Allosteric EGFR inhibitors and methods of use thereof

Abstract

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

Description

[Technical Field]

[0001] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT 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.

[0002] Related Applications This application claims priority to U.S. Provisional Application No. 62 / 933,776, filed November 11, 2019, and U.S. Provisional Application No. 63 / 030,655, filed May 27, 2020, the contents of which are incorporated herein in their entireties. [Background technology]

[0003] The epidermal growth factor receptor (EGFR, Erb-B1) belongs to the receptor tyrosine kinase family that mediates the proliferation, differentiation and survival of normal and malignant cells (Arteaga, CL, J. Clin. Oncol. 19, 2001, pp. 32-40). Deregulation of EGFR has been implicated in many types of human cancer, with the receptor being overexpressed in at least 70% of human cancers (Seymour, LK, Curr. Drug Targets 2, 2001, pp. 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, pp. 15-23, discussion pp. 41-2; Salomon, DS et al., Crit. Rev. Oncol. Hematol. 19, 1995, pp. 183-232; Voldborg BR et al., Ann. Oncol. 8, 1997, pp. 1197-1206). Therefore, EGFR has become known as an attractive target for the design and development of diagnostic and therapeutic agents that can specifically bind to and inhibit the tyrosine kinase activity and signal transduction pathway of the receptor in cancer cells. For example, the EGFR tyrosine kinase (EGFR-TK) reversible inhibitor TARCEVA R™ has been approved by the FDA for the treatment of NSCLC and advanced pancreatic cancer. Other anti-EGFR targeting molecules, including lapatinib R™ and IRESSA R™, have also been approved.

[0004] Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are an effective clinical treatment for patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC) (Mok, TS et al., N. Engl. J. Med. 361, 2009, pp. 947-57; Paez, JG et al., Science 304, 2004, pp. 1497-500; Lynch, TJ et al., N. Engl. J. Med. 350, 2004, pp. 2129-39; Rosell, R. et al., Lancet Oncol. 13, 2012, pp. 239-46). Randomized clinical trials have demonstrated that EGFR TKIs are more effective than chemotherapy when used as initial systemic treatment for advanced EGFR-mutated NSCLC, as assessed by response rate (RR) and progression-free survival (PFS) (Mok, TS et al., N. Engl. J. Med. 361, 2009, pp. 947-57; Rosell, R. et al., Lancet Oncol. 13, 2012, pp. 239-46; Sequest, LV et al., J. Clin. Oncol. 31, 2013, pp. 3327-34; Wu, YL et al., Lancet Oncol. 15, 2014, pp. 213-22; Maemondo, M. et al., N. Engl. J. Med. 362, 2010, pp. 2380-2388; Zhou, C. et al., Lancet Oncol. 12, 2011, pp. 735-42; Mitsudomi, T. et al., Lancet Oncol. 11, 2010, pp. 121-8). However, the majority of patients will experience disease progression after successful treatment with EGFR TKIs. The most common mechanism of acquired resistance, detected in 60% of patients, is a secondary mutation at position T790 in EGFR (T790M) (Yu, HA et al., Clin. Cancer Res. 19, 2013, pp. 2240-7). This mutation leads to increased affinity of ATP, which makes it more difficult for the reversible EGFR TKIs gefitinib and erlotinib to bind to the EGFR TKI domain (Yun CH et al., Proc. Natl. Acad. Sci. USA 105, 2008, pp. 2070-5).

[0005] Covalent EGFR inhibitors have become known to inhibit cancers containing EGFR T790M mutation. However, in lung cancer patients, only afatinib has been effective in EGFR TKI-naive EGFR-mutated cancers, with a RR of less than 10% in patients with NSCLC that has acquired resistance to gefitinib or erlotinib (Miller, VA et al., Lancet Oncol. 13, 2012, pp. 528-38). Afatinib is a potent inhibitor of both mutant and wild-type (WT) EGFR. Inhibition of WT EGFR leads to toxicities, including skin rash and diarrhea, limiting the ability to escalate afatinib doses in patients to those required to inhibit EGFR T790M mutation. 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, pp. 1070-1074; Walter, AO et al., Cancer Discov. 3, 2013, pp. 1404-1401; Cross, DAE et al., Cancer Discov. 4, 2014, pp. 1046-1046). Not only are they more potent against EGFR T790M, but they also inhibit the mutant more selectively than WT EGFR, leading to greater clinical efficacy and lower toxicity compared to afatinib (Zhou, W. et al.; Walter AO et al., Cross, DAE et al.). [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Arteaga, CL, J. Clin. Oncol. 19, 2001, pp. 32-40. [Non-patent document 2] Seymour, LK, Curr. Drug Targets 2, 2001, pp. 117-133. [Non-patent document 3] Raymond, E., Drugs 60 (Suppl. 1), 2000, pp. 15-23, discussion pp. 41-2

Non-patent document 4

Non-patented document 5

Non-patent document 6

Non-patent document 7

Non-patent document 8

Non-patented document 9

Non-patent document 10

Non-patent document 11

Non-patent document 12

Non-patent document 13

Non-patent document 14

Non-patent document 15

Non-patent document 16

Non-patent document 17

Non-patent document 18

Non-patent document 19

Non-patent document 20

Non-patent document 21

Non-patent document 22

Non-patent document 23

Non-patent document 24

Non-patented document 25

[0007] However, all current EGFR TKIs target the ATP site, and while third-generation irreversible inhibitors can overcome the T790M mutation, they are all rendered ineffective by the C797S mutation, which already occurs in treated patients. Because kinase activation by mutation is effectively "downstream" of receptor dimerization, the anti-EGFR antibody cetuximab, which blocks receptor dimerization, is ineffective in EGFR-mutant NSCLC. Therefore, alternative strategies for inhibiting EGFR are needed. Currently, no suitable compounds with alternative mechanisms of action that target mutant EGFR are available. Therefore, potent small-molecule EGFR inhibitors with alternative mechanisms of action that target mutant EGFR are needed. [Means for solving the problem]

[0008] In some embodiments, provided herein are compounds of formula I:

[0009] [ka]

[0010] or a pharmaceutically acceptable salt thereof (In the formula, 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 and provided that at least one of W, X, Y, or Z is CH; R 1 is selected from the group consisting of 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, and 3- to 10-membered cycloalkyl, all of which optionally contain one, two, or three R 8 is replaced by R 2 is selected from the group consisting of 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, and 3- to 10-membered cycloalkyl, all of which optionally contain one, two, or three R 6 is replaced by R 3 are independently defined for each occurrence as halogen, OR 4 , N.R. 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- to 6-membered heteroaryl, and 5- to 7-membered heterocyclyl, wherein alkyl, alkenyl, or alkynyl are each optionally selected from the group consisting of R 4 and each aryl, heteroaryl, or heterocyclyl is optionally substituted once, twice, or three times with R 5 is substituted once, twice or three times with R 4 are independently expressed as 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 heterocyclyl), wherein aryl, heteroaryl, or heterocyclyl is each optionally selected from the group consisting of R 5 is substituted once, twice or three times with R 5 is independently selected from each occurrence of 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 -(5-6 membered heteroaryl) and (CH2) 0~3 -(5- to 7-membered heterocyclyl), wherein aryl, heteroaryl, or heterocyclyl is each optionally selected from the group consisting of R 7 is substituted once, twice or three times with R 6 is independently at each occurrence 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 selected from the group consisting of NH2 or CN; Or, two R's 6 may, together with the atom to which they are attached, form a 5- to 10-membered heteroaryl, a 6- to 10-membered aryl, a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered cycloalkyl; R 7 is independently at each occurrence 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 is selected from the group consisting of substituents independently selected from —OH, C(O)(C1-C6 alkyl) and C(O)O(C1-C6 alkyl); Or, two R's 7 may, together with the atom to which they are attached, form a 5- to 10-membered heteroaryl, a 6- to 10-membered aryl, a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered cycloalkyl; R 8 is independently selected from each occurrence of 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).

[0011] In another aspect, provided herein are compounds of formula II:

[0012] [ka]

[0013] or a pharmaceutically acceptable salt thereof (In the formula, 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 and provided that at least one of W, X, Y, or Z is CH; R 1 is selected from the group consisting of 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, and 3- to 10-membered cycloalkyl, all of which optionally contain one, two, or three R 8 is replaced by R 2is selected from the group consisting of 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, and 3- to 10-membered cycloalkyl, all of which optionally contain one, two, or three R 6 is replaced by R 3 are independently defined for each occurrence as halogen, OR 4 , N.R. 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- to 6-membered heteroaryl, and 5- to 7-membered heterocyclyl, wherein alkyl, alkenyl, or alkynyl are each optionally selected from the group consisting of R 4 and each aryl, heteroaryl, or heterocyclyl is optionally substituted once, twice, or three times with R 5 is substituted once, twice or three times with R 4 are independently expressed as 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 heterocyclyl), wherein aryl, heteroaryl, or heterocyclyl is each optionally selected from the group consisting of R 5 is substituted once, twice or three times with R 5 is independently selected from each occurrence of 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 -(5-6 membered heteroaryl) and (CH2) 0~3 -(5- to 7-membered heterocyclyl), wherein aryl, heteroaryl, or heterocyclyl is each optionally selected from the group consisting of R 7 is substituted once, twice or three times with R 6 is independently at each occurrence 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 selected from the group consisting of NH2 or CN; Or, two R's 6 may, together with the atom to which they are attached, form a 5- to 10-membered heteroaryl, a 6- to 10-membered aryl, a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered cycloalkyl; R 7 is independently at each occurrence 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 is selected from the group consisting of substituents independently selected from —OH, C(O)(C1-C6 alkyl) and C(O)O(C1-C6 alkyl); Or, two R's 7 may, together with the atom to which they are attached, form a 5- to 10-membered heteroaryl, a 6- to 10-membered aryl, a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered cycloalkyl; R 8is independently selected from each occurrence of 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 selected from the group consisting of NH2 or CN; n is 1 or 2).

[0014] In yet another aspect, provided herein are compounds of formula III:

[0015] [ka]

[0016] or a pharmaceutically acceptable salt thereof (In the formula,

[0017] [ka]

[0018] is an optional double bond, B and D are each independently C or N; W and Z are each independently N, CH, C-halo, C-(C1-C3 alkyl) or C-(C1-C3 alkoxy); X and Y are each independently N, CH, or CR 3 and provided that at least one of W, X, Y, or Z is CH; R 1 is selected from the group consisting of 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, and 3- to 10-membered cycloalkyl, all of which optionally contain one, two, or three R 8 is replaced by R 2is selected from the group consisting of 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, and 3- to 10-membered cycloalkyl, all of which optionally contain one, two, or three R 6 is replaced by R 3 are independently defined for each occurrence as halogen, OR 4 , N.R. 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- to 6-membered heteroaryl, and 5- to 7-membered heterocyclyl, wherein alkyl, alkenyl, or alkynyl are each optionally selected from the group consisting of R 4 and each aryl, heteroaryl, or heterocyclyl is optionally substituted once, twice, or three times with R 5 is substituted once, twice or three times with R 4 are independently expressed as 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 heterocyclyl), wherein aryl, heteroaryl, or heterocyclyl is each optionally selected from the group consisting of R 5 is substituted once, twice or three times with R 5 is independently selected from each occurrence of 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 -(5-6 membered heteroaryl) and (CH2) 0~3 -(5- to 7-membered heterocyclyl), wherein aryl, heteroaryl, or heterocyclyl is each optionally selected from the group consisting of R 7 is substituted once, twice or three times with R 6 is independently at each occurrence 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 selected from the group consisting of NH2 or CN; Or, two R's 6 may, together with the atom to which they are attached, form a 5- to 10-membered heteroaryl, a 6- to 10-membered aryl, a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered cycloalkyl; R 7 is independently at each occurrence 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 is selected from the group consisting of substituents independently selected from —OH, C(O)(C1-C6 alkyl) and C(O)O(C1-C6 alkyl); Or, two R's 7 may, together with the atom to which they are attached, form a 5- to 10-membered heteroaryl, a 6- to 10-membered aryl, a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered cycloalkyl; R 8is independently selected from each occurrence of 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).

[0019] In one aspect, provided herein is a method for treating cancer or a proliferative disease, comprising 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 that prevents EGFR dimerization. In another embodiment, the subject is a human.

[0020] The present disclosure also provides a kit comprising a compound capable of inhibiting EGFR activity selected from the compounds of the present disclosure or pharmaceutically acceptable salts thereof, and instructions for use in treating cancer. In one embodiment, the kit further comprises components for performing a test to determine whether a subject has an activating mutation or drug resistance mutation in EGFR. In another embodiment, the kit further comprises a second active agent that prevents EGFR dimerization. DETAILED DESCRIPTION OF THE INVENTION

[0021] definition Listed below are definitions of various terms used to describe the compounds and compositions disclosed herein. These definitions apply to the terms as they are used throughout the specification and claims, either individually or as part of a larger group, unless otherwise limited in specific instances.

[0022] 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 known and commonly employed in the art.

[0023] As used herein, the articles "a" and "an" refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element. Furthermore, the use of the term "including" and other forms such as "include," "includes," and "included" is not limiting.

[0024] As used herein, the term "about" will be understood by one of ordinary skill in the art and will vary to some extent depending on the context in which it is used. When used herein when referring to a measurable value, such as an amount, a temporal duration, etc., the term "about" is meant to encompass a variation of ±20% or ±10%, including ±5%, ±1%, and ±0.1%, from the stated value, as long as such variations are appropriate to perform the disclosed method.

[0025] As used herein, "administration" and like terms refer to providing a therapeutic agent to a subject. Multiple techniques exist in the art for administering therapeutic agents, including, but not limited to, intravenous administration, oral administration, aerosol administration, parenteral administration, ophthalmic administration, pulmonary administration, and topical administration.

[0026] The terms "treat," "treated," "treating," or "treatment" include the diminishment or alleviation of at least one symptom associated with or caused by the condition, disorder, or disease being treated. In certain embodiments, treatment involves contacting wild-type or mutant EGFR with an effective amount of a compound disclosed herein in a subject suffering from a condition related to cancer.

[0027] As used herein, the term "prevent" or "prevention" means the absence of onset of a disorder or disease where none has occurred, or the absence of further onset of a disorder or disease where onset of a disorder or disease is already present. It may also be considered the ability to prevent some or all of the symptoms associated with a disorder or disease.

[0028] 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 companion animals, such as ovine, bovine, porcine, canine, feline, and marine mammals. Preferably, the patient, subject, or individual is human.

[0029] As used herein, the terms "effective amount," "pharmaceutically effective amount," and "therapeutically effective amount" refer to a nontoxic but sufficient amount of an agent that produces a desired biological result. This result may be a reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

[0030] As used herein, the term "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, that does not abrogate the biological activity or properties of a compound and is relatively non-toxic, i.e., that can be administered to an individual without causing undesired biological effects or interacting in a deleterious way with any ingredients in the composition in which it is contained.

[0031] As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds, where the parent compound is modified by converting an existing acid or base 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 or organic salts of acidic residues such as carboxylic acids, etc. The pharmaceutically acceptable salts of the present disclosure include conventional non-toxic salts of the parent compound, e.g., salts formed from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound containing a basic or acid moiety by conventional chemical methods. Typically, such salts can be prepared by reacting the free acid or free base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or in a mixture of the two (generally non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred). The phrase "pharmaceutically acceptable salt" is not limited to mono- or 1:1 salts. For example, "pharmaceutically acceptable salts" also includes bis salts, such as bis hydrochlorides. Lists of suitable salts can be 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.

[0032] As used herein, the term "prodrug" refers to a precursor compound that undergoes metabolic activation in vivo to yield an active drug. Thus, for example, a prodrug of a compound provided herein, when administered to a subject, will undergo metabolic activation to produce the compound.

[0033] 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. A pharmaceutical composition facilitates administration of a compound to a patient or subject. Multiple techniques for administering a compound exist in the art, including, but not limited to, intravenous administration, oral administration, aerosol administration, parenteral administration, ophthalmic administration, pulmonary administration, and topical administration.

[0034] The term "pharmaceutical combination" as used herein refers to a product obtained by mixing or combining more than one active ingredient, and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that both active ingredients, e.g., a disclosed compound and a co-agent, are administered to a patient simultaneously in the form of a single entity or single dosage. The term "non-fixed combination" means that both active ingredients, e.g., a disclosed compound and a co-agent, are administered to a patient as separate entities simultaneously, in parallel, or sequentially without specific time limit, such that such administration provides therapeutically effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0035] As used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, that is involved in carrying or transporting a compound useful within the present disclosure into or to a patient so that it can perform its intended function. Typically, such compositions are carried or transported from one organ or part of the body to another. 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 serve 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; buffers such as magnesium hydroxide and aluminum hydroxide; surface-active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solution; and other non-toxic, compatible substances employed in pharmaceutical formulations.

[0036] As used herein, "pharmaceutically acceptable carrier" also includes any and all coatings, antibacterial and antifungal agents, absorption delaying agents, and the like, that are compatible with the activity of the compounds useful within the present disclosure and are physiologically acceptable to the patient. Supplementary active compounds can also be incorporated into the compositions. "Pharmaceutically acceptable carriers" can further include 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.

[0037] As used herein, the term "EGFR" refers to the epidermal growth factor receptor (alternatively known as ErbB-1 or HER1), and may refer to the wild-type receptor or a receptor containing one or more mutations.

[0038] As used herein, the term "HER" or "Her" refers to members of the ErbB receptor tyrosine kinase family, including EGFR, ERBB2, HER3, and HER4.

[0039] As used herein, the term "allosteric site" refers to a site on EGFR other than the ATP-binding site, as characterized in the crystal structure of EGFR. An "allosteric site" may be a site proximal to the ATP-binding site, as characterized in the crystal structure of EGFR. For example, one allosteric site includes one or more of the following epidermal growth factor receptor (EGFR) amino acid residues: Lys745, Leu788, Ala743, Cys755, Leu777, Phe856, Asp855, Met766, Ile759, Glu762, and / or Ala763.

[0040] As used herein, the term "agents that prevent EGFR dimerization" or iterations thereof refers to agents that prevent dimerization in which the C-lobe of the "activator" subunit collides with the N-lobe of the "receiver" subunit. Examples of agents that prevent EGFR dimerization include, but are not limited to, cetuximab, trastuzumab, panitumumab, and Mig6.

[0041] As used herein, the term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon having the specified number of carbon atoms (i.e., C1-C6 alkyl means alkyl having 1 to 6 carbon atoms), including straight and branched chains. 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.

[0042] As used herein, the term "haloalkyl" refers to an alkyl group, as defined above, substituted with one or more halo substituents, where alkyl and halo are defined herein. Haloalkyl includes, by way of example, chloromethyl, trifluoromethyl, bromoethyl, chlorofluoroethyl, and the like.

[0043] As used herein, the term "alkoxy" refers to an -O-alkyl group, where alkyl is as defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy, and the like.

[0044] As used herein, the term "alkylamine" refers to an -NH-alkyl group, where alkyl is as defined herein. Alkylamines include, by way of example, methylamine, ethylamine, isopropylamine, n-propylamine, n-butylamine, sec-butylamine, t-butylamine, and the like.

[0045] As used herein, the term "haloalkoxy" refers to an -O-haloalkyl group, where haloalkyl is as defined herein. Haloalkoxy includes, by way of example, chloromethoxy, trifluoromethoxy, bromoethoxy, chlorofluoroethoxy, and the like.

[0046] As used herein, the term "alkenyl" refers, in certain embodiments, to a monovalent group derived from a hydrocarbon moiety containing 2 to 6 or 2 to 8 carbon atoms and having at least one carbon-carbon double bond. An alkenyl group may or may not be the point of attachment to another group. The term "alkenyl" includes, but is not limited to, ethenyl, 1-propenyl, 1-butenyl, heptenyl, octenyl, and the like.

[0047] As used herein, the term "alkynyl" refers, in certain embodiments, to a monovalent group derived from a hydrocarbon moiety containing 2 to 6 or 2 to 8 carbon atoms and having at least one carbon-carbon triple bond. An alkynyl group may or may not be the 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.

[0048] As used herein, unless otherwise stated, the terms “halo” or “halogen,” by themselves or as part of another substituent, mean a fluorine, chlorine, bromine, or iodine atom, preferably fluorine, chlorine, or bromine, and more preferably fluorine or chlorine.

[0049] As used herein, the term "cycloalkyl" refers to a fully saturated, non-aromatic carbocyclic ring system having one, two, or three rings, wherein such rings may be fused. The term "fused" means that a second ring is present (i.e., connected to or formed by) having two adjacent atoms in common (i.e., shared) with the first ring. Cycloalkyl also includes bicyclic structures that may be bridged or spirocyclic in nature, where the individual rings within the bicyclic ring vary within the range of 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]heptanyl, and bicyclo[1.1.1]pentyl.

[0050] As used herein, the term "cycloalkenyl" means a partially saturated non-aromatic carbocyclic ring system having one, two, or three rings, wherein such rings may be fused, and wherein at least one ring is a sp 2 Contains a carbon-carbon bond. The term "cycloalkenyl" includes, but is not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, bicyclo[3.1.0]hexenyl, spiro[3.3]heptanenyl, and bicyclo[1.1.1]pentenyl.

[0051] As used herein, the terms "heterocyclyl" or "heterocycloalkyl" mean a non-aromatic carbocyclic ring 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 are optionally fused, where fusion is defined above. Heterocyclyl also includes bicyclic ring systems which may be bridged or spirocyclic in nature, where the individual rings within the bicycle vary from 3 to 8 atoms and contain 0, 1, or 2 N, O, or S atoms. The term "heterocyclyl" includes cyclic esters (i.e., lactones) and cyclic amides (i.e., lactams), specifically epoxidyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl (i.e., oxanyl), pyranyl, dioxanyl, aziridinyl, azetidinyl, pyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, oxazolidinyl, thiazolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, 1,3-oxazinanyl, 1,3-thiazinanyl, 2-azabicyclo-[2.1.1]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 6-azabicyclo[3.1.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 2-azabicyclo[ 3.1.1]heptanyl, 3-azabicyclo[3.1.0]-hexanyl, 2-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 3-oxa-7-azabicyclo[3.3.1]nonanyl, 3-oxa-9-azabicyclo[3.3.1]nonanyl, 2-oxa-5-azabicyclo-[2.2.

