z [M+1]+ !H NMR (DMSO-c / s) 6 Starting materials 046 VvX' || J           HCOOH F 2-[(5-fluoro-1H-benzimidazol-2-yl)-(5-fluoro-2-hydroxy-phenyl)-methy!]-6-[4-(1 -methyl-4-pipendyl)phenyl]isofndoisn-1~ onejformic acid 565.3 !H NMR (methanol-A) 6: 8.53-8.57 (m, 1H), 8.04 (s, 1H), 7.87-7.92 (m, 1H). 7.617.70 (m, 3H), 7.51-7.56 (m, 1H), 7.38-7.44 (m, 2H), 7.237.29 (m. 1H), 7.14 (s, 1H), 7.00-7.08 (m, 2H), 6.89-6.95 (m, 1H), 6.77-6.83 (m, 1H), 4.80 (d, 1H), 4.29 (d, 1H), 3.45-3.55 (m, 2H), 2.77-3.04 (m, 6H), 2.06-2.17 (m, 2H), 1.94-2.06 (m, 2H) fjX 047 Qr £pX>-C> HCOOH 24(4-chloro-1H-benzimidazol-2-yl)-(5-fluoro-2-hydroxy-phenyl)-methyl]-6-[4-(1 -methyl-4-piperidyl)phenyl]isoindolin-1-onejformic acid 581.3 8.21 (s, 1H), 7.88-7.96 (m, 2H), 7.64-7.72 (m, 3H), 7.437.55 (m, 1H), 7.37 (d, 2H), 7.17-7.30 (m, 2H), 7.01-7.13 (m, 2H), 6.90-6.95 (m, 1H), 6.77-6.85 (m, 1H), 4.79 (d, 1H), 4.21 (d, 1H), 2.90-3.00 (m, 2H), 2.54-2.63 (m, 1H), 2.25-2.30 (m, 3H), 2.03-2.16 (m, 2H), 1.67-1.83 (m, 4H) z^NH2 'L^LnH2 048 'X' HO I b X XL      HCOOH 2-[(5-fluoro-2-hydroxy-phenyl)-(5-methoxy-1 H-benzimidazol-2-yl)methyl]-6-[4-(1 -methyl-4-pipendyl)phenyl]isofndoisn-1~ onejformic acid 577.3 8.22 (s, 1H), 7.86-7.94 (m, 2H), 7.67 (d, 3H), 7.32-7.47 (m, 3H), 7.04-7.10 (m, 1H), 7.00 (s, 1H), 6.89-6.94 (m, 1H), 6.76-6.84 (m, 2H), 4.81 (d, 1H), 4.17 (d, 1H), 3.77 (s, 3H). 2.96-3.05 (m, 2H), 2.552.64 (m, 1H), 2.32 (s, 3H), 2.13-2.24 (m, 2H), 1.69-1.85 (m, 4H) 2026234102   18 Sep 2026 050 ‘SA / - / HCOOH 2-[(5-fluora-2-hydroxy-phenyl)-(5-methy!-1 H-benzimidazol-2-yl)methyl]-6-[4-(1 -methyl-4-piperidyl)phenyl]isoindolin-1-one;formic acid 561.3 8.20 (s. 1H), 7.86-7.95 (m, 2H), 7.64-7.69 (m, 3H), 7.247.49 (m, 4H), 7.05-7.11 (m, 1H), 6.95-7.04 (m, 2H), 6.886.93 (m. 1H), 6.74-6.81 (m, 1H), 4.81 (d, 1H), 4.17 (d, 1H), 2.88-2.98 (m, 2H), 2.532.60 (m, 1H), 2.41 (s, 3H), 2.24 (s, 3H), 1.99-2.10 (m, 2H), 1.66-1.82 (m, 4H) 051 Q't KO 1 I HCOOH 24(5-fluoro-2-hydroxy-phenyl)-(4-methoxy-1 H-benzimidazol-2-yi)methyi]-6-[4-(1 -methyl-4-piperidyl)phenyl]isoindol!n-1-onejormic acid 577.3 8.12-8.19 (m, 1H). 7.79-7.86 (m, 2H), 7.55-7.63 (m, 3H), 7.28 (d, 2H), 6.90-7.07 (m, 4H), 6.79-6.86 (m, 1H), 6.596.74 (m, 2H), 4.72 (d, 1H). 4.09 (d, 1H), 3.81 (s, 3H), 2.83-2.98 (m, 2H), 2.46-2.54 (m, 1H), 2.19-2.29 (m, 3H), 2.00-2.17 (m, 2H), 1.60-1.79 (m, 4H) X'”- 052 / —vv" — — — HO,,^ & T I         HCOOH F 2-[(5-fluoro-2-hydroxy-phenyl)-(4-methyl-1 H-benzimidazol-2-yl)methy!]-6-[4-(1 -methyl-4-piperidyl)phenyl]isoindolin-1-onejformic acid 561.3 8.23 (s, 1H), 7.87-7.93 (m, 2H), 7.63-7.71 (m, 3H), 7.257.45 (m, 3H), 7.03-7.10 (m, 3H), 6.96-7.01 (m, 1H), 6.866.95 (m: 1H), 6.72-6.85 (m, 1H), 4.85 (d, 1H), 4.18 (d, 1H), 2.89-2.99 (m, 2H), 2.542.60 (m, 1H), 2.48 (s, 3H), 2.25 (s, 3H), 2.02-2.12 (m, 2H), 1.65-1.86 (m, 4H) CT 028 IX 6-[1H-benzimidazo!-2-yl-(5-f!uoro-2-hydroxy-phenyl)-methyl]-2-[4-(1-methyl-4-piperidyl)phenyl]-5H-pyrrolo-[3,4-b]pyridin-7-one 548.3 12.65 (brs, 1H), 9.98 (brs, 1H), 8.05-8.17 (m, 4H), 7.547.65 (m, 1H), 7.35-7.52 (m, 3H), 7.15-7.26 (m, 2H), 7.047.12 (m, 2H), 6.90-6.98 (m, 1H), 6.80-6.88 (m, 1H), 4.81 (d, 1H), 4.20 (d, 1H), 2.893.00 (m, 2H), 2.55-2.62 (m, 1H), 2.25 (S 3H), 2.01-2.16 (m, 2H) 1.68-1.84 (m, 4H) CT The following examples were prepared by a similar method to Example 6 from methyl 2-bromo-2-(5-fluoro-2-methoxy-phenyl)acetate and the corresponding bicyclic starting materials: 2026234102   18 Sep 2026 No. Structure / Name m / z [M+1]+ 1H NMR (DMSO-cfs) 6 Starting materials 053 .... । HCI 2-[1H-benzimidazol-2-yl-(5-fluoro- 2-hydroxy-phenyl)-methyl]-4-fluoro- 6-(4-(1 -methyl-4- piperidyl)phenyl] isoquinolin-1 -one;hydrochloride 577.3 10.19-10.46 (m, 2H), 8.338.39 (m, 1H), 7.98-8.05 (m, 2H), 7.86 (d, 2H). 7.60-7.71 (m, 3H), 7.34-7.51 (m, 5H), 7.15-7.23 (m, 1H), 6.89-7.03 (m, 2H), 3.49-3.54 (m, 2H), 3.05-3.16 (m, 2H), 2.76-2.92 (m, 4H), 2.00-2.09 (m, 4H) 1      Br AT r 054 F I Lt. 2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)-methyl]-4-fluoro-7-(4-(1-methyl-4- piperidyl)phenyl]isoquinolin-1 -one 577.3 12.78 (brs, 1H), 10.03 (brs, 1H), 8.51 (s, 1H), 8.18-8.23 (m, 1H), 7.88 (d, 1H), 7.73 (d, 2H), 7.58-7.67 (m, 2H), 7.46-7.55 (m, 1H), 7.36-7.43 (m, 3H), 7.17-7.27 (m, 2H), 7.10-7.16 (m, 1H), 6.90-6.95 (m, 1H), 6.72-6.77 (m, 1H), 2.91-3.01 (m, 2H), 2.54-2.62 (m, 1H), 2.27 (s, 3H), 2.042.17 (m, 2H), 1.66-1.85 (m, 4H) A 11. ---- The following examples were prepared by a similar method to Example 6 from methyl 2-bromo-2-(5-fluoro-2-methoxyphenyl)acetate or methyl 2-bromo-2-(5-fluoro-2-5 (methoxymethoxy)phenyl)acetate and the corresponding bicyclic starting materials: No. Structure / Name m / z [M+1]+ ’H NMR (DMSO-ds) 5 Starting materials 096 HO J. a “ci 2-[1H-Benzimidazol-2-yl-(7-methyl- 6-(4-(1 -methyl-4- piperidyl)phenyl]indazol-2- yl]methyl]-4-fluoro-phenol;dihydrochloride 546.4 10.92 (brs, 1H), 10.61 (brs, 1H), 8.64 (s, 1H), 7.91 (s, 1H), 7.75 (dd, 2H), 7.65 (d, 1H), 7.50 (dd, 2H), 7.26-7.42 (m, 4H), 7.14-7.23 (m, 1H), 7.05-7.13 (m, 1H), 7.01 (d, 1H), 6.78 (dd, 1H), 3.47 (d, 2H), 3.02-3.12 (m, 2H), 2.82-2.88 (m, 1H), 2.74 (d, 3H), 2.39 (s, 3H), 2.05-2.16 (m, 2H), 1.88-2.04 (m, 2H). 097 OH 548.1 12.60 (brs, 1H), 12.46 (brs, 1H), 9.37 (brs, 1H), 8.14 (s, 1H), 7.52-7.60 (m, 2H), 7.33-7.49 (m, 4H), 7.15-7.28 (m, 4H), 7.047.13 (m, 1H), 7.01 (s, 1H), 6.89 ccC H 2026234102   18 Sep 2026 2-[1H-Benzimidazol-2-y!-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[4-(1-methy!-4-piperidyf) phe nyl] indazof-5-ol (dd, 1H), 6.83 (dd, 1H), 3.263.31 (m, 1H), 2.88 (d, 2H), 2.20 (s, 3H), 1.92-2.04 (m, 2H) 1.631.79 (m, 4H). 