Allosteric EGFR inhibitors and methods of use thereof

Abstract

The present disclosure relates to compounds that act as allosteric inhibitors of epidermal growth factor receptor (EGFR); pharmaceutical compositions comprising such compounds; and methods of treating or preventing kinase-mediated conditions, including cancer and other proliferative diseases.

Description

[0001] This application is a divisional application of the patent application for invention titled "Allosteric EGFR Inhibitors and Methods of Use Thereof" with the application date of November 11, 2020, application number 202080092238.5.

[0002] Statement Regarding Federally Sponsored Research or Development

[0003] This invention was made with government support under Grant No. R01 CA201049 awarded by the National Institutes of Health (NIH). The government has certain rights in this invention.

[0004] Cross - Reference to Related Applications

[0005] This application claims the priority of U.S. Provisional Application No. 62 / 933,776 filed on November 11, 2019 and U.S. Provisional Application No. 63 / 030,655 filed on May 27, 2020, the contents of which are incorporated herein by reference in their entirety. Background Art

[0006] The epidermal growth factor receptor (EGFR, Erb - B1) belongs to the receptor tyrosine kinase family, which can mediate the proliferation, differentiation, and survival of normal and malignant cells (Arteaga, C.L., J. Clin. Oncol. 19, 2001, 32 - 40). The dysregulation of EGFR is involved in many types of human cancers, and the overexpression of this receptor is present in at least 70% of human cancers (Seymour, L.K., Curr. Drug Targets 2, 2001, 117 - 133), including non - small cell lung cancer, breast cancer, glioma, head and neck squamous cell carcinoma, and prostate cancer (Raymond, E., et al., Drugs 60 (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). Therefore, EGFR has become an attractive target for the design and development of diagnostic and therapeutic agents that can specifically bind and inhibit the receptor tyrosine kinase activity and signal transduction pathways in cancer cells. For example, reversible inhibitors of EGFR tyrosine kinase (EGFR - TK) have been approved by the FDA for the treatment of NSCLC and advanced pancreatic cancer. Other anti - EGFR targeting molecules have also been approved, including lapatinib and

[0007] Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective clinical therapies for patients with advanced non-small cell lung cancer (NSCLC) with EGFR mutations (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 confirmed that when used as initial systemic therapy for advanced EGFR-mutated NSCLC, EGFR TKIs are more effective than chemotherapy in terms of response rate (RR) and progression-free survival (PFS) (Mok, T.S., et al., N. Engl. J. Med. 361, 2009, 947-57;

[0008] Rosell, R., et al., Lancet Oncol. 13, 2012, 239-46; Sequest, L.V. et al., J. Clin. Oncol. 31, 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 experience disease progression after successful treatment with EGFR TKI. The most common mechanism of acquired resistance detected in 60% of patients is secondary mutation (T790M) at position T790 in EGFR (Yu, H.A., et al., Clin. Cancer Res. 19, 2013, 2240-7). This mutation leads to an increase in ATP affinity, making it more difficult for the reversible EGFR TKIs gefitinib and erlotinib to bind to the EGFR TKI domain (Yun C.H., et al., Proc. Natl. Acad. Sci. USA 105, 2008, 2070-5).

[0009] Covalent EGFR inhibitors have emerged for the inhibition of cancers harboring EGFR T790M. However, in lung cancer patients, afatinib is only effective against untreated EGFR mutant cancers and has an RR of less than 10% in NSCLC patients who 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 WT EGFR leads to toxicities, including rash and diarrhea, which limit the ability to escalate the dose of afatinib in patients to the levels required to inhibit EGFR T790M. Irreversible pyrimidine EGFR inhibitors, including the tool compound WZ4002 and the clinical compounds CO - 1686 and AZD9291, overcome many of the limitations of afatinib (Zhou, W., et al., Nature 462, 2009, 1070 - 4; Walter, A.O., et al., Cancer Discov. 3, 2013, 1404 - 15; Cross, D.A.E., et al., Cancer Discov. 4, 2014, 1046 - 61). They are not only more potent against EGFR T790M, but also selectively inhibit the mutant relative to WT EGFR and should thus result in increased clinical efficacy and less toxicity compared to afatinib (Zhou, W., et al.; Walter A.O., et al, Cross, D.A.E., et al.).

[0010] However, all current EGFR TKIs target the ATP - binding site, and while third - generation irreversible inhibitors can overcome T790M, they are all rendered impotent by the C797S mutation, which has emerged in treated patients. Cetuximab, an anti - EGFR antibody that blocks receptor dimerization, is ineffective in EGFR - mutant NSCLC because the mutant activation of the kinase is actually “downstream” of receptor dimerization. Thus, alternative strategies for inhibiting EGFR are needed. Currently, there are no suitable compounds with alternative mechanisms of action targeting mutant EGFR. Accordingly, there is a need for potent small - molecule EGFR inhibitors with alternative mechanisms of action targeting mutant EGFR. SUMMARY OF THE INVENTION

[0011] In one aspect, the present invention provides compounds of Formula I:

[0012]

[0013] or a pharmaceutically acceptable salt thereof;

[0014] Wherein:

[0015] A and A’ are each independently CH, CR8 or N;

[0016] W and Z are each independently N, CH, C-halo, C-(C1-C3 alkyl) or C-(C1-C3 alkoxy);

[0017] X and Y are each independently N, CH or CR 3 ;

[0018] provided that at least one of W, X, Y or Z is CH;

[0019] R 1 is selected from 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl and 3-10 membered cycloalkyl, all of which are optionally substituted by one, two or three R 8 substituents;

[0020] R 2 is selected from 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl and 3-10 membered cycloalkyl, all of which are optionally substituted by one, two or three R6 substituents;

[0021] R 3 is independently selected from halogen, OR 4 , NR 4 R 4 , SO2R 4 , SO2NHR 4 , NHSO2R 4 , C(O)OR 4 , C(O)NHR 4 , C(O)R 4 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, C4-C7 cycloalkenyl, C6-C 10 aryl, 5-6 membered heteroaryl and 5-7 membered heterocyclic group, wherein the alkyl, alkenyl or alkynyl is each optionally substituted by R 4 one, two or three times, and wherein the aryl, heteroaryl or heterocyclic group is each optionally substituted by R 5 one, two or three times;

[0022] R 4 is independently selected from H, (CH2) 0-3 -(C3-C7 cycloalkyl), (CH2) 0-3 -(C4-C7 cycloalkenyl), (CH2) 0-3 -(C6-C 10 aryl), (CH2) 0-3 -(5-6 membered heteroaryl) and (CH2) 0-3-(5- to 7-membered heterocyclic group), wherein each of said aryl, heteroaryl or heterocyclic group is optionally substituted by R 5 substituted one, two or three times;

[0023] R 5 is independently selected, each time it appears, from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C3 alkylamine, 3- to 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-C 10 aryl), (CH2) 0-3 -(5- to 6-membered heteroaryl) and (CH2) 0-3 -(5- to 7-membered heterocyclic group), wherein each of said aryl, heteroaryl or heterocyclic group is optionally substituted by R 7 substituted one, two or three times;

[0024] R 6 is independently selected, each time it appears, from 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) 1-4 OH, S(O) 0-2 H, S(O) 0- 2NH2 or CN;

[0025] Alternatively, two Rs 6 together with the atom to which they are attached can form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl or 3- to 10-membered cycloalkyl;

[0026] R 7 is independently selected, each time it appears, from 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);

[0027] Alternatively, two Rs 7Together with the atom to which it is attached, it can form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl or 3- to 10-membered cycloalkyl; and

[0028] R 8 independently selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, 3- to 6-membered cycloalkyl, halogen, OH, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, (CH2) 1-4 OH, S(O) 0-2 H, S(O) 0-2 NH2 or CN each time it appears.

[0029] In another aspect, the present invention provides a compound of formula II:

[0030]

[0031] or a pharmaceutically acceptable salt thereof;

[0032] wherein

[0033] W and Z are each independently N, CH, C-halo, C-(C1-C3 alkyl) or C-(C1-C3 alkoxy);

[0034] X and Y are each independently C, CH or CR 3 ;

[0035] provided that at least one of W, X, Y or Z is CH;

[0036] R1 is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl and 3- to 10-membered cycloalkyl, all of which are optionally substituted by one, two or three R 8 substituents;

[0037] R 2 is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl and 3- to 10-membered cycloalkyl, all of which are optionally substituted by one, two or three R 6 substituents;

[0038] R 3 is independently selected from halogen, OR 4 , NR 4 R 4 , SO2R 4 , SO2NHR 4 , NHSO2R 4 , C(O)OR 4 , C(O)NHR 4 , C(O)R4 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 7-membered cycloalkyl, C4-C7 cycloalkenyl, C6-C 10 aryl, 5- or 6-membered heteroaryl, and 5- to 7-membered heterocyclic group, wherein the alkyl, alkenyl, or alkynyl is each optionally substituted one, two, or three times by R 4 , and wherein the aryl, heteroaryl, or heterocyclic group is each optionally substituted one, two, or three times by R 5 ;

[0039] R 4 is independently selected, each time it appears, from H, (CH2) 0-3 -(C3-C7 cycloalkyl), (CH2) 0-3 -(C4-C7 cycloalkenyl), (CH2) 0-3 -(C6-C 10 aryl), (CH2) 0-3 -(5- or 6-membered heteroaryl), and (CH2) 0-3 -(5- to 7-membered heterocyclic group), wherein the aryl, heteroaryl, or heterocyclic group is each optionally substituted one, two, or three times by R 5 ;

[0040] R 5 is independently selected, each time it appears, from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C3 alkylamine, 3- to 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-C 10 aryl), (CH2) 0-3 -(5- or 6-membered heteroaryl), and (CH2) 0-3 -(5- to 7-membered heterocyclic group), wherein the aryl, heteroaryl, or heterocyclic group is each optionally substituted one, two, or three times by R 7 ;

[0041] R 6 is independently selected, each time it appears, from 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-

[0042] 4OH, S(O) 0-2 H, S(O) 0-2 NH2, or CN;

[0043] Alternatively, two Rs 6 together with the atom to which they are attached can form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl, or 3- to 10-membered cycloalkyl;

[0044] R 7 is independently selected, at each occurrence, from 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);

[0045] Alternatively, two Rs 7 together with the atom to which they are attached can form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl, or 3- to 10-membered cycloalkyl; and

[0046] R 8 is independently selected, at each occurrence, from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, 3- to 6-membered cycloalkyl, halogen, OH, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, (CH2) 1-4 OH, S(O) 0-2 H, S(O) 0-2 NH2, or CN; and

[0047] n is 1 or 2.

[0048] In yet another aspect, the present disclosure provides a compound of Formula III:

[0049]

[0050] or a pharmaceutically acceptable salt thereof;

[0051] wherein

[0052] is optionally a double bond;

[0053] B and D are each independently C or N;

[0054] W and Z are each independently N, CH, C-halo, C-(C1-C3 alkyl), or C-(C1-C3 alkoxy);

[0055] X and Y are each independently N, CH or CR 3 ;

[0056] provided that at least one of W, X, Y or Z is CH;

[0057] R 1 is selected from 6-10-membered aryl, 5-10-membered heteroaryl, 3-10-membered heterocycloalkyl and 3-10-membered cycloalkyl, all of which are optionally substituted by one, two or three R 8 substituents;

[0058] R 2 is selected from 6-10-membered aryl, 5-10-membered heteroaryl, 3-10-membered heterocycloalkyl and 3-10-membered cycloalkyl, all of which are optionally substituted by one, two or three R 6 substituents;

[0059] R 3 is independently selected from halogen, OR 4 , NR 4 R 4 , SO2R 4 , SO2NHR 4 , NHSO2R 4 , C(O)OR 4 , C(O)NHR 4 , C(O)R 4 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7-membered cycloalkyl, C4-C7 cycloalkenyl, C6-C 10 aryl, 5-6-membered heteroaryl and 5-7-membered heterocyclic group, wherein the alkyl, alkenyl or alkynyl is each optionally substituted by R 4 once, twice or three times, and wherein the aryl, heteroaryl or heterocyclic group is each optionally substituted by R 5 once, twice or three times;

[0060] R 4 is independently selected from H, (CH2) 0-3 -(C3-C7 cycloalkyl), (CH2) 0-3 -(C4-C7 cycloalkenyl), (CH2) 0-3 -(C6-C 10 aryl), (CH2) 0-3 -(5-6-membered heteroaryl) and (CH2) 0-3 -(5-7-membered heterocyclic group), wherein the aryl, heteroaryl or heterocyclic group is each optionally substituted by R 5 once, twice or three times;

[0061] R 5Independently selected from 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-C 10 aryl), (CH2) 0-3 -(5-6 membered heteroaryl) and (CH2) 0-3 -(5-7 membered heterocyclic group), wherein the aryl, heteroaryl or heterocyclic group is each optionally substituted by R 7 substituted one, two or three times;

[0062] R 6 Independently selected from 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) 1-4 OH, S(O) 0-2 H, S(O) 0- 2NH2 or CN;

[0063] Alternatively, two R 6 together with the atom to which they are attached can form a 5-10 membered heteroaryl, 6-10 membered aryl, 3-10 membered heterocycloalkyl or 3-10 membered cycloalkyl;

[0064] R 7 Independently selected from substituents, the 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);

[0065] Alternatively, two R 7 together with the atom to which they are attached can form a 5-10 membered heteroaryl, 6-10 membered aryl, 3-10 membered heterocycloalkyl or 3-10 membered cycloalkyl; and

[0066] R 8independently selected from 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) 1-4 OH, S(O) 0-2 H, S(O) 0-2 NH2 or CN.

[0067] In one aspect, the present disclosure provides a method for treating cancer or a proliferative disease, which comprises administering to a subject in need thereof an effective amount of a compound 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 active agent, wherein the second active agent prevents EGFR dimer formation. In another embodiment, the subject is a human.

[0068] The present disclosure also provides a kit, which comprises a compound capable of inhibiting EGFR activity, the compound being selected from the compounds disclosed in the present invention or pharmaceutically acceptable salts thereof, and instructions for use in the treatment of cancer. In one embodiment, the kit further comprises components for performing a test to determine whether the 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 the second active agent prevents EGFR dimer formation. DETAILED DESCRIPTION OF THE INVENTION

[0069] Definitions

[0070] The definitions of various terms used to describe the compounds and compositions disclosed herein are listed below. These definitions apply to the terms as used throughout the present specification and claims, except where otherwise limited in specific instances, and these terms are used either alone or as part of a larger group.

[0071] Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry and peptide chemistry are those well known and commonly used in the art.

[0072] As used herein, the article "a" or "an" means one or more than one (i.e., at least one) of the grammatical object of the article. For example, "an element" means one element or more than one element. In addition, the use of the term "including" and other forms such as "include", "includes" and "included" is not restrictive.

[0073] As used herein, the term "about" will be understood by those of ordinary skill in the art and will vary to some extent depending on the context in which it is used. As used herein, when referring to measurable values such as amounts, durations, etc., the term "about" is intended to cover variations of ±20% or ±10% on the basis of the specified value, including ±5%, ±1% and ±0.1%, as such variations are appropriate for achieving the disclosed methods.

[0074] As used herein, terms such as "administer" etc. refer to providing a therapeutic agent to a subject. There are various techniques for administering therapeutic agents in the art, including but not limited to intravenous, oral, aerosol, parenteral, ocular, pulmonary and topical administration.

[0075] The term "treat / treated / treating / treatment" includes reducing or alleviating at least one symptom associated with or caused by the condition, disorder or disease being treated. In certain embodiments, treatment includes contacting an effective amount of a compound disclosed herein with wild-type or mutant EGFR for a condition associated with cancer.

[0076] As used herein, the term "prevent / prevention" means that there is no development of a condition or disease if it has not occurred, or no further development of a condition or disease if it has already developed. The ability to prevent some or all of the symptoms associated with a condition or disease is also contemplated.

[0077] As used herein, the terms "patient", "individual" or "subject" refer to a human or non-human mammal. Non-human mammals include, for example, livestock and pets such as sheep, cattle, pigs, dogs, cats and marine mammals. Preferably, the patient, subject or individual is a human.

[0078] As used herein, the terms "effective amount", "pharmaceutically effective amount" and "therapeutically effective amount" refer to the amount of an agent that is non-toxic but sufficient to provide the desired biological result. The result can be a reduction or alleviation of the signs, symptoms or causes of a disease, or any other desired alteration of a biological system. The appropriate therapeutically effective amount in any individual case can be determined by those of ordinary skill in the art using routine experimentation.

[0079] As used herein, the term "pharmaceutically acceptable" refers to materials, such as a carrier or diluent, which do not abrogate the biological activity or properties of the compound and which are relatively non-toxic, i.e., the materials can be administered to an individual without causing undesirable biological effects or interacting in a harmful manner with any component of the composition in which it is contained.

[0080] As used herein, the term "pharmaceutically acceptable salt" refers to derivatives of the disclosed compounds in which the parent compound is modified by converting an existing acidic or basic moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali metal salts or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts of the present disclosure include conventional non-toxic salts of the parent compounds formed from, for example, non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compounds containing basic or acidic moieties 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 an organic solvent or in a mixture of both; non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are generally preferred. The phrase "pharmaceutically acceptable salt" is not limited to mono-salts or 1:1 salts. For example, "pharmaceutically acceptable salt" also includes double salts, such as dihydrochloride salts. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing 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.

[0081] As used herein, the term "prodrug" refers to a precursor compound that will undergo metabolic activation in vivo to produce the active drug. Thus, for example, a prodrug of a compound provided herein will undergo metabolic activation upon administration to a subject to generate the compound.

[0082] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound useful within the present disclosure and a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a patient or subject. There are a variety of techniques for administering compounds, including, but not limited to, intravenous, oral, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0083] As used herein, the term "drug combination" refers to a product resulting from the mixing or combining of more than one active ingredient and includes fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to active ingredients such as the compounds of the present disclosure and active adjuvants being administered to a patient simultaneously in the form of a single entity or dose. The term "non-fixed combination" refers to active ingredients such as the compounds of the present disclosure and active adjuvants being administered to a patient simultaneously, concurrently, or sequentially without a specific time limit as separate entities, where such administration provides a therapeutically effective level of both compounds in the patient. The latter also applies to cocktail therapies, such as the administration of three or more active ingredients.

[0084] As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickening agent, solvent, or encapsulating material, involved in the carrying or transporting of a compound useful within the present disclosure in or to a patient so that the compound can achieve its intended function. Generally, such constructs are carried or transported from one organ or part of the body to another organ or part 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 present disclosure, and not injurious to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: 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 tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository wax; 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 polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations.

[0085] As used herein, "pharmaceutically acceptable carrier" also includes any and all coatings, antibacterial and antifungal agents, absorption delaying agents, etc., which are compatible with the activity of the compound useful within the present disclosure and are physiologically acceptable to the patient. Supplementary active compounds can also be incorporated into the composition. "Pharmaceutically acceptable carrier" also includes pharmaceutically acceptable salts of the compounds disclosed herein. Other additional ingredients that can be included in pharmaceutical compositions are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0086] As used herein, the term "EGFR" refers to the epidermal growth factor receptor (also known as ErbB-1 or HER1) and may refer to the wild-type receptor or a receptor containing one or more mutations.

[0087] As used herein, the term "HER" or "Her" refers to members of the ErbB receptor tyrosine kinase family, including EGFR, ERBB2, HER3, and HER4.

[0088] As used herein, the term "allosteric site" refers to a site on EGFR that is not an ATP-binding site, such as a site characterized by the crystal structure of EGFR. An "allosteric site" can be a site near the ATP-binding site, such as a site characterized by the crystal structure of EGFR. For example, an allosteric site includes one or more of the following amino acid residues of the epidermal growth factor receptor (EGFR): Lys745, Leu788, Ala743, Cys755, Leu777, Phe856, Asp855, Met766, Ile759, Glu762, and / or Ala763.

[0089] As used herein, the term "agent that prevents EGFR dimer formation" or its iterations refers to an agent that prevents dimer formation, wherein the C-terminal half (C-lobe) of the "activator" subunit impacts the N-terminal half (N-lobe) of the "receptor" subunit. Examples of agents that prevent EGFR dimer formation include, but are not limited to, cetuximab, trastuzumab, panitumumab, and Mig6.

[0090] As used herein, unless otherwise specified, the term "alkyl" by itself or as part of another substituent refers to a straight-chain or branched-chain hydrocarbon having the specified number of carbon atoms (i.e., C1-C6 alkyl refers to an alkyl having one to six carbon atoms) and includes straight-chain and branched-chain forms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, and hexyl. Other examples of C1-C6 alkyl include ethyl, methyl, isopropyl, isobutyl, n-pentyl, and n-hexyl.

[0091] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more halogen substituents as defined above, where the alkyl and halogen are as defined herein. By way of example, haloalkyl includes chloromethyl, trifluoromethyl, bromoethyl, chlorofluoroethyl, and the like.

[0092] As used herein, the term "alkoxy" refers to the group -O-alkyl, where the alkyl is as defined herein. By way of example, alkoxy includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, and the like.

[0093] As used herein, the term "alkylamine" refers to the group -NH-alkyl, where alkyl is as defined herein. By way of example, alkylamines include methylamine, ethylamine, isopropylamine, n-propylamine, n-butylamine, sec-butylamine, tert-butylamine, and the like.

[0094] As used herein, the term "haloalkoxy" refers to the group -O-haloalkyl, where haloalkyl is as defined herein. By way of example, haloalkoxys include chloromethoxy, trifluoromethoxy, bromoethoxy, chlorofluoroethoxy, and the like.

[0095] As used herein, the term "alkenyl" refers to a monovalent group derived from a hydrocarbon moiety which, in certain embodiments, contains from two to six or two to eight carbon atoms and has at least one carbon-carbon double bond. The alkenyl group may or may not be a point of attachment to another group. The term "alkenyl" includes, but is not limited to, vinyl, 1-propenyl, 1-butenyl, heptenyl, octenyl, and the like.

[0096] As used herein, the term "alkynyl" refers to a monovalent group derived from a hydrocarbon moiety which, in certain embodiments, contains from two to six or two to eight carbon atoms and has at least one carbon-carbon triple bond. The alkynyl group may or may not be a point of attachment to another group. The term "alkynyl" includes, but is not limited to, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

[0097] As used herein, unless otherwise specified, the term "halo / halogen" alone or as part of another substituent refers to a fluorine, chlorine, bromine, or iodine atom, preferably fluorine, chlorine, or bromine, more preferably fluorine or chlorine

[0098] As used herein, the term "cycloalkyl" refers to a fully saturated non-aromatic carbocyclic system having 1, 2, or 3 rings, where such rings may be fused. The term "fused" means that a second ring exists (i.e., is connected or formed) by sharing two adjacent atoms with the first ring. Cycloalkyl also includes bicyclic structures which may be bridged or spiro in nature, where each individual ring within the bicyclic has from 3 to 8 atoms. The term "cycloalkyl" includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[3.1.0]hexyl, spiro[3.3]heptyl, and bicyclo[1.1.1]pentyl.

[0099] As used herein, the term "cycloalkenyl" refers to a partially saturated non-aromatic carbocyclic system having 1, 2 or 3 rings, wherein such rings may be fused and wherein at least one ring contains sp2 carbon-carbon bonds. The term "cycloalkenyl" includes, but is not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, bicyclo[3.1.0]hexenyl, spiro[3.3]heptenyl, and bicyclo[1.1.1]pentenyl.

[0100] As used herein, the term "heterocyclic group" or "heterocycloalkyl" refers to a non-aromatic carbocyclic system containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S and having 1, 2 or 3 rings, wherein such rings may be fused, as defined above. Heterocyclic groups also include bicyclic structures which may be bridged or spiro in nature, wherein each individual ring within the bicyclic has 3 - 8 atoms and contains 0, 1 or 2 N, O or S atoms. The term "heterocyclic group" includes cyclic esters (i.e., lactones) and cyclic amides (i.e., lactams), and specifically includes, but is not limited to, epoxy, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl (i.e., oxanyl), pyranyl, dioxanyl, aziridinyl, azetidinyl, pyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, oxazolidinyl, thiazolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, 1,3-oxazinyl, 1,3-thiazinyl, 2-azabicyclo-[2.1.1]hexyl, 5-azabicyclo[2.1.1]hexyl, 6-azabicyclo[3.1.1]heptyl, 2-azabicyclo[2.2.1]-heptyl, 3-azabicyclo[3.1.1]heptyl, 2-azabicyclo[3.1.1]heptyl, 3-azabicyclo[3.1.0]-hexyl, 2-azabicyclo-[3.1.0]hexyl, 3-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octyl, 3-oxa-7-azabicyclo[3.3.1]-nonyl, 3-oxa-9-azabicyclo[3.3.1]nonyl, 2-oxa-5-azabicyclo-[2.2.1]heptyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 2-azaspiro[3.3]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 2-oxaspiro[3.3]-heptyl, 2-oxaspiro[3.5]nonyl, 3-oxaspiro[5.3]-nonyl, and 8-oxabicyclo[3.2.1]octyl.

[0101] As used herein, the term "aromatic" refers to a carbocyclic or heterocyclic ring having one or more polyunsaturated rings and having aromatic character, i.e., having (4n + 2) delocalized π (pi) electrons, where n is an integer.

[0102] As used herein, the term "aryl" refers to an aromatic carbocyclic system having 1, 2 or 3 rings, wherein such rings may be fused, where fusion is defined above. If the rings are fused, one of the rings must be fully unsaturated and the fused rings 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-tetrahydronaphthyl. In some embodiments, the aryl group has 6 carbon atoms. In some embodiments, the aryl group has from six to ten carbon atoms. In some embodiments, the aryl group has from six to sixteen carbon atoms.

[0103] As used herein, the term "heteroaryl" refers to an aromatic carbocyclic system having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S and having 1, 2 or 3 rings, wherein such rings may be fused, where fusion is defined above. The term "heteroaryl" includes, but is not limited to, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, 5,6,7,8-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroquinolinyl, 6,7-dihydro-5H-cyclopenta[b]pyridyl, 6,7-dihydro-5H-cyclopenta[c]pyridyl, 1,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 2,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazolyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridyl, 4,5,6,7-tetrahydro-1H-indazolyl and 4,5,6,7-tetrahydro-2H-indazolyl.

[0104] It is understood that if an aryl, heteroaryl, cycloalkyl or heterocyclic moiety can be bonded or otherwise attached to the designated moiety through different ring atoms (i.e., the specific point of attachment is not specified when shown or described), all possible points, whether through a carbon atom or, for example, a trivalent nitrogen atom, are meant. For example, the term "pyridyl" refers to 2-, 3- or 4-pyridyl, the term "thienyl" refers to 2- or 3-thienyl, and so on.

[0105] As used herein, the term "substituted" means that an atom or group of atoms has replaced hydrogen as a substituent attached to another group.

[0106] As used herein, the term "optionally substituted" means that the group mentioned can be substituted or unsubstituted. In one embodiment, the group mentioned is optionally substituted with zero substituents, i.e., the group mentioned is unsubstituted. In another embodiment, the group mentioned is optionally substituted with one or more additional groups, and the additional groups are independently selected from the groups described herein.

[0107] Compounds

[0108] Compounds provided herein are allosteric inhibitors of epidermal growth factor receptor (EGFR) and can be used to treat kinase-mediated disorders, including cancer and other proliferative diseases.