[0033] Heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2-oxaspiro[3.3]heptanyl, 2-oxaspiro[3.5]nonanyl, 3-oxaspiro[5.3]nonanyl, and 8-oxabicyclo[3.2.1]octanyl.

[0052] As used herein, the term "aromatic" refers to a carbocyclic or heterocyclic ring with one or more polyunsaturated rings and having aromatic character, i.e., having (4n+2) delocalized π (pi) electrons, where n is an integer.

[0053] As used herein, the term "aryl" refers to an aromatic carbocyclic ring system containing one, two, or three rings, wherein such rings may be fused, where fused is defined above. If 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-tetrahydronaphthalenyl. In some embodiments, an aryl group has 6 carbon atoms. In some embodiments, an aryl group has 6 to 10 carbon atoms. In some embodiments, an aryl group has 6 to 16 carbon atoms.

[0054] As used herein, the term "heteroaryl" refers to an aromatic carbocyclic ring 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, where fusion is defined above. The term "heteroaryl" also refers to furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, 5,6,7,8-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroquinolinyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, 6,7-dihydro-5H-cyclopenta[c]pyridinyl, Examples include, but are not limited to, 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]pyridinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, 4,5,6,7-tetrahydro-1H-indazolyl and 4,5,6,7-tetrahydro-2H-indazolyl.

[0055] It should be understood that when an aryl, heteroaryl, cycloalkyl, or heterocyclyl moiety may be attached to the designated moiety through different ring atoms or may otherwise be attached (i.e., shown or described without a specific point of attachment indicated), all possible points are intended, whether through a carbon atom or, for example, through a trivalent nitrogen atom. For example, the term "pyridinyl" refers to 2-, 3-, or 4-pyridinyl, the term "thienyl" refers to 2- or 3-thienyl, etc.

[0056] As used herein, the term "substituted" means that an atom or group of atoms replaces a hydrogen as a substituent bonded to another group.

[0057] As used herein, the term "optionally substituted" means that the referenced group may be substituted or unsubstituted. In one embodiment, the referenced group is optionally substituted with zero substituents, i.e., the referenced group is unsubstituted. In another embodiment, the referenced group is optionally substituted with one or more additional groups, each independently selected from the groups described herein.

[0058] compound Provided herein are compounds that are allosteric inhibitors of the epidermal growth factor receptor (EGFR), useful in the treatment of disorders including kinase-mediated cancer and other proliferative diseases.

[0059] In some embodiments, provided herein are compounds of formula I:

[0060] [ka]

[0061] or a pharmaceutically acceptable salt thereof (In the formula, 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 and provided that at least one of W, X, Y, or Z is CH; R 1 is selected from the group consisting of 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, and 3- to 10-membered cycloalkyl, all of which optionally contain one, two, or three R8 is replaced by R 2 is selected from the group consisting of 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, and 3- to 10-membered cycloalkyl, all of which optionally contain one, two, or three R 6 is replaced by R 3 are independently defined for each occurrence as halogen, OR 4 , N.R. 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- to 6-membered heteroaryl, and 5- to 7-membered heterocyclyl, wherein alkyl, alkenyl, or alkynyl are each optionally selected from the group consisting of R 4 and each aryl, heteroaryl, or heterocyclyl is optionally substituted once, twice, or three times with R 5 is substituted once, twice or three times with R 4 are independently expressed as 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 heterocyclyl), wherein aryl, heteroaryl, or heterocyclyl is each optionally selected from the group consisting of R 5 is substituted once, twice or three times with R 5is independently selected from each occurrence of 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 -(5-6 membered heteroaryl) and (CH2) 0~3 -(5- to 7-membered heterocyclyl), wherein aryl, heteroaryl, or heterocyclyl is each optionally selected from the group consisting of R 7 is substituted once, twice or three times with R 6 is independently at each occurrence 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 selected from the group consisting of NH2 or CN; Or, two R's 6 may, together with the atom to which they are attached, form a 5- to 10-membered heteroaryl, a 6- to 10-membered aryl, a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered cycloalkyl; R 7 is independently at each occurrence 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 is selected from the group consisting of substituents independently selected from —OH, C(O)(C1-C6 alkyl) and C(O)O(C1-C6 alkyl); Or, two R's 7may, together with the atom to which they are attached, form a 5- to 10-membered heteroaryl, a 6- to 10-membered aryl, a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered cycloalkyl; R 8 is independently selected from each occurrence of 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).

[0062] In another aspect, provided herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein: W and Z are each independently N, CH, C-halo, C-(C1-C3 haloalkyl), C-(C1-C3 alkyl) or C-(C1-C3 alkoxy); where all other variables are defined above).

[0063] In certain embodiments, the compound of Formula I has Formula Ia:

[0064] [ka]

[0065] or a pharmaceutically acceptable salt thereof.

[0066] In certain embodiments of Formula Ia, R 3 is C6~C 10 aryl or 5- to 6-membered heteroaryl, both of which are optionally R 5 In another embodiment of Formula Ia, R 3 In some cases, R 5 C6~C substituted once with 10 aryl, where R 5 5-7 membered heterocyclyl, C6-C 10aryl, 3- to 10-membered cycloalkyl, or 5- to 6-membered heteroaryl, all of which are optionally R 7 In yet another embodiment of Formula Ia, R 3 In some cases, R 5 phenyl substituted once with, where R 5 5-7 membered heterocyclyl, C6-C 10 aryl, 3- to 10-membered cycloalkyl, or 5- to 6-membered heteroaryl, all of which are optionally R 7 In yet another embodiment of Formula Ia, R 3 In some cases, R 5 C6~C substituted once with 10 aryl, where R 5 In some cases, R 7 In certain embodiments of Formula Ia, R 3 is phenyl optionally substituted once with piperidine, wherein the piperidine is substituted once with R7.

[0067] In another embodiment, the compound of formula I has formula Ib

[0068] [ka]

[0069] or a pharmaceutically acceptable salt thereof.

[0070] In yet another embodiment, Z is CH. In yet another embodiment, Z is N. In some embodiments, Z is CF. In another embodiment, R6 is, independently at each occurrence, hydroxy or halo.

[0071] In yet another embodiment, R1 is selected from the group consisting of benzimidazole, imidazopyrazine, purine, imidazole, pyrazole, triazole, and imidazopyridine.

[0072] [ka]

[0073] and optionally one, two or three R 8 is replaced by .

[0074] In another embodiment, R 6 is hydroxy, halo, or two R 6 together with the atom to which they are attached form a 5- to 10-membered heteroaryl, a 6- to 10-membered aryl, a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered cycloalkyl. 6 is hydroxy, fluoro, or two R 6 together with the atom to which they are attached form a 5- to 10-membered heteroaryl, a 6- to 10-membered aryl, a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered cycloalkyl. 6 is hydroxy. In yet another embodiment, R 6 is fluoro. In another embodiment, R 6 is chloro. In some embodiments, two R are hydroxy and fluoro. 6 In another embodiment, there are two R 6 In yet another embodiment, two R 6 together with the atom to which they are attached form a 5- to 10-membered heteroaryl, a 6- to 10-membered aryl, a 3- to 10-membered heterocycloalkyl or a 3- to 10-membered cycloalkyl.

[0075] In certain embodiments, the compound of formula I is selected from the group consisting of:

[0076] [Table 1A]

[0077] [Table 1B]

[0078] [Table 1C]

[0079] or a pharmaceutically acceptable salt thereof.

[0080] In another embodiment, the compound of formula I is selected from the group consisting of:

[0081] [Table 2A]

[0082] [Table 2B]

[0083] [Table 2C]

[0084] [Table 2D]

[0085] [Table 2E]

[0086] [Table 2F]

[0087] or a pharmaceutically acceptable salt thereof.

[0088] In embodiments, compounds 112-117 provided herein have an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at 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).

[0089] In certain embodiments of compounds 112-117, each position specifically designated as deuterium has at least 95% deuterium incorporation.

[0090] In another aspect, provided herein are compounds of formula II:

[0091] [ka]

[0092] or a pharmaceutically acceptable salt thereof (In the formula, 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 and provided that at least one of W, X, Y, or Z is CH; R 1 is selected from the group consisting of 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, and 3- to 10-membered cycloalkyl, all of which optionally contain one, two, or three R 8 is replaced by R 2is selected from the group consisting of 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, and 3- to 10-membered cycloalkyl, all of which optionally contain one, two, or three R 6 is replaced by R 3 are independently defined for each occurrence as halogen, OR 4 , N.R. 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- to 6-membered heteroaryl, and 5- to 7-membered heterocyclyl, wherein alkyl, alkenyl, or alkynyl are each optionally selected from the group consisting of R 4 and each aryl, heteroaryl, or heterocyclyl is optionally substituted once, twice, or three times with R 5 is substituted once, twice or three times with R 4 are independently expressed as 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 heterocyclyl), wherein aryl, heteroaryl, or heterocyclyl is each optionally selected from the group consisting of R 5 is substituted once, twice or three times with R 5 is independently selected from each occurrence of 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 -(5-6 membered heteroaryl) and (CH2) 0~3 -(5- to 7-membered heterocyclyl), wherein aryl, heteroaryl, or heterocyclyl is each optionally selected from the group consisting of R 7 is substituted once, twice or three times with R 6 is independently at each occurrence 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 selected from the group consisting of NH2 or CN; Or, two R's 6 may, together with the atom to which they are attached, form a 5- to 10-membered heteroaryl, a 6- to 10-membered aryl, a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered cycloalkyl; R 7 is independently at each occurrence 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 is selected from the group consisting of substituents independently selected from —OH, C(O)(C1-C6 alkyl) and C(O)O(C1-C6 alkyl); Or, two R's 7 may, together with the atom to which they are attached, form a 5- to 10-membered heteroaryl, a 6- to 10-membered aryl, a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered cycloalkyl; R 8is independently selected from each occurrence of 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 selected from the group consisting of NH2 or CN; n is 1 or 2).

[0093] In certain embodiments of Formula II, R 5 is independently selected from each occurrence of 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 -(5-6 membered heteroaryl), O(CH2) 0~3 -(4-7 membered heterocyclyl) and (CH2) 0~3 -(4- to 7-membered heterocyclyl), wherein alkyl, alkoxy, aryl, heteroaryl, or heterocyclyl is each optionally selected from the group consisting of R 7 is substituted once, twice or three times with wherein all other variables are defined above.

[0094] In certain embodiments, the compound of Formula II has Formula IIa:

[0095] [ka]

[0096] or a pharmaceutically acceptable salt thereof.

[0097] In yet another aspect, provided herein are compounds of formula X:

[0098] [ka]

[0099] or a pharmaceutically acceptable salt thereof (In the formula, 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 and provided that at least one of W, X, Y, or Z is CH; R 1 is selected from the group consisting of 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, and 3- to 10-membered cycloalkyl, all of which optionally contain one, two, or three R 8 is replaced by R 2 is selected from the group consisting of 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, and 3- to 10-membered cycloalkyl, all of which optionally contain one, two, or three R 6 is replaced by R 3 are independently defined for each occurrence as halogen, OR 4 , N.R. 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 10aryl, 5- to 6-membered heteroaryl, and 5- to 7-membered heterocyclyl, wherein alkyl, alkenyl, or alkynyl are each optionally selected from the group consisting of R 4 and each aryl, heteroaryl, or heterocyclyl is optionally substituted once, twice, or three times with R 5 is substituted once, twice or three times with R 4 are independently expressed as 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 heterocyclyl), wherein aryl, heteroaryl, or heterocyclyl is each optionally selected from the group consisting of R 5 is substituted once, twice or three times with R 5 is independently selected from each occurrence of 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 -(5-6 membered heteroaryl), O(CH2) 0~3 -(4-7 membered heterocyclyl) and (CH2) 0~3 -(4- to 7-membered heterocyclyl), wherein alkyl, alkoxy, aryl, heteroaryl, or heterocyclyl is each optionally selected from the group consisting of R 7 is substituted once, twice or three times with R 6is independently at each occurrence 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 selected from the group consisting of NH2 or CN; Or, two R's 6 may, together with the atom to which they are attached, form a 5- to 10-membered heteroaryl, a 6- to 10-membered aryl, a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered cycloalkyl; R 7 is independently at each occurrence 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 is selected from the group consisting of substituents independently selected from —OH, C(O)(C1-C6 alkyl) and C(O)O(C1-C6 alkyl); Or, two R's 7 may, together with the atom to which they are attached, form a 5- to 10-membered heteroaryl, a 6- to 10-membered aryl, a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered cycloalkyl; R 8 is independently selected from each occurrence of 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 selected from the group consisting of NH2 or CN; n is 1 or 2).

[0100] In certain embodiments of Formula IIa, R 3 is C6~C10 aryl or 5- to 6-membered heteroaryl, both of which are optionally R 5 In another embodiment of Formula IIa, R 3 In some cases, R 5 C6~C substituted once with 10 aryl, where R 5 5-7 membered heterocyclyl, C6-C 10 aryl, 3- to 10-membered cycloalkyl, or 5- to 6-membered heteroaryl, all of which are optionally R 7 In yet another embodiment of Formula IIa, R 3 In some cases, R 5 phenyl substituted once with, where R 5 5-7 membered heterocyclyl, C6-C 10 aryl, 3- to 10-membered cycloalkyl, or 5- to 6-membered heteroaryl, all of which are optionally R 7 In yet another embodiment of Formula IIa, R 3 In some cases, R 5 C6~C substituted once with 10 aryl, where R 5 In some cases, R 7 In certain embodiments of Formula IIa, R 3 is phenyl optionally substituted once with piperidine, wherein the piperidine is substituted once with R7.

[0101] In another embodiment, the compound of formula II has formula IIb

[0102] [ka]

[0103] or a pharmaceutically acceptable salt thereof.

[0104] In another embodiment, the compound of formula II has formula IIc

[0105] [ka]

[0106] or a pharmaceutically acceptable salt thereof.

[0107] In yet another embodiment, R 6 is independently at each occurrence hydroxy, halo, or two R 6 together with the atom to which they are attached form a 5- to 10-membered heteroaryl, a 6- to 10-membered aryl, a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered cycloalkyl. 6 is hydroxy, fluoro, or two R 6 together with the atom to which they are attached form a 5- to 10-membered heteroaryl, a 6- to 10-membered aryl, a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered cycloalkyl. 6 is hydroxy. In yet another embodiment, R 6 is fluoro. In another embodiment, R 6 is chloro. In some embodiments, two R are hydroxy and fluoro. 6 In another embodiment, there are two R 6 In yet another embodiment, two R 6 together with the atom to which they are attached form a 5- to 10-membered heteroaryl, a 6- to 10-membered aryl, a 3- to 10-membered heterocycloalkyl or a 3- to 10-membered cycloalkyl.

[0108] In certain embodiments of Formula II, IIa, and IIb, R 1 is selected from the group consisting of benzimidazole, imidazopyrazine, purine, imidazole, pyrazole, triazole, and imidazopyridine.

[0109] [ka]

[0110] and optionally one, two or three R 8 is replaced by .

[0111] In another embodiment, R 3 is phenyl or C2-C3 alkynyl, where phenyl is optionally R 5 and the alkynyl is optionally substituted once or twice with R 4 In yet another embodiment, R 3 In some cases, R 5 In yet another embodiment, R 3 In some cases, R 4 In one embodiment, R is a C2-C3 alkynyl substituted once or twice with 3 is one or two R 5 is phenyl substituted with R 5 is selected from the group consisting of piperidine, pyridine, and thiomorpholine dioxide, all of which optionally have one or two R 7 is replaced by .

[0112] In another embodiment, the compound of formula II is as shown in Table 3:

[0113] [Table 3A]

[0114] [Table 3B]

[0115] [Table 3C]

[0116] [Table 3D]

[0117] [Table 3E]

[0118] [Table 3F]

[0119] [Table 3G]

[0120] [Table 3H]

[0121] [Table 3I]

[0122] or a pharmaceutically acceptable salt thereof.

[0123] In yet another embodiment, the compound of formula II is as shown in Table 4:

[0124] [Table 4]

[0125] or a pharmaceutically acceptable salt thereof.

[0126] In embodiments, compounds 036-039 provided herein have, for each designated deuterium atom, an isotopic enrichment factor of at least 3500 (52.5% deuterium incorporation at 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).

[0127] In certain embodiments of compounds 036-039, each position specifically designated as deuterium has at least 95% deuterium incorporation.

[0128] In another embodiment, the compound of formula X is as shown in Table 5:

[0129] [Table 5A]

[0130] [Table 5B]

[0131] [Table 5C]

[0132] [Table 5D]

[0133] [Table 5E]

[0134] or a pharmaceutically acceptable salt thereof.

[0135] In yet another aspect, provided herein are compounds of formula III:

[0136] [ka]

[0137] or a pharmaceutically acceptable salt thereof (In the formula,

[0138] [ka]

[0139] is an optional double bond, B and D are each independently C or N; W and Z are each independently N, CH, C-halo, C-(C1-C3 alkyl) or C-(C1-C3 alkoxy); X and Y are each independently N, CH, or CR 3 and provided that at least one of W, X, Y, or Z is CH; R 1 is selected from the group consisting of 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, and 3- to 10-membered cycloalkyl, all of which optionally contain one, two, or three R 8 is replaced by R 2 is selected from the group consisting of 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, and 3- to 10-membered cycloalkyl, all of which optionally contain one, two, or three R 6 is replaced by R 3 are independently defined for each occurrence as halogen, OR 4 , N.R. 4 R 4 , SO2R 4 , SO2NHR4 , 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- to 6-membered heteroaryl, and 5- to 7-membered heterocyclyl, wherein alkyl, alkenyl, or alkynyl are each optionally selected from the group consisting of R 4 and each aryl, heteroaryl, or heterocyclyl is optionally substituted once, twice, or three times with R 5 is substituted once, twice or three times with R 4 are independently expressed as 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 heterocyclyl), wherein aryl, heteroaryl, or heterocyclyl is each optionally selected from the group consisting of R 5 is substituted once, twice or three times with R 5 is independently selected from each occurrence of 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 -(5-6 membered heteroaryl) and (CH2) 0~3 -(5- to 7-membered heterocyclyl), wherein aryl, heteroaryl, or heterocyclyl is each optionally selected from the group consisting of R 7is substituted once, twice or three times with R 6 is independently at each occurrence 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 selected from the group consisting of NH2 or CN; Or, two R's 6 may, together with the atom to which they are attached, form a 5- to 10-membered heteroaryl, a 6- to 10-membered aryl, a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered cycloalkyl; R 7 is independently at each occurrence 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 is selected from the group consisting of substituents independently selected from —OH, C(O)(C1-C6 alkyl) and C(O)O(C1-C6 alkyl); Or, two R's 7 may, together with the atom to which they are attached, form a 5- to 10-membered heteroaryl, a 6- to 10-membered aryl, a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered cycloalkyl; R 8 is independently selected from each occurrence of 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).

[0140] In another aspect, provided herein is a compound of Formula III or a pharmaceutically acceptable salt thereof, wherein: R 4 is independently at each occurrence 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 -(5-6 membered heteroaryl) and (CH2) 0~3 -(5- to 7-membered heterocyclyl), wherein aryl, heteroaryl, or heterocyclyl is each optionally selected from the group consisting of R 5 is substituted once, twice or three times with where all other variables are defined above).

[0141] In certain embodiments, the compound of Formula III has Formula IIIa:

[0142] [ka]

[0143] or a pharmaceutically acceptable salt thereof.

[0144] In some embodiments of Formula IIIa, R 3 is C6~C 10 aryl or 5- to 6-membered heteroaryl, both of which are optionally R 5 In another embodiment of Formula IIIa, R 3 In some cases, R 5 C6~C substituted once with 10 aryl, where R 5 5-7 membered heterocyclyl, C6-C 10 aryl, 3- to 10-membered cycloalkyl, or 5- to 6-membered heteroaryl, all of which are optionally R 7 In yet another embodiment of Formula IIIa, R 3 In some cases, R 5phenyl substituted once with, where R 5 5-7 membered heterocyclyl, C6-C 10 aryl, 3- to 10-membered cycloalkyl, or 5- to 6-membered heteroaryl, all of which are optionally R 7 In yet another embodiment of Formula IIIa, R 3 In some cases, R 5 C6~C substituted once with 10 aryl, where R 5 In some cases, R 7 In certain embodiments of Formula IIIa, R 3 is phenyl optionally substituted once with piperidine, wherein the piperidine is substituted once with R7.

[0145] In another embodiment, the compound of formula III has formula IIIb:

[0146] [ka]

[0147] or a pharmaceutically acceptable salt thereof.

[0148] In yet another embodiment, the compound of formula III has formula IIIc:

[0149] [ka]

[0150] or a pharmaceutically acceptable salt thereof.

[0151] In yet another embodiment, R 1 is selected from the group consisting of benzimidazole, imidazopyrazine, purine, imidazole, pyrazole, triazole, and imidazopyridine. 1 teeth,

[0152] [ka]

[0153] and optionally one, two or three R 8 is replaced by .

[0154] In another embodiment, Y is CR 3 and R 3 is one or two R 5 In yet another embodiment, Z is CF. In yet another embodiment, Z is CH. In some embodiments, Z is N.