098 ' XaYA ' if J          2HCi 2-[1H-Benzimidazol-2-yl-[5-methyl-644-(1-methyl-4-piperidyl)phenyl]~ indazol-2-yl]methyl]-4-fluoro- phenol;dihydroch!oride 546.1 10.78 (brs, 1H), 8.60 (s, 1H), 7.85 (s, 1H), 7.74 (dd, 2H), 7.66 (s, 1H), 7.49 (dd, 2H), 7.39 (s, 1H), 7.26-7.36 (m, 4H), 7.117.21 (m, 1H), 7.04 (dd, 1H), 6.64 (dd, 1H), 3.47 (d, 2H), 3.04-3.12 (m, 2H) 2.83-2.87 (m, 1H), 2.75 (d, 3H), 2.21 (s, 3H), 1.97-2.13 (m, 4H). ’H'Y H 099 Qyh — X    N V-   - - N Xx 2-[1 H-Benzimidazol-2-yf-[5-methoxy-6-[4-(1 -methyl-4-piperidy!)phenyl]indazol-2-y i] m eth y l]-4-f lu o ro-ph e n o i 562.6 8.27 (s, 1H), 7.43-7.64 (m, 4H), 7.39 (d, 2H), 7.26 (d, 2H), 7.157.23 (m, 2H), 7.13 (s, 1H), 7.047.12 (m, 1H), 6.90 (dd, 1H), 6.83 (dd, 1H), 3.73 (s, 3H), 3.31-3.32 (m, 1H), 2.87 (d, 2H), 2.19 (s, 3H), 1.89-2.02 (m, 2H),1.62-1.80 (m, 4H). 'N "Y^Br h 100 X z^-nh     )        V HCS<Z tfa 2-((1H-Benzo[d]imidazol-2-yl)(6-(4-(1-methylpiperidin-4-yl)phenyl)-2H-indazol-2-yl)methyl)-4-fluorophenol; trifluoroacetate 531.9 10.20 (brs, 1H), 9.43 (brs, 1H), 8.50 (s, 1H), 7.84 (s, 1H), 7.83 (d, 1H), 7.70 (d, 2H), 7.60 (m, 3H), 7.39 (dd, 1H), 7.34 (d, 2H), 7.27 (m, 2H), 7.13 (m, 1H),6.94 (dd, 1H), 6.86 (dd, 1H), 3.54 (m, 2H), 3.10 (m, 2H), 2.85 (m, 1H), 2.83 (d, 3H), 2.06 (m, 2H), 1.86 (m, 2H) 0 Y -ZJ- 101 Ox rQ-C / O- F      y "N >• nxA, TFA TA 4-Fluoro-2-((4-fluoro-1 H-benzo[dj-imidazol-2-yl)(7-fluoro-6-(4-(1 -methylpiperidin-4-yl)phenyl)-2H-indazol-2-yl)methyl) phenol; tri fluoroacetate 567.9 10.21 (brs, 1H), 9.49 (brs, 1H), 8.59 (d, 1H), 7.64 (d, 1H), 7.59 (m, 3H), 7.38 (d, 2H), 7.22 (m, 1H), 7.16 (m, 2H), 7.03 (dd, 1H), 6.95 (dd, 1H), 6.90 (dd, 1H), 3.56 (m, 2H), 3.10 (m,2H), 2.87 (m, 1H), 2.83 (d, 3H), 2.07 (m, 2H), 1.88 (m, 2H) H 7 and xx NH? 102 2-((4-Fluoro-1H-benzo[d]imidazol- 2-yD(5-fluoro-2- hydroxyphenyl)methyl)-6-(4-(1- 576.9 10.05 (brs, 1H), 9.48 (brs, 1H), 8.30 (d, 1H), 7.97 (d, 1H), 7.85 (dd, 1H), 7.80 (d, 2H), 7.66 (s, 1H), 7.40 (d, 2H), 7.36 (d, 1H), 7.29 (d, 1H), 7.20 (m, 1H), 7.13 (m, 1H), 7.03 (dd, 1H), 6.92 (dd, 1H), 6.73 (d, 1H), 6.67 (dd, 1H), 3.56 (m, 2H), 3.10 (m, 2H), 2.88 (m, 1H), 2.83 (d, 3H), 2.07 (m, 2H), 1.88 (m, 2H) 81 and CT 2026234102   18 Sep 2026 methyl piperidin-4- yl)phenyl) isoquinolin-1 (2H)-one The following examples were prepared by a similar method to Example 7 from ethyl 2- amino-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetate and the corresponding boronate and acid starting materials: No. Structure / Name m / z [M+ir ’H NMR (DMSO-ds) 8 Starting materials 055 f \     N - XY 3-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)-methyl]-5-methyl-6-[4-(1 -methyl-4- piperidyl)phenyl]-quinazolin-4-one; dihydrochloride 574.3 10.29-10.47 (m, 2H), 8.21 (s, 1H), 7.64-7.71 (m, 3H), 7.577.64 (m, 1H), 7.47-7.54 (m, 1H), 7.30-7.44 (m, 6H), 7.177.24 (m, 1H), 7.00-7.06 (m, 1H), 6.91-6.98 (m, 1H), 3.463.55 (m, 2H), 3.01-3.14 (m, 2H), 2.84-2.94 (m, 1H), 2.79 (d, 3H), 2.64 (s, 3H), 1.932.15 (m, 4H) os YQ 007 “VAYMyY hoy yY. 3-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-5-fluoro-6-p-fluoro-4-(1 -methyl-4-piperidyl)phenyl]quinazolin-4-one;hydrochloride 596.3 10.20-10.48 (m. 2H), 8.29 (s. 1H), 7.99-8.06 (m, 1H), 7.617.70 (m, 3H), 7.40-7.54 (m, 4H), 7.33-7.38 (m, 2H), 7.177.23 (m, 1H), 6.99-7.05 (m, 1H), 6.90-6.97 (m, 1H), 3.493.55 (m, 2H), 3.07-3.21 (m, 3H), 2.69-2.86 (m, 3H), 1.962.17 (m, 4H) A O” X 1 1 and YBr The following example was prepared by a similar method to Example 8 from 2-(1 H- Benzimidazol-2-yl-[1-(2-trimethylsilylethoxymethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-3-yl]methy!]-6-bromo-isoindolin-1-one and 5-ethynylpyridin-2-amine in a similar manner to Example 4, step 3: No. Structure / Name m / z [M+1]+ ’H NMR (DMSO-cfe) 5 030 Qr fQ-O* —x 6-[2-(6-amino-3-pyridyl)ethynyl]-2- [1 H-benzimidazol-2-yl(1,4,5,6-tetrahydrocyclopenta-[c]pyrazol-3- yl)methyl]-isoindolin-1 -one 486.2 12.28-12.77 (m, 2H), 8.16 (d, 1H), 7.78 (s, 1H), 7.61-7.75 (m, 2H), 7.54 (m, 3H), 7.097.26 (m, 2H), 6.81 (s, 1H), 6.39-6.50 (m, 3H), 4.91 (d, 1H), 4.27-4.43 (m, 1H), 2.54-2.66 (m, 2H), 2.13-2.37 (m, 3H), 1.86-2.00 (m, 1H) 2026234102   18 Sep 2026 The following compounds were prepared by a similar method to Example 16 from 2-[1H-benzimidazol-2-yi-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-(4,4,5,5-tetramethyl-1,3!2-dioxaborolan-2-yl)isoindolin-1-one and the corresponding aryi halide starting materials: No. Structure / Name m / z [M+ir ’H NMR (DMSO-ds) 5 Starting materials 090 XT 'i    X tX 2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[4-[(1-methyl-4- piperidyl)oxy]phenyl]isoindolin-1-one 563.4 12.61 (brs, 1H), 9.94 (brs, 1H), 7.83-7.94 (m, 2H), 7.547.70 (m, 4H), 7.39-7.48 (m, 1H), 7.12-7.23 (m. 2H), 7.007.10 (m, 4H), 6.83-6.94 (m, 1H), 6.72-6.80 (m, 1H), 4.79 (d, 1H), 4.33-4.48 (m, 1H), 4.16 (d, 1H), 2.53-2.67 (m, 2H), 2.10-2.28 (m, 5H) 1.882.00 (m, 2H), 1.68-1.81 (m, 2H) 091 O--NH Y i 2Hci 'X'F 6-[4-(azetidin-3-yloxy)phenyl]-2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyi)methyijisoindolin-1-one;dihydrochloride 521.3 10.28 (brs, 1H), 9.30 (brs, 1H) 9.15 (brs, 1H), 7 897.99 (m, 2H), 7.61-7.80 (m, 5H), 7.36-7.51 (m, 2H), 6.927.24 (m, 6H), 5.09-5.20 (m, 1H), 4.78 (d.1H). 4.46-4.51 (m, 2H), 4.23 (d, 1H), 3.934.05 (m, 2H) I 0 A & Example 17: Preparation of 4~[3-fluoro-4-(4<4<5.5-tetramethyl-1,3,2-dioxaborolan~2~yl)~ phenyll-1-methyl-pipendine Scheme 20 A mixture of 1-bromo-2Tluoro-4-iodobenzene (10.0 g, 33.2 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (7.40 g, 33.2 mmol), 15 sodium carbonate (10.9 g, 99.6 mmol), 2026234102   18 Sep 2026 [1,T-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (2.42 g, 3.32 mmol), and dioxane / water (100 mL. 4 / 1) was degassed under nitrogen twice. The reaction mixture was heated at 100 °C for 16 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate three times. The combined organic 5 extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 50-67% ethyl acetate in petroleum ether to give the title compound (7.00 g, 78%). NMR (400 MHz, methanol-d4) 5:7.51-7.59 (m, 1H), 7.25-7.31 (m, 1H), 7.13-7.23 (m, 1H), 6.21-6.24 (m, 1H), 3.10-3.16 (m, 2H), 2.67-2.75 (m, 2H) 2.52-2.61 (m, 2H), 2.39 (s, 10   3H): MS 271.8 [M-MT . Step 2. 