[0109] In one aspect, compounds of formula I are provided herein:

[0110]

[0111] or a pharmaceutically acceptable salt thereof;

[0112] wherein:

[0113] A and A' are each independently CH, CR 8 or N;

[0114] W and Z are each independently N, CH, C-halo, C-(C1-C3 alkyl) or C-(C1-C3 alkoxy);

[0115] X and Y are each independently N, CH or CR 3 ;

[0116] provided that at least one of W, X, Y or Z is CH;

[0117] R 1 is selected from 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 R 8 substituents;

[0118] R 2 is selected from 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 R 6 substituents;

[0119] R 3 is independently selected from halogen, OR 4 , NR 4 R 4 SO2R 4 SO2NHR 4 NHSO2R4 、C(O)OR 4 、C(O)NHR 4 、C(O)R 4 、C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, C4-C7 cycloalkenyl, C6-C 10 aryl, 5-6 membered heteroaryl and 5-7 membered heterocyclic group, wherein the alkyl, alkenyl or alkynyl is each optionally substituted one, two or three times by R 4 and wherein the aryl, heteroaryl or heterocyclic group is each optionally substituted one, two or three times by R 5 ;

[0120] R 4 is independently selected, each time it appears, from H, (CH2) 0-3 -(C3-C7 cycloalkyl), (CH2) 0-3 -(C4-C7 cycloalkenyl), (CH2) 0-3 -(C6-C 10 aryl), (CH2) 0-3 -(5-6 membered heteroaryl) and (CH2) 0-3 -(5-7 membered heterocyclic group), wherein the aryl, heteroaryl or heterocyclic group is each optionally substituted one, two or three times by R 5 ;

[0121] R 5 is independently selected, each time it appears, from 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-C 10 aryl), (CH2) 0-3 -(5-6 membered heteroaryl) and (CH2) 0-3 -(5-7 membered heterocyclic group), wherein the aryl, heteroaryl or heterocyclic group is each optionally substituted one, two or three times by R 7 ;

[0122] R 6 is independently selected, each time it appears, from 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) 1-4 OH, S(O) 0-2 H, S(O)0- 2NH2 or CN;

[0123] Alternatively, two Rs 6 together with the atom to which they are attached can form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl or 3- to 10-membered cycloalkyl;

[0124] R 7 independently, at each occurrence, is selected from 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);

[0125] Alternatively, two Rs 7 together with the atom to which they are attached can form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl or 3- to 10-membered cycloalkyl; and

[0126] R 8 independently, at each occurrence, is selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, 3- to 6-membered cycloalkyl, halogen, OH, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, (CH2) 1-4 OH, S(O) 0-2 H, S(O) 0-2 NH2 or CN.

[0127] In another aspect, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein

[0128] W and Z are each independently N, CH, C-halo, C-(C1-C3 haloalkyl), C-(C1-C3 alkyl) or C-(C1-C3 alkoxy);

[0129] wherein all other variables are as defined above.

[0130] In one embodiment, the compound of formula I is a compound of formula Ia:

[0131]

[0132] or a pharmaceutically acceptable salt thereof.

[0133] In one embodiment of formula Ia, R 3 is C6-C 10 aryl or 5- to 6-membered heteroaryl, each optionally substituted once by R 5 In another embodiment of formula Ia, R 3 is C6-C 10 aryl optionally substituted once by R 5 wherein R 5 is 5- to 7-membered heterocyclic group, C6-C 10 aryl, 3- to 10-membered cycloalkyl or 5- to 6-membered heteroaryl, all of which are optionally substituted once by R 7 In yet another embodiment of formula Ia, R 3 is phenyl optionally substituted once by R 5 wherein R 5 is 5- to 7-membered heterocyclic group, C6-C 10 aryl, 3- to 10-membered cycloalkyl or 5- to 6-membered heteroaryl, all of which are optionally substituted once by R 7 In yet another embodiment of formula Ia, R 3 is C6-C 10 aryl optionally substituted once by R 5 wherein R 5 is 5-membered heterocyclic group optionally substituted once by R 7 In one embodiment of formula Ia, R 3 is phenyl optionally substituted once by piperidine, wherein piperidine is substituted once by R 7 substituted once.

[0134] In another embodiment, the compound of formula I is a compound of formula Ib:

[0135]

[0136] or a pharmaceutically acceptable salt thereof.

[0137] In yet another embodiment, Z is CH. In yet another embodiment, Z is N. In one embodiment, Z is CF. In another embodiment, R 6 is independently hydroxy or halogen at each occurrence.

[0138] In yet another embodiment, R 1 is selected from benzimidazole, imidazopyrazine, purine, imidazole, pyrazole, triazole and imidazopyridine. In yet another embodiment, R 1 is selected from the following:

[0139]

[0140] All of these are optionally substituted by one, two or three R8 Substituted.

[0141] In another embodiment, R 6 is hydroxy, halogen, or two Rs 6 together with the atom to which it is attached can form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl, or 3- to 10-membered cycloalkyl. In one embodiment, R 6 is hydroxy, fluoro, or or two Rs 6 together with the atom to which it is attached can form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl, or 3- to 10-membered cycloalkyl. In yet another embodiment, R 6 is hydroxy. In yet another embodiment, R 6 is fluoro. In another embodiment, R 6 is chloro. In one embodiment, having two Rs 6 are hydroxy and fluoro. In another embodiment, having two Rs 6 are hydroxy and chloro. In yet another embodiment, two Rs 6 together with the atom to which it is attached can form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl, or 3- to 10-membered cycloalkyl.

[0142] In one embodiment, the compound of formula I is selected from the compounds in Table 1.

[0143] Table 1.

[0144]

[0145]

[0146]

[0147] or a pharmaceutically acceptable salt thereof.

[0148] In one embodiment, the compound of formula I is selected from the compounds in Table 2.

[0149] Table 2.

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156] or a pharmaceutically acceptable salt thereof.

[0157] In embodiments, Compounds 112-117 provided herein, in the Examples, Compounds 112-117 provided herein have an isotope enrichment factor of at least 3500 (52.5% deuterium incorporation for each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), 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 (99.5% deuterium incorporation) for each designated deuterium atom.

[0158] In embodiments of Compounds 112-117, each position specifically designated as deuterium has at least 95% deuterium incorporation.

[0159] In another aspect, the present invention provides compounds of Formula II:

[0160]

[0161] or a pharmaceutically acceptable salt thereof;

[0162] wherein

[0163] W and Z are each independently N, CH, C-halo, C-(C1-C3 alkyl), or C-(C1-C3 alkoxy);

[0164] X and Y are each independently C, CH, or CR 3 ;

[0165] provided that at least one of W, X, Y, or Z is CH;

[0166] R 1 is selected from 6-10-membered aryl, 5-10-membered heteroaryl, 3-10-membered heterocycloalkyl, and 3-10-membered cycloalkyl, all of which are optionally substituted by one, two, or three R 8 substituents;

[0167] R 2 is selected from 6-10-membered aryl, 5-10-membered heteroaryl, 3-10-membered heterocycloalkyl, and 3-10-membered cycloalkyl, all of which are optionally substituted by one, two, or three R 6 substituents.

[0168] R 3 is independently selected from halogen, OR 4 , NR4 R 4 、 SO2R 4 、 SO2NHR 4 、 NHSO2R 4 、 C(O)OR 4 、 C(O)NHR 4 、 C(O)R 4 、 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, C4-C7 cycloalkenyl, C6-C 10 aryl, 5-6 membered heteroaryl and 5-7 membered heterocyclic group, wherein the alkyl, alkenyl or alkynyl is each optionally substituted by R 4 one, two or three times, and wherein the aryl, heteroaryl or heterocyclic group is each optionally substituted by R 5 one, two or three times;

[0169] R 4 is independently selected from H, (CH2) 0-3 -(C3-C7 cycloalkyl), (CH2) 0-3 -(C4-C7 cycloalkenyl), (CH2) 0-3 -(C6-C 10 aryl), (CH2) 0-3 -(5-6 membered heteroaryl) and (CH2) 0-3 -(5-7 membered heterocyclic group), wherein the aryl, heteroaryl or heterocyclic group is each optionally substituted by R 5 one, two or three times;

[0170] R 5 is independently selected from 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-C 10 aryl), (CH2) 0-3 -(5-6 membered heteroaryl) and (CH2) 0-3 -(5-7 membered heterocyclic group), wherein the aryl, heteroaryl or heterocyclic group is each optionally substituted by R 7 one, two or three times;

[0171] R 6independently selected from 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) 1-4 OH, S(O) 0-2 H, S(O) 0- 2NH2 or CN;

[0172] Alternatively, two Rs 6 together with the atom to which they are attached can form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl or 3- to 10-membered cycloalkyl;

[0173] R 7 independently selected from substituents, said 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);

[0174] Alternatively, two Rs 7 together with the atom to which they are attached can form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl or 3- to 10-membered cycloalkyl; and

[0175] R 8 independently selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, 3- to 6-membered cycloalkyl, halogen, OH, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, (CH2) 1-4 OH, S(O) 0-2 H, S(O) 0-2 NH2 or CN; and

[0176] n is 1 or 2.

[0177] In another aspect of Formula II

[0178] R 5Independently selected from 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-C 10 aryl), (CH2) 0-3 -(5-6 membered heteroaryl), O(CH2) 0-3 -(4-7 membered heterocyclic group) and (CH2) 0-3 -(4-7 membered heterocyclic group), wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclic group is each optionally substituted by R 7 substituted one, two or three times;

[0179] wherein all other variables are as defined above.

[0180] In one embodiment, the compound of formula II is a compound of formula IIa:

[0181]

[0182] or a pharmaceutically acceptable salt thereof.

[0183] In yet another aspect, the present invention provides a compound of formula X:

[0184]

[0185] or a pharmaceutically acceptable salt thereof;

[0186] wherein

[0187] A is O or S;

[0188] W and Z are each independently N, CH, C-halo, C-(C1-C3 alkyl) or C-(C1-C3 alkoxy);

[0189] X and Y are each independently N, CH or CR 3 ;

[0190] provided that at least one of W, X, Y or Z is CH;

[0191] R 1 is selected from 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl and 3-10 membered cycloalkyl, all of which are optionally substituted by one, two or three R 8 substituents;

[0192] R 2Selected from 6-10-membered aryl, 5-10-membered heteroaryl, 3-10-membered heterocycloalkyl, and 3-10-membered cycloalkyl, all of which are optionally substituted by one, two, or three R 6 substituted;

[0193] R 3 is independently selected, at each occurrence, from halogen, OR 4 , NR 4 R 4 , SO2R 4 , SO2NHR 4 , NHSO2R 4 , C(O)OR 4 , C(O)NHR 4 , C(O)R 4 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7-membered cycloalkyl, C4-C7 cycloalkenyl, C6-C 10 aryl, 5-6-membered heteroaryl, and 5-7-membered heterocyclic group, wherein the alkyl, alkenyl, or alkynyl is each optionally substituted by R 4 once, twice, or three times, and wherein the aryl, heteroaryl, or heterocyclic group is each optionally substituted by R 5 once, twice, or three times;

[0194] R 4 is independently selected, at each occurrence, from H, (CH2) 0-3 -(C3-C7 cycloalkyl), (CH2) 0-3 -(C4-C7 cycloalkenyl), (CH2) 0-3 -(C6-C 10 aryl), (CH2) 0-3 -(5-6-membered heteroaryl), and (CH2) 0-3 -(5-7-membered heterocyclic group), wherein the aryl, heteroaryl, or heterocyclic group is each optionally substituted by R 5 once, twice, or three times;

[0195] R 5 is independently selected, at each occurrence, from 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-C 10 aryl), (CH2) 0-3 -(5-6-membered heteroaryl), O(CH2) 0-3 -(4-7-membered heterocyclic group), and (CH2)0-3 -(4 - 7 - membered heterocyclic group), wherein each of said alkyl, alkoxy, aryl, heteroaryl or heterocyclic group is optionally substituted by R 7 substituted one, two or three times;

[0196] R 6 is independently selected from 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) 1-4 OH, S(O) 0-2 H, S(O) 0- 2NH2 or CN;

[0197] Alternatively, two Rs 6 together with the atoms to which they are attached can form a 5 - 10 - membered heteroaryl, 6 - 10 - membered aryl, 3 - 10 - membered heterocycloalkyl or 3 - 10 - membered cycloalkyl;

[0198] R 7 is independently selected from substituents which are 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);

[0199] Alternatively, two Rs 7 together with the atoms to which they are attached can form a 5 - 10 - membered heteroaryl, 6 - 10 - membered aryl, 3 - 10 - membered heterocycloalkyl or 3 - 10 - membered cycloalkyl; and

[0200] R 8 is independently selected from 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) 1-4 OH, S(O) 0-2 H, S(O) 0-2 NH2 or CN; and

[0201] n is 1 or 2.

[0202] In one embodiment of formula IIa, R3 is C6-C 10 aryl or 5- or 6-membered heteroaryl, each optionally substituted by R 5 once. In another embodiment of formula IIa, R 3 is C6-C 10 aryl optionally substituted by R 5 once, where R 5 is 5- to 7-membered heterocyclic, C6-C 10 aryl, 3- to 10-membered cycloalkyl or 5- or 6-membered heteroaryl, all of which are optionally substituted by R 7 once. In yet another embodiment of formula IIa, R 3 is phenyl optionally substituted by R 5 once, where R 5 is 5- to 7-membered heterocyclic, C6-C 10 aryl, 3- to 10-membered cycloalkyl or 5- or 6-membered heteroaryl, all of which are optionally substituted by R 7 once. In yet another embodiment of formula IIa, R 3 is C6-C 10 aryl optionally substituted by R 5 once, where R 5 is 5-membered heterocyclic optionally substituted by R 7 once. In one embodiment of formula IIa, R 3 is phenyl optionally substituted once by piperidine, where piperidine is substituted by R 7 once.

[0203] In another embodiment, the compound of formula II is a compound of formula IIb:

[0204]

[0205] or a pharmaceutically acceptable salt thereof.

[0206] In another embodiment, the compound of formula II is a compound of formula IIc:

[0207]

[0208] or a pharmaceutically acceptable salt thereof.

[0209] In yet another embodiment, where R 6 is, independently at each occurrence, hydroxy, halogen or two R 6 together with the atom to which they are attached can form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl or 3- to 10-membered cycloalkyl. In another embodiment, R 6 is hydroxy, fluoro or or two R 6Together with the atom to which it is attached, it can form a 5- to 10-membered heteroaryl group, a 6- to 10-membered aryl group, a 3- to 10-membered heterocycloalkyl group, or a 3- to 10-membered cycloalkyl group. In yet another embodiment, R 6 is a hydroxyl group. In yet another embodiment, R 6 is fluorine. In another embodiment, R 6 is chlorine. In one embodiment, two Rs 6 are hydroxyl and fluorine. In another embodiment, two Rs 6 are hydroxyl and chlorine. In yet another embodiment, two Rs 6 together with the atom to which they are attached can form a 5- to 10-membered heteroaryl group, a 6- to 10-membered aryl group, a 3- to 10-membered heterocycloalkyl group, or a 3- to 10-membered cycloalkyl group.

[0210] In embodiments of Formulas II, IIa, and IIb, R 1 is selected from benzimidazole, imidazopyrazine, purine, imidazole, pyrazole, triazole, and imidazopyridine. In one embodiment, R 1 is selected from the following:

[0211]

[0212] All of these are optionally substituted by one, two, or three Rs 8 .

[0213] In another embodiment, R 3 is phenyl or C2-C3 alkynyl, wherein the phenyl is optionally substituted one or two times by R 5 , and the alkynyl is optionally substituted one or two times by R 4 . In yet another embodiment, R 3 is phenyl optionally substituted one or two times by R 5 . In yet another embodiment, R 3 is C2-C3 alkynyl optionally substituted one or two times by R 4 . In one embodiment, R 3 is phenyl optionally substituted one or two times by R 5 , and R 5 is selected from piperidine, pyridine, and thiomorpholine dioxide, all of which are optionally substituted one or two times by R 7 .

[0214] In another embodiment, the compounds of Formula II are selected from the compounds in Table 3.

[0215] Table 3.

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225] or a pharmaceutically acceptable salt thereof.

[0226] In yet another embodiment, the compounds of Formula II are selected from the compounds in Table 4.

[0227] Table 4.

[0228]

[0229] or a pharmaceutically acceptable salt thereof.

[0230] In an embodiment, Compounds 112 - 117 provided herein, in the Examples, Compounds 112 - 117 provided herein have an isotope enrichment factor of at least 3500 (52.5% deuterium incorporation per designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), 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 (99.5% deuterium incorporation) for each designated deuterium atom.

[0231] In an embodiment of Compounds 112 - 117, each position specifically designated as deuterium has at least 95% deuterium incorporation.

[0232] In another embodiment, the compounds of Formula X are selected from the compounds in Table 5:

[0233] Table 5.

[0234]

[0235]

[0236]

[0237]

[0238] or a pharmaceutically acceptable salt thereof.

[0239] In yet another aspect, the present invention provides a compound of Formula III:

[0240]

[0241] or a pharmaceutically acceptable salt thereof;

[0242] wherein

[0243] is optionally a double bond;

[0244] B and D are each independently C or N;

[0245] W and Z are each independently N, CH, C-halo, C-(C1-C3 alkyl) or C-(C1-C3 alkoxy);

[0246] X and Y are each independently N, CH or CR 3 ;

[0247] provided that at least one of W, X, Y or Z is CH;

[0248] provided that at least one of W, X, Y or Z is CH;

[0249] R 1 is selected from 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl and 3-10 membered cycloalkyl, all of which are optionally substituted by one, two or three R 8 substituents.

[0250] R 2 is selected from 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl and 3-10 membered cycloalkyl, all of which are optionally substituted by one, two or three R 6 substituents.

[0251] R 3 is independently selected from halogen, OR 4 , NR 4 R 4 , SO2R 4 , SO2NHR 4 , NHSO2R 4 , C(O)OR 4 , C(O)NHR 4 , C(O)R 4, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, C4-C7 cycloalkenyl, C6-C 10 aryl, 5-6 membered heteroaryl and 5-7 membered heterocyclic group, wherein the alkyl, alkenyl or alkynyl is each optionally substituted by R 4 one, two or three times, and wherein the aryl, heteroaryl or heterocyclic group is each optionally substituted by R 5 one, two or three times;

[0252] R 4 is independently selected from H, (CH2) 0-3 -(C3-C7 cycloalkyl), (CH2) 0-3 -(C4-C7 cycloalkenyl), (CH2) 0-3 -(C6-C 10 aryl), (CH2) 0-3 -(5-6 membered heteroaryl) and (CH2) 0-3 -(5-7 membered heterocyclic group), wherein the aryl, heteroaryl or heterocyclic group is each optionally substituted by R 5 one, two or three times;

[0253] R 5 is independently selected from 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-C 10 aryl), (CH2) 0-3 -(5-6 membered heteroaryl) and (CH2) 0-3 -(5-7 membered heterocyclic group), wherein the aryl, heteroaryl or heterocyclic group is each optionally substituted by R 7 one, two or three times;

[0254] R 6 is independently selected from 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) 1-4 OH, S(O) 0-2 H, S(O) 0- 2NH2 or CN;

[0255] Alternatively, two R 6Together with the atom to which it is attached, it can form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl or 3- to 10-membered cycloalkyl;

[0256] R 7 independently selected from substituents at each occurrence, said 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);

[0257] Alternatively, two Rs 7 together with the atom to which they are attached can form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl or 3- to 10-membered cycloalkyl; and

[0258] R 8 independently selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, 3- to 6-membered cycloalkyl, halogen, OH, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, (CH2) 1-4 OH, S(O) 0-2 H, S(O) 0-2 NH2 or CN.

[0259] In another aspect, the present invention provides a compound of formula III, or a pharmaceutically acceptable salt thereof, wherein

[0260] R 4 independently selected from H, C1-C6 alkyl, (CH2) 0-3 -(C3-C7 cycloalkyl), (CH2) 0-3 -(C4-C7 cycloalkenyl), (CH2) 0-3 -(C6-C 10 aryl), (CH2) 0-3 -(5- to 6-membered heteroaryl) and (CH2) 0-3 -(5- to 7-membered heterocyclic group), wherein the aryl, heteroaryl or heterocyclic group is each optionally substituted by R 5 substituted one, two or three times;

[0261] wherein all other variables are as defined above.

[0262] In one embodiment, the compound of formula III is a compound of formula IIIa:

[0263]

[0264] or a pharmaceutically acceptable salt thereof.

[0265] In one embodiment of Formula IIIa, R 3 C6-C 10 Aryl or 5-6 membered heteroaryl, both of which are optionally substituted by R 5 In another embodiment of Formula IIIa, R 3 C6-C 10 The aryl group is optionally replaced by R 5 Replace once, where R 5 is a 5-7 membered heterocyclic group, a C6-C 10 aryl, 3-10 membered cycloalkyl or 5-6 membered heteroaryl, all of which are optionally replaced by R 7 In another embodiment of Formula IIIa, R 3 is phenyl and optionally replaced by R 5 Replace once, where R 5 is a 5-7 membered heterocyclic group, a C6-C 10 aryl, 3-10 membered cycloalkyl or 5-6 membered heteroaryl, all of which are optionally replaced by R 7 Replace once.

[0266] In yet another embodiment of Formula IIIa, R 3 C6-C 10 The aryl group is optionally replaced by R 5 Replace once, where R 5 is a 5-membered heterocyclic group optionally substituted by R 7 In one embodiment of Formula IIIa, R 3 is phenyl optionally substituted once with piperidine, wherein the piperidine is R 7 Replace once.

[0267] In another embodiment, the compound of formula III is a compound of formula IIIb:

[0268]

[0269] or a pharmaceutically acceptable salt thereof.

[0270] In yet another embodiment, the compound of formula III is a compound of formula IIIc:

[0271]

[0272] or a pharmaceutically acceptable salt thereof.

[0273] In yet another embodiment, R 1 is selected from benzimidazole, imidazopyrazine, purine, imidazole, pyrazole, triazole, and imidazopyridine. In one embodiment, R 1 is selected from the following:

[0274]

[0275] and

[0276] All of these are optionally substituted with one, two, or three R 8 .

[0277] In another embodiment, Y is CR 3 and R 3 is a 6- to 10-membered aryl substituted one or two times with R 5 . In yet another embodiment, Z is CF. In yet another embodiment, Z is CH. In yet another embodiment, Z is N.

[0278] In another embodiment, R 6 is hydroxy, halogen, or two R 6 together with the atom to which it is attached can form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl, or 3- to 10-membered cycloalkyl. In one embodiment, R 6 is hydroxy, fluoro, or or two R 6 together with the atom to which it is attached can form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl, or 3- to 10-membered cycloalkyl. In yet another embodiment, R 6 is hydroxy. In yet another embodiment, R 6 is fluoro. In another embodiment, R 6 is chloro. In one embodiment, having two R 6 is hydroxy and fluoro. In another embodiment, having two R 6 is hydroxy and chloro. In yet another embodiment, two R 6 together with the atom to which it is attached can form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl, or 3- to 10-membered cycloalkyl.

[0279] In one embodiment, the compound of formula III is selected from the compounds in Table 6.

[0280] Table 6.

[0281]

[0282]

[0283] or a pharmaceutically acceptable salt thereof.

[0284] In embodiments of Formulas I, II, and III, R 7 is C1-C3 alkyl.

[0285] The compounds disclosed herein may exist as tautomers and optical isomers (e.g., enantiomers, diastereomers, mixtures of diastereomers, racemic mixtures, etc.).

[0286] As is well known in the art, any compound that will be converted in vivo to provide a compound disclosed herein is a prodrug within the scope of this disclosure.

[0287] The compounds provided herein may also include all atomic isotopes that occur in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more of the constituent atoms of the compounds of the invention may be replaced or substituted with isotopes of atoms at natural or non-natural abundances. In some embodiments, the compound contains at least one deuterium atom. For example, one or more hydrogen atoms in the compounds disclosed herein may be replaced or substituted with deuterium. In some embodiments, the compound contains 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 incorporating isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, N.Y., Appleton-Century-Crofts, 1971); The Renaissance of H / D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can be used in various studies, such as NMR spectroscopy, metabolic experiments, and / or assays.

[0288] In the compounds provided herein, any atom not specifically designated as a particular isotope of that atom represents any stable isotope of that atom. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen", that position is understood to have hydrogen in its natural abundance isotopic composition. Additionally, unless otherwise indicated, when a position is specifically designated as "D" or "deuterium", that position is understood to have deuterium at an abundance at least 3000-fold greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 45% deuterium incorporation).

[0289] In one aspect, the present disclosure provides a pharmaceutical composition comprising any one of the compounds described herein or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

[0290] In one embodiment, the composition further comprises a second active agent. In another embodiment, the second active agent is selected from MEK inhibitors, PI3K inhibitors, and mTor inhibitors. In yet another embodiment, the second active agent prevents EGFR dimer formation in a subject. In another embodiment, the second active agent is selected from cetuximab, trastuzumab, and panitumumab. In one 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.

[0291] In another aspect, the present disclosure provides a pharmaceutical composition 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 and a pharmaceutically acceptable carrier, wherein the 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 formation is cetuximab.

[0292] Compounds that bind to allosteric sites in EGFR, such as the compounds of the present disclosure (e.g., compounds of the formulas disclosed herein), optionally in combination with a second active agent, are capable of modulating EGFR activity, wherein the second active agent prevents EGFR dimer formation. In some embodiments, the compounds of the present disclosure are capable of inhibiting or reducing EGFR activity in the absence of a second active agent (e.g., an antibody such as cetuximab, trastuzumab, or panitumumab). In other embodiments, the compounds of the present disclosure are combined with a second active agent. In one embodiment, the second active agent prevents EGFR dimer formation and / or is capable of inhibiting or reducing 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 active agent that prevents EGFR dimer formation is cetuximab. In one embodiment, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0293] Therapeutic Methods

[0294] In one aspect, the present disclosure provides a method of treating cancer in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Formula I. In one embodiment, the cancer is selected from lung cancer, colon cancer, breast cancer, endometrial cancer, thyroid cancer, glioma, squamous cell carcinoma, and prostate cancer. In another embodiment, the cancer is non-small cell lung cancer (NSCLC).

[0295] In another aspect, the present disclosure provides a method of inhibiting a kinase in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Formula I. In one embodiment, the kinase is EGFR.

[0296] In yet another aspect, the present disclosure provides 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 Formula I. In one embodiment, the kinase-mediated disorder is resistant to EGFR-targeted therapy. In another embodiment, the therapies for treating EGFR are selected from gefitinib, erlotinib, osimertinib, CO-1686, and WZ4002.

[0297] In some embodiments, the compounds of the present disclosure are capable of modulating (e.g., inhibiting or reducing) the activity of an EGFR containing one or more mutations. In some embodiments, the mutant EGFR contains one or more mutations selected from T790M, L718Q, L844V, V948R, L858R, I941R, 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, Del / T790M / L844V, L858R / L718Q, L858R / L844V, L858R / T790M, L858R / T790M / I941R, 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, Del / T790M / C797S, and 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.

[0298] In some embodiments, the compounds of the present disclosure in combination with a second active agent are capable of modulating (e.g., inhibiting or reducing) the activity of an EGFR containing one or more mutations, wherein the second active agent prevents EGFR dimer formation. In some embodiments, the mutant EGFR contains one or more mutations selected from T790M, L718Q, L844V, V948R, L858R, I941R, 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, DEL / T790M / L844V, L858R / L718Q, L858R / L844V, L858R / T790M, L858R / T790M / I941R, 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 / C797S, and 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 a further embodiment, the second active agent that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In a further embodiment, the second active agent that prevents EGFR dimer formation is cetuximab. In one embodiment, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib, gefitinib, or erlotinib.

[0299] In some embodiments, the compounds of the present disclosure are capable of modulating (e.g., inhibiting or reducing) the activity of an EGFR containing one or more mutations without affecting the activity of wild-type EGFR.

[0300] In other embodiments, the compounds of the present disclosure in combination with a second active agent are capable of modulating (e.g., inhibiting or reducing) the activity of an EGFR containing one or more mutations without affecting the activity of wild-type EGFR, wherein the 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 formation is cetuximab. In one 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.