[0155] In another embodiment, R 6 is hydroxy, halo, or two R 6 together with the atom to which they are attached form a 5- to 10-membered heteroaryl, a 6- to 10-membered aryl, a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered cycloalkyl. 6 is hydroxy, fluoro, or two R 6 together with the atom to which they are attached form a 5- to 10-membered heteroaryl, a 6- to 10-membered aryl, a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered cycloalkyl. 6 is hydroxy. In yet another embodiment, R 6 is fluoro. In another embodiment, R 6 is chloro. In some embodiments, two R are hydroxy and fluoro. 6 In another embodiment, there are two R 6 In yet another embodiment, two R 6 together with the atom to which they are attached form a 5- to 10-membered heteroaryl, a 6- to 10-membered aryl, a 3- to 10-membered heterocycloalkyl or a 3- to 10-membered cycloalkyl.

[0156] In another embodiment, the compound of formula III is as shown in Table 6:

[0157] [Table 6A]

[0158] [Table 6B]

[0159] [Table 6C]

[0160] or a pharmaceutically acceptable salt thereof.

[0161] In some embodiments of Formulas I, II, and III, R 7 is C1-C3 alkyl.

[0162] Compounds disclosed herein can exist as tautomers and optical isomers (eg, enantiomers, diastereomers, diastereomeric mixtures, racemic mixtures, etc.).

[0163] Within the scope of this disclosure, it is generally known in the art that any compound that will be converted in vivo to provide a compound disclosed herein is a prodrug.

[0164] The compounds provided herein may also include all isotopes of atoms present in intermediates or final compounds. Isotopes include atoms with the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more constituent atoms of the compounds of the present invention may be replaced, i.e., substituted, with an isotope of the atom in its natural or unnatural abundance. In some embodiments, the compounds contain at least one deuterium atom. For example, one or more hydrogen atoms in the compounds of the present disclosure may be replaced, i.e., substituted, with deuterium. In some embodiments, the compounds contain two or more deuterium atoms. In some embodiments, the compounds contain 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, NY, 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, pp. 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 studies and / or assays.

[0165] In the compounds provided herein, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen," it is understood that the position has hydrogen at its natural abundance isotopic composition. Furthermore, unless otherwise stated, when a position is specifically designated as "D" or "deuterium," it is understood that the position has deuterium at an abundance of at least 0.015% (i.e., at least 45% deuterium incorporation), which is 3000 times greater than the natural abundance of deuterium.

[0166] In certain aspects, provided herein is a pharmaceutical composition comprising any one of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0167] In one embodiment, the composition further comprises a second active agent. In another embodiment, the second active agent is selected from the group consisting of a MEK inhibitor, a PI3K inhibitor, and an mTor inhibitor. In yet another embodiment, the second active agent prevents EGFR dimerization in a subject. In yet another embodiment, the second active agent is selected from the group consisting of 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.

[0168] In another aspect, provided herein is 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 that prevents EGFR dimerization and a pharmaceutically acceptable carrier. In some embodiments, the second active agent that prevents EGFR dimerization is an antibody. In a further embodiment, the second active agent that prevents EGFR dimerization is cetuximab, trastuzumab, or panitumumab. In a further embodiment, the second active agent that prevents EGFR dimerization is cetuximab.

[0169] Compounds that bind to an allosteric site in EGFR, such as compounds of the present disclosure (e.g., compounds of the formulae disclosed herein), optionally combined with a second active agent that prevents EGFR dimerization, can modulate EGFR activity. In some embodiments, compounds of the present disclosure can inhibit or reduce EGFR activity without the use of a second active agent (e.g., an antibody such as cetuximab, trastuzumab, or panitumumab). In other embodiments, compounds of the present disclosure are combined with a second active agent. In certain embodiments, the second active agent can prevent EGFR dimerization and / or inhibit or reduce EGFR activity. In some embodiments, the second active agent that prevents EGFR dimerization is an antibody. In further embodiments, the second active agent that prevents EGFR dimerization is cetuximab, trastuzumab, or panitumumab. In a further embodiment, the second active agent that prevents EGFR dimerization is cetuximab. In certain embodiments, 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.

[0170] Treatment method In one aspect, provided herein is a method for treating cancer in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound disclosed herein. In one embodiment, the cancer is selected from the group consisting of lung cancer, colon cancer, breast cancer, endometrial cancer, thyroid cancer, glioma, squamous cell carcinoma, and prostate cancer. In another embodiment, the cancer is non-small cell lung cancer (NSCLC).

[0171] In another aspect, provided herein is a method for inhibiting a kinase in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound provided herein. In one embodiment, the kinase is EGFR.

[0172] In yet another aspect, provided herein is a method for treating or preventing a kinase-mediated disorder in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of the present disclosure. In certain embodiments, the kinase-mediated disorder is resistant to an EGFR-targeted therapy. In another embodiment, the EGFR-targeting therapy is selected from the group consisting of gefitinib, erlotinib, osimertinib, CO-1686, and WZ4002.

[0173] In some embodiments, compounds of the present disclosure can modulate (e.g., inhibit or reduce) the activity of EGFR containing one or more mutations. In some embodiments, the mutant EGFR contains one or more mutations selected from T790M, L718Q, L844V, V948R, L858R, I941R, C797S, and Del. In other embodiments, the mutant EGFR contains a combination of mutations, wherein the combination of mutations 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 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 selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M.

[0174] In some embodiments, a compound of the present disclosure in combination with a second active agent that prevents EGFR dimerization can modulate (e.g., inhibit or reduce) 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 of mutations 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 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 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 dimerization is an antibody. In a further embodiment, the second active agent that prevents EGFR dimerization is cetuximab, trastuzumab, or panitumumab. In a further embodiment, the second active agent that prevents EGFR dimerization 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.

[0175] In some embodiments, compounds of the present disclosure can modulate (e.g., inhibit or reduce) the activity of EGFR containing one or more mutations, but do not affect the activity of wild-type EGFR.

[0176] In other embodiments, a compound of the present disclosure in combination with a second active agent that prevents EGFR dimerization can modulate (e.g., inhibit or reduce) the activity of EGFR containing one or more mutations, but does not affect the activity of wild-type EGFR. In some embodiments, the second active agent that prevents EGFR dimerization is an antibody. In further embodiments, the second active agent that prevents EGFR dimerization is cetuximab, trastuzumab, or panitumumab. In a further embodiment, the second active agent that prevents EGFR dimerization is cetuximab. In certain embodiments, 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.

[0177] Modulation of EGFR containing one or more mutations such as those described herein, rather than modulation of wild-type EGFR, provides an approach to the treatment, prevention, or amelioration of diseases including, but not limited to, cancer and metastasis, inflammation, arthritis, systemic lupus erythematosus, skin-related disorders, pulmonary disorders, cardiovascular disease, ischemia, neurodegenerative disorders, liver disease, gastrointestinal disorders, viral and bacterial infections, central nervous system disorders, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, and peripheral neuropathy.

[0178] In some embodiments, compounds of the present disclosure exhibit greater inhibition of EGFR containing one or more mutations described herein compared to wild-type EGFR. In certain embodiments, compounds of the present disclosure exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold greater inhibition of EGFR containing one or more mutations described herein compared to wild-type EGFR. In various embodiments, compounds of the present disclosure exhibit up to 1000-fold greater inhibition of EGFR containing one or more mutations described herein compared to wild-type EGFR. In various embodiments, compounds of the present disclosure exhibit up to 10,000-fold greater inhibition of EGFRs with the mutation combinations described herein (e.g., L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M) compared to wild-type EGFR.

[0179] In other embodiments, compounds of the present disclosure in combination with a second active agent that prevents EGFR dimerization exhibit greater inhibition of EGFR containing one or more mutations described herein compared to wild-type EGFR. In certain embodiments, compounds of the present disclosure in combination with a second active agent that prevents EGFR dimerization exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold greater inhibition of EGFR containing one or more mutations described herein compared to wild-type EGFR. In various embodiments, compounds of the present disclosure in combination with a second active agent that prevents EGFR dimerization exhibit up to 1000-fold greater inhibition of EGFR containing one or more mutations described herein compared to wild-type EGFR. In various embodiments, compounds of the present disclosure in combination with a second active agent that prevents EGFR dimerization exhibit up to 10,000-fold greater inhibition of EGFR with the mutation combinations described herein (e.g., L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M) compared to wild-type EGFR. In some embodiments, the second active agent that prevents EGFR dimerization is an antibody. In further embodiments, the second active agent that prevents EGFR dimerization is cetuximab, trastuzumab, or panitumumab. In a further embodiment, the second active agent that prevents EGFR dimerization is cetuximab. In certain embodiments, 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.

[0180] In some embodiments, compounds of the present disclosure exhibit about 2-fold to about 10-fold greater inhibition of EGFR containing one or more mutations described herein compared to wild-type EGFR. In various embodiments, compounds of the present disclosure exhibit about 10-fold to about 100-fold greater inhibition of EGFR containing one or more mutations described herein compared to wild-type EGFR. In various embodiments, compounds of the present disclosure exhibit about 100-fold to about 1000-fold greater inhibition of EGFR containing one or more mutations described herein compared to wild-type EGFR. In various embodiments, compounds of the present disclosure exhibit about 1000-fold to about 10,000-fold greater inhibition of EGFR containing one or more mutations described herein compared to wild-type EGFR.

[0181] In other embodiments, compounds of the present disclosure in combination with a second active agent that prevents EGFR dimerization exhibit about 2-fold to about 10-fold greater inhibition of EGFR containing one or more mutations described herein compared to wild-type EGFR. In other embodiments, compounds of the present disclosure in combination with a second active agent that prevents EGFR dimerization exhibit about 10-fold to about 100-fold greater inhibition of EGFR containing one or more mutations described herein compared to wild-type EGFR. In other embodiments, compounds of the present disclosure in combination with a second active agent that prevents EGFR dimerization exhibit about 100-fold to about 1000-fold greater inhibition of EGFR containing one or more mutations described herein compared to wild-type EGFR. In other embodiments, compounds of the present disclosure in combination with a second active agent that prevents EGFR dimerization exhibit about 1000-fold to about 10,000-fold greater inhibition of EGFR containing one or more mutations described herein compared to wild-type EGFR. In other embodiments, the second active agent that prevents EGFR dimerization is an antibody. In further embodiments, the second active agent that prevents EGFR dimerization is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that prevents EGFR dimerization is cetuximab. In certain embodiments, 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.

[0182] In certain embodiments, compounds of the present disclosure exhibit at least a two-fold greater inhibition of EGFRs having a combination of mutations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M compared to wild-type EGFR. In certain embodiments, compounds of the present disclosure exhibit at least a three-fold greater inhibition of EGFRs having a combination of mutations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M compared to wild-type EGFR. In certain embodiments, compounds of the present disclosure exhibit at least 5-fold greater inhibition of EGFRs having a combination of mutations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M compared to wild-type EGFR. In certain embodiments, compounds of the present disclosure exhibit at least 10-fold greater inhibition of EGFRs having a combination of mutations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M compared to wild-type EGFR. In certain embodiments, compounds of the present disclosure exhibit at least 25-fold greater inhibition of EGFRs having a combination of mutations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M compared to wild-type EGFR. In certain embodiments, compounds of the present disclosure exhibit at least 50-fold greater inhibition of EGFRs having a combination of mutations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M compared to wild-type EGFR.In certain embodiments, compounds of the present disclosure exhibit at least 100-fold greater inhibition of EGFRs with mutation combinations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M compared to wild-type EGFR.

[0183] In certain embodiments, compounds of the present disclosure in combination with a second active agent that prevents EGFR dimerization exhibit at least a 2-fold greater inhibition of EGFR with a combination of mutations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M compared to wild-type EGFR. In certain embodiments, compounds of the present disclosure in combination with a second active agent that prevents EGFR dimerization exhibit at least a three-fold greater inhibition of EGFR with a combination of mutations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M compared to wild-type EGFR. In certain embodiments, compounds of the present disclosure in combination with a second active agent that prevents EGFR dimerization exhibit at least 5-fold greater inhibition of EGFR with a combination of mutations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M compared to wild-type EGFR. In certain embodiments, compounds of the present disclosure in combination with a second active agent that prevents EGFR dimerization exhibit at least 10-fold greater inhibition of EGFR with a combination of mutations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M compared to wild-type EGFR. In certain embodiments, compounds of the present disclosure in combination with a second active agent that prevents EGFR dimerization exhibit at least 25-fold greater inhibition of EGFR with a combination of mutations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M compared to wild-type EGFR.In certain embodiments, compounds of the present disclosure in combination with a second active agent that prevents EGFR dimerization exhibit at least 50-fold greater inhibition of EGFR with a combination of mutations selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M compared to wild-type EGFR. In certain embodiments, a compound of the present disclosure in combination with a second active agent that prevents EGFR dimerization exhibits 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 compared to wild-type EGFR. In some embodiments, the second active agent that prevents EGFR dimerization is an antibody. In further embodiments, the second active agent that prevents EGFR dimerization is cetuximab, trastuzumab, or panitumumab. In a further embodiment, the second active agent that prevents EGFR dimerization is cetuximab. In certain embodiments, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0184] In some embodiments, the inhibition of activity of EGFR is 50 It is measured by

[0185] In some embodiments, the inhibition of EGFR activity is 50 It is measured by

[0186] In some embodiments, inhibition of EGFR by the disclosed compounds can be measured by biochemical assays. By way of illustrative and non-limiting example, a homogenous time-resolved fluorescence (HTRF) assay can be used to determine inhibition of EGFR activity using the conditions and experimental parameters disclosed herein. HTRF assays 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. Disclosed compounds screened under these conditions exhibit IC values ​​of, for example, about 1 nM to >1 μM, about 1 nM to about 400 nM, about 1 nM to about 150 nM, about 1 nM to about 75 nM, about 1 nM to about 40 nM, about 1 nM to about 25 nM, about 1 nM to about 15 nM, or about 1 nM to about 10 nM. 50 In certain embodiments, compounds of the disclosure screened under the above conditions for inhibition of EGFR having a mutation or combination of mutations selected from L858R / T790M, L858R and T790M exhibit an IC value of, for example, about 1 nM to >1 μM, about 1 nM to about 400 nM, about 1 nM to about 150 nM, about 1 nM to about 75 nM, about 1 nM to about 40 nM, about 1 nM to about 25 nM, about 1 nM to about 15 nM, or about 1 nM to about 10 nM. 50 Indicates the value.

[0187] In some embodiments, compounds of the present disclosure bind to an allosteric site within EGFR. In some embodiments, compounds of the present disclosure interact with at least one amino acid residue of epidermal growth factor receptor (EGFR) selected from Lys745, Leu788, and Ala743. In other embodiments, 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, 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, compounds of the present disclosure interact with at least one amino acid residue of epidermal growth factor receptor (EGFR) selected from Lys745, Leu788, and Ala743; 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, 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.

[0188] In some embodiments, the present disclosure provides compounds, including allosteric kinase inhibitors, that are more potent inhibitors of drug-resistant EGFR mutants than wild-type EGFR. For example, 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 drug-resistant EGFR mutants than wild-type EGFR. In some embodiments, the drug-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.

[0189] In some embodiments, drug-resistant EGFR mutations include sensitizing mutations such as Del and L858R.

[0190] In some embodiments, the present disclosure provides compounds comprising an allosteric kinase inhibitor in combination with a second active agent that prevents EGFR dimerization, the compounds being more potent inhibitors of drug-resistant EGFR mutants than wild-type EGFR. For example, the compounds in combination with a second active agent that prevents EGFR dimerization 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 drug-resistant EGFR mutants than wild-type EGFR. In some embodiments, the drug-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. In some embodiments, the drug-resistant EGFR mutants include sensitizing mutations such as Del and L858R. In some embodiments, the second active agent that prevents EGFR dimerization is an antibody. In a further embodiment, the second active agent that prevents EGFR dimerization is cetuximab, trastuzumab, or panitumumab. In a further embodiment, the second active agent that prevents EGFR dimerization 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.

[0191] In some embodiments, the present disclosure provides compounds, including allosteric kinase inhibitors, that inhibit the kinase activity of drug-resistant EGFR mutants that carry sensitizing mutations (e.g., Del and L858R) and drug-resistance mutations (e.g., T790M, L718Q, C797S, and L844V) by potency (e.g., IC 50In 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.

[0192] In other embodiments, the disclosure provides compounds comprising an allosteric kinase inhibitor in combination with a second active agent that prevents EGFR dimerization, and that inhibit the kinase activity of drug-resistant EGFR mutants that carry sensitizing mutations (e.g., Del and L858R) and drug-resistance mutations (e.g., T790M, L718Q, C797S, and L844V) by increasing potency (e.g., IC 50 In some embodiments, the difference in potency is less than about 9-fold, 8-fold, 7-fold, 6-fold, 5-fold, 4-fold, 3-fold, or 2-fold. In some embodiments, the second active agent that prevents EGFR dimerization is an antibody. In further embodiments, the second active agent that prevents EGFR dimerization is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that prevents EGFR dimerization is cetuximab. In certain embodiments, 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.

[0193] In some embodiments, the disclosure provides compounds, including allosteric kinase inhibitors, that are more potent in inhibiting the activity of EGFRs containing one or more mutations described herein, e.g., T790M, L718Q, L844V, L858R, C797S, and Del, than one or more known EGFR inhibitors, including, but not limited to, gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib. For example, the compounds are at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or about 100-fold more potent (e.g., IC ) than gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib in inhibiting the activity of EGFRs containing one or more mutations described herein. 50 (measured by

[0194] In other embodiments, the present disclosure provides compounds comprising an allosteric kinase inhibitor in combination with a second active agent that prevents EGFR dimerization, wherein the compound in combination with the second active agent is more potent in inhibiting the activity of EGFR containing one or more of the mutations described herein, e.g., T790M, L718Q, L844V, L858R, C797S, and Del, than one or more known EGFR inhibitors, including but not limited to, gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib. For example, the compounds in combination with a second active agent that prevents EGFR dimerization are at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or about 100-fold more potent (e.g., IC ) than gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib in inhibiting the activity of EGFR containing one or more mutations described herein. 50(measured by). In some embodiments, the second active agent that prevents EGFR dimerization is an antibody. In further embodiments, the second active agent that prevents EGFR dimerization is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that prevents EGFR dimerization is cetuximab. In certain embodiments, 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.

[0195] In some embodiments, the present disclosure provides compounds, including allosteric kinase inhibitors, that are less potent at inhibiting the activity of wild-type EGFR than one or more known EGFR inhibitors, including, but not limited to, gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib. For example, the compounds are at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or about 100-fold less potent (e.g., IC ) at inhibiting the activity of wild-type EGFR than gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib. 50 (measured by

[0196] In other embodiments, the present disclosure provides compounds comprising an allosteric kinase inhibitor in combination with a second active agent that prevents EGFR dimerization, wherein the compound in combination with the second active agent is less potent at inhibiting wild-type EGFR activity than one or more known EGFR inhibitors, including, but not limited to, gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib. For example, the compound in combination with the second active agent that prevents EGFR dimerization is at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or about 100-fold less potent (e.g., IC 50 In some embodiments, the second active agent that prevents EGFR dimerization is an antibody. In further embodiments, the second active agent that prevents EGFR dimerization is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that prevents EGFR dimerization is cetuximab. In certain embodiments, 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.

[0197] The potency of the inhibitors was determined by the EC 50 The EC value can be determined under substantially similar conditions. 50 Compounds with low EC 50 In some embodiments, substantially similar conditions include determining the level of EGFR-dependent phosphorylation in vitro or in vivo (e.g., in 3T3 cells expressing wild-type EGFR, mutant EGFR, or any fragment thereof).

[0198] The potency of the inhibitor is expressed as IC 50It can also be determined by IC values ​​determined under substantially similar conditions. 50 Compounds with low IC 50 In some embodiments, substantially similar conditions include determining the level of EGFR-dependent phosphorylation in vitro or in vivo (e.g., in 3T3 cells expressing wild-type EGFR, mutant EGFR, or any fragment thereof).

[0199] EGFR sensitizing mutations include, but are not limited to, L858R, G719S, G719C, G719A, L861Q, a deletion in exon 19 and / or an insertion in exon 20. Drug-resistant EGFR mutants may have drug-resistance mutations including, but are not limited to, T790M, T854A, L718Q, C797S, or D761Y.

[0200] Selectivity between wild-type EGFR and EGFR containing one or more mutations described herein can also be measured using a cell proliferation assay in which cell proliferation depends on kinase activity. For example, murine Ba / F3 cells transfected with a suitable version of wild-type EGFR (e.g., 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. Proliferation assays were performed at various inhibitor concentrations (10 μM, 3 μM, 1.1 μM, 330 nM, 110 nM, 33 nM, 11 nM, 3 nM, 1 nM) and EC 50 is calculated.

[0201] An alternative method for 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 inhibitors to inhibit EGFR phosphorylation (using the concentrations described above) can be assayed. Cells are exposed to increasing concentrations of inhibitor for 6 hours and stimulated with EGF for 10 minutes. The effect on EGFR phosphorylation is assayed by Western blot using a phosphorylation site (Y1068)-specific EGFR antibody.

[0202] In another aspect, the present disclosure relates to compounds that bind to an allosteric site within EGFR and exhibit greater than 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, 100-fold, or 1000-fold inhibition of EGFR containing one or more mutations described herein (e.g., L858R / T790M, Del / T790M, Del / T790M / L718Q, L858R / T790M / C797S, Del / T790M / C797S, L858R / T790M / I941R, or L858R / T790M / L718Q) compared to wild-type EGFR.

[0203] In other embodiments, the disclosure provides compounds that bind to an allosteric site within EGFR in combination with a second active agent that prevents EGFR dimerization, wherein the second active agent exhibits greater than 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, 100-fold, or 1000-fold inhibition of EGFR containing one or more mutations described herein (e.g., L858R / T790M, Del / T790M, Del / T790M / L718Q, Del / T790M / C797S, L858R / T790M / C797S, L858R / T790M / I941R, or L858R / T790M / L718Q) compared to wild-type EGFR. In some embodiments, the second active agent that prevents EGFR dimerization is an antibody. In a further embodiment, the second active agent that prevents EGFR dimerization is cetuximab, trastuzumab, or panitumumab. In a further embodiment, the second active agent that prevents EGFR dimerization 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.