4-[3-fluoro-4-(4,4,5,5-tetramethy!-1.3,2-dioxaborolan-2-yl)phenyi1-1-methyl-3,6-dihydro-2H-pyridine A mixture of 4-(4-bromo-3-fluoro-phenyl)-1-methyl-3,6-dihydro-2H-pyridine (1.00 g, 3.70 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.40 g, 5.55 mmol), [1,T-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (0.541 g, 0.740 mmol), potassium acetate (1.08 g, 11.1 mmol) and dioxane (20 mL) was degassed under nitrogen 20 twice. The reaction mixture was heated at 100 °C for 3 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate three times. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 50-100% ethyl acetate in petroleum ether to give the title 25 compound (0.432 g, 37%). ''H NMR (400 MHz, methanol-cW 5: 7.60-7.68 (m, 1H), 7.22-7.27 (m, 1H), 7.06-7.13 (m, 1H), 6.20-6.27 (m, 1H), 3.16-3.23 (m, 2H), 2.74-2.81 (m, 2H), 2.572.64 (m, 2H), 2.44 (s, 3H), 1.34 (s, 12H); MS m / z: 318.1 [M+1]+. Step 3. 4-[3-fiuoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-piperidine 2026234102   18 Sep 2026 To a solution of palladium (10% on carbon, 0.900g, 0.851 mmol) in methanol (54 mL) was added 4-[3-f!uoro-4-(4,4,5,5-tetramethy!-1,3,2-dioxaboro!an-2-yl)phenyl]-1-methyl-3,6-dihydro-2H-pyridine (2.70 g, 8.51 mmol). The flask was evacuated and backfilled with hydrogen and the reaction mixture was allowed to stir at 30 °C under an atmosphere of 5 hydrogen (50 psi) for 48 h. The reaction mixture was filtered through a pad of Celite which was washed several times with methanol. The filtrate was concentrated under reduced pressure to give the title compound (1.89 g, 70%). 1H NMR (400 MHz, methanol-^) 6: 7.617.67 (m, 1H), 7.06-7.11 (m, 1H), 6.89-7.00 (m, 1H), 2.98-3.11 (m, 2H), 2.53-2.69 (m, 1H), 2.37 (s, 3H) 2.16-2.27 (m, 2H), 1.72-1.93 (m, 4H) 1.35 (s, 12H); MS m / z: 320.1 [M+1]\ 0 Example 18: Preparation of 7-fluoro-2-[(R)-(5~fluoro-2-hydroxy-phenyl)~(4~methyl-1H~ imidazol-2-yl)methy!l-6-!4-( 1-methyl-4-piperidyl)phenyl]iso!ndolin- 1-one and 7-fluoro-2-[(S)-(541uoro-2-hydroxy-phenyl)-(4-methyl-1H4mfdazol-2-yl)methyl1-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one (094 and 09§) 7-Fluoro-2-[(5-fluoro-2-hydroxy-phenyl)-(5-methyl-1H-imidazol-2-yl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one (093, 0.020 g, 0.038 mmol) was purified by prep SFC with a Chiral Technologies Chiralpak IA (5micron 250x10mm) column @ 40 °C eluting with 45% (0.3% TEA in MeOH) / 55% CO2 at 10 MPa to separate enantiomers. Absolute 20 configuration of the chiral center for each isolated enantiomer is unknown. First eluting peak (094) (6 mg, 30% yield, 100:0 er); [a]20D-78.3 (c= 0.035, MeOH); 1H NMR (DMSO-ds) 6: 11.77-12.05 (m, 1H), 10.08 (br s, 1H), 7.65-7.74 (m, 1H), 7.43-7.50 (m, 3H), 7.37 (d, 2H), 6.97-7.07 (m, 1H), 6.77-6.88 (m, 2H), 6.73 (s, 1H). 6.53-6.65 (m, 1H), 4.73 (d, 1H), 4.09 (d, 1H), 2.88 (d, 2H), 2.41-2.49 (m, 1H), 2.20 (s, 3H), 2.12 (s, 3H), 1.94-2.03 (m, 2H), 1.64-1.81 25   (m, 4H); MS m / z: 529.3 [M+1]*. Second eluting peak (095) (6 mg, 30% yield, 97.8:2.2 er); [o]2% +55.3 (c= 0.038, MeOH); 1H NMR (DMSO-ds) 5: 11.78-12.05 (m, 1H), 10.06 (brs, 1H), 7.66-7.75 (m, 1H), 7.44-7.51 (m, 3H), 7.38 (d, 2H), 6.97-7.07 (m, 1H), 6.77-6.88 (m 2H), 6.73 (s, 1H), 6.52-6.65 (m, 1H), 4.74 (d, 1H), 4.10 (d, 1H), 2.89 (d, 2H), 2.41-2.49 (m, 1H), 2.21 (s, 3H), 2.13 (s, 3H), 1.94-2.05 (m, 2H), 1.64-1.82 (m, 4H); MS m / z: 529.3 [M+1]+. 2026234102   18 Sep 2026 Example 19: 2-[(5-Fluoro-2-hYdmxv-phenvl)-[5-(trifluoromethyl)-1H-imidazol-2-Yllmethvl1-6- [4-( 1-methvl-4-pipendvl)phenylJisoindolin-1 -one:hydrochloride (103) Scheme 21 Step 1.2-Methyl-N-[[5-(trifluoromethyl)-1 H-imidazol-2-yllmethyiene]propane-2-sulfinamide f3c / -NH , 8 To a solution of 5-(trifluoromethyl)-1H-imidazole-2-carbaldehyde (9.80 g, 59.7 mmol) and 2-methylpropane-2-sulfinamide (10.8 g, 98.5 mmol) in THF (300 mL) was added 10 tetraethyl orthotitanate (20.4 g, 89.5 mmol). After stirring at 75 °C for 5 h, the reaction mixture was quenched by water and extracted with ethyl acetate three times. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 0-100% ethyl acetate in petroleum ether to give the title 2026234102   18 Sep 2026 compound (9.6 g, 60%). !H NMR (400 MHz, CDCI3) 6: 11.34 (brs, 1H), 8.52 (s, 1H). 7.49 (s, 1H), 1.16 (s, 9H); MS m / z: 267.9 [M+1]+. Step2..2.-.Met}Tyl-N-[{:5-(trifiLp.ro.methyi)-% 5 vnmethyienelpropane-2-suifinamide To a solution of 2-methyl-N-[[5-(trifluoromethyl)-1H-imfdazo!-2-yl]methylene]propane-2-sulfinamide (9.60 g, 35.9 mmol) in DMF (200 mL) was added sodium hydride (1.29 g, 53.8 mmol) at 0 °C. After stirring at the same temperature for 15 min, 2 10 (trimethylsilyl)ethoxymethyl chloride (8.96 g, 53.8 mmol) was added. After stirring at room temperature for 2 h, the reaction mixture was quenched by water and extracted with ethyl acetate three times. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 0-10% ethyl acetate in petroleum 15 ether to give the title compound (6.5 g, 46%). 1H NMR (400 MHz, CDCb) 6: 8.65 (s, 1H), 7.60 (s, 1H), 5.90 (d, 1H), 5.71 (d, 1H), 3.50-3.68 (m, 2H), 1.28 (s, 9H), 0.87-0.97 (m, 2H), -0.01-0.01 (m, 9H); MS m / z: 398.0 [M-r-1]+ Step 3. N-[(5-Fluoro-2-methoxy-phenvl)-F5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)- 20 imidazol-2-vnmethvll-2-methvl-propane-2-sulfinamide To a solution of 2-methyl-N-[[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]methylene]propane-2-sulf!namide (6.50 g, 16.3 mmol) in THF (100 mL) was added dropwise a solution of 5-fluoro-2- 25 methoxyphenylmagnesium bromide in THF (0.5 M, 97.8 mL, 48.9 mmol) at -78 °C. After stirring at room temperature for 16 h, the reaction mixture was poured into sat. ammonium chloride solution and extracted with ethyl acetate three times. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC eluting with 0-100% 2026234102   18 Sep 2026 ACN / water containing 10 mM ammonium acetate to give the title compound (1.9 g, 22%). !H NMR (400 MHz. CDCh) 6: 7.24-7.33 (m, 1H), 6.93-7.07 (m, 2H), 6.84 (dd, 1H), 6.15 (d, 1H), 5.17-5.26 (m, 2H), 4.92 (d, 1H), 3.85 (s, 3H), 3.24-3.45 (m, 2H), 1.21 (s, 9H), 0.74-0.89 (m, 2H), -0.06-0.00 (m, 9H); MS m / z: 524.1 [M+1]+. 5 Step 4. (5-Fiuoro-2-methoxv-phen¥l)-[5-(trifluoromethyl)-1-(2-trimethyisilylethoxymethyO-imidazol-2-vllmethanamine To a solution of N-[(5-f!uoro-2-methoxy-phenyl)-[5-(trifluoromethyl)-1-(2-trimethylsilyl-10 ethoxymethyl)imidazol-2-yl]methyl]-2-methyl-propane-2-sulfinamide (1.90 g, 3.62 mmol) in methanol (80 mL) was added HCI in methanol (4 M, 9.05 mL, 36.2 mmol) at 0 °C. After stirring at room temperature for 2 h, the solvent was removed under reduced pressure. The crude product was purified by reverse phase HPLC eluting with 0-100% ACN / water containing 10 mM ammonium acetate to give the title compound (1.1 g, 73%). 1H NMR (400 15 MHz, CDCh) 5: 7.24-7.33 (m, 1H), 6.90-6.98 (m, 1H), 6.79-6.89 (m, 2H), 5.63 (s, 1H), 5.025.13 (m, 2H), 3.85 (s, 3H), 3.24-3.41 (m, 2H), 0.70-0.86 (m, 2H), -0.03 (s, 9H); MS m / z: 420.0 [M+1]+ Step 5. Methyl 5-bromo-2-[[[(5-fluoro-2-methoxv-pherwD-[5-(trifluoromethyl)-1-(2-20 trimethylsilylethoxymethyl)imidazol-2-yl1methynaminolmethyllbenzoate To a solution of (5-fluoro-2-methoxy-phenyl)-[5-(trifluoromethyl)-1-(2-trimethylsi!ylethoxymethyl)imidazol-2-yl]methanamine (1.05 g, 2.50 mmol) and methyl 5-bromo-2-(bromomethyl)benzoate (0.846 g, 2.75 mmol) in DMF (50 mL) was added DI PEA 25   (2.05 mL, 12.5 mmol). The reaction mixture was heated at 90 °C for 1 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyi acetate three times. The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title 2026234102   18 Sep 2026 compound (1.61 g, quant.) which was used in the next reaction without further purification. MSm / z 646.0 [M+1]+. Step 6. 6-Bromo-24(5-fluoro-2-methoxy-phenyl)-|'5-(trifluoromethyl)-1-(2- 5 trimethyisiivSethoxvmethvi)imidazoi-2-yi1methyilisoindoiin-1-one To a solution of methyl 5-bromo-2-[[[(5-fluoro-2-methoxy-phenyl)-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazo!-2-yljmethyl]amino]methyl]benzoate (1.61 g, 2.49 mmol) in toluene (50 mL) was added trimethylaluminum (0.179 g, 2.49 mmol). The reaction 10 mixture was heated at 90 °C for 16 h. After cooling to room temperature, the solvent was removed under reduced pressure. The crude product was purified by reverse phase HPLC eluting with 0-100% ACN / water containing 10 mM ammonium acetate to give the title compound (1.2 g, 78%). 'H NMR (400 MHz, CDCh) 6: 7.98 (d, 1H), 7.65 (dd, 1H), 7.29-7.35 (m, 2H), 7.26 (s, 1H), 7.18 (dd, 1H), 6.98-7.07 (m, 1H), 6.86 (dd, 1H), 5.59 (d, 1H), 5.22 (d, 15    1H), 4.96 (d, 1H), 4.06 (d, 1H), 3.75-3.84 (m, 3H), 3.21-3.44 (m, 2H), 0.53-0.78 (m, 2H), - 0.12-0.00 (m, 9H); MS m / z: 614.1 [M+1]+. Step 7. 6-Bromo-2-[(5-fluoro-2-methoxy-phenyi)-[5-(trifiuoromethyl)-1 H-imidazol-2-vnmethyl]isoindolin-1-one To a solution of 6-bromo-2-[(5-fluoro-2-methoxy-phenyl)-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]methyl]isoindo!in~1-one (0.540 g, 0.878 mmol) in methanol (5 mL) was added aq. HCI (12 M, 10.0 mL, 120 mmol) at 0 °C. After stirring at room temperature for 4 h, the solvent was removed under reduced pressure and lyophilized 25 to give the title compound (0.425 g, quant.). 1H NMR (400 MHz, methanol-ck) 5: 7.94 (d, 1H), 7.69-7.82 (m, 2H), 7.48 (d, 1H), 7.07-7.29 (m, 2H), 6.82-7.03 (m, 2H), 4.65 (d, 1H), 4.134.18 (m, 1H), 3.79 (s, 3H); MS m / z: 485.9 [M+1]+. 2026234102   18 Sep 2026 St.si7S.JTK5-f Lyo^ methv!-4-piperidyi)pheny!lisoindo!in-1-one A mixture of 6-bromo-2-[(5-fluoro-2-methoxy-phenyl)-[5-(trifluoromethyl)-1H-imidazol- 5 2-yl]methyl]isoindolin-1-one (0.425 g, 0.878 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (0.403 g, 1.34 mmol), Pd(dppf)Cl2 (0.032 g, 0.044 mmol) and potassium carbonate (0.372 g, 2.68 mmol) in dioxane:water (9:1, 10 mL) was heated at 100 °C for 2 h under nitrogen. After cooling, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography 10 eluting with 0-15% methanol in dichloromethane to give the title compound (0.3 g, 58%). !H NMR (400 MHz, CDCh) 5: 7.94 (d, 1H), 7.72-7.79 (m, 1H), 7.45-7.55 (m, 3H), 7.32-7.41 (m, 4H), 6.96-7.07 (m, 1H), 6.89-6.95 (m, 1H), 6.71-6.82 (m, 1H), 4.82-4.96 (m, 1H), 4.34-4.53 (m, 1H). 3.57-3.67 (m, 3H), 2.99-3.09 (m, 2H), 2.48-2.63 (m, 1H), 2.34-2.39 (m, 4H), 2.072.16 (m, 3H), 1.86-1.97 (m, 2H); MS m / z: 579.3 [M+1]+. 15 Step 9. 2-[(5-Fluoro-2-hydroxy-phenyl)-[5-(trifluoromethyl)-1H-imidazol-2-yl1methyn-644-(1-methyl"4-piperidyl)phenvl1isoindolin-1-one;hvdrochloride To a solution of 2-[(5-fluoro-2-methoxy-phenyl)-[5-(trifluoromethyl)-1H-imidazol-2- 20 yl]methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isojndolin-1-one (0.250 g, 0.432 mmol) in dichloromethane (5 mL) at 0 °C was added boron tribromide (0.407 g, 4.32 mmol). After stirring at room temperature for 1 h, the reaction mixture was diluted with dichloromethane and poured into ice-water. The aqueous phase was extracted with dichloromethane three times. The combined organic extracts were washed with brine, dried over sodium sulfate, 25 filtered and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC eluting with 0-100% ACN / water (0.05% HCI modifier) to give the title compound (0.122 g, 50%). NMR (400 MHz, DMSO-d6) 6: 10.58 (brs, 1H), 9.98 (brs, 1H), 7.88-7.96 (m, 2H), 7.80 (d, 1H), 7.63-7.76 (m, 3H), 7.36 (d, 2H), 7.02-7.12 (m, 1H), 6.84- 2026234102   18 Sep 2026 6.98 (m, 2H), 6.70 (dd, 1H), 4.67 (d, 1H), 4.12 (d, 1H), 3.49 (d, 2H), 2.99-3.16 (m, 2H), 2.80 2.89 (m, 1H), 2.77 (d, 3H), 1.96-2.12 (m, 4H); MS m / z: 565.5 [M+1J+. Example 20: Preparation of 2-[(R)-(5-fluoro-2-hydroxy-phenyl)-(4-methyl-1H-imidazol-2- 