[0301] Modulating an EGFR containing one or more mutations (such as those described herein) without modulating wild-type EGFR provides a method of treating, preventing, or ameliorating a disease, including but not limited to cancer and metastasis, inflammation, arthritis, systemic lupus erythematosus, skin-related disorders, lung disorders, cardiovascular diseases, ischemia, neurodegenerative disorders, liver diseases, 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.

[0302] In some embodiments, the compounds of the present disclosure exhibit higher inhibition of an EGFR containing one or more mutations as described herein relative to wild-type EGFR. In certain embodiments, the compounds of the present disclosure exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold higher inhibition of an EGFR containing one or more mutations as described herein relative to wild-type EGFR. In various embodiments, the compounds of the present disclosure exhibit up to 1000-fold higher inhibition of an EGFR containing one or more mutations as described herein relative to wild-type EGFR. In various embodiments, the compounds of the present disclosure exhibit up to 1-fold higher inhibition of an 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 wild-type EGFR.

[0303] In other embodiments, the compounds of the present disclosure in combination with a second active agent exhibit higher inhibition of EGFR containing one or more mutations as described herein relative to wild-type EGFR, wherein the second active agent prevents EGFR dimer formation. In certain embodiments, the compounds of the present disclosure in combination with a second active agent exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold higher inhibition of EGFR containing one or more mutations as described herein relative to wild-type EGFR, wherein the second active agent prevents EGFR dimer formation. In various embodiments, the compounds of the present disclosure in combination with a second active agent exhibit up to 1000-fold higher inhibition of EGFR containing one or more mutations as described herein relative to wild-type EGFR, wherein the second active agent prevents EGFR dimer formation. In various embodiments, the compounds of the present disclosure in combination with a second active agent exhibit up to 10,000-fold higher inhibition of EGFR with combinations of mutations described herein (e.g., L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, DEL / T790M, DEL / T790M / C797S, and L858R / T790M) relative to wild-type EGFR, wherein the 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 formation is cetuximab. In one 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.

[0304] In some embodiments, the compounds of the present disclosure exhibit from about 2-fold to about 10-fold higher inhibition of EGFR containing one or more mutations as described herein relative to wild-type EGFR. In various embodiments, the compounds of the present disclosure exhibit from about 10-fold to about 100-fold higher inhibition of EGFR containing one or more mutations as described herein relative to wild-type EGFR. In various embodiments, the compounds of the present disclosure exhibit from about 100-fold to about 1000-fold higher inhibition of EGFR containing one or more mutations as described herein relative to wild-type EGFR. In various embodiments, the compounds of the present disclosure exhibit from about 1000-fold to about 10,000-fold higher inhibition of EGFR containing one or more mutations as described herein relative to wild-type EGFR.

[0305] In other embodiments, the compounds of the present disclosure in combination with a second active agent exhibit from about 2-fold to about 10-fold higher inhibition of EGFR containing one or more mutations as described herein relative to wild-type EGFR, wherein the second active agent prevents EGFR dimer formation. In other embodiments, the compounds of the present disclosure in combination with a second active agent exhibit from about 10-fold to about 100-fold higher inhibition of EGFR containing one or more mutations as described herein relative to wild-type EGFR, wherein the second active agent prevents EGFR dimer formation. In other embodiments, the compounds of the present disclosure in combination with a second active agent exhibit from about 100-fold to about 1000-fold higher inhibition of EGFR containing one or more mutations as described herein relative to wild-type EGFR, wherein the second active agent prevents EGFR dimer formation. In other embodiments, the compounds of the present disclosure in combination with a second active agent exhibit from about 1000-fold to about 10000-fold higher inhibition of EGFR containing one or more mutations as described herein relative to wild-type EGFR, wherein the second active agent prevents EGFR dimer formation. In other embodiments, the second active agent that prevents EGFR dimer formation is an antibody. In a further embodiment, the second active agent that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In a further embodiment, the second active agent that prevents EGFR dimer formation is cetuximab. In one 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.

[0306] In certain embodiments, the compounds of the present disclosure exhibit at least 2-fold greater inhibition of EGFR with a mutation combination selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M relative to wild-type EGFR. In certain embodiments, the compounds of the present disclosure exhibit at least 3-fold greater inhibition of EGFR with a mutation combination selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M relative to wild-type EGFR. In certain embodiments, the compounds of the present disclosure exhibit at least 5-fold greater inhibition of EGFR with a mutation combination selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M relative to wild-type EGFR. In certain embodiments, the compounds of the present disclosure exhibit at least 10-fold greater inhibition of EGFR with a mutation combination selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M relative to wild-type EGFR. In certain embodiments, the compounds of the present disclosure exhibit at least 25-fold greater inhibition of EGFR with a mutation combination selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M relative to wild-type EGFR. In certain embodiments, the compounds of the present disclosure exhibit at least 50-fold greater inhibition of EGFR with a mutation combination selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M relative to wild-type EGFR. In certain embodiments, the compounds of the present disclosure exhibit at least 100-fold greater inhibition of EGFR with a mutation combination selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M relative to wild-type EGFR.

[0307] In certain embodiments, the compounds of the present disclosure in combination with a second active agent exhibit at least 2-fold higher inhibition against EGFR with a mutation combination selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M relative to wild-type EGFR, wherein the second active agent prevents EGFR dimer formation. In certain embodiments, the compounds of the present disclosure in combination with a second active agent exhibit at least 3-fold higher inhibition against EGFR with a mutation combination selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M relative to wild-type EGFR, wherein the second active agent prevents EGFR dimer formation. In certain embodiments, the compounds of the present disclosure in combination with a second active agent exhibit at least 5-fold higher inhibition against EGFR with a mutation combination selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M relative to wild-type EGFR, wherein the second active agent prevents EGFR dimer formation. In certain embodiments, the compounds of the present disclosure in combination with a second active agent exhibit at least 10-fold higher inhibition against EGFR with a mutation combination selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M relative to wild-type EGFR, wherein the second active agent prevents EGFR dimer formation. In certain embodiments, the compounds of the present disclosure in combination with a second active agent exhibit at least 25-fold higher inhibition against EGFR with a mutation combination selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M relative to wild-type EGFR, wherein the second active agent prevents EGFR dimer formation.In certain embodiments, the compounds of the present disclosure in combination with a second active agent exhibit at least 50-fold greater inhibition of EGFR with a mutation combination selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M relative to wild-type EGFR, wherein the second active agent prevents EGFR dimer formation. In certain embodiments, the compounds of the present disclosure in combination with a second active agent exhibit at least 100-fold greater inhibition of EGFR with a mutation combination selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M relative to wild-type EGFR, wherein the 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 formation is cetuximab. In one embodiment, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0308] In some embodiments, inhibition of EGFR activity is measured by IC 50 assay.

[0309] In some embodiments, inhibition of EGFR activity is measured by EC 50 assay.

[0310] In some embodiments, inhibition of the EGFR by the compounds of the present disclosure can be measured via biochemical assays. As a schematic and non-limiting example, inhibition of EGFR activity can be determined using a homogeneous time-resolved fluorescence (HTRF) assay using the conditions and experimental parameters disclosed herein. The HTRF assay can employ, for example, a substrate (e.g., biotin-Lck-peptide substrate) concentration of about 1 μM; an EGFR (mutant or WT) concentration of about 0.2 nM to about 40 nM; and an inhibitor concentration of about 0.000282 μM to about 50 μM. Compounds of the present disclosure screened under these conditions can, for example, exhibit an IC 50Value. In certain embodiments, the compounds of the present disclosure screened under the above conditions for inhibiting EGFR having mutations or combinations selected from L858R / T790M, L858R, and T790M may, for example, exhibit an IC 50 value.

[0311] In some embodiments, the compounds of the present disclosure bind to allosteric sites in EGFR. In some embodiments, the compounds of the present disclosure interact with at least one amino acid residue of epidermal growth factor receptor (EGFR) selected from Lys745, Leu788, and Ala 743. In other embodiments, the compounds of the present 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 present disclosure interact with at least one amino acid residue of epidermal growth factor receptor (EGFR) selected from Met766, Ile759, Glu762, and Ala763. In other embodiments, the compounds of the present 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 factor receptor (EGFR) selected from Met766, Ile759, Glu762, and Ala763. In other embodiments, the compounds of the present disclosure do not interact with any amino acid residue of epidermal growth factor receptor (EGFR) selected from Met793, Gly796, and Cys797.

[0312] In some embodiments, the present disclosure provides compounds comprising allosteric kinase inhibitors, wherein the compounds are more potent inhibitors of resistant EGFR mutants relative to wild-type EGFR. For example, relative to wild-type EGFR, the compounds may be at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or about 100-fold more potent in inhibiting the kinase activity of resistant EGFR mutants. In some embodiments, the resistant EGFR mutants are resistant to one or more known EGFR inhibitors, including but not limited to gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib.

[0313] In some embodiments, the drug-resistant EGFR mutants comprise sensitizing mutations, such as Del and L858R.

[0314] In some embodiments, the present disclosure provides a combination of a compound comprising an allosteric kinase inhibitor and a second active agent, wherein the second active agent prevents EGFR dimer formation, and wherein the compound is a more potent inhibitor of the drug-resistant EGFR mutant relative to wild-type EGFR. For example, relative to wild-type EGFR, the combination of the compound and the second active agent can be at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or about 100-fold more potent in inhibiting the kinase activity of the drug-resistant EGFR mutant, wherein the second active agent prevents EGFR dimer formation. 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 mutants comprise sensitizing mutations, such as Del and L858R. 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 one embodiment, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0315] In some embodiments, the present disclosure provides a compound comprising an allosteric kinase inhibitor, wherein the compound inhibits the kinase activity of a drug-resistant EGFR mutant carrying a sensitizing mutation (e.g., Del and L858R) and a drug-resistant mutation (e.g., T790M, L718Q, C797S, and L844V), and the potency (e.g., as measured by IC 50 ) differs by less than 10-fold relative to an EGFR mutant carrying a sensitizing mutation but not a drug-resistant 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.

[0316] In other embodiments, the present disclosure provides a combination of a compound comprising an allosteric kinase inhibitor and a second active agent, wherein the second active agent prevents EGFR dimer formation, and wherein the combination of the compound and the second active agent inhibits the kinase activity of resistant EGFR mutants carrying sensitizing mutations (e.g., Del and L858R) and resistant mutations (e.g., T790M, L718Q, C797S, and L844V), and the potency (e.g., as measured by IC 50 is less than 10-fold different relative to an EGFR mutant carrying a sensitizing mutation but not a resistant mutation. In some embodiments, the potency difference is less than about 9-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 panitumumab. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab. In one 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.

[0317] In some embodiments, the present 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) in 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 potency of the compound in inhibiting the activity of EGFR containing one or more mutations as described herein (e.g., as measured by IC 50 can be at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or about 100-fold more potent than gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib.

[0318] In other embodiments, the present disclosure provides a combination of a compound comprising an allosteric kinase inhibitor and a second active agent, wherein the second active agent prevents EGFR dimer formation, and wherein the combination of the compound and 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) in inhibiting the activity of an EGFR containing one or more mutations such as T790M, L718Q, L844V, L858R, C797S, and Del as described herein. For example, the combination of the compound and the second active agent is more potent (e.g., as measured by IC 50 as measured) than gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib by at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or about 100-fold in inhibiting the activity of an EGFR containing one or more mutations as described herein, wherein the 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 formation is cetuximab. In one embodiment, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is ositinib, gefitinib, or erlotinib. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0319] In some embodiments, the present disclosure provides a compound comprising an allosteric kinase inhibitor, wherein the compound 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) in inhibiting the activity of wild-type EGFR. For example, the compound is less potent (e.g., as measured by IC 50 as measured) than gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib by at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or about 100-fold.

[0320] In other embodiments, the present disclosure provides a combination of a compound comprising an allosteric kinase inhibitor and a second active agent, wherein the second active agent prevents EGFR dimer formation, and wherein the combination of the compound and 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) in inhibiting the activity of wild-type EGFR. For example, the combination of the compound and the second active agent is at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or about 100-fold less potent than gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib in inhibiting the activity of wild-type EGFR, wherein the 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 formation is cetuximab. In one 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. 50 (as measured). Comparable to gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib, the combination may be at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or about 100-fold less potent in inhibiting the activity of wild-type EGFR, wherein the 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 formation is cetuximab. In one 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.

[0321] The potency of an inhibitor can be determined by the EC 50 value. As measured under substantially similar conditions, a compound with a lower EC 50 value is a more potent inhibitor relative to a compound with a higher EC 50 value. In some embodiments, the substantially similar conditions include in vitro or in vivo determination of EGFR-dependent phosphorylation levels (e.g., in 3T3 cells expressing wild-type EGFR, mutant EGFR, or any fragment thereof).

[0322] The potency of an inhibitor can also be determined by the IC 50 value. As measured under substantially similar conditions, a compound with a lower IC 50 value is a more potent inhibitor relative to a compound with a higher IC 50 value. In some embodiments, the substantially similar conditions include in vitro or in vivo determination of EGFR-dependent phosphorylation levels (e.g., in 3T3 cells expressing wild-type EGFR, mutant EGFR, or any fragment thereof).

[0323] EGFR sensitizing mutations include, but are not limited to, L858R, G719S, G719C, G719A, L861Q, deletions in exon 19 and / or insertions in exon 20. Resistance EGFR mutants can have, but are not limited to, resistance mutations that include T790M, T854A, L718Q, C797S or D761Y.

[0324] The selectivity between wild-type EGFR and EGFR containing one or more mutations as described herein can also be measured using a cell proliferation assay, wherein cell proliferation is dependent on kinase activity. For example, murine Ba / F3 cells transfected with a suitable form of wild-type EGFR (such as VIII; containing the 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 exon 19 deletion / T790M can be used. The proliferation assay is performed at inhibitor concentration ranges (10 μM, 3 μM, 1.1 μM, 330 nM, 110 nM, 33 nM, 11 nM, 3 nM, 1 nM) and the EC 50 .

[0325] An alternative method of measuring the effect on EGFR activity is to assay EGFR phosphorylation. Wild-type or mutant (L858R / T790M, Del / T790M, Del / T790M / L718Q, 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 an inhibitor (using the concentrations described above) to inhibit EGFR phosphorylation can be assayed. The cells are exposed to increasing concentrations of the inhibitor for 6 hours and stimulated with EGF for 10 minutes. The effect on EGFR phosphorylation is determined by Western Blotting using a phospho-specific (Y1068) EGFR antibody.

[0326] In another aspect, the present disclosure relates to a compound that binds to an allosteric site in EGFR, wherein the compound exhibits 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, 100-fold, or 1000-fold higher inhibition relative to wild-type EGFR against EGFR containing one or more mutations as described herein (e.g., L858R / T790M, Del / T790M, Del / T790M / L718Q, L858R / T790M / C797S, Del / T790M / C797S, L858R / T790M / I941R, or L858R / T790M / L718Q).

[0327] In other embodiments, the present disclosure provides a combination of a compound that binds to an allosteric site in EGFR and a second active agent, wherein the second active agent prevents EGFR dimer formation, and wherein the combination of the compound and the second active agent exhibits 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, 100-fold, or 1000-fold higher inhibition relative to wild-type EGFR against 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). 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 one 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.

[0328] In another aspect, the present disclosure provides a method of inhibiting epidermal growth factor receptor (EGFR), the method 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 method further comprises administering a second active agent, wherein the 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 formation is cetuximab. In one embodiment, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0329] In another aspect, the present disclosure provides a method of treating or preventing a disease, the method 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 disease is mediated by a kinase. In further embodiments, the kinase comprises a mutated cysteine residue. In further embodiments, the mutated cysteine residue is located in or near the position in EGFR corresponding to Cys 797, 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 the second active agent prevents dimer formation of the kinase. In some embodiments, the 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 one 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.

[0330] In some embodiments, the disease is mediated by EGFR (e.g., EGFR plays a role in the onset or development of the disease). In some embodiments, the disease is mediated by Her-kinase. In further embodiments, the Her-kinase is HER1, HER2 or HER4.

[0331] In certain embodiments, the disease is resistant to known EGFR inhibitors, including but not limited to gefitinib, erlotinib, osimertinib, CO-1686, or WZ4002. In certain embodiments, a diagnostic test is performed to determine whether the disease is associated with an activating mutation in EGFR. In certain embodiments, a diagnostic test is performed to determine whether the disease is associated with EGFR carrying an activating mutation and / or a resistance mutation. Activating mutations include but are not limited to L858R, G719S, G719C, G719A, L718Q, L861Q, deletions in exon 19 and / or insertions in exon 20. The resistant EGFR mutants can have, but are not limited to, resistance mutations comprising T790M, T854A, L718Q, C797S, or D761Y. The diagnostic test can include sequencing, pyrosequencing, PCR, RT-PCR, or similar analytical techniques known to those skilled in the art for detecting nucleotide sequences.

[0332] In certain embodiments, the disease is cancer or a proliferative disease.

[0333] In further embodiments, the disease is lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreatic 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 cell carcinoma, head and neck squamous cell carcinoma, leukemia, lymphoma, myeloma, 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.

[0334] In certain embodiments, the disease is resistant to known EGFR inhibitors, including but not limited to gefitinib, erlotinib, osimertinib, CO-1686, or WZ4002. In certain embodiments, a diagnostic test is performed to determine whether the disease is associated with an activating mutation in EGFR. In certain embodiments, a diagnostic test is performed to determine whether the disease is associated with EGFR carrying an activating mutation and / or a resistance mutation. Activating mutations include but are not limited to L858R, G719S, G719C, G719A, L718Q, L861Q, deletions in exon 19 and / or insertions in exon 20. The resistant EGFR mutants can have, but are not limited to, resistance mutations comprising T790M, T854A, L718Q, C797S, or D761Y. The diagnostic test can include sequencing, pyrosequencing, PCR, RT-PCR, or similar analytical techniques known to those skilled in the art for detecting nucleotide sequences.

[0335] In yet another aspect, provided herein is a method of treating a kinase-mediated disorder, which comprises 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, an additional therapeutic agent is administered to the subject. In other embodiments, the compound and the additional therapeutic agent are administered simultaneously or sequentially.

[0336] In another aspect, the present 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 disclosed herein or a pharmaceutically acceptable salt thereof and a second active agent, wherein the second active agent prevents EGFR dimer formation. In some embodiments, the compound is an inhibitor of HER1, HER2, or HER4. In other embodiments, an additional therapeutic agent is administered to the subject. In other embodiments, the compound, the second active agent that prevents EGFR dimer formation, 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 active agent that prevents EGFR dimer formation is cetuximab. In one 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.

[0337] In other embodiments, the disease is cancer. In further embodiments, the cancer is lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreatic 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 cell carcinoma, head and neck squamous cell carcinoma, leukemia, lymphoma, myeloma, or solid tumor. 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.

[0338] In another aspect, provided herein is a method of treating cancer, wherein the cancer cells comprise activated EGFR, the method comprising administering to a subject in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0339] In another aspect, the present disclosure provides a method of treating cancer, wherein the cancer cells comprise activated EGFR, the method 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 the 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 formation is cetuximab. In one 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.

[0340] In certain embodiments, the EGFR activation is selected from mutations of EGFR, amplifications of EGFR, expressions of EGFR, and ligand-mediated activation of EGFR.

[0341] In further embodiments, the mutations of EGFR are selected from G719S, G719C, G719A, L858R, L861Q, exon 19 deletion mutations, and exon 20 insertion mutations.

[0342] In yet another aspect, the present disclosure provides a method of treating cancer in a subject, wherein the subject is identified as in need of EGFR inhibition for treating cancer, the method comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0343] In certain embodiments, the subject identified as in need of EGFR inhibition is resistant to known EGFR inhibitors, including but not limited to gefitinib, erlotinib, osimertinib, CO-1686 or WZ4002. In certain embodiments, a diagnostic test is performed to determine whether the subject has an activating mutation in EGFR. In certain embodiments, a diagnostic test is performed to determine whether the subject has EGFR carrying an activating mutation and / or a drug-resistant mutation. Activating mutations include but are not limited to L858R, G719S, G719C, G719A, L718Q, L861Q, deletions in exon 19 and / or insertions in exon 20. The drug-resistant EGFR mutants can have, but are not limited to, drug-resistant mutations comprising T790M, T854A, L718Q, C797S or D761Y. The diagnostic test can include sequencing, pyrosequencing, PCR, RT-PCR or similar analytical techniques known to those skilled in the art for detecting nucleotide sequences.

[0344] In one aspect, the present disclosure provides a method of preventing resistance to a known EGFR inhibitor (including but not limited to gefitinib, erlotinib, osimertinib, CO-1686, or WZ4002) in a subject, which comprises administering to the subject in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0345] In another aspect, the present disclosure provides a method of preventing resistance to a known EGFR inhibitor (including but not limited to gefitinib, erlotinib, osimertinib, CO-1686, or WZ4002) in a disease, which comprises administering to the subject in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and a second active agent, wherein the 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 formation is cetuximab.

[0346] In one embodiment of the methods disclosed herein, the subject is a human.

[0347] In another aspect, the present disclosure provides a compound disclosed herein or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment or prevention of a disease in which EGFR plays a role.

[0348] In one aspect, the present disclosure provides a method of treating or preventing a condition selected from the group consisting of: autoimmune diseases, inflammatory diseases, proliferative and hyperproliferative diseases, immune-mediated diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cardiovascular diseases, hormone-related diseases, allergies, asthma, and Alzheimer's disease. In other embodiments, the condition is selected from the group consisting of proliferative disorders and neurodegenerative disorders.

[0349] One aspect of the present disclosure provides compounds that can be used to treat diseases, disorders, and conditions characterized by excessive or abnormal cell proliferation. Such diseases include, but are not limited to, proliferative or hyperproliferative diseases and neurodegenerative diseases. Examples of proliferative and hyperproliferative diseases include, but are not limited to, cancer. The term "cancer" includes, but is not limited to, the following cancers: breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, urogenital cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratoacanthoma, lung cancer, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, colorectal cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer and biliary tract cancer, kidney cancer, bone marrow disorders, lymphatic disorders, Hodgkin's disease, hairy cell carcinoma, oral and pharyngeal (mouth) cancer, lip cancer, tongue cancer, oral cancer, pharyngeal cancer, small intestine cancer, colon cancer, rectal cancer, colorectal cancer, rectal cancer, brain cancer and central nervous system cancer, chronic myelogenous leukemia (CML) and leukemia. The term "cancer" includes, but is not limited to, the following cancers: myeloma, lymphoma or cancers selected from gastric cancer, kidney cancer, head and neck cancer, oropharyngeal cancer, non-small cell lung cancer (NSCLC), endometrial cancer, liver cancer, non-Hodgkin's lymphoma and lung cancer.

[0350] The term "cancer" refers to any cancer caused by the proliferation of malignant tumor cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, lymphomas, etc. For example, cancers include but are not limited to mesothelioma, leukemias and lymphomas such as cutaneous T-cell lymphoma (CTCL), non-cutaneous peripheral T-cell lymphoma, lymphoma associated with human T-cell lymphotropic virus (HTLV) such as adult T-cell leukemia / lymphoma (ATLL), B-cell lymphoma, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, lymphoma and multiple myeloma, non-Hodgkin lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hodgkin lymphoma, Burkitt lymphoma, adult T-cell leukemia lymphoma, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or hepatocellular carcinoma. Other examples include myelodysplastic syndromes, pediatric solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilms tumor, bone tumors and soft tissue sarcomas, common adult solid tumors such as head and neck cancers (e.g., oral cancer, laryngeal cancer, nasopharyngeal cancer and esophageal cancer), urogenital cancers (e.g., prostate cancer, bladder cancer, kidney cancer, uterine cancer, ovarian cancer, testicular cancer), lung cancers (e.g., small cell lung cancer and non-small cell lung cancer), breast cancer, pancreatic cancer, melanoma and other skin cancers, gastric cancer, brain tumors, tumors associated with Gorlin syndrome (e.g., medulloblastoma, meningioma, etc.) and liver cancer. Additional exemplary forms of cancer that can be treated by the subject compounds include but are not limited to skeletal or smooth muscle carcinomas, gastric cancer, small intestine cancer, rectal cancer, salivary gland cancer, endometrial cancer, adrenal cancer, anal cancer, rectal cancer, parathyroid cancer and pituitary cancer.

[0351] Additional cancers for which the compounds described herein can be used for prevention, treatment and research include, for example, colon cancer, familial adenomatous polyposis carcinoma and hereditary non-polyposis colorectal cancer or melanoma. In addition, cancers include but are not limited to lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, thyroid cancer (medullary thyroid cancer and papillary thyroid cancer), kidney cancer, renal parenchymal cancer, cervical cancer, corpus uteri cancer, endometrial cancer, choriocarcinoma, testicular cancer, urethral cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral primitive neuroectodermal tumors, gallbladder cancer, bronchial cancer, multiple myeloma, basal cell carcinoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma and plasmacytoma. In one aspect of the present disclosure, the present disclosure provides the use of one or more of the compounds of the present disclosure in the manufacture of a medicament for treating cancer, said cancer including but not limited to the various types of cancer disclosed herein.

[0352] In some embodiments, the compounds of the present disclosure can be used to treat cancers such as colorectal cancer, thyroid cancer, breast cancer, and lung cancer; and myeloproliferative disorders such as polycythemia vera, thrombocytosis, myeloid metaplasia with myelofibrosis, chronic myelogenous leukemia, chronic myelomonocytic leukemia, hypereosinophilic syndrome, juvenile myelomonocytic leukemia, and systemic mastocytosis. In some embodiments, the compounds of the present disclosure can be used to treat hematopoietic disorders, particularly acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), acute promyelocytic leukemia, and acute lymphoblastic leukemia (ALL).

[0353] As provided herein, the term "cancer cell" includes cells afflicted with any of the above-described conditions.

[0354] The present disclosure also provides a method of treating or preventing cell proliferative disorders such as hyperplasia, dysplasia, and pre-cancerous lesions. Dysplasia is the earliest form of pre-cancerous lesion that can be recognized by a pathologist in a biopsy. The subject compounds can be administered for the purpose of preventing the hyperplasia, dysplasia, or pre-cancerous lesion from progressing further or becoming cancerous. Examples of pre-cancerous lesions can occur in skin, esophageal tissue, breast, and cervical intraepithelial tissue.

[0355] Examples of neurodegenerative diseases include, but are not limited to, adrenoleukodystrophy (ALD), Alexander disease, Alpers' 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 encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, familial fatal insomnia, frontotemporal dementia, Huntington's disease, HIV-associated dementia, Kennedy disease, Krabbe disease, Lewy body dementia, neuroborreliosis, Machado-Joseph disease (spinocerebellar ataxia type 3), multiple system atrophy, multiple sclerosis, narcolepsy, Niemann Pick disease, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prion disease, progressive supranuclear palsy, Refsum's disease, Sandhoff disease, Schilder's disease, subacute combined degeneration of the spinal cord secondary to pernicious anemia, Spielmeyer-Vogt-Sjogren-Batten disease (also known as Batten disease), spinocerebellar ataxia (multiple types with different characteristics), spinal muscular atrophy, Steele-Richardson-Olszewski disease, tabes dorsalis, and toxic encephalopathy.

[0356] Another aspect of the present disclosure provides a method for treating or reducing the severity of a disease selected from proliferative or hyperproliferative diseases or neurodegenerative diseases, the method comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable composition comprising the compound. In other embodiments, the method further comprises administering a second active agent, wherein the 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 formation is cetuximab. In one 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.

[0357] The activity of the compounds and compositions of the present disclosure as EGFR kinase inhibitors can be determined in vitro, in vivo, or in cell lines. In vitro assays include assays that determine inhibition of kinase activity or the ATPase activity of the activated kinase. Alternative in vitro assays quantify the ability of the inhibitor to bind to the protein kinase and can be measured either by radiolabeling the inhibitor prior to binding, separating the inhibitor / kinase complex, and determining the amount of radiolabel bound or by performing a competition experiment in which the new inhibitor is incubated with the kinase that is bound to a known radioligand. The detailed conditions for determining the compounds used as inhibitors of various kinases in the present disclosure will be set forth in the Examples below.