[0204] In yet another aspect, the disclosure provides a method for inhibiting epidermal growth factor receptor (EGFR), 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 that prevents EGFR dimerization. In some embodiments, the second active agent that prevents EGFR dimerization is an antibody. In further embodiments, the second active agent that prevents EGFR dimerization is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that prevents EGFR dimerization is cetuximab. In certain embodiments, 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.

[0205] In another aspect, provided herein are methods for 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 kinase-mediated. In further embodiments, the kinase comprises a mutated cysteine ​​residue. In further embodiments, the mutated cysteine ​​residue is located at or near a position corresponding to Cys797 in EGFR, including such positions in Jak3, Blk, Bmx, Btk, HER2 (ErbB2), HER4 (ErbB4), Itk, Tec, and Txk. In some embodiments, the method further comprises administering a second active agent that prevents kinase dimerization. In some embodiments, the second active agent that prevents kinase dimerization is an antibody. In further embodiments, the second active agent prevents EGFR dimerization. In further embodiments, the second active agent that prevents EGFR dimerization is cetuximab, trastuzumab, or panitumumab. In a further embodiment, the second active agent that prevents EGFR dimerization 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.

[0206] In some embodiments, the disease is EGFR-mediated (e.g., EGFR contributes to the initiation or development of the disease). In some embodiments, the disease is Her-kinase-mediated. In further embodiments, the Her-kinase is HER1, HER2, or HER4.

[0207] 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 harboring an activating mutation and / or a drug-resistant mutation. Activating mutations include, but are not limited to, L858R, G719S, G719C, G719A, L718Q, L861Q, a deletion in exon 19, and / or an insertion in exon 20. Drug-resistant EGFR mutants can have drug-resistant mutations, including, but not limited to, T790M, T854A, L718Q, C797S, or D761Y. Diagnostic tests may include sequencing, pyrosequencing, PCR, RT-PCR, or similar analytical techniques known to those skilled in the art that are capable of detecting nucleotide sequences.

[0208] In certain embodiments, the disease is cancer or a proliferative disease.

[0209] 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 carcinoma, head and neck squamous cell carcinoma, leukemia, lymphoma, myeloma, or a solid tumor. In further embodiments, the disease is lung cancer, breast cancer, glioma, squamous cell carcinoma, or prostate cancer. In yet still further embodiments, the disease is non-small cell lung cancer.

[0210] 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 harboring an activating mutation and / or a drug-resistant mutation. Activating mutations include, but are not limited to, L858R, G719S, G719C, G719A, L718Q, L861Q, a deletion in exon 19, and / or an insertion in exon 20. Drug-resistant EGFR mutants can have drug-resistant mutations, including, but not limited to, T790M, T854A, L718Q, C797S, or D761Y. Diagnostic tests may include sequencing, pyrosequencing, PCR, RT-PCR, or similar analytical techniques known to those skilled in the art that are capable of detecting nucleotide sequences.

[0211] In yet another aspect, provided herein are methods for treating a kinase-mediated disorder, comprising administering to a subject in need thereof an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is an inhibitor of HER1, HER2, or HER4. In other embodiments, an additional therapeutic agent is administered to the subject. In other embodiments, the compound and the additional therapeutic agent are administered simultaneously or sequentially.

[0212] In another aspect, the disclosure provides a method for treating a kinase-mediated disorder, 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 that prevents EGFR dimerization. In some embodiments, the compound is a HER1, HER2, or HER4 inhibitor. In other embodiments, an additional therapeutic agent is administered to the subject. In other embodiments, the compound, the second active agent that prevents EGFR dimerization, and the additional therapeutic agent are administered simultaneously or sequentially. In some embodiments, the second active agent that prevents EGFR dimerization is an antibody. In a further embodiment, the second active agent that prevents EGFR dimerization is cetuximab, trastuzumab, or panitumumab. In a further embodiment, the second active agent that prevents EGFR dimerization is cetuximab. In certain embodiments, 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.

[0213] 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 carcinoma, head and neck squamous cell carcinoma, leukemia, lymphoma, myeloma, or a solid tumor. In further embodiments, the disease is lung cancer, breast cancer, glioma, squamous cell carcinoma, or prostate cancer. In yet still further embodiments, the disease is non-small cell lung cancer.

[0214] In another aspect, provided herein is a method for treating cancer in which the cancer cells contain activated EGFR, comprising administering to a subject in need thereof an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0215] In another aspect, provided herein are methods for treating cancer in which cancer cells contain activated EGFR, 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 that prevents EGFR dimerization. In some embodiments, the second active agent that prevents EGFR dimerization is an antibody. In further embodiments, the second active agent that prevents EGFR dimerization is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that prevents EGFR dimerization is cetuximab. In certain embodiments, 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.

[0216] In certain embodiments, the activation of EGFR is selected from EGFR mutation, EGFR amplification, EGFR expression, and a ligand that mediates EGFR activation.

[0217] In a further embodiment, the EGFR mutation is selected from G719S, G719C, G719A, L858R, L861Q, an exon 19 deletion mutation, and an exon 20 insertion mutation.

[0218] In yet another aspect, provided herein is a method for treating cancer in a subject identified as being in need of EGFR inhibition for such treatment, comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0219] In certain embodiments, the subject identified as needing 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 an EGFR harboring an activating mutation and / or a drug-resistant mutation. Activating mutations include, but are not limited to, L858R, G719S, G719C, G719A, L718Q, L861Q, a deletion in exon 19, and / or an insertion in exon 20. Drug-resistant EGFR mutants can have drug-resistant mutations, including, but not limited to, T790M, T854A, L718Q, C797S, or D761Y. Diagnostic tests may include sequencing, pyrosequencing, PCR, RT-PCR, or similar analytical techniques known to those skilled in the art that are capable of detecting nucleotide sequences.

[0220] In certain aspects, provided herein is a method of preventing resistance in a subject to a known EGFR inhibitor (including but not limited to gefitinib, erlotinib, osimertinib, CO-1686, or WZ4002), comprising administering to a subject in need thereof an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0221] In another aspect, provided herein is a method of preventing resistance in a disease to known EGFR inhibitors (including but not limited to gefitinib, erlotinib, osimertinib, CO-1686, or WZ4002), 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 that prevents EGFR dimerization. In some embodiments, the second active agent that prevents EGFR dimerization is an antibody. In further embodiments, the second active agent that prevents EGFR dimerization is cetuximab, trastuzumab, or panitumumab. In a further embodiment, the second active agent that prevents EGFR dimerization is cetuximab.

[0222] In certain embodiments of the methods disclosed herein, the subject is a human.

[0223] 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 is a contributing factor.

[0224] In certain aspects, provided herein are methods for 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 a proliferative disorder and a neurodegenerative disorder.

[0225] One aspect of the present disclosure provides compounds useful for treating 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, genitourinary tract 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 system disorders, Hodgkin's disease, hairy cell, buccal and pharyngeal (oral) cancer, lip cancer, tongue cancer, mouth cancer, pharyngeal cancer, small intestine cancer, colon cancer, rectal cancer, large intestine cancer, rectal cancer, brain cancer and central nervous system cancer, chronic myeloid leukemia (CML), and leukemia. The term "cancer" includes, but is not limited to, myeloma, lymphoma, or a cancer selected from the following: gastric cancer, renal cancer, head and neck cancer, oropharyngeal cancer, non-small cell lung cancer (NSCLC), endometrial cancer, hepatocellular carcinoma, non-Hodgkin's lymphoma, and lung cancer.

[0226] The term "cancer" refers to any cancer resulting from the proliferation of malignant new cells, such as tumor, neoplasm, carcinoma, sarcoma, leukemia, lymphoma, etc. For example, cancers include, but are not limited to, mesothelioma, leukemias and lymphomas, e.g., cutaneous T-cell lymphoma (CTCL), non-cutaneous peripheral T-cell lymphoma, lymphomas 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's lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), Hodgkin's lymphoma, Burkitt's lymphoma, adult T-cell leukemia / lymphoma, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or hepatocellular carcinoma. Further examples include myelodysplastic syndromes, pediatric solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors, and soft tissue sarcoma, solid tumors common in adults such as head and neck cancer (e.g., oral cavity, larynx, nasopharynx, and esophagus), genitourinary cancer (e.g., prostate, bladder, kidney, uterus, ovaries, testes), lung cancer (e.g., small cell and non-small cell), breast cancer, pancreatic cancer, melanoma and other skin cancers, gastric cancer, brain tumors, tumors associated with Gorlin's syndrome (e.g., medulloblastoma, meningioma, etc.), and liver cancer. Further exemplary forms of cancer that may be treated by the subject compounds include, but are not limited to, skeletal or smooth muscle cancer, gastric cancer, cancer of the small intestine, rectal cancer, salivary gland cancer, endometrial cancer, adrenal cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer.

[0227] Further cancers that the compounds described herein may be useful in the prevention, treatment and study are, for example, colon cancer, familial polyposis coli cancer and hereditary non-polyposis colorectal cancer, or melanoma. Further, cancers include, but are not limited to, labia cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, thyroid cancer (medullary and papillary thyroid cancer), kidney cancer, renal parenchymal cancer, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, testicular cancer, urinary tract cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumor, gallbladder cancer, bronchial carcinoma, 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 compounds of the present disclosure in the manufacture of a medicament for the treatment of cancer, including, but not limited to, the various types of cancer disclosed herein.

[0228] In some embodiments, compounds of the present disclosure are useful for treating cancer, such as colorectal cancer, thyroid cancer, breast cancer, and lung cancer, and myeloproliferative disorders, such as polycythemia vera, thrombocythemia, myeloid metaplasia with myelofibrosis, chronic myelogenous leukemia, chronic myelomonocytic leukemia, hypereosinophilic syndrome, juvenile myelomonocytic leukemia, and systemic mastocytosis. In some embodiments, compounds of the present disclosure are useful for treating hematopoietic disorders, specifically acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), acute promyelocytic leukemia, and acute lymphocytic leukemia (ALL).

[0229] As provided herein, the term "cancerous cell" includes a cell damaged by any one of the above-identified conditions.

[0230] The present disclosure further provides a method for treating or preventing cell proliferative disorders, such as hyperplasia, dysplasia, and precancerous lesions. Dysplasia is the earliest form of precancerous lesion that can be recognized in a biopsy by a pathologist. The subject compounds can be administered for the purpose of preventing the hyperplasia, dysplasia, or precancerous lesion from continuing to grow or becoming cancerous. Examples of precancerous lesions can occur in tissues within the skin, esophagus, breast, and cervical epithelium.

[0231] Examples of neurodegenerative diseases include 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, fatal familial insomnia, frontotemporal lobar degeneration, Huntington's disease, HIV-associated dementia, Kennedy disease, Krabbe disease, dementia with Lewy bodies, neuroborreliosis, Machado-Joseph disease (spinocerebellar ataxia type 3), multiple system atrophy, multiple sclerosis, narcolepsy, Niemann-Pick disease, Parkinson's disease, and Pelizaeus disease. These include, but are not limited to, Merzbach disease, Pick's disease, primary lateral sclerosis, prion diseases, progressive supranuclear palsy, Refsum disease, Sandhoff disease, Schilder's disease, subacute combined degeneration of the spinal cord secondary to pernicious anemia, Spielmeyer-Vogt-Sjögren-Batten disease (also known as Batten disease), spinocerebellar ataxias (various types with different characteristics), spinal muscular atrophy, Steele-Richardson-Olszewski disease, spinal fistula, and toxic encephalopathy.

[0232] Another aspect of the present disclosure provides a method for treating or lessening the severity of a disease selected from a proliferative or hyperproliferative disease or a neurodegenerative disease, 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 that prevents EGFR dimerization. In some embodiments, the second active agent that prevents EGFR dimerization is an antibody. In further embodiments, the second active agent that prevents EGFR dimerization is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that prevents EGFR dimerization is cetuximab. In certain embodiments, 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.

[0233] The activity of the compounds and compositions of the present disclosure as EGFR kinase inhibitors can be assayed in vitro, in vivo, or in cell lines. In vitro assays include assays that determine inhibition of either the kinase activity or ATPase activity of activated kinases. An alternative in vitro assay quantifies the ability of an inhibitor to bind to a protein kinase, which can be measured either by radiolabeling the inhibitor before binding, dissociating the inhibitor / kinase complex, and determining the amount of bound radiolabel, or by performing a competition experiment in which new inhibitors are incubated with a kinase bound to a known radioligand. Detailed conditions for assaying the compounds utilized in this disclosure as inhibitors of various kinases are set forth in the Examples below.

[0234] In accordance with the above, the present disclosure further provides a method for preventing or treating any of the above diseases or disorders in a subject in need of such treatment, 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 that prevents EGFR dimerization. For any of the above uses, the required dosage will vary depending on the mode of administration, the particular condition being treated, and the desired effect.

[0235] In other embodiments, the compound and the second active agent that prevents EGFR dimerization are administered simultaneously or sequentially.

[0236] Administration / Dosage / Formulation Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings, and fragrances.

[0237] Injectable preparations (e.g., sterile injectable aqueous or oleaginous suspensions) can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, USP, and isotonic saline. Additionally, sterile, fixed oils are conventionally employed as solvents or suspending media. For this purpose, any bland, fixed oil can be employed, including synthetic mono- or diglycerides. Additionally, fatty acids such as oleic acid are used in the preparation of injectables.

[0238] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material that is poorly soluble in water. In this case, the rate of absorption of the drug depends on its rate of dissolution, which may depend on the size and crystalline form of the crystals. Alternatively, delayed absorption of a parenterally administered drug form can be accomplished by dissolving or suspending the drug in an oil vehicle.

[0239] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing a compound of the present disclosure with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax which is solid at room temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity to liberate the active compound.

[0240] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0241] The active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.Solid dosage forms such as tablets, sugar-coated tablets, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings known in the pharmaceutical formulation field.In such solid dosage forms, the active compound can be mixed with at least one inert diluent, such as sucrose, lactose, or starch.Such dosage forms can also contain, as is common practice, additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose.In the case of capsules, tablets, and pills, dosage forms can also contain buffering agents.

[0242] 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 under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers, as required. Eye drops, ear drops, eye ointments, powders, and solutions are also contemplated as being within the scope of the present disclosure.

[0243] The ointments, pastes, creams and gels may contain, in addition to the active compounds of the present disclosure, excipients such as animal or vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0244] Powders and sprays can contain, in addition to the compounds of this disclosure, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can also contain customary propellants such as chlorofluorohydrocarbons.

[0245] Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0246] According to the treatment methods of the present disclosure, disorders are treated or prevented in a subject, such as a human or other animal, by administering to the subject a therapeutically effective amount of a compound of the present disclosure, in an amount and for a period of time necessary to achieve the desired result. The term "therapeutically effective amount" of a compound of the present disclosure, as used herein, means an amount of the compound sufficient to reduce the symptoms of the disorder in the subject. As is well understood in the medical field, a therapeutically effective amount of a compound of the present disclosure will be at a reasonable benefit / risk ratio applicable to any medical treatment.

[0247] In general, the compounds of the present disclosure will be administered in a therapeutically effective amount, either alone or in combination with one or more therapeutic agents, by any conventional and accepted method 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. In general, good results have been shown to be obtained systemically at a daily dosage of about 0.03 to 2.5 mg / kg of body weight. In larger mammals, such as humans, the recommended daily dosage ranges from about 0.5 mg to about 100 mg, conveniently administered, for example, in divided doses up to four times a day, or in retard form. A suitable unit dosage form for oral administration contains about 1 to 50 mg of active ingredient.

[0248] In certain embodiments, the therapeutic amount or dose of a compound of the present disclosure may range from about 0.1 mg / Kg to about 500 mg / Kg, or from about 1 to about 50 mg / Kg. Generally, treatment regimens according to the present disclosure involve administration of about 10 mg to about 1000 mg of a compound of the present disclosure per day to a patient in need of such treatment, in a single dose or multiple doses. The therapeutic amount or dose will also vary depending on the route of administration and the possibility of co-administration with other drugs.

[0249] When the subject's condition has improved, a maintenance dose of the disclosed compound, composition, or combination can be administered, if necessary. Thereafter, the dose or frequency of administration, or both, should be reduced as a function of the symptoms to a level at which the improved condition is maintained, and treatment should be terminated when the symptoms have been alleviated to the desired level. However, the subject may require intermittent treatment on a long-term basis upon the recurrence of any disease symptoms.

[0250] However, it will be understood that the total daily usage amount of the compounds and compositions of the present disclosure will be determined by the attending physician within the scope of sound medical judgment.The specific inhibitory dose for any particular patient will depend on various factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the patient's age, weight, general health, sex and diet; the timing, route of administration and excretion rate of the specific compound employed; the duration of treatment; drugs used in combination with or simultaneously with the specific compound employed; and similar factors known in the medical field.

[0251] The present disclosure also provides a combination pharmaceutical, such as a kit, comprising: a) a first agent that is a compound disclosed herein in free form or pharmaceutically acceptable salt form; and b) at least one concomitant agent. The kit may include instructions for administration thereof.

[0252] In certain embodiments, these compositions may optionally further comprise one or more additional therapeutic agents, for example, agents that prevent EGFR dimerization, chemotherapeutic agents, or other anti-proliferative agents can be combined with the compounds of the present disclosure to treat proliferative diseases and cancer.

[0253] Some examples of materials that can serve as pharmaceutically acceptable carriers include ion exchangers; alumina; aluminum stearate; lecithin; serum proteins such as human serum albumin; buffer substances such as phosphate, glycine, sorbic acid or potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes such as protamine sulfate; disodium hydrogen phosphate; potassium hydrogen phosphate; sodium chloride; zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; polyacrylates; waxes; polyethylene polyoxypropylene block polymers; wool fat; lactose, glucose, and sucrose; corn starch and potatoes. Examples of suitable soluble and soluble starches include, but are not limited to, starches such as cellulose acetate, cellulose acetate, cellulose acetate, and cellulose acetate derivatives; 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 or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; and phosphate buffer solution. Additionally, non-toxic, compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweeteners, flavorings, and perfuming agents, preservatives, and antioxidants may also be present in the composition, at the discretion of the formulator. Protein kinase inhibitors or pharmaceutical salts thereof can be formulated into pharmaceutical compositions for administration to animals or humans. These pharmaceutical compositions, which comprise an amount of the protein inhibitor effective to treat or prevent a protein kinase-mediated condition, and a pharmaceutically acceptable carrier, are other embodiments of the present disclosure.

[0254] kit In certain aspects, provided herein are kits comprising a compound capable of inhibiting kinase activity, or a pharmaceutically acceptable salt thereof, selected from one or more compounds disclosed herein, and instructions for use in treating cancer. In certain embodiments, the kit further comprises components for performing a test to determine whether a subject has an activating and / or drug resistance mutation in EGFR.

[0255] In another aspect, the present disclosure provides a kit comprising a compound capable of inhibiting EGFR activity selected from the compounds disclosed herein or a pharmaceutically acceptable salt thereof.

[0256] In another aspect, the present disclosure provides a kit comprising a compound capable of inhibiting kinase activity selected from one or more compounds disclosed herein or a pharmaceutically acceptable salt thereof, a second active agent that prevents EGFR dimerization, and instructions for use in treating cancer. In certain embodiments, the kit further comprises components for performing a test to determine whether a subject has an activating and / or drug-resistant mutation in EGFR. In some embodiments, the second active agent that prevents EGFR dimerization is an antibody. In further embodiments, the second active agent that prevents EGFR dimerization is cetuximab, trastuzumab, or panitumumab. In a further embodiment, the second active agent that prevents EGFR dimerization is cetuximab.

[0257] In another aspect, the present disclosure provides a kit comprising a compound capable of inhibiting EGFR activity selected from the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, and a second active agent that prevents EGFR dimerization. In some embodiments, the second active agent that prevents EGFR dimerization is an antibody. In further embodiments, the second active agent that prevents EGFR dimerization is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that prevents EGFR dimerization is cetuximab. In certain embodiments, 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.

[0258] The present disclosure is further illustrated by the following examples and synthetic schemes, which should not be construed as limiting the disclosure in scope or spirit to the specific procedures described therein. It should be understood that the examples are provided to illustrate particular embodiments, and no limitation on the scope of the disclosure is intended thereby. It should further be understood that resort may be made to various other embodiments, modifications, and equivalents thereof, which may suggest themselves to those skilled in the art, without departing from the spirit of the present disclosure and / or the scope of the appended claims. [Example]

[0259] This application is further illustrated by the following examples, which should not be construed as further limiting. The practice of the present disclosure will employ, unless otherwise indicated, conventional techniques of organic synthesis, cell biology, cell culture, and molecular biology, within the skill of the art.