5 yl)methyll-6-[4-(1-methvl-4-pipendyl)phenylliso!ndol!n- 1-one and 2-[(S)-(5-fluoro-2-hydroxy-phenyl)-(4-methvl-1H-imidazol-2-yl)methvH-6-f4-(1-methyl-4-p!peridyl)phenyllisoindolin-1-one (104 and 105) 2-[(5-Fluoro-2-hydroxy-phenyl)-(4-methyl-1H-imidazol-2-yl)methyl]-6-[4-(1-methyl-4- 10 piperidyl)phenyl]isoindolin-1-one (085, 0.020 g, 0.039 mmol) was purified by prep SFC with a Chiral Technologies Chiralpak IA (5micron 250x10mm) column @ 40 CC eluting with 35% (0.3% TEA in MeOH) / 65% CO2 at 12 MPa to separate enantiomers. Absolute configuration of the chiral center for each isolated enantiomer is unknown. First eluting peak (104) (6.5 mg, 33% yield, 97.9:2.1 er); [a]20D -88.2 (c = 0.0465, MeOH): NMR (DMSO-ds) 5: 11.74 15    12.04 (m, 1H), 10.06 (brs, 1H), 7.84-7.88 (m, 2H), 7.64 (br d, J-8.2 Hz, 3H), 7.35 (d, J-8.2 Hz, 2H), 7.02 (td, >8 5, 3.1 Hz, 1H), 6.51-6.90 (m, 4H), 4.72 (br d, >17.7 Hz, 1H), 4.11 (br d, >17.4 Hz, 1H), 2.88 (br d, J-10.9 Hz, 2H), 2.20 (s, 3H), 2.08-2.17 (m, 3H), 1.92-2.02 (m, 2H), 1.59-1.81 (m, 4H); MS m / z: 511.3 [M+1]+. Second eluting peak (105) (7.3 mg, 37% yield, 97.7:2.3 er); M2%+67.3 (c - 0.049, MeOH); 1H NMR (DMSO-ds) 5: 11.74-12.20 (m, 20   1H), 10.08 (brs, 1H), 7.82-7.90 (m, 2H), 7.65 (brd, >8.2 Hz, 3H), 7.36 (d, J-8.2 Hz, 2H), 7.02 (td, >8.6, 3.2 Hz, 1H), 6.52-6.91 (m, 4H), 4.72 (d, >17.9 Hz, 1H), 4.11 (d, >17.9 Hz, 1H), 2.88 (brd, >11.1 Hz, 2H), 2.21 (s, 3H), 2.13 (s, 3H), 1.98 (td, >11.3,2.1 Hz, 2H), 1.59-1.84 (m, 4H); MS m / z: 511.3 [M+1]+. 25 Example 21: Preparation of 6-f(R)-1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-2-(4-( 1-methyl-4-piperidyl)phenyll-5H-pywolo[3,4-b]pyridin-7-one and 6-[(S)~1H-benzimidazol-2-yl-(5-fluoro-2-hvdroxv-phenyl)methyll-2-[4-(1-methyl-4-piperidyl)phenyll-5H-pymlo[3,4-b]pyndin-7-one (106 and 107) 2026234102   18 Sep 2026 6-[1H-Benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-2-[4-(1-methyl-4-piperidyi)pheny!]-5H-pyrrolo[3,4-b]pyridin-7-one (028, 0.020 g, 0.037 mmol) was purified by prep SFC with a Chiral Technologies Chiralpak IA (5micron 250x10mm) column @ 40 °C eluting with 55% (0.3% TEA in MeOH) / 45% CO2 at 10 MPa to separate enantiomers. 5 Absolute configuration of the chiral center for each isolated enantiomer is unknown. First eluting peak (106) (2.8 mg, 14% yield, 98.5:1.5 er); [a]20D -12.3 (c= 0.06, MeOH); !H NMR (DMSO-cfe) 6: 7.96-8.09 (m, 4H), 7.39-7.51 (m, 2H), 7.33 (d, >8 3 Hz, 2H), 7.06-7.16 (m, 2H), 6.94-7.06 (m, 2H), 6.83 (dd, >8.9, 4.8 Hz, 1H), 6.76 (dd, >9.3, 3.1 Hz, 1H), 4.72 (d, >17.9 Hz, 1H), 4.14 (brd, >17.7 Hz, 1H), 2.75-2.86 (m, 2H), 2.13 (s, 3H), 1.91 (td, >11.0, 10   1.5 Hz, 2H) 1.56-1.78 (m, 4H): MS m / z: 548.3 (M+1j\ Second eluting peak (107) (6.1 mg, 30% yield, 97.2:2.8 er); [a]2%+21.8 (c = 0.055, MeOH); 'H NMR (DMSO-de) 3: 12.56 (br s, 1H), 9.92 (brs, 1H), 7.94-8.13 (m, 4H), 7.46-7.57 (m, 1H), 7.36- 7.44 (m, 1H), 7.33 (d, >8.3 Hz, 2H), 7.11 (brs, 2H), 7.00-7.05 (m, 1H), 6.99 (s, 1H), 6.84 (dd, >8.9, 4.8 Hz, 1H), 6.75 (dd, >9.3, 3.1 Hz, 1H), 4.73 (d, >17.9 Hz, 1H), 4.11 (d, >17.9 Hz, 1H), 2.73-2.88 (m, 2H), 15   2.13 (s, 3H), 1.80-1.97 (m, 2H), 1.53-1.78 (m, 4H); MS m / z: 548.3 [M+1]+. The following examples were prepared by a similar method to Compound 069 from methyl 2-bromo-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate and the corresponding boronate starting material: No. Structure / Name m / z [M+1p > NMR (DMSO-de) 6 Starting materials 108 - 2-[1H-Benzimidazol-2-yi-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[4-(3-methyl-3-azabicyclo[4.1 .Ojheptan-6-yl)phenyl)isoquinolin-1- onejdihydrochloride 571.3 10.15-10.41 (m, 2H), 8.29 (d, >3.3 Hz, 1H), 8.01 (s, 1H), 7.86 (brd, >8.4 Hz, 1H), 7.78 (d, 4=8.3 Hz, 2H), 7.43-7.70 (m, 5H), 7.28-7.42 (m, 3H), 7.127.22 (m, 1H), 6.96-7.05 (m, 1H), 6.84-6.94 (m, 1H), 6.70-6.82 (m, 1H), 3.80-3.94 (m, 1H), 3.233.36 (m, 1H), 2.99-3.12 (m, 1H), 2.84-2.96 (m, 1H), 2.70 (brd, >4.4 Hz, 4H), 2.27-2.41 (m, 1H), 1.47-1.61 (m, 1H), 1.081.38 (m, 2H) 9 O" "VS 109 XT 9xcaup XX 2hu 2-[1H-Benzimidazol-2-yi-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[3-flu oro-4-(1 -methyi-4- 577.3 10.48 (brs, 1H), 10.26 (brs, 1H), 8.30 (d, >8.3 Hz, 1H), 8.07 (s, 1H), 7.90 (brd, >8.3 Hz, 1H), 7.71 (brd, >10.0 Hz, 2H), 7.61-7.67 (m, 3H), 7.44 (br t, J-7.8 Hz, 1H), 7.31-7.40 (m, 3H), 7.12-7.23 (m, 1H), 6.967.06 (m, 1H), 6.89 (brd, >7.8 Hz, 1H), 6.78 (d, >7.6 Hz, 1H), 3.43-3.57 (m, 2H), 3.06-3.22 (m, A FX £ O' 2026234102   18 Sep 2026 piperidyl)phenyl]isoquinolin-1 - one;dihydrochloride 3H), 2.73-2.85 (m, 3H), 1.83 2.22 (m, 4H) The following examples were prepared by a similar method to Compound 070 from methyl 2-bromo-2-(5-fiuoro-2-(methoxymethoxy)phenyl)acetate and the corresponding boronate starting material: No. Structure! Name m / z [M+1]+ !H NMR (DMSO-ds) 6 Starting materials 110 2HCI 2-[1H-Benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-8-fluoro-6-[4-(3-methy!-3-azabicyclo[4.1.0]-heptan-6-yl) phenyl] isoquinolin-1 -one;dihydrochlonde 589.3 10.06-10.33 (m, 1H), 7.80-7.89 (m, 3H), 7.45-7.69 (m, 6H), 7.287.41 (m, 3H), 7.17 (brs, 1H), 6.93-7.02 (m, 1H), 6.79-6.91 (m, 1H), 6.68-6.78 (m, 1H), 3.813.96 (m, 2H), 3.24-3.38 (m, 1H), 2.99-3.12 (m, 1H), 2.84-2.99 (m, 1H), 2.64-2.83 (m, 4H), 2.242.39 (m, 1H), 1.46-1.62 (m, 1H), 1.07-1.30 (m, 2H) p / 111 .... rY7 Q-™ OCY: f|                  2HCI 2-[1H-Benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-8-fluoro-6-p-fluoro~4-(1-methyl-4-piperidyl)-phenyl] isoquinolin-1-one; dihydrochloride 595.3 10.41 (brs, 1H), 10.25 (brs, 1H), 7.93 (s, 1H), 7.61-7.81 (m, 5H), 7.57 (s, 1H), 7.44 (brt, J=3.0 Hz, 1H), 7.32-7.40 (m, 3H), 7.11-7.23 (m, 1H), 6.957.03 (m. 1H), 6.83-6.93 (m, 1H), 6.75 (br d, J=7.2 Hz, 1H), 3.453.57 (m, 2H), 3.06-3.22 (m, 3H), 2.75-2.84 (m, 3H), 1.92-2.16 (m, 4H) & O' '0 Example 22: 2-[ 1 H-Benz!midazol-2-y!