[0358] In accordance with the foregoing, the present disclosure also provides a method of preventing or treating any of the above diseases or disorders in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof and optionally a second active agent, wherein the second active agent prevents EGFR dimer formation. For any of the above uses, the required dosage will vary with the mode of administration, the particular condition to be treated, and the desired effect.

[0359] In other embodiments, the compound and the second active agent that prevents EGFR dimer formation are administered simultaneously or sequentially.

[0360] Administration / Dosage / Formulations

[0361] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage forms may also contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents, and emulsifying agents, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 - butanediol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan and mixtures thereof. In addition to the inert diluent, the oral compositions may also contain adjuvants such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, and perfuming agents.

[0362] Injectable formulations (e.g., sterile injectable aqueous or oleaginous suspensions) may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable formulations may also be sterile injectable solutions, suspensions or emulsions in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3 - butanediol. Acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. Additionally, a sterile non-volatile oil is commonly employed as a solvent or suspending medium. For this purpose, any bland non-volatile oil may be used, including synthetic mono- or di-glycerides of fatty acids. Additionally, fatty acids such as oleic acid are used in the preparation of injectables.

[0363] To prolong the action of a drug, it is often necessary to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be achieved by using a liquid suspension of a crystalline or amorphous material with poor water solubility. Then, the rate of absorption of the drug depends on its rate of dissolution, which may in turn depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is achieved by dissolving or suspending the drug in an oily vehicle.

[0364] Compositions for rectal or vaginal administration are preferably suppositories, which may be prepared by mixing the compounds of the present disclosure with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol, or suppository wax, which excipient or carrier is solid at ambient temperature but liquid at body temperature and will thus melt in the rectal or vaginal cavity and release the active compound.

[0365] Solid compositions of a similar type may also be used as fillers in soft and hard gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols, etc.

[0366] The active compounds may also be in microencapsulated form with one or more of the excipients described above. Solid dosage forms tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings, release controlling coatings, and other coatings well known in the art of pharmaceutical formulation. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose, lactose, or starch. In addition to the inert diluent, such dosage forms may also conventionally contain additional substances, such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents.

[0367] Dosage forms for topical or transdermal administration of the compounds of the present disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed with a pharmaceutically acceptable carrier and any necessary preservatives or buffering agents, as required, under sterile conditions. Ophthalmic formulations, ear drops, eye ointments, powders, and solutions are also encompassed within the scope of the present disclosure.

[0368] In addition to the active compounds of the present disclosure, ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acids, talc and zinc oxide or mixtures thereof.

[0369] In addition to the compounds of the present disclosure, powders and sprays may also contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays may additionally contain conventional propellants such as chlorofluorocarbons.

[0370] Transdermal patches have the additional advantage of providing a controlled delivery of the compound to the body. Such dosage forms can be prepared by dissolving or dispensing the compound in a suitable medium. Penetration enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymeric matrix or gel.

[0371] In the treatment methods according to the present disclosure, a disease or disorder is treated or prevented in a subject by administering a therapeutically effective amount of a compound of the present disclosure to the subject, such as a human or other animal, in an amount and for a time required to achieve the desired result. As used herein, the term "therapeutically effective amount" of a compound of the present disclosure refers to the amount of the compound sufficient to reduce the symptoms of a disorder in a subject. As is well understood in the medical arts, the therapeutically effective amount of a compound of the present disclosure will be under a reasonable benefit / risk ratio applicable to any medical treatment.

[0372] Generally, the compounds of the present disclosure will be administered in a therapeutically effective amount, alone or in combination with one or more therapeutic agents, via any common and acceptable manner known in the art. The therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. Generally, a daily dose of about 0.03 to 2.5 mg / kg body weight is indicated to achieve satisfactory results systemically. In larger mammals such as humans, the indicated daily dose is in the range of about 0.5 mg to about 100 mg, conveniently administered in divided doses, such as up to four times a day, or in a delayed release form. Suitable unit dosage forms for oral administration contain about 1 to 50 mg of the active ingredient.

[0373] In certain embodiments, the therapeutic amount or dose of a compound of the present disclosure can be in the range of about 0.1 mg / Kg to about 500 mg / Kg, or about 1 to about 50 mg / Kg. Generally, a treatment regimen according to the present disclosure includes administering about 10 mg to about 1000 mg of one or more compounds of the present disclosure to a patient in need of such treatment, in a single dose or multiple doses per day. The therapeutic amount or dose will also vary depending on the route of administration and the possibility of co-use with other agents.

[0374] After the condition of the subject has improved, if necessary, a maintenance dose of a compound, composition or combination of the present disclosure may be administered. Subsequently, the dose or frequency of administration or both may be reduced to a level that maintains the improved condition, depending on the symptoms; treatment should be discontinued when the symptoms have been reduced to the desired level. However, once the disease symptoms recur, the subject may require long-term intermittent treatment.

[0375] However, it should be understood that the total daily dosage of the compounds and compositions of the present disclosure will be determined by the attending physician within the scope of reasonable medical judgment. The specific inhibitory dose for any particular patient will depend on 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, weight, general health, sex and diet of the patient; the time of administration, the route of administration and the excretion rate of the specific compound employed; the duration of the treatment; drugs used in combination with or concurrently with the specific compound employed; and similar factors well known in the medical arts.

[0376] The present disclosure also provides a pharmaceutical combination, such as a kit, comprising a) a first agent, which is a compound of the present disclosure as disclosed herein in free form or in a pharmaceutically acceptable salt form, and b) at least one active adjuvant. The kit may comprise instructions regarding its administration.

[0377] In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents. For example, an agent that prevents EGFR dimer formation, a chemotherapeutic agent or other anti-proliferative agent may be combined with a compound of the present disclosure to treat proliferative diseases and cancer.

[0378] Some examples of materials that can be used as pharmaceutically acceptable carriers include, but are not limited to: ion exchangers; alumina; aluminum stearate; lecithin; serum proteins such as human serum albumin; buffering substances such as phosphates, glycine, sorbic acid or potassium sorbate; mixtures of partial glycerides of saturated vegetable fatty acids; water; salts or electrolytes such as protamine sulfate; disodium hydrogen phosphate; potassium hydrogen phosphate; sodium chloride; zinc salts; colloidal silicon dioxide; magnesium trisilicate; polyvinylpyrrolidone; polyacrylates; waxes; polyethylene-polyoxyethylene block polymers; lanolin; 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 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; diols such as 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; ethanol; and phosphate buffer solutions. In addition, depending on the judgment of the formulator, non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate and coloring agents, release agents, coating agents, sweetening agents, flavoring agents and fragrances, preservatives and antioxidants may also be present in the composition. The protein kinase inhibitor or its pharmaceutically acceptable salt can be formulated into a pharmaceutical composition for administration to an animal or a human. These pharmaceutical compositions comprising an amount of the protein inhibitor effective for treating or preventing a protein kinase-mediated condition and a pharmaceutically acceptable carrier are other embodiments of the present disclosure.

[0379] Kits

[0380] In one aspect, the present disclosure provides a kit comprising a compound capable of inhibiting kinase activity, the compound being selected from one or more of the compounds disclosed herein or a pharmaceutically acceptable salt thereof; and instructions for use in the treatment of cancer. In certain embodiments, the kit further comprises components for performing a test to determine whether the subject has an activating and / or resistant mutation in EGFR.

[0381] In another aspect, the present disclosure provides a kit comprising a compound capable of inhibiting EGFR activity, the compound being selected from the compounds disclosed herein or a pharmaceutically acceptable salt thereof.

[0382] In another aspect, the present disclosure provides a kit comprising a compound capable of inhibiting kinase activity, said compound being selected from one or more of the compounds disclosed herein or a pharmaceutically acceptable salt thereof; a second active agent, wherein the second active agent prevents EGFR dimer formation; and instructions for use in the treatment of cancer. In certain embodiments, the kit further comprises components for performing a test to determine whether the subject has an activating and / or resistance mutation in the 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 panitumumab. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab.

[0383] In another aspect, the present disclosure provides a kit comprising a compound capable of inhibiting EGFR activity, said compound being selected from the compounds disclosed herein or a pharmaceutically acceptable salt thereof; and a second active agent, wherein the 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 formation is cetuximab. In one 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.

[0384] The present disclosure is further illustrated by the following examples and synthetic schemes, which should not be construed as limiting the scope or spirit of the present disclosure to the specific procedures described herein. It should be understood that these examples are provided to illustrate certain embodiments and are not intended to limit the scope of the present disclosure thereby. It should also be understood that various other embodiments, modifications, and their equivalents contemplated by those skilled in the art may be made without departing from the spirit and / or scope of the appended claims. Examples

[0385] This application is further illustrated by the following examples, which should not be construed as further limiting.

[0386] Unless otherwise specified, the practice of the present disclosure will employ conventional techniques of organic synthesis, cell biology, cell culture, and molecular biology within the skill of the art.

[0387] Abbreviations

[0388] ACN Acetonitrile

[0389] dba Dibenzylideneacetone

[0390] DCM Dichloromethane

[0391] DIPEA Diisopropylethylamine

[0392] DMF N,N - Dimethylformamide

[0393] DMSO Dimethyl sulfoxide

[0394] dppf 1,1'-Bis(diphenylphosphino)ferrocene EtOAc Ethyl acetate

[0395] EtOH Ethanol

[0396] HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate LDA Lithium diisopropylamide

[0397] MeOH Methanol

[0398] SPhos 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl TBTU 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate TEA Triethylamine

[0399] TFA Trifluoroacetic acid

[0400] THF Tetrahydrofuran

[0401] XPhos 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

[0402] Example 1: Preparation of 2 - [1H - Benzimidazol - 2 - yl - (3 - fluorophenyl)methyl] - 6 - [4 - (1 - methyl - 4 - piperidinyl)phenyl] Isoindolin - 1 - one (Compound 026)

[0403] Scheme 1.

[0404]

[0405] Step 1. Methyl 2 - (6 - bromo - 1 - oxo - isoindolin - 2 - yl) - 2 - (3 - fluorophenyl)acetate

[0406]

[0407] 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). After the reaction mixture was stirred at room temperature for 5 minutes, methyl 5-bromo-2-(bromomethyl)benzoate (6.71 g, 21.8 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 three times with ethyl acetate. 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 / hexane to give the title compound (4.75 g, 58%). MS m / z: 379.1 [M+1] + 。

[0408] Step 2. Methyl 2 - (3 - fluorophenyl) - 2 - [6 - [4 - (1 - methyl - 4 - piperidinyl)phenyl] - 1 - oxo - isoindolin - 2 - yl]acetate

[0409]

[0410] A mixture of methyl 2-(6-bromo-1-oxoisoindolin-2-yl)-2-(3-fluorophenyl)acetate (4.13 g, 10.9 mmol), 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine (4.91 g, 16.3 mmol), 1.0 M sodium carbonate (21.8 mL, 21.8 mmol) and dioxane (109 mL) was degassed twice under nitrogen. A complex of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (0.534 g, 0.654 mmol) and XPhos (0.519 g, 1.09 mmol) were added, and then the reaction was degassed once more under nitrogen. The reaction mixture was heated at 100 °C for 2 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted twice with dichloromethane. 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% acetonitrile / water containing 10 mM ammonium acetate to give the title compound (4.17 g, 81%). MS m / z: 473.2 [M+1] + 。

[0411] Step 3. 2 - (3 - fluorophenyl) - 2 - [6 - [4 - (1 - methyl - 4 - piperidinyl)phenyl] - 1 - oxo - isoindolin - 2 - yl]acetic acid

[0412]

[0413] A mixture of methyl 2-(6-bromo-1-oxoisoindolin-2-yl)-2-(3-fluorophenyl)acetate (4.13 g, 10.9 mmol), 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine (4.91 g, 16.3 mmol), 1.0 M sodium carbonate (21.8 mL, 21.8 mmol), and dioxane (109 mL) was degassed twice under nitrogen. A complex of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (0.534 g, 0.654 mmol) and XPhos (0.519 g, 1.09 mmol) were added, and then the reaction was degassed one more time under nitrogen. 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 twice with dichloromethane. 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% acetonitrile / water containing 10 mM ammonium acetate to give the title compound (4.17 g, 81%). MS m / z: 473.2 [M+1] + 。

[0414] Step 4: 2 - [1H - Benzimidazol - 2 - yl - (3 - fluorophenyl)methyl] - 6 - [4 - (1 - methyl - 4 - piperidinyl)phenyl] Isoindolin - 1 - one (026)

[0415]

[0416] To a solution of 2-(3-fluorophenyl)-2-[6-[4-(1-methylpiperidin-4-yl)phenyl]-1-oxoisoindolin-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 DIPEA (0.150 mL, 0.872 mmol). After stirring overnight at room temperature, saturated sodium chloride solution 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 step without further purification. MS m / z: 549.3 [M+1] + 。

[0417] Acetic acid (5 mL) was added to the above amide intermediate. After stirring overnight at 80 °C, the solvent was removed under reduced pressure. The crude product was purified by C18 column chromatography, eluting with 0 - 80% acetonitrile / water containing 10 mM ammonium acetate to give the title compound (18 mg, 17%). 11H NMR (400 MHz, DMSO-d6) δ: 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 [M+1] + 。

[0418] Compound 025 was prepared from the starting material 2-(3-fluorophenyl)-2-[6-[4-(1-methylpiperidin-4-yl)phenyl]-1-oxoisoindolin-2-yl]acetic acid and pyridine-2,3-diamine by a method similar to that of Example 1:

[0419]

[0420] Example 2: Preparation of 2 - [(5 - fluoro - 2 - hydroxy - phenyl) - (1H - imidazo[4,5 - c]pyridin - 2 - yl)methyl] - 6 - [4 - (1 - methyl - 4 - piperidinyl)

[0421] phenyl]isoindolin - 1 - one; hydrochloride (Compound 015)

[0422] Scheme 2.

[0423]

[0424] Step 1. 2 - Bromo - 4 - fluoro - 1 - (methoxymethoxy)benzene

[0425]

[0426] To a solution of 2-bromo-4-fluorophenol (100 g, 523 mmol) in THF (1 L) at 0 °C was added sodium cyanide (23.0 g, 575 mmol, 60% in mineral oil) over 4 h, followed by methoxymethyl chloride (44.9 mL, 601 mmol). After stirring at room temperature for 10 h, the reaction mixture was quenched with water and extracted three times with ethyl acetate. 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 / petroleum ether to give the title compound (80 g, 65%). 1 1H NMR (400 MHz, CDCl3) δ: 7.30 (dd, 1H), 7.12 (dd, 1H), 6.97 (m, 1H), 5.07 - 5.24 (m, 2H), 3.46 - 3.62 (m, 3H).

[0427] Step 2. Ethyl 2 - [5 - fluoro - 2 - (methoxymethoxy)phenyl] - 2 - oxo - acetate

[0428]

[0429] At -78 °C, n-butyllithium (2.5 M in hexane, 142 mL, 357 mmol) was added dropwise to a solution of 2-bromo-4-fluoro-1-(methoxymethoxy)benzene (80.0 g, 340 mmol) in THF (1 L). After stirring for 1 h at -78 °C, the reaction mixture was cannulated into a pre-cooled (-78 °C) solution of diethyl oxalate (74.4 g, 510 mmol) in THF (500 mL). After the addition was complete, the reaction mixture was allowed to warm to room temperature. The reaction mixture was quenched with water and extracted three times with ethyl acetate. 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 10% ethyl acetate / petroleum ether, to give the title compound (70 g, 80%). 1 1H NMR (400 MHz, CDCl3) δ: 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).

[0430] Step 3. Ethyl 2 - [5 - fluoro - 2 - (methoxymethoxy)phenyl] - 2 - hydroxyimino - acetate

[0431]

[0432] To a solution of hydroxylamine hydrochloride (37.9 g, 546 mmol) in ethanol (500 mL) were added ethyl 2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-oxoacetate (70.0 g, 273 mmol) and sodium acetate (44.7 g, 132 mmol). After stirring for 2.5 h at 80 °C, the solvent was 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%). 1 1H NMR (400 MHz, CDCl3) δ: 9.76 (br s, 1H), 7.17 - 7.23 (m, 1H), 7.07 - 7.14 (m, 2H), 5.10 (s, 2H), 4.31 - 4.39 (m, 2H), 3.44 - 3.48 (m, 3H), 1.35 - 1.40 (m, 3H).

[0433] Step 4. Ethyl 2 - amino - 2 - [5 - fluoro - 2 - (methoxymethoxy)phenyl]acetate

[0434]

[0435] To a solution of Raney nickel (1.46 g, 25.0 mmol) in EtOH / THF (650 mL, 4 / 1) was added (650 mL, 4 / 1)

[0436] Ethyl 2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-hydroxyimino-acetate (34.0 g, 125 mmol). The flask was evacuated, backfilled with hydrogen, and the reaction mixture was stirred at 70 °C for 24 h under a hydrogen atmosphere (50 psi). The reaction mixture was filtered through a Celite pad, 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 / petroleum ether to afford the title compound (30.6 g, 48%). 1 1H NMR (400 MHz, DMSO-d6) δ: 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).

[0437] Step 5. Ethyl 2 - (6 - bromo - 1 - oxo - isoindolin - 2 - yl) - 2 - [5 - fluoro - 2 - (methoxymethoxy)phenyl]acetate Step 6. Ethyl 2 - [5 - fluoro - 2 - (methoxymethoxy)phenyl] - 2 - [6 - [4 - (1 - methyl - 4 - piperidinyl)phenyl] - 1 -

[0438]

[0439] To a solution of ethyl 2-amino-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetate (30.6 g, 118 mmol) in DMF (300 mL) was added DIPEA (58.4 mL, 354 mmol). After the reaction mixture was stirred at room temperature for 5 min, 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 three times with ethyl acetate. 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 33% ethyl acetate / petroleum ether to afford the title compound (35 g, 66%). 11H NMR (400 MHz, CDCl3) δ: 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), 1.24 - 1.28 (m, 3H); MS m / z: 453.8 [M + 1] + 。

[0440] oxo - isoindolin - 2 - yl]acetate Step 7. 2 - [5 - fluoro - 2 - (methoxymethoxy)phenyl] - 2 - [6 - [4 - (1 - methyl - 4 - piperidinyl)phenyl] - 1 -

[0441]

[0442] A mixture of ethyl 2-(6-bromo-1-oxo-isoindolin-2-yl)-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetate (5.34 g, 11.8 mmol), 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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 twice under nitrogen. [1,1′-Bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with dichloromethane (1.44 g, 1.77 mmol) was added and then the reaction was degassed again under nitrogen. 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 three times with ethyl acetate. 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 - 15% methanol / dichloromethane to give the title compound (4.91 g, 76%). MS m / z: 547.3 [M + 1] + 。

[0443] oxo - isoindolin - 2 - yl]acetic acid Step 8. 2 - [[5 - fluoro - 2 - (methoxymethoxy)phenyl] - (1H - imidazo[4,5 - c]pyridin - 2 - yl)methyl] - 6 - [4 - (1 - methyl - 4 - piperidinyl)phenyl]isoindolin - 1 - one

[0444]

[0445] To a solution of ethyl 2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-[6-[4-(1-methylpiperidin-4-yl)phenyl]-1-oxoisoindolin-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 for 2 h at room temperature, the solvent was removed under reduced pressure and the resulting residue was neutralized with concentrated hydrochloric acid. The crude product was purified by silica gel 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] + 。

[0446] Step 9. 2 - [(5 - fluoro - 2 - hydroxy - phenyl) - (1H - imidazo[4,5 - c]pyridin - 2 - yl)methyl] - 6 - [4 - (1 - methyl - 4 - piperidinyl)phenyl]isoindolin - 1 - one; hydrochloride (Compound 015)

[0447]

[0448] To a solution of 2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-[6-[4-(1-methylpiperidin-4-yl)phenyl]-1-oxoisoindolin-2-yl]acetic acid (0.200 g, 0.385 mmol), 3,4-diaminopyridine (0.084 g, 0.770 mmol) and HATU (0.219 g, 0.577 mmol) in DMF (4 mL) was added DIPEA (0.265 mL, 1.53 mmol). After stirring for 2 h at room temperature, the reaction mixture was diluted with ethyl acetate and washed twice with saturated 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 - 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] + 。

[0449] To the above amide intermediate (0.172 g, 0.282 mmol) was added acetic acid (3.66 mL). After stirring for 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 containing 0.1% formic acid. The product fractions were combined and concentrated under reduced pressure to remove the organic solvent. The residual aqueous solution was basified with saturated 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: 592.3 [M+1] + 。

[0450] Example 3: 2 - [(R) - 1H - Benzimidazol - 2 - yl - (5 - fluoro - 2 - hydroxy - phenyl)methyl] - 6 - [4 - (1 - methyl - 4 - piperidinyl)phenyl]isoindolin - 1 - one and 2 - [(S) - 1H - Benzimidazol - 2 - yl - (5 - fluoro - 2 - hydroxy - phenyl)methyl] -

[0451]

[0452] HCl / dioxane (4 M, 0.6 mL, 2.40 mmol) was added to a solution of 2-[[5-fluoro-2-(methoxymethoxy)phenyl]-(1H-imidazo[4,5-c]pyridin-2-yl)methyl]-6-[4-(1-methylpiperidin-4-yl)phenyl]isoindolin-1-one (0.143 g, 0.241 mmol) in dichloromethane (5.2 mL). After stirring at room temperature for 1 h, the solvent was removed under reduced pressure. Ether was added to the residue and the resulting solid was separated by filtration to afford the title compound (131 mg, 93%). 1H NMR (400 MHz, DMSO-d6) δ: 10.52 (br s, 1H), 10.09 (s, 1H), 9.31 (br s, 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] + 。

[0453] The following compounds were prepared from the starting materials ethyl 2-amino-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetate and methyl 5-bromo-2-(bromomethyl)benzoate or methyl 5-bromo-2-(bromomethyl)nicotinate and the corresponding boronic esters and diaminoaryl by a method similar to that of Example 2:

[0454]

[0455]

[0456]

[0457] The following compounds were prepared from the starting materials ethyl 2-amino-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate and methyl 5-bromo-2-(bromomethyl)benzoate or methyl 6-(bromomethyl)-3-chloro-2-fluorobenzoate and the corresponding boronic esters and diaminoaryl by a method similar to that of Example 2:

[0458]

[0459]

[0460] ​ ​ Preparation of 6-[4-(1-Methyl-4-piperidinyl)phenyl]isoindolin-1-one

[0461] (Compounds 022 and 023)

[0462]

[0463] 2-[1H-Benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[4-(1-methyl-4-piperidinyl)-phenyl]isoindolin-1-one; hydrochloride (0.600 g, 1.02 mmol) was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The aqueous phase was extracted three times with additional ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative SFC using a Chiralpak IA column, eluting with 45% (0.3% TEA / MeOH) / 55% CO2 at 10 MPa to separate the enantiomers. The absolute configuration of the chiral centers of each separated enantiomer was unknown. First elution peak (022) (120 mg, 22% yield, 94:6 er); [a] 20 D -34.2° (c = 0.12, MeOH); 1 1H NMR (400 MHz, methanol-d4) δ: 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 elution peak (023) (154 mg, 28% yield, 89:11 er); [a] 20 D +28.0° (c = 0.1, MeOH); 11H NMR (400 MHz, methanol-d4) δ: 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] + 。

[0464] Example 4: Preparation of 6-[2-(6-Amino-3-pyridinyl)ethynyl]-2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy phenyl)methyl]

[0465] Isoindolin-1-one (Compound 012)

[0466] Scheme 3.

[0467]

[0468] Step 1. 2-(6-Bromo-1-oxo-isoindolin-2-yl)-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetic acid

[0469]

[0470] 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 / H2O (300 mL, 1 / 1 / 1) 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 with HCl (1 M). The resulting solid was collected by filtration and washed with water to give the title compound (18.2 g, 88%). 1 1H NMR (400 MHz, CDCl3) δ: 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, 2H), 4.63 (d, 1H), 3.89 (d, 1H), 3.27 - 3.36 (m, 3H).

[0471] Step 2. 2-[1H-Benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-bromo-isoindol in-1-one

[0472]

[0473] To a solution of 2-(6-bromo-1-oxo-isoindolin-2-yl)-2-[5-fluoro-2-(methoxymethoxy)-phenyl]acetic 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 twice with saturated 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 afford the amide intermediate (15.5 g, 70%) as a yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ: 9.72 (s, 1H), 7.88 (d, 1H), 7.75 - 7.85 (m, 1H), 7.51 - 7.69 (m, 1H), 7.08 - 7.23 (m, 4H), 6.89 - 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).

[0474] To the above amide intermediate (15.5 g, 30.1 mmol) was added acetic acid (150 mL). After stirring at 80 °C for 30 min, the solvent was removed under reduced pressure. The reaction mixture was neutralized with saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was recrystallized from ethyl acetate to afford the title compound (12.5 g, 84%). MS m / z: 497.3 [M+1] + .

[0475] Step 3. 6-[2-(6-Amino-3-pyridinyl)ethynyl]-2-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxy methoxy)-phenyl]methyl]isoindolin-1-one

[0476]

[0477] A mixture of 2-[1H-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(II) dichloride (0.012 g, 0.017 mmol), copper(I) iodide (0.006 g, 0.030 mmol) and TEA / DMF (3 mL, 1 / 1) was degassed twice under nitrogen. The reaction mixture was heated at 100 °C overnight. After cooling to room temperature, the reaction mixture was poured into water and extracted twice with ethyl acetate. 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 5 - 100% ACN / containing 0.1% formic acid to give the title compound (66 g, 41%). MS m / z: 534.2 [M+1] + 。

[0478] Step 4. 6-[2-(6-Amino-3-pyridinyl)ethynyl]-2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy- phenyl)methyl]isoindolin-1-one (Compound 012)

[0479]

[0480] To a solution of 6-[2-(6-amino-3-pyridinyl)ethynyl]-2-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]isoindolin-1-one (0.066 g, 0.123 mmol) in dichloromethane (2.6 mL) was added HCl / dioxane (4 M, 0.305 mL, 1.22 mmol). 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 (6 mg, 10%). 1 1H NMR (400 MHz, DMSO-d6) δ: 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] + 。

[0481] The following compounds were prepared from the starting material 2-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-bromo-isoindolin-1-one and the corresponding acetylene by a method similar to Example 4:

[0482]

[0483]

[0484] Example 5: Preparation of 2-[1H-Benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-7-fluoro-6-[4-(1-meth yl-4-piperidinyl)phenyl]isoindolin-1-one; Hydrochloride (Compound 032)

[0485] Scheme 4.

[0486]

[0487] Step 1: 3-Chloro-2-fluoro-6-methyl-benzoic acid

[0488]

[0489] To a solution of 1-chloro-2-fluoro-4-methyl-benzene (10.0 g, 69.1 mmol) in THF (100 mL) was added dropwise LDA (2 M in THF, 36.2 mL, 72.5 mmol) at -70 °C. After stirring for 0.5 h at -70 °C, 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 twice with ethyl acetate. The aqueous phase was adjusted to pH 1 with HCl (1 M) and extracted three times 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 (3.5 g, 27%). 1H NMR (400 MHz, DMSO-d6) δ: 13.38 (br s, 1H), 7.51 - 7.58 (m, 1H), 7.16 (d, 1H), 2.33 (s, 3H).

[0490] Step 2: Methyl 3-chloro-2-fluoro-6-methyl-benzoate

[0491]

[0492] To a solution of 3-chloro-2-fluoro-6-methyl-benzoic acid (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 for 0.5 h at the same temperature, the solvent was removed under reduced pressure. The residue was dissolved in methanol (20 mL) and triethylamine (7.47 g, 74.0 mmol) was added. After stirring for 1 h at room temperature, the solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography, eluting with 3% ethyl acetate / petroleum ether to give the title compound (1.9 g, 51%). 11H NMR (400 MHz, DMSO-d6) δ: 7.60 - 7.66 (m, 1H), 7.20 (d, 1H), 3.90 (s, 3H), 2.32 (s, 3H).