[0260] Abbreviation ACN Acetonitrile dba Dibenzylideneacetone DCM dichloromethane DIPEA Diisopropylethylamine DMF Dimethylformamide DMSO dimethyl sulfoxide dppf 1,1'-bis(diphenylphosphino)ferrocene EtOAc ethyl acetate EtOH ethanol HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate LDA Lithium diisopropylamide MeOH Methanol SPhos 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl TBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate TEA Triethylamine TFA trifluoroacetic acid THF tetrahydrofuran XPhos 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0261] Example 1 Preparation of 2-[1H-benzimidazol-2-yl-(3-fluorophenyl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one (Compound 026) Scheme 1

[0262] [ka]

[0263] Step 1. Methyl 2-(6-bromo-1-oxo-isoindolin-2-yl)-2-(3-fluorophenyl)acetate

[0264] [ka]

[0265] To a solution of methyl 2-amino-2-(3-fluorophenyl)acetate (4.00 g, 21.8 mmol) in DMF (109 mL) was added DIPEA (10.6 mL, 61.0 mmol). The reaction mixture was stirred at room temperature for 5 minutes, and then 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 in hexane to give the title compound (4.75 g, 58%). MS m / z: 379.1 [M+1]+. Step 2. Methyl 2-(3-fluorophenyl)-2-[6-[4-(1-methyl-4-piperidyl)phenyl]-1-oxo-isoindolin-2-yl]acetate

[0266] [ka]

[0267] A mixture of methyl 2-(6-bromo-1-oxo-isoindolin-2-yl)-2-(3-fluorophenyl)acetate (4.13 g, 10.9 mmol), 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine (4.91 g, 16.3 mmol), 1.0 M sodium carbonate solution (21.8 mL, 21.8 mmol), and dioxane (109 mL) was degassed twice with nitrogen. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.534 g, 0.654 mmol) and XPhos (0.519 g, 1.09 mmol) was added, and the reaction was degassed once more with 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% ACN / water containing 10 mM ammonium acetate to give the title compound (4.17 g, 81%). MS m / z: 473.2 [M+1]+. Step 3. 2-(3-Fluorophenyl)-2-[6-[4-(1-methyl-4-piperidyl)phenyl]-1-oxo-isoindolin-2-yl]acetic acid

[0268] [ka]

[0269] A mixture of methyl 2-(6-bromo-1-oxo-isoindolin-2-yl)-2-(3-fluorophenyl)acetate (4.13 g, 10.9 mmol), 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine (4.91 g, 16.3 mmol), 1.0 M sodium carbonate solution (21.8 mL, 21.8 mmol), and dioxane (109 mL) was degassed twice with nitrogen. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.534 g, 0.654 mmol) and XPhos (0.519 g, 1.09 mmol) was added, and the reaction was degassed once more with 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% ACN / water containing 10 mM ammonium acetate to give the title compound (4.17 g, 81%). MS m / z: 473.2 [M+1]+. Step 4. 2-[1H-benzimidazol-2-yl-(3-fluorophenyl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one (026)

[0270] [ka]

[0271] To a solution of 2-(3-fluorophenyl)-2-[6-[4-(1-methyl-4-piperidyl)phenyl]-1-oxo-isoindolin-2-yl]acetic acid (0.100 g, 0.218 mmol), 1,2-diaminobenzene (0.053 g, 0.491 mmol), and HATU (0.166 g, 0.436 mmol) in DMF (4.4 mL) was added 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 reaction without further purification. MS m / z: 549.3 [M+1]+.

[0272] To the above amide intermediate was added acetic acid (5 mL). After stirring at 80° C. overnight, the solvent was removed under reduced pressure. The crude product was purified by C18 column chromatography eluting with 0-100% ACN / water containing 10 mM ammonium acetate to give the title compound (18 mg, 17%). 1 H 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] + .

[0273] Compound 025 was prepared from 2-(3-fluorophenyl)-2-[6-[4-(1-methyl-4-piperidyl)phenyl]-1-oxo-isoindolin-2-yl]acetic acid and pyridine-2,3-diamine in a manner similar to that described in Example 1.

[0274] [Table 7]

[0275] Example 2 Preparation of 2-[(5-fluoro-2-hydroxy-phenyl)-(1H-imidazo[4,5-c]pyridin-2-yl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one; Hydrochloride (Compound 015) Scheme 2

[0276] [ka]

[0277] Step 1. 2-Bromo-4-fluoro-1-(methoxymethoxy)benzene

[0278] [ka]

[0279] To a solution of 2-bromo-4-fluorophenol (100 g, 523 mmol) in THF (1 L) was added sodium hydride (23.0 g, 575 mmol, 60% in mineral oil) over 4 h at 0 °C, followed by the addition of 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 in petroleum ether to give the title compound (80 g, 65%). 1 H 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). Step 2. Ethyl 2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-oxoacetate

[0280] [ka]

[0281] To a solution of 2-bromo-4-fluoro-1-(methoxymethoxy)benzene (80.0 g, 340 mmol) in THF (1 L) at −78° C., n-butyllithium (2.5 M in hexanes, 142 mL, 357 mmol) was added dropwise. After stirring at −78° C. for 1 hour, the reaction mixture was cannulated into a pre-cooled (−78° C.) solution of diethyl oxalate (74.4 g, 510 mmol) in THF (500 mL). Upon completion of the addition, 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 in petroleum ether to give the title compound (70 g, 80%). 1 H 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). Step 3. Ethyl 2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-hydroxyiminoacetate

[0282] [ka]

[0283] 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-oxo-acetate (70.0 g, 273 mmol) and sodium acetate (44.7 g, 132 mmol). After stirring at 80° C. for 2.5 hours, 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 H 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). Step 4. Ethyl 2-amino-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetate

[0284] [ka]

[0285] To a solution of Raney nickel (1.46 g, 25.0 mmol) in EtOH / THF (650 mL, 4 / 1) was added 2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-hydroxyimino-ethyl acetate (34.0 g, 125 mmol). The flask was evacuated and refilled with hydrogen, and the reaction mixture was stirred under a hydrogen atmosphere (50 psi) at 70° C. for 24 hours. The reaction mixture was filtered through a pad of Celite, which was washed multiple times with ethanol. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography, eluting with 33% ethyl acetate in petroleum ether, to give the title compound (30.6 g, 48%). 1H NMR (400 MHz, DMSO-d6) 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). Step 5. Ethyl 2-(6-bromo-1-oxo-isoindolin-2-yl)-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetate

[0286] [ka]

[0287] To a solution of ethyl 2-amino-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetate (30.6 g, 118 mmol) in 300 mL of DMF was added DIPEA (58.4 mL, 354 mmol). The reaction mixture was stirred at room temperature for 5 minutes, and then methyl 5-bromo-2-(bromomethyl)benzoate (32.6 g, 106 mmol) was added. The reaction mixture was heated at 100° C. for 10 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. The crude product was purified by silica gel column chromatography eluting with 33% ethyl acetate in petroleum ether to give the title compound (35 g, 66%). 1 H 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), MS m / z: 453.8 [M+1] + . Step 6. Ethyl 2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-[6-[4-(1-methyl-4-piperidyl)phenyl]-1-oxo-isoindolin-2-yl]acetate

[0288] [ka]

[0289] 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 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 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 in dichloromethane to give the title compound (4.91 g, 76%). MS m / z: 547.3 [M+1]+. Step 7. 2-[5-Fluoro-2-(methoxymethoxy)phenyl]-2-[6-[4-(1-methyl-4-piperidyl)phenyl]-1-oxo-isoindolin-2-yl]acetic acid

[0290] [ka]

[0291] To a solution of ethyl 2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-[6-[4-(1-methyl-4-piperidyl)phenyl]-1-oxo-isoindolin-2-yl]acetate (4.91 g, 8.98 mmol) in THF / MeOH / water (90 mL, 1 / 1 / 1) was added lithium hydroxide monohydrate (1.50 g, 35.9 mmol). After stirring at room temperature for 2 h, the solvent was removed under reduced pressure, and the resulting residue was neutralized with concentrated HCl. The crude product was purified by C18 column chromatography eluting with 0-45% ACN / water containing 0.1% formic acid to give the title compound (4.01 g, 86%). MS m / z: 519.3 [M+1]+. Step 8. 2-[[5-fluoro-2-(methoxymethoxy)phenyl]-(1H-imidazo[4,5-c]pyridin-2-yl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one

[0292] [ka]

[0293] To a solution of 2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-[6-[4-(1-methyl-4-piperidyl)-phenyl]-1-oxo-isoindolin-2-yl]acetic acid (0.200 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 at room temperature for 2 h, the reaction mixture was diluted with ethyl acetate and washed twice with saturated sodium bicarbonate solution and brine. The organic phase 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 as a white solid (172 mg, 73%). MS m / z: 610.3 [M+1]+.

[0294] To the above amide intermediate (0.172 g, 0.282 mmol) was added acetic acid (3.66 mL). After stirring at 80 °C for 30 min, 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 pooled and concentrated under reduced pressure to remove the organic solvent. The remaining 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]+. Step 9. 2-[(5-Fluoro-2-hydroxy-phenyl)-(1H-imidazo[4,5-c]pyridin-2-yl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one; Hydrochloride (Compound 015)

[0295] [ka]

[0296] To a solution of 2-[[5-fluoro-2-(methoxymethoxy)phenyl]-(1H-imidazo[4,5-c]pyridin-2-yl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one (0.143 g, 0.241 mmol) in dichloromethane (5.2 mL) was added HCl in dioxane (4 M, 0.6 mL, 2.40 mmol). After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure. Diethyl ether was added to the residue, and the resulting solid was isolated by filtration to give 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] + .

[0297] The following compounds were prepared by a method similar to Example 2 from ethyl 2-amino-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetate and either methyl 5-bromo-2-(bromo-methyl)-benzoate or methyl 5-bromo-2-(bromomethyl)nicotinate and the corresponding boronate and diaminoaryl starting materials.

[0298] [Table 8A]

[0299] [Table 8B]

[0300] [Table 8C]

[0301] The following compounds were prepared by a method similar to Example 2 from ethyl 2-amino-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate and either methyl 5-bromo-2-(bromo-methyl)-benzoate or methyl 6-(bromomethyl)-3-chloro-2-fluorobenzoate and the corresponding boronate and diaminoaryl starting materials.

[0302] [Table 9]

[0303] Example 3 Preparation of 2-[(R)-1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one and 2-[(S)-1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one (Compounds 022 and 023)

[0304] [ka]

[0305] 2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxyphenyl)methyl]-6-[4-(1-methyl-4-piperidyl)-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 prep SFC on a Chiralpak IA column, eluting with 45% (0.3% TEA in MeOH) / 55% CO2 at 10 MPa to separate the enantiomers. The absolute configuration of the chiral center of each isolated enantiomer is unknown. First eluting peak (022) (120 mg, 22% yield, 94:6 er); [α] 20 D -34.2° (c = 0.12, MeOH); 1 H 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 eluting peak (023) (154 mg, 28% yield, 89:11 er); [α] 20 D +28.0° (c = 0.1, MeOH); 1H 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] + .

[0306] Example 4 Preparation of 6-[2-(6-amino-3-pyridyl)ethynyl]-2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]isoindolin-1-one (Compound 012) Scheme 3

[0307] [ka]

[0308] Step 1. 2-(6-Bromo-1-oxo-isoindolin-2-yl)-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetic acid

[0309] [ka]

[0310] To a solution of ethyl 2-(6-bromo-1-oxo-isoindolin-2-yl)-2-[5-fluoro-2-(methoxymethoxy)-phenyl]acetate (22.0 g, 48.6 mmol) in THF / MeOH / water (300 mL, 1 / 1 / 1) was added lithium hydroxide monohydrate (6.10 g, 145 mmol). After stirring at room temperature for 3 hours, the solvent was removed under reduced pressure and the resulting residue was adjusted to pH 3 with HCl (1 M). The solid was collected by filtration and washed with water to give the title compound (18.2 g, 88%). 1 H 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). Step 2. 2-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-bromo-isoindolin-1-one

[0311] [ka]

[0312] 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 phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with NH4OH / MeOH / DCM (1 / 5 / 100) to give the amide intermediate as a yellow solid (15.5 g, 70%). 1H NMR (400 MHz, DMSO-d6) δ: 9.72 (s, 1 H), 7.88 (d, 1H), 7.75-7.85 (m, 1H), 7.51-7.69 (m, 1H), 7.08-7.23 (m, 4H), 6.89-6.96 (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).

[0313] To the above amide intermediate (15.5 g, 30.1 mmol) was added acetic acid (150 mL). After stirring at 80° C. for 30 minutes, 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 (12.5 g, 84%). MS m / z: 497.3 [M+1]+. Step 3. 6-[2-(6-amino-3-pyridyl)ethynyl]-2-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)-phenyl]methyl]isoindolin-1-one

[0314] [ka]

[0315] 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 / water containing 0.1% formic acid to give the title compound (66 g, 41%). MS m / z: 534.2 [M+1]+. Step 4. 6-[2-(6-amino-3-pyridyl)ethynyl]-2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]isoindolin-1-one (Compound 012)

[0316] [ka]

[0317] To a solution of 6-[2-(6-amino-3-pyridyl)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 in 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%). 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 MS m / z: 490.2 [M+1] + .

[0318] The following compounds were prepared from 2-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-bromo-isoindolin-1-one and the corresponding acetylene starting materials in a manner analogous to Example 4.

[0319] [Table 10]

[0320] Example 5 Preparation of 2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-7-fluoro-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one; Hydrochloride (Compound 032) Scheme 4

[0321] [ka]

[0322] Step 1: 3-chloro-2-fluoro-6-methyl-benzoic acid

[0323] [ka]

[0324] To a solution of 1-chloro-2-fluoro-4-methyl-benzene (10.0 g, 69.1 mmol) in THF (100 mL) at −70° C., LDA (2 M in THF, 36.2 mL, 72.5 mmol) was added dropwise. After stirring at −70° C. for 0.5 h, CO (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). Step 2: Methyl 3-chloro-2-fluoro-6-methyl-benzoate

[0325] [ka]

[0326] 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 at the same temperature for 0.5 h, 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 at room temperature for 1 h, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography eluting with 3% ethyl acetate in petroleum ether to give the title compound (1.9 g, 51%). 1 H NMR (400 MHz, DMSO-d6) δ: 7.60-7.66 (m, 1H), 7.20 (d, 1H), 3.90 (s, 3H), 2.32 (s, 3H). Step 3: 6-(bromomethyl)-3-chloro-2-fluoro-benzoate methyl

[0327] [ka]

[0328] To a solution of methyl 3-chloro-2-fluoro-6-methylbenzoate (1.90 g, 9.37 mmol) in carbon tetrachloride (20 mL) was added N-bromosuccinimide (1.66 g, 9.37 mmol) and benzoyl peroxide (0.452 g, 1.87 mmol). After stirring at 80 °C for 12 hours, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 1% ethyl acetate in petroleum ether to give the title compound (0.9 g, 34%). 1 H NMR (400 MHz, CDCl3) δ: 7.45-7.52 (m, 1H), 7.19 (d, 1H), 4.62 (s, 2H), 4.02 (s, 3H). Step 4: 2-(6-chloro-7-fluoro-1-oxo-isoindolin-2-yl)-2-[5-fluoro-2-(methoxymethoxy)-phenyl]ethyl acetate

[0329] [ka]

[0330] To a solution of ethyl 2-amino-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetate (1.06 g, 4.14 mmol) in 15 mL of DMF was added DIPEA (1.23 g, 9.57 mmol). The reaction mixture was stirred at room temperature for 5 minutes, and then methyl 6-(bromomethyl)-3-chloro-2-fluorobenzoate (0.900 g, 3.19 mmol) was added. The reaction mixture was heated at 100° C. for 1 hour. 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 in petroleum ether to give the title compound (800 mg, 59%). MS m / z: 426.1 [M+1]+. Step 5: 2-(6-chloro-7-fluoro-1-oxo-isoindolin-2-yl)-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetic acid

[0331] [ka]

[0332] To a solution of ethyl 2-(6-chloro-7-fluoro-1-oxo-isoindolin-2-yl)-2-[5-fluoro-2-(methoxy-methoxy)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 hour, 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 (750 mg, quantitative). MS m / z: 398.0 [M+1]+. Step 6: 2-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-chloro-7-fluoro-isoindolin-1-one

[0333] [ka]

[0334] To a solution of 2-(6-chloro-7-fluoro-1-oxo-isoindolin-2-yl)-2-[5-fluoro-2-(methoxy-methoxy)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 overnight at room temperature, 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 reaction without further purification. MS m / z: 488.3 [M+1]+.

[0335] To the above amide intermediate was added acetic acid (15 mL). 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]+. Step 7: 2-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-7-fluoro-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one

[0336] [ka]

[0337] 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), Pd(dba) (0.321 g, 0.351 mmol), and dioxane (10 mL) was degassed twice with nitrogen. The reaction mixture was heated at 105 °C for 4 hours. After cooling to room temperature, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 10% methanol in dichloromethane to give the title compound (120 mg, 17%). MS m / z: 609.3 [M+1]+. Step 8: 2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-7-fluoro-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one; Hydrochloride (Compound 032)

[0338] [ka]

[0339] To a solution of 2-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-7-fluoro-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one (0.120 g, 0.197 mmol) in dichloromethane (5 mL) was added HCl in dioxane (4 M, 0.985 mL, 3.94 mmol). After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure. Diethyl ether was added to the residue, and the resulting solid was isolated 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] + .

[0340] Example 6 Preparation of 2-[1H-benzimidazol-2-yl-(5-fluoro-2-methoxy-phenyl)methyl]-7-fluoro-6-[4-(1-methyl-4-piperidyl)phenyl]indazole (035) and 2-[1H-benzimidazol-2-yl-[7-fluoro-6-[4-(1-methyl-4-piperidyl)phenyl]indazol-2-yl]methyl]-4-fluoro-phenol; hydrochloride salt (034) Scheme 5

[0341] [ka]

[0342] Step 1. Methyl 2-(5-fluoro-2-methoxy-phenyl)acetate

[0343] [ka]

[0344] 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 hours, the solvent was removed under reduced pressure, and the resulting residue was diluted with ethyl acetate, washed three times with saturated sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (900 mg, 93%). 1 H 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). Step 2. Methyl 2-bromo-2-(5-fluoro-2-methoxy-phenyl)acetate

[0345] [ka]

[0346] To a solution of methyl 2-(5-fluoro-2-methoxyphenyl)acetate (0.900 g, 5.44 mmol) in carbon tetrachloride (20 mL) was 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 hours, the solvent was removed under reduced pressure. The crude compound was purified by silica gel column chromatography eluting with 12% ethyl acetate in petroleum ether to give the title compound (1.2 g, 96%). 1 H 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). Step 3. 2-(6-Bromo-7-fluoro-indazol-2-yl)-2-(5-fluoro-2-methoxy-phenyl)acetic acid

[0347] [ka]

[0348] To a solution of methyl 2-bromo-2-(5-fluoro-2-methoxy-phenyl)acetate (0.579 g, 2.09 mmol) and 6-bromo-7-fluoro-1H-indazole (0.450 g, 2.09 mmol) in acetonitrile (15 mL) was added cesium carbonate (0.814 g, 2.50 mmol). After stirring at 0° C. for 30 minutes and then at room temperature for 1 hour, 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 ester intermediate. MS m / z: 412.9 [M+1]+.

[0349] To a solution of the above intermediate in THF / MeOH / water (15 mL, 1 / 1 / 1) was added lithium hydroxide monohydrate (0.336 g, 8.01 mmol). After stirring at room temperature for 1 h, the solvent was removed under reduced pressure, and the resulting residue was partitioned between water and ethyl acetate. The aqueous phase was adjusted to pH 3 with 5% citric acid and extracted 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 in 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] + . Step 4. 2-[1H-benzimidazol-2-yl-(5-fluoro-2-methoxy-phenyl)methyl]-6-bromo-7-fluoro-indazole

[0350] [ka]

[0351] To a solution of 2-(6-bromo-7-fluoro-indazol-2-yl)-2-(5-fluoro-2-methoxy-phenyl)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 h, the reaction mixture was partitioned between saturated sodium chloride and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate, and 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 in petroleum ether to give the amide intermediate. MS m / z: 488.8 [M+1]+.

[0352] To the above amide intermediate was added acetic acid (15 mL). 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. The organic phase 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] + . Step 5. 2-[1H-benzimidazol-2-yl-(5-fluoro-2-methoxy-phenyl)methyl]-7-fluoro-6-[4-(1-methyl-4-piperidyl)phenyl]indazole (Compound 035)

[0353] [ka]

[0354] A mixture of 2-[1H-benzimidazol-2-yl-(5-fluoro-2-methoxyphenyl)methyl]-6-bromo-7-fluoroindazole (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 dioxane / water (8 mL, 4 / 1) was degassed twice with 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 in 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] + . Step 6. 2-[1H-benzimidazol-2-yl-[7-fluoro-6-[4-(1-methyl-4-piperidyl)phenyl]indazol-2-yl]methyl]-4-fluoro-phenol; hydrochloride salt (Compound 034)

[0355] [ka]

[0356] To a solution of 2-[1H-benzimidazol-2-yl-(5-fluoro-2-methoxy-phenyl)methyl]-7-fluoro-6-[4-(1-methyl-4-piperidyl)phenyl]indazole (0.150 g, 0.266 mmol) in dichloromethane (8 mL) at 0 °C was added boron tribromide (0.666 g, 2.66 mmol). After stirring at room temperature for 2 h, the reaction mixture was diluted with dichloromethane and poured into ice water. The aqueous phase was extracted 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 (25 mg, 30%). 1 H 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, MS m / z: 550.3 [M+1] + .

[0357] The following examples were prepared by a method analogous to Example 6 from methyl 2-bromo-2-(5-fluoro-2-methoxyphenyl)acetate or methyl 2-bromo-2-phenylacetate and the corresponding bicyclic starting material.