-deuterio-(5-fluoro~2-hydroxy~phenyl)methyl]-6-[4-( 1- methyl-4-pipendyl)phenyl]isoquinolin- 1-one (112) Scheme 22 10          Rac-2-(1H-1,3-benzodiazol-2-y!)(5-fluoro-2-hydroxyphenyl)methy!]-6-[4-(1- methylpiperidin-4-yl)pheny!]-1,2-dihydroisoquinolin-1-one (069, 20.4 mg, 0.0365 mmol) was dissolved in dry tetrahydrofuran (1 ml) in a vial equipped with a stir bar. Deuterium oxide (350 pL, 19.3 mmol) was then added with stirring followed by N,N-diisopropylethylamine 2026234102   18 Sep 2026 (38.1 pL, 219 pmol). The reaction vial was sealed and the reaction was allowed to stir at 70 °C for 60 hours. An 1HNMR (DMSO-de) of the reaction solution indicated -100% incorporation of deuterium on the methine carbon based on the disappearance of the methine peak @ --7.67 ppm. The reaction was cooled to room temperature and the solvents 5 were removed under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 0-15% (7N NH3 in methanol) in DCM to give the title compound (14 mg, 68%). 1H NMR (DMSO-cfe, 400 MHz) 6: 11.9-13.5 (m, 1H), 9.6-10.9 (m, 1H), 8.28 (d, 1H), 7.94 (s, 1H), 7.81 (d, 1H), 7.7-7.8 (m, 2H), 7.54 (br s, 2H), 7.3-7.4 (m, 2H), 7.29 (d, 1H), 7.19 (brdd, 2H), 7.08 (dt, 1H), 6.88 (dd, 1H), 6.6-6.7 (m, 2H), 2.88 (brd, 2H), 2.5-2.7 (m, 10    1H), 2.20 (s, 3H), 1.9-2.0 (m, 2H), 1.6-1.8 (m, 4H); MS m / z: 560.3 [M+1]+. The following example was prepared by a similar method to Example 22 from benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)rnethyl]-8-fluoro-6-[4-(1-methyl-4- piperidyl)phenyi]isoquinolin-1-one (070): No. Structure / Name m / z [M+1]+ NMR (DMSO-ds) 6 113 ho 1 A £ 2-[1H-Benzimidazol-2-yl-deuterio-(5-fluoro-2-hydroxy-phenyl)methyH-8-fluoro-6-[4-(1 -methyl-4-piperidyl)phenyl] isoquinolin-1-one 578.3 12.7-12.8 (m, 1H), 9.9-10.1 (m, 1H), 7.7-7.8 (m, 3H), 7.4-7.6 (m, 3H), 7.39 (br d, 2H, J=7.9 Hz), 7.29 (d, 1H, J=7.6 Hz), 7.20 (br s, 2H), 7.0-7.2 (m, 1H), 6.90 (dd, 1H, J=4.8, 8.7 Hz), 6.6-6.7 (m, 2H), 2.89 (brd, 2H, J=10.6 Hz), 2.5-2.6 (m, 1H), 2.21 (s, 3H), 2.00 (br t, 2H, J=10.8 Hz), 1.6-1.8 (m, 4H) Example 23: Preparation of 2-[(S)-1H-benzimidazol-2-vl-deuteho-(5-fluoro-2-hydroxv-phen\4)methyl]-6-[4-(1-methyl-4-pipend}4)phenyl1isoauinolin-1-one and 2-[(R)-1H-benzimidazol-2-vl-deuterio-(5-fluoro-2-hvdroxy-phenvl)methYl]-6-[4-(1-methyl-4-piperidvl)phenvllisoguinolin-1~one (114 and 115) 20 Scheme 23 Rac-2-(1 H-1,3-benzodiazol-2-y!)(5-fluoro-2-hydroxyphenyl)methy!]-6-[4-(1-methylpiperidin-4-yl)phenyl]-1,2-dihydroisoquinolin-1-one (069, 50 mg, 0.090 mmol) was dissolved in dry tetrahydrofuran (2 ml) in a vial equipped with a stir bar. Deuterium oxide 2026234102   18 Sep 2026 (1000 pL, 55.4 mmol) was then added with stirring followed by N,N-diisopropylethylamine (62.2 pL, 358 pmol). The reaction vial was sealed then the reaction was allowed to stir at 70 °C for 60 hours. An 1HNMR (DMSO-cfe) of the reaction solution indicated --100% incorporation of deuterium on the methine carbon based on the disappearance of the 5 methine peak @ -7.67 ppm. The reaction was cooled to room temperature then evaporated to leave crude product which was dissolved in 5 ml THF. 75 uL of a 35 wt% DO in DaO solution was then added dropwise with stirring. After 10 minutes, the reaction solution was concentrated, and the residue was dried under vacuum overnight to give crude product as the bis DCI salt. The crude product was purified to separate enantiomers using a Chiraipak 10 IG (10x250 mm 5 micron) column eluting with 55% (0.3% TEA in MeOH) / 45% CO2 at back pressure regulator (BPR) value of 10 MPa and flow rate of 7 mL / min on a Jasco semi-prep SFC. Absolute configuration of the chiral center for each isolated enantiomer is unknown. First eluting peak (114) (19.7 mg, 37%, 100:0 er); [a]20D-13.6 (c= 0.0515, MeOH); "H NMR (DMSO-cfe, 400 MHz) 5: 11.9-13.5 (m, 1H), 9.6-10.9 (m, 1H), 8.28 (d, 1H), 7.94 (s, 1H), 7.81 15    (d, 1H), 7.7-7.8 (m, 2H), 7.54 (br s, 2H), 7.3-7.4 (m, 2H), 7.29 (d, 1H), 7.19 (br dd, 2H), 7.08 (dt, 1H), 6.88 (dd, 1H), 6.6-6.7 (m, 2H), 2.88 (br d, 2H), 2.5-2.7 (m, 1H), 2.20 (s, 3H), 1.9-2.0 (m, 2H), 1.6-1.8 (m, 4H); MS m / z: 560.3 [M+lf. Second eluting peak (115) (18.8 mg, 36%, 99.7:0.3 er); [ap°D+14.2 (c = 0.0705, MeOH); 1H NMR (DMSO-cfe, 400 MHz) 8: 11.9-13.5 (m, 1H), 9.6-10.9 (m, 1H), 8.28 (d, 1H), 7.94 (s, 1H), 7.81 (d, 1H), 7.7-7.8 (m, 2H), 7.54 (brs, 20   2H), 7.3-7.4 (m, 2H), 7.29 (d, 1H), 7.19 (br dd, 2H), 7.08 (dt, 1H), 6.88 (dd, 1H), 6.6-6.7 (m, 2H), 2.88 (brd, 2H), 2.5-2.7 (m, 1H), 2.20 (s, 3H), 1.9-2.0 (m, 2H), 1.6-1.8 (m, 4H); MS m / z: 560.3 [M+1]+. The following examples were prepared by a similar method to Example 23 from 2-[1H- 25 benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-8-fluoro-6-[4-(1-methyl-4- piperidyl)phenyl]isoquinolin-1-one (070). The absolute configuration of the chiral center for each isolated enantiomer is unknown: No. Structure / Name m / z [M+1F ’H NMR (DMSO-cfe) 5 Optical rotation 116 HO,      0 F 2-[1H-Benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-8-fluoro-6-[4-(3-methyl-3-azabicyclo[4.1.0)- 578.3 12.7-12.8 (m, 1H), 9.9-10.1 (m, 1H), 7.7-7.8 (m, 3H), 7.47.6 (m, 3H), 7.39 (brd, 2H, 7=7.9 Hz), 7.29 (d, 1H, 7=7.6 Hz), 7.20 (brs, 2H), 7.0-7.2 (m, 1H), 6.90 (dd, 1H, 7=4.8, 8.7 Hz), 6.6-6.7 (m, 2H), 2.89 (brd, 2H, 7=10.6 Hz), 2.5-2.6 (m, 1H), 2.21 (s, 3H), 2.00 (br t, 2H, 7=10.8 Hz), 1.6-1.8 (m, 4H) [0]¾ -11.8 (c = 0.0595, MeOH) 2026234102   18 Sep 2026 heptan-6-yl) phenyl] isoquinolin-1-one;dihydrochlonde 2-(1H-Benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-8-fluoro-643-fluoro-4-(1 -methyl-4-piperidy!)phenyl] isoquinolin-1 -one;dihydrochloride 12.7-12.8 (m, 1H). 