[0493] Step 3: Methyl 6-(bromomethyl)-3-chloro-2-fluoro-benzoate

[0494]

[0495] To a solution of methyl 3-chloro-2-fluoro-6-methyl-benzoate (1.90 g, 9.37 mmol) in carbon tetrachloride (20 mL) were added N-bromosuccinimide (1.66 g, 9.37 mmol) and benzoyl peroxide (0.452 g, 1.87 mmol). The mixture was stirred at 80 °C for 12 h, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography, eluting with 1% ethyl acetate / petroleum ether, to give the title compound (0.9 g, 34%). 1 1H NMR (400 MHz, CDCl3) δ: 7.45 - 7.52 (m, 1H), 7.19 (d, 1H), 4.62 (s, 2H), 4.02 (s, 3H).

[0496] Step 4: Ethyl 2-(6-chloro-7-fluoro-1-oxo-isoindolin-2-yl)-2-[5-fluoro-2-(methoxymethoxy)-ben zyl]acetate

[0497]

[0498] 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). After the reaction mixture was stirred at room temperature for 5 min, 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 three times with ethyl acetate. 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 33% ethyl acetate / petroleum ether, to give the title compound (800 mg, 59%). MS m / z: 426.1 [M+1] + .

[0499] Step 5: 2-(6-Chloro-7-fluoro-1-oxo-isoindolin-2-yl)-2-[5-fluoro-2-(methoxymethoxy)benz yl]acetic acid

[0500]

[0501] To a solution of ethyl 2-(6-chloro-7-fluoro-1-oxoisoindolin-2-yl)-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetate (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 with HCl (1 M). The solid obtained was collected by filtration and washed with water to give the title compound (750 mg, quantitative). MS m / z: 398.0 [M+1] + 。

[0502] Step 6: 2-[1H-Benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-chloro-7-fluoro- isoindolin-1-one

[0503]

[0504] To a solution of 2-(6-chloro-7-fluoro-1-oxoisoindolin-2-yl)-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetic acid (0.750 g, 1.88 mmol), 1,2-diaminobenzene (0.213 g, 1.97 mmol) and HATU (1.07 g, 2.82 mmol) in DMF (10 mL) was added DIPEA (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 three times with additional ethyl acetate. 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 step without further purification. MS m / z: 488.3 [M+1] + 。

[0505] Acetic acid (15 mL) was added to the above amide intermediate. After stirring at 80 °C for 0.5 h, the solvent was removed under reduced pressure. The reaction mixture was neutralized with saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was recrystallized from ethyl acetate to give the title compound (550 mg, 72%). MS m / z: 470.0 [M+1] + 。

[0506] Step 7: 2-[1H-Benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-7-fluoro-6-[4- (1-methyl-4-piperidinyl)phenyl]isoindolin-1-one

[0507]

[0508] A mixture of 2-[1H-benzimidazol-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-dioxaborolan-2-yl)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 twice under nitrogen. The reaction mixture was heated at 105 °C for 4 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 / dichloromethane to give the title compound (120 mg, 17%). MS m / z: 609.3 [M+1] + 。

[0509] Step 8: 2-[1H-Benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-7-fluoro-6-[4-(1-methyl- 4-piperidinyl)phenyl]isoindolin-1-one; Hydrochloride (Compound 032)

[0510]

[0511] HCl / dioxane (4 M, 0.985 mL, 3.94 mmol) was added to a solution of 2-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-7-fluoro-6-[4-(1-methylpiperidin-4-yl)phenyl]isoindolin-1-one (0.120 g, 0.197 mmol) in dichloromethane (5 mL). After stirring at room temperature for 1 h, the solvent was removed under reduced pressure. Ether was added to the residue and the resulting solid was separated by filtration to give the title compound (112 mg, 94%). 1H NMR (400 MHz, DMSO-d6) δ: 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), 2.73 - 2.81 (m, 3H), 1.91 - 2.15 (m, 4H); MS m / z: 565.3 [M+1] + 。

[0512] Example 6: Preparation of 2-[1H-Benzimidazol-2-yl-(5-fluoro-2-methoxy-phenyl)methyl]-7-fluoro-6-[4-(1-meth yl-4-piperidinyl)phenyl]indazole (035) and 2-[1H-Benzimidazol-2-yl-[7-fluoro-6-[4-(1-methyl-4-piperidinyl) phenyl]indazol-2-yl]methyl]-4-fluoro-phenol; Hydrochloride (034)

[0513] Scheme 5.

[0514]

[0515] Step 1. Ethyl 2-(5-fluoro-2-methoxy-phenyl)acetate

[0516]

[0517] To a solution of 2-(5-fluoro-2-methoxyphenyl)acetic acid (0.900 g, 4.88 mmol) in 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. The resulting residue was diluted with ethyl acetate and washed three times with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (900 mg, 93%). 1 1H NMR (400 MHz, CDCl3) δ: 7.01 - 6.90 (m, 2H), 6.85 - 6.77 (m, 1H), 3.81 (s, 3H), 3.72 (s, 3H), 3.66 - 3.61 (m, 2H).

[0518] Step 2. Methyl 2-bromo-2-(5-fluoro-2-methoxyphenyl)acetate

[0519]

[0520] To a solution of methyl 2-(5-fluoro-2-methoxyphenyl)acetate (0.900 g, 5.44 mmol) in carbon tetrachloride (20 mL) were added N-bromosuccinimide (0.968 g, 5.44 mmol) and 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 / petroleum ether to give the title compound (1.2 g, 96%). 1 1H NMR (400 MHz, CDCl3) δ: 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).

[0521] Step 3. 2-(6-Bromo-7-fluoro-1H-indazol-2-yl)-2-(5-fluoro-2-methoxyphenyl)acetic acid

[0522]

[0523] To a solution of methyl 2-bromo-2-(5-fluoro-2-methoxyphenyl)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 added cesium carbonate (0.814 g, 2.50 mmol). The reaction mixture was stirred at 0 °C for 30 minutes and then at room temperature for 1 hour, after which it was partitioned between water and ethyl acetate. The aqueous phase was extracted three times with additional ethyl acetate. 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] + 。

[0524] 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 hour, 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 three times with ethyl acetate. The combined 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 / petroleum ether to give the title compound (280 mg, 26%). 1H NMR (400 MHz, DMSO-d6) δ: 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] + 。

[0525] Step 4. 2-[1H-Benzimidazol-2-yl-(5-fluoro-2-methoxyphenyl)methyl]-6-bromo-7-fluoro-1H-indazole

[0526]

[0527] To a solution of 2-(6-bromo-7-fluoro-indazol-2-yl)-2-(5-fluoro-2-methoxyphenyl)acetic 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 hours, the reaction mixture was partitioned between saturated sodium chloride and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate, the combined 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 / petroleum ether to give the amide intermediate. MS m / z: 488.8 [M+1] + 。

[0528] Acetic acid (15 mL) was added to the above amide intermediate. After stirring at 80 °C for 30 minutes, the solvent was removed under reduced pressure. The reaction mixture was diluted with ethyl acetate and washed three times with saturated sodium bicarbonate solution. 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, CDCl3) δ: 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] + 。

[0529] Step 5. 2-[1H-Benzimidazol-2-yl-(5-fluoro-2-methoxyphenyl)methyl]-7-fluoro-6-[4-(1-meth yl-4-piperidinyl)phenyl]-1H-indazole (Compound 035)

[0530]

[0531] 2-[1H - Benzimidazol - 2 - yl - (5 - fluoro - 2 - methoxyphenyl)methyl] - 6 - bromo - 7 - fluoro - indazole (0.200 g, 0.426 mmol), 1 - methyl - 4 - [4 - (4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)phenyl]piperidine (0.140 g, 0.468 mmol), sodium carbonate (0.146 g, 1.06 mmol), [1,1′ - bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.047 g, 0.064 mmol) and a mixture of dioxane / water (8 mL, 4 / 1) were degassed under nitrogen. The reaction mixture was heated at 100 °C for 20 h. After cooling to room temperature, the reaction mixture was poured into water and extracted three times with ethyl acetate. 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 6% methanol / dichloromethane to give the title compound (150 mg, 62%). 1H NMR (400 MHz, DMSO - d6) δ: 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] + 。

[0532] Step 6. 2-[1H-Benzimidazol-2-yl-[7-fluoro-6-[4-(1-methyl-4-piperidinyl)phenyl]-1H-indazol-2-yl] methyl]-4-fluoro-phenol; hydrochloride (Compound 034)

[0533]

[0534] At 0 °C, boron tribromide (0.666 g, 2.66 mmol) was added to a solution of 2-[1H-benzoimidazol-2-yl-(5-fluoro-2-methoxyphenyl)methyl]-7-fluoro-6-[4-(1-methylpiperidin-4-yl)phenyl]indazole (0.150 g, 0.266 mmol) in dichloromethane (8 mL). After stirring at room temperature for 2 hours, the reaction mixture was diluted with dichloromethane and poured into ice water. The aqueous phase was extracted three times with dichloromethane. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure.

[0535] The crude product was purified by reverse HPLC, eluting with 0 - 100% ACN / water (0.05% HCl modifier) to give the title compound (25 mg, 30%). 1 1H NMR (400 MHz, DMSO-d6) δ: 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+1] + 。

[0536] The following examples were prepared from the starting materials methyl 2-bromo-2-(5-fluoro-2-methoxyphenyl)acetate or methyl 2-bromo-2-phenylacetate and the corresponding bicyclic by a method similar to Example 6:

[0537]

[0538]

[0539]

[0540]

[0541] Compounds 067 and 068: 2-[(R)-1H-Benzimidazol-2-yl-(5-fluoro-2-hydroxyphenyl)methyl]-6-[4- (1-methyl-4-piperidinyl)phenyl]isoquinolin-1-one and 2-[(S)-1H-benzimidazol-2-yl-(5-fluoro-2-hydroxyphenyl) methyl]-6-[4-(1-methyl-4-piperidinyl)phenyl]isoquinolin-1-one

[0542]

[0543] 2-[(rac)-1H-Benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[4-(1-methyl-4-piperidinyl)-phenyl]isoquinolin-1-one; dihydrochloride (069, 0.050 g, 0.079 mmol) was purified by preparative SPC with a Chiral Technologies Chiralpak IG (5 micron 250 x 10 mm) column (at 40 °C), eluting with 55% (0.3% TEA / MeOH) / 45% CO2 at BPR 10 MPa to separate the enantiomers. The absolute configuration of the chiral centers of each separated enantiomer was unknown. First elution peak (067) (17.0 mg, 38% yield, 98.5:1.5 er); [α] 20 D -12.9 (c = 0.31, MeOH); 1 H NMR (DMSO-d6) δ: 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, 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 elution peak (068) (14.1 mg, 31% yield, 1.5:98.5 er); [α] 20 D +14.1 (c = 0.64, MeOH); 1 H NMR (DMSO-d6) δ: 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, 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

[0544] [M+1] + 。

[0545] Compounds 065 and 066: 2-[(R)-1H-Benzimidazol-2-yl-(5-fluoro-2-hydroxyphenyl)methyl]-8-fluoro- 6-[4-(1-methyl-4-piperidinyl)phenyl]isoquinolin-1-one and 2-[(S)-1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy- phenyl)methyl]-8-fluoro-6-[4-

[0546] Preparation of (1-Methyl-4-piperidinyl)phenyl]isoquinolin-1-one

[0547]

[0548] 2-[1H-Benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-8-fluoro-6-[4-(1-methyl-4-piperidinyl)phenyl]isoquinolin-1-one; hydrochloride (070, 0.012 g, 0.020 mmol) was purified by preparative SPC equipped with a Phenomenex LuxCellulose-4 column, eluted with 55% (0.3% TEA / MeOH) / 45% CO2 at 10 MPa to separate the enantiomers. The absolute configuration of the chiral centers of each separated enantiomer was unknown. First elution peak (065) (3 mg, 27% yield, 100:0 er); [α] 20 D -13.3 (c = 0.37, MeOH); 1 H NMR (DMSO-d6) δ: 12.69 (br s, 1H), 9.95 (br s, 1H), 7.68 - 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 elution peak (066) (4 mg, 36% yield, 100:0 er); [α] 20 D +14.8 (c = 0.27, MeOH); 11H NMR (DMSO-d6) δ: 12.69 (br s, 1H), 9.98 (br s, 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 (s, 3H), 1.83 - 1.96 (m, 2H), 1.57 - 1.73 (m, 4H); MS m / z: 577.3 [M+1] + 。

[0549] Example 7: Preparation of 3-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxyphenyl)methyl]-6-[4-(1-methyl-4-piper idinyl)phenyl]quinazolin-4-one; hydrochloride (Compound 006)

[0550] Scheme 6.

[0551]

[0552] Step 1. Ethyl 2-[(2-amino-5-bromobenzoyl)amino]-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetate Step 2. Ethyl 2-(6-bromo-4-oxo-3-quinazolinyl)-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetate

[0553]

[0554] To a solution of ethyl 2-amino-2-[5-fluoro-2-(methoxymethoxy)phenyl]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 column chromatography, eluting with 25% ethyl acetate / petroleum ether to give the title compound (5 g, 28%). 1 1H NMR (400 MHz, DMSO-d6) δ: 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).

[0555] Step 3. Ethyl 2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-[6-[4-(1-methyl-4-piperidinyl)phenyl]-4- oxo-3-quinazolinyl]acetate

[0556]

[0557] A solution of ethyl 2-[(2-amino-5-bromobenzoyl)amino]-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetate (5.25 g, 11.5 mmol) in triethoxymethane (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 / petroleum ether to give the title compound (2.2 g, 41%). 1 1H NMR (400 MHz, DMSO-d6) δ: 8.25 - 8.29 (m, 2H), 8.02 (dd, 1H), 7.66 (d, 1H), 7.26 - 7.37 (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).

[0558] Step 4. 2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-[6-[4-(1-methyl-4-piperidinyl)phenyl]-4- oxo-3-quinazolinyl]acetic acid

[0559]

[0560] A mixture of ethyl 2-(6-bromo-4-oxoquinazolin-3-yl)-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetate (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 under nitrogen. A complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (0.690 g, 0.944 mmol) was added and then the reaction was degassed again under nitrogen. 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 three times with ethyl acetate. 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 - 15% methanol / dichloromethane to give the title compound (1.8 g, 68%). MS m / z: 560.4 [M+1] + 。

[0561] Step 5. 3-[1H-Benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-[4-(1-meth yl-4-piperidinyl)phenyl]quinazolin-4-one

[0562]

[0563] To a solution of ethyl 2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-[6-[4-(1-methylpiperidin-4-yl)phenyl]-4-oxoquinazolin-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 room temperature for 3 h, the solvent was removed under reduced pressure and the resulting residue was adjusted to pH 3 with HCl (1 M). The solid obtained was collected by filtration and washed with water to give the title compound (1.5 g, 88%). MS m / z: 532.1 [M+1] + 。

[0564] Step 6. 3-[1H-Benzimidazol-2-yl-(5-fluoro-2-hydroxyphenyl)methyl]-6-[4-(1-methyl-4-piperidin yl)phenyl]quinazolin-4-one; hydrochloride (Compound 006)

[0565]

[0566] To a solution of 2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-[6-[4-(1-methylpiperidin-4-yl)phenyl]-4-oxoquinazolin-3-yl]acetic acid (0.900 g, 1.69 mmol), 1,2-diaminobenzene (0.218 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, saturated sodium chloride was added to the reaction mixture. The solid obtained was collected by filtration and washed with water. The crude product was purified by silica gel column chromatography, eluting with 0-10% methanol / dichloromethane to give the amide intermediate. MS m / z: 622.3

[0567] [M+1] + 。

[0568] Acetic acid (8 mL) was added to the above amide intermediate. After stirring at 80 °C for 3 h, the solvent was removed under reduced pressure. The reaction mixture was neutralized with saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was recrystallized from ethyl acetate to give the title compound (170 mg, 50%). MS m / z: 604.3 [M+1] + 。

[0569] ​ ​

[0570]

[0571] To a solution of 3-[1H-benzoimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-[4-(1-methylpiperidin-4-yl)phenyl]quinazolin-4-one (0.120 g, 0.198 mmol) in dichloromethane (10 mL) was added HCl / dioxane (4 M, 0.495 mL, 1.98 mmol). After stirring at room temperature for 1 h, the solvent was removed under reduced pressure. Ether was added to the residue and the resulting solid was separated by filtration to give the title compound (160 mg, 91%). 1 H NMR (400 MHz, DMSO-d6) δ: 10.28 - 10.48 (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] + 。

[0572] The following compounds were prepared from the starting materials ethyl 2-(6-bromo-4-oxoquinazolin-3-yl)-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetate and the corresponding boronic esters, or from 2-amino-2-phenylacetate by a method similar to that of Example 7:

[0573]

[0574] Example 8: Preparation of 2-[1H-benzimidazol-2-yl(1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)methyl]-6- [4-(1-methylpiperidin-4-yl)phenyl]isoindolin-1-one (Compound 033)

[0575] Scheme 7.

[0576]

[0577] Step 1. 2-(6-Bromo-1-oxoisoindolin-2-yl)-2-[1-(2-trimethylsilylethoxymethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-3-yl]acetonitrile Step 2. 2-(6-Bromo-1-oxoisoindolin-2-yl)-2-[1-(2-trimethylsilylethoxymethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-3-yl]acetic acid

[0578]

[0579] To a solution of 1-(2-(Trimethylsilylethoxymethyl))-5,6-dihydro-4H-cyclopenta[c]pyrazole-3-carbaldehyde (3.25 g, 11.5 mmol) in acetonitrile (30 mL) was added 2-(Aminomethyl)-5-bromobenzoic acid 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 three times with ethyl acetate. 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 1-20% ethyl acetate / petroleum ether to give the title compound (1.77 g, 32%). MS m / z: 488.2 [M+1] + 。

[0580] Step 3: 2-[1H-Benzimidazol-2-yl-[1-(2-trimethylsilylethoxymethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-3-yl]methyl]-6-bromo-isoindolin-1-one Step 4. 2-[1H-Benzimidazol-2-yl-[1-(2-trimethylsilylethoxymethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-3-yl]methyl]-6-[4-(1-methylpiperidin-4-yl)phenyl]isoindolin-1-one

[0581]

[0582] 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]acetonitrile (0.950 g, 1.94 mmol) in ethanol (10 mL) was added dropwise an aqueous lithium hydroxide solution (2 M, 4.85 mL, 9.70 mmol) under an ice bath. After stirring at 100 °C for 2 h, the reaction mixture was diluted with water and adjusted to pH 5 with acetic acid. The aqueous phase was extracted three times with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and 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] + 。

[0583] Step 5. 2-[1H-Benzimidazol-2-yl(1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)methyl]-6- [4-(1-methylpiperidin-4-yl)phenyl]isoindolin-1-one (Compound 033)

[0584]

[0585] 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) was added DIPEA (0.342 mL, 1.97 mmol). After stirring at room temperature for 5 h, saturated 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

[0586] [M+1] + 。

[0587] Acetic acid (8 mL) was added to the above amide intermediate. After stirring at 80 °C 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] + 。

[0588] Example 9: Preparation of 3-((1H-benzo[d]imidazol-2-yl)(5-fluoro-2-hydroxyphenyl)methyl)-6-(4-(1-methylpiperidin-4-yl)phenyl)pyrido[3,2-d]pyrimidin-4(3H)-one 2,2,2-trifluoroacetate (Compound 009) Step 1. Methyl 3-amino-6-bromopicolinate

[0589]

[0590] A mixture of 2-[1H-benzoimidazol-2-yl-[1-(2-trimethylsilylethoxymethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-3-yl]methyl]-6-bromo-isoindolin-1-one (0.100 g, 0.173 mmol), 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-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 under nitrogen. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.028 g, 0.035 mmol) was added and then the reaction was degassed again under nitrogen. 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 three times with ethyl acetate. 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 0.1% formic acid to give the title compound (88 mg, 76%). MS m / z: 673.4 [M+1]+ .

[0591] Step 2. 3-Amino-6-bromopicolinic acid Step 3. Ethyl 2-(3-amino-6-bromopyridinecarboxamide)-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate

[0592]

[0593] To a solution of 2-[1H-benzimidazol-2-yl-[1-(2-trimethylsilylethoxymethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-3-yl]methyl]-6-[4-(1-methylpiperidin-4-yl)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% ACN / water containing 0.1% formic acid to give the title compound (44 mg, 63%). 1 1H NMR (400 MHz, DMSO-d6) δ: 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+1] + .

[0594] Compound 031 was prepared from the starting materials 2-(6-bromo-1-oxoisoindolin-2-yl)-2-[1-(2-trimethylsilylethoxymethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-3-yl]acetic acid and pyridine-2,3-diamine by a method similar to that of Example 8:

[0595]

[0596] Step 4. Ethyl 2-(6-bromo-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate Step 5. 2-(5-Fluoro-2-(methoxymethoxy)phenyl)-2-(6-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)acetic acid

[0597] Scheme 8.

[0598]

[0599] Step 6. 3-((1H-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

[0600]

[0601] A mixture of methyl 3-aminopicolinate (650 mg, 4.27 mmol) in 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 to pH 6 with 10N NaOH. The mixture was extracted three times with EtOAc. 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% ethyl acetate / hexane, to give the title compound (600 mg, 61%).

[0602] HNMR (500 MHz, DMSO-d6) δ ppm 7.45 (d, 1H) 7.22 (d, 1H) 6.89 (s, 2H) 3.82 (s, 3H); MS m / z: 232.9 [M+1] 1 + 。

[0603] Step 7. 3-((1H-benzo[d]imidazol-2-yl)(5-fluoro-2-hydroxyphenyl)methyl)-6-(4-(1-methylpiperidin-4-yl)phenyl)pyrido[3,2-d]pyrimidin-4(3H)-one 2,2,2-trifluoroacetate (Compound 009)

[0604]

[0605] 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 stirred at room temperature for 45 minutes. The solvent was removed under reduced pressure. The residue was dissolved in water (20 mL) and adjusted to pH 6 with 2N HCl. The white solid was collected by filtration, washed with cold water and dried, to give the title compound (400 mg, 71%). 1 H NMR (500 MHz, DMSO-d6) δ ppm

[0606] 7.19 (d, 1H) 7.43 (d, 1H); MS m / z: 218.9 [M+1] + 。

[0607] ​

[0608]

[0609] ​A mixture of 3-amino-6-bromopicolinic acid (167 mg, 0.77 mmol), ethyl 2-amino-2-(5-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 Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0 - 55% EtOAc / hexane, to afford the title compound (315 mg, 90%). MS m / z: 458.0 [M+1] + 。

[0610] ​ ​

[0611]

[0612] A mixture of ethyl 2-(3-amino-6-bromopicolinamide)-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate (315 mg, 0.68 mmol) in triethyl orthoformate (4 mL) in a sealed vial was heated in a microwave at 210 °C for 2 h. After cooling, the excess triethyl orthoformate was removed under reduced pressure and the residue was purified by silica gel column chromatography, eluting with 0 - 65% ethyl acetate / hexane, to afford the title compound (310 mg, 98%). 1 1H NMR (500 MHz, DMSO-d6) δ 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, 1H) 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] + 。

[0613] ​ ​

[0614]

[0615] A mixture of ethyl 2-(6-bromo-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate (310 mg, 0.73 mmol), 1-methyl-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, 0.146 mmol), and sodium carbonate (232 mg, 2.19 mmol) in dioxane:water (4:1, 7.5 mL) was heated at 100 °C under nitrogen for 24 h. After cooling, the reaction mixture was filtered, 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%). 1 1H NMR (500 MHz, DMSO-d6) δ ppm 9.36 (brs, 1H) 8.43 (d, 1H) 8.33 (d, 1H) 8.20 (m, 3H) 7.44 (d, 2H) 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+1] + 。

[0616] ​ ​

[0617]

[0618] A mixture of 2-(5-fluoro-2-(methoxymethoxy)phenyl)-2-(6-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)acetic acid (75 mg, 0.14 mmol), o-phenylenediamine (31 mg, 0.28 mmol), HATU (106 mg, 0.28 mmol), and DIPEA (156 μL, 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] + 。

[0619] The above amide intermediate was dissolved in acetic acid (5 mL) and heated at 110 °C for 1 hour. Excess acetic acid was removed under reduced pressure to afford the title compound, which was used without further purification. MS m / z: 605.4 [M+1] + 。

[0620] ​ ​

[0621]

[0622] The above material of 3-((1H-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 treated with 5 mL of 1:1 DCM / TFA for 6 hours. The solvent was removed under reduced pressure and the residue was purified by reverse-phase HPLC, eluting with 0 - 80% ACN / water (0.035% TFA modifier) to afford the title compound (14 mg, 15%). 1 H NMR (500 MHz, DMSO-d6) δ 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, 2H) 2.90 (m, 1H) 2.85 (d, 3H) 2.08 (m, 2H) 1.87 (m, 2H); MS m / z: 561.3 [M+1] + 。

[0623] The following compounds were prepared from the corresponding amines and acids of the starting materials by a method similar to Example 9:

[0624]

[0625]

[0626] The following compounds were prepared from ethyl 2-amino-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate and the corresponding acids by a method similar to Example 9:

[0627]

[0628]

[0629] Compound 077: 3 - [1H - Benzimidazol - 2 - yl - (5 - fluoro - 2 - hydroxy - phenyl)methyl] - 5 - methoxy - 6 - [4 - (1 - methyl - 4 - piperidinyl)

[0630] phenyl]quinazolin - 4 - one; dihydrochloride

[0631] Scheme 9

[0632]

[0633] Step 1. 6 - Amino - N - [1H - benzimidazol - 2 - yl - [5 - fluoro - 2 - (methoxymethoxy)phenyl]methyl] - 3 - bromo - 2 - methoxy - benzamide

[0634]

[0635] To a solution of 6-bromo-5-methoxy-2,4-dihydro-1H-3,1-benzoxazine-2,4-dione (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 afford the title compound (0.21 g, 31%). 1 1H NMR (DMSO-d6) δ: 12.28-12.38 (m, 1H), 9.34-9.45 (m, 1H), 7.52-7.60 (m, 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] + 。

[0636] Step 2. 3 - [1H - Benzimidazol - 2 - yl - [5 - fluoro - 2 - (methoxymethoxy)phenyl]methyl] - 6 - bromo - 5 - meth oxy - quinazolin - 4 - one

[0637]

[0638] A mixture of 6-amino-N-[1H-benzoimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]-methyl]-3-bromo-2-methoxy-benzamide (0.200 g, 0.377 mmol) in triethyl orthoformate (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 afford the title compound (0.14 g, 69%). 11H NMR (DMSO-d6) δ: 12.88 (br s, 1H), 8.18 - 8.32 (m, 1H), 7.94 - 8.14 (m, 1H), 7.59 - 7.75 (m, 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] + 。

[0639] Step 3. 3 - [1H - Benzimidazol - 2 - yl - [5 - fluoro - 2 - (methoxymethoxy)phenyl]methyl] - 5 - methoxy - 6 - [4 - (1 - methyl - 4 - piperidinyl)phenyl]quinazolin - 4 - one

[0640]

[0641] 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-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (0.056 g, 0.185 mmol), Pd(dppf)Cl2 (0.014 g, 0.019 mmol) and potassium carbonate (0.050 g, 0.370 mmol) were heated in a solution of dioxane:DMF:water (1:1:1, 10 mL) under nitrogen at 100 °C for 12 h. After cooling, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, purified by reverse phase HPLC, eluted with 0 - 100% ACN / water (0.035% TFA modifier) to give the title compound (0.085 g, 73%). 1 1H NMR (400 MHz, methanol-d4) δ: 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, 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] + 。