[0358] [Table 11A]

[0359] [Table 11B]

[0360] [Table 11C]

[0361] Compounds 067 and 068: Preparation of 2-[(R)-1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoquinolin-1-one and 2-[(S)-1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoquinolin-1-one

[0362] [ka]

[0363] 2-[(rac)-1H-benzimidazol-2-yl-(5-fluoro-2-hydroxyphenyl)methyl]-6-[4-(1-methyl-4-piperidyl)-phenyl]isoquinolin-1-one; dihydrochloride (069, 0.050 g, 0.079 mmol) was purified by prep SFC on a Chiral Technologies Chiralpak IG (5 micron, 250 x 10 mm) column at 40 °C, eluting with 55% (0.3% TEA in MeOH) / 45% CO2 under 10 MPa BPR. The absolute configuration of the chiral center of each isolated enantiomer is unknown. The first eluting peak (067) (17.0 mg, 38% yield, 98.5:1.5 er); [α] 20 D -12.9 (c = 0.31, MeOH); 11H 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 1H 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, ........ + . Compounds 065 and 066: Preparation of 2-[(R)-1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-8-fluoro-6-[4-(1-methyl-4-piperidyl)phenyl]isoquinolin-1-one and 2-[(S)-1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-8-fluoro-6-[4-(1-methyl-4-piperidyl)phenyl]isoquinolin-1-one

[0364] [ka]

[0365] 2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxyphenyl)methyl]-8-fluoro-6-[4-(1-methyl-4-piperidyl)phenyl]isoquinolin-1-one hydrochloride (070, 0.012 g, 0.020 mmol) was purified by prep SFC on a Phenomenex Lux Cellulose-4 column, eluting with 55% (0.3% TEA in MeOH) / 45% CO2 at 10 MPa, to separate the enantiomers. The absolute configuration of the chiral center of each isolated enantiomer is unknown. The first eluting 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]+ The second eluting peak (066) (4 mg, 36% yield, 100:0 er); [α] 20 D +14.8 (c = 0.27, MeOH); 1 H 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] + .

[0366] Example 7 Preparation of 3-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]quinazolin-4-one; Hydrochloride (Compound 006) Scheme 6

[0367] [ka]

[0368] Step 1. Ethyl 2-[(2-amino-5-bromo-benzoyl)amino]-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetate

[0369] [ka]

[0370] 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 80 mL of THF was added triethylamine (7.85 g, 77.6 mmol). After stirring at 40° C. for 3 hours, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 25% ethyl acetate in petroleum ether to give the title compound (5 g, 28%). 1 H 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). Step 2. Ethyl 2-(6-bromo-4-oxo-quinazolin-3-yl)-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetate

[0371] [ka]

[0372] A solution of ethyl 2-[(2-amino-5-bromo-benzoyl)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 in petroleum ether to give the title compound (2.2 g, 41%). 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). Step 3. Ethyl 2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-[6-[4-(1-methyl-4-piperidyl)phenyl]-4-oxo-quinazolin-3-yl]acetate

[0373] [ka]

[0374] A mixture of ethyl 2-(6-bromo-4-oxo-quinazolin-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 with nitrogen gas. [1,1'-Bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with dichloromethane (0.690 g, 0.944 mmol) was added, and the reaction was degassed once more 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 in dichloromethane to give the title compound (1.8 g, 68%). MS m / z: 560.4 [M+1] + . Step 4. 2-[5-Fluoro-2-(methoxymethoxy)phenyl]-2-[6-[4-(1-methyl-4-piperidyl)phenyl]-4-oxo-quinazolin-3-yl]acetic acid

[0375] [ka]

[0376] To a solution of ethyl 2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-[6-[4-(1-methyl-4-piperidyl)-phenyl]-4-oxo-quinazolin-3-yl]acetate (1.80 g, 3.21 mmol) in THF / MeOH / water (30 mL, 1 / 1 / 1) was added lithium hydroxide monohydrate (0.404 g, 9.62 mmol). After stirring at room temperature for 3 hours, 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 (1.5 g, 88%). MS m / z: 532.1 [M+1] + . Step 5. 3-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]quinazolin-4-one

[0377] [ka]

[0378] To a solution of 2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-[6-[4-(1-methyl-4-piperidyl)-phenyl]-4-oxo-quinazolin-3-yl]acetic acid (0.900 g, 1.69 mmol), 1,2-diaminobenzene (0.218 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 resulting solid was collected by filtration and washed with water. The crude product was purified by silica gel column chromatography eluting with 0–10% methanol in dichloromethane to give the amide intermediate. MS m / z: 622.3 [M+1]+.

[0379] To the above amide intermediate was added acetic acid (8 mL). After stirring at 80° C. for 3 hours, the solvent was removed under reduced pressure. The reaction mixture was neutralized with saturated sodium bicarbonate 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]+. Step 6. 3-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[4-(1-methyl-4-piperidyl)-phenyl]quinazolin-4-one; Hydrochloride (Compound 006)

[0380] [ka]

[0381] To a solution of 3-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]quinazolin-4-one (0.120 g, 0.198 mmol) in dichloromethane (10 mL) was added HCl in dioxane (4 M, 0.495 mL, 1.98 mmol). After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure. Diethyl ether was added to the residue, and the resulting solid was isolated 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] + .

[0382] The following compounds were prepared by methods similar to Example 7 from ethyl 2-(6-bromo-4-oxo-quinazolin-3-yl)-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetate and the corresponding boronate, or from ethyl 2-amino-2-phenylacetate.

[0383] [Table 12]

[0384] Example 8 Preparation of 2-[1H-benzimidazol-2-yl(1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one (Compound 033) Scheme 7

[0385] [ka]

[0386] Step 1. 2-(6-Bromo-1-oxo-isoindolin-2-yl)-2-[1-(2-trimethylsilylethoxymethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-3-yl]acetonitrile

[0387] [ka]

[0388] 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 methyl 2-(aminomethyl)-5-bromobenzoate hydrochloride (3.25 g, 11.5 mmol), DIPEA (4.73 mL, 28.7 mmol), and trimethylsilyl cyanide (1.35 g, 13.7 mmol). The reaction mixture was heated at 75 °C for 16 h. After cooling to room temperature, the reaction mixture was poured into water and extracted 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 in petroleum ether to give the title compound (1.77 g, 32%). MS m / z: 488.2[M+1]+. Step 2. 2-(6-Bromo-1-oxo-isoindolin-2-yl)-2-[1-(2-trimethylsilylethoxymethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-3-yl]acetic acid

[0389] [ka]

[0390] 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 aqueous potassium hydroxide (2 M, 4.85 mL, 9.70 mmol) in 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]+. 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

[0391] [ka]

[0392] 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 hours, 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 [M+1]+.

[0393] To the above amide intermediate was added acetic acid (8 mL). After stirring at 80° C. for 1 hour, 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]+. Step 4. 2-[1H-benzimidazol-2-yl-[1-(2-trimethylsilylethoxymethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-3-yl]methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one

[0394] [ka]

[0395] A mixture of 2-[1H-benzimidazol-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 twice with nitrogen. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.028 g, 0.035 mmol) was added, and the reaction was degassed once more with nitrogen. The reaction mixture was heated at 105 °C for 1.5 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 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]+. Step 5. 2-[1H-benzimidazol-2-yl(1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one (Compound 033)

[0396] [ka]

[0397] 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-methyl-4-piperidyl)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 H 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] + .

[0398] Compound 031 was prepared from 2-(6-bromo-1-oxo-isoindolin-2-yl)-2-[1-(2-trimethylsilylethoxymethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-3-yl]acetic acid and pyridine-2,3-diamine in a manner similar to that described in Example 8.

[0399] [Table 13]

[0400] 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) Scheme 8

[0401] [ka]

[0402] Step 1. Methyl 3-amino-6-bromopicolinate

[0403] [ka]

[0404] A mixture of methyl 3-aminopicolinate (650 mg, 4.27 mmol) in a solution of H2SO4 (207 mL, 4 mmol) and water (13 mL) was treated with a solution of bromine (200 mL, 4.27 mmol) in acetic acid (800 mL) added dropwise over 1 min. The reaction mixture was stirred at room temperature for 15 min and basified to pH 6 with 10 N 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% EtOAc in hexanes to give the title compound (600 mg, 61%). 1 H NMR (500 MHz, DMSO-d6) d ppm 7.45 (d, 1H) 7.22 (d, 1H) 6.89 (s, 2 H) 3.82 (s, 3 H); MS m / z: 232.9 [M+1] + . Step 2. 3-Amino-6-bromopicolinic acid

[0405] [ka]

[0406] 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 treated with 2N HCl to pH 6. 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) d ppm 7.19 (d, 1H) 7.43 (d, 1H); MS m / z: 218.9 [M+1] + . Step 3. Ethyl 2-(3-amino-6-bromopicolinamido)-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate

[0407] [ka]

[0408] 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 NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0–55% EtOAc in hexane to give the title compound (315 mg, 90%). MS m / z: 458.0 [M+1]. Step 4. 2-(6-bromo-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2-(5-fluoro-2-(methoxymethoxy)-phenyl)acetic acid ethyl ester

[0409] [ka]

[0410] A mixture of ethyl 2-(3-amino-6-bromopicolinamido)-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 for 2 hours at 210° C. After cooling, excess triethyl orthoformate was removed under reduced pressure and the residue was purified by silica gel chromatography eluting with 0-65% EtOAc in hexanes to give the title compound (310 mg, 98%). 1H NMR (500 MHz, DMSO-d6) d ppm 8.37 (s, 1H) 8.06-8.09 (m, 2H) 7.36 (dd, 1H) 7.25-7.32 (m, 1H) 7.17-7.23 (m, 1H) 6.71 (s, 1 H) 5.19-5.25 (m, 2H) 4.27 (q, 2H) 3.29 (s, 3H) 1.19-1.23 (m, 3H); MS m / z: 468.0 [M+1] + . Step 5. 2-(5-fluoro-2-(methoxymethoxy)phenyl)-2-(6-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)acetic acid

[0411] [ka]

[0412] 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)Cl. 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 for 24 h under nitrogen. After cooling, the reaction mixture was filtered and the filtrate was concentrated and purified by reverse phase HPLC eluting with 0-80% ACN / water (0.035% TFA modifier) ​​to give the title compound (151 mg, 39%). 1H NMR (500 MHz, DMSO-d6) d ppm 9.36 (br s, 1H) 8.43 (d, 1H) 8.33 (d, 1H) 8.20 (m, 3H) 7.44 (d, 2H) 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] + . 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

[0413] [ka]

[0414] 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), orthophenylenediamine (31 mg, 0.28 mmol), HATU (106 mg, 0.28 mmol), and DIPEA (156 mL, 0.90 mmol) in degassed DMF (3 mL) was stirred at 60 °C for 1.5 h. The reaction mixture was purified by reverse-phase HPLC eluting with 0-80% ACN / water (0.035% TFA modifier) ​​to give the amide intermediate. MS m / z: 623.7 [M+1]+.

[0415] The above amide intermediate was dissolved in acetic acid (5 mL) and heated at 110° C. for 1 h. Excess acetic acid was removed under reduced pressure to give the title compound, which was used without further purification. MS m / z: 605.4 [M+1]+. 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)

[0416] [ka]

[0417] The above material, 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 give the title compound (14 mg, 15%). 1 H NMR (500 MHz, DMSO-d6) d ppm 10.20 (s, 1H) 9.30 (br s, 1H) 8.46 (d, 1H) 8.31 (s, 1H) 8.23 ​​(d, 1H) 8.21 (d, 2H) 7.58 (m, 3H) 7.43 (d, 2H) 7.24 (m, 2H) 7.17 (m, 1H) 6.94 (dd, 1H) 6.80 (m, 1H) 3.55 (d, 2H) 3.10 (m, 2H) 2.90 (m,, 1H) 2.85 (d, 3H) 2.08 (m, 2H) 1.87 (m, 2H); MS m / z: 561.3 [M+1] + .

[0418] The following compounds were prepared from the corresponding amine and acid starting materials in a manner analogous to Example 9.

[0419] [Table 14]

[0420] The following compounds were prepared by a method similar to Example 9 from ethyl 2-amino-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate and the corresponding acid starting materials.

[0421] [Table 15]

[0422] Compound 077: 3-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-5-methoxy-6-[4-(1-methyl-4-piperidyl)phenyl]quinazolin-4-one; dihydrochloride salt Scheme 9

[0423] [ka]

[0424] Step 1. 6-amino-N-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-3-bromo-2-methoxy-benzamide

[0425] [ka]

[0426] 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 give the title compound (0.21 g, 31%). 1 H 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 MS m / z: 529.1 [M+1] + . Step 2. 3-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-bromo-5-methoxy-quinazolin-4-one

[0427] [ka]

[0428] A mixture of 6-amino-N-[1H-benzimidazol-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 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and purified by reverse-phase HPLC, eluting with 0-100% ACN / water (0.035% TFA modifier), to give the title compound (0.14 g, 69%). 1H 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, MS m / z: 539.1 [M+1] + . Step 3. 3-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-5-methoxy-6-[4-(1-methyl-4-piperidyl)phenyl]quinazolin-4-one

[0429] [ka]

[0430] A mixture of 3-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-bromo-5-methoxy-quinazolin-4-one (0.100 g, 0.185 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (0.056 g, 0.185 mmol), Pd(dppf)Cl (0.014 g, 0.019 mmol) and potassium carbonate (0.050 g, 0.370 mmol) in dioxane:DMF:water (1:1:1, 10 mL) was heated at 100 °C for 12 hours under nitrogen. After cooling, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure and purified by reverse phase HPLC eluting with 0-100% ACN / water (0.035% TFA modifier) ​​to give the title compound (0.085 g, 73%). 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] + . Step 4. 3-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-5-methoxy-6-[4-(1-methyl-4-piperidyl)phenyl]quinazolin-4-one; dihydrochloride

[0431] [ka]

[0432] To a solution of 3-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-5-methoxy-6-[4-(1-methyl-4-piperidyl)phenyl]quinazolin-4-one (0.075 g, 0.118 mmol) in dichloromethane (10 mL) was added HCl in methanol (4 M, 0.590 mL, 2.36 mmol). 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%). 1H 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, 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-piperidyl)phenyl]isoindoline-1-thione; dihydrochloride Scheme 10

[0433] [ka]

[0434] Step 1. 2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindoline-1-thione; dihydrochloride

[0435] [ka]

[0436] To a solution of 2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxyphenyl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one (1.00 g, 1.82 mmol) in toluene (20 mL) was added Lawesson's reagent (3.68 g, 9.10 mmol). 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%). 1 H 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 MS m / z: 563.1 [M+1] + . Compounds 083 and 084: Preparation of 2-[(R)-1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindoline-1-thione and 2-[(S)-1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindoline-1-thione

[0437] [ka]

[0438] 2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxyphenyl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindoline-1-thione dihydrochloride (0.013 g, 0.020 mmol) was purified by prep SFC on a Phenomenex Lux Cellulose-4 column, eluting with 45% (0.3% TEA in MeOH) / 55% CO2 at 10 MPa, to separate the enantiomers. The absolute configuration of the chiral center of each isolated enantiomer is unknown. The first eluting peak (083) (4 mg, 31% yield, 100:0 er); [α] 20 D -88.9 (c = 0.18, MeOH); 1 H NMR (DMSO-d6) δ: 12.74 (br s, 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] + Second eluting peak (084) (4 mg, 31% yield, 99:1 er); [α] 20 D +56.0(c=0.25, MeOH); 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] + . Compound 085: 2-[(5-fluoro-2-hydroxy-phenyl)-(4-methyl-1H-imidazol-2-yl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one Scheme 11

[0439] [ka]

[0440] Step 1. 2-Methyl-N-[(4-methyl-1H-imidazol-2-yl)methylene]propane-2-sulfinamide

[0441] [ka]

[0442] To a solution of 4-methyl-1H-imidazole-2-carboxaldehyde (5.00 g, 45.4 mmol) and 2-methylpropane-2-sulfinamide (8.25 g, 68.1 mmol) in THF (80 mL) was added tetraethyl 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 to 100% ethyl acetate in petroleum ether to give the title compound (3 g, 31%). 1 H 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]. Step 2. N-[(5-fluoro-2-methoxy-phenyl)-(4-methyl-1H-imidazol-2-yl)methyl]-2-methyl-propane-2-sulfinamide

[0443] [ka]

[0444] To a solution of 2-methyl-N-[(4-methyl-1H-imidazol-2-yl)methylene]propane-2-sulfinamide (2.30 g, 10.7 mmol) in THF (50 mL) was added dropwise a solution of 5-fluoro-2-methoxyphenylmagnesium bromide in THF (0.5 M, 64.0 mL, 32.0 mmol) at -78 °C. After stirring at room temperature for 16 h, the reaction mixture was poured into 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 in ethyl acetate to give the title compound (0.5 g, 14%). MS m / z: 340.1 [M+1]+. Step 3. (5-Fluoro-2-methoxy-phenyl)-(4-methyl-1H-imidazol-2-yl)methanamine

[0445] [ka]

[0446] To a solution of N-[(5-fluoro-2-methoxy-phenyl)-(4-methyl-1H-imidazol-2-yl)methyl]-2-methyl-propane-2-sulfinamide (0.560 g, 1.64 mmol) in methanol (10 mL) was added HCl in dioxane (4 M, 1.23 mL, 4.92 mmol) at 0° C. After stirring at room temperature for 16 h, the solvent was removed under reduced pressure to give the title compound (0.385 g, quantitative), which was used in the next reaction without further purification. MS m / z: 236.0 [M+1]+. Step 4. 6-Bromo-2-[(5-fluoro-2-methoxy-phenyl)-(4-methyl-1H-imidazol-2-yl)methyl]isoindolin-1-one

[0447] [ka]

[0448] To a solution of (5-fluoro-2-methoxy-phenyl)-(4-methyl-1H-imidazol-2-yl)methanamine (0.380 g, 1.61 mmol) in DMF (5 mL) was added DIPEA (1.31 mL, 8.04 mmol). The reaction mixture was stirred at room temperature for 5 minutes, and then methyl 5-bromo-2-(bromomethyl)benzoate (0.495 g, 1.61 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. The crude product was purified by silica gel column chromatography eluting with 0 to 100% ethyl acetate in petroleum ether to give the title compound (0.28 g, 40%).1 H 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). Step 5. 2-[(5-fluoro-2-methoxy-phenyl)-(4-methyl-1H-imidazol-2-yl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one

[0449] [ka]

[0450] A mixture of 6-bromo-2-[(5-fluoro-2-methoxy-phenyl)-(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)Cl (0.024 g, 0.033 mmol) and potassium carbonate (0.271 g, 1.95 mmol) in dioxane:water (9:1, 5 mL) was heated at 100 °C for 16 h under nitrogen. After cooling, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by reverse-phase HPLC eluting with 0-100% ACN / water (0.05% HCl modifier) ​​to give the title compound (0.2 g, 59%). MS m / z: 525.3 [M+1]+. Step 6. 2-[(5-fluoro-2-hydroxy-phenyl)-(4-methyl-1H-imidazol-2-yl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one

[0451] [ka]

[0452] To a solution of 2-[(5-fluoro-2-methoxy-phenyl)-(4-methyl-1H-imidazol-2-yl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one (0.150 g, 0.285 mmol) in dichloromethane (15 mL) at 0 °C was added boron tribromide (0.713 g, 2.85 mmol). After stirring at room temperature for 2 h, the reaction mixture was diluted with dichloromethane and poured into ice water. The aqueous phase was extracted 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 H 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] + .

[0453] The following compound was prepared from (5-fluoro-2-methoxy-phenyl)-(4-methyl-1H-imidazol-2-yl)methanamine and methyl 6-(bromomethyl)-3-chloro-2-fluorobenzoate in a manner similar to compound 085:

[0454] [Table 16]

[0455] Compound 086: 2-[(3-fluorophenyl)-(4-methyl-1H-imidazol-2-yl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one

[0456] [ka]

[0457] The title compound was prepared from 2-methyl-N-[(4-methyl-1H-imidazol-2-yl)methylene]propane-2-sulfinamide and 3-fluorophenylmagnesium bromide in the same manner as compound 085. 1 H 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-piperidyl)phenyl]isoindolin-1-one

[0458] [ka]

[0459] The title compound was prepared from 4,5-dimethyl-1H-imidazole-2-carbaldehyde and 2-methylpropane-2-sulfinamide in the same manner as compound 085. 1 H 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] + Compound 088: 2-[(5-fluoro-2-hydroxy-phenyl)-(2-methyl-1H-imidazol-5-yl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one; dihydrochloride salt

[0460] [ka]

[0461] The title compound was prepared from 2-methyl-1H-imidazole-5-carbaldehyde and 2-methylpropane-2-sulfinamide in the same manner as compound 085. 1H 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] + Compound 089: 2-[(5-fluoro-2-hydroxy-phenyl)-(5-methyl-4H-1,2,4-triazol-3-yl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one; Hydrochloride Scheme 12

[0462] [ka]

[0463] Step 1. 2-(6-bromo-1-oxo-isoindolin-2-yl)-2-[5-fluoro-2-(methoxymethoxy)phenyl]-acetohydrazide

[0464] [ka]

[0465] 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 hours, the reaction mixture was concentrated under reduced pressure to give the title compound (0.75 g, 86%). 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] + . Step 2. 6-Bromo-2-[[5-fluoro-2-(methoxymethoxy)phenyl]-(5-methyl-4H-1,2,4-triazol-3-yl)methyl]isoindolin-1-one

[0466] [ka]

[0467] To a suspension of 2-(6-bromo-1-oxo-isoindolin-2-yl)-2-[5-fluoro-2-(methoxymethoxy)-phenyl]acetohydrazide (0.400 g, 0.912 mmol) and ethanimidamide hydrochloride (0.258 g, 2.73 mmol) in butanol (80 mL) was added potassium tert-butoxide in 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 in dichloromethane to give the title compound (0.185 g, 44%). 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] + . Step 3. 2-[[5-fluoro-2-(methoxymethoxy)phenyl]-(5-methyl-4H-1,2,4-triazol-3-yl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one

[0468] [ka]

[0469] A mixture of 6-bromo-2-[[5-fluoro-2-(methoxymethoxy)phenyl]-(5-methyl-4H-1,2,4-triazol-3-yl)methyl]isoindolin-1-one (0.100 g, 0.216 mmol), [4-(1-methylpiperidin-4-yl)phenyl]boronic acid (0.057 g, 0.259 mmol), Pd(dppf)Cl (0.016 g, 0.022 mmol), and sodium carbonate (0.071 g, 0.648 mmol) in dioxane:water (4:1, 5 mL) was heated at 100 °C for 16 h under nitrogen. After cooling, the reaction mixture was poured into water and extracted 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 in dichloromethane to give the title compound (0.07 g, 58%). MS m / z: 556.3 [M+1]+. Step 4. 2-[(5-fluoro-2-hydroxy-phenyl)-(5-methyl-4H-1,2,4-triazol-3-yl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one; Hydrochloride

[0470] [ka]

[0471] The title compound was prepared from 2-[[5-fluoro-2-(methoxymethoxy)phenyl]-(5-methyl-4H-1,2,4-triazol-3-yl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one in analogy to step 4 of example 076. 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, MS m / z: 512.4 [M+1] + .