9.9-10.1 (m, 1H), 7.7-7.8 (m, 3H), 7.47.6 (m, 3H), 7.39 (brd, 2H, / =7.9 Hz), 7.29 (d, 1H, / =7.6 Hz), 7.20 (brs, 2H), 7.0-7.2 (m, 1H), 6.90 (dd, 1H, . / =4.8, 8.7 Hz), 6.6-6.7 (m, 2H), 2.89 (brd, 2H, / =10.6 Hz), 2.5-2.6 (m, 1H), 2.21 (s, 3H), 2.00 (br t, 2H, / =10.8 Hz), 1.6-1.8 (m, 4H) M20d14.8 (C = 0.061, MeOH) Example 24: 2-((1 H-Benzo[dlimidazol-2~yl)(5~fluoro-6-(4-(1-methylpiperidin-4-yl)phenyl)-2H- indazol-2-yl)methyl)-4-fluorophenol (118) Scheme 24 F Step 1, Methyl 2-(6-bromo-5-fluoro-2H-indazo!-2-yl)-2-(5-fluoro-2-(methoxymethoxy)phenyl) acetate Methyl 2-bromo-2-(5-fluoro-2-(methoxymethoxy)pheny!)acetate (513 mg, 1.67 mmol) was 10 added to a suspension of 6-bromo-5-fluoro-2H-indazole (360 mg, 1.67 mmoi) and cesium 2026234102   18 Sep 2026 carbonate (651 mg, 2.09 mmol) in CH3CN (16 mL) and the mixture was stirred at 0°C for 1 hr, and then at RT for 16 hrs. The mixture was partitioned between water and EtOAc, and the aqueous layer extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine, dried (NazSO^, filtered and the residue purified by silica chromatography 5   (0 - 20% EtOAc in Hex) to give the title compound (204 mg, 19%) as a solid. 1H NMR (CDCI3<) 5: 8.00 (d, 1H), 7.92 (s, 1H), 7.31 (d, 1H), 7.20 (dd, 1H), 7.13 (m, 1H), 7.11 (d, 1H), 6.80 (s, 1H), 5.18 (d, 1H), 5.14 (d, 1H), 3.86 (s, 3H), 3.35 (s, 3H); MS m / z: 442.8 [M+1]+. 10 Step 2. 2-(5-Fluoro-2-(methoxymethoxy)phenyl)-2-(5-fluoro-6-(4-(1-methyip!peridin-4-yi)phenyl)-2H-indazoi-2-yl)acetic add A mixture of methyl 2-(6-bromo-5-fluoro~2H-indazol-2-yl)-2-(5-fluoro-2-(methoxymethoxy)-phenyl)acetate (2Q5 mg, 0.47 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-d!Oxaborolan-15 2-yl)phenyl)piperidine (147 mg, 0.49 mmol), Pd(dppf)Cl2.DCM (38 mg, 0.047 mmol) and sodium carbonate (149 mg, 1.41 mmol) in dioxane:water (3:1, 3 mL) was degassed and resuffused with nitrogen three times. The mixture was heated at 100°C for 4 hours under nitrogen. After cooling, the reaction mixture was filtered and purified by reverse phase HPLC, eluting with 0-80% ACN / water (0.035 %TFA modifier) to give the title compound (117 20 mg, 48%). !H NMR (DMSO-d6) 0: 9.35 (brs, 1H), 8.47 (s, 1H), 7.72 (d, 1H), 7.56 (m, 3H), 7.36 (d, 2H), 7.27 (m, 1H), 7.22 (dd, 1H), 7.16 (dd, 1H), 6.83 (s, 1H), 5.25 (d, 2H), 5.22 (d, 2H), 3.56 (d, 2H), 3.32 (s, 3H), 3.11 (m, 2H), 2.87 (m, 1H), 2.84 (d, 3H), 2.08 (m, 2H), 1.87 (m, 2H); MS m / z: 521.9 [M+1f. 25 Step 3. A / -(2-Aminophenyl)-2-(5-fluoro-2-(methoxymethoxy)phenyl)-2-(5-fluoro-6-(4-(1-methvlpiperidin-4-yl)phenyl)-2H-indazoi-2-vl)acetamide A mixture of 2-(6-bromo-(5-Fluoro-2-(methoxymethoxy)phenyl)-2-(5-fluoro-6-(4-(1-methylpiperidin-4-yi)phenyi)-2H-indazoi-2-yl)acetic acid (117 mg, 0.48 mmol), benzene-1,2- 2026234102   18 Sep 2026 diamine (156 mg, 1.44 mmol), HATU (365 mg, 0.96 mmol), DIEA (250 mL, 1.44 mmol) and degassed DMF (3 mL) was stirred for 1 hour. The reaction mixture was purified by reverse phase HPLC, eluting with 0-80% ACN / water (0.035 %TFA modifier) to give the title compound. 1H NMR (DMSO-cfe) 5: 9.92 (s, 1H), 9.33 (br s, 1H), 8.31 (s, 1H), 7.73 (d, 1H), 5    7.57 (m, 3H), 7.36 (d, 2H), 7.29 (m, 1H), 7.27 (dd, 1H), 7.18 (dd, 1H), 7.01 (dd, 1H), 6.99 (s, 1H), 6.96 (m, 1H), 6.74 (d, 1H), 6.58 (m, 1H), 5.24 (d, 1H), 5.19 (d, 1H), 3.55 (d, 2H), 3.25 (s, 3H), 3.11 (m, 2H), 2.87 (m, 1H), 2.84 (d, 3H), 2.08 (m, 2H), 1.86 (m, 2H). 10 15 Step 4. 2-((1 H-Benzo[d1imidazoi-2-¥l)(5-fiuoro-6-(4-(1-methvlpiperidin-4-vQphenvl)-2H indazol-2-yl)methyl)-4-fluorophenol (118) The material from step 3 was heated in AcOH (5 mL) at 100°C for 1 hr. The solvent was removed under reduced pressure, and the residue was dissolved in 1:1 TFA:DCM (5 mL) for 5 hrs. The reaction mixture was purified by reverse phase HPLC, eluting with 0-80% ACN / water (0.035 %TFA modifier) to give the title compound (39 mg, 13% over 3 steps). 1H NMR (DMSO-cfe) 6: 10.18 (brs, 1H), 9.36 (brs, 1H), 8.46 (s, 1H), 7.71 (d, 1H), 7.59 (d, 2H), 7.57 (m, 4H), 7.35 (d, 2H), 7.24 (m, 2H), 7.12 (dd, 1H), 6.93 (dd, 1H), 6.87 (dd, 1H), 3.54 (d, 2H), 3.10 (m, 2H), 2.86 (m, 1H), 2.84 (d, 3H), 2.08 (m, 2H), 1.86 (m, 2H); MS m / z: 550.0 20 The following example was prepared by a similar method to Example 24 from methyl 2-bromo-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate and the corresponding bicyclic starting material: No. Structure / Name m / z [M+1]H !H NMR (DMSO-cfe) 5 Starting materials 119 F^___ hoyA tfa 2-((1 H-Benzo[d]imidazol-2-yl)(4-f!uoro-6-(4-(1-methylpiperidin-4-yl)phenyl)-2H-indazol-2-yl)methyl)- 4-fluorophenol; trifluoroacetate 550.0 10.21 (brs, 1H), 9.43 (brs, 1H), 8.70 (s, 1H), 7.74 (m, 3H), 7.61 (s, 1H), 7.58 (m, 2H), 7.34 (d, 2H), 7.24 (m, 2H), 7.20 (d, 2H), 7.13 (m, 1H), 6.94 (m, 2H), 3.54 (d, 2H), 3.10 (m, 2H), 2.85 (m, 1H), 2.83 (d, 3H), 2.06 (m, 2H), 1.86 (m, 2H) 4 2026234102   18 Sep 2026 Scheme 25 Ste o ethyl2~.br.^ 5          To a solution of methyl 5-f!uoro-2-(methoxymethoxy)benzeneacetate (5.00 g, 21.9 mmol) in chloroform (80 mL) was added N-bromosuccinimide (4.66 g, 26.2 mmol) and benzoyl peroxide (0.530 g, 2.19 mmol). After stirring at 80 °C for 16 h, the solvent was removed under reduced pressure. The crude compound was purified by silica gel column chromatography eluting with 0-5% ethyl acetate in petroleum ether to give the title 10 compound (2.4 g, 36%). 1H NMR (400 MHz, CDCh) 6: 7.31 (dd, 1H), 6.97-7.03 (m, 1H), 6.87-6.95 (m, 1H), 5.76 (s, 1H), 5.12 (d, 2H), 3.72 (s, 3H), 3.41 (s, 3H). EGFR biochemical activity measurements were carried out using the homogeneous 15 time-resolved fluorescence (HTRF) assay (Cisbio). Inhibitors and DMSO normalizations were first dispensed to empty black low-volume 384-well plates (Corning) with D300 digital liquid dispenser (HP). All reactions were carried out at room temperature and solutions were added to plates with a Multidrop Combi Reagent Dispenser (ThermoFisher). The reaction mixture (10 pL final volume) contained 1 pM tyrosine kinase peptide-biotin substrate and 20 mutant EGFR in a reaction buffer (50 mM HEPES pH 7.0, 5 mM MgCEJ mM MnCh, 0.01% BSA, 2 mM TCEP, 0.1 mM NaVO4). Enzyme concentrations were adjusted to accommodate varying kinase activities (L858R 0.1 nM, L858R / T790M 0.02 nM). Enzyme reaction solution (2x concentrations, 5 pL) was added to 384-well plates containing compounds and incubated for 30 mins. Enzyme reactions were initiated with the addition of 5 pL of ATP to a 25 final concentration of 100 pM and reacted for 20 mins. React...