[0642] Step 4. 3 - [1H - Benzimidazol - 2 - yl - (5 - fluoro - 2 - hydroxy - phenyl)methyl] - 5 - methoxy - 6 - [4 - (1 - meth yl - 4 - piperidinyl)phenyl]quinazolin - 4 - one; dihydrochloride

[0643]

[0644] HCl / methanol (4 M, 0.590 mL, 2.36 mmol) was added to a solution of 3-[1H-benzoimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-5-methoxy-6-[4-(1-methylpiperidin-4-yl)phenyl]quinazolin-4-one (0.075 g, 0.118 mmol) in dichloromethane (10 mL). After stirring at room temperature for 12 h, the solvent was removed under reduced pressure. The crude product was purified by reverse phase HPLC, eluting with 0 - 100% ACN / water (0.05% HCl modifier) to give the title compound (0.026 g, 37%). 1 H NMR (400 MHz, methanol-d4) δ: 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 - yl - (5 - fluoro - 2 - hydroxy - phenyl)methyl] - 6 - [4 - (1 - methyl - 4 - piperidinyl) phenyl]isoindoline - 1 - thione; dihydrochloride

[0645] Scheme 10

[0646]

[0647] Step 1. 2 - [1H - Benzimidazol - 2 - yl - (5 - fluoro - 2 - hydroxy - phenyl)methyl] - 6 - [4 - (1 - methyl - 4 - piperidin yl)phenyl]isoindoline - 1 - thione; dihydrochloride

[0648]

[0649] Lawesson's reagent (3.68 g, 9.10 mmol) was added to a solution of 2-[1H-benzoimidazol-2-yl-(5-fluoro-2-hydroxyphenyl)methyl]-6-[4-(1-methylpiperidin-4-yl)phenyl]isoindolin-1-one (1.00 g, 1.82 mmol) in toluene (20 mL). After stirring at 120 °C for 72 h, the solvent was removed under reduced pressure. The crude product was purified by reverse phase HPLC, eluting with 0 - 100% ACN / water (0.05% HCl modifier) to give the title compound (0.026 g, 3%). 11H NMR (DMSO-d6) δ: 10.33 - 10.99 (m, 2H), 7.96 - 8.21 (m, 2H), 7.63 - 7.90 (m, 6H), 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] + 。

[0650] Compounds 083 and 084: Preparation of 2 - [(R) - 1H - benzimidazol - 2 - yl - (5 - fluoro - 2 - hydroxy - phenyl)methyl] - 6 - [4 - (1 - methyl - 4 - piperidinyl)phenyl]isoindoline - 1 - thione and 2 - [(S) - 1H - benzimidazol - 2 - yl - (5 - fluoro - 2 - hydroxy - phenyl)methyl] - 6 - [4 - (1 - methyl - 4 - piperidinyl)phenyl]isoindoline - 1 - thione

[0651]

[0652] 2-[1H-Benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[4-(1-methyl-4-piperidinyl)phenyl]isoindoline-1-thione; dihydrochloride (0.013 g, 0.020 mmol) was purified by preparative SFC using a Phenomenex Lux Cellulose-4 column, eluting with 45% (0.3% TEA / MeOH) / 55% CO2 at 10 MPa to separate the enantiomers. The absolute configuration of the chiral centers of each separated enantiomer was unknown. The first eluting peak (083) (4 mg, 31% yield, 100:0 er); [α] 20 D -88.9 (c = 0.18, MeOH); 1 1H NMR (DMSO-d6) δ: 12.74 (brs, 1H), 10.06 (br s, 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), 6.88 - 6.98 (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] + 。The second eluting peak (084) (4 mg, 31% yield, 99:1 er); [α] 20 D+56.0 (c = 0.25, MeOH); 1 1H NMR (DMSO-d6) δ: 12.74 (br s, 1H), 10.08 (br s, 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] + 。

[0653] Compound 085: 2 - [(5 - fluoro - 2 - hydroxy - phenyl) - (4 - methyl - 1H - imidazol - 2 - yl)methyl] - 6 - [4 - (1 - meth yl - 4 - piperidinyl)phenyl]isoindolin - 1 - one

[0654] Scheme 11

[0655]

[0656] Step 1. 2 - Methyl - N - [(4 - methyl - 1H - imidazol - 2 - yl)methylene]propane - 2 - sulfinamide

[0657]

[0658] To a solution of 4-methyl-1H-imidazole-2-carbaldehyde (5.00 g, 45.4 mmol) and 2-methylpropane-2-sulfinamide (8.25 g, 68.1 mmol) in THF (80 mL) was added tetraethyl orthotitanate (15.5 g, 68.1 mmol). After stirring at 75 °C for 16 h, the reaction mixture was quenched with water and extracted three times with ethyl acetate. 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 / petroleum ether to give the title compound (3 g, 31%). 1 1H NMR (400 MHz, CDCl3) δ: 10.13 - 10.62 (m, 1H), 8.41 (s, 1H), 6.76 - 7.04 (m, 1H), 2.19 - 2.45 (m, 3H), 1.09 - 1.25 (m, 9H); MS m / z: 214.2 [M+1].

[0659] Step 2. N - [(5 - fluoro - 2 - methoxy - phenyl) - (4 - methyl - 1H - imidazol - 2 - yl)methyl] - 2 - methyl - propane - 2 - sulfinamide

[0660]

[0661] 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) at -78 °C was added dropwise a solution of 5-fluoro-2-methoxyphenylmagnesium bromide in THF (0.5 M, 64.0 mL, 32.0 mmol). After stirring at room temperature for 16 h, the reaction mixture was poured into saturated ammonium chloride solution and extracted three times with ethyl acetate. 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 / ethyl acetate to give the title compound (0.5 g, 14%). MS m / z: 340.1 [M+1] + 。

[0662] Step 3. (5 - Fluoro - 2 - methoxy - phenyl) - (4 - methyl - 1H - imidazol - 2 - yl)methylamine

[0663]

[0664] To a solution of N-[(5-fluoro-2-methoxyphenyl)-(4-methyl-1H-imidazol-2-yl)methyl]-2-methylpropane-2-sulfinamide (0.560 g, 1.64 mmol) in methanol (10 mL) at 0 °C was added HCl / dioxane (4 M, 1.23 mL, 4.92 mmol). After stirring at room temperature for 16 h, the solvent was removed under reduced pressure to give the title compound (0.385 g, quantitative), which was used in the next reaction without further purification. MS m / z: 236.0 [M+1] + 。

[0665] Step 4. 6 - Bromo - 2 - [(5 - fluoro - 2 - methoxy - phenyl) - (4 - methyl - 1H - imidazol - 2 - yl)methyl]isoind oline - 1 - one

[0666]

[0667] To a solution of (5-fluoro-2-methoxyphenyl)-(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 and then 5-bromo-2-(bromomethyl)benzoic acid methyl ester (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 three times with ethyl acetate. 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 - 100% ethyl acetate / petroleum ether to give the title compound (0.28 g, 40%). 11H NMR (DMSO-d6) δ: 11.76 - 12.10 (m, 1H), 7.75 - 7.84 (m, 2H), 7.50 - 7.60 (m, 1H), 7.17 - 7.26 (m, 1H), 7.02 - 7.13 (m, 1H), 6.88 - 6.96 (m, 1H), 6.74 - 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).

[0668] Step 5. 2 - [(5 - fluoro - 2 - methoxy - phenyl) - (4 - methyl - 1H - imidazol - 2 - yl)methyl] - 6 - [4 - (1 - meth yl - 4 - piperidinyl)phenyl]

[0669] isoindolin - 1 - one

[0670]

[0671] 6-Bromo-2-[(5-fluoro-2-methoxyphenyl)-(4-methyl-1H-imidazol-2-yl)methyl]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)Cl2 (0.024 g, 0.033 mmol) and potassium carbonate (0.271 g, 1.95 mmol) in a mixture of dioxane:water (9:1, 5 mL) were heated at 100 °C under nitrogen for 16 h. After cooling, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure and purified by reverse phase HPLC, eluting with 0 - 100% ACN / H2O ACN / H2O (0.05% HCl modifier) to give the title compound (0.2 g, 59%). MS m / z: 525.3 [M+1] + 。

[0672] Step 6. 2-[(5-Fluoro-2-hydroxy-phenyl)-(4-methyl-1H-imidazol-2-yl)methyl]-6-[4-(1-methyl- 4-piperidinyl)phenyl]isoindolin-1-one

[0673]

[0674] To a solution of 2-[(5-fluoro-2-methoxyphenyl)-(4-methyl-1H-imidazol-2-yl)methyl]-6-[4-(1-methylpiperidin-4-yl)phenyl]isoindoline-1-one (0.150 g, 0.285 mmol) in dichloromethane (15 mL) was added boron tribromide (0.713 g, 2.85 mmol) at 0 °C. 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 three times with dichloromethane. 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% ACN / water containing 10 mM ammonium acetate to give the title compound (0.068 g, 47%). 1 1H NMR (400 MHz, DMSO-d6) δ: 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, 5H), 1.62 - 1.80 (m, 4H); MS m / z: 511.4 [M+1] + 。

[0675] The following compounds were prepared from the starting materials (5-fluoro-2-methoxyphenyl)-(4-methyl-1H-imidazol-2-yl)methanamine and methyl 6-(bromomethyl)-3-chloro-2-fluorobenzoate by a method similar to that of compound 085:

[0676]

[0677]

[0678] Compound 086: 2-[(3-Fluorophenyl)-(4-methyl-1H-imidazol-2-yl)methyl]-6-[4-(1-methyl-4-piper idinyl)phenyl]isoindolin-1-one

[0679]

[0680] The title compound was prepared from the starting materials 2-methyl-N-[(4-methyl-1H-imidazol-2-yl)methylene]propane-2-sulfinamide and 3-fluorophenylmagnesium bromide by a method similar to that of compound 085. 11H NMR (DMSO-d6) δ: 11.80 - 12.26 (m, 1H), 8.19 (s, 1H), 7.86 - 7.96 (m, 2H), 7.63 - 7.71 (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 (m, 5H), 1.67 - 1.84 (m, 4H); MS m / z: 495.3 [M+1] + Compound 087: 2-[(4,5-Dimethyl-1H-imidazol-2-yl)-(5-fluoro-2-hydroxy-phenyl)methyl]-6- [4-(1-methyl-4-piperidinyl)

[0681] phenyl]isoindolin-1-one

[0682]

[0683] The title compound was prepared from the starting materials 4,5-dimethyl-1H-imidazole-2-carbaldehyde and 2-methylpropane-2-sulfinamide by a method similar to that of compound 085. 1 1H NMR (DMSO-d6) δ: 11.75 (br s, 1H), 10.19 (br s, 1H), 7.84 - 7.89 (m, 2H), 7.59 - 7.70 (m, 3H), 7.36 (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] +

[0684] Compound 088: 2-[(5-Fluoro-2-hydroxy-phenyl)-(2-methyl-1H-imidazol-5-yl)methyl]-6-[4-(1-meth yl-4-piperidinyl)phenyl]isoindolin-1-one; dihydrochloride

[0685]

[0686] The title compound was prepared from the starting materials 2-methyl-1H-imidazole-5-carbaldehyde and 2-methylpropane-2-sulfinamide by a method similar to that of compound 085. 11H NMR (DMSO-d6) δ: 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] +

[0687] Compound 089: 2-[(5-Fluoro-2-hydroxy-phenyl)-(5-methyl-4H-1,2,4-triazol-3-yl)methyl]-6- [4-(1-methyl-4-piperidinyl)

[0688] phenyl]isoindolin-1-one; hydrochloride

[0689] Scheme 12

[0690]

[0691] Step 1. 2-(6-Bromo-1-oxo-isoindolin-2-yl)-2-[5-fluoro-2-(methoxymethoxy)phenyl]-ac ylhydrazine

[0692]

[0693] To a solution of ethyl 2-(6-bromo-1-oxo-isoindolin-2-yl)-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 afford the title compound (0.75 g, 86%). 1 1H NMR (DMSO-d6) δ: 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+1] + .

[0694] Step 2. 6-Bromo-2-[[5-fluoro-2-(methoxymethoxy)phenyl]-(5-methyl-4H-1,2,4-triazol-3-yl) methyl]isoindolin-1-one

[0695]

[0696] 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 ethylenediamine hydrochloride (0.258 g, 2.73 mmol) in butanol (80 mL) was added potassium tert-butoxide / 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 three times with ethyl acetate. 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 / dichloromethane to give the title compound (0.185 g, 44%). 1 1H NMR (DMSO-d6) δ: 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] + 。

[0697] Step 3. 2-[[5-Fluoro-2-(methoxymethoxy)phenyl]-(5-methyl-4H-1,2,4-triazol-3-yl)meth yl]-6-[4-(1-methyl-4-piperidinyl)phenyl]isoindolin-1-one

[0698]

[0699] 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 carbonate (0.071 g, 0.648 mmol) in a solution of dioxane:water (4:1, 5 mL) were heated at 100 °C for 16 h under nitrogen. After cooling, the reaction mixture was poured into water and extracted three times with ethyl acetate. 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 15% methanol / dichloromethane to give the title compound (0.07 g, 58%). MS m / z: 556.3 [M+1] + 。

[0700] Step 4. 2-[(5-Fluoro-2-hydroxy-phenyl)-(5-methyl-4H-1,2,4-triazol-3-yl)methyl]-6-[4-(1- methyl-4-piperidinyl)phenyl]isoindolin-1-one; hydrochloride

[0701]

[0702] The title compound was prepared from the starting material 2-[[5-fluoro-2-(methoxymethoxy)phenyl]-(5-methyl-4H-1,2,4-triazol-3-yl)methyl]-6-[4-(1-methylpiperidin-4-yl)phenyl]isoindolin-1-one by a method similar to that of Example 076, Step 4. 1 H NMR (400 MHz, methanol-d4) δ: 8.02 (d, 1H), 7.85 - 7.93 (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, 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] + 。

[0703] Example 10: Preparation of 3-((1H-Benz[d]imidazol-2-yl)(phenyl)methyl)-5-fluoro-6-(4-(1-methylpiperidin-4- yl)phenyl)quinazolin-4(3H)-one 2,2,2-trifluoroacetate (Compound 003)

[0704] Scheme 13.

[0705]

[0706] Step 1. 6-Amino-3-bromo-2-fluorobenzoic acid

[0707]

[0708] A mixture of 6-amino-3-bromo-2-fluorobenzonitrile (2.56 mg, 11.8 mmol), lithium hydroxide monohydrate (4.99 g, 118 mmol) and water (70 mL) was heated under reflux for 1 hour. After cooling, the solution was treated with 6N HCl to pH 4. The resulting precipitate was filtered, washed with water and dried to give the title compound (2.51 g, 92%). 1 H NMR (500 MHz, DMSO-d6) d ppm 7.39 (dd, 1H) 6.57 (dd, 1H); MS m / z: 234.0 [M+1] + 。

[0709] Step 2. 6-Bromo-5-fluoroquinazolin-4(3H)-one

[0710]

[0711] 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 ethyl acetate. The combined organic extracts were washed with saturated brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with 0 - 35% EtOAc / hexane to give the title compound (490 mg, 50%). 1 1H NMR (500 MHz, DMSO-d6) δ ppm 8.13 (d, 1H) 8.05 (dd, 1H) 7.45 (dd, 1H); MS m / z: 241.9 [M+1] + .

[0712] Step 3. Methyl 2-(6-bromo-5-fluoro-4-oxoquinazolin-3(4H)-yl)-2-phenylacetate

[0713]

[0714] To a solution of 6-bromo-5-fluoroquinazolin-4(3H)-one (440 mg, 1.9 mmol) and Cs2CO3 (1.20 g, 3.7 mmol) in DMF (3 mL) was added methyl 2-bromo-2-phenylacetate (349 μL, 2.2 mmol) and the mixture was heated at 30 °C for 1 h. After cooling, the reaction mixture was poured into water (250 mL) and extracted three times with EtOAc. The combined organic extracts were washed with saturated brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with 0 - 30% EtOAc / hexane to give the title compound (290 mg, 39%). 1 1H NMR (500 MHz, CDCl3-d) δ ppm 7.82 - 7.91 (m, 2H) 7.45 - 7.52 (m, 3H) 7.33 - 7.43 (m, 3H) 6.72 (s, 1H) 3.88 (s, 3H); MS m / z: 390.0 [M+1] + .

[0715] Step 4. 2-(5-Fluoro-6-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxoquinazolin-3(4H)-yl)-2-phen ylacetic acid

[0716]

[0717] The title compound was prepared from the starting materials methyl 2-(6-bromo-5-fluoro-4-oxoquinazolin-3(4H)-yl)-2-phenylacetate and 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine by a method similar to that of Example 9, Step 5. 11H NMR (500 MHz, DMSO-d6) δ ppm 9.35 (br s, 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) 2.05 - 2.13 (m, 2H) 1.80 - 1.93 (m, 2H); MS m / z: 472.2

[0718] [M+1] + 。

[0719] Step 5. 3-((1H-Benz[d]imidazol-2-yl)(phenyl)methyl)-5-fluoro-6-(4-(1-methylpiperidin-4-yl) phenyl)quinazolin-4(3H)-one 2,2,2-trifluoroacetate (Compound 003)

[0720]

[0721] The title compound was prepared from the starting material 2-(5-fluoro-6-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxoquinazolin-3(4H)-yl)-2-phenylacetic acid by a method similar to that in Example 9, Step 6. 1 1H NMR (500 MHz, DMSO-d6) δ ppm 9.29 (br s, 1H) 8.32 (s, 1H) 7.94 - 8.03 (m, 1H) 7.56 - 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)

[0722] 2.04 - 2.13 (m, 2H) 1.79 - 1.93 (m, 2H); MS m / z: 544.3 [M+1] +

[0723] Example 11: Preparation of intermediates

[0724] Scheme 14.

[0725]

[0726] Step 1. 4-(4-Bromo-2-fluoro-phenyl)-1-methyl-piperidin-4-ol

[0727]

[0728] To a solution of 4-bromo-2-fluoro-1-iodobenzene (24.0 g, 79.7 mmol) in THF (400 mL) at -70 °C was added dropwise n-butyllithium (2.5 M in hexanes, 31.9 mL, 79.7 mmol). After stirring for 30 min at -70 °C, a solution of 1-methylpiperidin-4-one (9.01 g, 79.7 mmol) in THF (20 mL) was added dropwise. After stirring for 1 h at -70 °C, the reaction mixture was poured into saturated ammonium chloride solution and extracted three times with ethyl acetate. 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 / petroleum ether to give the title compound (13.0 g, 57%). MS m / z: 289.8 [M+1] + 。

[0729] Step 2. 4-(4-Bromo-2-fluoro-phenyl)-1-methyl-3,6-dihydro-2H-pyridine

[0730]

[0731] A mixture of 4-(4-bromo-2-fluorophenyl)-1-methylpiperidin-4-ol (13.0 g, 45.1 mmol) and 6 M HCl (70 mL) was heated at 85 °C overnight. After cooling to room temperature, the reaction mixture was poured into water and the reaction mixture was adjusted to pH 8 with saturated sodium bicarbonate and extracted three times with ethyl acetate. 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 / petroleum ether to give the title compound (4.0 g, 31%). MS m / z: 271.7 [M+1] + 。

[0732] Step 3. 4-[2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1- methyl-3,6-dihydro-2H-pyridine

[0733]

[0734] A mixture of 4-(4-bromo-2-fluorophenyl)-1-methyl-3,6-dihydro-2H-pyridine (3.00 g, 11.1 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.81 g, 11.1 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.812 g, 1.11 mmol), potassium acetate (3.26 g, 33.3 mmol) and dioxane (30 mL) was degassed twice under nitrogen. 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 three times with ethyl acetate. The combined organic extracts were washed with brine,

[0735] 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 / petroleum ether to give the title compound (3.0 g, 85%). 1 1H NMR (400 MHz, methanol-d4) δ: 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).

[0736] Step 4. 4-[2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1- methyl-piperidine

[0737]

[0738] To a solution of palladium (10% on carbon, 1.10 g, 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-3,6-dihydro-2H-pyridine (3.00 g, 9.45 mmol). The flask was evacuated and backfilled with hydrogen, and the reaction mixture was stirred at 30 °C for 16 h under a hydrogen atmosphere (30 psi). 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%). 11H NMR (400 MHz, methanol-d4) δ: 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, 2H), 1.79 - 1.89 (m, 4H), 1.27 - 1.39 (m, 12H).

[0739] Scheme SM-1

[0740]

[0741] Step 1. 3-Methyl-6-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]- 3-azabicyclo-[4.1.0]heptane

[0742]

[0743] To a solution of diethylzinc (1 M in hexane, 10.0 mL, 10.0 mmol) in dichloromethane (5 mL) at 0 °C was added diiodomethane (2.67 g, 10.0 mmol). After stirring for 0.5 h at the same temperature, a solution of 4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenylboronic 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 saturated ammonium chloride solution and extracted three times with ethyl acetate. 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 / petroleum ether to give the title compound (0.310 g, 59%). MS m / z: 314.2 [M+1] + .

[0744] Scheme SM-2

[0745]

[0746] Step 1. 5-Ethyl-6-iodo-3H-quinazolin-4-one

[0747]

[0748] 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 by filtration and washed with ethanol to give the title compound (2.10 g, 58%). 11H NMR (DMSO-d6) δ: 8.19 (d, 1H), 8.06 (s, 1H), 7.26 (d, 1H), 3.41 - 3.59 (m, 2H), 1.04 - 1.16 (m, 3H).

[0749] Example 12: 2-((1H-Benzimidazol-2-yl)(5-fluoro-2-hydroxyphenyl)methyl-d)-6-(4-(1-meth ylpiperidin-4-yl)phenyl)

[0750] isoindolin-1-one (Compound 036) Preparation

[0751] Scheme 15.

[0752]

[0753] 2 - ((1H - Benzo[d]imidazol - 2 - yl)(5 - fluoro - 2 - hydroxyphenyl)methyl)-6-(4-(1 - methylpiperidin - 4 - yl)phenyl)isoindolin - 1 - one (101 mg, 0.185 mmol) was stirred in CD3OD (10 g) and D2O (1 mL) to give a heterogeneous mixture. Then formic acid (40 μL, 1.07 mmol) was added and the resulting solution was stirred overnight. After 16 h, 1H NMR 1 (methanol - d4) showed that based on the integral area of the methine peak at 7.16 ppm, approximately 50% deuterium incorporation occurred at the methine carbon. The reaction was heated to 50 °C and stirred for an additional 8 h, and 1H NMR 1 (methanol - d4) showed >90% deuterium incorporation. Another 40 μL of formic acid (1.07 mmol) was added and the reaction was stirred for an additional 6 h at 50 °C under a nitrogen atmosphere. 1 1H NMR (methanol - d4) showed 100% deuterium incorporation at the methine carbon. DCl solution (100 μL, 35 weight% in D2O) was added to the reaction solution. After 10 min, the reaction solution was concentrated and the residue was dried under vacuum overnight to give 96 mg of a white solid.

[0754] The crude product was purified by silica gel column chromatography, eluting with 100% ethyl acetate to 60% ethyl acetate / 40% [10% (28% aqueous ammonia / water) / 90% MeOH] to give the title compound as a white powder. 11H NMR (400 MHz, methanol-d4) δ: 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 - 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

[0755] [M + 1]+。

[0756] Compounds 037 and 038 were prepared by the method of Example 12. The crude product was then purified on a Jasco semi-preparative SFC using Chiralpak IA (10 x 250 mm 5 micron), eluting with 45% (0.3% TEA / MeOH) / 55% CO2 at a back pressure regulator (BPR) value of 10 MPa and a flow rate of 10 mL / min to separate the corresponding isomers. The absolute configuration of the chiral centers of each separated enantiomer was unknown. First elution peak (27.4 mg, 27%); 1 1H NMR (400 MHz, methanol-d4) δ: 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 - 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] + 。Second elution peak (31 mg, 28%); 11H NMR (400 MHz, methanol-d4) δ: 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), 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+1] + 。

[0757] Example 13: 2-((1H-Benzimidazol-2-yl)(5-fluoro-2-hydroxyphenyl)methyl-d)-6-(4-(1- methylpiperidin-4-yl)phenyl)isoindolin-1-one-3,3-d2 Preparation of (Compound 039)

[0758] Scheme 16.

[0759]

[0760] 2-((1H-Benzimidazol-2-yl)(5-fluoro-2-hydroxyphenyl)methyl)-6-(4-(1-methylpiperidin-4-yl)phenyl)isoindolin-1-one (24.5 mg, 0.047 mmol) was stirred in CD3OD (1 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 h. The 1 1H NMR (methanol-d4) of the reaction mixture showed >95% deuterium incorporation at the methine carbon and ~60% deuterium incorporation at the lactam methylene carbon based on the integration area of the methine peak at 7.16 ppm. The reaction was stirred for an additional 48 h at 60 °C. The 1 1H NMR (methanol-d4) of the reaction mixture showed complete deuteration of both the methine carbon and the lactam methylene carbon. The reaction was cooled to room temperature and then a solution of 35 wt% DCl in D2O (50 μL, 0.48 mmol) was added. After stirring for a few minutes, the reaction was concentrated and the residue was purified by silica gel chromatography, eluting with 100% DCM to 100% (10% 7N NH3 / MeOH / DCM) to give the title compound (18 mg, 70%) as a white powder. 11H NMR (400 MHz, DMSO-d6) δ ppm 12.08 - 13.11 (m, 1H) 9.72 - 10.71 (m, 1H) 7.86 - 7.92 (m, 2H) 7.60 - 7.69 (m, 3H) 7.52 (br s, 2H) 7.35 (d, J = 8.19 Hz, 2H) 7.17 (br dd, J = 5.81, 3.00 Hz, 2H) 7.01 - 7.11 (m, 1H)) 6.91 (dd, J = 8.80, 4.77 Hz, 1H) 6.80 (dd, J = 9.41, 3.06 Hz, 1H) 3.05 - 3.21 (m, 1H) 2.87 (br d, J = 11.25 Hz, 2H) 1.87 - 2.06 (m, 2H) 2.19 (s, 3H) 1.62 - 1.81 (m, 4H); MS m / z: 550.3 [M+1] + 。

[0761] Example 14: 2-[1H-Benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[4-[2-(dimethyl- amino)ethoxy]phenyl]isoindolin-1-one; hydrochloride (Compound 040)

[0762] Scheme 17

[0763]

[0764] Step 1. N-(1H-Benzimidazol-2-ylmethylene)-2-methyl-propane-2-sulfinamide

[0765]

[0766] To a solution of 1H-1,3-benzodiazole-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) ethoxide (175 g, 769 mmol). After stirring at 75 °C for 16 h, water was added and the reaction mixture was extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. To the residue was added a solution of ethyl acetate and petroleum ether (1 / 1), and the resulting solid was separated by filtration to give the title compound (65 g, 51%). 1 1H NMR (400 MHz, CDCl3) δ: 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).

[0767] Step 2. N-[1H-Benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-2-methyl-prop ane-2-sulfinamide

[0768]

[0769] At -65 °C, n-butyllithium (2.5 M in hexanes, 158 mL, 396 mmol) was added dropwise to a solution of 2-bromo-4-fluoro-1-(methoxymethoxy)benzene (84.6 g, 360 mmol) in THF (600 mL). After stirring for 20 minutes at -65 °C, the reaction mixture was cannulated into a pre-cooled (-65 °C) solution of N-(1H-benzoimidazol-2-ylmethylene)-2-methyl-propane-2-sulfinamide (45.0 g, 180 mmol) in THF (1100 mL). After stirring for 40 minutes at -65 °C, the reaction mixture was warmed to 15 °C. The reaction mixture was quenched with saturated ammonium chloride solution and extracted three times with ethyl acetate. 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 / petroleum ether to give the title compound (40 g, 38%). 1 1H NMR (400 MHz, CDCl3) δ: 11.26 (s, 1H), 7.32 - 7.77 (m, 2H), 7.14 - 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).