[0472] Example 10 Preparation of 3-((1H-benzo[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) Scheme 13

[0473] [ka]

[0474] Step 1. 6-Amino-3-bromo-2-fluorobenzoic acid

[0475] [ka]

[0476] 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 to reflux for 1 h. After cooling, the solution was treated with 6 N 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] + . Step 2. 6-Bromo-5-fluoroquinazolin-4(3H)-one

[0477] [ka]

[0478] A mixture of 6-amino-3-bromo-2-fluorobenzoic acid (950 mg, 4.0 mmol) and formamide (20 mL) was heated at 160 °C for 8 h. After cooling, the reaction mixture was poured into water (100 mL) and extracted three times with EtOAc. The combined organic extracts were washed with saturated brine, dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluting with 0 to 35% EtOAc in hexanes, to give the title compound (490 mg, 50%). 1 H NMR (500 MHz, DMSO-d6) d ppm 8.13 (d, 1H) 8.05 (dd, 1H) 7.45 (dd, 1H); MS m / z: 241.9 [M+1] + . Step 3. 2-(6-bromo-5-fluoro-4-oxoquinazolin-3(4H)-yl)-2-phenylacetate methyl

[0479] [ka]

[0480] Methyl 2-bromo-2-phenylacetate (349 mL, 2.2 mmol) was added to 6-bromo-5-fluoroquinazolin-4(3H)-one (440 mg, 1.9 mmol) and CsCO (1.20 g, 3.7 mmol) in DMF (3 mL), and the mixture was heated to 30 °C for 1 h. After cooling, the reaction mixture was poured into water (250 mL) and extracted three times with EtOAc. The combined organic extracts were washed with saturated brine, dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluting with 0 to 30% EtOAc in hexanes, to give the title compound (290 mg, 39%). 1 H NMR (500 MHz, CDCl3-d) d 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] + . Step 4. 2-(5-fluoro-6-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxoquinazolin-3(4H)-yl)-2-phenylacetic acid

[0481] [ka]

[0482] The title compound was prepared from 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 in analogy to Step 5 of Example 9. 1H NMR (500 MHz, DMSO-d6) d 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 [M+1] + . Step 5. 3-((1H-benzo[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)

[0483] [ka]

[0484] The title compound was prepared analogously to Step 6 of Example 9 from 2-(5-fluoro-6-(4-(1-methylpiperidin-4-yl)phenyl)-4-oxoquinazolin-3(4H)-yl)-2-phenylacetic acid. 1 H NMR (500 MHz, DMSO-d6) d 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) MS m / z: 544.3 [M+1] +

[0485] Example 11 Preparation of intermediates Scheme 14

[0486] [ka]

[0487] Step 1. 4-(4-Bromo-2-fluoro-phenyl)-1-methyl-piperidin-4-ol

[0488] [ka]

[0489] To a solution of 4-bromo-2-fluoro-1-iodo-benzene (24.0 g, 79.7 mmol) in THF (400 mL) at −70°C, n-butyllithium (2.5 M in hexane, 31.9 mL, 79.7 mmol) was added dropwise. After stirring at −70°C for 30 min, a solution of 1-methylpiperidin-4-one (9.01 g, 79.7 mmol) in THF (20 mL) was added dropwise. After stirring at 70°C for 1 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 5–66% ethyl acetate in petroleum ether to give the title compound (13.0 g, 57%). MS m / z: 289.8 [M+1]+. Step 2. 4-(4-Bromo-2-fluoro-phenyl)-1-methyl-3,6-dihydro-2H-pyridine

[0490] [ka]

[0491] A mixture of 4-(4-bromo-2-fluoro-phenyl)-1-methyl-piperidin-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, 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 in petroleum ether to give the title compound (4.0 g, 31%). MS m / z: 271.7 [M+1]+. 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

[0492] [ka]

[0493] A mixture of 4-(4-bromo-2-fluoro-phenyl)-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, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 5-50% ethyl acetate in petroleum ether to give the title compound (3.0 g, 85%). 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). Step 4. 4-[2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-piperidine

[0494] [ka]

[0495] 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 refilled with hydrogen, and the reaction mixture was stirred under a hydrogen atmosphere (30 psi) at 30° C. for 16 hours. The reaction mixture was filtered through a Celite pad, which was washed multiple times with methanol. The filtrate was concentrated under reduced pressure to give the title compound (2.7 g, 85%). 1 H 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). Scheme SM-1

[0496] [ka]

[0497] Step 1. 3-Methyl-6-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-azabicyclo-[4.1.0]heptane

[0498] [ka]

[0499] 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 at the same temperature for 0.5 h, 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 in petroleum ether to give the title compound (0.310 g, 59%). MS m / z: 314.2 [M+1]+. Scheme SM-2

[0500] [ka]

[0501] Step 1. 5-Ethyl-6-iodo-3H-quinazolin-4-one

[0502] [ka]

[0503] 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 hours. 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%). 1 H 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).

[0504] Example 12 Preparation of 2-((1H-benzo[d]imidazol-2-yl)(5-fluoro-2-hydroxyphenyl)methyl-d)-6-(4-(1-methylpiperidin-4-yl)phenyl)isoindolin-1-one (Compound 036) Scheme 15

[0505] [ka]

[0506] 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 DO (1 mL) to give a heterogeneous mixture. Formic acid (40 μL, 1.07 mmol) was then added and the resulting solution was stirred overnight. After 16 h, the reaction mixture 1 H NMR (methanol-d4) showed approximately 50% deuterium incorporation at the methine carbon based on the integrated area of ​​the methine peak at 7.16 ppm. The reaction was heated to 50 °C and stirred for an additional 8 h. 1 H NMR (methanol-d4) showed greater than 90% deuterium incorporation. An additional 40 uL (1.07 mmol) of formic acid was added and the reaction was stirred under a nitrogen atmosphere for an additional 6 hours at 50°C. 1H NMR (methanol-d4) showed 100% deuterium incorporation at the methine carbon. A solution of DCl (100 μL, 35 wt % in DO) 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.

[0507] The crude product was purified by silica chromatography eluting with 100% ethyl acetate to 60% ethyl acetate / 40% [10% (28% ammonia in water) / 90% MeOH] to give the title compound as a white powder. 1 H 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]+.

[0508] Compounds 037 and 038 were prepared according to the procedure of Example 12. The crude product was then purified to separate the enantiomers on a JASCO semi-prep SFC using a Chiralpak IA (10 x 250 mm 5 micron) column eluted with 45% (0.3% TEA in MeOH) / 55% CO2 at a back pressure regulator (BPR) value of 10 MPa and a flow rate of 10 mL / min. The absolute configuration of the chiral center of each isolated enantiomer is unknown. The first eluting peak (27.4 mg, 27%): 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 eluting peak (31 mg, 28%); 1 H 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] + .

[0509] Example 13 Preparation of 2-((1H-benzo[d]imidazol-2-yl)(5-fluoro-2-hydroxyphenyl)methyl-d)-6-(4-(1-methylpiperidin-4-yl)phenyl)isoindolin-1-one-3,3-d2 (Compound 039) Scheme 16

[0510] [ka]

[0511] 2-((1H-benzo[d]imidazol-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) and DO (0.5 mL), sodium carbonate (9.84 mg, 0.093 mmol) was added, and the mixture was stirred at 50 °C in a sealed vial for 18 h. 1 H NMR (methanol-d4) showed greater than 95% deuterium incorporation at the methine carbon based on the integrated area of ​​the methine peak at 7.16 ppm, and approximately 60% deuterium incorporation at the methylene carbon of the lactam. The reaction was stirred at 60 °C for an additional 48 h. 1 H NMR (methanol-d4) showed complete deuteration of both the methine carbon and the methylene carbon of the lactam. The reaction was cooled to room temperature, and then a 35% by weight solution of DCl in DO (50 μL, 0.48 mmol) was added. After stirring for several minutes, the reaction was concentrated, and the residue was purified by silica chromatography eluting with 100% DCM to 100% (10% 7N NH3 in MeOH / DCM) to give the title compound as a white powder (18 mg, 70%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.08 - 13.11 (m, 1 H) 9.72 - 10.71 (m, 1 H) 7.86 - 7.92 (m, 2 H) 7.60 - 7.69 (m, 3 H) 7.52 (br s, 2 H) 7.35 (d, J=8.19 Hz, 2 H) 7.17 (br dd, J=5.81, 3.00 Hz, 2 H) 7.01 - 7.11 (m, 1 H) ) 6.91 (dd, J=8.80, 4.77 Hz, 1 H) 6.80 (dd, J=9.41, 3.06 Hz, 1 H) 3.05 - 3.21 (m, 1 H) 2.87 (br d, J=11.25 Hz, 2 H) 1.87 - 2.06 (m, 2 H) 2.19 (s, 3 H) 1.62 - 1.81 (m, 4 H); MS m / z: 550.3 [M+1] + .

[0512] Example 14 2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxyphenyl)methyl]-6-[4-[2-(dimethylamino)ethoxy]phenyl]isoindolin-1-one; Hydrochloride (Compound 040) Scheme 17

[0513] [ka]

[0514] Step 1. N-(1H-benzimidazol-2-ylmethylene)-2-methyl-propane-2-sulfinamide

[0515] [ka]

[0516] 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. A solution of ethyl acetate and petroleum ether (1 / 1) was added to the residue, and the resulting solid was isolated by filtration to give the title compound (65 g, 51%). 1 H 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). Step 2. N-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-2-methyl-propane-2-sulfinamide

[0517] [ka]

[0518] To a solution of 2-bromo-4-fluoro-1-(methoxymethoxy)benzene (84.6 g, 360 mmol) in THF (600 mL) at −65° C., n-butyllithium (2.5 M in hexanes, 158 mL, 396 mmol) was added dropwise. After stirring at −65° C. for 20 minutes, the reaction mixture was added via cannula to a precooled (−65° C.) solution of N-(1H-benzimidazol-2-ylmethylene)-2-methyl-propane-2-sulfinamide (45.0 g, 180 mmol) in THF (1100 mL). After stirring at 65° C. for 40 minutes, the reaction mixture was allowed to warm to 15° C. The reaction mixture was quenched 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 in petroleum ether to give the title compound (40 g, 38%). 1 H 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). Step 3. 1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methanamine

[0519] [ka]

[0520] To a solution of N-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-2-methyl-propane-2-sulfinamide (30.0 g, 73.9 mmol) in methanol (600 mL) was added HCl in dioxane (4 M, 55.2 mL, 221 mmol) at 0° C. After stirring for 15 h 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 H 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] + . Step 4. 2-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-bromo-isoindolin-1-one

[0521] [ka]

[0522] To a solution of 1H-benzimidazol-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). The reaction mixture was stirred at room temperature for 5 minutes, and then methyl 5-bromo-2-(bromomethyl)benzoate (28.1 g, 91.5 mmol) was added. The reaction mixture was heated at 90° C. for 16 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%). 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, MS m / z: 496.1 [M+1] + . Step 5. 2-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-[4-[2-(dimethylamino)ethoxy]phenyl]isoindolin-1-one

[0523] [ka]

[0524] A mixture of 2-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-bromoisoindolin-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. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (41.1 mg, 0.050 mmol) was added, and the reaction mixture was degassed once more 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%). 1H 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] + . Step 6. 2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[4-[2-(dimethylamino)-ethoxy]phenyl]isoindolin-1-one; Hydrochloride (Compound 040)

[0525] [ka]

[0526] To a solution of 2-[1H-benzimidazol-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) was added HCl in dioxane (4 M, 0.462 mL, 1.85 mmol). After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure. Diethyl ether was added to the residue, and the resulting solid was isolated by filtration to give the title compound (91 mg, 86%). 1H 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 MS m / z: 537.3 [M+1] + .

[0527] 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) Scheme 18

[0528] [ka]

[0529] 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

[0530] [ka]

[0531] A mixture of 2-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-bromoisoindolin-1-one (191 mg, 0.384 mmol), tert-butyl 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]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 the reaction mixture was degassed once more 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 in hexane to give the title compound (164 mg, 66%). 1 H 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] + . Step 2. 6-[4-(azetidin-3-yl)phenyl]-2-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)-phenyl]methyl]isoindolin-1-one

[0532] [ka]

[0533] To a solution of tert-butyl 3-[4-[2-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)-phenyl]methyl]-3-oxo-isoindolin-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 1N NaOH solution and methanol, and the resulting solid was isolated by filtration to give the title compound (44 mg, 32%). MS m / z: 549.3 [M+1]+. Step 3. 2-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-[4-(1-methyl-azetidin-3-yl)phenyl]isoindolin-1-one

[0534] [ka]

[0535] To a solution of 6-[4-(azetidin-3-yl)phenyl]-2-[1H-benzimidazol-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, and then sodium cyanoborohydride (10.3 mg, 91.5 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, brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC eluting with 10-100% ACN / water containing 0.1% formic acid to give the title compound (14 mg, 30%). 1H NMR (400 MHz, methanol-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] + . Step 4. 2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[4-(1-methylazetidin-3-yl)phenyl]isoindolin-1-one (Compound 049)

[0536] [ka]

[0537] To a solution of 2-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-[4-(1-methylazetidin-3-yl)phenyl]isoindolin-1-one (14.0 mg, 0.0248 mmol) in dichloromethane (1 mL) was added HCl in 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%). 1H 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] + .

[0538] Example 16 2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxyphenyl)methyl]-6-[4-(1-methylazetidin-3-yl)oxyphenyl]isoindolin-1-one; dihydrochloride (Compound 056) Scheme 19

[0539] [ka]

[0540] Step 1. 2-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one

[0541] [ka]

[0542] A mixture of 2-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-bromoisoindolin-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. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.921 mg, 1.26 mmol) was added, and the reaction mixture was degassed once more under nitrogen. The reaction mixture was heated at 100 °C for 12 hours. After cooling to room temperature, the reaction mixture was filtered through a pad of Celite. 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%). 1 H 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, MS m / z: 544.1 [M+1] + . Step 2. 2-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-[4-(1-methylazetidin-3-yl)oxyphenyl]isoindolin-1-one

[0543] [ka]

[0544] A mixture of 2-[1H-benzimidazol-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 the reaction mixture was degassed once more 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 in dichloromethane to give the title compound (150 mg, 50%). MS m / z: 579.1 [M+1]+. Step 3. 2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[4-(1-methylazetidin-3-yl)oxyphenyl]isoindolin-1-one; dihydrochloride (Compound 056)

[0545] [ka]

[0546] To a solution of 2-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-[4-(1-methylazetidin-3-yl)oxyphenyl]isoindolin-1-one (0.150 g, 0.259 mmol) in dioxane (5 mL) was added HCl in dioxane (4 M, 3.0 mL, 12.0 mmol). After stirring at room temperature for 3 hours, 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 (22 mg, 15%). 1 H 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] + .

[0547] The following examples were prepared by a method similar to Example 14 from 2-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-bromo-isoindolin-1-one and the corresponding boronate starting materials.

[0548] [Table 17A]

[0549] [Table 17B]

[0550] [Table 17C]

[0551] The following examples were prepared from the corresponding halogen-substituted phenol and boronate starting materials in a manner analogous to Example 14. The corresponding phenol was protected as the methoxymethyl derivative before reaction with the sulfinamide.

[0552] [Table 18]

[0553] The following examples were prepared in a manner analogous to Example 14 from the corresponding aldehyde and boronate starting materials.

[0554] [Table 19]

[0555] The following examples were prepared by a method similar to Example 2 from ethyl 2-amino-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetate and either methyl 5-bromo-2-(bromo-methyl)-benzoate or methyl 6-bromo-3-(bromomethyl)picolinate; and the corresponding diaminoaryl starting material.

[0556] [Table 20A]

[0557] [Table 20B]

[0558] The following examples were prepared in a manner analogous to Example 6 from methyl 2-bromo-2-(5-fluoro-2-methoxy-phenyl)acetate and the corresponding bicyclic starting material.

[0559] [Table 21]

[0560] The following examples were prepared by a method similar to Example 6 from methyl 2-bromo-2-(5-fluoro-2-methoxyphenyl)acetate or methyl 2-bromo-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate and the corresponding bicyclic starting material.

[0561] [Table 22A]

[0562] [Table 22B]

[0563] The following example was prepared by a method analogous to Example 7 from ethyl 2-amino-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetate and the corresponding boronate and acid starting materials.

[0564] [Table 23]

[0565] The following example was prepared in a manner analogous to Example 8 from 2-[1H-benzimidazol-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, as in Step 3 of Example 4.

[0566] [Table 24]

[0567] The following compounds were prepared from 2-[1H-benzimidazol-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 halide starting materials in a manner similar to Example 16.

[0568] [Table 25]

[0569] Example 17 Preparation of 4-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-1-methyl-piperidine Scheme 20

[0570] [ka]

[0571] Step 1. 4-(4-Bromo-3-fluoro-phenyl)-1-methyl-3,6-dihydro-2H-pyridine

[0572] [ka]

[0573] 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 in petroleum ether to give the title compound (7.00 g, 78%). 1 H 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] + . Step 2. 4-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-3,6-dihydro-2H-pyridine

[0574] [ka]

[0575] A mixture of 4-(4-bromo-3-fluorophenyl)-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 in petroleum ether to give the title compound (0.432 g, 37%). 1 H 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] + . Step 3. 4-[3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-piperidine

[0576] [ka]

[0577] 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 refilled with hydrogen, and the reaction mixture was stirred under a hydrogen atmosphere (50 psi) at 30° C. for 48 hours. The reaction mixture was filtered through a pad of Celite, which was washed multiple times with methanol. The filtrate was concentrated under reduced pressure to give the title compound (1.89 g, 70%). 1 H 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] + .

[0578] 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-piperidyl)phenyl]isoindolin-1-one and 7-fluoro-2-[(S)-(5-fluoro-2-hydroxy-phenyl)-(4-methyl-1H-imidazol-2-yl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one (094 and 095)

[0579] [ka]

[0580] 7-Fluoro-2-[(5-fluoro-2-hydroxyphenyl)-(5-methyl-1H-imidazol-2-yl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one (093, 0.020 g, 0.038 mmol) was purified and enantiomers separated by prep SFC on a Chiral Technologies Chiralpak IA (5 micron 250 x 10 mm) column at 40 °C, eluting with 45% (0.3% TEA in MeOH) / 55% CO2 at 10 MPa. The absolute configuration of the chiral center of each isolated enantiomer is unknown. The first eluting peak (094) (6 mg, 30% yield, 100:0 er); [α] 20 D -78.3 (c = 0.035, MeOH); 1 H NMR (DMSO-d6) δ: 11.77-12.05 (m, 1H), 10.08 (br s, 1H), 7.65-7.74 (m, 1H), 7.43-7.50 (m, 3H), 7.37 (d, 2H), 6.97-7.07 (m, 1H), 6.77-6.88 (m, 2H), 6.73 (s, 1H), 6.53-6.65 (m, 1H), 4.73 (d, 1H), 4.09 (d, 1H), 2.88 (d, 2H), 2.41-2.49 (m, 1H), 2.20 (s, 3H), 2.12 (s, 3H), 1.94-2.03 (m, 2H), 1.64-1.81 (m, 4H); MS m / z: 529.3 [M+1] + Second eluting peak (095) (6 mg, 30% yield, 97.8:2.2 er); [α] 20 D +55.3 (c = 0.038, MeOH); 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] + .