Claims

1. A compound of Formula IIa:or a pharmaceutically acceptable salt thereof;whereinW and Z are each, independently, N, CH, C-halo, C-(C1-C3 alkyl), or C-(C1-C3 alkoxy);10          R1 is selected from the group consisting of 6-10 membered aryl, 5-10 memberedheteroaryl, 3-10 membered heterocycloalkyl, and 3-10 membered cycloalkyl, all of which are optionally substituted with one, two, or three R8;R3 is independently, at each occurrence, selected from the group consisting of phenyl and C2-C6 alkynyl, wherein phenyl is substituted with (CH2)0-3-(5-6 membered heteroaryl) or 15 piperidin-4-yl, wherein the heteroaryl or piperidin-4-yl are each optionally substituted one, two, or three times with R7, and alkynyl is optionally substituted one, two, or three times with R4;R4 is independently, at each occurrence, selected from the group consisting of H, (CH2)0-3-(C3-C7 cycloalkyl), (CH2)0-3-(C4-C7 cycloalkenyl), (CH2)0-3-(C6-C10 aryl), (CH2)0-3-(5-6 membered heteroaryl), and (CH2)0-3-(5-7 membered heterocyclyl), wherein the aryl, heteroaryl, 20 or heterocyclyl are each optionally substituted one, two, or three times with R5;R5 is independently, at each occurrence, selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C3 alkylamine, 3-10 membered cycloalkyl, halogen, COOH, C(O)O(C1-C6 alkyl), O(CH2)1-3-OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, OH, CN, (CH2)0-3-(C6-C10 aryl), (CH2)0-3-(5-6 membered heteroaryl), O(CH2)0-3-(4-7 25 membered heterocyclyl), and (CH2)0-3-(4-7 membered heterocyclyl), wherein the alkyl, alkoxy, aryl, heteroaryl, or heterocyclyl are each optionally substituted one, two, or three times with R7;R6 is independently, at each occurrence, selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, halogen, OH, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, (CH2)1-4OH, S(O)0-2H, S(O)0-2NH2, or CN;2026234102   18 Sep 2026alternatively, two R6, together with the atoms to which they are attached, can form 5-10 membered heteroaryl, 6-10 membered aryl, 3-10 membered heterocycloalkyl, or 3-10 membered cycloalkyl;R7 is independently, at each occurrence, selected from the group consisting of5 substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halogen, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, SO2NH2, SO2NH(C1-C6 alkyl), SO2N(C1-C6 alkyl)2, (CH2)1-2-OH, C(O)(CH2)1-2-OH, C(O)(C1-C6 alkyl), and C(O)O(C1-C6 alkyl);alternatively, two R7, together with the atoms to which they are attached, can form 5-10 membered heteroaryl, 6-10 membered aryl, 3-10 membered heterocycloalkyl, or 3-10 0 membered cycloalkyl; andR8 is independently, at each occurrence, selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, 3-6 membered cycloalkyl, halogen, OH, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, (CH2)1-4OH, S(O)0-2H, S(O)0-2NH2, or CN.

152. The compound of claim 1, wherein R6 is independently, at each occurrence, hydroxy orhalo.

3. The compound of claim 1 or claim 2, wherein R1 is selected from the group consisting of20 benzimidazole, imidazopyrazine, purine, imidazole, pyrazole, triazole, and imidazopyridine; all of which are optionally substituted with one, two, or three R8.

4. The compound of claim 3, wherein R1 is selected from the group consisting of:andall of which are optionally substituted with one, two, or three R8.

5. The compound of any one of claims 1-4, wherein R3 is phenyl or C2-C3 alkynyl, whereinphenyl is optionally substituted one or two times with R5, and alkynyl is optionally substituted30 one or two times with R4.2026234102   18 Sep 20266.     The compound of claim 1, wherein the compound is selected from the group consistingof:1751761771782026234102   18 Sep 2026or a pharmaceutically acceptable salt thereof.

7. A compound selected from the group consisting of:2026234102   18 Sep 2026or a pharmaceutically acceptable salt thereof.

8. A compound selected from the group consisting of:2026234102   18 Sep 20269.     A pharmaceutical composition comprising a compound of any one of the precedingclaims, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically5 acceptable carrier.

10. A method of treating a cancer in a subject in need thereof, comprising administering to the subject a compound according to any one of claims 1-8 or a pharmaceutical composition according to claim 9.1011. The method according to claim 10, wherein the cancer is selected from the group consisting of lung cancer, colon cancer, breast cancer, endometrial cancer, thyroid cancer, glioma, squamous cell carcinoma, and prostate cancer.15   12. The method according to claim 10, wherein the cancer is non-small cell lung cancer(NSCLC).2026234102   18 Sep 20261513. The method according to any one of claims 10-12, comprising further administering a therapeutically effective amount of osimertinib to the subject.

14. Use of a compound according to any one of claims 1-8 in the manufacture of a medicament for treating a cancer.

15. The use according to claim 14, wherein the cancer is selected from the group consisting of lung cancer, colon cancer, breast cancer, endometrial cancer, thyroid cancer, glioma, squamous cell carcinoma, and prostate cancer.

16. The use according to claim 14, wherein the cancer is non-small cell lung cancer (NSCLC).

17. The use according to any one of claims 14-16, wherein a therapeutically effective amount of osimertinib is to be administered to the subject.