[0770] Step 3. 1H-Benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methanamine

[0771]

[0772] At 0 °C, HCl / dioxane (4 M, 55.2 mL, 221 mmol) was added to a solution of N-[1H-benzoimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-2-methyl-propane-2-sulfinamide (30.0 g, 73.9 mmol) in methanol (600 mL). After stirring for 15 hours at room temperature, the reaction mixture was diluted with water and adjusted to pH 8 with saturated sodium bicarbonate solution. The aqueous phase was extracted three times 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 (30.0 g, quantitative). 1 1H NMR (400 MHz, CDCl3) δ: 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] + 。

[0773] Step 4. 2-[1H-Benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-bromo-isoind olin-1-one

[0774]

[0775] To a solution of 1H-benzoimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methanamine (23.0 g, 76.3 mmol) in DMF (250 mL) was added DIPEA (37.5 mL, 228 mmol). After the reaction mixture was stirred at room temperature for 5 minutes, then 5-bromo-2-(bromomethyl)-benzoic acid methyl ester (28.1 g, 91.5 mmol) was added. The reaction mixture was heated at 90 °C for 16 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted three times with ethyl acetate. The 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%). 1 1H NMR (400 MHz, DMSO-d6) δ: 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+1] + 。

[0776] Step 5. 2-[1H-Benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-[4-[2- (dimethylamino)ethoxy]phenyl]isoindolin-1-one

[0777]

[0778] A mixture of 2-[1H-benzoimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-bromo-isoindolin-1-one (160 mg, 0.322 mmol), N-[2-(dimethylamino)ethyl]-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (132 mg, 0.436 mmol), sodium carbonate (89.0 mg, 0.840 mmol) and dioxane / water (5 mL, 4 / 1) was degassed twice under nitrogen. A complex of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (41.1 mg, 0.050 mmol) was added, and then the reaction mixture was degassed once again under nitrogen. 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 three times with ethyl acetate. 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, to give the title compound (101 mg, 53%). 1 H NMR (400 MHz, methanol-d4) δ: 8.00 (s, 1H), 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+1] + 。

[0779] Step 6. 2-[1H-Benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[4-[2-(dimethylamino -ethyl)ethoxy]phenyl]isoindolin-1-one; hydrochloride (Compound 040)

[0780]

[0781] HCl / hexane (4 M, 0.462 mL, 1.85 mmol) was added to a solution of 2-[1H-benzoimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-[4-[2-(dimethylamino)ethoxy]phenyl]isoindolin-1-one (0.108 g, 0.185 mmol) in dichloromethane (3.97 mL). After stirring at room temperature for 1 h, the solvent was removed under reduced pressure. Diethyl ether was added to the residue, and the resulting solid was separated by filtration to give the title compound (91 mg, 86%). 11H NMR (400 MHz, DMSO-d6) δ: 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), 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] + 。

[0782] Example 15: 2-[1H-Benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[4-(1-methylazetidin- 3-yl)phenyl]isoindolin-1-one (Compound 049)

[0783] Scheme 18

[0784]

[0785] Step 1. tert-butyl 3-[4-[2-[1H-Benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl] methyl]-3-oxo-isoindolin-5-yl]phenyl]azetidine-1-carboxylate

[0786]

[0787] A mixture of 2-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-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 twice under nitrogen. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (62.7 mg, 0.077 mmol) was added, and then the reaction mixture was degassed once again under nitrogen. 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 three times with ethyl acetate. 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 / hexane to give the title compound (164 mg, 66%). 11H NMR (400 MHz, methanol-d4) δ: 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] + 。

[0788] Step 2. 6-[4-(Azetidin-3-yl)phenyl]-2-[1H-benzoimidazol-2-yl-[5-fluoro-2-(methoxymeth yloxy)phenyl]methyl]isoindolin-1-one

[0789]

[0790] To a solution of tert-butyl 3-[4-[2-[1H-benzoimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-3-oxoisoindolin-5-yl]phenyl]azetidine-1-carboxylate (164 mg, 0.252 mmol) in dichloromethane (5 mL) was added ethanol (73.5 μL, 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 1 N NaOH solution and methanol, and the resulting solid was separated by filtration to give the title compound (44 mg, 32%). MS m / z: 549.3 [M+1] + 。

[0791] Step 3. 2-[1H-benzoimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-[4-(1-meth yl-azetidin-3-yl)phenyl]isoindolin-1-one

[0792]

[0793] To a solution of 6-[4-(azetidin-3-yl)phenyl]-2-[1H-benzo[d]imidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]isoindolin-1-one (45 mg, 0.082 mmol) in methanol (0.983 mL) was added formaldehyde (37% in water, 60.9 μL, 0.164 mmol). The reaction mixture was stirred at room temperature for 5 minutes, then sodium cyanoborohydride (10.3 mg, 0.164 mmol) was added. The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic extracts were washed with water and 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%). 1 1H NMR (400 MHz, methanol-d4) δ: 8.57 (s, 1H), 8.07 (d, 1H), 7.89 - 7.96 (m, 1H), 7.53 - 7.74 (m, 5H), 7.44 - 7.49 (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); MS m / z: 563.3 [M+1] + 。

[0794] Step 4. 2-[1H-benzoimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[4-(1-methylazetidin -3-yl)phenyl]isoindolin-1-one (Compound 049)

[0795]

[0796] To a solution of 2-[1H-benzo[d]imidazol-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 HCl / dioxane (4 M, 62.0 μL, 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 10 - 100% ACN / water containing 0.1% formic acid to give the title compound (3 mg, 23%). 11H NMR (400 MHz, methanol-d4) δ: 8.06 (s, 1H), 7.88 - 7.94 (m, 1H), 7.68 - 7.74 (m, 2H), 7.63 - 7.67 (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 - 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] + 。

[0797] Example 16: 2-[1H-benzoimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[4-(1-methylazetidin -3-yl)oxyphenyl]isoindolin-1-one; dihydrochloride (Compound 056)

[0798] Scheme 19

[0799]

[0800] Step 1. 2-[1H-benzoimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolane-2-yl)isoindolin-1-one

[0801]

[0802] A mixture of 2-[1H-benzoimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-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 twice under nitrogen. A complex of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (0.921 mg, 1.26 mmol) was added, and then the reaction mixture was degassed once again under nitrogen. 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 diatomaceous earth. The filtrate was concentrated and triturated with a mixture of ethyl acetate and petroleum ether (1 / 1) to give the title compound (5.10 g, 75%). 11H NMR (400 MHz, CDCl3) δ: 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] + 。

[0803] Step 2. 2-[1H-benzoimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-[4-(1-meth ylazetidin-3-yl)

[0804] oxyphenyl]isoindolin-1-one

[0805]

[0806] A mixture of 2-[1H-benzoimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-(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 twice under nitrogen. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (75.3 mg, 0.259 mmol) was added, and then the reaction mixture was degassed once again under nitrogen. 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 three times with ethyl acetate. 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 / dichloromethane to give the title compound (150 mg, 50%). MS m / z: 579.1 [M+1] + 。

[0807] Step 3. 2-[1H-benzoimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[4-(1-methylazetidin -3-yl)oxyphenyl]isoindolin-1-one; dihydrochloride (Compound 056)

[0808]

[0809] To a solution of 2-[1H-benzoimidazol-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 HCl / dioxane (4 M, 3.0 mL, 12.0 mmol). After stirring at room temperature for 3 h, the solvent was removed under reduced pressure. The crude product was purified by reverse phase HPLC, eluting with 0 - 100% ACN / H2O (0.05% HCl modifier) to give the title compound (22 mg, 15%). 1 1H NMR (400 MHz, DMSO-d6) δ: 10.59 - 10.96 (m, 1H), 10.28 (br s, 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] + 。

[0810] The following examples were prepared from the starting materials 2-[1H-benzoimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-bromo-isoindolin-1-one and the corresponding boronic esters by a method similar to Example 14:

[0811]

[0812]

[0813]

[0814] The following examples were prepared from the corresponding halogen-substituted phenols and boronic esters as starting materials by a method similar to Example 14. The corresponding phenols were protected with methoxymethyl derivatives prior to reaction with the sulfonamide.

[0815]

[0816]

[0817] The following examples were prepared from the corresponding aldehydes and boronic esters as starting materials by a method similar to Example 14:

[0818]

[0819] The following examples were prepared from the starting materials ethyl 2-amino-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetate and methyl 5-bromo-2-(bromomethyl)benzoate or methyl 6-bromo-3-(bromomethyl)picolinate; and the corresponding diaminoaryl by a method similar to that of Example 2;

[0820]

[0821]

[0822]

[0823] The following examples were prepared from the starting material methyl 2-bromo-2-(5-fluoro-2-methoxyphenyl)acetate and the corresponding bicyclic by a method similar to that of Example 6:

[0824]

[0825] The following examples were prepared from the starting materials methyl 2-bromo-2-(5-fluoro-2-methoxyphenyl)acetate or methyl 2-bromo-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate and the corresponding bicyclic by a method similar to that of Example 6:

[0826]

[0827]

[0828]

[0829] The following examples were prepared from the starting material ethyl 2-amino-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetate and the corresponding borate and acid by a method similar to that of Example 7:

[0830]

[0831]

[0832] The following examples were prepared from the starting material 2-[1H-benzoimidazol-2-yl-[1-(2-trimethylsilylethoxymethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-3-yl]methyl]-6-bromo-isoindolin-1-one and 5-ethynylpyridin-2-amine in a manner similar to that of Example 4, Step 3:

[0833]

[0834] The following compounds were prepared from the starting material 2-[1H-benzoimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one and the corresponding aryl halides by a method similar to that of Example 16:

[0835]

[0836]

[0837] Example 17: Preparation of 4-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-ben zyl]-1-methyl-piperidine

[0838] Scheme 20

[0839]

[0840] Step 1. 4-(4-Bromo-3-fluoro-phenyl)-1-methyl-3,6-dihydro-2H-pyridine

[0841]

[0842] A mixture of 1-bromo-2-fluoro-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), sodium carbonate (10.9 g, 99.6 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.42 g, 3.32 mmol) and dioxane / water (100 mL, 4 / 1) was degassed twice under nitrogen. 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 three times with ethyl acetate. 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 - 67% ethyl acetate / petroleum ether to give the title compound (7.00 g, 78%). 1 1H NMR (400 MHz, methanol-d4) δ: 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, 3H); MS m / z: 271.8 [M + 1] + 。

[0843] Step 2. 4-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)phenyl]-1- methyl-3,6-dihydro-2H-pyridine

[0844]

[0845] 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), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.541 g, 0.740 mmol), potassium acetate (1.08 g, 11.1 mmol) and dioxane (20 mL) was degassed twice under nitrogen. 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 three times with ethyl acetate. 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 / petroleum ether to give the title compound (0.432 g, 37%). 1 1H NMR (400 MHz, methanol-d4) δ: 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), 2.57 - 2.64 (m, 2H), 2.44 (s, 3H), 1.34 (s, 12H); MS m / z: 318.1 [M+1] + 。

[0846] Step 3. 4-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)phenyl]-1- methyl-piperidine

[0847]

[0848] To a solution of palladium (10% on carbon, 0.900 g, 0.851 mmol) in methanol (54 mL) was added 4-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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 stirred at 30 °C under a hydrogen atmosphere (50 psi) for 48 h. The reaction mixture was filtered through a pad of diatomaceous earth, which was washed several times with methanol. The filtrate was concentrated under reduced pressure to give the title compound (1.89 g, 70%). 11H NMR (400 MHz, methanol-d4) δ: 7.61 - 7.67 (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] + 。

[0849] Example 18: Preparation of 7-fluoro-2-[(R)-(5-fluoro-2-hydroxy-phenyl)-(4-methyl-1H-imidazol-2-yl)methyl]-6- [4-(1-methyl-4-piperidinyl)phenyl]isoindolin-1-one and 7-fluoro-2-[(S)-(5-fluoro-2-hydroxy-phenyl)-(4-meth yl-1H-imidazol-2-yl)methyl]-6-[4-(1-methyl-4-piperidinyl)phenyl]isoindolin-1-one (094 and 095) Preparation

[0850]

[0851] 7-Fluoro-2-[(5-fluoro-2-hydroxy-phenyl)-(5-methyl-1H-imidazol-2-yl)methyl]-6-[4-(1-methyl-piperidin-4-yl)phenyl]

[0852] Isoindolin-1-one (093, 0.020 g, 0.038 mmol) was purified by preparative SFC with a Chiral Technologies Chiralpak IA (5 micron 250 x 10 mm) column (at 40 °C), eluting with 45% (0.3% TEA / MeOH) / 55% CO2 at 10 MPa to separate the enantiomers. First elution peak (094) (6 mg, 30% yield, 100:0 er);

[0853] [α] 20 D -78.3 (c = 0.035, MeOH); 1 1H NMR (DMSO-d6) δ: 11.77 - 12.05 (m, 1H), 10.08 (brs, 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 (m, 4H); MS m / z: 529.3 [M+1] + 。Second elution peak

[0854] (095)(6 mg, 30% yield, 97.8:2.2 er); [α] 20 D +55.3 (c = 0.038, MeOH); 1 1H NMR (DMSO-d6) δ: 11.78 - 12.05 (m, 1H), 10.06 (br s, 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] + 。

[0855] Example 19: 2-[(5-fluoro-2-hydroxy-phenyl)-[5-(trifluoromethyl)-1H-imidazol-2-yl]methyl]-6-[4- (1-Methyl-4-piperidinyl)phenyl]isoindolin-1-one; hydrochloride (103)

[0856] Scheme 21

[0857]

[0858] Step 1. 2-Methyl-N-[[5-(trifluoromethyl)-1H-imidazol-2-yl]methylene]propane-2-sulfinamide

[0859]

[0860] 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 tetraethyl orthotitanate (20.4 g, 89.5 mmol). The reaction mixture was stirred at 75 °C for 5 h, quenched with water, and extracted three times with ethyl acetate. 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 / petroleum ether to give the title compound (9.6 g, 60%). 1 1H NMR (400 MHz, CDCl3) δ: 11.34 (br s, 1H), 8.52 (s, 1H), 7.49 (s, 1H), 1.16 (s, 9H); MS m / z: 267.9 [M+1] + 。

[0861] Step 2. 2-Methyl-N-[[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2- yl]methylene]propane-2-sulfinamide

[0862]

[0863] At 0 °C, sodium cyanide (1.29 g, 53.8 mmol) was added to a solution of 2-methyl-N-[[5-(trifluoromethyl)-1H-imidazol-2-yl]methylene]propane-2-sulfinamide (9.60 g, 35.9 mmol) in DMF (200 mL). After stirring for 15 minutes at the same temperature, 2-(trimethylsilyl)ethoxymethyl chloride (8.96 g, 53.8 mmol) was added. After stirring for 2 hours at room temperature, the reaction mixture was quenched with water and extracted three times with ethyl acetate. 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 / petroleum ether to give the title compound (6.5 g, 46%). 1 1H NMR (400 MHz, CDCl3) δ: 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+1] + 。

[0864] Step 3. N-[(5-Fluoro-2-methoxyphenyl)-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxy methyl)imidazol-2-yl]methyl]-2-methylpropane-2-sulfinamide

[0865]

[0866] At -78 °C, a solution of 5-fluoro-2-methoxyphenylmagnesium bromide in THF (0.5 M, 97.8 mL, 48.9 mmol) was added to a solution of 2-methyl-N-[[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]methylene]propane-2-sulfinamide (6.50 g, 16.3 mmol) in THF (100 mL). After stirring for 16 hours at room temperature, the reaction mixture was poured into saturated ammonium chloride solution and extracted three times with ethyl acetate. 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% ACN / water containing 10 mM ammonium acetate to give the title compound (1.9 g, 22%). 11H NMR (400 MHz, CDCl3) δ: 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] + 。

[0867] Step 4. (5-Fluoro-2-methoxyphenyl)-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymeth yl)imidazol-2-yl]

[0868] methylamine

[0869]

[0870] To a solution of N-[(5-fluoro-2-methoxyphenyl)-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]methyl]-2-methylpropane-2-sulfinamide (1.90 g, 3.62 mmol) in methanol (80 mL) was added HCl / 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%). 1 1H NMR (400 MHz, CDCl3) δ: 7.24 - 7.33 (m, 1H), 6.90 - 6.98 (m, 1H), 6.79 - 6.89 (m, 2H), 5.63 (s, 1H), 5.02 - 5.13 (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] + 。

[0871] Step 5. Methyl 5-bromo-2-[[[(5-fluoro-2-methoxyphenyl)-[5-(trifluoromethyl)-1-(2-trimethylsilyl ethoxymethyl)imidazol-2-yl]methyl]amino]methyl]benzoate

[0872]

[0873] To a solution of (5-fluoro-2-methoxyphenyl)-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)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 DIPEA (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 three times with ethyl acetate. The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (1.61 g, quantitative), which was used in the next reaction without further purification. MS m / z: 646.0 [M+1] + 。

[0874] Step 6. 6-Bromo-2-[(5-fluoro-2-methoxyphenyl)-[5-(trifluoromethyl)-1-(2-trimethylsilyl ethoxymethyl)imidazol-2-yl]methyl]isoindolin-1-one

[0875]

[0876] To a solution of methyl 5-bromo-2-[[[(5-fluoro-2-methoxyphenyl)-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]methyl]amino]methyl]benzoate (1.61 g, 2.49 mmol) in toluene (50 mL) was added trimethylaluminum (0.179 g, 2.49 mmol). The reaction 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%). 1 H NMR (400 MHz, CDCl3) δ: 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, 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] + 。

[0877] Step 7. 6-Bromo-2-[(5-fluoro-2-methoxyphenyl)-[5-(trifluoromethyl)-1H-imidazol-2-yl]methyl]iso indolin-1-one

[0878]

[0879] To a solution of 6-bromo-2-[(5-fluoro-2-methoxyphenyl)-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]methyl]isoindolin-1-one (0.540 g, 0.878 mmol) in methanol (5 mL) was added an aqueous solution of HCl (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 the residue was lyophilized to give the title compound (0.425 g, quantitative). 1 1H NMR (400 MHz, methanol-d4) δ: 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), 4.13 - 4.18 (m, 1H), 3.79 (s, 3H); MS m / z: 485.9 [M+1] + 。

[0880] Step 8. 2-[(5-fluoro-2-methoxyphenyl)-[5-(trifluoromethyl)-1H-imidazol-2-yl]methyl]-6-[4- (1-methyl-4-piperidinyl)

[0881] phenyl]isoindolin-1-one

[0882]

[0883] A mixture of 6-bromo-2-[(5-fluoro-2-methoxyphenyl)-[5-(trifluoromethyl)-1H-imidazol-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 under nitrogen for 2 h. After cooling, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography, eluting with 0 - 15% methanol / dichloromethane to give the title compound (0.3 g, 58%). 11H NMR (400 MHz, CDCl3) δ: 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), 2.07 - 2.16 (m, 3H), 1.86 - 1.97 (m, 2H); MS m / z: 579.3 [M+1] + 。

[0884] Step 9. 2-[(5-fluoro-2-hydroxyphenyl)-[5-(trifluoromethyl)-1H-imidazol-2-yl]methyl]-6-[4-(1- methyl-4-piperidinyl)phenyl]isoindolin-1-one; hydrochloride

[0885]

[0886] To a solution of 2-[(5-fluoro-2-methoxyphenyl)-[5-(trifluoromethyl)-1H-imidazol-2-yl]methyl]-6-[4-(1-methylpiperidin-4-yl)phenyl]isoindoline-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 three times with dichloromethane. 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% ACN / water (0.05% HCl modifier) to give the title compound (0.122 g, 50%). 1 1H NMR (400 MHz, DMSO-d6) δ: 10.58 (br s, 1H), 9.98 (br s, 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 - 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+1]+.

[0887] Example 20: Preparation of 2-[(R)-(5-fluoro-2-hydroxyphenyl)-(4-methyl-1H-imidazol-2-yl)methyl]-6-[4- (1-methyl-4-piperidinyl)phenyl]isoindolin-1-one and 2-[(S)-(5-fluoro-2-hydroxyphenyl)-(4-methyl-1H-imidazol-2-yl)methyl]-6-[4-(1-methyl-4-piperidinyl)phenyl]isoindolin-1-one( 104 and 105) Preparation)

[0888]

[0889] 2-[(5-Fluoro-2-hydroxy-phenyl)-(4-methyl-1H-imidazol-2-yl)methyl]-6-[4-(1-methyl-4-piperidinyl)phenyl]isoindolin-1-one (085, 0.020 g, 0.039 mmol) was purified by preparative SFC using a Technologies Chiralpak IA (5 micron

[0890] 250 x 10 mm) column (at 40 °C), eluting with 35% (0.3% TEA / MeOH) / 65% CO2 at 12 MPa to separate the enantiomers. The absolute configuration of the chiral centers of each separated enantiomer was unknown. First elution peak (104) (6.5 mg, 33% yield, 97.9:2.1 er); [α] 20 D -88.2 (c = 0.0465, MeOH); 1 1H NMR (DMSO-d6) δ: 11.74 - 12.04 (m, 1H), 10.06 (br s, 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, J = 8.5, 3.1 Hz, 1H), 6.51 - 6.90 (m, 4H), 4.72 (br d, J = 17.7 Hz, 1H), 4.11 (br d, J = 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 elution peak (105) (7.3 mg, 37% yield, 97.7:2.3 er); [α] 20 D +67.3 (c = 0.049, MeOH); 11H NMR (DMSO-d6) δ: 11.74 - 12.20 (m, 1H), 10.08 (br s, 1H), 7.82 - 7.90 (m, 2H), 7.65 (br d, J = 8.2 Hz, 3H), 7.36 (d, J = 8.2 Hz, 2H), 7.02 (td, J = 8.6, 3.2 Hz, 1H), 6.52 - 6.91 (m, 4H), 4.72 (d, J = 17.9 Hz, 1H), 4.11 (d, J = 17.9 Hz, 1H), 2.88 (br d, J = 11.1 Hz, 2H), 2.21 (s, 3H), 2.13 (s, 3H), 1.98 (td, J = 11.3, 2.1 Hz, 2H), 1.59 - 1.84 (m, 4H); MS m / z: 511.3 [M+1] + 。

[0891] Example 21: Preparation of 6-[(R)-1H-benzimidazol-2-yl-(5-fluoro-2-hydroxyphenyl)methyl]-2-[4-(1-meth yl-4-piperidinyl)phenyl]-5H-pyrrolo[3,4-b]pyridin-7-one and 6-[(S)-1H-benzimidazol-2-yl-(5-fluoro-2- hydroxyphenyl)methyl]-2-[4-(1-methyl-4-piperidinyl)phenyl]-5H-pyrrolo[3,4-b]pyridin-7-one (106 and 107)

[0892]

[0893] 6-[1H-Benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-2-[4-(1-methyl-4-piperidinyl)phenyl]-5H-pyrrolo[3,4-b]pyridin-7-one (028, 0.020 g, 0.037 mmol) was purified by preparative SFC using a Chiral Technologies Chiralpak IA (5 micron 250x10 mm) column (at 40 °C), eluting with 55% (0.3% TEA / MeOH) / 45% CO2 at 10 MPa to separate the enantiomers. The absolute configuration of the chiral centers of each separated enantiomer was unknown. First elution peak (106) (2.8 mg, 14% yield, 98.5:1.5 er); [α] 20 D -12.3 (c = 0.06, MeOH); 11H NMR (DMSO-d6) δ: 7.96 - 8.09 (m, 4H), 7.39 - 7.51 (m, 2H), 7.33 (d, J = 8.3 Hz, 2H), 7.06 - 7.16 (m, 2H), 6.94 - 7.06 (m, 2H), 6.83 (dd, J = 8.9, 4.8 Hz, 1H), 6.76 (dd, J = 9.3, 3.1 Hz, 1H), 4.72 (d, J = 17.9 Hz, 1H), 4.14 (br d, J = 17.7 Hz, 1H), 2.75 - 2.86 (m, 2H), 2.13 (s, 3H), 1.91 (td, J = 11.0, 1.5 Hz, 2H), 1.56 - 1.78 (m, 4H); MS m / z: 548.3 [M+1] + The second elution peak (107) (6.1 mg, 30% yield, 97.2:2.8 er); [α] 20 D +21.8 (c = 0.055, MeOH); 1 1H NMR (DMSO-d6) δ: 12.56 (br s, 1H), 9.92 (br s, 1H), 7.94 - 8.13 (m, 4H), 7.46 - 7.57 (m, 1H), 7.36 - 7.44 (m, 1H), 7.33 (d, J = 8.3 Hz, 2H), 7.11 (br s, 2H), 7.00 - 7.05 (m, 1H), 6.99 (s, 1H), 6.84 (dd, J = 8.9, 4.8 Hz, 1H), 6.75 (dd, J = 9.3, 3.1 Hz, 1H), 4.73 (d, J = 17.9 Hz, 1H), 4.11 (d, J = 17.9 Hz, 1H), 2.73 - 2.88 (m, 2H), 2.13 (s, 3H), 1.80 - 1.97 (m, 2H), 1.53 - 1.78 (m, 4H); MS m / z: 548.3 [M+1] + 。

[0894] The following examples were prepared from the starting material methyl 2-bromo-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate and the corresponding boronic ester by a method similar to that of compound 069:

[0895]

[0896] The following examples were prepared from the starting material methyl 2-bromo-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate and the corresponding boronic ester by a method similar to that of compound 070:

[0897]

[0898] Example 22: 2-[1H-benzimidazol-2-yl-deuterio-(5-fluoro-2-hydroxyphenyl)methyl]-6-[4-(1-methyl- (4-Piperidinyl)phenyl]isoquinolin-1-one 112)

[0899] Scheme 22

[0900]

[0901] Rac-2-(1H-1,3-benzodiazol-2-yl)(5-fluoro-2-hydroxyphenyl)methyl]-6-[4-(1-methylpiperidin-4-yl)phenyl]-1,2-dihydroisoquinolin-1-one (069, 20.4 mg, 0.0365 mmol) was dissolved in anhydrous tetrahydrofuran (1 mL) in a vial with a stir bar. Then deuterium oxide (350 μL, 19.3 mmol) was added with stirring, followed by N,N-diisopropylethylamine (38.1 μL, 219 μmol). The reaction vial was sealed and the reaction was stirred at 70 °C for 60 h. 1 1H NMR (DMSO-d6) indicated approximately 100% deuterium incorporation at the methine carbon based on the disappearance of the methine peak at approximately 7.67 ppm. The reaction was cooled to room temperature and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography, eluting with 0 - 15% (7N NH3 / methanol) / DCM to give the title compound (14 mg, 68%). 1 1H NMR (DMSO-d6, 400 MHz) δ: 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 (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);

[0902] MS m / z: 560.3 [M+1] + 。

[0903] The following examples were prepared from the starting material 2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-8-fluoro-6-[4-(1-methyl-4-piperidinyl)phenyl]isoquinolin-1-one (070) by a method similar to Example 22:

[0904]

[0905] Example 23: 2-[(S)-1H-Benzimidazol-2-yl-deuterio-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[4-(1-Methyl-4-piperidinyl)phenyl]isoquinolin-1-one and 2-[(R)-1H-benzimidazol-2-yl-deuterio-(5-fluoro-2-hydroxy-phenyl) Methyl]-6-[4-(1-methyl-4-piperidinyl)phenyl]isoquinolin-1-one (114 and 115) Preparation

[0906] Scheme 23

[0907]

[0908] Rac-2-(1H-1,3-benzodiazol-2-yl)(5-fluoro-2-hydroxyphenyl)methyl]-6-[4-(1-methylpiperidin-4-yl)phenyl]-1,2-dihydroisoquinolin-1-one (069, 50 mg, 0.090 mmol) was dissolved in anhydrous tetrahydrofuran (2 ml) in a vial with a stir bar. Then deuterium oxide (1000 μL, 55.4 mmol) was added under stirring, and then N,N-diisopropylethylamine (62.2 μL, 358 μmol). The reaction vial was sealed and the reaction was stirred at 70 °C for 60 h. The 1 1H NMR (DMSO-d6) indicated approximately 100% deuterium incorporation at the methine carbon based on the disappearance of the methine peak at approximately 7.67 ppm. The reaction was cooled to room temperature and then evaporated to afford the crude product, which was dissolved in 5 ml of THF. A solution of 75 μL of 35 wt% DCl in D2O was added dropwise under stirring. After 10 min, the reaction solution was concentrated and the residue was dried in vacuo overnight to give the crude product as the bis-DCI salt. The crude product was purified on a Jasco semi-preparative SFC using Chiralpak IG (10 x 250 mm 5 micron), eluting with 55% (0.3% TEA / MeOH) / 45% CO2 at a back pressure regulator (BPR) value of 10 MPa and a flow rate of 7 mL / min to separate the enantiomers. The absolute configuration of the chiral centers of each separated enantiomer was unknown. First elution peak (114) (19.7 mg, 37%, 100:0 er); [α] 20 D -13.6 (c = 0.0515, MeOH); 11H NMR (DMSO-d6, 400 MHz) δ: 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 (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+1] + 。The second elution peak (115) (18.8 mg, 36%, 99.7:0.3 er); [α] 20 D +14.2 (c = 0.0705, MeOH); 1 1H NMR (DMSO-d6, 400 MHz) δ: 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 (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+1] + 。

[0909] The following examples were prepared from the starting material 2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-8-fluoro-6-[4-(1-methylpiperidin-4-yl)phenyl]isoquinolin-1-one (070) by a method similar to Example 23. The absolute configuration of the chiral centers of each isolated enantiomer is unknown.