[0581] Example 19 2-[(5-Fluoro-2-hydroxyphenyl)-[5-(trifluoromethyl)-1H-imidazol-2-yl]methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one; Hydrochloride (103) Scheme 21

[0582] [ka]

[0583] Step 1. 2-Methyl-N-[[5-(trifluoromethyl)-1H-imidazol-2-yl]methylene]propane-2-sulfinamide

[0584] [ka]

[0585] 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). After stirring at 75 °C for 5 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 to 100% ethyl acetate in petroleum ether to give the title compound (9.6 g, 60%). 1 H 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] + . Step 2. 2-Methyl-N-[[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]methylene]propane-2-sulfinamide

[0586] [ka]

[0587] 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) was added sodium hydride (1.29 g, 53.8 mmol) at 0 °C. After stirring at the same temperature for 15 min, 2-(trimethylsilyl)ethoxymethyl chloride (8.96 g, 53.8 mmol) was added. After stirring at room temperature for 2 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 0–10% ethyl acetate in petroleum ether to give the title compound (6.5 g, 46%). 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] + . Step 3. N-[(5-fluoro-2-methoxy-phenyl)-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)-imidazol-2-yl]methyl]-2-methyl-propane-2-sulfinamide

[0588] [ka]

[0589] 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) was added dropwise a solution of 5-fluoro-2-methoxyphenylmagnesium bromide in THF (0.5 M, 97.8 mL, 48.9 mmol) at −78° C. After stirring at room temperature for 16 h, the reaction mixture was poured into 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%). 1H 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] + . Step 4. (5-Fluoro-2-methoxy-phenyl)-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)-imidazol-2-yl]methanamine

[0590] [ka]

[0591] To a solution of N-[(5-fluoro-2-methoxy-phenyl)-[5-(trifluoromethyl)-1-(2-trimethylsilyl-ethoxymethyl)imidazol-2-yl]methyl]-2-methyl-propane-2-sulfinamide (1.90 g, 3.62 mmol) in methanol (80 mL) was added HCl in methanol (4 M, 9.05 mL, 36.2 mmol) at 0 °C. After stirring at room temperature for 2 h, the solvent was removed under reduced pressure. The crude product was purified by reverse-phase HPLC eluting with 0-100% ACN / water containing 10 mM ammonium acetate to give the title compound (1.1 g, 73%). 1 H 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] + . Step 5. Methyl 5-bromo-2-[[[(5-fluoro-2-methoxy-phenyl)-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]methyl]amino]methyl]benzoate

[0592] [ka]

[0593] To a solution of (5-fluoro-2-methoxy-phenyl)-[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]+. Step 6. 6-Bromo-2-[(5-fluoro-2-methoxy-phenyl)-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]methyl]isoindolin-1-one

[0594] [ka]

[0595] To a solution of methyl 5-bromo-2-[[[(5-fluoro-2-methoxy-phenyl)-[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] + . Step 7. 6-Bromo-2-[(5-fluoro-2-methoxy-phenyl)-[5-(trifluoromethyl)-1H-imidazol-2-yl]methyl]isoindolin-1-one

[0596] [ka]

[0597] To a solution of 6-bromo-2-[(5-fluoro-2-methoxy-phenyl)-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]methyl]isoindolin-1-one (0.540 g, 0.878 mmol) in methanol (5 mL) was added aqueous 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 lyophilized to give the title compound (0.425 g, quantitative). 1 H 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] + . Step 8. 2-[(5-fluoro-2-methoxy-phenyl)-[5-(trifluoromethyl)-1H-imidazol-2-yl]methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one

[0598] [ka]

[0599] A mixture of 6-bromo-2-[(5-fluoro-2-methoxy-phenyl)-[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)Cl (0.032 g, 0.044 mmol) and potassium carbonate (0.372 g, 2.68 mmol) in dioxane:water (9:1, 10 mL) was heated at 100 °C for 2 h under nitrogen. After cooling, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluting with 0-15% methanol in dichloromethane to give the title compound (0.3 g, 58%). 1 H 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] + . Step 9. 2-[(5-fluoro-2-hydroxy-phenyl)-[5-(trifluoromethyl)-1H-imidazol-2-yl]methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one; Hydrochloride

[0600] [ka]

[0601] To a solution of 2-[(5-fluoro-2-methoxy-phenyl)-[5-(trifluoromethyl)-1H-imidazol-2-yl]methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-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 H 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]+.

[0602] Example 20 Preparation of 2-[(R)-(5-fluoro-2-hydroxy-phenyl)-(4-methyl-1H-imidazol-2-yl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one and 2-[(S)-(5-fluoro-2-hydroxy-phenyl)-(4-methyl-1H-imidazol-2-yl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one (104 and 105)

[0603] [ka]

[0604] 2-[(5-Fluoro-2-hydroxy-phenyl)-(4-methyl-1H-imidazol-2-yl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one (085, 0.020 g, 0.039 mmol) was purified by prep SFC on a Chiral Technologies Chiralpak IA (5 micron 250 x 10 mm) column at 40 °C, eluting with 35% (0.3% TEA in MeOH) / 65% CO2 at 12 MPa to separate the enantiomers. The absolute configuration of the chiral center of each isolated enantiomer is unknown. First eluting peak (104) (6.5 mg, 33% yield, 97.9:2.1 er); [α] 20 D -88.2 (c = 0.0465, MeOH); 1 H 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] + The second eluting peak (105) (7.3 mg, 37% yield, 97.7:2.3 er); [α] 20 D +67.3 (c=0.049, MeOH); 1H 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 (brd, 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] + .

[0605] Example 21 Preparation of 6-[(R)-1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-2-[4-(1-methyl-4-piperidyl)phenyl]-5H-pyrrolo[3,4-b]pyridin-7-one and 6-[(S)-1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-2-[4-(1-methyl-4-piperidyl)phenyl]-5H-pyrrolo[3,4-b]pyridin-7-one (106 and 107)

[0606] [ka]

[0607] 6-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxyphenyl)methyl]-2-[4-(1-methyl-4-piperidyl)phenyl]-5H-pyrrolo[3,4-b]pyridin-7-one (028, 0.020 g, 0.037 mmol) was purified by prep SFC on a Chiral Technologies Chiralpak IA (5 micron 250 x 10 mm) column at 40 °C, eluting with 55% (0.3% TEA in MeOH) / 45% CO2 at 10 MPa to separate the enantiomers. The absolute configuration of the chiral center of each isolated enantiomer is unknown. The first eluting peak (106) (2.8 mg, 14% yield, 98.5:1.5 er); [α] 20 D -12.3 (c = 0.06, MeOH); 1 H 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 eluting peak (107) (6.1 mg, 30% yield, 97.2:2.8 er); [α] 20 D +21.8 (c = 0.055, MeOH); 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, MS m / z: 548.3 [M+1] + .

[0608] The following example was prepared in an analogous manner to compound 069 from methyl 2-bromo-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate and the corresponding boronate starting materials.

[0609] [Table 26]

[0610] The following example was prepared in a manner analogous to compound 070 from methyl 2-bromo-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate and the corresponding boronate starting materials.

[0611] [Table 27]

[0612] Example 22 2-[1H-benzimidazol-2-yl-deuterio-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoquinolin-1-one (112) Scheme 22

[0613] [ka]

[0614] 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 dry tetrahydrofuran (1 mL) in a vial equipped with a stir bar. Deuterium oxide (350 μL, 19.3 mmol) was then added with stirring, followed by N,N-diisopropylethylamine (38.1 μL, 219 μmol). The reaction vial was sealed and the reaction was allowed to stir at 70° C. for 60 hours. 1 H NMR (DMSO-d6) showed 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 in methanol) in DCM to give the title compound (14 mg, 68%). 1 H 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] + .

[0615] The following example was prepared from 2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-8-fluoro-6-[4-(1-methyl-4-piperidyl)phenyl]isoquinolin-1-one (070) in a manner analogous to Example 22.

[0616] [Table 28]

[0617] Example 23 Preparation of 2-[(S)-1H-benzimidazol-2-yl-deuterio-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoquinolin-1-one and 2-[(R)-1H-benzimidazol-2-yl-deuterio-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoquinolin-1-one (114 and 115) Scheme 23

[0618] [ka]

[0619] 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 dry tetrahydrofuran (2 mL) in a vial equipped with a stir bar. Deuterium oxide (1000 μL, 55.4 mmol) was then added with stirring, followed by N,N-diisopropylethylamine (62.2 μL, 358 μmol). The reaction vial was sealed, and the reaction was allowed to stir at 70° C. for 60 hours. 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 leave the crude product, which was dissolved in 5 mL of THF. 75 μL of a 35% by weight solution of DCl in DO was then added dropwise with stirring. After 10 min, the reaction solution was concentrated, and the residue was dried under vacuum overnight to give the crude product as the bis-DCl salt. The crude product was purified and enantiomer-separated on a JASCO semi-prep SFC using a Chiralpak IG (10 × 250 mm, 5 micron) column eluted with 55% (0.3% TEA in MeOH) / 45% CO2 at a backpressure regulator (BPR) of 10 MPa and a flow rate of 7 mL / min. The absolute configuration of the chiral centers of each isolated enantiomer is unknown. First eluting peak (114) (19.7 mg, 37%, 100:0 er); [α] 20 D -13.6 (c = 0.0515, MeOH); 1 H 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 eluting peak (115) (18.8 mg, 36%, 99.7:0.3 er); [α] 20 D +14.2 (c = 0.0705, MeOH); 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] + .

[0620] The following example was prepared from 2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-8-fluoro-6-[4-(1-methyl-4-piperidyl)phenyl]isoquinolin-1-one (070) by a method similar to that described in Example 23. The absolute configuration of the chiral centers in each isolated enantiomer is unknown.

[0621] [Table 29]

[0622] Example 24 2-((1H-benzo[d]imidazol-2-yl)(5-fluoro-6-(4-(1-methylpiperidin-4-yl)phenyl)-2H-indazol-2-yl)methyl)-4-fluorophenol (118) Scheme 24

[0623] [ka]

[0624] Step 1. Methyl 2-(6-bromo-5-fluoro-2H-indazol-2-yl)-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate

[0625] [ka]

[0626] Methyl 2-bromo-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate (513 mg, 1.67 mmol) was added to a suspension of 6-bromo-5-fluoro-2H-indazole (360 mg, 1.67 mmol) and cesium carbonate (651 mg, 2.09 mmol) in CHCN (16 mL), and the mixture was stirred at 0 °C for 1 h and then at RT for 16 h. The mixture was partitioned between water and EtOAc, and the aqueous phase was extracted with EtOAc (3 × 30 mL). The combined organic phases were washed with brine, dried (NaSO), filtered, and the residue was purified by silica chromatography (0–20% EtOAc in Hex) to give the title compound as a solid (204 mg, 19%). 1 H 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] + . Step 2. 2-(5-fluoro-2-(methoxymethoxy)phenyl)-2-(5-fluoro-6-(4-(1-methylpiperidin-4-yl)phenyl)-2H-indazol-2-yl)acetic acid

[0627] [ka]

[0628] A mixture of 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)Cl.DCM (38 mg, 0.047 mmol), and sodium carbonate (149 mg, 1.41 mmol) in dioxane:water (3:1, 3 mL) was degassed and refilled 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 H 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] + . Step 3. N-(2-aminophenyl)-2-(5-fluoro-2-(methoxymethoxy)phenyl)-2-(5-fluoro-6-(4-(1-methylpiperidin-4-yl)phenyl)-2H-indazol-2-yl)acetamide

[0629] [ka]

[0630] 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), benzene-1,2-diamine (156 mg, 1.44 mmol), HATU (365 mg, 0.96 mmol), DIEA (250 mL, 1.44 mmol), and degassed DMF (3 mL) was stirred for 1 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. 1 H 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). Step 4. 2-((1H-benzo[d]imidazol-2-yl)(5-fluoro-6-(4-(1-methylpiperidin-4-yl)phenyl)-2H-indazol-2-yl)methyl)-4-fluorophenol (118)

[0631] [ka]

[0632] 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 give the title compound (39 mg, 13% over three steps). 1 H 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 [M+1] + .

[0633] The following examples were prepared from methyl 2-bromo-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate and the corresponding bicyclic starting material in a manner analogous to Example 24.

[0634] [Table 30]

[0635] Scheme 25

[0636] [ka]

[0637] Step 1: 2-bromo-2-(5-fluoro-2-(methoxymethoxy)phenyl)methyl acetate

[0638] [ka]

[0639] To a solution of methyl 5-fluoro-2-(methoxymethoxy)benzeneacetate (5.00 g, 21.9 mmol) in chloroform (80 mL) was added N-bromosuccinimide (4.66 g, 26.2 mmol) and benzoyl peroxide (0.530 g, 2.19 mmol). After stirring at 80 °C for 16 h, the solvent was removed under reduced pressure. The crude compound was purified by silica gel column chromatography eluting with 0-5% ethyl acetate in petroleum ether to give the title compound (2.4 g, 36%). 1 H 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).

[0640] Example 25 HTRF-based EGFR biochemical assay Biochemical activity measurements of EGFR were performed using a homogeneous time-resolved fluorescence (HTRF) assay (Cisbio). First, inhibitors and DMSO standard solutions (DMSO normalization) were dispensed into an empty black low-volume 384-well plate (Corning) using a D300 digital liquid dispenser (HP). All reactions were performed at room temperature, and solutions were added to the plate using a Multidrop Combi reagent dispenser (ThermoFisher). The reaction mixture (final volume 10 μl) contained 1 μM of 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). The enzyme concentrations were adjusted to the different kinase activities (L858R 0.1 nM, L858R / T790M 0.02 nM). The enzyme reaction solution (2x concentration, 5 μL) was added to the 384-well plate containing the compounds and incubated for 30 minutes. The enzyme reaction was initiated by adding 5 μL of ATP to a final concentration of 100 μM and allowed to react for 20 minutes. The reaction was quenched by adding 10 μL of phosphotyrosine antibody-europium(III) cryptate (1:180 volume ratio) and streptavidin-XL665 (46.7 nM) in detection buffer containing EDTA, followed by incubation at room temperature for 1 hour and reading on a PHERAstar plate reader (excitation = 337 nm, emission = 620 nm and 665 nm). IC 50 Values ​​were determined from inhibition curves in triplicate (11-point curves from 1.0 μM to 0.130 nM or 23-point curves from 1.0 μM to 0.130 pM) using nonlinear least-squares fitting in GraphPad Prism 7.0d. The resulting data are shown in Table 7 below.

[0641] [Table 31A]

[0642] [Table 31B]

[0643] [Table 31C]

[0644] [Table 31D]

[0645] Example 26 Ba / F3 cell proliferation model EGFR mutants L858R and L858R / T790M were expressed in Ba / F3 cells as previously described (Zhou, W. et al., Nature 462, 2009, pp. 1070-1074). All cell lines were maintained in RPMI 1640 medium (Cellgro; Mediatech, Herndon, CA) supplemented with 10% FBS, 100 units / mL penicillin, and 100 units / mL streptomycin. The EGFR I941R mutation was introduced by site-directed mutagenesis using the Quick Change Site-Directed Mutagenesis Kit (Stratagene; La Jolla, CA) according to the manufacturer's instructions. All constructs were verified by DNA sequencing. Constructs were shuttled into the retroviral vector JP1540 using the Cre recombination system (Agilent Technologies, Santa Clara, CA). Ba / F3 cells were then infected with the retrovirus according to standard protocols as previously described (Zhou et al., Nature 2009). Stable clones were obtained by selection in puromycin (2 μg / ml).

[0646] Proliferation and growth inhibition were assessed by the Cell Titer Glo assay (Promega, Madison, WI) according to the manufacturer's instructions. The Cell Titer Glo assay is a luminescence-based method used to determine viable cell number based on quantification of ATP present, which is directly proportional to the amount of metabolically active cells present. Ba / F3 cells of different EGFR genotypes were exposed to compounds as single agents or in combination with 1 μg / ml cetuximab for 72 hours. The number of cells used per experiment was determined empirically as previously established (Zhou et al., Nature 2009). All experimental points were arranged in triplicate in a 384-well plate, and all experiments were repeated at least three times. Luminescence signals were detected using a spectrometer, and data were displayed graphically using GraphPad Prism version 5.0 for Windows (GraphPad Software; www.graphpad.com). Curves were fitted using a nonlinear regression model with a sigmoidal dose-response relationship. The results of this assay for the compounds disclosed herein are shown in Table 8.

[0647] [Table 32A]

[0648] [Table 32B]

[0649] [Table 32C]

[0650] [Table 32D]

[0651] The subject matter of the present disclosure is not limited in scope by the specific embodiments and examples described herein. Indeed, various modifications of the present disclosure in addition to those described will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to be within the scope of the appended claims.

[0652] All references (e.g., publications or patents or patent applications) cited herein are incorporated by reference in their entirety for all purposes to the same 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 scope of the following claims.

Claims

1. Formula Ia: 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof (In the formula, A and A' are each independently CH, CR 8 or N, W and Z are each independently N, CH, C-halo, C-(C 1 ~C 3 alkyl) or C-(C 1 ~C 3 alkoxy), provided that at least one of W or Z is CH; R1 is 【Chemistry 2】 all of which are optionally substituted with one, two or three R 8 ; R 3 Each occurrence is independent, C 2 to C 6 Alkynyl or C 6 ~C 10 aryl, wherein alkynyl is optionally selected from the group consisting of R 4 and aryl is optionally substituted once, twice or three times with R 5 is substituted once, twice or three times by R 4 H, (CH 2 ) 0～3 -(C 3 ~C 7 Cycloalkyl), (CH 2 ) 0～3 -(C 4 ~C 7 Cycloalkenyl), (CH 2 ) 0～3 -(C 6 ~C 10 Aryl), (CH 2 ) 0～3 -(5-6 membered heteroaryl) and (CH 2 ) 0～3 -(5- to 7-membered heterocyclyl), wherein aryl, heteroaryl, or heterocyclyl is each optionally selected from the group consisting of R 5 is substituted once, twice or three times by R 5 independently for each occurrence, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkoxy, C 1 ~C 3 Alkylamine, 3-10 membered cycloalkyl, halogen, COOH, C(O)O(C 1 ~C 6 alkyl), O(CH 2 ) 1～3 -OH, NH 2 , NH(C 1 ~C 6 alkyl), N(C 1 ~C 6 Alkyl) 2 , OH, CN, (CH 2 ) 0～3 -(C 6 ~C 10 Aryl), (CH 2 ) 0～3 -(5-6 membered heteroaryl) and (CH 2 ) 0～3 -(5- to 7-membered heterocyclyl), wherein aryl, heteroaryl, or heterocyclyl is each optionally selected from the group consisting of R 7 is substituted once, twice or three times by R 6 independently for each occurrence, C 1 ~C 3 Alkyl, C 1 ~C 3 Haloalkyl, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, C 1 ~C 3 Alkylamine, halogen, OH, NO 2 , N.H. 2 , NH(C 1 ~C 6 alkyl), N(C 1 ~C 6 Alkyl) 2 , (CH 2 ) 1～4 OH, S(O) 0～2 H, S(O) 0～2 NH 2 or CN; Or, two R's 6 may, together with the atom to which they are attached, form a 5- to 10-membered heteroaryl, a 6- to 10-membered aryl, a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered cycloalkyl; R 7 independently for each occurrence, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkoxy, halogen, NH 2 , NH(C 1 ~C 6 alkyl), N(C 1 ~C 6 Alkyl) 2 , S.O. 2 NH 2 , S.O. 2 NH(C 1 ~C 6 Alkyl), SO 2 N(C 1 ~C 6 Alkyl) 2 , (CH 2 ) 1～2 -OH, C(O)(CH 2 ) 1～2 -OH, C(O)(C 1 ~C 6 alkyl) and C(O)O(C 1 ~C 6 alkyl); Or, two R's 7 may, together with the atom to which they are attached, form a 5- to 10-membered heteroaryl, a 6- to 10-membered aryl, a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered cycloalkyl; R 8 independently for each occurrence, C 1 ~C 3 Alkyl, C 1 ~C 3 Haloalkyl, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, C 1 ~C 3 Alkylamine, 3-6 membered cycloalkyl, halogen, OH, NO 2 , N.H. 2 , NH(C 1 ~C 6 alkyl), N(C 1 ~C 6 Alkyl) 2 , (CH 2 ) 1～4 OH, S(O) 0～2 H, S(O) 0～2 NH 2 or CN).

2. The compound of claim 1, wherein R 7 is C 1 -C 3 alkyl.

3. A is CH and A' is CH, CR 8 or N; W is CH and Z is N, CH, C-halo, C-(C 1 -C 3 alkyl) or C-(C 1 -C 3 alkoxy); R1 is benzimidazole optionally substituted with halogen; R3 is phenyl substituted once or twice by R5; R5 is either halogen, piperidin-4-yl substituted with methyl, or 3-azabicyclo[4.1.0]heptan-6-yl substituted with methyl; R 6 is independently selected at each occurrence from the group consisting of halogen and OH; 3. The compound of claim 1 or 2, wherein R8 is H or halogen.

4. The compound of formula Ib: 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof.

5. 5. The compound according to claim 1, wherein Z is CH.

6. 5. The compound according to claim 1, wherein Z is N.

7. 5. The compound of claim 1, wherein Z is CF.

8. R 6 8. The compound of claim 1, wherein each occurrence is independently hydroxy or fluoro.

9. A compound comprising: 【Table 1A】 【Table 1B】 or a pharma- ceutically acceptable salt thereof.

10. A compound comprising: 【Table 2A】 【Table 2B】 【Table 2C】 or a pharma- ceutically acceptable salt thereof.

11. 11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable carrier.

12. 12. The pharmaceutical composition of claim 11, further comprising a second active agent.

13. 13. The pharmaceutical composition of claim 12, wherein the second active agent is selected from the group consisting of a MEK inhibitor, a PI3K inhibitor, and an mTor inhibitor.

14. The pharmaceutical composition of claim 12, wherein the second active agent prevents EGFR dimerization in the subject.

15. 13. The pharmaceutical composition of claim 12, wherein the second active agent is selected from the group consisting of cetuximab, trastuzumab and panitumumab.

16. 13. The pharmaceutical composition of claim 12, wherein the second active agent is an ATP-competitive EGFR inhibitor.

17. 13. The pharmaceutical composition of claim 12, wherein the ATP-competitive EGFR inhibitor is osimertinib, gefitinib or erlotinib.

18. A composition for treating cancer in a subject in need thereof, comprising a compound described in any one of claims 1 to 10 or a pharmaceutical composition described in any one of claims 11 to 17.

19. 19. The composition of claim 18, wherein the cancer is selected from the group consisting of lung cancer, colon cancer, breast cancer, endometrial cancer, thyroid cancer, glioma, squamous cell carcinoma and prostate cancer.

20. 19. The composition of claim 18, wherein the cancer is non-small cell lung cancer (NSCLC).

21. A composition for inhibiting a kinase in a subject in need thereof, comprising a compound according to any one of claims 1 to 10 or a pharmaceutical composition according to any one of claims 11 to 17.

22. 22. The composition of claim 21, wherein the kinase is EGFR.

23. A composition for the treatment or prevention of a kinase-mediated disorder in a subject in need thereof, comprising a compound described in any one of claims 1 to 10 or a pharmaceutical composition described in any one of claims 11 to 17.

24. 24. The composition of claim 23, wherein the kinase-mediated disorder is resistant to EGFR-targeted therapy.

25. 25. The composition of claim 24, wherein the EGFR treatment therapy is selected from the group consisting of gefitinib, erlotinib, and osimertinib.

Images