[0910]

[0911]

[0912] Example 24: 2-((1H-Benz[d]imidazol-2-yl)(5-fluoro-6-(4-(1-methylpiperidin-4-yl)phenyl)- 2H-indazol-2-yl)methyl)-4-fluorophenol (118)

[0913] Scheme 24

[0914]

[0915] Step 1. Methyl 2-(6-bromo-5-fluoro-2H-indazol-2-yl)-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate Step 2. 2-(5-Fluoro-2-(methoxymethoxy)phenyl)-2-(5-fluoro-6-(4-(1-methylpiperidin-4-yl)benz

[0916]

[0917] To a suspension of 6-bromo-5-fluoro-2H-indazole (360 mg, 1.67 mmol) and cesium carbonate (651 mg, 2.09 mmol) in CH3CN (16 mL) was added methyl 2-bromo-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate (513 mg, 1.67

[0918] mmol). The mixture was stirred at 0 °C for 1 h and then at room temperature for 16 h. The mixture was partitioned between water and ethyl acetate, and the aqueous phase was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and purified by silica gel chromatography, eluting with (0–20% EtOAc / hexane) to give the title compound (204 mg, 19%) as a solid. 1 1H NMR (CDCl3-d) δ: 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] + 。

[0919] yl)-2H-indazol-2-yl) Acetic acid

[0920] Step 3. N-(2-Aminophenyl)-2-(5-fluoro-2-(methoxymethoxy)phenyl)-2-(5-fluoro-6-(4-(1-meth

[0921]

[0922] Methyl 2-(6-bromo-5-fluoro-2H-indazol-2-yl)-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate (205 mg, 0.47 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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 a mixture of dioxane:water (3:1, 3 mL) were degassed and flushed with nitrogen three times. The mixture was heated at 100 °C under nitrogen for 4 h. 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 mg, 48%). 1 1H NMR (DMSO-d6) δ: 9.35 (br s, 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+1] + 。

[0923] ylpiperidin-4-yl)phenyl)-2H-indazol-2-yl)acetamide Step 4. 2-((1H-Benz[d]imidazol-2-yl)(5-fluoro-6-(4-(1-methylpiperidin-4-yl)phenyl)-2H-ind

[0924]

[0925] A mixture of 2-(6-bromo-(5-fluoro-2-(methoxymethoxy)phenyl)-2-(5-fluoro-6-(4-(1-methylpiperidin-4-yl)phenyl)-2H-indazol-2-yl)acetic acid (117 mg, 0.48 mmol), 1,2-phenylenediamine (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 h. The reaction mixture was purified by reverse phase HPLC, eluting with 0 - 80% ACN / water (0.035% TFA modifier) to give the title compound. 11H NMR (DMSO-d6) δ: 9.92 (s, 1H), 9.33 (br s, 1H), 8.31 (s, 1H), 7.73 (d, 1H), 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).

[0926] azol-2-yl)methyl)-4-fluorophenol (118) Step 1. Methyl 2-bromo-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate

[0927]

[0928] The material from Step 3 was heated in AcOH (5 mL) at 100 °C for 1 h. The solvent was removed under reduced pressure and the residue was dissolved in 1:1 TFA:DCM (5 mL) for 5 h. The reaction mixture was purified by reverse-phase HPLC, eluting with 0 - 80% ACN / water (0.035% TFA modifier) to afford the title compound (39 mg, 13% over 3 steps). 1 1H NMR (DMSO-d6) δ: 10.18 (br s, 1H), 9.36 (br s, 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

[0929] [M+1] + .

[0930] The following examples were prepared from the starting material methyl 2-bromo-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate and the corresponding bicyclic by a method similar to Example 24:

[0931]

[0932] Scheme 25

[0933]

[0934] Example 25: HTRF-based EGFR biochemical assay

[0935]

[0936] To a solution of methyl 5-fluoro-2-(methoxymethoxy)phenylacetate (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 product was purified by silica gel column chromatography, eluting with 0 - 5% ethyl acetate / petroleum ether to give the title compound (2.4 g, 36%). 1 1H NMR (400 MHz, CDCl3) δ: 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).

[0937] Example 26: Ba / F3 cell proliferation model

[0938] EGFR biochemical activity measurements were performed using the homogeneous time-resolved fluorescence (HTRF) assay (Cisbio). First, inhibitors and DMSO standards were dispensed into empty black low-volume 384-well plates (Corning) using a D300 digital liquid dispenser (HP). All reactions were carried out at room temperature and solutions were added to the plates using a Multidrop Combi reagent dispenser (ThermoFisher). The reaction mixture (final volume 10 μL) contained 1 μM tyrosine kinase peptide-biotin substrate and mutant EGFR in reaction buffer (50 mM HEPES pH 7.0, 5 mM MgCl2, 1 mM MnCl2, 0.01% BSA, 2 mM TCEP, 0.1 mM NaVO4). Enzyme concentrations were adjusted to accommodate different kinase activities (L858R 0.1 nM, L858R / T790M 0.02 nM). The enzyme reaction solution (2× concentration, 5 μL) was added to the 384-well plates containing the compounds and incubated for 30 minutes. 5 μL of ATP was added to a final concentration of 100 μM to initiate the enzyme reaction and the reaction was carried out for 20 minutes. 10 μL of phosphotyrosine antibody-europium(III) cryptate (volume ratio 1:180) and streptavidin-XL665 (46.7 nM) in detection buffer containing EDTA was added to quench the reaction, which was then incubated at room temperature for 1 hour and read using a PHERAstar plate reader (excitation = 337 nm, emission = 620 nm and 665 nm). IC50 values were determined in triplicate in parallel from inhibition curves (11-point curves from 1.0 μM to 0.130 nM or 23-point curves from 1.0 μM to 0.130 pM) and nonlinear least squares fitting was performed in GraphPad Prism 7.0d. The results of the HTRF-based EGFR biochemical assay are summarized in Table 7 below.

[0939] Table 7.

[0940]

[0941]

[0942]

[0943]

[0944] ​

[0945] The EGFR mutants L858R, Del E746_A750, L858R / T790M, Del E746_A750 / T790M, L858R / T790M / C797S, and Del / T790M / C797S Ba / F3 cells have been previously described (Zhou, W. et al. Nature 462, 2009, 1070-1074). All cell lines were maintained in RPMI 1640 (Cellgro; Mediatech Inc., Herndon, VA) supplemented with 10% FBS, 100 units / mL penicillin, and 100 units / mL streptomycin. The EGFR I941R mutation was introduced via site-directed mutagenesis using the Quick Change site-directed mutagenesis kit (Stratagene; La Jolla, CA) according to the manufacturer's instructions. All constructs were confirmed by DNA sequencing. The constructs were shuttled into the retroviral vector JP1540 using the Cre-recombinase system (Agilent Technologies, Santa Clara, CA). Ba / F3 cells were then infected with the retrovirus according to the standard protocol as previously described (Zhou et al., Nature 2009). Stable clones were obtained by selection in puromycin (2 μg / ml).

[0946] Growth and growth inhibition were evaluated by the Cell Titer Glo assay (Promega, Madison, WI) and performed according to the manufacturer's instructions. The Cell Titer Glo assay is a luminescence-based method for determining the number of viable cells based on the quantification of ATP present, where the ATP present is proportional to the amount of metabolically active cells present. Ba / F3 cells with different EGFR genotypes were exposed to the compound as a single agent or in combination with 1 μg / ml cetuximab for 72 hours and the number of cells used per experiment was determined empirically as previously established (Zhou et al., Nature 2009). All experimental points were set up in triplicate in 384-well plates and all experiments were repeated at least three times. The luminescence signal was detected using a spectrophotometer and the data were graphed using GraphPad Prism version 5.0 for Windows (GraphPad Software;

[0947] www.graphpad.com). Curves were fitted using a non-linear regression model with a sigmoidal dose response. The measured IC50 values are shown in Table 8 below.

[0948] Table 8.

[0949]

[0950]

[0951]

[0952] The disclosed subject matter is not limited to the scope of the specific embodiments and examples described herein. Indeed, various modifications to the present disclosure, in addition to those described, will become apparent to those skilled in the art in light of the foregoing description. Such modifications are intended to fall within the scope of the appended claims.

[0953] All references cited herein (e.g., publications or patents or patent applications) are incorporated by reference in their entirety for all purposes to the extent as if each individual reference (e.g., publication or patent or patent application) was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Other embodiments are within the following claims.

Claims

1. A compound of formula I: or a pharmaceutically acceptable salt thereof; wherein: A and A' are each independently CH, CR 8 or N; W and Z are each independently N, CH, C-halo, C-(C1-C3 alkyl) or C-(C1-C3 alkoxy); X and Y are each independently N, CH or CR 3 ; provided that at least one of W, X, Y or Z is CH; R 1 selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, and 3- to 10-membered cycloalkyl, all of which are optionally substituted with one, two or three R 8 substituents; R 2 selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl and 3- to 10-membered cycloalkyl, all of which are optionally substituted with one, two or three R 6 substituents; R 3 is independently selected from halogen, OR 4 , NR 4 R 4 , SO2R 4 , SO2NHR 4 , NHSO2R 4 , C(O)OR 4 , C(O)NHR 4 , C(O)R 4 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, C4-C7 cycloalkenyl, C6-C 10 aryl, 5-6 membered heteroaryl and 5-7 membered heterocyclic group, wherein the alkyl, alkenyl or alkynyl is each optionally substituted one, two or three times by R 4 , and wherein the aryl, heteroaryl or heterocyclic group is each optionally substituted one, two or three times by R 5 ; R 4 independently selected from H, (CH2) 0-3 -(C3-C7 cycloalkyl), (CH2) 0-3 -(C4-C7 cycloalkenyl), (CH2) 0-3 -(C6-C 10 aryl), (CH2) 0-3 -(5-6 membered heteroaryl) and (CH2) 0-3 -(5-7 membered heterocyclic group), wherein the aryl, heteroaryl or heterocyclic group is each optionally substituted by R 5 substituted one, two or three times; R 5 independently selected from 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-C 10 aryl), (CH2) 0-3 -(5-6 membered heteroaryl) and (CH2) 0-3 -(5-7 membered heterocyclic group), wherein the aryl, heteroaryl or heterocyclic group is each optionally substituted by R 7 one, two or three times; R 6 independently selected from 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) 1-4 OH, S(O) 0-2 H, S(O) 0-2 NH2 or CN; Alternatively, two Rs 6 together with the atom to which they are attached can form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl or 3- to 10-membered cycloalkyl; R 7 independently selected from substituents at each occurrence, said 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 Rs 7 together with the atoms to which they are attached can form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl or 3- to 10-membered cycloalkyl; and R 8 independently selected from 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) 1-4 OH, S(O) 0- 2H, S(O) 0-2 NH2 or CN at each occurrence 2. The compound according to claim 1, wherein the compound of formula I is a compound of formula Ia: or a pharmaceutically acceptable salt thereof.

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

4. A compound of formula I: or a pharmaceutically acceptable salt thereof; wherein: A and A' are each independently CH, CR 8 or N; W and Z are each independently N, CH, C-halo, C-(C1-C3 haloalkyl), C-(C1-C3 alkyl) or C-(C1-C3 alkoxy); X and Y are each independently N, CH or CR 3 ; provided that at least one of W, X, Y or Z is CH; R 1 selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, and 3- to 10-membered cycloalkyl, all of which are optionally substituted with one, two or three R 8 substituents; R 2 selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl and 3- to 10-membered cycloalkyl, all of which are optionally substituted with one, two or three R 6 substituents; R 3 independently selected from halogen, OR each time it appears 4 , NR 4 R 4 , SO2R 4 , SO2NHR 4 , NHSO2R 4 , C(O)OR 4 , C(O)NHR 4 , C(O)R 4 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 7-membered cycloalkyl, C4-C7 cycloalkenyl, C6-C 10 aryl, 5- or 6-membered heteroaryl and 5- to 7-membered heterocyclic group, wherein the alkyl, alkenyl or alkynyl is each optionally substituted one, two or three times by R 4 , and wherein the aryl, heteroaryl or heterocyclic group is each optionally substituted one, two or three times by R 5 ; R 4 independently selected from H, (CH2) 0-3 -(C3-C7 cycloalkyl), (CH2) 0-3 -(C4-C7 cycloalkenyl), (CH2) 0-3 -(C6-C 10 aryl), (CH2) 0-3 -(5-6 membered heteroaryl) and (CH2) 0-3 -(5-7 membered heterocyclic group), wherein the aryl, heteroaryl or heterocyclic group is each optionally substituted by R 5 substituted one, two or three times; R 5 independently selected from 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-C 10 aryl), (CH2) 0-3 -(5-6 membered heteroaryl) and (CH2) 0-3 -(5-7 membered heterocyclic group), wherein the aryl, heteroaryl or heterocyclic group is each optionally substituted by R 7 one, two or three times; R 6 independently selected from 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) 1-4 OH, S(O) 0-2 H, S(O) 0-2 NH2 or CN at each occurrence; Alternatively, two Rs 6 together with the atoms to which they are attached can form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl, or 3- to 10-membered cycloalkyl; R 7 independently selected from substituents at each occurrence, said substituents being 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 Rs 7 together with the atoms to which they are attached can form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl, or 3- to 10-membered cycloalkyl; and R 8 independently selected from 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) 1-4 OH, S(O) 0- 2H, S(O) 0-2 NH2 or CN at each occurrence 5. The compound according to any one of claims 1-4, wherein Z is CH.

6. The compound according to any one of claims 1-4, wherein Z is N.

7. The compound according to any one of claims 1-4, wherein Z is CF.

8. The compound according to any one of claims 1-7, wherein R 6 is independently, at each occurrence, a hydroxyl group or a halogen group.

9. The compound according to any one of claims 1-8, wherein R 1 is selected from benzimidazole, imidazopyrazine, purine, imidazole, pyrazole, triazole and imidazopyridine.

10. The compound according to any one of claims 1-8, wherein R 1 is selected from: All of these are optionally substituted by one, two or three R 8 substituents.

11. The compound according to claim 1, wherein the compound of formula I is selected from: or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 1, wherein the compound of formula I is selected from: or a pharmaceutically acceptable salt thereof.

13. A compound of formula II: or a pharmaceutically acceptable salt thereof; wherein W and Z are each independently N, CH, C-halo, C-(C1-C3 alkyl) or C-(C1-C3 alkoxy); X and Y are each independently C, CH or CR 3 ; provided that at least one of W, X, Y or Z is CH; R 1 selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, and 3- to 10-membered cycloalkyl, all of which are optionally substituted by one, two, or three R 8 substituents; R 2 selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, and 3- to 10-membered cycloalkyl, all of which are optionally substituted with one, two, or three R 6 substituents; R 3 independently selected from halogen, OR, each time it appears 4 , NR 4 R 4 , SO2R 4 , SO2NHR 4 , NHSO2R 4 , C(O)OR 4 , C(O)NHR 4 , C(O)R 4 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, C4-C7 cycloalkenyl, C6-C 10 aryl, 5-6 membered heteroaryl and 5-7 membered heterocyclic group, wherein the alkyl, alkenyl or alkynyl is each optionally substituted one, two or three times by R 4 , and wherein the aryl, heteroaryl or heterocyclic group is each optionally substituted one, two or three times by R 5 ; R 4 independently selected from H, (CH2) 0-3 -(C3-C7 cycloalkyl), (CH2) 0-3 -(C4-C7 cycloalkenyl), (CH2) 0-3 -(C6-C 10 aryl), (CH2) 0-3 -(5-6 membered heteroaryl) and (CH2) 0-3 -(5-7 membered heterocyclic group), wherein the aryl, heteroaryl or heterocyclic group is each optionally substituted by R 5 substituted one, two or three times; R 5 independently selected from 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-C 10 aryl), (CH2) 0-3 -(5-6 membered heteroaryl) and (CH2) 0-3 -(5-7 membered heterocyclic group), wherein the aryl, heteroaryl or heterocyclic group is each optionally substituted by R 7 one, two or three times; R 6 independently selected from 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) 1-4 OH, S(O) 0-2 H, S(O) 0-2 NH2 or CN; Alternatively, two Rs 6 together with the atom to which they are attached can form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl, or 3- to 10-membered cycloalkyl; R 7 independently selected from substituents at each occurrence, said 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 Rs 7 together with the atom to which they are attached can form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl or 3- to 10-membered cycloalkyl; and R 8 independently selected from 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) 1-4 OH, S(O) 0- 2H, S(O) 0-2 NH2 or CN at each occurrence; and n is 1 or 2.

14. The compound according to claim 13, wherein the compound of formula II is a compound of formula IIa: or a pharmaceutically acceptable salt thereof.

15. A compound of formula X: or a pharmaceutically acceptable salt thereof; wherein A is O or S; W and Z are each independently N, CH, C-halo, C-(C1-C3 alkyl) or C-(C1-C3 alkoxy); X and Y are each independently N, CH or CR 3 ; provided that at least one of W, X, Y or Z is CH; R 1 selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, and 3- to 10-membered cycloalkyl, all of which are optionally substituted with one, two, or three R 8 substituents; R 2 selected from 6-10-membered aryl, 5-10-membered heteroaryl, 3-10-membered heterocycloalkyl and 3-10-membered cycloalkyl, all of which are optionally substituted by one, two or three R 6 substituents; R 3 independently selected from halogen, OR, at each occurrence 4 , NR 4 R 4 , SO2R 4 , SO2NHR 4 , NHSO2R 4 , C(O)OR 4 , C(O)NHR 4 , C(O)R 4 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, C4-C7 cycloalkenyl, C6-C 10 aryl, 5-6 membered heteroaryl and 5-7 membered heterocyclic group, wherein the alkyl, alkenyl or alkynyl is each optionally substituted one, two or three times by R 4 , and wherein the aryl, heteroaryl or heterocyclic group is each optionally substituted one, two or three times by R 5 ; R 4 independently selected from H, (CH2) 0-3 -(C3-C7 cycloalkyl), (CH2) 0-3 -(C4-C7 cycloalkenyl), (CH2) 0-3 -(C6-C 10 aryl), (CH2) 0-3 -(5-6 membered heteroaryl) and (CH2) 0-3 -(5-7 membered heterocyclic group), wherein the aryl, heteroaryl or heterocyclic group is each optionally substituted by R 5 substituted one, two or three times; R 5 independently selected from 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-C 10 aryl), (CH2) 0-3 -(5-6 membered heteroaryl), O(CH2) 0-3 -(4-7 membered heterocyclic group) and (CH2) 0-3 -(4-7 membered heterocyclic group), wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclic group is each optionally substituted by R 7 one, two or three times; R 6 independently selected from 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) 1-4 OH, S(O) 0-2 H, S(O) 0-2 NH2 or CN; Alternatively, two Rs 6 together with the atom to which they are attached can form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl, or 3- to 10-membered cycloalkyl; R 7 independently selected from substituents at each occurrence, said substituents being 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 Rs 7 together with the atom to which they are attached can form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl, or 3- to 10-membered cycloalkyl; and R 8 independently selected from 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) 1-4 OH, S(O) 0- 2H, S(O) 0-2 NH2 or CN; and n is 1 or 2.

16. The compound according to any one of claims 13 - 15, wherein R 6 is independently, in each occurrence, a hydroxyl group or a halogen group.

17. A compound according to any one of claims 13-16, wherein R 1 is selected from benzimidazole, imidazopyrazine, purine, imidazole, pyrazole, triazole and imidazopyridine.

18. The compound according to any one of claims 13-16, wherein R 1 is selected from: All of these are optionally substituted by one, two, or three R 8 groups.

19. A compound according to any one of claims 13 - 18, wherein R 3 is phenyl or C2 - C3 alkynyl, wherein the phenyl is optionally substituted one or two times by R 5 and the alkynyl is optionally substituted one or two times by R 4 one or two times.

20. The compound according to any one of claims 13-19, wherein R 3 is phenyl substituted by one or two R 5 groups, and R 5 is selected from piperidine, pyridine and thiomorpholine dioxide, all of which are optionally substituted by one or two R 7 groups.

21. The compound according to any one of claims 13-18, wherein the compound of formula II is a compound of formula IIb: or a pharmaceutically acceptable salt thereof.

22. The compound according to claim 13, wherein the compound of formula II is selected from: or a pharmaceutically acceptable salt thereof.

23. The compound according to claim 15, wherein the compound of formula X is selected from or a pharmaceutically acceptable salt thereof.

24. A compound of formula III: or a pharmaceutically acceptable salt thereof; wherein is a single bond or a double bond; B and D are each independently C or N; W and Z are each independently N, CH, C-halo, C-(C1-C3 alkyl) or C-(C1-C3 alkoxy); X and Y are each independently N, CH or CR 3 ; provided that at least one of W, X, Y or Z is CH; provided that at least one of W, X, Y or Z is CH; R 1 selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, and 3- to 10-membered cycloalkyl, all of which are optionally substituted with one, two or three R 8 substituents; R 2 selected from 6-10-membered aryl, 5-10-membered heteroaryl, 3-10-membered heterocycloalkyl and 3-10-membered cycloalkyl, all of which are optionally substituted by one, two or three R 6 substituents; R 3 independently selected from halogen, OR each time it appears 4 , NR 4 R 4 , SO2R 4 , SO2NHR 4 , NHSO2R 4 , C(O)OR 4 , C(O)NHR 4 , C(O)R 4 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 7-membered cycloalkyl, C4-C7 cycloalkenyl, C6-C 10 aryl, 5- to 6-membered heteroaryl and 5- to 7-membered heterocyclic group, wherein the alkyl, alkenyl or alkynyl is each optionally substituted one, two or three times by R 4 and wherein the aryl, heteroaryl or heterocyclic group is each optionally substituted one, two or three times by R 5 ; R 4 independently selected from H, (CH2) 0-3 -(C3-C7 cycloalkyl), (CH2) 0-3 -(C4-C7 cycloalkenyl), (CH2) 0-3 -(C6-C 10 aryl), (CH2) 0-3 -(5-6 membered heteroaryl) and (CH2) 0-3 -(5-7 membered heterocyclic group), wherein the aryl, heteroaryl or heterocyclic group is each optionally substituted by R 5 substituted one, two or three times; R 5 independently selected from 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-C 10 aryl), (CH2) 0-3 -(5-6 membered heteroaryl) and (CH2) 0-3 -(5-7 membered heterocyclic group), wherein the aryl, heteroaryl or heterocyclic group is each optionally substituted by R 7 substituted one, two or three times; R 6 independently selected from 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) 1-4 OH, S(O) 0-2 H, S(O) 0-2 NH2 or CN; Alternatively, two Rs 6 together with the atom to which they are attached can form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl or 3- to 10-membered cycloalkyl; R 7 independently selected from substituents at each occurrence, said 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 Rs 7 together with the atom to which they are attached can form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl or 3- to 10-membered cycloalkyl; and R 8 independently selected from 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) 1-4 OH, S(O) 0- 2H, S(O) 0-2 NH2 or CN each time it appears.

25. The compound according to claim 24, wherein the compound of formula III is a compound of formula IIIa: or a pharmaceutically acceptable salt thereof.

26. The compound according to claim 24, wherein the compound of formula III is a compound of formula IIIb: or a pharmaceutically acceptable salt thereof.

27. The compound according to any one of claims 24-26, wherein R 1 is selected from benzimidazole, imidazopyrazine, purine, imidazole, pyrazole, triazole and imidazopyridine.

28. A compound according to any one of claims 24 - 26, wherein R 1 is selected from: All of these are optionally substituted by one, two or three R 8 groups.

29. The compound according to any one of claims 24-28, wherein Y is CR 3 , and R 3 is a 6- to 10-membered aryl group which is substituted with one or two R 5 substituents.

30. The compound according to claim 24, wherein the compound of formula III is a compound of formula IIIc: or a pharmaceutically acceptable salt thereof.

31. The compound according to any one of claims 24 - 30, wherein Z is CF.

32. The compound according to any one of claims 24 - 30, wherein Z is CH.

33. The compound according to any one of claims 24 - 30, wherein Z is N.

34. The compound according to claim 24, wherein the compound of formula III is selected from: or a pharmaceutically acceptable salt thereof.

35. A compound according to any one of claims 1-10, 13-21 and 24-33, wherein R 7 is C1-C3 alkyl.

36. A pharmaceutical composition comprising the compound according to any one of claims 1 - 35 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

37. The pharmaceutical composition according to claim 36, wherein the composition further comprises a second active agent.

38. The pharmaceutical composition according to claim 37, wherein the second active agent is selected from MEK inhibitors, PI3K inhibitors, and mTor inhibitors.

39. The pharmaceutical composition according to claim 37, wherein the second active agent prevents EGFR dimer formation in a subject.

40. The pharmaceutical composition according to claim 37, wherein the second active agent is selected from cetuximab, trastuzumab, and panitumumab.

41. The pharmaceutical composition according to claim 37, wherein the second active agent is an ATP - competitive EGFR inhibitor.

42. The pharmaceutical composition according to claim 37, wherein the ATP - competitive EGFR inhibitor is osimertinib, gefitinib, or erlotinib.

43. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound according to any one of claims 1 - 35 or the composition according to any one of claims 36 - 42.

44. The method according to claim 43, wherein the cancer is selected from lung cancer, colon cancer, breast cancer, endometrial cancer, thyroid cancer, glioma, squamous cell carcinoma, and prostate cancer.

45. The method according to claim 43, wherein the cancer is non - small cell lung cancer (NSCLC).

46. A method of inhibiting a kinase in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound according to any one of claims 1 - 35 or the composition according to any one of claims 36 - 42.

47. The method according to claim 46, wherein the kinase is EGFR.

48. A method of treating or preventing a kinase-mediated disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-35 or a composition according to any one of claims 36-42.

49. The method according to claim 48, wherein the kinase-mediated disorder is resistant to EGFR-targeted therapy.

50. The method according to claim 49, wherein the therapy for treating EGFR is selected from gefitinib, erlotinib, osimertinib, CO-1686, and WZ4002.

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